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1. Survival associated with the use of one-step nucleic acid amplification (OSNA) to detect sentinel lymph node metastasis in cervical cancer

Author

Bizzarri, Nicolò, Fedele, Camilla, Teodorico, Elena, Certelli, Camilla, Pedone Anchora, Luigi, Carbone, Maria Vittoria, Giannarelli, Diana, Fagotti, Anna, Zannoni, Gian Franco, Valente, Michele, Querleu, Deni, Ferrandina, Maria Gabriella, Scambia, Giovanni, Fanfani, Francesco, Carbone, Vittoria, Fagotti, Anna (ORCID:0000-0001-5579-335X), Zannoni, Gian Franco (ORCID:0000-0003-1809-129X), Ferrandina, Gabriella (ORCID:0000-0003-4672-4197), Scambia, Giovanni (ORCID:0000-0003-2758-1063), Fanfani, Francesco (ORCID:0000-0003-1991-7284), Bizzarri, Nicolò, Fedele, Camilla, Teodorico, Elena, Certelli, Camilla, Pedone Anchora, Luigi, Carbone, Maria Vittoria, Giannarelli, Diana, Fagotti, Anna, Zannoni, Gian Franco, Valente, Michele, Querleu, Deni, Ferrandina, Maria Gabriella, Scambia, Giovanni, Fanfani, Francesco, Carbone, Vittoria, Fagotti, Anna (ORCID:0000-0001-5579-335X), Zannoni, Gian Franco (ORCID:0000-0003-1809-129X), Ferrandina, Gabriella (ORCID:0000-0003-4672-4197), Scambia, Giovanni (ORCID:0000-0003-2758-1063), and Fanfani, Francesco (ORCID:0000-0003-1991-7284)

Abstract

Introduction: Sentinel lymph node (SLN) biopsy is part of surgical treatment of apparent early-stage cervical cancer. SLN is routinely analyzed by ultrastaging and immunohistochemistry. The aim of this study was to assess the survival of patients undergoing SLN analyzed by one-step nucleic acid amplification (OSNA) compared with ultrastaging. Methods: Single-center, retrospective, cohort study. Patients undergoing primary surgery and SLN mapping ( ±pelvic lymphadenectomy) for apparent early-stage cervical cancer between May 2017 and January 2021 were included. SLN was analyzed exclusively with OSNA or with ultrastaging. Patients with bilateral SLN mapping failure, with SLN analyzed alternatively/serially with OSNA and ultrastaging, and undergoing neo-adjuvant therapy were excluded. Baseline clinic-pathological differences between the two groups were balanced with propensity-match analysis. Results: One-hundred and fifty-seven patients were included, 50 (31.8%) in the OSNA group and 107 (68.2%) in the ultrastaging group. Median follow up time was 41 months (95%CI:37.9-42.2). 5-year DFS in patients undergoing OSNA versus ultrastaging was 87.0% versus 91.0% (p = 0.809) and 5-year overall survival was 97.9% versus 98.6% (p = 0.631), respectively. No difference in the incidence of lymph node recurrence between the two groups was noted (OSNA 20.0% versus ultrastaging 18.2%, p = 0.931). In the group of negative SLN, no 5-year DFS difference was noted between the two groups (p = 0.692). No 5-year DFS and OS difference was noted after propensity-match analysis (87.6% versus 87.0%, p = 0.726 and 97.4% versus 97.9%, p = 0.998, respectively). Conclusion: The use of OSNA as method to exclusively process SLN in cervical cancer was not associated with worse DFS compared to ultrastaging. Incidence of lymph node recurrence in the two groups was not different.

Published
2024

2. ESGO–ESMO–ESP consensus conference recommendations on ovarian cancer: pathology and molecular biology and early, advanced and recurrent disease

Author

Ledermann, J. A., Matias-Guiu, X., Amant, F., Concin, N., Davidson, B., Fotopoulou, C., González-Martin, A., Gourley, C., Leary, A., Lorusso, Domenica, Banerjee, S., Chiva, L., Cibula, D., Colombo, N., Croce, S., Eriksson, A. G., Falandry, C., Fischerova, D., Harter, P., Joly, F., Lazaro, C., Lok, C., Mahner, S., Marmé, F., Marth, C., Mccluggage, W. G., Mcneish, I. A., Morice, P., Nicum, S., Oaknin, A., Pérez-Fidalgo, J. A., Pignata, S., Ramirez, P. T., Ray-Coquard, I., Romero, I., Scambia, Giovanni, Sehouli, J., Shapira-Frommer, R., Sundar, S., Tan, D. S. P., Taskiran, C., van Driel, W. J., Vergote, I., Planchamp, F., Sessa, C., Fagotti, Anna, Lorusso, D., Scambia, G. (ORCID:0000-0003-2758-1063), Fagotti, A. (ORCID:0000-0001-5579-335X), Ledermann, J. A., Matias-Guiu, X., Amant, F., Concin, N., Davidson, B., Fotopoulou, C., González-Martin, A., Gourley, C., Leary, A., Lorusso, Domenica, Banerjee, S., Chiva, L., Cibula, D., Colombo, N., Croce, S., Eriksson, A. G., Falandry, C., Fischerova, D., Harter, P., Joly, F., Lazaro, C., Lok, C., Mahner, S., Marmé, F., Marth, C., Mccluggage, W. G., Mcneish, I. A., Morice, P., Nicum, S., Oaknin, A., Pérez-Fidalgo, J. A., Pignata, S., Ramirez, P. T., Ray-Coquard, I., Romero, I., Scambia, Giovanni, Sehouli, J., Shapira-Frommer, R., Sundar, S., Tan, D. S. P., Taskiran, C., van Driel, W. J., Vergote, I., Planchamp, F., Sessa, C., Fagotti, Anna, Lorusso, D., Scambia, G. (ORCID:0000-0003-2758-1063), and Fagotti, A. (ORCID:0000-0001-5579-335X)

Abstract

The European Society of Gynaecological Oncology, the European Society for Medical Oncology (ESMO) and the European Society of Pathology held a consensus conference (CC) on ovarian cancer on 15-16 June 2022 in Valencia, Spain. The CC panel included 44 experts in the management of ovarian cancer and pathology, an ESMO scientific advisor and a methodologist. The aim was to discuss new or contentious topics and develop recommendations to improve and harmonise the management of patients with ovarian cancer. Eighteen questions were identified for discussion under four main topics: (i) pathology and molecular biology, (ii) early-stage disease and pelvic mass in pregnancy, (iii) advanced stage (including older/frail patients) and (iv) recurrent disease. The panel was divided into four working groups (WGs) to each address questions relating to one of the four topics outlined above, based on their expertise. Relevant scientific literature was reviewed in advance. Recommendations were developed by the WGs and then presented to the entire panel for further discussion and amendment before voting. This manuscript focuses on the recommendation statements that reached a consensus, their voting results and a summary of evidence supporting each recommendation.

Published
2024

3. New windows of surgical opportunity for gynecological cancers in the era of targeted therapies

Author

Peters, I., Marchetti, Claudia, Scambia, Giovanni, Fagotti, Anna, Marchetti C. (ORCID:0000-0001-7098-8956), Scambia G. (ORCID:0000-0003-2758-1063), Fagotti A. (ORCID:0000-0001-5579-335X), Peters, I., Marchetti, Claudia, Scambia, Giovanni, Fagotti, Anna, Marchetti C. (ORCID:0000-0001-7098-8956), Scambia G. (ORCID:0000-0003-2758-1063), and Fagotti A. (ORCID:0000-0001-5579-335X)

Abstract

Precision medicine through molecular profiling has taken a prominent role in the treatment of solid tumors and it is widely expected that this will continue to expand. With respect to gynecological cancers, a major change has particularly been observed in the treatment landscape of epithelial ovarian, endometrial, and cervical cancers. Regarding the former, maintenance therapy with either poly(ADP-ribose) polymerase inhibitors (PARPi) and/or bevacizumab has become an indispensable treatment option following the traditional combination of cytoreductive surgery and platinum-based chemotherapy. Considering endometrial cancer, the molecular classification system has now been incorporated into virtually every guideline available and molecular-directed treatment strategies are currently being researched, presumably leading to a further transformation of its treatment paradigm. After all, treatment with immune-checkpoint inhibitors that target the programmed cell death 1 (PD-1) receptor has already been shown to significantly improve disease outcomes in these patients, especially in those with mismatch repair deficient, microsatellite stability-high (MMRd-MSI-H) disease. Similarly, in recurrent/metastatic cervical cancer patients, these agents elicited improved survival rates when being added to platinum-based chemotherapy with or without bevacizumab. Interestingly, implications of these targeted therapies for surgical management have been touched on to a minor extent, but are at least as intriguing. This review therefore aims to address the wide-ranging opportunities the molecular tumor characteristics and their corresponding targeted therapies have to offer for the surgical management of epithelial ovarian, endometrial, and cervical cancers, both in the primary and recurrent setting.

Published
2024

4. ESGO–ESMO–ESP consensus conference recommendations on ovarian cancer: pathology and molecular biology and early, advanced and recurrent disease

Author

Ledermann, J. A., Matias-Guiu, X., Amant, F., Concin, N., Davidson, B., Fotopoulou, C., Gonzalez-Martin, A., Gourley, C., Leary, A., Lorusso, D., Banerjee, S., Chiva, L., Cibula, D., Colombo, N., Croce, S., Eriksson, A. G., Falandry, C., Fischerova, D., Harter, P., Joly, F., Lazaro, C., Lok, C., Mahner, S., Marme, F., Marth, C., Mccluggage, W. G., Mcneish, I. A., Morice, P., Nicum, S., Oaknin, A., Perez-Fidalgo, J. A., Pignata, S., Ramirez, P. T., Ray-Coquard, I., Romero, I., Scambia, Giovanni, Sehouli, J., Shapira-Frommer, R., Sundar, S., Tan, D. S. P., Taskiran, C., van Driel, W. J., Vergote, I., Planchamp, F., Sessa, C., Fagotti, Anna, Scambia G. (ORCID:0000-0003-2758-1063), Fagotti A. (ORCID:0000-0001-5579-335X), Ledermann, J. A., Matias-Guiu, X., Amant, F., Concin, N., Davidson, B., Fotopoulou, C., Gonzalez-Martin, A., Gourley, C., Leary, A., Lorusso, D., Banerjee, S., Chiva, L., Cibula, D., Colombo, N., Croce, S., Eriksson, A. G., Falandry, C., Fischerova, D., Harter, P., Joly, F., Lazaro, C., Lok, C., Mahner, S., Marme, F., Marth, C., Mccluggage, W. G., Mcneish, I. A., Morice, P., Nicum, S., Oaknin, A., Perez-Fidalgo, J. A., Pignata, S., Ramirez, P. T., Ray-Coquard, I., Romero, I., Scambia, Giovanni, Sehouli, J., Shapira-Frommer, R., Sundar, S., Tan, D. S. P., Taskiran, C., van Driel, W. J., Vergote, I., Planchamp, F., Sessa, C., Fagotti, Anna, Scambia G. (ORCID:0000-0003-2758-1063), and Fagotti A. (ORCID:0000-0001-5579-335X)

Abstract

The European Society of Gynaecological Oncology, the European Society for Medical Oncology (ESMO) and the European Society of Pathology held a consensus conference (CC) on ovarian cancer on 15-16 June 2022 in Valencia, Spain. The CC panel included 44 experts in the management of ovarian cancer and pathology, an ESMO scientific advisor and a methodologist. The aim was to discuss new or contentious topics and develop recommendations to improve and harmonise the management of patients with ovarian cancer. Eighteen questions were identified for discussion under four main topics: (i) pathology and molecular biology, (ii) early-stage disease and pelvic mass in pregnancy, (iii) advanced stage (including older/frail patients) and (iv) recurrent disease. The panel was divided into four working groups (WGs) to each address questions relating to one of the four topics outlined above, based on their expertise. Relevant scientific literature was reviewed in advance. Recommendations were developed by the WGs and then presented to the entire panel for further discussion and amendment before voting. This manuscript focuses on the recommendation statements that reached a consensus, their voting results and a summary of evidence supporting each recommendation.

Published
2024

5. Indocyanine green fluorescence applied to gynecologic oncology: beyond sentinel lymph node

Author

Loverro, M, Bizzarri, Nicolo', Capomacchia, Filippo Maria, Watrowski, Rafał, Querleu, D, Gioè, A, Naldini, A, Santullo, F, Foschi, Nazario, Fagotti, Anna, Scambia, Giovanni, Fanfani, Francesco, Bizzarri, N, Capomacchia, F M, Foschi, N, Fagotti, A (ORCID:0000-0001-5579-335X), Scambia, G (ORCID:0000-0003-2758-1063), Fanfani, F (ORCID:0000-0003-1991-7284), Loverro, M, Bizzarri, Nicolo', Capomacchia, Filippo Maria, Watrowski, Rafał, Querleu, D, Gioè, A, Naldini, A, Santullo, F, Foschi, Nazario, Fagotti, Anna, Scambia, Giovanni, Fanfani, Francesco, Bizzarri, N, Capomacchia, F M, Foschi, N, Fagotti, A (ORCID:0000-0001-5579-335X), Scambia, G (ORCID:0000-0003-2758-1063), and Fanfani, F (ORCID:0000-0003-1991-7284)

Abstract

Indocyanine green (ICG), a well-known molecule employed in medicine for over five decades, has emerged as a versatile dye widely embraced across various surgical disciplines. In gynecologic oncology, its prevalent use revolves around the detection of sentinel lymph nodes. However, the true potential of ICG extends beyond this singular application, owing to its pragmatic utility, cost-effectiveness, and safety profile. Furthermore, ICG has been introduced in the theranostic landscape, marking a significant juncture in the evolution of its clinical utility. This narrative review aims to describe the expanding horizons of ICG fluorescence in gynecologic oncology, beyond the sentinel lymph node biopsy. The manifold applications reported within this manuscript include: 1) lymphography; 2) angiography; 3) nerve visualization; 4) ICG-driven resections; and 5) theranostic. The extensive exploration across these numerous applications, some of which are still in the pre-clinical phase, serves as a hypothesis generator, aiming to stimulate the development of clinical studies capable of expanding the use of this drug in our field, enhancing the care of gynecological cancer patients.

Published
2024

6. A cost-effectiveness analysis of an integrated clinical-radiogenomic screening program for the identification of BRCA 1/2 carriers (e-PROBE study

Author

Di Pilla, Andrea, Nero, Camilla, Specchia, Maria Lucia, Ciccarone, Francesca, Boldrini, Luca, Lenkowicz, Jacopo, Alberghetti, B, Fagotti, Anna, Testa, Antonia Carla, Valentini, Vincenzo, Sala, Evi, Scambia, Giovanni, Di Pilla A, Nero C, Specchia ML (ORCID:0000-0002-3859-4591), Ciccarone F, Boldrini L, Lenkowicz J, Fagotti A (ORCID:0000-0001-5579-335X), Testa AC (ORCID:0000-0003-2217-8726), Valentini V (ORCID:0000-0003-4637-6487), Sala E, Scambia G (ORCID:0000-0003-2758-1063), Di Pilla, Andrea, Nero, Camilla, Specchia, Maria Lucia, Ciccarone, Francesca, Boldrini, Luca, Lenkowicz, Jacopo, Alberghetti, B, Fagotti, Anna, Testa, Antonia Carla, Valentini, Vincenzo, Sala, Evi, Scambia, Giovanni, Di Pilla A, Nero C, Specchia ML (ORCID:0000-0002-3859-4591), Ciccarone F, Boldrini L, Lenkowicz J, Fagotti A (ORCID:0000-0001-5579-335X), Testa AC (ORCID:0000-0003-2217-8726), Valentini V (ORCID:0000-0003-4637-6487), Sala E, and Scambia G (ORCID:0000-0003-2758-1063)

Abstract

Current approach to identify BRCA 1/2 carriers in the general population is ineffective as most of the carriers remain undiagnosed. Radiomics is an emerging tool for large scale quantitative analysis of features from standard diagnostic imaging and has been applied also to identify gene mutational status. The objective of this study was to evaluate the clinical and economic impact of integrating a radiogenomics model with clinical and family history data in identifying BRCA mutation carriers in the general population. This cost‐effective analysis compares three different approaches to women selection for BRCA testing: established clinical criteria/family history (model 1); established clinical criteria/family history and the currently available radiogenomic model (49% sensitivity and 87% specificity) based on ultrasound images (model 2); same approach used in model 2 but simulating an improvement of the performances of the radiogenomic model (80% sensitivity and 95% specificity) (model 3). All models were trained with literature data. Direct costs were calculated according to the rates currently used in Italy. The analysis was performed simulating different scenarios on the generation of 18‐year‐old girls in Italy (274,000 people). The main outcome was to identify the most effective model comparing the number of years of BRCA‐cancer healthy life expectancy (HLYs). An incremental cost‐effectiveness ratio (ICER) was also derived to determine the cost in order to increase BRCA carriers‐healthy life span by 1 year. Compared to model 1, model 2 increases the detection rate of BRCA carriers by 41.8%, reduces the rate of BRCA‐related cancers by 23.7%, generating over a 62‐year observation period a cost increase by 2.51 €/Year/Person. Moreover, model 3 further increases BRCA carriers detection (+ 68.3%) and decrease in BRCA‐related cancers (− 38.4%) is observed compared to model 1. Model 3 increases costs by 0.7 €/Year/Person. After one generation, the estimated ICER in the

Published
2024

7. Sentinel-node biopsy in apparent early stage ovarian cancer: final results of a prospective multicentre study (SELLY)

Author

Nero, Camilla, Bizzarri, Nicolo', Di Berardino, Stefano, Sillano, F., Vizzielli, Giuseppe, Cosentino, F., Vargiu, V., De Iaco, P., Perrone, A. M., Vizza, E., Chiofalo, B., Uccella, S., Ghezzi, F., Turco, L. C., Corrado, Giacomo, Giannarelli, Diana, Pasciuto, Tina, Zannoni, Gian Franco, Fagotti, Anna, Scambia, Giovanni, Nero C., Bizzarri N., Di Berardino S., Vizzielli G., Corrado G., Giannarelli D., Pasciuto T. (ORCID:0000-0003-2959-8571), Zannoni G. F. (ORCID:0000-0003-1809-129X), Fagotti A. (ORCID:0000-0001-5579-335X), Scambia G. (ORCID:0000-0003-2758-1063), Nero, Camilla, Bizzarri, Nicolo', Di Berardino, Stefano, Sillano, F., Vizzielli, Giuseppe, Cosentino, F., Vargiu, V., De Iaco, P., Perrone, A. M., Vizza, E., Chiofalo, B., Uccella, S., Ghezzi, F., Turco, L. C., Corrado, Giacomo, Giannarelli, Diana, Pasciuto, Tina, Zannoni, Gian Franco, Fagotti, Anna, Scambia, Giovanni, Nero C., Bizzarri N., Di Berardino S., Vizzielli G., Corrado G., Giannarelli D., Pasciuto T. (ORCID:0000-0003-2959-8571), Zannoni G. F. (ORCID:0000-0003-1809-129X), Fagotti A. (ORCID:0000-0001-5579-335X), and Scambia G. (ORCID:0000-0003-2758-1063)

Abstract

Aim: To evaluate the sensitivity and specificity of sentinel-lymph-node mapping compared with the gold standard of systematic lymphadenectomy in detecting lymph node metastasis in apparent early stage ovarian cancer. Methods: Multicenter, prospective, phase II trial, conducted in seven centers from March 2018 to July 2022. Patients with presumed stage I-II epithelial ovarian cancer planned for surgical staging were eligible. Patients received injection of indocyanine green in the infundibulo-pelvic and, when feasible, utero-ovarian ligaments and sentinel lymph node biopsy followed by pelvic and para-aortic lymphadenectomy was performed. Histopathological examination of all nodes was performed including ultra-staging protocol for the sentinel lymph node. Results: 174 patients were enrolled and 169 (97.1 %) received study interventions. 99 (58.6 %) patients had successful mapping of at least one sentinel lymph node and 15 (15.1 %) of them had positive nodes. Of these, 11 of 15 (73.3 %) had a correct identification of the disease in the sentinel lymph node; 7 of 11 (63.6 %) required ultra-staging protocol to detect nodal metastasis. Four (26.7 %) patients with node-positive disease had a negative sentinel-lymph-node (sensitivity 73.3 % and specificity 100.0 %). Conclusions: In a multicenter setting, identifying sentinel-lymph nodes in apparent early stage epithelial ovarian cancer did not reach the expected sensitivity: 1 of 4 patients might have metastatic lymphatic disease unrecognized by sentinel-lymph-node biopsy. Nevertheless, 35.0 % of node positive patients was identified only thanks to ultra-staging protocol on sentinel-lymph-nodes.

Published
2024

8. The potential role of systemic inflammatory markers in predicting recurrence in early-stage cervical cancer

Author

Bruno, Matteo, Bizzarri, Nicolò, Teodorico, Elena, Certelli, Camilla, Gallotta, Valerio, Pedone Anchora, Luigi, Fagotti, Anna, Fanfani, Francesco, Scambia, Giovanni, Ferrandina, Maria Gabriella, Fagotti, Anna (ORCID:0000-0001-5579-335X), Fanfani, Francesco (ORCID:0000-0003-1991-7284), Scambia, Giovanni (ORCID:0000-0003-2758-1063), Ferrandina, Gabriella (ORCID:0000-0003-4672-4197), Bruno, Matteo, Bizzarri, Nicolò, Teodorico, Elena, Certelli, Camilla, Gallotta, Valerio, Pedone Anchora, Luigi, Fagotti, Anna, Fanfani, Francesco, Scambia, Giovanni, Ferrandina, Maria Gabriella, Fagotti, Anna (ORCID:0000-0001-5579-335X), Fanfani, Francesco (ORCID:0000-0003-1991-7284), Scambia, Giovanni (ORCID:0000-0003-2758-1063), and Ferrandina, Gabriella (ORCID:0000-0003-4672-4197)

Abstract

Introduction: The influence of systemic inflammatory markers on early-stage cervical cancer (ECC) patients is contradictory. No previous study analyzed whether these markers may be suggestive of recurrence. The aim of this study was to assess whether the inflammatory markers level of patients with recurrence during surveillance was different from those of patients without recurrence representing a risk factor for recurrence. Methods: Retrospective, single-center, observational study. Patients with 2009 FIGO EEC surgically treated between 2012 and 2019 were included. Baseline inflammatory markers were evaluated on the results of the complete blood count (CBC) and coagulation tests. Inflammatory markers of relapsed patients were evaluated on the last CBC performed before the relapse diagnosis. Inflammatory markers of patients with no recurrence were evaluated on the available CBC taken at the same median follow-up time as the one from relapsed patients. Results: 174 patients were included. Baseline Systemic immune inflammation index (SII) > 663 and Systemic inflammation response index (SIRI) > 0.98 were associated with significant risk of recurrence. SII>663 and Neutrophil to lymphocyte ratio (NLR) > 2.41 were associated with increased risk of death. Significant changes between relapsed (n = 23) and non-relapsed (n = 151) patients in median values of SII (615 versus 490, p-value = 0.001), SIRI (0.74 versus 1.05, p-value = 0.005), NRL (2.95 versus 2.15, p-value = 0.0035), and MLR (0.26 versus 0.22 p-value = 0.020), showed that different levels of inflammatory markers could help identifying recurrent disease during surveillance. Conclusion: Baseline SII>663 and SIRI>0.98 were associated with increased risk of recurrence. Higher median values of SII, SIRI, NLR and MLR in relapsed patients highlight their potential association with recurrence.

Published
2024

9. Imaging in gynecological disease (27): clinical and ultrasound characteristics of recurrent ovarian stromal cell tumors

Author

Moro, Francesca, Giudice, M. T., Bolomini, G., Moruzzi, M. C., Mascilini, F., Quagliozzi, L., Ciccarone, F., Scambia, Giovanni, Fagotti, Anna, Valentin, L., Testa, Antonia Carla, Moro, F., Scambia, G. (ORCID:0000-0003-2758-1063), Fagotti, A. (ORCID:0000-0001-5579-335X), Testa, A. C. (ORCID:0000-0003-2217-8726), Moro, Francesca, Giudice, M. T., Bolomini, G., Moruzzi, M. C., Mascilini, F., Quagliozzi, L., Ciccarone, F., Scambia, Giovanni, Fagotti, Anna, Valentin, L., Testa, Antonia Carla, Moro, F., Scambia, G. (ORCID:0000-0003-2758-1063), Fagotti, A. (ORCID:0000-0001-5579-335X), and Testa, A. C. (ORCID:0000-0003-2217-8726)

Abstract

Objective To describe the clinical and ultrasound characteristics of recurrent granulosa cell and Sertoli-Leydig cell tumors. Methods This was a retrospective observational study performed at Fondazione Policlinico Universitario A. Gemelli, Istituto di Ricovero e Cura a Carattere Scientifico, IRCCS, Rome (Gemelli center). Patients with a histological diagnosis of recurrent granulosa cell tumor or Sertoli-Leydig cell tumor were identified from the database of the Department of Gynecological Oncology. Those who had undergone a preoperative ultrasound examination at the Gemelli center between 2012 and 2020 were included, and the data retrieved from the original ultrasound reports. In all of these reports, the recurrent tumors were described using International Ovarian Tumor Analysis (IOTA) terminology. If a patient had more than one episode of relapse, information from all episodes was collected. If there was more than one recurrent tumor at the same ultrasound examination, all tumors were included. One expert sonographer also reviewed all available ultrasound images to identify typical ultrasound patterns using pattern recognition. Results We identified 30 patients with a histological diagnosis of recurrent granulosa cell tumor (25 patients, 55 tumors) or Sertoli-Leydig cell tumor (five patients, seven tumors). All 30 had undergone at least one preoperative ultrasound examination at the Gemelli center and were included. These women had a total of 66 episodes of relapse, of which a preoperative ultrasound examination had been performed at the Gemelli center in 34, revealing 62 recurrent lesions: one in 22/34 (64.7%) episodes of relapse, two in 4/34 (11.8%) episodes and three or more in 8/34 (23.5%) episodes. Most recurrent granulosa cell tumors (38/55, 69.1%) and recurrent Sertoli-Leydig tumors (6/7, 85.7%) were classified as solid or multilocular-solid tumors, while 8/55 (14.5%) recurrent granulosa cell tumors and 1/7 (14.3%) recurrent Sertoli-Leydig cell tumors were

Published
2024

10. Epithelial ovarian cancer and brain metastases: might the BRCA status, PARP inhibitor administration, and surgical treatment impact the survival?

Author

Sassu, Carolina Maria, Marchetti, Claudia, Russo, G., Minucci, Angelo, Boccia, S. M., Benato, Alberto, Nero, Camilla, Piermattei, Angelo, Mattogno, Pier Paolo, Giannarelli, Diana, Ferrandina, Maria Gabriella, Olivi, Alessandro, Fagotti, Anna, Scambia, Giovanni, Sassu C. M., Marchetti C. (ORCID:0000-0001-7098-8956), Minucci A., Benato A., Nero C., Piermattei A. (ORCID:0000-0002-6835-1179), Mattogno P. P., Giannarelli D., Ferrandina G. (ORCID:0000-0003-4672-4197), Olivi A. (ORCID:0000-0002-4489-7564), Fagotti A. (ORCID:0000-0001-5579-335X), Scambia G. (ORCID:0000-0003-2758-1063), Sassu, Carolina Maria, Marchetti, Claudia, Russo, G., Minucci, Angelo, Boccia, S. M., Benato, Alberto, Nero, Camilla, Piermattei, Angelo, Mattogno, Pier Paolo, Giannarelli, Diana, Ferrandina, Maria Gabriella, Olivi, Alessandro, Fagotti, Anna, Scambia, Giovanni, Sassu C. M., Marchetti C. (ORCID:0000-0001-7098-8956), Minucci A., Benato A., Nero C., Piermattei A. (ORCID:0000-0002-6835-1179), Mattogno P. P., Giannarelli D., Ferrandina G. (ORCID:0000-0003-4672-4197), Olivi A. (ORCID:0000-0002-4489-7564), Fagotti A. (ORCID:0000-0001-5579-335X), and Scambia G. (ORCID:0000-0003-2758-1063)

Abstract

inglese

Published
2024

11. Transvaginal ultrasound-guided biopsy in patients with suspicious primary advanced tubo-ovarian carcinoma

Author

Mascilini, F., Quagliozzi, L., Mirandola, M., Moro, Francesca, D'Alessandris, N., De Felice, F., Testa, Antonia Carla, Scambia, Giovanni, Fagotti, Anna, Moro F., Testa A. C. (ORCID:0000-0003-2217-8726), Scambia G. (ORCID:0000-0003-2758-1063), Fagotti A. (ORCID:0000-0001-5579-335X), Mascilini, F., Quagliozzi, L., Mirandola, M., Moro, Francesca, D'Alessandris, N., De Felice, F., Testa, Antonia Carla, Scambia, Giovanni, Fagotti, Anna, Moro F., Testa A. C. (ORCID:0000-0003-2217-8726), Scambia G. (ORCID:0000-0003-2758-1063), and Fagotti A. (ORCID:0000-0001-5579-335X)

Abstract

Objective To assess the accuracy of pathological diagnosis by transvaginal ultrasound-guided biopsy versus surgery in patients with suspicious primary advanced tubo-ovarian carcinoma. The Feasibility, adequacy, and safety of the procedure were also evaluated. Methods Consecutive women with pre-operative suspicious primary advanced tubo-ovarian carcinoma presenting between July 2019 and September 2021 were enrolled. Accuracy was calculated including only cases who underwent surgery. Feasibility was defined as the number of cases in which ultrasound-guided biopsy was possible according to tumor characteristics (morphology and site). Adequacy was defined as the number of conclusive diagnoses out of the samples collected. Safety was defined by the number of major complications which were defined as hospitalization, surgery, and/or blood transfusion. Results A total of 278 patients were eligible for the study; 158 were enrolled, while 120 were excluded for logistic reasons or patient refusal. Ultrasound-guided biopsy was not feasible in 30 (19%) patients. The samples obtained in the remaining 128 patients were all adequate (100%), and no major complications were noted. A total of 26 (20%) patients started neoadjuvant chemotherapy on the basis of the diagnosis obtained by ultrasound, whereas 102 (80%) patients underwent surgery. Accuracy of ultrasound-guided biopsy versus surgery was 94% (96/102), with six false negative cases at ultrasound (6%). Site (prevesical peritoneum) and size (<8 mm) of the nodules resulted as major predictive factors for ultrasound-guided biopsy failure (false negative). Ultrasound-guided biopsy correctly identified 86 primary invasive tubo-ovarian carcinomas and 10 metastatic tumors. Conclusion Ultrasound-guided biopsy is a feasible, safe, and accurate method to provide histological diagnosis in suspicious advanced tubo-ovarian cancer patients.

Published
2023

12. Effect of bevacizumab in advanced low grade serous ovarian cancer: Data from the MITO 22 trial

Author

Musacchio, Lucia, Turinetto, Margherita, Arenare, Laura, Bartoletti, Michele, Califano, Daniela, Tuninetti, Valentina, Marchetti, Claudia, Cormio, Gennaro, Loizzi, Vera, Pisano, Carmela, Salutari, Vanda, Valabrega, Giorgio, Priolo, Domenico, Cecere, Sabrina Chiara, Ventriglia, Jole, Raspagliesi, Francesco, Perrone, Francesco, Fagotti, Anna, Lorusso, Domenica, Scambia, Giovanni, Pignata, Sandro, Marchetti, Claudia (ORCID:0000-0001-7098-8956), Fagotti, Anna (ORCID:0000-0001-5579-335X), Scambia, Giovanni (ORCID:0000-0003-2758-1063), Musacchio, Lucia, Turinetto, Margherita, Arenare, Laura, Bartoletti, Michele, Califano, Daniela, Tuninetti, Valentina, Marchetti, Claudia, Cormio, Gennaro, Loizzi, Vera, Pisano, Carmela, Salutari, Vanda, Valabrega, Giorgio, Priolo, Domenico, Cecere, Sabrina Chiara, Ventriglia, Jole, Raspagliesi, Francesco, Perrone, Francesco, Fagotti, Anna, Lorusso, Domenica, Scambia, Giovanni, Pignata, Sandro, Marchetti, Claudia (ORCID:0000-0001-7098-8956), Fagotti, Anna (ORCID:0000-0001-5579-335X), and Scambia, Giovanni (ORCID:0000-0003-2758-1063)

Abstract

Objective: The aim of the present analysis was to explore the efficacy of Bevacizumab (Bev) on survival outcome in advanced low grade serous ovarian cancer (LGSOC) both in first line and in recurrent setting. Methods: In retrospective observational multicenter study, we described the outcome of LGSOC patients enrolled in the MITO 22 study and treated with chemotherapy (CT) with or without Bev. Patients receiving Bev in first-line or in recurrence were considered and compared with patients receiving CT alone (stage III and IV in first line; platinum based-CT in second line). Descriptive and survival analyses were performed for each group. Results: Out of 128 patients included in MITO 22, 46 LGSOC patients receiving Bev in first line setting or at the time of first recurrence were identified. In first line, 30 patients received Bev + CT and 65 CT alone and the median PFS were 47.86 months (95% CI: 31.48 - NR) and 22.63 months (95% CI 15-39.24) (p-value 0.0392), respectively. In the recurrent setting, 16 patients who received Bev + CT were compared to 33 women treated with platinum-based CT alone. Median PFS were 37.1 months (95% CI: 13.42-40.56) and 11.22 months (95% CI: 8.26-15.63) (p-value 0.013), respectively. Conclusions: Our study suggests that Bev might be effective in LGSOC both at diagnosis and at the time of relapse. These data warrants further studies.

Published
2023

13. Cytoreductive surgery for advanced epithelial ovarian cancer in the poly(ADP-ribose) polymerase inhibitors era—Is it time for a new paradigm shift? A systematic review and meta-analysis

Author

Peters, I. T. A., Marchetti, Claudia, De Palma, Antonella, Giannarelli, Diana, Carcagnì, A., Scambia, Giovanni, Fagotti, Anna, Marchetti C. (ORCID:0000-0001-7098-8956), De Palma A., Giannarelli D., Scambia G. (ORCID:0000-0003-2758-1063), Fagotti A. (ORCID:0000-0001-5579-335X), Peters, I. T. A., Marchetti, Claudia, De Palma, Antonella, Giannarelli, Diana, Carcagnì, A., Scambia, Giovanni, Fagotti, Anna, Marchetti C. (ORCID:0000-0001-7098-8956), De Palma A., Giannarelli D., Scambia G. (ORCID:0000-0003-2758-1063), and Fagotti A. (ORCID:0000-0001-5579-335X)

Abstract

Introduction: In patients with newly diagnosed advanced high-grade serous and endometrioid epithelial ovarian cancer (EOC) first-line maintenance therapy with poly(ADP-ribose) polymerase inhibitors (PARPi) tremendously improved progression-free survival (PFS). Yet, data on the effect of PARPi in proportion to postoperative residual disease status were lacking. Material and methods: A systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items of Systematic reviews and Meta-Analysis (PRISMA) guidelines. We searched Medline/Pubmed, Embase and Cochrane databases as well as meeting abstracts until 18th March 2023. Hazard ratios (HRs) alongside their 95% confidence intervals (CIs) for PFS were extracted from the studies. A subgroup analysis was conducted to examine the effect of PARPi according to postoperative residual disease. Results: A total of six phase III randomised controlled trials were included and comprised SOLO 1, PAOLA 1, PRIMA, PRIME, ATHENA-MONO and VELIA. Patients who received PARPi following complete gross resection showed greatest PFS benefit. Compared with placebo, maintenance with PARPi significantly improved PFS in patients with macroscopic residual disease (pooled HR 0.55; 95% CI 0.44-0.68). This magnitude was comparable to that found in patients with complete gross resection (pooled HR 0.53; 95% CI 0.41-0.67). Conclusions: Patients with macroscopic residual disease benefit from PARPi at the same extent as cases with complete gross resection. However, patients with complete gross resection who were treated with PARPi show the most favourable PFS rates. Hence, the pursuit of achieving complete cytoreduction remains valid in the PARPi era.

Published
2023

14. Ovarian cancer onset across different BRCA mutation types: a view to a more tailored approach for BRCA mutated patients

Author

Marchetti, Claudia, Ataseven, Beyhan, Cassani, Chiara, Sassu, Carolina Maria, Congedo, Luigi, D'Indinosante, Marco, Cappuccio, Serena, Rhiem, Kerstin, Hahnen, Eric, Lucci Cordisco, Emanuela, Arbustini, Eloisa, Harter, Philipp, Minucci, Angelo, Scambia, Giovanni, Fagotti, Anna, Marchetti, Claudia (ORCID:0000-0001-7098-8956), Lucci Cordisco, Emanuela (ORCID:0000-0002-6279-7604), Scambia, Giovanni (ORCID:0000-0003-2758-1063), Fagotti, Anna (ORCID:0000-0001-5579-335X), Marchetti, Claudia, Ataseven, Beyhan, Cassani, Chiara, Sassu, Carolina Maria, Congedo, Luigi, D'Indinosante, Marco, Cappuccio, Serena, Rhiem, Kerstin, Hahnen, Eric, Lucci Cordisco, Emanuela, Arbustini, Eloisa, Harter, Philipp, Minucci, Angelo, Scambia, Giovanni, Fagotti, Anna, Marchetti, Claudia (ORCID:0000-0001-7098-8956), Lucci Cordisco, Emanuela (ORCID:0000-0002-6279-7604), Scambia, Giovanni (ORCID:0000-0003-2758-1063), and Fagotti, Anna (ORCID:0000-0001-5579-335X)

Abstract

ObjectiveTo evaluate the role of different specific types of germline breast cancer susceptibility BRCA mutations on the age of onset of high grade serous ovarian cancer. MethodsThis was a multicenter, international, retrospective cohort of 474 patients diagnosed with recurrent or newly diagnosed high grade serous ovarian cancer, with known germline mutations in BRCA1/2 genes, treated between January 2011 and December 2020 in three academic centers in Europe. Patients were classified into four groups related to the type of BRCA1/2 genes mutation: frameshift, missense, nonsense, and splicing. Data from patients with splicing mutations were removed from the analysis because of the small numbers. The other three groups were compared. ResultsExcluding the 29 patients with a splicing mutation, 474 patients were enrolled: 309 (65.2%) with frameshift mutations, 102 (21.5%) with nonsense mutations, and 63 (13.3%) with missense mutations. The BRCA1 gene was affected in 324 (68.4%) cases, while BRCA2 was involved in 150 (31.6%) women (p=0.06). We found a difference of more than 5 years in the age of onset of high grade serous ovarian cancer between BRCA1 and BRCA2 patients (mean 53.3 years vs 58.4 years; p=0.001), with a mean age of 55.1 years. Patients with nonsense germline mutations had the youngest age of onset, while women with frameshift mutations had the oldest age of onset of high grade serous ovarian cancer (mean 52.2 years vs mean 55.9 years), both in the BRCA1 and BRCA2 subgroups. There was no statistically significant difference in age of onset between early and advanced groups (mean 55.8 years vs 55.0 years; p=0.55). ConclusionDifferent types of germline BRCA mutations could determine different ages for onset of high grade serous ovarian cancer. If confirmed in larger series, this finding might have a clinical impact, potentially leading to a more tailored approach for risk reducing surgery for the prevention of high grade serous ovarian cancer.

Published
2023

15. Visual Peritoneal Evaluation of Residual Disease After Neoadjuvant Chemotherapy in Advanced Ovarian Cancer Patients: The VIPER Study

Author

Costantini, Barbara, Rosati, A., Vargiu, V., Gallitelli, Vitalba, Di Ilio, Chiara, Moroni, R., Scambia, Giovanni, Fagotti, Anna, Costantini B., Gallitelli V., Di Ilio C., Scambia G. (ORCID:0000-0003-2758-1063), Fagotti A. (ORCID:0000-0001-5579-335X), Costantini, Barbara, Rosati, A., Vargiu, V., Gallitelli, Vitalba, Di Ilio, Chiara, Moroni, R., Scambia, Giovanni, Fagotti, Anna, Costantini B., Gallitelli V., Di Ilio C., Scambia G. (ORCID:0000-0003-2758-1063), and Fagotti A. (ORCID:0000-0001-5579-335X)

Abstract

Background: Chemotherapy induces histopathological tumor necrosis and fibrosis which results in macroscopic tissue changes, making surgeons’ intraoperative visual evaluation of the disease distribution more difficult to interpret. The aim of the study was to assess the sensitivity, specificity, and accuracy of intraoperative laparoscopic visual evaluation of the diaphragmatic peritoneum and compare it with histopathological examination. Methods: Patients receiving diaphragmatic peritonectomy at time of IDS were retrospectively included. The population was grouped based on the surgeon’s assessment of the diaphragmatic peritoneum during diagnostic laparoscopy. Group 1 included patients with a “visually pathologic” diaphragmatic peritoneum, and group 2 included patients with a “visually dubious” diaphragmatic peritoneum. Sensitivity, specificity, predictive values, and accuracy were calculated considering the final formalin-fixed pathology as the reference standard. Results: 155 patients were included (92 in group 1 and 63 in group 2). The accuracy rate of visual examination was 67.1%, the negative predictive value was 19%, specificity was 100%, and sensitivity was 64.3%. Conclusion: NACT strongly affects the ability of the surgeon to discern between peritoneal scars and truly pathologic peritoneum. The diaphragmatic laparoscopic visual examination showed a low overall accuracy. We propose an algorithm that can guide the surgeon towards a more tailored approach to diaphragmatic peritonectomy during IDS.

Published
2023

16. Prognostic Significance of Ultrasound Characteristics and Body Mass Index in Patients with Apparent Early-Stage Cervical Cancer: A Single-Center, Retrospective, Cohort Study

Author

Bizzarri, Nicolò, Biscione, Antonella, Moro, Francesca, Pedone Anchora, Luigi, Catinella, Valeria, Certelli, Camilla, Teodorico, Elena, Fagotti, Anna, Fanfani, Francesco, Kucukmetin, Ali, Querleu, Deni, Ferrandina, Maria Gabriella, Scambia, Giovanni, Testa, Antonia Carla, Fagotti, Anna (ORCID:0000-0001-5579-335X), Fanfani, Francesco (ORCID:0000-0003-1991-7284), Ferrandina, Gabriella (ORCID:0000-0003-4672-4197), Scambia, Giovanni (ORCID:0000-0003-2758-1063), Testa, Antonia Carla (ORCID:0000-0003-2217-8726), Bizzarri, Nicolò, Biscione, Antonella, Moro, Francesca, Pedone Anchora, Luigi, Catinella, Valeria, Certelli, Camilla, Teodorico, Elena, Fagotti, Anna, Fanfani, Francesco, Kucukmetin, Ali, Querleu, Deni, Ferrandina, Maria Gabriella, Scambia, Giovanni, Testa, Antonia Carla, Fagotti, Anna (ORCID:0000-0001-5579-335X), Fanfani, Francesco (ORCID:0000-0003-1991-7284), Ferrandina, Gabriella (ORCID:0000-0003-4672-4197), Scambia, Giovanni (ORCID:0000-0003-2758-1063), and Testa, Antonia Carla (ORCID:0000-0003-2217-8726)

Abstract

The primary aim of the present study was to investigate the prognostic impact (defined as disease-free-DFS and overall survival-OS) of the ultrasound scan tumor parameters, patients' anthropometric parameters, and their combination in early-stage cervical cancer. The secondary aim was to assess the relation between ultrasound characteristics and pathological parametrial infiltration. This is a retrospective, single-center, observational cohort study. Consecutive patients with clinical FIGO 2018 stage IA1-IB2 and IIA1 cervical cancer who underwent preoperative ultrasound examination and radical surgery between 02/2012 and 06/2019 were included. Patients who underwent neo-adjuvant treatment, fertility sparing surgery, and pre-operative conization were excluded. Data from 164 patients were analyzed. Body mass index (BMI) <= 20 Kg/m(2) (p < 0.001) and ultrasound tumor volume (p = 0.038) were related to a higher risk of recurrence. The ratios between ultrasound tumor volume and BMI, ultrasound tumor volume and height, and ultrasound largest tumor diameter and BMI were significantly related to a higher risk of recurrence (p = 0.011, p = 0.031, and p = 0.017, respectively). The only anthropometric characteristic related to a higher risk of death was BMI <= 20 Kg/m(2) (p = 0.021). In the multivariate analysis, the ratio between ultrasound-measured largest tumor diameter and cervix-fundus uterine diameter (with 37 as the cut-off) was significantly associated with pathological microscopic parametrial infiltration (p = 0.018). In conclusion, a low BMI was the most significant anthropometric biomarker impairing DFS and OS in patients with apparent early-stage cervical cancer. The ratios between ultrasound tumor volume and BMI, ultrasound tumor volume and height, and ultrasound largest tumor diameter and BMI significantly affected DFS but not OS. The ratio between ultrasound-measured largest tumor diameter and cervix-fundus uterine diameter was related to parametrial in

Published
2023

17. Role of minimally invasive secondary cytoreduction in patients with recurrent ovarian cancer

Author

Conte, Carmine, Marchetti, Claudia, Loverro, Matteo, Giudice, M. T., Rosati, A., Gallotta, Valerio, Scambia, Giovanni, Fagotti, Anna, Conte C., Marchetti C. (ORCID:0000-0001-7098-8956), Loverro M., Gallotta V., Scambia G. (ORCID:0000-0003-2758-1063), Fagotti A. (ORCID:0000-0001-5579-335X), Conte, Carmine, Marchetti, Claudia, Loverro, Matteo, Giudice, M. T., Rosati, A., Gallotta, Valerio, Scambia, Giovanni, Fagotti, Anna, Conte C., Marchetti C. (ORCID:0000-0001-7098-8956), Loverro M., Gallotta V., Scambia G. (ORCID:0000-0003-2758-1063), and Fagotti A. (ORCID:0000-0001-5579-335X)

Abstract

Objective Retrospective series have shown minimally invasive secondary cytoreductive surgery is a feasible approach in selected cases of recurrent ovarian cancer. However, no predictors of minimally invasive secondary cytoreductive surgery feasibility are currently available. This study aims to identify predictive factors of minimally invasive secondary cytoreductive surgery feasibility and to compare perioperative and survival outcomes in a matched series of recurrent ovarian cancer patients who underwent secondary cytoreduction via an open or minimally invasive surgical approach. Methods We retrospectively identified all platinum-sensitive recurrent epithelial ovarian cancer patients who underwent minimally invasive or laparotomic secondary cytoreductive surgery between January 2013 and July 2020. Each patient underwent a preoperative positron emission tomography (PET) computerized tomography (CT) scan and diagnostic laparoscopy before secondary cytoreductive surgery. A 1:2 propensity score-matched analysis was performed to balance predictive factors of minimally invasive secondary cytoreductive surgery. Results Overall, 276 patients were identified (62 minimally invasive and 214 open), and a complete gross resection was achieved in 262 (94.9%) patients. At multivariate analysis, predictive factors for minimally invasive secondary cytoreductive surgery were neoadjuvant chemotherapy at first diagnosis (p=0.007), site of recurrence (p=0.031), and number of lesions (p=0.001). In the 1:2 propensity-matched population (39 minimally invasive and 78 open), complete gross resection was similar for both groups (p=0.082). Early post-operative complications were significantly higher in the laparotomy (33.3%) than in the minimally invasive surgery (10.3%) group (p=0.004). Only one (2.6%) patient experienced a grade >3 early post-operative complication in the minimally invasive surgery group compared with 13 (16.7%) patients in the open cohort (p<0.001). The median follo

Published
2023

18. Trabectedin plus pegylated liposomal doxorubicin in patients with disease progression after PARP inhibitor maintenance: a real-life case-control study

Author

Vertechy, Laura, Boccia, Serena Maria, Tiberi, Giordana, Avesani, Giacomo, Corrado, Giacomo, Fagotti, Anna, Scambia, Giovanni, Marchetti, Claudia, Fagotti, Anna (ORCID:0000-0001-5579-335X), Scambia, Giovanni (ORCID:0000-0003-2758-1063), Marchetti, Claudia (ORCID:0000-0001-7098-8956), Vertechy, Laura, Boccia, Serena Maria, Tiberi, Giordana, Avesani, Giacomo, Corrado, Giacomo, Fagotti, Anna, Scambia, Giovanni, Marchetti, Claudia, Fagotti, Anna (ORCID:0000-0001-5579-335X), Scambia, Giovanni (ORCID:0000-0003-2758-1063), and Marchetti, Claudia (ORCID:0000-0001-7098-8956)

Abstract

Objective Poly (ADP-ribose) polymerase (PARP) inhibitor resistance is problematic in epithelial ovarian cancer management and sequencing strategies may be performed to overcome this issue. In this context, our study evaluated the role of non-platinum doublet pegylated liposomal doxorubicin/trabectedin in ovarian cancer platinum-sensitive patients who experienced disease progression under PARP inhibitor maintenance.Methods This case-control study includes patients with recurrent epithelial ovarian cancer treated between March 2016 and April 2021 who progressed under PARP inhibitor maintenance. Data of patients treated with pegylated liposomal doxorubicin/trabectedin (experimental group) were matched 1:1 with a series of patients who received platinum-based treatment (control group). The study outcomes were overall clinical benefit (including complete, partial, and stable response), progression-free survival, and overall survival. The safety of both treatments was also evaluated.Results A total of 26 patients in both groups were analyzed. Clinical benefit was achieved in 15 (57%) patients in the study group and 17 (65%) patients in the control group (p=0.38). Patients receiving pegylated liposomal doxorubicin/trabectedin had 5 months of progression-free survival, compared with 5 months in patients treated with platinum-based treatment (p=0.62). Patients in the experimental group achieved a median overall survival of 16 months compared with 19 months in the control group (p=0.26) There was no difference concerning severe toxicities (G3-G4) between groups, except for hepatic toxicity, which was experienced in 30% of the patients receiving pegylated liposomal doxorubicin/trabectedin and none in the control group (p<0.009).Conclusions Pegylated liposomal doxorubicin/trabectedin might be an alternative option to platinum-based treatment in patients experiencing disease progression during PARP inhibitor maintenance with an acceptable toxicity profile. This might be a the

Published
2023

19. Survival outcomes in patients with BRCA mutated, variant of unknown significance, and wild type ovarian cancer treated with PARP inhibitors

Author

Musacchio, Lucia, Boccia, Serena, Marchetti, Claudia, Minucci, Angelo, Camarda, Floriana, Cassani, Chiara, Ventriglia, Jole, Salutari, Vanda, Ghizzoni, Viola, Giudice, Elena, Perri, Maria Teresa, Carbone, Maria Vittoria, Ricci, Caterina, Pignata, Sandro, Fagotti, Anna, Scambia, Giovanni, Lorusso, Domenica, Marchetti, Claudia (ORCID:0000-0001-7098-8956), Fagotti, Anna (ORCID:0000-0001-5579-335X), Scambia, Giovanni (ORCID:0000-0003-2758-1063), Musacchio, Lucia, Boccia, Serena, Marchetti, Claudia, Minucci, Angelo, Camarda, Floriana, Cassani, Chiara, Ventriglia, Jole, Salutari, Vanda, Ghizzoni, Viola, Giudice, Elena, Perri, Maria Teresa, Carbone, Maria Vittoria, Ricci, Caterina, Pignata, Sandro, Fagotti, Anna, Scambia, Giovanni, Lorusso, Domenica, Marchetti, Claudia (ORCID:0000-0001-7098-8956), Fagotti, Anna (ORCID:0000-0001-5579-335X), and Scambia, Giovanni (ORCID:0000-0003-2758-1063)

Abstract

ObjectiveCorrelation between BRCA1/2 (BRCA) pathogenic variants and the response to poly (ADP-ribose) polymerase inhibitors (PARPi) has been recognized in patients with ovarian cancer. Moreover, data on the clinical implications of variants of unknown significance are lacking. The aim of this study was to evaluate differences in survival outcomes in patients with BRCA variants of unknown significance, mutated, and wild type relapsed ovarian cancer treated with PARPi. MethodsPatients with ovarian cancer whose somatic BRCA testing was available and who were receiving PARPi as maintenance treatment at the first recurrence between January 2014 and January 2021 were included in the present study and analyzed. Patients were divided into three groups according to BRCA mutational status (variant of unknown significance, mutated, and wild type). Progression-free survival was assessed in each study group. ResultsOf 67 patients identified, 20 (29.9%), 24 (35.8%), and 23 (34.3%) had BRCA variant of unknown significance, mutated, and wild type, respectively. Patients received PARPi as maintenance treatment at the time of the first relapse after a complete response or partial response to platinum-based chemotherapy without differences in the previous platinum-free interval among the analyzed groups. The median progression-free survival of patients with BRCA mutation was significantly longer than for those with BRCA wild type or variant of unknown significance (not reached vs 4 months vs 7 months, respectively; p<0.001). Additionally, no significant difference was found between patients with BRCA wild type and BRCA variant of unknown significance (p=0.50). ConclusionOur study suggests that carriers of BRCA variant of unknown significance have survival outcomes comparable to patients with BRCA wild type and shorter progression-free survival than women harboring BRCA pathogenic variants.

Published
2023

20. Lymph node staging in grade 1–2 endometrioid ovarian carcinoma apparently confined to the ovary: Is it worth?

Author

Bizzarri, Nicolo', Imterat, M., Fruscio, R., Giannarelli, Diana, Perrone, A. M., Mancari, R., Traut, A., Rosati, A., du Bois, A., Ferrari, D., De Iaco, P., Ergasti, R., Ataseven, B., Bianchi, T., Di Stanislao, M., Perri, M. T., Heitz, F., Concin, N., Fanfani, Francesco, Vizza, E., Scambia, Giovanni, Harter, P., Fagotti, Anna, Bizzarri N., Giannarelli D., Fanfani F. (ORCID:0000-0003-1991-7284), Scambia G. (ORCID:0000-0003-2758-1063), Fagotti A. (ORCID:0000-0001-5579-335X), Bizzarri, Nicolo', Imterat, M., Fruscio, R., Giannarelli, Diana, Perrone, A. M., Mancari, R., Traut, A., Rosati, A., du Bois, A., Ferrari, D., De Iaco, P., Ergasti, R., Ataseven, B., Bianchi, T., Di Stanislao, M., Perri, M. T., Heitz, F., Concin, N., Fanfani, Francesco, Vizza, E., Scambia, Giovanni, Harter, P., Fagotti, Anna, Bizzarri N., Giannarelli D., Fanfani F. (ORCID:0000-0003-1991-7284), Scambia G. (ORCID:0000-0003-2758-1063), and Fagotti A. (ORCID:0000-0001-5579-335X)

Abstract

Objective: The aim of this study was to assess the disease-free survival (DFS) and overall survival (OS) of patients with grade 1–2 endometrioid ovarian carcinoma apparently confined to the ovary, according to surgical staging. Methods: Multicenter, retrospective, observational cohort study. Patients with endometrioid ovarian carcinoma, surgical procedure performed between May 1985 and December 2019, stage pT1 N0/N1/Nx, grade 1–2 were included. Patients were stratified according to lymphadenectomy (defined as removal of any lymph node versus no lymph node assessment), and subgroup analyses according to tumor grade were performed. Kaplan-Meier curves and cox regression analyses were used to perform survival analyses. Results: 298 patients were included. 199 (66.8 %) patients underwent lymph node assessment. Of these, 166 (83.4 %) had unilateral/bilateral pelvic and para-aortic/caval lymphadenectomy. Eleven (5.5 %) patients of those who underwent lymph node assessment showed pathologic metastatic lymph nodes (FIGO stage IIIA1). Twenty-seven patients (9.1 %) had synchronous endometrioid endometrial cancer. After a median follow up of 45 months (95 %CI:37.5–52.5), 5-year DFS and OS of the entire cohort were 89.8 % and 96.2 %, respectively. Age ≤ 51 years (HR=0.24, 95 %CI:0.06–0.91; p = 0.036) and performance of lymphadenectomy (HR=0.25, 95 %CI: 0.07–0.82; p = 0.022) represented independent protective factors toward risk of death. Patients undergoing lymphadenectomy had better 5-year DFS and OS compared to those not receiving lymphadenectomy, 92.0 % versus 85.6 % (p = 0.016) and 97.7 % versus 92.8 % (p = 0.013), respectively. This result was confirmed after exclusion of node-positive patients. When stratifying according to tumor grade (node-positive excluded), patients with grade 2 who underwent lymphadenectomy had better 5-year DFS and OS than those without lymphadenectomy (93.0 % versus 83.1 %, p = 0.040 % and 96.5 % versus 90.6 %, p = 0.037, respectively). Conclusion

Published
2023

21. Survival outcomes in patients with BRCA mutated, variant of unknown significance, and wild type ovarian cancer treated with PARP inhibitors

Author

Musacchio, Lucia, Boccia, Serena, Marchetti, Claudia, Minucci, Angelo, Camarda, Floriana, Cassani, Chiara, Ventriglia, Jole, Salutari, Vanda, Ghizzoni, Viola, Giudice, Elena, Perri, Maria Teresa, Carbone, Maria Vittoria, Ricci, Caterina, Pignata, Sandro, Fagotti, Anna, Scambia, Giovanni, Lorusso, Domenica, Marchetti, Claudia (ORCID:0000-0001-7098-8956), Fagotti, Anna (ORCID:0000-0001-5579-335X), Scambia, Giovanni (ORCID:0000-0003-2758-1063), Musacchio, Lucia, Boccia, Serena, Marchetti, Claudia, Minucci, Angelo, Camarda, Floriana, Cassani, Chiara, Ventriglia, Jole, Salutari, Vanda, Ghizzoni, Viola, Giudice, Elena, Perri, Maria Teresa, Carbone, Maria Vittoria, Ricci, Caterina, Pignata, Sandro, Fagotti, Anna, Scambia, Giovanni, Lorusso, Domenica, Marchetti, Claudia (ORCID:0000-0001-7098-8956), Fagotti, Anna (ORCID:0000-0001-5579-335X), and Scambia, Giovanni (ORCID:0000-0003-2758-1063)

Abstract

ObjectiveCorrelation between BRCA1/2 (BRCA) pathogenic variants and the response to poly (ADP-ribose) polymerase inhibitors (PARPi) has been recognized in patients with ovarian cancer. Moreover, data on the clinical implications of variants of unknown significance are lacking. The aim of this study was to evaluate differences in survival outcomes in patients with BRCA variants of unknown significance, mutated, and wild type relapsed ovarian cancer treated with PARPi. MethodsPatients with ovarian cancer whose somatic BRCA testing was available and who were receiving PARPi as maintenance treatment at the first recurrence between January 2014 and January 2021 were included in the present study and analyzed. Patients were divided into three groups according to BRCA mutational status (variant of unknown significance, mutated, and wild type). Progression-free survival was assessed in each study group. ResultsOf 67 patients identified, 20 (29.9%), 24 (35.8%), and 23 (34.3%) had BRCA variant of unknown significance, mutated, and wild type, respectively. Patients received PARPi as maintenance treatment at the time of the first relapse after a complete response or partial response to platinum-based chemotherapy without differences in the previous platinum-free interval among the analyzed groups. The median progression-free survival of patients with BRCA mutation was significantly longer than for those with BRCA wild type or variant of unknown significance (not reached vs 4 months vs 7 months, respectively; p<0.001). Additionally, no significant difference was found between patients with BRCA wild type and BRCA variant of unknown significance (p=0.50). ConclusionOur study suggests that carriers of BRCA variant of unknown significance have survival outcomes comparable to patients with BRCA wild type and shorter progression-free survival than women harboring BRCA pathogenic variants.

Published
2023

22. Quality of life in patients with advanced ovarian cancer after primary debulking surgery versus neoadjuvant chemotherapy: Results from the randomised SCORPION trial (NCT01461850)

Author

Marchetti, Claudia, Giannarelli, Diana, Vizzielli, Giuseppe, Ferrandina, Maria Gabriella, Tortorella, Lucia, Fanfani, Francesco, Costantini, Barbara, Pasciuto, Tina, Scambia, Giovanni, Fagotti, Anna, Marchetti, Claudia (ORCID:0000-0001-7098-8956), Ferrandina, Maria Gabriella. (ORCID:0000-0003-4672-4197), Fanfani, Francesco (ORCID:0000-0002-4354-5735), Pasciuto, Tina (ORCID:0000-0003-2959-8571), Scambia, Giovanni (ORCID:0000-0003-2758-1063), Fagotti, Anna (ORCID:0000-0001-5579-335X), Marchetti, Claudia, Giannarelli, Diana, Vizzielli, Giuseppe, Ferrandina, Maria Gabriella, Tortorella, Lucia, Fanfani, Francesco, Costantini, Barbara, Pasciuto, Tina, Scambia, Giovanni, Fagotti, Anna, Marchetti, Claudia (ORCID:0000-0001-7098-8956), Ferrandina, Maria Gabriella. (ORCID:0000-0003-4672-4197), Fanfani, Francesco (ORCID:0000-0002-4354-5735), Pasciuto, Tina (ORCID:0000-0003-2959-8571), Scambia, Giovanni (ORCID:0000-0003-2758-1063), and Fagotti, Anna (ORCID:0000-0001-5579-335X)

Abstract

Objective To investigate the effect of treatment with neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS), versus primary debulking surgery (PDS), on quality of life (QoL) in patients with advanced epithelial ovarian cancer (EOC).Design Randomised trial conducted in a single institution.Setting Division of Gynaecologic Oncology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.Sample Patients with stage-IIIC/IV EOC and high tumour load.Methods Patients were randomised (1:1) to undergo either PDS (PDS group) or NACT followed by IDS (NACT/IDS group).Main outcome measures Quality-of-life (QoL) data, assessed using the European Organization for Research and Treatment of Cancer core QoL questionnaire (QLQ-C30) and ovarian cancer module (OV28); co-primary outcomes were the QLQ-C30 global health score at 12 months (cross-sectional analysis) and the difference in mean QLQ-C30 global health score over time between treatment groups (longitudinal analysis).Results From October 2011 to May 2016, 171 patients were enrolled (PDS = 84; NACT/IDS = 87). We observed no clinical or statistically significant difference between treatment groups in any of the QoL functioning scales at 12 months, including QLQ-C30 global health score (NACT/IDS group vs PDS group, mean difference 4.7, 95% CI -4.99 to 14.4, p = 0.340). Over time, we found lower global health scores for those undergoing PDS than for those receiving NACT (difference in mean score 6.27, 95% CI 0.440-12.11, p = 0.035), albeit this was not clinically relevant.Conclusions We found no difference in global QoL related to treatment approach at 12 months, even though patients in the NACT/IDS group reported better global health scores across the 12-month period compared with the PDS group; these findings further confirm that NACT/IDS might be a feasible option for patients unsuitable for PDS.

Published
2023

23. A common pattern of somatic mutations in t-MDS/AML of patients treated with PARP inhibitors for metastatic ovarian cancer

Author

Chiusolo, Patrizia, Marchetti, Claudia, Rossi, M., Minnella, Gessica, Salutari, Vanda, Distefano, M., Giammarco, S., Metafuni, Elisabetta, Minucci, Angelo, Frioni, Filippo, Gasbarrino, C., Colangelo, M., Orteschi, D., Fagotti, Anna, Lorusso, D., Pagano, Livio, De Stefano, Valerio, Scambia, Giovanni, Sica, S., Chiusolo P. (ORCID:0000-0002-1355-1587), Marchetti C. (ORCID:0000-0001-7098-8956), Minnella G., Salutari V., Metafuni E., Minucci A., Frioni F., Fagotti A. (ORCID:0000-0001-5579-335X), Pagano L. (ORCID:0000-0001-8287-928X), De Stefano V. (ORCID:0000-0002-5178-5827), Scambia G. (ORCID:0000-0003-2758-1063), Chiusolo, Patrizia, Marchetti, Claudia, Rossi, M., Minnella, Gessica, Salutari, Vanda, Distefano, M., Giammarco, S., Metafuni, Elisabetta, Minucci, Angelo, Frioni, Filippo, Gasbarrino, C., Colangelo, M., Orteschi, D., Fagotti, Anna, Lorusso, D., Pagano, Livio, De Stefano, Valerio, Scambia, Giovanni, Sica, S., Chiusolo P. (ORCID:0000-0002-1355-1587), Marchetti C. (ORCID:0000-0001-7098-8956), Minnella G., Salutari V., Metafuni E., Minucci A., Frioni F., Fagotti A. (ORCID:0000-0001-5579-335X), Pagano L. (ORCID:0000-0001-8287-928X), De Stefano V. (ORCID:0000-0002-5178-5827), and Scambia G. (ORCID:0000-0003-2758-1063)

Abstract

NA

Published
2022

24. Prognostic factors for survival in patients with lung metastases from gynaecological tract cancers

Author

Chiappetta, M., Gallotta, Valerio, Pogliani, L., Zanfrini, E., Fagotti, Anna, Ferrandina, Maria Gabriella, Fanfani, Francesco, Nachira, Dania, Meacci, Elisa, Congedo, Maria Teresa, Lococo, Filippo, Giudice, M. T., Scambia, Giovanni, Margaritora, Stefano, Gallotta V., Fagotti A. (ORCID:0000-0001-5579-335X), Ferrandina G. (ORCID:0000-0003-4672-4197), Fanfani F. (ORCID:0000-0003-1991-7284), Nachira D. (ORCID:0000-0003-2937-9678), Meacci E. (ORCID:0000-0001-8424-3816), Congedo M. T., Lococo F. (ORCID:0000-0002-9383-5554), Scambia G. (ORCID:0000-0003-2758-1063), Margaritora S. (ORCID:0000-0002-9796-760X), Chiappetta, M., Gallotta, Valerio, Pogliani, L., Zanfrini, E., Fagotti, Anna, Ferrandina, Maria Gabriella, Fanfani, Francesco, Nachira, Dania, Meacci, Elisa, Congedo, Maria Teresa, Lococo, Filippo, Giudice, M. T., Scambia, Giovanni, Margaritora, Stefano, Gallotta V., Fagotti A. (ORCID:0000-0001-5579-335X), Ferrandina G. (ORCID:0000-0003-4672-4197), Fanfani F. (ORCID:0000-0003-1991-7284), Nachira D. (ORCID:0000-0003-2937-9678), Meacci E. (ORCID:0000-0001-8424-3816), Congedo M. T., Lococo F. (ORCID:0000-0002-9383-5554), Scambia G. (ORCID:0000-0003-2758-1063), and Margaritora S. (ORCID:0000-0002-9796-760X)

Abstract

OBJECTIVES: Lung metastases from gynaecological tract cancers are rare, and prognostic factors are still undefined. The goal of this study was to analyse prognostic factors for survival in this group of patients. METHODS: Data of patients with lung metastases from gynaecological tract cancers who underwent surgical resections from 1 January 2005 to 31 May 2019 were reviewed retrospectively. All patients were treated surgically if the primitive tumour was under control and the lung was the only organ involved. Clinical and pathological data associated with metastatic patterns and previous treatment types were correlated with overall survival (OS) and disease-free survival using Kaplan-Meier curves, whereas the log-rank test was used to assess differences between subgroups. RESULTS: The analysis was conducted on 55 patients. OS was 65% at 5 years. With univariable analysis, age >45 years (P = 0.022) and the absence of pleural infiltration (P = 0.001) were determined to be favourable prognostic factors. The 5-year OS was 69.9% versus 53.3% in patients with pleural involvement. Multivariable analysis confirmed the absence of pleural infiltration as a favourable independent prognostic factor; the hazard ratio was 0.06; the 95% confidence interval was 0.00-0.23 (P = 0.011).At univariable analysis, the absence of pleural infiltration was determined to be a favourable prognostic factor (P = 0.034) for disease-free survival. The numbers and dimensions of the metastases did not influence survival in these patients.In uterine cancers of endometrial or cervical origin, the presence of pleural infiltration (P = 0.001), lymph node involvement (P = 0.001) and young age (P = 0.044) were considered unfavourable prognostic factors for OS. CONCLUSIONS: Surgical treatment in technically resectable gynaecological tract metastases may represent an important option. Pleural infiltration and lymph node metastases seem to be adverse prognostic factors.

Published
2022

25. The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study

Author

Adamina, M., Ademuyiwa, A., Adisa, A., Bhangu, A. A., Bravo, A. M., Cunha, M. F., Emile, S., Ghosh, D., Glasbey, J. C., Harris, B., Keller, D., Lawday, S., Lederhuber, H., Leventoglu, S., Li, E., Modolo, M. M., Mittal, R., Mohan, H. M., Nepogodiev, D., Parreno-Sacdalan, M. D., Pata, F., Pockney, P., Rutegard, M., Smart, N., Varghese, C., Siaw-Acheampong, K., Benson, R. A., Bywater, E., Chaudhry, D., Dawson, B. E., Evans, J. P., Gujjuri, R. R., Heritage, E., Jones, C. S., Kamarajah, S. K., Khatri, C., Khaw, R. A., Keatley, J. M., Knight, A., Mann, H. S., Marson, E. J., Mclean, K. A., Mckay, S. C., Mills, E. C., Pellino, Giuseppe, Picciochi, M., Taylor, E. H., Tiwari, A., Trout, I. M., Venn, M. L., JW Wilkin, R., Bhangu, A., Smart, N. J., Minaya-Bravo, A., Gallo, Giuseppe, Moug, S., Saverio, S. D., Vallance, A., Vimalchandran, D., Griffiths, E. A., Evans, R. P. T., Townend, P., Roberts, K., Mckay, S., Isaac, J., Satoi, S., Edwards, J., Coonar, A. S., Marchbank, A., Caruana, E. J., Layton, G. R., Patel, A., Brunelli, A., Ford, S., Desai, A., Gronchi, A., Fiore, M., Almond, M., Tirotta, F., Dumitra, S., Kolias, A., Price, S. J., Fountain, D. M., Jenkinson, M. D., Hutchinson, P., Marcus, H. J., Piper, R. J., Lippa, L., Servadei, Franco, Esene, I., Freyschlag, C., Neville, I., Rosseau, G., Schaller, K., Demetriades, A. K., Robertson, F., Alamri, A., Shaw, R., Schache, A. G., Winter, S. C., Ho, M., Nankivell, P., Biel, J. R., Batstone, M., Ganly, I., Vidya, R., Wilkins, A., Singh, J. K., Thekinkattil, D., Sundar, S., Fotopoulou, C., Leung, E. Y. L., Khan, T., Chiva, L., Sehouli, J., Fagotti, Anna, Cohen, P., Gutelkin, M., Ghebre, R., Konney, T., Pareja, R., Bristow, R., Dowdy, S., Shylasree, T. S., Seenivasagam, R. K., Ng, J., Fujiwara, K., Stewart, G. D., Lamb, B., Narahari, K., Mcneill, A., Colquhoun, A., Mcgrath, J. S., Bromage, S., Barod, R., Kasivisvanathan, V., Klatte, T., Abbott, T. E. F., Abukhalaf, S., Ademuyiwa, A. O., Agarwal, A., Akkulak, M., Alameer, E., Alderson, D., Alakaloko, F., Albertsmeier, M., Alser, O., Alshaar, M., Alshryda, S., Arnaud, A. P., Augestad, K. M., Ayasra, F., Azevedo, J., Bankhead-Kendall, B. K., Barlow, E., Beard, D., Blanco-Colino, R., Brar, A., Breen, K. A., Bretherton, C., Buarque, I. L., Burke, J., Chaar, M., Chakrabortee, S., Christensen, P., Cox, D., Cukier, M., Davidson, G. H., Drake, T. M., Edwards, J. G., Elhadi, M., Farik, S., Fitzgerald, J. E., Garmanova, T., Gomes, G. M. A., Grecinos, G., Gruendl, M., Halkias, C., Harrison, E. M., Hisham, I., Hutchinson, P. J., Hwang, S., Isik, A., Jonker, P., Kaafarani, H. M. A., Kruijff, S., Lawani, I., Litvin, A., Loehrer, A., Loffler, M. W., Lorena, M. A., Major, P., Martin, J., Mashbari, H. N., Mazingi, D., Metallidis, S., Moore, R., Moszkowicz, D., Ng-Kamstra, J. S., Maimbo, M., Negoi, I., Niquen, M., Ntirenganya, F., Olivos, M., Oussama, K., Outani, O., Rivera, C. J. P., Pinkney, T. D., van der Plas, W., Qureshi, A., Radenkovic, D., Ramos-De la Medina, A., Richards, T., Roslani, A. C., Segura-Sampedro, J. J., Santos, I., Sayyed, R., Schache, A., Schnitzbauer, A. A., Seyi-Olajide, J. O., Sharma, N., Shaw, C. A., Shu, S., Soreide, K., Spinelli, A., Sund, M., Tabiri, S., Tsoulfas, G., van Ramshorst, G. H., Vimalachandran, D., Warren, O. J., Wedderburn, D., Wright, N., Valenzuela, J. I., Alurralde, C., Caram, E. L., Eskinazi, D. G., Badra, R., Garcia, J. S., Lucchini, S. M., Vasey, C., Watson, E., Cecire, J., Salindera, S., Sutherland, A., Ahn, J. H., Chen, S., Gauri, N., Jang, S., Jia, F., Mulligan, C. S., Yang, W., Ye, G., Zhang, H., Moss, J., Thian, A., Vo, U. G., Bagraith, K., Chan, E., Ho, D., Jeyarajan, E., Jordan, S., Nolan, G. J., Von Papen, M., Wullschleger, M., Dawson, A. C., Drane, A., Egoroff, N., Gani, J., Lott, N., Phan, D., Townend, D., Bong, C., Gundara, J., Bowman, S., Guerra, G. R., Gerns, N., Riddell, A., Dudi-Venkata, N. N., Kroon, H. M., Sammour, T., Mitchell, D., Swinson, B., Waldron, A., Walker, P., Lun, E. W. Y., Messner, F., Ofner, D., Emmanuel, K., Grechenig, M., Gruber, R., Harald, M., Jager, T., Ohlberger, L., Presl, J., Wimmer, A., Namazov, I., Samadov, E., Barker, D., Boyce, R., Doyle, A., Eastmond, A., Gill, R., O'Shea, M., Padmore, G., Paquette, N., Phillips, E., St John, S., Walkes, K., Flamey, N., Pattyn, P., Ceelen, W., Van de Putte, D., Van Nieuwenhove, Y., Van Ramshorst, G., Willaert, W., Oosterlinck, W., Van den Eynde, J., Van den Eynde, R., Aguiar Junior, S., Marques, T., Camara, P., De Lima, R. K., Della Giustina, E., Hoffmann, P. V., Nacif, L., Carvalho Ferro, C., Lima Buarque, I., Lira dos Santos Leite, A., Pol-Fachin, L., Santos Bezerra, T., Silva, Angela, Silvestre, D., Vieira Barros, A., Laporte, G., Salem, M., Barakat Awada, J., Ijichi, T. R., Kim, N. J., Marreiro, A., Muller, B., Nunes, R., Bodanese, B., Isoton, J. C., Regina de Sampaio, L., Vendrame, C., Sokolov, M., Gribnev, P., Boutros, M., Caminsky, N., Ghitulescu, G., Groot, G., Persad, A., Pham, H., Wood, M., Demyttenaere, S., Garfinkle, R., Brown, C., Karimuddin, A., Lee, N., Liu, J., Madani Kia, T., Phang, P. T., Raval, M., Tom, K., Martel, A., Nessim, C., Stevenson, J., Al Riyami, S., Bali, K., Bigam, D., Dajani, K., Turco, Enrico Maria, Bellolio, F., Besser, N., Grasset, E., Inzunza, M., Quintana Martinic, M., Riquoir Altamirano, C., Ruiz Esquide, M., Arias-Amezquita, F., Cetares, C., Cortes Murgueitio, N., Gomez-Mayorga, J. L., Abadia, M., Bonilla, A., Facundo, H., Guevara, O., Herrera Mora, D. R., Jimenez Ramirez, L. J., Manrique, E., Pinilla Morales, R. E., Rey Ferro, M., Velasquez Cuasquen, B. G., Bacic, G., Karlovic, D., Krsul, D., Zelic, M., Bakmaz, B., Coza, I., Dijan, E., Katusic, Z., Mihanovic, J., Rakvin, I., Almezghwi, H., Arslan, K., Ozant, A., Ozcay, N., Frantzeskou, K., Gouvas, N., Kokkinos, G., Papatheodorou, P., Pozotou, I., Stavrinidou, O., Yiallourou, A., Martinek, L., Skrovina, M., Szubota, I., Peteja, M., Zatecky, J., Avlund, T., Harbjerg, J. L., Iversen, L. H., Kjaer, D. W., Kristensen, H. O., Mekhael, M., Ebbehoj, A. L., Krarup, P., Schlesinger, N., Smith, H., Crespo, A., Diaz, P., Rivas, R., Tactuk, N., El Kassas, M., Omar, W., Tawheed, A., Talaat, M., Abdelsamed, A., Azzam, A. Y., Salem, H., Seleim, A., AL Sayed, M., Ashoush, F., Elazzazy, E., Essam, E., Ewedah, M., Hassan, E., Metwalli, M., Mourad, M., Qatora, M. S., Sabry, A., Samih, A., Samir Abdelaal, A., Shehata, S., Shenit, K., Attia, D., Kamal, N., Osman, N., Alaa, S., Hamza, H. M., M. elghazaly, S., Mohammed, M. M., Nageh, M. A., Saad, M. M., Yousof, E. A., Eldaly, A., Alrahawy, M., Sakr, A., Soliman, H., Soltan, H., Amira, G., Sallam, I., Sherief, M., Sherif, A., Ghaly, G., Hamdy, R., Morsi, A., Sherif, G., Abdeldayem, H., Abdelkader Salama, I., Balabel, M., Fayed, Y., Sherif, A. E., Elmorsi, R., Refky, B., Bekele, K., Kauppila, J. H., Sarjanoja, E., Helminen, O., Huhta, H., Beyrne, C., Jouffret, L., Marie-Macron, L., Fredon, F., Roux, A., Lakkis, Z., Manfredelli, S., Chebaro, A., El Amrani, M., Lecolle, K., Piessen, G., Eveno, C., Noiret, B., Veziant, J., Pruvot, F. R., Zerbib, P., Ballouhey, Q., Barrat, B., Taibi, A., Bergeat, D., Merdrignac, A., Le Roy, B., Perotto, L. O., Scalabre, A., Aime, A., Ezanno, A. C., Malgras, B., Bouche, P. A., Tzedakis, S., Cotte, E., Glehen, O., Bendjemar, L., Braham, H., Charre, L., El Arbi, N., Police, A., Volpin, E., D'Urso, Antonio, Mutter, D., Seeliger, B., Bonnet, S., Denet, C., Fuks, D., Laforest, A., Pourcher, G., Seguin-givelet, A., Tribillon, E., Duchalais, E., Bork, U., Fritzmann, J., Praetorius, C., Weitz, J., Welsch, T., Beyer, K., Kamphues, C., Lauscher, J., Loch, F. N., Schineis, C., Kappenberger, A., Schiergens, T., Werner, J., Becker, R., Jonescheit, J., Pergolini, I., Reim, D., Herzberg, J., Honarpisheh, H., Strate, T., Boeker, C., Hakami, I., Mall, J. W., Nowak, K., Reinhard, T., Kleeff, J., Michalski, C., Ronellenfitsch, U., Bertolani, E., Konigsrainer, A., Quante, M., Steidle, C., Uberruck, L., Yurttas, C., Izbicki, J., Nitschke, C., Perez, D., Uzunoglu, F. G., Antonakis, P., Contis, I., Dellaportas, D., Gklavas, A., Konstadoulakis, M., Memos, N., Papaconstantinou, I., Polydorou, A., Theodosopoulos, T., Vezakis, A., Antonopoulou, M. I., Manatakis, D. K., Tasis, N., Arkadopoulos, N., Danias, N., Economopoulou, P., Frountzas, M., Kokoropoulos, P., Larentzakis, A., Michalopoulos, N., Parasyris, S., Selmani, J., Sidiropoulos, T., Vassiliu, P., Bouchagier, K., Klimopoulos, S., Paspaliari, D., Stylianidis, G., Akrivou, D., Baxevanidou, K., Bouliaris, K., Chatzikomnitsa, P., Delinasios, G., Doudakmanis, C., Efthimiou, M., Giaglaras, A., Kalfountzos, C., Kolla, C., Koukoulis, G., Zervas, K., Zourntou, S., Baloyiannis, I., Diamantis, A., Perivoliotis, K., Tzovaras, G., Christidis, P., Ioannidis, O., Loutzidou, L., Karaitianos, I. G., Geroukalis, A., Tsirlis, T., Baili, E., Charalabopoulos, A., Liakakos, T., Schizas, D., Spartalis, E., Syllaios, A., Zografos, C., Christou, C., Papadopoulos, V., Tooulias, A., Athanasakis, E., Chrysos, E., Tsiaoussis, I., Xenaki, S., Xynos, E., Futaba, K., Ho, M. F., Hon, S., Mak, T. W. C., Ng, S., Foo, C. C., Banky, B., Susztak, N., Misra, S., Pareek, P., Vishnoi, J. R., Jain, A., Mishra, S., Mishra, T., Mitra, J. K., Muduly, D., Agrawal, A., Garg, P. K., Kottayasamy Seenivasagam, R., Majumdar, K. S., Mishra, N., Singh, M. P., Chyau Patnaik, S., Rao, S., Reddy, P., S, R., Saksena, A. R., Y, J., Ayloor Seshadri, R., Haque, P. D., Jeyaraj, P., Kannummal Veetil, S., Mahajan, A., Devarakonda, S., Jesudason, M. R., Moorthy, M., Yezzaji, H., Aggarwal, M., Dhamija, P., Kumar, A., Chisthi, M., D, G., George, G., Kollengode, V. V., Kuttanchettiyar, K. G., Yadev, I., Dharanipragada, K., Kalayarasan, R., Penumadu, P., B, L., Mathew, S., Akhtar, N., Chaturvedi, A., Gupta, S., Kumar, V., Rajan, S., Agrawal, N., Arora, A., Chaturvedi, H., Jain, M., Kumar, S., Singh, S., Bhat, G. A., Chowdri, N., Mehraj, A., Parray, F. Q., Shah, Z. A., Wani, R., Ahmed, Z., Bhat, M. A., Laharwal, A., Mahmood, M., Mir, I., Mohammad, Z., Muzamil, J., Rashid, A., Singh, R., Ahmed, A., Jain, D., Pipara, A., Desoouza, A., Pandey, D., Pramesh, C. S., Saklani, A., Islam, A. A., Kembuan, G., Pajan, H., Aremu, M., Canas-Martinez, A., Cullivan, O., Murphy, C., Owens, P., Pickett, L., Corrigan, M., Daly, A., Fleming, C. A., Jordan, P., Kayyal, M. Y., Killeen, S., Lynch, N., O'Brien, S., Syed, W. A. S., Vernon, L., Hanly, A., Heneghan, H., Kennelly, R., Martin, S. T., Winter, D., Fahey, B. A., Larkin, J., Mccormick, P., Mehigan, B. J., Shokuhi, P., Smith, Jenovia Amisti, Bashir, Y., Bass, G., Connelly, T., Creavin, B., Earley, H., Elliott, J. A., Gillis, A. E., Kavanagh, D., Neary, P., O'Riordan, J., Reynolds, I. S., Rice, D., Ridgway, P. F., Umair, M., Whelan, M., Corless, K., Finnegan, L., Fowler, A., Hogan, A., Lowery, A., Mckevitt, K., Nugent, E., Ryan, E. J., Coffey, J. C., Cunningham, R. M., Devine, M., Nally, D., Peirce, C., Hardy, N. P., Neary, P. M., O'Malley, S., Ryan, M., Gaziants, V., Gold-Deutch, R., Lavy, R., Zmora, O., Macina, S., Mariani, N. M., Opocher, E., Pisani Ceretti, A., Bianco, Flaviana, Marino, M., Marino, M. V., Mirabella, A., Vaccarella, G., Sena, G., Agostini, C., Alemanno, G., Bartolini, I., Bergamini, C., Bruscino, A., De Vincenti, R., Di Bella, A., Fortuna, Ludovica, Maltinti, G., Muiesan, P., Prosperi, P., Ringressi, M. N., Risaliti, M., Taddei, A., Tucci, R., Campagnaro, T., Guglielmi, A., Pedrazzani, C., Rattizzato, S., Ruzzenente, A., Turri, G., Altomare, D. F., Papagni, V., Picciariello, A., Bellora, P., D'Aloisio, G., Ferrari, M., Francone, E., Gentilli, S., Nikaj, H., Bianchini, M., Chiarugi, M., Coccolini, F., Cremonini, Cinzia, Di Franco, G., Furbetta, N., Gianardi, D., Guadagni, S., Morelli, Lorenzo, Musetti, S., Palmeri, M., Tartaglia, D., Anania, G., Carcoforo, P., Chiozza, M., De Troia, A., Koleva Radica, M., Portinari, M., Sibilla, M. G., Urbani, A., Fabbri, N., Feo, C. V., Gennari, S., Parini, S., Righini, E., Annessi, V., Castro Ruiz, C., Giunta, A., Montella, M. T., Zizzo, M., Grossi, U., Novello, S., Romano, M., Rossi, S., Zanus, G., Esposito, G., Frongia, F., Pisanu, A., Podda, Maria Vittoria, Belluco, C., Lauretta, A., Montori, G., Moras, L., Olivieri, M., De Feo, Claudia Francesca, Perra, T., Porcu, A., Scanu, A. M., Aversano, A., Carbone, F., Delrio, P., Di Lauro, K., Fares Bucci, A., Rega, D., Spiezio, G., Pirozzolo, G., Recordare, A., Vignotto, C., Calabro, M., Farnesi, F., Lunghi, E. G., Muratore, A., Pipitone Federico, N. S., De Palma, G., Luglio, G., Pagano, G., Tropeano, F. P., Baldari, L., Boni, L., Cassinotti, E., Cosimelli, M., Guaglio, M., Sorrentino, L., Agnes, Annamaria, Alfieri, S., Belia, Francesco, Biondi, Alberto, Cozza, Valerio, D'Ugo, Domenico, De Simone, V., Litta, Francesco, Lorenzon, L., Marra, Angelo Alessandro, Marzi, Federica, Parello, Angelo, Persiani, Roberto, Ratto, Carlo, Rosa, F., Scrima, Ottavio, Sganga, Gabriele, Belli, Andrea, Izzo, Filippo, Patrone, R., Foppa, C., Carvello, M. M., De Lucia, Francesca, Aprile, A., Batistotti, P., Massobrio, A., Pertile, D., Scabini, S., Soriero, D., De Manzoni Garberini, A., Mazzotti, F., Pasini, F., Ugolini, G., Barone, Roberto, Birolo, S. L., Caccetta, M., Deirino, A., Garino, M., Grasso, M., Marafante, C., Masciandaro, A., Moggia, E., Mungo, S., Murgese, A., Raggio, E., Federico, Paola, Maida, P., Marra, E., Marte, G., Petrillo, A., Tammaro, P., Tufo, A., Berselli, M., Borroni, Giulia, Cocozza, E., Conti, L., Desio, M., Rizzi, A., Baldi, C., Corbellini, C., Sampietro, G. M., Bordoni, P., Clarizia, G., Fleres, F., Franzini, Manila, Grechi, A., Longhini, A., Spolini, A., Baldini, E., Capelli, Paolo, Isolani, S. M., Ribolla, M., Bondurri, A., Colombo, F., Ferrario, L., Guerci, C., Maffioli, A., Armao, T., Ballabio, M., Bisagni, P., Longhi, Mattia, Madonini, M., Impellizzeri, H., Inama, M., Moretto, G., Mochet, S., Usai, Alessandro, Incollingo, P., Giacometti, M., Zonta, S., Marino Cosentino, L., Sagnotta, A., Nespoli, L. C., Tamini, N., Anastasi, A., Bartalucci, B., Bellacci, A., Canonico, G., Capezzuoli, L., Di Martino, C., Ipponi, P., Linari, C., Montelatici, M., Nelli, T., Spagni, Gregorio, Tirloni, L., Vitali, A., Abate, E., Casati, Mirta, Laface, L., Schiavo, Martina, Arminio, A., Cotoia, A., Lizzi, V., Vovola, F., Vergari, R., D'Ugo, S., Depalma, N., Spampinato, M. G., Annicchiarico, A., Catena, F., Giuffrida, M., Perrone, G., Baronio, G., Carissimi, F., Montuori, M., Pinotti, E., Brachini, G., Chiappini, A., Cicerchia, P. M., Cirillo, B., De Toma, G., Fiori, Micol Eleonora, Fonsi, G. B., Iannone, I., La Torre, F., Lapolla, P., Meneghini, S., Mingoli, A., Sapienza, P., Zambon, M., Capolupo, G. T., Carannante, F., Mazzotta, E., Gattolin, A., Migliore, M., Rimonda, R., Sasia, D., Travaglio, E., Chessa, A., Fiorini, A., Norcini, C., Colletti, Guido Carlo, Confalonieri, Marco, Costanzi, A., Frattaruolo, C., Mari, G., Monteleone, M., Locatelli, A., Riva, C., Balconi, A., De Nardi, P., Parise, P., Vignali, A., Belvedere, A., Bernante, P., Droghetti, M., Jovine, E., Neri, J., Parlanti, D., Pezzuto, A. P., Poggioli, G., Rottoli, M., Russo, I. S., Tanzanu, M., Violante, T., Borghi, F., Cianflocca, D., Di Maria Grimaldi, S., Donati, Davide, Gelarda, E., Giraudo, G., Giuffrida, M. C., Marano, A., Palagi, S., Pellegrino, Luca, Peluso, C., Testa, V., Agresta, F., Prando, D., Zese, M., Armatura, G., Frena, A., Bertelli, G., Marinello, P., Notte, F., Scotton, G., Cervellera, M., Gori, A., Sartarelli, L., Tonini, V., Sammarco, Maria Grazia, Vescio, G., Di Marzo, F., Kanemitsu, Y., Moritani, K., Al Abdallah, M., Ayasra, Y., Qasem, A., Fahmawee, T., Hmedat, A., Obeidat, K., Abou Chaar, M. K., Al-Masri, M., Al-Najjar, H., Alawneh, F., Aldokali, N., Senossi, O., Subhi, M. T., Algallai, M., Alwarfly, S., Alzaede, S., Gahwagi, M., Moftah, M., Burgan, D., Kamoka, E., Kilani, A. I., Abdelkabir, M., Altomi, I., Abdulwahed, E., Alshareea, E., Aribi, N., Aribi, S., Biala, M., Ghamgh, R., Alsoufi, A., Ellojli, I., Kredan, A., Msherghi, A., Alshareef, K., Alkadiki, G. Z., Almaadany, F. S., Bradulskis, S., Dainius, E., Kubiliute, E., Kutkevicius, J., Parseliunas, A., Subocius, A., Venskutonis, D., Rasoaherinomenjanahary, F., Razafindrahita, J. B., Samison, L. H., Ngo, C. W., Ramasamy, S., Hamdan, K. H., Mdrazal, i. I K. H., Tan, J. A., Thanapal, M. R., Choong, E., Lim, R. Z. M., Sahid, N. A., Hayati, F., Jayasilan, J., Sriram, R. K., Subramaniam, S., Ibrahim, A. F., Che jusoh, A., Hussain, A. H., Mohamed Sidek, A. S., Mohd Yunus, M. F., Soh, J. Y., Wong, M. P., Zakaria, A. D., Zakaria, Z., Mohd Azman, Z. A., Fathi, N. Q., Xavier, R., Alvarez, M. R., Cordera, F., Hernandez, R., Soule Martinez, C. E., Aboharp Hasan, Z., Otoniel, L. R., Sosa Duran, E. E., Melchor-Ruan, J., Romero Banuelos, E., Vilar-Compte, D., Buerba, G. A., Mercado, M. A., Posadas-Trujillo, O. E., Salgado-Nesme, N., Sarre, C., Amrani, L., Benkabbou, A., El Ahmadi, B., El Bouazizi, Y., Belkhadir, Z. H., Ghannam, A., Majbar, A. M., Mohsine, R., Souadka, A., Hompes, R., Meima-van Praag, E. M., Pronk, A. J. M., Sharabiany, S., Grotenhuis, B. A., Hartveld, L., Ebben, L., Kuiper, S., Melenhorst, J., Poeze, M., Posma-Bouman, L., Derksen, T., Franken, J., Oosterling, S., Konsten, J., Van Heinsbergen, M., Adeyeye, A., Enoch, E., Nwabuoku, S. E., Sholadoye, T. T., Tolani, M. A., Olaogun, J., Abiyere, H., Babalola, O., Okunlola, A., Ali Sani, S., Chinda, J., Garba, S., Mshelbwala, P., Olori, S., Olute, A., Osagie, O., Pius Ogolekwu, I., Umar, A., Abdur-Rahman, L. O., Bello, J. O., Olasehinde, O., Popoola, A. A., Abassy, J., Ahmed, K., Alvi, A., Khan, S., Pirzada, A., Saleem, A., Siddiqui, M. T., Turk, K., Jamal, A., Kerawala, A. A., Memon, A. S., Nafees Ahmed, R., Rai, L., Ali, A. A., Afzal, M. F., Khokhar, M. I., Ayub, B., Ramesh, P., Ayyaz, M., Butt, U., Kashif, M., Qureshi, A. U., Farooka, M. W., Ayubi, A., Waqar, S. H., Al-Slaibi, I., Alzeerelhouseini, H. I. A., Jobran, F., Abukhalaf, S. A., Jocson, R., Teh, C., Uy Magadia, E., Bak, M., Dubienska, K., Lawnicka, A., Murawa, D., Janik, M., Kowalewski, P., Kwiatkowski, A., Roszkowski, R., Sroczynski, P., Waledziak, M., Azevedo, C., Machado, D., Mendes, F., De Sousa, X., Fernandes, U., Ferreira, C., Guidi, G., Marcal, A., Marques, R., Martins, D., Vaz-Pereira, R., Vieira, B., Almeida, J. I., Almeida-Reis, R., Correia de Sa, T., Costa, M. J. M. A., Fernandes, V., Ferraz, I., Lima da Cruz, L., Lima da Silva, C., Lopes, L., Machado, N., Marialva, J., Nunes Coelho, M., Pedro, J., Pereira, C., Ribeiro, A., Ribeiro, C. 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R., Parreira, R., Abreu da Silva, A., Claro, M., Costa Santos, D., Deus, A. C., Grilo, J. V., Castro Borges, F., Corte Real, J., Henriques, S., Lima, M. J., Matos Costa, P., Alagoa Joao, A., Camarneiro, R., Capunge, I., Fragoso, M., Frazao, J., Martins, A., Pedro, V., Pera, R., Ramalho de Almeida, F., Sampaio Soares, A., Vale, R., Vasconcelos, M., Brito da Silva, F., Caiado, A., Fonseca, F., Angelo, M., Baiao, J. M., Martins Jordao, D., Vieira Caroco, T., Baia, C., Canotilho, R., Correia, A. M., Ferreira Pinto, A. P., Peyroteo, M., Videira, J. F., Kassir, R., Sauvat, F., Bonci, E., Gata, V., Titu, S., Bezede, C., Chitul, A., Ciofic, E., Cristian, D., Grama, F., Ciubotaru, C., Negoita, V. M., Stoica, B., Ginghina, O., Iordache, N., Iosifescu, R. V., Mardare, M., Mirica, R. M., Spanu, A., Vacaras, A. B., Zamfir-Chiru-Anton, M., Tsarkov, P., Tulina, I., Abelevich, A., Bazaev, A., Kokobelyan, A. K., Yanishev, A., Litvina, Y., Provozina, A., Agapov, M., Kazachenko, E., Markaryan, D., Galliamov, E., Kakotkin, V., Kubyshkin, V., Semina, E., Kamalov, A., Novikova, A., Zakharenko, A., Alshahrani, M., Alsharif, F., Eskander, M., Majrashi, S., Mashat, A., Alharthi, M., Aljiffry, M., Basendowah, M., Malibary, N., Nassif, M., Samkari, A., Trabulsi, N., Azab, M. A., Alqahtani, D., Jaloun, H., Mudawi, I., Al Awwad, S., Alghamdi, M., Alnumani, T., Awad, S., I Sharara, M., Al Habes, H., Alqannas, M., Alyami, M., Alzamanan, M., Cortes-Guiral, D., Elawad, A., Adi, H., Al ahmad, F., Al Ayed, A., Alishi, Y., Alaamer, O., Alselaim, N., Alfaifi, J., D'Souza, J., Al-Khayal, K., Alhassan, N., Alobeed, O., Alshammari, S., Bin Nasser, A., Bin Traiki, T., Nouh, T., Zubaidi, A., Abdulfattah, F., Al-Kharashi, E., Alanazi, F., Albaqami, F., Alghuliga, A., Alsowaina, K., Arab, N., Badahdah, F., Alobaysi, S., Alshahrani, A., Alzahrani, A., Aleksic, L., Antic, A., Barisic, G., Ceranic, M., Grubac, Z., Jelenkovic, J., Kecmanovic, D., Kmezic, S., Knezevic, D., Krivokapic, Z., Latincic, S., Markovic, V., Matic, S., Miladinov, M., Pavlov, M., Pejovic, I., Tadic, B., Vasljevic, J., Velickovic, D., Doklestic, K., Gregoric, P., Ivancevic, N., Loncar, Z., Micic, D., Buta, M., Cvetkovic, A., Gacic, S., Goran, M., Jeftic, N., Markovic, I., Milanovic, M., Nikolic, S., Pejnovic, L., Savkovic, N., Stevic, D., Vucic, N., Zegarac, M., Karamarkovic, A., Kenic, M., Milic, L. J., Kovacevic, B., Krdzic, I., Lieske, B., Almgla, N., Boutall, A., Herman, A., Kloppers, C., Nel, D., Rayamajhi, S., Paniagua Garcia Senorans, M., Vigorita, V., Acrich, E., Baena Sanfeliu, E., Barrios, O., Golda, T., Santanach, C., Serrano-Navidad, M., Sorribas Grifell, M., Vives, R. V., Escola, D., Jimenez, A., Alcazar, J. A., Angoso-Clavijo, M., Blanco-Antona, F., Carabias-Orgaz, A., Diaz Maag, R., Garcia, J., Garcia-Plaza, A. G. P., Gonzalez-Munoz, J. I., Munoz-Bellvis, L., Sanchez Tocino, J. M., Sanchez-Casado, A. B., Trebol, J., Hernandez Gutierrez, J., Tebar Zamora, A., Palma, Pietro, Cayetano Paniagua, L., Gomez Fernandez, L., Collera Ormazabal, P., Diaz del Gobbo, R., Farre Font, R., Flores Clotet, R., Gomez Diaz, C. J., Guardia, N., Guariglia, C. A., Osorio Ramos, A., Sanchez Jimenez, R., Sanchon, L., Soto Montesinos, C., Alonso-Lamberti, L., Garcia-Quijada, J., Jimenez Miramon, J., Jimenez, V., Jover, J. M., Leon, R., Rodriguez, J. L., Salazar, A., Valle Rubio, A., Aguado Lopez, H., Bravo Infante, R., De Lacy, F. B., Lacy, A. M., Otero, A., Turrado-Rodriguez, V., Valverde, S., Anula, R., Avellana, R., Camarero Rodriguez, E., Catalan Garza, V., Dziakova, J., Garcia Alonso, M., Lasses Martinez, B., Lopez Antonanzas, L., Muguerza, J. M., Ochagavia, S., Pena Soria, M. J., Rivera-Alonso, D., Saez Carlin, P., Sanchez del Pueblo, C., Sanz Ortega, G., Sanz-Lopez, R., Torres, A., Martin-Arevalo, J., Moro-Valdezate, D., Pla-Marti, V., Beltran de Heredia, J., De Andres-Asenjo, B., Gomez Sanz, T., Jezieniecki, C., Nunez Del Barrio, H., Ortiz de Solorzano Aurusa, F. J., Romero de Diego, A., Ruiz Soriano, M., Trujillo Diaz, J., Vazquez Fernandez, A., Lora-Cumplido, P., Sosa-Rodriguez, M. V., Galvan Perez, A., Gonzalez-Gonzalez, E., Minaya Bravo, A. M., San Miguel, C., Alonso de la Fuente, N., Jimenez Toscano, M., Grau-Talens, E. J., Martin-Perez, B., Benavides Buleje, J. 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L., Cros, B., Escartin, J., Garcia Egea, J., Nogues, A., Talal El-Abur, I., Yanez, C., Mora-Guzman, I., Achalandabaso Boira, M., Sales Mallafre, R., Marin, H., Prieto Calvo, M., Villalabeitia Ateca, I., De Andres Olabarria, U., Duran Ballesteros, M., Fernandez Pablos, F. J., Ibanez-Aguirre, F. J., Sanz Larrainzar, A., Ugarte-Sierra, B., Acosta Merida, M. A., Ortiz Lopez, D., Yepes Cano, A. F., Correa Bonito, A., Delgado Burdalo, L., Di Martino, M., Garcia Septiem, J., Maqueda Gonzalez, R., Martin-Perez, E., Calvo Espino, P., Guillamot Ruano, P., Colao Garcia, L., Diaz Perez, D., Esteban Agusti, E., Galindo Jara, P., Gutierrez Samaniego, M., Hernandez Bartolome, M. A., Serrano Gonzalez, J., Alonso Poza, A., Dieguez, B., Garcia-Conde, M., Hernandez-Garcia, M., Losada, M., Alvarez, E., Chavarrias, N., Gegundez Simon, A., Gortazar de las Casas, S., Guevara-Martinez, J., Prieto Nieto, M. 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M., Sion, M., Ullrich, S., Al-Naggar, H., Al-Shehari, M., Almassaudi, A., Alsayadi, M., Alsayadi, R., Shream, S., Pellino G., Gallo G., Servadei F., Fagotti A. (ORCID:0000-0001-5579-335X), Silva A., Dell A. (ORCID:0000-0001-9978-0868), D'Urso A., Smith J., Bianco F., Fortuna L., Cremonini C. (ORCID:0000-0002-1739-841X), Morelli L. (ORCID:0000-0003-0475-2712), Podda M. (ORCID:0000-0002-2779-8417), Feo C. F., Agnes A., Belia F., Biondi A. (ORCID:0000-0002-2470-7858), Cozza V., D'Ugo D. (ORCID:0000-0001-6657-6318), Litta F., Marra A. A. (ORCID:0000-0001-8384-5081), Marzi F., Parello A., Persiani R. (ORCID:0000-0002-1537-5097), Ratto C. (ORCID:0000-0002-0556-0037), Scrima O., Sganga G. (ORCID:0000-0001-5079-0395), Belli A., Izzo F., De Lucia F., Barone R., Federico P., Borroni G., Franzini M., Capelli P., Longhi M., Usai A., Spagni G., Casati M., Schiavo M., Fiori E., Colletti G., Confalonieri M. 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R., Jain, A., Mishra, S., Mishra, T., Mitra, J. K., Muduly, D., Agrawal, A., Garg, P. K., Kottayasamy Seenivasagam, R., Majumdar, K. S., Mishra, N., Singh, M. P., Chyau Patnaik, S., Rao, S., Reddy, P., S, R., Saksena, A. R., Y, J., Ayloor Seshadri, R., Haque, P. D., Jeyaraj, P., Kannummal Veetil, S., Mahajan, A., Devarakonda, S., Jesudason, M. R., Moorthy, M., Yezzaji, H., Aggarwal, M., Dhamija, P., Kumar, A., Chisthi, M., D, G., George, G., Kollengode, V. V., Kuttanchettiyar, K. G., Yadev, I., Dharanipragada, K., Kalayarasan, R., Penumadu, P., B, L., Mathew, S., Akhtar, N., Chaturvedi, A., Gupta, S., Kumar, V., Rajan, S., Agrawal, N., Arora, A., Chaturvedi, H., Jain, M., Kumar, S., Singh, S., Bhat, G. A., Chowdri, N., Mehraj, A., Parray, F. Q., Shah, Z. A., Wani, R., Ahmed, Z., Bhat, M. A., Laharwal, A., Mahmood, M., Mir, I., Mohammad, Z., Muzamil, J., Rashid, A., Singh, R., Ahmed, A., Jain, D., Pipara, A., Desoouza, A., Pandey, D., Pramesh, C. S., Saklani, A., Islam, A. A., Kembuan, G., Pajan, H., Aremu, M., Canas-Martinez, A., Cullivan, O., Murphy, C., Owens, P., Pickett, L., Corrigan, M., Daly, A., Fleming, C. A., Jordan, P., Kayyal, M. Y., Killeen, S., Lynch, N., O'Brien, S., Syed, W. A. S., Vernon, L., Hanly, A., Heneghan, H., Kennelly, R., Martin, S. T., Winter, D., Fahey, B. A., Larkin, J., Mccormick, P., Mehigan, B. J., Shokuhi, P., Smith, Jenovia Amisti, Bashir, Y., Bass, G., Connelly, T., Creavin, B., Earley, H., Elliott, J. A., Gillis, A. E., Kavanagh, D., Neary, P., O'Riordan, J., Reynolds, I. S., Rice, D., Ridgway, P. F., Umair, M., Whelan, M., Corless, K., Finnegan, L., Fowler, A., Hogan, A., Lowery, A., Mckevitt, K., Nugent, E., Ryan, E. J., Coffey, J. C., Cunningham, R. M., Devine, M., Nally, D., Peirce, C., Hardy, N. P., Neary, P. M., O'Malley, S., Ryan, M., Gaziants, V., Gold-Deutch, R., Lavy, R., Zmora, O., Macina, S., Mariani, N. M., Opocher, E., Pisani Ceretti, A., Bianco, Flaviana, Marino, M., Marino, M. V., Mirabella, A., Vaccarella, G., Sena, G., Agostini, C., Alemanno, G., Bartolini, I., Bergamini, C., Bruscino, A., De Vincenti, R., Di Bella, A., Fortuna, Ludovica, Maltinti, G., Muiesan, P., Prosperi, P., Ringressi, M. N., Risaliti, M., Taddei, A., Tucci, R., Campagnaro, T., Guglielmi, A., Pedrazzani, C., Rattizzato, S., Ruzzenente, A., Turri, G., Altomare, D. F., Papagni, V., Picciariello, A., Bellora, P., D'Aloisio, G., Ferrari, M., Francone, E., Gentilli, S., Nikaj, H., Bianchini, M., Chiarugi, M., Coccolini, F., Cremonini, Cinzia, Di Franco, G., Furbetta, N., Gianardi, D., Guadagni, S., Morelli, Lorenzo, Musetti, S., Palmeri, M., Tartaglia, D., Anania, G., Carcoforo, P., Chiozza, M., De Troia, A., Koleva Radica, M., Portinari, M., Sibilla, M. G., Urbani, A., Fabbri, N., Feo, C. V., Gennari, S., Parini, S., Righini, E., Annessi, V., Castro Ruiz, C., Giunta, A., Montella, M. T., Zizzo, M., Grossi, U., Novello, S., Romano, M., Rossi, S., Zanus, G., Esposito, G., Frongia, F., Pisanu, A., Podda, Maria Vittoria, Belluco, C., Lauretta, A., Montori, G., Moras, L., Olivieri, M., De Feo, Claudia Francesca, Perra, T., Porcu, A., Scanu, A. M., Aversano, A., Carbone, F., Delrio, P., Di Lauro, K., Fares Bucci, A., Rega, D., Spiezio, G., Pirozzolo, G., Recordare, A., Vignotto, C., Calabro, M., Farnesi, F., Lunghi, E. G., Muratore, A., Pipitone Federico, N. S., De Palma, G., Luglio, G., Pagano, G., Tropeano, F. P., Baldari, L., Boni, L., Cassinotti, E., Cosimelli, M., Guaglio, M., Sorrentino, L., Agnes, Annamaria, Alfieri, S., Belia, Francesco, Biondi, Alberto, Cozza, Valerio, D'Ugo, Domenico, De Simone, V., Litta, Francesco, Lorenzon, L., Marra, Angelo Alessandro, Marzi, Federica, Parello, Angelo, Persiani, Roberto, Ratto, Carlo, Rosa, F., Scrima, Ottavio, Sganga, Gabriele, Belli, Andrea, Izzo, Filippo, Patrone, R., Foppa, C., Carvello, M. M., De Lucia, Francesca, Aprile, A., Batistotti, P., Massobrio, A., Pertile, D., Scabini, S., Soriero, D., De Manzoni Garberini, A., Mazzotti, F., Pasini, F., Ugolini, G., Barone, Roberto, Birolo, S. L., Caccetta, M., Deirino, A., Garino, M., Grasso, M., Marafante, C., Masciandaro, A., Moggia, E., Mungo, S., Murgese, A., Raggio, E., Federico, Paola, Maida, P., Marra, E., Marte, G., Petrillo, A., Tammaro, P., Tufo, A., Berselli, M., Borroni, Giulia, Cocozza, E., Conti, L., Desio, M., Rizzi, A., Baldi, C., Corbellini, C., Sampietro, G. M., Bordoni, P., Clarizia, G., Fleres, F., Franzini, Manila, Grechi, A., Longhini, A., Spolini, A., Baldini, E., Capelli, Paolo, Isolani, S. M., Ribolla, M., Bondurri, A., Colombo, F., Ferrario, L., Guerci, C., Maffioli, A., Armao, T., Ballabio, M., Bisagni, P., Longhi, Mattia, Madonini, M., Impellizzeri, H., Inama, M., Moretto, G., Mochet, S., Usai, Alessandro, Incollingo, P., Giacometti, M., Zonta, S., Marino Cosentino, L., Sagnotta, A., Nespoli, L. C., Tamini, N., Anastasi, A., Bartalucci, B., Bellacci, A., Canonico, G., Capezzuoli, L., Di Martino, C., Ipponi, P., Linari, C., Montelatici, M., Nelli, T., Spagni, Gregorio, Tirloni, L., Vitali, A., Abate, E., Casati, Mirta, Laface, L., Schiavo, Martina, Arminio, A., Cotoia, A., Lizzi, V., Vovola, F., Vergari, R., D'Ugo, S., Depalma, N., Spampinato, M. G., Annicchiarico, A., Catena, F., Giuffrida, M., Perrone, G., Baronio, G., Carissimi, F., Montuori, M., Pinotti, E., Brachini, G., Chiappini, A., Cicerchia, P. M., Cirillo, B., De Toma, G., Fiori, Micol Eleonora, Fonsi, G. B., Iannone, I., La Torre, F., Lapolla, P., Meneghini, S., Mingoli, A., Sapienza, P., Zambon, M., Capolupo, G. T., Carannante, F., Mazzotta, E., Gattolin, A., Migliore, M., Rimonda, R., Sasia, D., Travaglio, E., Chessa, A., Fiorini, A., Norcini, C., Colletti, Guido Carlo, Confalonieri, Marco, Costanzi, A., Frattaruolo, C., Mari, G., Monteleone, M., Locatelli, A., Riva, C., Balconi, A., De Nardi, P., Parise, P., Vignali, A., Belvedere, A., Bernante, P., Droghetti, M., Jovine, E., Neri, J., Parlanti, D., Pezzuto, A. P., Poggioli, G., Rottoli, M., Russo, I. S., Tanzanu, M., Violante, T., Borghi, F., Cianflocca, D., Di Maria Grimaldi, S., Donati, Davide, Gelarda, E., Giraudo, G., Giuffrida, M. C., Marano, A., Palagi, S., Pellegrino, Luca, Peluso, C., Testa, V., Agresta, F., Prando, D., Zese, M., Armatura, G., Frena, A., Bertelli, G., Marinello, P., Notte, F., Scotton, G., Cervellera, M., Gori, A., Sartarelli, L., Tonini, V., Sammarco, Maria Grazia, Vescio, G., Di Marzo, F., Kanemitsu, Y., Moritani, K., Al Abdallah, M., Ayasra, Y., Qasem, A., Fahmawee, T., Hmedat, A., Obeidat, K., Abou Chaar, M. K., Al-Masri, M., Al-Najjar, H., Alawneh, F., Aldokali, N., Senossi, O., Subhi, M. T., Algallai, M., Alwarfly, S., Alzaede, S., Gahwagi, M., Moftah, M., Burgan, D., Kamoka, E., Kilani, A. I., Abdelkabir, M., Altomi, I., Abdulwahed, E., Alshareea, E., Aribi, N., Aribi, S., Biala, M., Ghamgh, R., Alsoufi, A., Ellojli, I., Kredan, A., Msherghi, A., Alshareef, K., Alkadiki, G. Z., Almaadany, F. S., Bradulskis, S., Dainius, E., Kubiliute, E., Kutkevicius, J., Parseliunas, A., Subocius, A., Venskutonis, D., Rasoaherinomenjanahary, F., Razafindrahita, J. B., Samison, L. H., Ngo, C. W., Ramasamy, S., Hamdan, K. H., Mdrazal, i. I K. H., Tan, J. A., Thanapal, M. R., Choong, E., Lim, R. Z. M., Sahid, N. A., Hayati, F., Jayasilan, J., Sriram, R. K., Subramaniam, S., Ibrahim, A. F., Che jusoh, A., Hussain, A. H., Mohamed Sidek, A. S., Mohd Yunus, M. F., Soh, J. Y., Wong, M. P., Zakaria, A. D., Zakaria, Z., Mohd Azman, Z. A., Fathi, N. Q., Xavier, R., Alvarez, M. R., Cordera, F., Hernandez, R., Soule Martinez, C. E., Aboharp Hasan, Z., Otoniel, L. R., Sosa Duran, E. E., Melchor-Ruan, J., Romero Banuelos, E., Vilar-Compte, D., Buerba, G. A., Mercado, M. A., Posadas-Trujillo, O. E., Salgado-Nesme, N., Sarre, C., Amrani, L., Benkabbou, A., El Ahmadi, B., El Bouazizi, Y., Belkhadir, Z. H., Ghannam, A., Majbar, A. M., Mohsine, R., Souadka, A., Hompes, R., Meima-van Praag, E. M., Pronk, A. J. M., Sharabiany, S., Grotenhuis, B. A., Hartveld, L., Ebben, L., Kuiper, S., Melenhorst, J., Poeze, M., Posma-Bouman, L., Derksen, T., Franken, J., Oosterling, S., Konsten, J., Van Heinsbergen, M., Adeyeye, A., Enoch, E., Nwabuoku, S. E., Sholadoye, T. T., Tolani, M. A., Olaogun, J., Abiyere, H., Babalola, O., Okunlola, A., Ali Sani, S., Chinda, J., Garba, S., Mshelbwala, P., Olori, S., Olute, A., Osagie, O., Pius Ogolekwu, I., Umar, A., Abdur-Rahman, L. O., Bello, J. O., Olasehinde, O., Popoola, A. A., Abassy, J., Ahmed, K., Alvi, A., Khan, S., Pirzada, A., Saleem, A., Siddiqui, M. T., Turk, K., Jamal, A., Kerawala, A. A., Memon, A. S., Nafees Ahmed, R., Rai, L., Ali, A. A., Afzal, M. F., Khokhar, M. I., Ayub, B., Ramesh, P., Ayyaz, M., Butt, U., Kashif, M., Qureshi, A. U., Farooka, M. W., Ayubi, A., Waqar, S. H., Al-Slaibi, I., Alzeerelhouseini, H. I. A., Jobran, F., Abukhalaf, S. A., Jocson, R., Teh, C., Uy Magadia, E., Bak, M., Dubienska, K., Lawnicka, A., Murawa, D., Janik, M., Kowalewski, P., Kwiatkowski, A., Roszkowski, R., Sroczynski, P., Waledziak, M., Azevedo, C., Machado, D., Mendes, F., De Sousa, X., Fernandes, U., Ferreira, C., Guidi, G., Marcal, A., Marques, R., Martins, D., Vaz-Pereira, R., Vieira, B., Almeida, J. I., Almeida-Reis, R., Correia de Sa, T., Costa, M. J. M. A., Fernandes, V., Ferraz, I., Lima da Cruz, L., Lima da Silva, C., Lopes, L., Machado, N., Marialva, J., Nunes Coelho, M., Pedro, J., Pereira, C., Ribeiro, A., Ribeiro, C. G., Santos, R., Saraiva, P., Silva, R., Tavares, F., Teixeira, M., Almeida, A. C., Amaral, M. J., Andrade, R., Camacho, C., Costa, M., Lazaro, A., Nogueira, O., Oliveira, A., Ruivo, A., Silva, Matteo, Simoes, J. F. F., Devezas, V., Jacome, F., Nogueiro, J., Pereira, A., Santos-Sousa, H., Vaz, S., Pinto, J., Tojal, A., Cardoso, P., Martins, R., Martins dos Santos, G., Henriques, P., Morais, H., Sousa, S., Cardoso, N., Teixeira, J., Pereira, R., Revez, T., Ribeiro, R., Manso, I., Domingues, J., Amorim, E., Baptista, V. H., Sampaio da Novoa Gomes Miguel, I. I., Bandovas, J. P., Borges, N., Chumbinho, B., Figueiredo de Barros, I., Frade, S., Gomes, J., Kam da Silva Andrade, A., Pereira Rodrigues, A., Pina, S., Silva, N., Silveira Nunes, I., Sousa, R., Azevedo, P., Costeira, B., Cunha, C., Garrido, R., Miranda, P., Peralta Ferreira, M., Sousa Fernandes, M., Galvao, D., Vieira, A., Patricio, B., Santos, P. M. D. D., Vieira Paiva Lopes, A. C., Cunha, R., Faustino, A., Freitas, A., Mendes, J. R., Parreira, R., Abreu da Silva, A., Claro, M., Costa Santos, D., Deus, A. C., Grilo, J. V., Castro Borges, F., Corte Real, J., Henriques, S., Lima, M. J., Matos Costa, P., Alagoa Joao, A., Camarneiro, R., Capunge, I., Fragoso, M., Frazao, J., Martins, A., Pedro, V., Pera, R., Ramalho de Almeida, F., Sampaio Soares, A., Vale, R., Vasconcelos, M., Brito da Silva, F., Caiado, A., Fonseca, F., Angelo, M., Baiao, J. M., Martins Jordao, D., Vieira Caroco, T., Baia, C., Canotilho, R., Correia, A. M., Ferreira Pinto, A. P., Peyroteo, M., Videira, J. F., Kassir, R., Sauvat, F., Bonci, E., Gata, V., Titu, S., Bezede, C., Chitul, A., Ciofic, E., Cristian, D., Grama, F., Ciubotaru, C., Negoita, V. M., Stoica, B., Ginghina, O., Iordache, N., Iosifescu, R. V., Mardare, M., Mirica, R. M., Spanu, A., Vacaras, A. B., Zamfir-Chiru-Anton, M., Tsarkov, P., Tulina, I., Abelevich, A., Bazaev, A., Kokobelyan, A. K., Yanishev, A., Litvina, Y., Provozina, A., Agapov, M., Kazachenko, E., Markaryan, D., Galliamov, E., Kakotkin, V., Kubyshkin, V., Semina, E., Kamalov, A., Novikova, A., Zakharenko, A., Alshahrani, M., Alsharif, F., Eskander, M., Majrashi, S., Mashat, A., Alharthi, M., Aljiffry, M., Basendowah, M., Malibary, N., Nassif, M., Samkari, A., Trabulsi, N., Azab, M. A., Alqahtani, D., Jaloun, H., Mudawi, I., Al Awwad, S., Alghamdi, M., Alnumani, T., Awad, S., I Sharara, M., Al Habes, H., Alqannas, M., Alyami, M., Alzamanan, M., Cortes-Guiral, D., Elawad, A., Adi, H., Al ahmad, F., Al Ayed, A., Alishi, Y., Alaamer, O., Alselaim, N., Alfaifi, J., D'Souza, J., Al-Khayal, K., Alhassan, N., Alobeed, O., Alshammari, S., Bin Nasser, A., Bin Traiki, T., Nouh, T., Zubaidi, A., Abdulfattah, F., Al-Kharashi, E., Alanazi, F., Albaqami, F., Alghuliga, A., Alsowaina, K., Arab, N., Badahdah, F., Alobaysi, S., Alshahrani, A., Alzahrani, A., Aleksic, L., Antic, A., Barisic, G., Ceranic, M., Grubac, Z., Jelenkovic, J., Kecmanovic, D., Kmezic, S., Knezevic, D., Krivokapic, Z., Latincic, S., Markovic, V., Matic, S., Miladinov, M., Pavlov, M., Pejovic, I., Tadic, B., Vasljevic, J., Velickovic, D., Doklestic, K., Gregoric, P., Ivancevic, N., Loncar, Z., Micic, D., Buta, M., Cvetkovic, A., Gacic, S., Goran, M., Jeftic, N., Markovic, I., Milanovic, M., Nikolic, S., Pejnovic, L., Savkovic, N., Stevic, D., Vucic, N., Zegarac, M., Karamarkovic, A., Kenic, M., Milic, L. J., Kovacevic, B., Krdzic, I., Lieske, B., Almgla, N., Boutall, A., Herman, A., Kloppers, C., Nel, D., Rayamajhi, S., Paniagua Garcia Senorans, M., Vigorita, V., Acrich, E., Baena Sanfeliu, E., Barrios, O., Golda, T., Santanach, C., Serrano-Navidad, M., Sorribas Grifell, M., Vives, R. V., Escola, D., Jimenez, A., Alcazar, J. A., Angoso-Clavijo, M., Blanco-Antona, F., Carabias-Orgaz, A., Diaz Maag, R., Garcia, J., Garcia-Plaza, A. G. P., Gonzalez-Munoz, J. I., Munoz-Bellvis, L., Sanchez Tocino, J. M., Sanchez-Casado, A. B., Trebol, J., Hernandez Gutierrez, J., Tebar Zamora, A., Palma, Pietro, Cayetano Paniagua, L., Gomez Fernandez, L., Collera Ormazabal, P., Diaz del Gobbo, R., Farre Font, R., Flores Clotet, R., Gomez Diaz, C. J., Guardia, N., Guariglia, C. A., Osorio Ramos, A., Sanchez Jimenez, R., Sanchon, L., Soto Montesinos, C., Alonso-Lamberti, L., Garcia-Quijada, J., Jimenez Miramon, J., Jimenez, V., Jover, J. M., Leon, R., Rodriguez, J. 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A., Carrasco Prats, M., Gimenez Frances, C., Munoz Camarena, J. M., Parra Banos, P. A., Pena Ros, E., Ramirez Faraco, M., Ruiz-Marin, M., Valero Soriano, M., Allue, M., Colsa, P., Garcia Dominguez, M., Gimenez Maurel, T., Martin Anoro, L. F., Ponchietti, L., Rodriguez Artigas, J. M., Roldon Golet, M., Utrilla Fornals, A., Estaire Gomez, M., Fernandez Camunas, A., Garcia Santos, E. P., Jimenez Higuera, E., Martinez-Pinedo, C., Munoz-Atienza, V., Padilla-Valverde, D., Picon Rodriguez, R., Sanchez-Garcia, S., Sanchez-Pelaez, D., Curtis Martinez, C., Sanchez-Guillen, L., Colombari, R. C., Del valle, E., Fernandez, M., Lozano Lominchar, P., Martin, L., Rey Valcarcel, C., Zorrilla Ortuzar, J., Alcaide Matas, F., Garcia Perez, J. M., Troncoso Pereira, P., Blas Laina, J. L., Cros, B., Escartin, J., Garcia Egea, J., Nogues, A., Talal El-Abur, I., Yanez, C., Mora-Guzman, I., Achalandabaso Boira, M., Sales Mallafre, R., Marin, H., Prieto Calvo, M., Villalabeitia Ateca, I., De Andres Olabarria, U., Duran Ballesteros, M., Fernandez Pablos, F. J., Ibanez-Aguirre, F. J., Sanz Larrainzar, A., Ugarte-Sierra, B., Acosta Merida, M. A., Ortiz Lopez, D., Yepes Cano, A. F., Correa Bonito, A., Delgado Burdalo, L., Di Martino, M., Garcia Septiem, J., Maqueda Gonzalez, R., Martin-Perez, E., Calvo Espino, P., Guillamot Ruano, P., Colao Garcia, L., Diaz Perez, D., Esteban Agusti, E., Galindo Jara, P., Gutierrez Samaniego, M., Hernandez Bartolome, M. A., Serrano Gonzalez, J., Alonso Poza, A., Dieguez, B., Garcia-Conde, M., Hernandez-Garcia, M., Losada, M., Alvarez, E., Chavarrias, N., Gegundez Simon, A., Gortazar de las Casas, S., Guevara-Martinez, J., Prieto Nieto, M. I., Ramos-Martin, P., Rubio-Perez, I., Saavedra, J., Urbieta, A., Aparicio-Lopez, D., Cantalejo diaz, M., De Miguel Ardevines, M. D. C., Dobon Rascon, M. A., Duque-Mallen, V., Gascon Ferrer, I., Gonzalez-Nicolas Trebol, M. T., Gracia-Roche, C., Herrero Lopez, M., Kalviainen, H., Martinez German, A., Matute, M., Sanchez Fuentes, N., Santero-Ramirez, M. S., Saudi, S., Blazquez Martin, A., Diez Alonso, M., Hernandez, P., Mendoza-Moreno, F., Ovejero Merino, E., Vera Mansilla, C., Matias-Garcia, B., Quiroga-Valcarcel, A., Barranquero, A. G., Cerro Zaballos, C., Nunez, J., Ocana, J., Ramos, D., Acebes Garcia, F., Bailon-Cuadrado, M., Bueno Canones, A. D., Choolani Bhojwani, E., Marcos-Santos, P., Miguel, T., Pacheco Sanchez, D., Perez-Saborido, B., Sanchez Gonzalez, J., Tejero-Pintor, F. J., Alconchel, F., Conesa, A., Gil Martinez, J., Gutierrez Fernandez, A. I., Lopez Abad, A., Nicolas-Lopez, T., Ramirez Romero, P., Roca Calvo, M. J., Rodrigues, K., Ruiz Manzanera, J. J., Soriano, A. I., Cano, A., Capitan-Morales, L., Cintas Catena, J., Gomez-Rosado, J., Oliva Mompean, F., Perez Sanchez, M. A., Rio Lafuente, F. D., Torres Arcos, C., Valdes-Hernandez, J., Cholewa, H., Frasson, M., Martinez Chicote, C., Sancho-Muriel, J., Estraviz, B., Fernandez Gomez Cruzado, L., Gonzalez de Miguel, M., Landaluce-olavarria, A., Abad-Gurumeta, A., Abad-Motos, A., Martinez-Hurtado, E., Ripolles-Melchor, J., Ruiz-Escobar, A., Cuadrado-Garcia, A., Garcia-Sancho Tellez, L., Heras Aznar, J., Mate Mate, P., Ortega Vazquez, I., Picardo, A. L., Rojo Lopez, J. A., Sanchez Cabezudo Noguera, F., Serralta de Colsa, D., Cagigas Fernandez, C., Caina Ruiz, R., Gomez Ruiz, M., Martinez-Perez, P., Santarrufina Martinez, S., Valbuena Jabares, V., Cagigal Ortega, E. P., Cervera, I., Diaz Pena, P., Gonzalez, J., Marqueta De Salas, M., Perez Gonzalez, M., Ramos Bonilla, A., Rodriguez Gomez, L., Alfonso Garcia, M., Craus-Miguel, A., Fernandez Vega, L., Ferrer-Inaebnit, E., Gil Catalan, A., Gonzalez Argente, F. X., Jeri, S., Oseira, A., Pujol Cano, N., Soldevila Verdeguer, C., Villalonga, B., Espin-Basany, E., Srishankar, S., Thalgaspitiya, S. P. B., Arulanantham, A., Bandara, G. B. K. D., Jayarajah, U., Ravindrakumar, S., Rodrigo, V. S. D., Ali karar, A. A., Elhafiz, M. H. Y., Adam Essa Adam, M. E., Saleh, M., Arkani, S., Freedman, J., Angenete, E., Park, J., Alga, A., Heinius, G., Nordberg, M., Pieniowski, E., Lofgren, N., Arigoni, M., Bernasconi, M., Christoforidis, D., Di Giuseppe, M., La Regina, D., Mongelli, F., Chevallay, M., Dwidar, O., Gialamas, E., Sauvain, M., Crugnale, A. S., Guglielmetti, L., Peros, G., Gass, M., Metzger, J., Scheiwiller, A., Turina, M., Al Asadi, T., Alkhateb, S., Altom, R., Bakkar, B., Maa Albared, S., Melhem, S., Hammed, A., Hammed, S., Kacem, M. J., Maghrebi, H., Sebai, A., Aghayeva, A., Hamzaoglu, I., Sahin, I., Akaydin, E., Aliyeva, Z., Aytac, E., Baca, B., Ozben, V., Ozmen, B. B., Arikan, A. E., Bilgin, I. A., Kara, H., Karahasanoglu, T., Uras, C., Akbas, A., Altinel, Y., Calikoglu, F., Ercan, G., Ercetin, C., Hacim, N. A., Meric, S., Tokocin, M., Vartanoglu, T., Yigitbas, H., Dogangun, M., Iflazoglu, N., Yalkin, O., Cennet, O., Dincer, H. A., Erol, T., Alhamed, A., Ergun, S., Ozcelik, M. F., Sanli, A. N., Uludag, S. S., Velidedeoglu, M., Zengin, A. K., Kara, Y., Bozkurt, M. A., Kocatas, A., Eyuboglu, K., Guner, A., Usta, M. A., Azamat, I. F., Balik, E., Bugra, D., Kulle, C. B., Guler, S. A., Guresin, A., Tatar, O. C., Utkan, N. Z., Yildirim, A., Yuksel, E., Abbasov, A., Yanar, H., Akin, E., Altintoprak, F., Cakmak, G., Celebi, F., Demir, H., Dikicier, E., Firat, N., Gonullu, E., Kamburoglu, M. B., Kucuk, I. F., Mantoglu, B., Colak, E., Kucuk, G. O., Uyanik, M. S., Goksoy, B., Bozkurt, E., Capkinoglu, E., Guven, O., Mihmanli, M., Omeroglu, S., Tanal, M., Yetkin, G., Akalin, M., Arican, C., Avci, E. K., Aydin, C., Demirli Atici, S., Emiroglu, M., Kaya, T., Kebabci, E., Kilinc Tuncer, G., Kirmizi, Y., Ogucu, H., Salimoglu, S., Sert, I., Tugmen, C., Tuncer, K., Uslu, G., Yesilyurt, D., Yildiz, A., Gultekin, F. A., Lule, H., Oguttu, B., Agilinko, J., Ahmeidat, A., Bekheit, M., Cheung, L. K., Kamera, B. S., Mignot, G., Shaikh, S., Sharma, P., Al-Mohammad, A., Ali, S., Ashcroft, J., Baker, O., Coughlin, P., Davies, R. J., Kyriacou, H., Mitrofan, C., Morris, A., Raby-Smith, W., Rooney, S. M., Singh, A. A., Tan, X. S., Townson, A., Tweedle, E., Kattakayam, A., Lunevicius, R., Sheel, A., Sud, A., Sundhu, M., Angelou, D., Choynowski, M., Mcaree, B., Mccanny, A., Neely, D., Kamel, F., Kumar, L., Madani, R., Nisar, P., Creanga, M., Elniel, M., Law, J., Mosley, F., Arrowsmith, L., Campbell, W., Grove, T., Kontovounisios, C., Warren, O., Doulias, T., Li, M., Martin, E., Rodwell, H., Clifford, R., Eardley, N., Krishnan, E., Manu, N., Roy Mahapatra, S., Serevina, O. L., Smith, C., Emslie, K., Labib, P. L., Minto, G., Natale, J., Panahi, P., Rogers, L. J., Abubakar, A., Akhter Rahman, M. M., O'Brien, H., Sasapu, K., Ng, H. J., Day, A., Hunt, A., Laskar, N., Gupta, A., Steinke, J., Thrumurthy, S., Massie, E., Mcgivern, K., Rutherford, D., Wilson, M., Bacarese-Hamilton, T., Ip, M., James, A., Salerno, Gilda, Stockdale, T., Handa, S., Kaushal, M., Kler, A., Patel, P., Redfern, J., Tezas, S., Aawsaj, Y., Barry, C., Blackwell, L., Emerson, H., Fisher, A., Katory, M., Mustafa, A., Kretzmer, L., Lalou, L., Manku, B., Parwaiz, I., Stafford, J., Abdelkarim, M., Asqalan, A., Gala, T., Ibrahim, S., Maw, A., Mithany, R., Morgan, R., Sundaram Venkatesan, G., Banfield, D., Boal, M., Brown, O., Dean, H., Boulton, A. J., Hardie, C. M., Mcnaught, C., Karandikar, S., Naumann, D., Chen, F., Cheung, J., Ayorinde, J., Chase, T., Cuming, T., Ghanbari, A., Humphreys, L., Tayeh, S., Aboelkassem Ibrahim, A., Evans, C., Ikram, H., Loubani, M., Nazir, S., Robinson, A., Sehgal, T., Dixon, J., Jha, M., Thulasiraman, S. V., Viswanath, Y., Curl-Roper, T., Delimpalta, C., Liao, C. C. L., Velchuru, V., Westwood, E., Bond-Smith, G., Mastoridis, S., Tebala, G. D., Verberne, C., Anscomb, N., Baldwin-Smith, R., Davies, M., Grainger, C., Haji, A., Haq, A., Nunoo-Mensah, J. W., Rizk, M., Bhatti, M. I., Boyd-Carson, H., Elsey, E., Gemmill, E., Herrod, P., Mohammedjibreel, M., Lenzi, E., Saafan, T., Sapre, D., Sian, T., Watson, N., Athanasiou, A., Costigan, F., Elkadi, H., Johnstone, J., Nahm, C., Annamalai, S., Ashmore, C., Kourdouli, A., Chean, C. S., Dharamavaram, S., Kulkarni, N., Pereira, I., Shanthakunalan, K., Srikumar, B., Askari, A., Cirocchi, N., Kudchadkar, S., Patel, K., Sagar, J., Talwar, R., Abdalla, M., Ismail, O., Newton, K., Stylianides, N., Aderombi, A., Bajomo, O., Beatson, K., Garrett, W. V., Ng, V., Al-Habsi, R., Divya, G. S., Dixon, F., Keeler, B. D., Egan, R. J., Fabre, I., Harries, R., Li, Z., Parkins, K., Spencer, N., Thompson, D., Gemmell, C., Grieco, C., Hunt, L., Mahmoud Ali, F., Seebah, K., Shaikh, I., Sreedharan, L., Youssef, M., Shah, J., Baguley, M., Heer, B., Rogers, M., Woods, R., Mills, S. J., Sahnan, K., Ahmed, M. E., Bukhari, S. I., Illingworth, B., Kanthasamy, S., Knights, E., Ong, S. L., Pujari, R., Tan, K. H. M., Vanker, R., Michel, M., Patil, S., Ravindran, S., Sarveswaran, J., Scott, L., Khan, J., Cato, L. D., Kamal, M., Kulkarni, R., Parente, A., Saeed, S., Vijayan, D., English, C., Evans, J., Fell, A., Merh, R., Nikolaou, S., Kaul, S., Khan, A. H., Khan, F., Mukherjee, S., Patel, M., Sarigul, M., Adiamah, A., Brewer, H., Chowdhury, A., Humes, D., Jackman, J., Koh, A., Lewis-Lloyd, C., Oyende, O., Reilly, J., Worku, D., Bisset, C., Chadha, R., Math, S., Sarantitis, I., Timbrell, S., Vitone, L., Faulkner, G., Brixton, G., Findlay, L., Majkowska, A., Manson, J., Potter, R., Bhalla, A., Chia, Z., Daliya, P., Grimley, E., Malcolm, F. L., Theophilidou, E., Daniels, I. R., Fowler, G. E., Massey, L. H., Mcdermott, F. D., Rajaretnam, N., Angamuthu, N., Chowdhury, S., Gilliland, J., Hart, C., Knowles, J., Mirnezami, R., Varcada, M., Beamish, A. J., Magowan, D., Nassa, H., Price, C., Smith, L., Solari, F., Tang, A. M., Williams, G., Davies, E., Hawkin, P., Raymond, T., Ryska, O., Baron, R., Gahunia, S., Mcnicol, F., Russ, J., Szatmary, P., Thomas, A., Jayasinghe, J. D., Knowles, C., Ledesma, F. S., Minicozzi, A., Navaratne, L., Ramamoorthy, R., Sohrabi, C., Thaha, M. A., Venn, M., Atherton, R., Brocklehurst, M., Mcaleer, J., Parkin, E., Aladeojebi, A., Ali, M., Gaunt, A., Hammer, C., Stebbing, J., Coomber, E., Williams, O., Bunni, J., Fairhurst, K., Mitchell, S., Richards, S., Hraishawi, I., Mcilmunn, C., Mcintosh, S., Bhasin, S., Bodla, A. S., Burahee, A., Crichton, A., Fossett, R., Yassin, N., Barlow, C., Ding, D., Foster, J., Longstaff, L., Brown, S. R., Lee, M., Newman, T., Steele, C., Baker, A., Konstantinou, C., Ramcharan, S., Wilkin, R. J. W., Colvin, H. V., Shakoor, Z., Lyons, A., Newman, S., Chung, E., Hagger, R., Hainsworth, A., Karim, A., Owen, H., Ramwell, A., Williams, K., Hall, J., Harris, G., Royle, T., Watson, L. J., Asaad, P., Brown, Brendon, Duff, S., Khan, A., Moura, F., Wadham, B., Mccluney, S., Parmar, C., Shah, S., Babar, M. S., Goodrum, S., Whitmore, H., Balasubramaniam, D., Jayasankar, B., Kapoor, S., Ramachandran, A., Beech, N., Chand, M., Green, L., Kiconco, H., Mcewen, R., Pereca, J., Arumugam, S., Ibrahim, B., Khan, K., Gash, K., Gourbault, L., Maccabe, T. A., Newton, C., Baig, M., Bates, H., Dunne, N., Khajuria, A., Sarma, D. R., Shortland, T., Tewari, N., Akhtar, M. A., Brunt, A., Mcintyre, J., Milne, K., Rashid, M. M., Sgro, A., Stewart, K. E., Turnbull, A., Gossedge, G., O'Donnell, S., Oldfield, F., Aguilar Gonzalez, M., Talukder, S., Eskander, P., Hanna, M., Olivier, J., Basnyat, P., Davis, H., Montauban, P., Shrestha, A., Magee, C., Powell, S., Flindall, I., Hanson, A., Mahendran, V., Green, S., Lim, M., Macdonald, L., Miu, V., Onos, L., Sheridan, K., Young, R., Alam, F., Griffiths, O., Houlden, C., Kolli, V. S., Lala, A. K., Seymour, Z., Consorti, E., Gonzalez, R., Kwan-Feinberg, R., Liu, T., Cooper, Z., Hirji, S., Mahvi, D., Okafor, B., Roxo, V., Salim, A., Telma, K., Bokenkamp, M., Haynes, A. B., Hill, C., Leede, E., Mcelhinney, K., Olson, K. A., Riley, C., Bigelow, B., Etchill, E. W., Gabre-Kidan, A., Jenny, H. E., Kent, A., Ladd, M. R., Long, C., Malapati, H., Margalit, A., Rapaport, S., Rose, J., Stevens, K., Tsai, L., Vervoort, D., Yesantharao, P., Klaristenfeld, D., Huynh, K. T., Kaafarani, H., Naar, L., Qadan, M., Cha, D. E., Gleeson, E., Horn, C., Sarpel, U., Bhama, A., Colling, K., Najarian, M., Azam, M., Choudhry, A., Marx, W., Chokshi, R., Glass, N., Tsui, G., Abel, M. K., Boeck, M., Chern, H., Kornblith, L. Z., Nunez-Garcia, B., Ozgediz, D., Sarin, A., Varma, M. G., Abbott, D., Acher, A., Aiken, T., Barrett, J., Foley, E., Schwartz, P. B., Zafar, S. N., Hawkins, A. T., Maiga, A., Ruzgar, N. M., Sion, M., Ullrich, S., Al-Naggar, H., Al-Shehari, M., Almassaudi, A., Alsayadi, M., Alsayadi, R., Shream, S., Pellino G., Gallo G., Servadei F., Fagotti A. (ORCID:0000-0001-5579-335X), Silva A., Dell A. (ORCID:0000-0001-9978-0868), D'Urso A., Smith J., Bianco F., Fortuna L., Cremonini C. (ORCID:0000-0002-1739-841X), Morelli L. (ORCID:0000-0003-0475-2712), Podda M. (ORCID:0000-0002-2779-8417), Feo C. F., Agnes A., Belia F., Biondi A. (ORCID:0000-0002-2470-7858), Cozza V., D'Ugo D. (ORCID:0000-0001-6657-6318), Litta F., Marra A. A. (ORCID:0000-0001-8384-5081), Marzi F., Parello A., Persiani R. (ORCID:0000-0002-1537-5097), Ratto C. (ORCID:0000-0002-0556-0037), Scrima O., Sganga G. (ORCID:0000-0001-5079-0395), Belli A., Izzo F., De Lucia F., Barone R., Federico P., Borroni G., Franzini M., Capelli P., Longhi M., Usai A., Spagni G., Casati M., Schiavo M., Fiori E., Colletti G., Confalonieri M. (ORCID:0000-0002-3708-379X), Donati D., Pellegrino L., Sammarco G., Silva M., Palma P., Salerno G., and Brown B.

Abstract

Aim: The SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery. Methods: This was an international prospective cohort study of consecutive colorectal cancer patients with a decision for curative surgery (January–April 2020). Surgical delay was defined as an operation taking place more than 4 weeks after treatment decision, in a patient who did not receive neoadjuvant therapy. A subgroup analysis explored the effects of delay in elective patients only. The impact of longer delays was explored in a sensitivity analysis. The primary outcome was complete resection, defined as curative resection with an R0 margin. Results: Overall, 5453 patients from 304 hospitals in 47 countries were included, of whom 6.6% (358/5453) did not receive their planned operation. Of the 4304 operated patients without neoadjuvant therapy, 40.5% (1744/4304) were delayed beyond 4 weeks. Delayed patients were more likely to be older, men, more comorbid, have higher body mass index and have rectal cancer and early stage disease. Delayed patients had higher unadjusted rates of complete resection (93.7% vs. 91.9%, P = 0.032) and lower rates of emergency surgery (4.5% vs. 22.5%, P < 0.001). After adjustment, delay was not associated with a lower rate of complete resection (OR 1.18, 95% CI 0.90–1.55, P = 0.224), which was consistent in elective patients only (OR 0.94, 95% CI 0.69–1.27, P = 0.672). Longer delays were not associated with poorer outcomes. Conclusion: One in 15 colorectal cancer patients did not receive their planned operation during the first wave of COVID-19. Surgical delay did not appear to compromise resectability, raising the hypothesis that any reduction in long-term survival attributable to delays is likely to be due to micro-metastatic disease.

Published
2022

26. A commentary on the discrepancy between blood and tumour BRCA testing: An open question

Author

De Paolis, Elisa, Marchetti, Claudia, Concolino, Paola, Scambia, Giovanni, Urbani, Andrea, Fagotti, Anna, Minucci, Angelo, De Paolis E., Marchetti C. (ORCID:0000-0001-7098-8956), Concolino P., Scambia G. (ORCID:0000-0003-2758-1063), Urbani A. (ORCID:0000-0001-9168-3174), Fagotti A. (ORCID:0000-0001-5579-335X), Minucci A., De Paolis, Elisa, Marchetti, Claudia, Concolino, Paola, Scambia, Giovanni, Urbani, Andrea, Fagotti, Anna, Minucci, Angelo, De Paolis E., Marchetti C. (ORCID:0000-0001-7098-8956), Concolino P., Scambia G. (ORCID:0000-0003-2758-1063), Urbani A. (ORCID:0000-0001-9168-3174), Fagotti A. (ORCID:0000-0001-5579-335X), and Minucci A.

Abstract

NA

Published
2022

27. Rucaparib Maintenance in Upfront Ovarian Cancer: The Long-Lasting Challenge of Predicting Response to Poly (ADP-ribose) Polymerase Inhibitors

Author

Marchetti, Claudia, Fagotti, Anna, Scambia, Giovanni, Marchetti, Claudia (ORCID:0000-0001-7098-8956), Fagotti, Anna (ORCID:0000-0001-5579-335X), Scambia, Giovanni (ORCID:0000-0003-2758-1063), Marchetti, Claudia, Fagotti, Anna, Scambia, Giovanni, Marchetti, Claudia (ORCID:0000-0001-7098-8956), Fagotti, Anna (ORCID:0000-0001-5579-335X), and Scambia, Giovanni (ORCID:0000-0003-2758-1063)

Abstract

n/a

Published
2022

28. The prognostic role of systemic inflammatory markers in apparent early-stage ovarian cancer

Author

Bizzarri, Nicolò, D'Indinosante, Marco, Marchetti, Claudia, Tudisco, Riccardo, Turchiano, Francesca, Scambia, Giovanni, Fagotti, Anna, Marchetti, Claudia (ORCID:0000-0001-7098-8956), Scambia, Giovanni (ORCID:0000-0003-2758-1063), Fagotti, Anna (ORCID:0000-0001-5579-335X), Bizzarri, Nicolò, D'Indinosante, Marco, Marchetti, Claudia, Tudisco, Riccardo, Turchiano, Francesca, Scambia, Giovanni, Fagotti, Anna, Marchetti, Claudia (ORCID:0000-0001-7098-8956), Scambia, Giovanni (ORCID:0000-0003-2758-1063), and Fagotti, Anna (ORCID:0000-0001-5579-335X)

Abstract

Background: Few studies analyzed the prognostic role of systemic inflammatory markers in early-stage ovarian cancer. The primary endpoint of the present study was to assess the prognostic impact of baseline inflammatory markers in early-stage ovarian cancer. The secondary endpoints were to compare the disease-free survival (DFS) of inflammatory markers with standard risk factors and to correlate these with BRCA mutational status. Methods: Retrospective, single-center, observational study. Patients with FIGO-stage I-II and IIIA1 epithelial ovarian cancer undergoing primary surgery between 10/2012 and 12/2019 were included. Inflammatory markers were evaluated on the results of the complete blood count and coagulation tests, performed before ovarian cancer surgery. The Receiver Operating Characteristic curve was used to determine the optimal cut-off value of different baseline inflammatory biomarkers for the DFS analysis. Results: Three hundred fifty-nine patients were included in the study period. Baseline neutrophil-lymphocyte ratio (NLR) ≥ 3 and systemic immune inflammation index (SII, defined as platelet x neutrophil-lymphocyte ratio) ≥ 1000 were associated with worse 3 year DFS and baseline SII ≥ 1000 was associated with worse 3 year OS. BRCA-mutated patients with SII ≥ 1000 and with NLR ≥ 3 had significantly worse DFS compared to SII < 1000 and with NLR < 3. FIGO stage > I was the only independent risk factor for higher risk of recurrence. Conclusion: SII ≥ 1000 and NLR ≥ 3 were associated with worse 3 year DFS and SII ≥ 1000 was associated with worse 3 year OS. The subgroups of BRCA-mutated patients with higher inflammation markers (SII ≥ 1000 and NLR ≥ 3) were associated with worse DFS. These findings might be helpful to design personalized treatment and more intensive surveillance.

Published
2022

29. Analysis of risk factors for recurrence in cervical cancer patients after fertility-sparing treatment: The FERTIlity Sparing Surgery retrospective multicenter study

Author

Slama, J., Runnebaum, I. B., Scambia, Giovanni, Angeles, M. A., Bahrehmand, K., Kommoss, S., Fagotti, Anna, Narducci, F., Matylevich, O., Holly, J., Martinelli, Felice, Koual, M., Kopetskyi, V., El-Balat, A., Corrado, Giacomo, Căpîlna, M. E., Schröder, W., Novàk, Z., Shushkevich, A., Fricová, L., Cibula, D., Scambia G. (ORCID:0000-0003-2758-1063), Fagotti A. (ORCID:0000-0001-5579-335X), Martinelli F., Corrado G., Slama, J., Runnebaum, I. B., Scambia, Giovanni, Angeles, M. A., Bahrehmand, K., Kommoss, S., Fagotti, Anna, Narducci, F., Matylevich, O., Holly, J., Martinelli, Felice, Koual, M., Kopetskyi, V., El-Balat, A., Corrado, Giacomo, Căpîlna, M. E., Schröder, W., Novàk, Z., Shushkevich, A., Fricová, L., Cibula, D., Scambia G. (ORCID:0000-0003-2758-1063), Fagotti A. (ORCID:0000-0001-5579-335X), Martinelli F., and Corrado G.

Abstract

Background: Fertility-sparing treatment in patients with cervical cancer should, in principle, follow identical algorithms to that in patients without future reproductive plans. In recent years, a trend toward nonradical procedures, such as conization or simple trachelectomy, has become apparent in medical literature, because of their associations with better pregnancy outcomes. However, the published reports included small numbers of patients and heterogenous treatment strategies to ascertain the safety of such approaches. Objective: This study aimed to collect multi-institutional data regarding the oncological outcomes after fertility-sparing treatment in patients with cervical cancer and to identify prognostic risk factors, including the influence of the radicality of individual cervical procedures. Study design: Patients aged 18 to 40 years with International Federation of Gynecology and Obstetrics 2018 stage IA1 with positive lymphovascular space invasion or ≥IA2 cervical cancer who underwent any type of fertility-sparing procedure were eligible for this retrospective observational study, regardless of their histotype, tumor grade, and history of neoadjuvant chemotherapy. Associations between disease- and treatment-related characteristics with the risk of recurrence were analyzed. Results: A total of 733 patients from 44 institutions across 13 countries were included in this study. Almost half of the patients had stage IB1 cervical cancer (49%), and two-thirds of patients were nulliparous (66%). After a median follow-up of 72 months, 51 patients (7%) experienced recurrence, of whom 19 (2.6%) died because of the disease. The most common sites of recurrence were the cervix (53%) and pelvic nodes (22%). The risk of recurrence was 3 times higher in patients with tumors >2 cm in size than in patients with smaller tumors, irrespective of the treatment radicality (19.4% vs 5.7%; hazard ratio, 2.982; 95% confidence interval, 1.383-6.431; P=.005). The recurrence risk

Published
2022

30. A common pattern of somatic mutations in t-MDS/AML of patients treated with PARP inhibitors for metastatic ovarian cancer

Author

Chiusolo, Patrizia, Marchetti, Claudia, Rossi, Monica, Minnella, Gessica, Salutari, Vanda, Distefano, Mariagrazia, Giammarco, Sabrina, Metafuni, Elisabetta, Minucci, Angelo, Frioni, Filippo, Gasbarrino, Cristiana, Colangelo, Maria, Orteschi, Daniela, Fagotti, Anna, Lorusso, Domenica, Pagano, Livio, De Stefano, Valerio, Scambia, Giovanni, Sica, Simona, Chiusolo, Patrizia (ORCID:0000-0002-1355-1587), Marchetti, Claudia (ORCID:0000-0001-7098-8956), Fagotti, Anna (ORCID:0000-0001-5579-335X), Pagano, Livio (ORCID:0000-0001-8287-928X), De Stefano, Valerio (ORCID:0000-0002-5178-5827), Scambia, Giovanni (ORCID:0000-0003-2758-1063), Sica, Simona (ORCID:0000-0003-2426-3465), Chiusolo, Patrizia, Marchetti, Claudia, Rossi, Monica, Minnella, Gessica, Salutari, Vanda, Distefano, Mariagrazia, Giammarco, Sabrina, Metafuni, Elisabetta, Minucci, Angelo, Frioni, Filippo, Gasbarrino, Cristiana, Colangelo, Maria, Orteschi, Daniela, Fagotti, Anna, Lorusso, Domenica, Pagano, Livio, De Stefano, Valerio, Scambia, Giovanni, Sica, Simona, Chiusolo, Patrizia (ORCID:0000-0002-1355-1587), Marchetti, Claudia (ORCID:0000-0001-7098-8956), Fagotti, Anna (ORCID:0000-0001-5579-335X), Pagano, Livio (ORCID:0000-0001-8287-928X), De Stefano, Valerio (ORCID:0000-0002-5178-5827), Scambia, Giovanni (ORCID:0000-0003-2758-1063), and Sica, Simona (ORCID:0000-0003-2426-3465)

Abstract

inglese

Published
2022

31. Cytoreductive Surgery (CRS) and HIPEC for Advanced Ovarian Cancer with Peritoneal Metastases: Italian PSM Oncoteam Evidence and Study Purposes

Author

Marrelli, D., Ansaloni, L., Federici, O., Asero, S., Carbone, Luigi, Marano, Luigi, Baiocchi, G., Vaira, M., Coccolini, F., Di Giorgio, Andrea, Framarini, M., Gelmini, R., Palopoli, C., Accarpio, F., Fagotti, Anna, Carbone L., Marano L. (ORCID:0000-0002-9833-8055), Di Giorgio A., Fagotti A. (ORCID:0000-0001-5579-335X), Marrelli, D., Ansaloni, L., Federici, O., Asero, S., Carbone, Luigi, Marano, Luigi, Baiocchi, G., Vaira, M., Coccolini, F., Di Giorgio, Andrea, Framarini, M., Gelmini, R., Palopoli, C., Accarpio, F., Fagotti, Anna, Carbone L., Marano L. (ORCID:0000-0002-9833-8055), Di Giorgio A., and Fagotti A. (ORCID:0000-0001-5579-335X)

Abstract

Ovarian cancer is the eighth most common neoplasm in women with a high mortality rate mainly due to a marked propensity for peritoneal spread directly at diagnosis, as well as tumor recurrence after radical surgical treatment. Treatments for peritoneal metastases have to be designed from a patient’s perspective and focus on meaningful measures of benefit. Hyperthermic intraperitoneal chemotherapy (HIPEC), a strategy combining maximal cytoreductive surgery with regional chemotherapy, has been proposed to treat advanced ovarian cancer. Preliminary results to date have shown promising results, with improved survival outcomes and tumor regression. As knowledge about the disease process increases, practice guidelines will continue to evolve. In this review, we have reported a broad overview of advanced ovarian cancer management, and an update of the current evidence. The future perspectives of the Italian Society of Surgical Oncology (SICO) are discussed conclusively.

Published
2022

32. SUCCOR quality: validation of ESGO quality indicators for surgical treatment of cervical cancer

Author

Boria, F., Chiva, L., Chacon, E., Zanagnolo, V., Fagotti, A., Kucukmetin, A., Mom, C., Chakalova, G., Shamistan, A., Malzoni, M., Narducci, F., Arencibia, O., Raspagliesi, F., Toptas, T., Cibula, D., Kaidarova, D., Meydanli, M. M., Tavares, M., Golub, D., Perrone, A. M., Poka, R., Zusterzeel, P. L. M., Aluloski, I., Goffin, F., Haidopoulos, D., Haller, H., Jach, R., Yezhova, I., Bernardino, M., Bharathan, R., Maenpaa, M. M., Sukhin, V., Feron, J. -G., Fruscio, R., Kukk, K., Ponce, J., Demirkiran, F., Vorgias, G., Povolotskaya, N., Coronado Martin, P. J., Marina, T., Zapardiel, I., Bizzarri, N., Gorostidi, M., Gutierrez, M., Manzour, N., Berasaluce, A., Fagotti A. (ORCID:0000-0001-5579-335X), Bizzarri N., Boria, F., Chiva, L., Chacon, E., Zanagnolo, V., Fagotti, A., Kucukmetin, A., Mom, C., Chakalova, G., Shamistan, A., Malzoni, M., Narducci, F., Arencibia, O., Raspagliesi, F., Toptas, T., Cibula, D., Kaidarova, D., Meydanli, M. M., Tavares, M., Golub, D., Perrone, A. M., Poka, R., Zusterzeel, P. L. M., Aluloski, I., Goffin, F., Haidopoulos, D., Haller, H., Jach, R., Yezhova, I., Bernardino, M., Bharathan, R., Maenpaa, M. M., Sukhin, V., Feron, J. -G., Fruscio, R., Kukk, K., Ponce, J., Demirkiran, F., Vorgias, G., Povolotskaya, N., Coronado Martin, P. J., Marina, T., Zapardiel, I., Bizzarri, N., Gorostidi, M., Gutierrez, M., Manzour, N., Berasaluce, A., Fagotti A. (ORCID:0000-0001-5579-335X), and Bizzarri N.

Abstract

Objective To evaluate whether compliance with European Society of Gynaecological Oncology (ESGO) surgery quality indicators impacts disease-free survival in patients undergoing radical hysterectomy for cervical cancer. Methods In this retrospective cohort study, 15 ESGO quality indicators were assessed in the SUCCOR database (patients who underwent radical hysterectomy for International Federation of Gynecology and Obstetrics (FIGO) stage 2009 IB1, FIGO 2018 IB1, and IB2 cervical cancer between January 2013 and December 2014), and the final score ranged between 0 and 16 points. Centers with more than 13 points were classified as high-quality indicator compliance centers. We constructed a weighted cohort using inverse probability weighting to adjust for the variables. We compared disease-free survival and overall survival using Cox proportional hazards regression analysis in the weighted cohort. Results A total of 838 patients were included in the study. The mean number of quality indicators compliance in this cohort was 13.6 (SD 1.45). A total of 479 (57.2%) patients were operated on at high compliance centers and 359 (42.8%) patients at low compliance centers. High compliance centers performed more open surgeries (58.4% vs 36.7%, p<0.01). Women who were operated on at centers with high compliance with quality indicators had a significantly lower risk of relapse (HR=0.39; 95% CI 0.25 to 0.61; p<0.001). The association was reduced, but remained significant, after further adjustment for conization, surgical approach, and use of manipulator surgery (HR=0.48; 95% CI 0.30 to 0.75; p=0.001) and adjustment for adjuvant therapy (HR=0.47; 95% CI 0.30 to 0.74; p=0.001). Risk of death from disease was significantly lower in women operated on at centers with high adherence to quality indicators (HR=0.43; 95% CI 0.19 to 0.97; p=0.041). However, the association was not significant after adjustment for conization, surgical approach, use of manipulator surgery, and adjuvant t

Published
2022

33. Use of Laparoscopic and Laparotomic J-Plasma Handpiece in Gynecological Malignancies: Results From A Pilot Study in A Tertiary Care Center

Author

Gueli Alletti, S., Rosati, A., Capozzi, V. A., Pavone, M., Gioe, A., Cianci, S., Chiantera, V., Vizzielli, G., Scaglione, G., Fagotti, A., Scambia, G., Gueli Alletti S., Pavone M., Gioe A., Cianci S., Vizzielli G., Fagotti A. (ORCID:0000-0001-5579-335X), Scambia G. (ORCID:0000-0003-2758-1063), Gueli Alletti, S., Rosati, A., Capozzi, V. A., Pavone, M., Gioe, A., Cianci, S., Chiantera, V., Vizzielli, G., Scaglione, G., Fagotti, A., Scambia, G., Gueli Alletti S., Pavone M., Gioe A., Cianci S., Vizzielli G., Fagotti A. (ORCID:0000-0001-5579-335X), and Scambia G. (ORCID:0000-0003-2758-1063)

Abstract

Introduction: The J-Plasma has recently been introduced into the surgical community with different intrinsic characteristics aimed to further reduce the thermal effect and enhance precision when compared to standard radiofrequency. This study aimed to investigate the role of this new technology in different conditions of gynecological carcinomatosis characterized by the indication for regional peritonectomy and/or ablation, either in laparotomy (LPT) or in laparoscopy (LPS), in the context of a modern personalized approach to the surgical management of gynecological malignancies. Material and Methods: From January 2019 to April 2019, 12 patients were selected for this prospective pilot study at the Division of Gynecologic Oncology, Fondazione Policlinico Universitario A. Gemelli IRCCS in Rome. In this single surgeon experience, the inclusion criteria were: histologically proven advanced ovarian/endometrial cancer, primary or interval debulking surgery, and intraoperative indication for regional peritonectomy. Six patients were treated by LPS (Group 1) and 6 by LPT (Group 2). Results: In Group 1 the indication for debulking surgery was in 4 cases an interval debulking surgery and 2 advanced endometrial cancer. All patients in Group 2 underwent primary debulking surgery for advanced ovarian cancer. The whole cohort achieved a complete tumor excision after surgery. The median OT and median EBL were 195 min and 100 ml in Group 1, and 420 min and 500 ml in Group 2. The median hospital stay was 4 days in Group 1 and 13 days in Group 2, respectively. No intra and postoperative complications were registered within 60 days after surgery. Conclusions: J-Plasma allows to approach delicate maneuvers on viscera, mesentery, and blood vessels with a high degree of safety and precision thanks to its limited vertical and lateral thermal spread, favoring the surgeon to push ever higher the cytoreduction/morbidity tradeoff. The use of J-Plasma in cytoreductive surg

Published
2022

34. Diagnostic performance of ultrasound in assessing the extension of disease in advanced ovarian cancer

Author

Moruzzi, M. C., Bolomini, G., Esposito, R., Mascilini, F., Ciccarone, Francesca, Quagliozzi, L., Giudice, M. T., Beneduce, Giuliana, Ficarelli, S., Moroni, R., Scambia, Giovanni, Fagotti, Anna, Testa, Antonia Carla, Moro, Francesca, Ciccarone F., Beneduce G., Scambia G. (ORCID:0000-0003-2758-1063), Fagotti A. (ORCID:0000-0001-5579-335X), Testa A. C. (ORCID:0000-0003-2217-8726), Moro F., Moruzzi, M. C., Bolomini, G., Esposito, R., Mascilini, F., Ciccarone, Francesca, Quagliozzi, L., Giudice, M. T., Beneduce, Giuliana, Ficarelli, S., Moroni, R., Scambia, Giovanni, Fagotti, Anna, Testa, Antonia Carla, Moro, Francesca, Ciccarone F., Beneduce G., Scambia G. (ORCID:0000-0003-2758-1063), Fagotti A. (ORCID:0000-0001-5579-335X), Testa A. C. (ORCID:0000-0003-2217-8726), and Moro F.

Abstract

Background: Surgical exploration remains the gold standard for evaluating the extension of disease and predicting resectability. A laparoscopy-based scoring model was developed by Fagotti and colleagues in 2006 and updated in 2015, based on the intraoperative presence or absence of some specific cancer features. The model proved an overall accuracy rate of 77% to 100% and is considered the reference test for assessing resectability in our institution. Objective: The primary aim of the study was to analyze the agreement between preoperative ultrasound examination and laparoscopic findings in assessing the extension of intraabdominal disease using 6 parameters described by Fagotti's score. Study Design: This was a prospective single-center observational study. Between January 2019 and June 2020, consecutive patients with clinical or radiological suspicion of ovarian or peritoneal cancer were assessed with preoperative ultrasound examination and assigned a score based on the 6 Fagotti score parameters (great omentum, liver surface, lesser omentum/stomach/spleen, parietal peritoneum, diaphragms, bowel disease). Presence of mesenteral retraction of the small bowel and miliary carcinomatosis on the serosa were also evaluated. Each parameter was correlated with laparoscopic findings. Concordance was calculated between ultrasound and laparoscopic parameters using Cohen's kappa. Results: Cohen's kappa ranged from 0.70 to 0.90 for carcinomatosis on the small or large bowel, supracolic omentum, liver surface, and diaphragms. Cohen's kappa test was lower for carcinomatosis on the parietal peritoneum (k=0.63) and on the lesser omentum or lesser curvature of the stomach or spleen (k=0.54). The agreement between ultrasound and surgical predictive index value (score) was k=0.74. For the evaluation of mesenteral retraction and miliary carcinomatosis, the agreement was low (k=0.57 and k=0.36, respectively). Conclusion: The results of ultrasound and laparoscopy in the assessment of in

Published
2022

35. Implementing a Personalized Antimicrobial Stewardship Program for Women with Gynecological Cancers and Healthcare-Associated Infections

Author

Di Giambenedetto, Simona, Borghetti, Alberto, Quagliozzi, L., Gallucci, V., Lombardi, Francesca, Ciccullo, A., Fagotti, Anna, Tamburrini, Enrica, Scambia, Giovanni, Di Giambenedetto S. (ORCID:0000-0001-6990-5076), Borghetti A., Lombardi F. (ORCID:0000-0001-5757-8346), Fagotti A. (ORCID:0000-0001-5579-335X), Tamburrini E. (ORCID:0000-0003-4930-426X), Scambia G. (ORCID:0000-0003-2758-1063), Di Giambenedetto, Simona, Borghetti, Alberto, Quagliozzi, L., Gallucci, V., Lombardi, Francesca, Ciccullo, A., Fagotti, Anna, Tamburrini, Enrica, Scambia, Giovanni, Di Giambenedetto S. (ORCID:0000-0001-6990-5076), Borghetti A., Lombardi F. (ORCID:0000-0001-5757-8346), Fagotti A. (ORCID:0000-0001-5579-335X), Tamburrini E. (ORCID:0000-0003-4930-426X), and Scambia G. (ORCID:0000-0003-2758-1063)

Abstract

Healthcare-associated infections (HCAIs) represent a major cause of morbidity and mortality in gynecologic cancer patients, requiring personalized cures. A retrospective study on gynecologic patients with HCAIs, managed through an antimicrobial stewardship program, was performed, focusing on rates of clinical cure, breakthrough/relapse of infections, death, and time of hospital stay (THS). In total, 27 patients (median 60 years, mainly suffering from ovarian, cervical, and uterine cancer) were evaluated by a specialist in infectious diseases and were mainly diagnosed with compli-cated urinary tract (cUTIs, 12 cases, 44.4%) and bloodstream infections (BSIs, 9 cases, 33.3%). A total of 15 cases (11 cUTIs, 73.3%) were managed with no need for hospitalization and received a median of 11 days of outpatient parenteral antimicrobial therapy (OPAT). In the remaining 12 cases (BSIs in 8 cases, 66.7%), the median THS was 11 days, with 15 days median overall duration of antimicrobial therapy (median 5-day reduction in THS). The management of patients also included source control and wound care. All patients reached clinical cure, with no case of breakthrough infection, one case of relapse, and one death within 30 days (not attributable to the infection). HCAIs in patients with gynecologic tumors can be managed through a patient-centered, multidisciplinary antimicrobial stewardship program.

Published
2022

36. Nomogram to predict feasibility of minimally invasive interval debulking surgery in advanced ovarian cancer

Author

Conte, Carmine, Rosati, A., Marchetti, Claudia, Iacobelli, V., Quagliozzi, L., Gallucci, V., Gueli Alletti, Salvatore, Scambia, Giovanni, Fagotti, Anna, Conte C., Marchetti C. (ORCID:0000-0001-7098-8956), Gueli Alletti S., Scambia G. (ORCID:0000-0003-2758-1063), Fagotti A. (ORCID:0000-0001-5579-335X), Conte, Carmine, Rosati, A., Marchetti, Claudia, Iacobelli, V., Quagliozzi, L., Gallucci, V., Gueli Alletti, Salvatore, Scambia, Giovanni, Fagotti, Anna, Conte C., Marchetti C. (ORCID:0000-0001-7098-8956), Gueli Alletti S., Scambia G. (ORCID:0000-0003-2758-1063), and Fagotti A. (ORCID:0000-0001-5579-335X)

Abstract

OBJECTIVE: Currently, there is no clear guidance defining the ideal candidate for minimally invasive interval debulking surgery. This study aimed to identify predictive factors for a minimally invasive approach in patients with advanced ovarian cancer who are candidates for interval debulking surgery after neoadjuvant chemotherapy. METHODS: This was a single institution retrospective study conducted between January 2014 and June 2020 Perioperative variables were used to predict the likelihood of minimally invasive interval debulking surgery using multivariable models. A nomogram was developed, and internal validation was performed using the bootstrapping correction technique. This nomogram was built to visualize the effect of perioperative variables on the estimated probability of minimally invasive interval debulking surgery in patients with a clinical response after neoadjuvant chemotherapy. We used the four significant perioperative variables according to logistic regression. RESULTS: A total of 108 (28.4%) and 272 (71.6%) patients underwent interval debulking surgery by a minimally invasive or open approach, respectively. Absence of omental cake (odds ratio (OR) 9.15, 95% confidence interval (CI) 4.26 to 19.64, p<0.001), high volume surgeon (OR 5.43, 95% CI 2.75 to 10.71, p<0.001), less than two peritoneal sites involved (OR 2.94, 95% CI 1.34 to 6.43, p=0.007), and CA125 normalization (OR 1.79, 95% CI 1.05 to 3.36, p=0.049) correlated with the feasibility of minimally invasive interval debulking surgery at multivariate analysis. The calibration plot demonstrated good agreement between the predicted and actual probability of minimally invasive interval debulking surgery (p=0.93, Hosmer-Lemeshow test). CONCLUSIONS: Our nomogram may serve as a useful tool to choose the surgical approach in patients with advanced ovarian cancer undergoing interval debulking surgery.

Published
2022

37. Neoadjuvant Chemotherapy in Pregnant Patients with Cervical Cancer: A Monocentric Retrospective Study

Author

Bernardini, F., Ferrandina, Maria Gabriella, Ricci, C., Fagotti, Anna, Fanfani, Francesco, Cavaliere, Anna Franca, Gui, Benedetta, Scambia, Giovanni, De Vincenzo, Rosa Pasqualina, Ferrandina G. (ORCID:0000-0003-4672-4197), Fagotti A. (ORCID:0000-0001-5579-335X), Fanfani F. (ORCID:0000-0003-1991-7284), Cavaliere A. F., Gui B., Scambia G. (ORCID:0000-0003-2758-1063), De Vincenzo R. (ORCID:0000-0001-7408-0435), Bernardini, F., Ferrandina, Maria Gabriella, Ricci, C., Fagotti, Anna, Fanfani, Francesco, Cavaliere, Anna Franca, Gui, Benedetta, Scambia, Giovanni, De Vincenzo, Rosa Pasqualina, Ferrandina G. (ORCID:0000-0003-4672-4197), Fagotti A. (ORCID:0000-0001-5579-335X), Fanfani F. (ORCID:0000-0003-1991-7284), Cavaliere A. F., Gui B., Scambia G. (ORCID:0000-0003-2758-1063), and De Vincenzo R. (ORCID:0000-0001-7408-0435)

Abstract

Background: To date, little and discordant data still exists on the management of cervical cancer (CC) during pregnancy. In this paper, we report our experience of the treatment of these patients analyzing the oncologic, obstetric, and neonatal outcomes. Methods: Between January 2010 and December 2021, 13 patients were diagnosed with CC during pregnancy. All patients underwent platinum-based neoadjuvant chemotherapy (NACT) and 11/13 patients underwent a cesarean radical hysterectomy (CRH). Results: All 13 patients were diagnosed with squamous-cell carcinoma, FIGO-2018 stage between IB2-IIIC1. The majority of patients had a partial (61.5%) or complete (15.4%) response to NACT. Most patients had a regular course of pregnancy and the obstetric complications observed were gestational diabetes mellitus in 23.1% and IUGR in 15.4% of cases. CRH was performed in the absence of major complications. Only 2 patients (15.4%) had disease recurrence and only 1 patient (7.7%) died of disease. All children are currently healthy. At birth, we observed mainly prematurity-related complications (38.5% respiratory distress syndrome and 7.7% neonatal jaundice) and only a case of congenital malformation (hypospadias). In our pediatric population, we reported a case of malignancy (acute myeloid leukemia). Conclusion: NACT seems to be safe and efficacious in controlling tumor burden during pregnancy. CRH following NACT appears to be feasible, avoiding repeated surgery and treatment delays. This approach is also reasonably safe from a maternal, obstetric, and neonatal point of view.

Published
2022

38. SUCCOR cone study: conization before radical hysterectomy

Author

Chacon, E., Manzour, N., Zanagnolo, V., Querleu, D., Nunez-Cordoba, J. M., Martin-Calvo, N., Capilna, M. E., Fagotti, Anna, Kucukmetin, A., Mom, C., Chakalova, G., Shamistan, A., Gil Moreno, A., Malzoni, M., Narducci, F., Arencibia, O., Raspagliesi, F., Toptas, T., Cibula, D., Kaidarova, D., Meydanli, M. M., Tavares, M., Golub, D., Perrone, A. M., Poka, R., Tsolakidis, D., Vujic, G., Jedryka, M. A., Zusterzeel, P. L. M., Beltman, J. J., Goffin, F., Haidopoulos, D., Haller, H., Jach, R., Yezhova, I., Berlev, I., Bernardino, M., Bharathan, R., Lanner, M., Maenpaa, M. M., Sukhin, V., Feron, J. -G., Fruscio, R., Kukk, K., Ponce, J., Minguez, J. A., Vazquez-Vicente, D., Castellanos, T., Boria, F., Alcazar, J. L., Chiva, L., Fagotti A. (ORCID:0000-0001-5579-335X), Chacon, E., Manzour, N., Zanagnolo, V., Querleu, D., Nunez-Cordoba, J. M., Martin-Calvo, N., Capilna, M. E., Fagotti, Anna, Kucukmetin, A., Mom, C., Chakalova, G., Shamistan, A., Gil Moreno, A., Malzoni, M., Narducci, F., Arencibia, O., Raspagliesi, F., Toptas, T., Cibula, D., Kaidarova, D., Meydanli, M. M., Tavares, M., Golub, D., Perrone, A. M., Poka, R., Tsolakidis, D., Vujic, G., Jedryka, M. A., Zusterzeel, P. L. M., Beltman, J. J., Goffin, F., Haidopoulos, D., Haller, H., Jach, R., Yezhova, I., Berlev, I., Bernardino, M., Bharathan, R., Lanner, M., Maenpaa, M. M., Sukhin, V., Feron, J. -G., Fruscio, R., Kukk, K., Ponce, J., Minguez, J. A., Vazquez-Vicente, D., Castellanos, T., Boria, F., Alcazar, J. L., Chiva, L., and Fagotti A. (ORCID:0000-0001-5579-335X)

Abstract

OBJECTIVE: To evaluate disease-free survival of cervical conization prior to radical hysterectomy in patients with stage IB1 cervical cancer (International Federation of Gynecology and Obstetrics (FIGO) 2009). METHODS: A multicenter retrospective observational cohort study was conducted including patients from the Surgery in Cervical Cancer Comparing Different Surgical Aproaches in Stage IB1 Cervical Cancer (SUCCOR) database with FIGO 2009 IB1 cervical carcinoma treated with radical hysterectomy between January 1, 2013, and December 31, 2014. We used propensity score matching to minimize the potential allocation biases arising from the retrospective design. Patients who underwent conization but were similar for other measured characteristics were matched 1:1 to patients from the non-cone group using a caliper width ≤0.2 standard deviations of the logit odds of the estimated propensity score. RESULTS: We obtained a weighted cohort of 374 patients (187 patients with prior conization and 187 non-conization patients). We found a 65% reduction in the risk of relapse for patients who had cervical conization prior to radical hysterectomy (hazard ratio (HR) 0.35, 95% confidence interval (CI) 0.16 to 0.75, p=0.007) and a 75% reduction in the risk of death for the same sample (HR 0.25, 95% CI 0.07 to 0.90, p=0.033). In addition, patients who underwent minimally invasive surgery without prior conization had a 5.63 times higher chance of relapse compared with those who had an open approach and previous conization (HR 5.63, 95% CI 1.64 to 19.3, p=0.006). Patients who underwent minimally invasive surgery with prior conization and those who underwent open surgery without prior conization showed no differences in relapse rates compared with those who underwent open surgery with prior cone biopsy (reference) (HR 1.94, 95% CI 0.49 to 7.76, p=0.349 and HR 2.94, 95% CI 0.80 to 10.86, p=0.106 respectively). CONCLUSIONS: In this retrospective study, patients undergoing cervical conizatio

Published
2022

39. Preclinical models of epithelial ovarian cancer: practical considerations and challenges for a meaningful application

Author

Ciucci, A., Buttarelli, M., Fagotti, Anna, Scambia, Giovanni, Gallo, D., Fagotti A. (ORCID:0000-0001-5579-335X), Scambia G. (ORCID:0000-0003-2758-1063), Ciucci, A., Buttarelli, M., Fagotti, Anna, Scambia, Giovanni, Gallo, D., Fagotti A. (ORCID:0000-0001-5579-335X), and Scambia G. (ORCID:0000-0003-2758-1063)

Abstract

Despite many improvements in ovarian cancer diagnosis and treatment, until now, conventional chemotherapy and new biological drugs have not been shown to cure the disease, and the overall prognosis remains poor. Over 90% of ovarian malignancies are categorized as epithelial ovarian cancers (EOC), a collection of different types of neoplasms with distinctive disease biology, response to chemotherapy, and outcome. Advances in our understanding of the histopathology and molecular features of EOC subtypes, as well as the cellular origins of these cancers, have given a boost to the development of clinically relevant experimental models. The overall goal of this review is to provide a comprehensive description of the available preclinical investigational approaches aimed at better characterizing disease development and progression and at identifying new therapeutic strategies. Systems discussed comprise monolayer (2D) and three-dimensional (3D) cultures of established and primary cancer cell lines, organoids and patient-derived explants, animal models, including carcinogen-induced, syngeneic, genetically engineered mouse, xenografts, patient-derived xenografts (PDX), humanized PDX, and the zebrafish and the laying hen models. Recent advances in tumour-on-a-chip platforms are also detailed. The critical analysis of strengths and weaknesses of each experimental model will aid in identifying opportunities to optimize their translational value.

Published
2022

40. Isolated tumour cells in a sentinel lymph node of apparent early-stage ovarian cancer: Ultrastaging of all other 27 lymph nodes

Author

Uccella, S., Bosco, M., Fagotti, A., Garzon, S., Zorzato, P. C., Tinelli, R., Biletta, E., Porcari, I., Liscia, D., Scambia, G., Franchi, M., Bosco M., Fagotti A. (ORCID:0000-0001-5579-335X), Scambia G. (ORCID:0000-0003-2758-1063), Uccella, S., Bosco, M., Fagotti, A., Garzon, S., Zorzato, P. C., Tinelli, R., Biletta, E., Porcari, I., Liscia, D., Scambia, G., Franchi, M., Bosco M., Fagotti A. (ORCID:0000-0001-5579-335X), and Scambia G. (ORCID:0000-0003-2758-1063)

Abstract

Sentinel lymph node (SLN) biopsy in apparent early-stage ovarian cancer may spare the surgical staging with extensive retroperitoneal dissection and its associated morbidity. However, SLN biopsy in ovarian cancer is still experimental and under investigation. A 46-year-old post-menopausal woman with bilateral apparent stage IC1 endometrioid ovarian cancer underwent surgical staging by SLN biopsy and subsequent comprehensive laparoscopic pelvic and para-aortic lymphadenectomy. Out of 4 SLNs submitted to ultrastaging, one was positive for isolated tumour cells (ITCs). We submitted to ultra-staging all the other 24 pelvic and para-aortic non-SLNs, which were reported negative for disease. This is the first reported case of comprehensive lymphadenectomy after SLN biopsy with universal ultrastaging of all non-SLNs in ovarian cancer. The presence of ITCs in only one SLN, with all other 27 lymph nodes negative at ultrastaging, is consistent with the SLN concept and the assumption of a reliable lymphatic pathway in ovarian cancer.

Published
2022

41. CT-Based Radiomics and Deep Learning for BRCA Mutation and Progression-Free Survival Prediction in Ovarian Cancer Using a Multicentric Dataset

Author

Avesani, Giacomo, Tran, H. E., Cammarata, G., Botta, Francesca, Raimondi, Saveria, Russo, Luca, Persiani, S., Bonatti, Matteo, Tagliaferri, Tiziana, Dolciami, M., Celli, V., Boldrini, Luca, Lenkowicz, Jacopo, Pricolo, P., Tomao, F., Rizzo, S. M. R., Colombo, N., Manganaro, L., Fagotti, Anna, Scambia, Giovanni, Gui, Benedetta, Manfredi, Riccardo, Avesani G., Botta F., Raimondi S., Russo L., Bonatti M., Tagliaferri T., Boldrini L., Lenkowicz J., Fagotti A. (ORCID:0000-0001-5579-335X), Scambia G. (ORCID:0000-0003-2758-1063), Gui B., Manfredi R. (ORCID:0000-0002-4972-9500), Avesani, Giacomo, Tran, H. E., Cammarata, G., Botta, Francesca, Raimondi, Saveria, Russo, Luca, Persiani, S., Bonatti, Matteo, Tagliaferri, Tiziana, Dolciami, M., Celli, V., Boldrini, Luca, Lenkowicz, Jacopo, Pricolo, P., Tomao, F., Rizzo, S. M. R., Colombo, N., Manganaro, L., Fagotti, Anna, Scambia, Giovanni, Gui, Benedetta, Manfredi, Riccardo, Avesani G., Botta F., Raimondi S., Russo L., Bonatti M., Tagliaferri T., Boldrini L., Lenkowicz J., Fagotti A. (ORCID:0000-0001-5579-335X), Scambia G. (ORCID:0000-0003-2758-1063), Gui B., and Manfredi R. (ORCID:0000-0002-4972-9500)

Abstract

Purpose: Build predictive radiomic models for early relapse and BRCA mutation based on a multicentric database of high-grade serous ovarian cancer (HGSOC) and validate them in a test set coming from different institutions. Methods: Preoperative CTs of patients with HGSOC treated at four referral centers were retrospectively acquired and manually segmented. Hand-crafted features and deep radiomics features were extracted respectively by dedicated software (MODDICOM) and a dedicated convolutional neural network (CNN). Features were selected with and without prior harmonization (ComBat harmonization), and models were built using different machine learning algorithms, including clinical variables. Results: We included 218 patients. Radiomic models showed low performance in predicting both BRCA mutation (AUC in test set between 0.46 and 0.59) and 1-year relapse (AUC in test set between 0.46 and 0.56); deep learning models demonstrated similar results (AUC in the test of 0.48 for BRCA and 0.50 for relapse). The inclusion of clinical variables improved the performance of the radiomic models to predict BRCA mutation (AUC in the test set of 0.74). Conclusions: In our multicentric dataset, representative of a real-life clinical scenario, we could not find a good radiomic predicting model for PFS and BRCA mutational status, with both traditional radiomics and deep learning, but the combination of clinical and radiomic models improved model performance for the prediction of BRCA mutation. These findings highlight the need for standardization through the whole radiomic pipelines and robust multicentric external validations of results.

Published
2022

42. A Laparoscopic Adjusted Model Able to Predict the Risk of Intraoperative Capsule Rupture in Early-stage Ovarian Cancer: Laparoscopic Ovarian Cancer Spillage Score (LOChneSS Study)

Author

Ghirardi, V., De Felice, F., Rosati, A., Ergasti, Raffaella, Gueli Alletti, Salvatore, Mascilini, F., Scambia, Giovanni, Fagotti, Anna, Ergasti R., Gueli Alletti S., Scambia G. (ORCID:0000-0003-2758-1063), Fagotti A. (ORCID:0000-0001-5579-335X), Ghirardi, V., De Felice, F., Rosati, A., Ergasti, Raffaella, Gueli Alletti, Salvatore, Mascilini, F., Scambia, Giovanni, Fagotti, Anna, Ergasti R., Gueli Alletti S., Scambia G. (ORCID:0000-0003-2758-1063), and Fagotti A. (ORCID:0000-0001-5579-335X)

Abstract

Study Objective: To identify preoperative/intraoperative patient and tumor characteristics associated with an increased risk of tumor spillage during minimally invasive surgery (MIS) for early-stage ovarian cancer (OC). The secondary end point was to develop a score system able to estimate the risk of tumor rupture during MIS. Design: Retrospective observational study. Setting: Patients with International Federation of Gynecology and Obstetrics stage I OC. Patients: Patients aged ≥18 years old, with International Federation of Gynecology and Obstetrics stage IA to IC1 OC of any histology. Interventions: Preoperative and intraoperative characteristics of patients treated with MIS for early-stage OC at Policlinico Universitario Agostino Gemelli, IRCCS in Rome, Italy, from January 1, 2001, to December 31, 2017, were collected. Measurements and Main Results: A total of 151 patients were included. Previous pelvic surgery was more represented in patients with nonruptured tumors (46.0% vs 63.4%; p = .042). In addition, a larger tumor diameter (p <.001), a higher body mass index (p = .032), ultrasound characteristics (p = .029), and adhesions to large bowel (14% vs 2.0%; p = .003), uterus (44% vs 6.9%; p <.001), contralateral ovary (8.0% vs 0%; p = .004), ovarian fossa (64% vs 14.9%; p <.001), and pouch of Douglas peritoneum (32% vs 4.0%; p <.001) increased rupture rate. At multivariate analysis, a larger tumor diameter (p <.001) and adhesions to ovarian fossa peritoneum (p = .007) were independently associated with intraoperative cancer spillage and included in the score calculation. A disease-free survival (DFS) difference between the rupture group and the no-rupture group was detected (5-year DFS, 74.9% vs 94.4%; p = .011), with superimposable overall survival (5-year overall survival, 91.2% vs 97.9%; p = .089). Conclusion: Some preoperative/intraoperative characteristics increase the risk of tumor rupture during MIS for early-stage OC. A laparoscopic pred

Published
2022

43. Role of tertiary cytoreductive surgery in recurrent epithelial ovarian cancer: Systematic review and meta-analysis

Author

Guida, Fiorenza, Dioun, S., Fagotti, Anna, Melamed, A., Grossi, A., Scambia, Giovanni, Wright, J. D., Tergas, A. I., Guida F., Fagotti A. (ORCID:0000-0001-5579-335X), Scambia G. (ORCID:0000-0003-2758-1063), Guida, Fiorenza, Dioun, S., Fagotti, Anna, Melamed, A., Grossi, A., Scambia, Giovanni, Wright, J. D., Tergas, A. I., Guida F., Fagotti A. (ORCID:0000-0001-5579-335X), and Scambia G. (ORCID:0000-0003-2758-1063)

Abstract

Objective: To evaluate the clinical utility of tertiary cytoreductive surgery (TCS) in recurrent ovarian cancer. Methods: MEDLINE via PubMed, Embase (Elsevier), ClinicalTrials.gov, Scopus (Elsevier) and Web of Science for studies from inception to 4/09/2021. Studies reporting disease specific survival (DSS) and overall survival (OS) among women who underwent optimal cytoreductive surgery as compared to those who had a suboptimal cytoreductive surgery at time of TCS were abstracted. Study quality was assessed with the Quality In Prognosis Studies (QUIPS) tool. The data were extracted independently by multiple observers. Random-effects models were used to pool associations and to analyze the association between survival and surgical outcomes. Results: 10 studies met all the criteria for inclusion in the systematic review. Patients with optimal tertiary cytoreductive surgery had better DSS (HR = 0.35; 95% CI, 0.19–0.64, P < 0.001), with low heterogeneity (I2 = 0%, P = 0.41) when compared to those with suboptimal tertiary cytoreductive surgery. Pooled results from these studies also demonstrated a better OS (HR = 0.34; 95% CI, 0.15–0.74, P < 0.007) with moderate heterogeneity (I2 = 59%, P = 0.09) when compared to patients with a suboptimal tertiary cytoreductive surgery. This remained significant in a series of sensitivity analyses. Due to the limited number of studies, we were unable to do further subgroup analyses looking at outcomes comparing tertiary cytoreductive surgery to chemotherapy. Conclusion: In this systematic review and meta-analysis of observational studies examining tertiary cytoreductive surgery for recurrent ovarian cancer, optimal tertiary cytoreductive surgery was associated with improved OS and DSS survival compared to suboptimal tertiary cytoreductive surgery.

Published
2022

44. BRCA testing on buccal swab to improve access to healthcare and cancer prevention: A performance evaluation

Author

De Paolis, Elisa, Perrucci, Alessia, Marchetti, Claudia, Pietragalla, A., Scambia, Giovanni, Urbani, Andrea, Fagotti, Anna, Minucci, Angelo, De Paolis E., Perrucci A., Marchetti C. (ORCID:0000-0001-7098-8956), Scambia G. (ORCID:0000-0003-2758-1063), Urbani A. (ORCID:0000-0001-9168-3174), Fagotti A. (ORCID:0000-0001-5579-335X), Minucci A., De Paolis, Elisa, Perrucci, Alessia, Marchetti, Claudia, Pietragalla, A., Scambia, Giovanni, Urbani, Andrea, Fagotti, Anna, Minucci, Angelo, De Paolis E., Perrucci A., Marchetti C. (ORCID:0000-0001-7098-8956), Scambia G. (ORCID:0000-0003-2758-1063), Urbani A. (ORCID:0000-0001-9168-3174), Fagotti A. (ORCID:0000-0001-5579-335X), and Minucci A.

Abstract

Objective: BRCA1/2 (BRCA) genetic testing allows patients with high-grade serous ovarian cancer to receive appropriate medical management with molecular target therapy and prevention strategies. Most of the BRCA sequencing methods use blood as the primary source of germline DNA. Buccal swab emerged as an alternative collection device due to its convenient and non-invasive characteristics. This study assessed the suitability of buccal swabs as the DNA source in next-generation sequencing-based BRCA genotyping. Methods: Matched buccal swabs and blood samples were collected from 51 patients with high-grade serous ovarian cancer, including 29 BRCA-mutated patients, from June to December 2021. Buccal swabs were self-collected using COPAN FLOQSwabs hDNA Free. BRCA genes were amplified using Devyser's BRCA next-generation sequencing kit and sequenced on the Illumina MiSeq platform. We evaluated collection and extraction procedures, amplification and sequencing performances, coverage data, blood/swab variant calling concordance, and interpretation. Results: Comparable sequencing parameters were observed between the two sample types in term of mean total number of reads passing filter for indexed sample (p>0.05) and sequencing coverage distribution, with a widespread overlap of mean depth of coverage/target region between blood and swab samples. An overall concordance of 100% in both polymorphisms and pathogenic variants calling between the two DNA sources were observed, including the copy number variation prediction. Conclusions: Data from this study support the use of buccal swabs as an alternative source of DNA for BRCA evaluation. The use of this alternative delivery mode of BRCA testing may facilitate access to care without compromising patient outcomes.

Published
2022

45. OVA-LEAK: Prognostic score for colo-rectal anastomotic leakage in patients undergoing ovarian cancer surgery

Author

Lago, V., Segarra-Vidal, B., Cappucio, S., Angeles, M. A., Fotopoulou, C., Muallem, M. Z., Manzanedo, I., Iglesias, J. L. S., Chacon, E., Padilla-Iserte, P., Fagotti, Anna, Ferron, G., Kluge, L., Vargiu, V., Del, M., Scambia, Giovanni, Minig, L., Tejerizo, A., Segovia, M. G., Cascales-Campos, P. A., Gil-Moreno, A., Chiva, L., Rinne, N., Martinez, A., Matute, L., Gurrea, M., Sala Climent, L., Montesinos, M., Hervas, D., Domingo, S., Fagotti A. (ORCID:0000-0001-5579-335X), Scambia G. (ORCID:0000-0003-2758-1063), Lago, V., Segarra-Vidal, B., Cappucio, S., Angeles, M. A., Fotopoulou, C., Muallem, M. Z., Manzanedo, I., Iglesias, J. L. S., Chacon, E., Padilla-Iserte, P., Fagotti, Anna, Ferron, G., Kluge, L., Vargiu, V., Del, M., Scambia, Giovanni, Minig, L., Tejerizo, A., Segovia, M. G., Cascales-Campos, P. A., Gil-Moreno, A., Chiva, L., Rinne, N., Martinez, A., Matute, L., Gurrea, M., Sala Climent, L., Montesinos, M., Hervas, D., Domingo, S., Fagotti A. (ORCID:0000-0001-5579-335X), and Scambia G. (ORCID:0000-0003-2758-1063)

Abstract

Objective: The objective of the present study was to define and validate an anastomotic leak prognostic score based on previously described and reported anastomotic leak risk factors (OVA-LEAK: https://n9.cl/ova-leakscore) and to establish if the use of OVA-LEAK score is better than clinical criteria (surgeon's choice) selecting anastomosis to be protected with a diverting ileostomy. Material & methods: This is a retrospective, multicentre cohort study that included patients who underwent cytoreductive surgery for primary advanced or relapsed ovarian cancer with colorectal resection and anastomosis between January 2011 and June 2021. Data from patients already included in the previous predictive model were not considered in the present analysis. To validate the performance of our logistic regression model, we used the OVA-LEAK formula (Annex I: https://n9.cl/ova-leakscore) for estimating leakage probabilities in a new independent cohort. Then, receiver operating characteristic (ROC) analysis was performed and area under the curve (AUC) was used to measure the performance of the model. Additionally, the Brier score was also estimated. 95% confidence intervals (CI) for each of the estimated performance measures were also calculated. Results: 848 out of 1159 recruited patients were finally included in the multivariable logistic regression model validation. The AUC of the new cohort was 0.63 for predicting anastomotic leak. Considering a cut-off point of 22.1% to be ‘positive’ (to get a leak) this would provide a sensitivity of 0.45, specificity of 0.80, positive predictive value of 0.09 and negative predictive value of 0.97 for anastomotic leak. If we consider this cut-off point to select patients at risk of leak for bowel diversion, up to 22.5% of the sampled patients would undergo a diverting ileostomy and 47% (18/40) of the anastomotic leaks would be ‘protected’ with the stoma. Nevertheless, if we consider only the ‘clinical criteria’ for performing or not a div

Published
2022

46. SUCCOR Risk: Design and Validation of a Recurrence Prediction Index for Early-Stage Cervical Cancer

Author

Manzour, N., Chiva, L., Chacon, E., Martin-Calvo, N., Boria, F., Minguez, J. A., Alcazar, J. L., Zanagnolo, V., Querleu, D., Capilna, M., Fagotti, Anna, Kucukmetin, A., Mom, C., Chakalova, G., Aliyev, S., Malzoni, M., Narducci, F., Arencibia, O., Raspagliesi, F., Toptas, T., Cibula, D., Kaidarova, D., Meydanli, M., Tavares, M., Golub, D., Perrone, A., Poka, R., Tsolakidis, D., Vujic, G., Jedryka, M., Zusterzeel, P., Beltman, J., Goffin, F., Haidopoulos, D., Haller, H., Jach, R., Yezhova, I., Berlev, I., Bernardino, M., Bharathan, R., Lanner, M., Sukhin, V., Feron, J. G., Fruscio, R., Kukk, K., Ponce, J., Abdalla, N., Akbayir, O., Akgol, S., Aksahin, E., Alonso-Espias, M., Aluloski, I., Andrade, C., Badzakov, N., Barrachina, R., Bogani, G., Bonci, E. -A., Bonsang-Kitzis, H., Brucker, C., Cardenas, L., Casajuana, A., Cavalle, P., Cea, J., Chiofalo, B., Cordeiro, G., Coronado, P., Cuadra, M., Diez, J., da Costa, T. D., Domingo, S., Dostalek, L., Demirkiran, F., Erasun, D., Fehr, M., Fernandez-Gonzalez, S., Fidalgo, S., Fiol, G., Galaal, K., Garcia, J., Gebauer, G., Ghezzi, F., Gilabert, J., Gomes, N., Goncalves, E., Gonzalez, V., Grandjean, F., Guijarro, M., Guyon, F., Haesen, J., Hernandez-Cortes, G., Herrero, S., Pete, I., Kalogiannidis, I., Karaman, E., Kavallaris, A., Klasa, L., Kotsopoulos, I., Kovachev, S., Leht, M., Lekuona, A., Luyckx, M., Mallmann, M., Mancebo, G., Mandic, A., Marina, T., Martin, V., Martin-Salamanca, M. B., Martinez, A., Meili, G., Mendinhos, G., Mereu, L., Mitrovic, M., Morales, S., Moratalla, E., Morillas, B., Myriokefalitaki, E., Pakizimre, M., Petousis, S., Pirtea, L., Povolotskaya, N., Prader, S., Quesada, A., Redecha, M., Roldan, F., Rolland, P., Saaron, R., Sarac, C. -P., Scharf, J. -P., Smrkolj, S., Sousa, R., Stepanyan, A., Student, V., Tauste, C., Trum, H., Turan, T., Undurraga, M., Uppin, A., Vazquez, A., Vergote, I., Vorgias, G., Zapardiel, I., Fagotti A. (ORCID:0000-0001-5579-335X), Manzour, N., Chiva, L., Chacon, E., Martin-Calvo, N., Boria, F., Minguez, J. A., Alcazar, J. L., Zanagnolo, V., Querleu, D., Capilna, M., Fagotti, Anna, Kucukmetin, A., Mom, C., Chakalova, G., Aliyev, S., Malzoni, M., Narducci, F., Arencibia, O., Raspagliesi, F., Toptas, T., Cibula, D., Kaidarova, D., Meydanli, M., Tavares, M., Golub, D., Perrone, A., Poka, R., Tsolakidis, D., Vujic, G., Jedryka, M., Zusterzeel, P., Beltman, J., Goffin, F., Haidopoulos, D., Haller, H., Jach, R., Yezhova, I., Berlev, I., Bernardino, M., Bharathan, R., Lanner, M., Sukhin, V., Feron, J. G., Fruscio, R., Kukk, K., Ponce, J., Abdalla, N., Akbayir, O., Akgol, S., Aksahin, E., Alonso-Espias, M., Aluloski, I., Andrade, C., Badzakov, N., Barrachina, R., Bogani, G., Bonci, E. -A., Bonsang-Kitzis, H., Brucker, C., Cardenas, L., Casajuana, A., Cavalle, P., Cea, J., Chiofalo, B., Cordeiro, G., Coronado, P., Cuadra, M., Diez, J., da Costa, T. D., Domingo, S., Dostalek, L., Demirkiran, F., Erasun, D., Fehr, M., Fernandez-Gonzalez, S., Fidalgo, S., Fiol, G., Galaal, K., Garcia, J., Gebauer, G., Ghezzi, F., Gilabert, J., Gomes, N., Goncalves, E., Gonzalez, V., Grandjean, F., Guijarro, M., Guyon, F., Haesen, J., Hernandez-Cortes, G., Herrero, S., Pete, I., Kalogiannidis, I., Karaman, E., Kavallaris, A., Klasa, L., Kotsopoulos, I., Kovachev, S., Leht, M., Lekuona, A., Luyckx, M., Mallmann, M., Mancebo, G., Mandic, A., Marina, T., Martin, V., Martin-Salamanca, M. B., Martinez, A., Meili, G., Mendinhos, G., Mereu, L., Mitrovic, M., Morales, S., Moratalla, E., Morillas, B., Myriokefalitaki, E., Pakizimre, M., Petousis, S., Pirtea, L., Povolotskaya, N., Prader, S., Quesada, A., Redecha, M., Roldan, F., Rolland, P., Saaron, R., Sarac, C. -P., Scharf, J. -P., Smrkolj, S., Sousa, R., Stepanyan, A., Student, V., Tauste, C., Trum, H., Turan, T., Undurraga, M., Uppin, A., Vazquez, A., Vergote, I., Vorgias, G., Zapardiel, I., and Fagotti A. (ORCID:0000-0001-5579-335X)

Abstract

Objective: Based on the SUCCOR study database, our primary objective was to identify the independent clinical pathological variables associated with the risk of relapse in patients with stage IB1 cervical cancer who underwent a radical hysterectomy. Our secondary goal was to design and validate a risk predictive index (RPI) for classifying patients depending on the risk of recurrence. Methods: Overall, 1116 women were included from January 2013 to December 2014. We randomly divided our sample into two cohorts: discovery and validation cohorts. The test group was used to identify the independent variables associated with relapse, and with these variables, we designed our RPI. The index was applied to calculate a relapse risk score for each participant in the validation group. Results: A previous cone biopsy was the most significant independent variable that lowered the rate of relapse (odds ratio [OR] 0.31, 95% confidence interval [CI] 0.17–0.60). Additionally, patients with a tumor diameter >2 cm on preoperative imaging assessment (OR 2.15, 95% CI 1.33–3.5) and operated by the minimally invasive approach (OR 1.61, 95% CI 1.00–2.57) were more likely to have a recurrence. Based on these findings, patients in the validation cohort were classified according to the RPI of low, medium, or high risk of relapse, with rates of 3.4%, 9.8%, and 21.3% observed in each group, respectively. With a median follow-up of 58 months, the 5-year disease-free survival rates were 97.2% for the low-risk group, 88.0% for the medium-risk group, and 80.5% for the high-risk group (p < 0.001). Conclusion: Previous conization to radical hysterectomy was the most powerful protective variable of relapse. Our risk predictor index was validated to identify patients at risk of recurrence.

Published
2022

47. BRCA status and platinum sensitivity in advanced ovarian cancer according to Chemotherapy Response Score

Author

Ergasti, Raffaella, Marchetti, Claudia, Tudisco, Riccardo, Iervolino, A., Naldini, A., Oliva, Riccardo, Inzani, Frediano, Scambia, Giovanni, Fagotti, Anna, Ergasti R., Marchetti C. (ORCID:0000-0001-7098-8956), Tudisco R., Oliva R., Inzani F., Scambia G. (ORCID:0000-0003-2758-1063), Fagotti A. (ORCID:0000-0001-5579-335X), Ergasti, Raffaella, Marchetti, Claudia, Tudisco, Riccardo, Iervolino, A., Naldini, A., Oliva, Riccardo, Inzani, Frediano, Scambia, Giovanni, Fagotti, Anna, Ergasti R., Marchetti C. (ORCID:0000-0001-7098-8956), Tudisco R., Oliva R., Inzani F., Scambia G. (ORCID:0000-0003-2758-1063), and Fagotti A. (ORCID:0000-0001-5579-335X)

Abstract

Objective To evaluate a relation between BRCA1/2 status and the Chemotherapy Response Score in patients with epithelial ovarian cancer undergoing neoadjuvant chemotherapy and interval debulking surgery. Methods Data were retrospectively collected on patients with unresectable disease undergoing three or four cycles of neoadjuvant chemotherapy and interval debulking surgery at the Gynecologic Oncology Unit of the Catholic University of the Sacred Heart from January 2016 to December 2020. All patients were assessed for BRCA1/2 somatic mutation at diagnosis. The omental specimens obtained at the interval surgery were evaluated according to Bohm's Chemotherapy Response Score System. Results A total of 172 patients were included in the analysis, 69 (40%) patients were BRCA1/2 mutation carriers and 103 (60%) patients were wild type. In the wild-type group (BRCAwt), 73 (70.9%) patients had a Chemotherapy Response Score of 1 or 2 and 30 (29.1%) patients had a score of 3. In the BRCA1/2 carriers group (BRCAmut), 39 (56.5%) patients had a score of 1 or 2 and 30 (43.5%) patients had a score of 3. Among the BRCAwt group, those with a Chemotherapy Response Score of 3 had a prolonged median progression-free survival (22 vs 15 months, p=0.003). Among the BRCAmut carriers group, no differences were found (30 vs 27 months, p=0.55). No difference in overall survival was observed in either the BRCAmut carriers population (p=0.23) or the BRCAwt population (60 vs 44 months, p=0.06). Conclusions Patients with BRCA1/2mut seem to achieve a score of 1, 2 or 3 with the same frequency. In contrast, patients with BRCAwt seem to have a score of 1 or 2 more frequently than a score of 3. In patients with BRCA1/2mut, this score may not be an indicator of chemosensitivity.

Published
2022

48. Risk reducing surgery with peritoneal staging in BRCA1-2 mutation carriers. A prospective study

Author

Marchetti, Claudia, Arcieri, M., Vertechy, L., Ergasti, Raffaella, Russo, Giorgia, Zannoni, Gian Franco, Minucci, Angelo, Ercoli, Alfredo, Scambia, Giovanni, Fagotti, Anna, Marchetti C. (ORCID:0000-0001-7098-8956), Ergasti R., Russo G., Zannoni G. F. (ORCID:0000-0003-1809-129X), Minucci A., Ercoli A., Scambia G. (ORCID:0000-0003-2758-1063), Fagotti A. (ORCID:0000-0001-5579-335X), Marchetti, Claudia, Arcieri, M., Vertechy, L., Ergasti, Raffaella, Russo, Giorgia, Zannoni, Gian Franco, Minucci, Angelo, Ercoli, Alfredo, Scambia, Giovanni, Fagotti, Anna, Marchetti C. (ORCID:0000-0001-7098-8956), Ergasti R., Russo G., Zannoni G. F. (ORCID:0000-0003-1809-129X), Minucci A., Ercoli A., Scambia G. (ORCID:0000-0003-2758-1063), and Fagotti A. (ORCID:0000-0001-5579-335X)

Abstract

Introduction: International guidelines recommend risk-reducing salpingo-oophorectomy (RRSO) in BRCA1-2 mutations carriers to decrease ovarian cancer occurrence. In this prospective study, we describe the incidence of occult malignancies and the surgical outcomes in asymptomatic BRCA mutation carriers submitted to RRSO. Methods: Data on BRCA1-2 carriers undergoing RRSO with peritoneal washing and peritoneal/omental biopsies (PeS), between January 2019 until March 2021, were prospectively collected. Results: A total of 132 patients were enrolled: 74 BRCA1 and 58 BRCA2 mutation carriers. 31.1% women underwent RRSO and PeS (16.2% of BRCA1 and 50% of BRCA2 carriers), while 68.9% patients were submitted also to concomitant hysterectomy. Almost all the procedures (99.2%) were performed by minimally invasive surgery. Postoperative complications occurred in twelve patients (9.1%): 10 in the concomitant hysterectomy group and two complications in the RRSO group. At the final pathological examination, 6 (4.5%) occult carcinomas were diagnosed: 3 fallopian tube carcinomas, one ovarian carcinoma and two serous tubal intraepithelial carcinomas (STICs), with negative PeS. Median age of occult carcinomas patients at RRSO was 54 (range: 48–79) years. The mean follow up was 20 (range: 7–34) months. During the follow up, no primary peritoneal cancer has been diagnosed. Conclusions: Occult pathologic findings in RRSO occurred in 4.5% (3% invasive carcinomas, STIC 1.5%) among our patients. The routine use of peritoneal biopsies does not improve the detection of occult malignancies. Our data confirm the importance of timely performing RRSO in BRCA1-2 carriers.

Published
2022

49. Outcomes of gynecologic cancer surgery during the COVID-19 pandemic: an international, multicenter, prospective CovidSurg-Gynecologic Oncology Cancer study

Author

Fotopoulou, C., Khan, T., Bracinik, J., Glasbey, J., Abu-Rustum, N., Chiva, L., Fagotti, Anna, Fujiwara, K., Ghebre, R., Gutelkin, M., Konney, T. O., Ng, J., Pareja, R., Kottayasamy Seenivasagam, R., Sehouli, J., Surappa, S. T. S., Bhangu, A., Leung, E., Sundar, S., Fagotti A. (ORCID:0000-0001-5579-335X), Fotopoulou, C., Khan, T., Bracinik, J., Glasbey, J., Abu-Rustum, N., Chiva, L., Fagotti, Anna, Fujiwara, K., Ghebre, R., Gutelkin, M., Konney, T. O., Ng, J., Pareja, R., Kottayasamy Seenivasagam, R., Sehouli, J., Surappa, S. T. S., Bhangu, A., Leung, E., Sundar, S., and Fagotti A. (ORCID:0000-0001-5579-335X)

Abstract

Background: The CovidSurg-Cancer Consortium aimed to explore the impact of COVID-19 in surgical patients and services for solid cancers at the start of the pandemic. The CovidSurg-Gynecologic Oncology Cancer subgroup was particularly concerned about the magnitude of adverse outcomes caused by the disrupted surgical gynecologic cancer care during the COVID-19 pandemic, which are currently unclear. Objective: This study aimed to evaluate the changes in care and short-term outcomes of surgical patients with gynecologic cancers during the COVID-19 pandemic. We hypothesized that the COVID-19 pandemic had led to a delay in surgical cancer care, especially in patients who required more extensive surgery, and such delay had an impact on cancer outcomes. Study Design: This was a multicenter, international, prospective cohort study. Consecutive patients with gynecologic cancers who were initially planned for nonpalliative surgery, were recruited from the date of first COVID-19-related admission in each participating center for 3 months. The follow-up period was 3 months from the time of the multidisciplinary tumor board decision to operate. The primary outcome of this analysis is the incidence of pandemic-related changes in care. The secondary outcomes included 30-day perioperative mortality and morbidity and a composite outcome of unresectable disease or disease progression, emergency surgery, and death. Results: We included 3973 patients (3784 operated and 189 nonoperated) from 227 centers in 52 countries and 7 world regions who were initially planned to have cancer surgery. In 20.7% (823/3973) of the patients, the standard of care was adjusted. A significant delay (>8 weeks) was observed in 11.2% (424/3784) of patients, particularly in those with ovarian cancer (213/1355; 15.7%; P<.0001). This delay was associated with a composite of adverse outcomes, including disease progression and death (95/424; 22.4% vs 601/3360; 17.9%; P=.024) compared with those who had operat

Published
2022

50. Quality of training in cervical cancer radical surgery: a survey from the European Network of Young Gynaecologic Oncologists (ENYGO)

Author

Bizzarri, Nicolo', Pletnev, A., Razumova, Z., Zalewski, K., Theofanakis, C., Selcuk, I., Nikolova, T., Lanner, M., Gomez-Hidalgo, N. R., Kacperczyk-Bartnik, J., Querleu, D., Cibula, D., Verheijen, R. H. M., Fagotti, Anna, Bizzarri N., Fagotti A. (ORCID:0000-0001-5579-335X), Bizzarri, Nicolo', Pletnev, A., Razumova, Z., Zalewski, K., Theofanakis, C., Selcuk, I., Nikolova, T., Lanner, M., Gomez-Hidalgo, N. R., Kacperczyk-Bartnik, J., Querleu, D., Cibula, D., Verheijen, R. H. M., Fagotti, Anna, Bizzarri N., and Fagotti A. (ORCID:0000-0001-5579-335X)

Abstract

BACKGROUND: The European Society of Gynaecological Oncology (ESGO) and partners are committed to improving the training for gynecologic oncology fellows. The aim of this survey was to assess the type and level of training in cervical cancer surgery and to investigate whether the Laparoscopic Approach to Cervical Cancer (LACC) trial results impacted training in radical surgery for gynecologic oncology fellows. METHODS: In June 2020, a 47-question electronic survey was shared with European Network of Young Gynaecologic Oncologists (ENYGO) members. Specialist fellows in obstetrics and gynecology, and gynecologic oncology, from high- and low-volume centers, who started training between January 1, 2017 and January 1, 2020 or started before January 1, 2017 but finished their training at least 6 months after the LACC trial publication (October 2018), were included. RESULTS: 81 of 125 (64.8%) respondents were included. The median time from the start of the fellowship to completion of the survey was 28 months (range 6-48). 56 (69.1%) respondents were still fellows-in-training. 6 of 56 (10.7%) and 14 of 25 (56.0%) respondents who were still in training and completed the fellowship, respectively, performed ≥10 radical hysterectomies during their training. Fellows trained in an ESGO accredited center had a higher chance to perform sentinel lymph node biopsy (60.4% vs 30.3%; p=0.027). There was no difference in the mean number of radical hysterectomies performed by fellows during fellowship before and after the LACC trial publication (8±12.0 vs 7±8.4, respectively; p=0.46). A significant reduction in number of minimally invasive radical hysterectomies was noted when comparing the period before and after the LACC trial (38.5% vs 13.8%, respectively; p<0.001). CONCLUSION: Exposure to radical surgery for cervical cancer among gynecologic oncology fellows is low. Centralization of cervical cancer cases to high-volume centers may provide an increase in fellows' exposure to radical

Published
2022

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