42 results on '"Betella I"'
Search Results
2. INCIDENCE AND SURVIVAL IMPACT OF ABDOMINAL WALL METASTASES IN ADVANCED LOW-GRADE SEROUS EPITHELIAL OVARIAN CANCER: A SINGLE CENTER EXPERIENCE: EP850
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Garbi, A, Multinu, F, Achilarre, M, Betella, I, Aloisi, A, Bogliolo, S, Maruccio, M, Personeni, C, Palumbo, M, Aletti, G, Maggioni, A, Colombo, N, and Zanagnolo, V
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- 2019
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3. Advanced low grade serous ovarian cancer: A retrospective analysis of surgical and chemotherapeutic management in two high volume oncological centers
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Di Lorenzo P., Conteduca V., Scarpi E., Adorni M., Multinu F., Garbi A., Betella I., Grassi T., Bianchi T., Di Martino G., Amadori A., Maniglio P., Strada I., Carinelli S., Jaconi M., Aletti G., Zanagnolo V., Maggioni A., Savelli L., De Giorgi U., Landoni F., Colombo N., Fruscio R., Di Lorenzo, P, Conteduca, V, Scarpi, E, Adorni, M, Multinu, F, Garbi, A, Betella, I, Grassi, T, Bianchi, T, Di Martino, G, Amadori, A, Maniglio, P, Strada, I, Carinelli, S, Jaconi, M, Aletti, G, Zanagnolo, V, Maggioni, A, Savelli, L, De Giorgi, U, Landoni, F, Colombo, N, and Fruscio, R
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low-grade serous ovarian cancer ,Cancer Research ,Oncology ,primary cytoreduction ,adjuvant treatment ,residual disease ,secondary cytoreductive surgery ,neoadjuvant chemotherapy - Abstract
Simple summaryLow-grade serous ovarian cancer (LGSOC) represents an uncommon histotype of serous ovarian cancer (accounting for approximately 5% of all ovarian cancer) with a distinct behavior compared to its high-grade serous counterpart, characterized by a better prognosis and low response rate to chemotherapeutic agents. Similar to high-grade serous ovarian cancer, cytoreductive surgery is considered crucial for patient survival. This retrospective study aimed to analyze the outcomes of women affected by advanced stages (III–IV FIGO) of LGSOC from two high-volume oncological centers for ovarian neoplasm. In particular, we sought to evaluate the impact on survival outcomes of optimal cytoreductive surgery [i.e., residual disease (RD) BackgroundLow-grade serous ovarian cancer (LGSOC) is a rare entity with different behavior compared to high-grade serous (HGSOC). Because of its general low chemosensitivity, complete cytoreductive surgery with no residual disease is crucial in advanced stage LGSOC. We evaluated the impact of optimal cytoreduction on survival outcome both at first diagnosis and at recurrence.MethodsWe retrospectively studied consecutive patients diagnosed with advanced LGSOCs who underwent cytoreductive surgery in two oncological centers from January 1994 to December 2018. Survival curves were estimated by the Kaplan–Meier method, and 95% confidence intervals (95% CI) were estimated using the Greenwood formula.ResultsA total of 92 patients were included (median age was 47 years, IQR 35–64). The median overall survival (OS) was 142.3 months in patients with no residual disease (RD), 86.4 months for RD 1–10 mm and 35.2 months for RD >10 mm (p = 0.002). Progression-free survival (PFS) was inversely related to RD after primary cytoreductive surgery (RD = 0 vs RD = 1–10 mm vs RD >10 mm, p = 0.002). On multivariate analysis, RD 1–10 mm (HR = 2.30, 95% CI 1.30–4.06, p = 0.004), RD >10 mm (HR = 3.89, 95% CI 1.92–7.88, p = 0.0004), FIGO stage IV (p = 0.001), and neoadjuvant chemotherapy (NACT) (p = 0.010) were independent predictors of PFS. RD >10 mm (HR = 3.13, 95% CI 1.52–6.46, p = 0.004), FIGO stage IV (p ConclusionsOptimal cytoreductive surgery improves survival outcomes in advanced stage LGSOCs. When complete debulking is impossible, a RD 10 mm in this setting of patients.
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- 2022
4. 88 Cervical re-injection to improve sentinel lymph node detection in endometrial cancer
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Achilarre, MT, Multinu, F, Garbi, A, Betella, I, Bogliolo, S, Maruccio, M, Aloisi, A, Minicucci, V, Personeni, C, Palumbo, M, Aletti, G, Colombo, N, Maggioni, A, and Zanagnolo, V
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- 2019
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5. EPV084/#549 Role of dose-dense neoadjuvant chemotherapy with paclitaxel and carboplatin in locally advanced cervical cancer
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Multinu, F, primary, Lapresa, M, additional, Minicucci, V, additional, Gandini, S, additional, Parma, G, additional, Peccatori, F, additional, Tomao, F, additional, Betella, I, additional, Garbi, A, additional, Schivardi, G, additional, Aletti, G, additional, Zanagnolo, V, additional, Maggioni, A, additional, and Colombo, N, additional
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- 2021
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6. 1223P Homologous recombination deficiency (HRD) testing on ovarian cancer ascites: A feasibility study
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Ranghiero, A., Guerini Rocco, E., Rappa, A., Varcica, D., Taormina, S.V., Adorisio, R., Marinucci, L., Betella, I., Aletti, G., Colombo, N., Fusco, N., C. casadio, Di Tonno, C., and Barberis, M.
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- 2023
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7. ESMO Guidelines: Cancer patient management during the COVID-19 pandemic
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Aapro, M., Addeo, A., Acierto, P., Balermpas, P., Berg, T., Berghoff, A., Betella, I., Blay, J. -Y., Bosetti, D. G., Bossi, P., Bouchaab, H., Brandt, J., Buske, C., Caraceni, A., Cardoso, F., Carles, J., Catanese, S., Cherny, N., Colombo, I., Colombo, N., Cortes, J., Criscitiello, C., Curigliano, G., de Azambuja, E., Delagoge, S., Del Grande, M., De Santis, M., Douillard, J. -Y., Dummer, R., Dziadziuszko, R., Escudier, B., Fizazi, K., Fleitas, T., Franceschi, E., Hoeller, C., Gillessen, S., Gonzalez Martin, A., Gralla, R., Grigorescu, A., Gronchi, A., Hassan, A., Hui, D., Jerkeman, M., Jones, R., Jordan, K., Keilholz, U., Kreye, G., Ledermann, J., Loibl, S., Lordick, F., Lorigan, P., Loriot, Y., Machiels, J. -P., Broto, J. M., Mei, U., Michielin, O., Mori, M., Multinu, F., Paluch-Shimon, S., Parker, C., Passaro, A., Pentheroudakis, G., Peters, S., Piazza, C., Porta, C., Powles, T., Preusser, M., Reck, M., Ripamonti, C., Rubach, M., Rukhadze, T., Schmidinger, M., Sensus-Konefka, E., Sessa, C., Shaulov, A., Stacchiotti, S., Stevens, A. -M., Stintzing, S., Szturz, P., Trapani, D., van Akkooi, A., Vecchione, L., van Bommel, F., Vogl, U., Von Garnier, C., Weller, M., Wood, J., Zaccarelli, E., and Zimmermann, C.
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- 2020
8. Pelvic exenteration in gynecologic oncology: Analysis of short- and long-term surgical outcomes
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Maruccio, M., primary, Aloisi, A., additional, Minicucci, V., additional, Personeni, C., additional, Palumbo, M., additional, Betella, I., additional, Multinu, F., additional, Bogliolo, S., additional, Garbi, A.L., additional, Achilarre, M.T., additional, Aletti, G.D., additional, Zanagnolo, V., additional, Colombo, N., additional, and Maggioni, A., additional
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- 2020
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9. Role of pelvic exenteration in the treatment of persistent or recurrent gynecological cancers
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Aloisi, A., primary, Maruccio, M., additional, Personeni, C., additional, Palumbo, M., additional, Minicucci, V., additional, Betella, I., additional, Multinu, F., additional, Bogliolo, S., additional, Garbi, A.L., additional, Achilarre, M.T., additional, Aletti, G.D., additional, Zanagnolo, V., additional, Colombo, N., additional, and Maggioni, A., additional
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- 2020
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10. EP850 Incidence and survival impact of abdominal wall metastases in advanced low-grade serous epithelial ovarian cancer: a single center experience
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Garbi, A, primary, Multinu, F, additional, Achilarre, M, additional, Betella, I, additional, Aloisi, A, additional, Bogliolo, S, additional, Maruccio, M, additional, Personeni, C, additional, Palumbo, M, additional, Aletti, G, additional, Maggioni, A, additional, Colombo, N, additional, and Zanagnolo, V, additional
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- 2019
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11. 88 Cervical re-injection to improve sentinel lymph node detection in endometrial cancer
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Achilarre, MT, primary, Multinu, F, additional, Garbi, A, additional, Betella, I, additional, Bogliolo, S, additional, Maruccio, M, additional, Aloisi, A, additional, Minicucci, V, additional, Personeni, C, additional, Palumbo, M, additional, Aletti, G, additional, Colombo, N, additional, Maggioni, A, additional, and Zanagnolo, V, additional
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- 2019
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12. Tumor associated macrophages (TAMs) mediate the oncogenic effect of fibroblast growth factor -18 (FGF18) in ovarian cancer
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Roane, B.M., primary, Mok, S.C., additional, Wei, W., additional, Betella, I., additional, Goldsberry, W., additional, Arend, R.C., additional, and Birrer, M.J., additional
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- 2019
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13. DKK1, a Wnt signaling modulator, promotes ovarian cancer progression and immune evasion in mice
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Betella, I., primary, Szul, T., additional, Turbitt, W.J., additional, Wu, B., additional, Martinez, A. Alba, additional, Arend, R.C., additional, Katre, A.A., additional, Norian, L.A., additional, and Birrer, M.J., additional
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- 2019
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14. Dkn-01: A promising strategy for targeting the Wnt pathway in ovarian cancer
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Betella, I., primary, Turbitt, W.J., additional, Szul, T., additional, Wu, B., additional, Martinez, A. Alba, additional, Arend, R.C., additional, Katre, A.A., additional, Norian, L.A., additional, and Birrer, M.J., additional
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- 2019
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15. The role of transforming growth factor-β (TGF-β) in epithelial ovarian cancer progression via immunosuppression
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Roane, B.M., primary, Meza-Perez, S., additional, Betella, I., additional, Goldsberry, W., additional, and Arend, R.C., additional
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- 2019
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16. Inhibition of the Wnt/β-catenin pathway enhances anti-tumor immunity in ovarian cancer
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Doo, D.W., primary, Meza-Perez, S., additional, Londono, A., additional, Boone, J.D., additional, Moore, D.J., additional, Hudson, C., additional, Betella, I., additional, Luke, J.J., additional, Yang, E.S., additional, Birrer, M.J., additional, Starenki, D., additional, Buchsbaum, D.J., additional, Norian, L.A., additional, Randall, T., additional, and Arend, R.C., additional
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- 2019
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17. In-house testing for homologous recombination repair deficiency (HRD) testing in ovarian carcinoma: a feasibility study comparing AmoyDx HRD Focus panel with Myriad myChoiceCDx assay
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Caterina, Fumagalli, Ilaria, Betella, Alberto, Ranghiero, Elena, Guerini-Rocco, Giulio, Bonaldo, Alessandra, Rappa, Davide, Vacirca, Nicoletta, Colombo, Massimo, Barberis, Fumagalli, C, Betella, I, Ranghiero, A, Guerini-Rocco, E, Bonaldo, G, Rappa, A, Vacirca, D, Colombo, N, and Barberis, M
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BRCA2 Protein ,Ovarian Neoplasms ,Adenosine Diphosphate Ribose ,BRCA1 Protein ,Recombinational DNA Repair ,Reproducibility of Results ,Carcinoma, Ovarian Epithelial ,Genomic Instability ,Pathology and Forensic Medicine ,ovarian cancer ,homologous recombination deficiency ,Formaldehyde ,HRD ,Feasibility Studies ,Humans ,Female ,genomic scar - Abstract
Background. Homologous recombination repair (HRR) is the main mechanism of repair of DNA double-strand breaks. Its deficiency (HRD) is a common feature of epithelial ovarian cancers (EOCs). BRCA1/2 mutations and/or other aberrations in genes of HRR are well known causes of HRD and genomic instability. Poly ADP-ribose polymerase inhibitors (PARPi) have revolutionized the management of BRCA mutant EOCs and demonstrated activity in HRD tumor cells. Determining HRD status can provide informations on the magnitude of benefit for PARPi therapy. Myriad MyChoice CDx is a next generation sequencing- based in vitro diagnostic test that assesses the Genomic Instability Score (GIS) which is an algorithmic measurement of loss of heterozygosity, telomeric allelic imbalance, and large-scale state transitions using DNA isolated from formalin-fixed paraffin embedded tumor tissue specimens. However Myriad MyChoice CDx, is a centrally performed and costly assay, with no reimbursement scheduled, at least in Italy. Methods. In this report, we described our experience in performing the HRD Focus AmoyDx (Amoy Diagnostics Ltd, Xiamen, Fujian, China) on the same samples of EOCs evaluated with Myriad MyChoiceCDx assay. Results. The overall percent agreement between AmoyDx and Myriad was 87.8% (65 of 74 tumors tested). All the 36 AmoyDx negative cases were confirmed to be negative by Myriad (negative predictive value, 100%). Conclusions. The concordance of the results with the gold standard Myriad MyChoice CDx assay suggest the feasibility and reliability of HRD testing in diagnostic laboratories with high-throughput NGS platforms and qualified personnel.
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- 2022
18. Cervical re-injection of indocyanine green to improve sentinel lymph node detection in endometrial cancer
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Maria Teresa Achilarre, Matteo Maruccio, C. Quatrale, Angelo Maggioni, Ilaria Betella, Annalisa Garbi, Giovanni Aletti, Stefano Bogliolo, Andrea Mariani, Vanna Zanagnolo, Nicoletta Colombo, M. Maramai, Francesco Multinu, Alessia Aloisi, Maramai, M, Achilarre, M, Aloisi, A, Betella, I, Bogliolo, S, Garbi, A, Maruccio, M, Quatrale, C, Aletti, G, Mariani, A, Colombo, N, Maggioni, A, Multinu, F, and Zanagnolo, V
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0301 basic medicine ,medicine.medical_specialty ,Sentinel lymph node algorithm ,medicine.medical_treatment ,Sentinel lymph node ,Salpingo-oophorectomy ,Surgical staging ,Hysterectomy ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Robotic Surgical Procedures ,Endometrial cancer ,Biopsy ,medicine ,Humans ,In patient ,Stage (cooking) ,Neoplasm Staging ,Retrospective Studies ,Re-injection ,Chemotherapy ,medicine.diagnostic_test ,business.industry ,Obstetrics and Gynecology ,Middle Aged ,medicine.disease ,Indocyanine green ,Endometrial Neoplasms ,030104 developmental biology ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Lymph Node Excision ,Female ,Lymph Nodes ,Radiology ,Sentinel Lymph Node ,business - Abstract
Objectives To evaluate the role of cervical re-injection of indocyanine green (ICG) to increase the detection rate of sentinel lymph node (SLN) in patients with endometrial cancer (EC) who underwent robotic-assisted surgical staging. Methods We retrospectively identified consecutive EC patients undergoing robotic-assisted staging with SLN biopsy at our Institution between June 2016 and April 2020. Patients were excluded if they had open abdominal surgical approach, neoadjuvant chemotherapy, and advanced stage [International Federation of Gynecology and Obstetrics (FIGO) stage III-IV] at diagnosis. According to our SLN protocol, in case of either unilateral or no SLN detection, we performed an ipsilateral or bilateral cervical re-injection of ICG. Results In total, 251 patients meeting inclusion criteria were included in the analysis. At first injection, bilateral detection was achieved in 184 (73.3%), unilateral detection in 57 (22.7%), and no detection in 10 (4.0%) patients. Cervical re-injection was performed in 51 of 67 patients with failed bilateral mapping. After cervical re-injection, bilateral detection rate increased to 94.5% (222/235), while unilateral and no detection were 5.1% (12/235) and 0.4% (1/235), respectively. Conclusions Our results suggest that cervical re-injection of ICG, in case of failed bilateral mapping of SLN, brings about a significant improvement in SLN detection rates, therefore reducing the number of side-specific required lymphadenectomies.
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- 2021
19. Tumor BRCA Testing in Epithelial Ovarian Cancers: Past and Future-Five-Years' Single-Institution Experience of 762 Consecutive Patients
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Caterina Fumagalli, Ilaria Betella, Alessandra Rappa, Maria di Giminiani, Michela Gaiano, Luigi Antonio De Vitis, Benedetta Zambetti, Davide Vacirca, Francesco Multinu, Konstantinos Venetis, Nicoletta Colombo, Massimo Barberis, Elena Guerini Rocco, Fumagalli, C, Betella, I, Rappa, A, Di Giminiani, M, Gaiano, M, De Vitis, L, Zambetti, B, Vacirca, D, Multinu, F, Venetis, K, Colombo, N, Barberis, M, and Rocco, E
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Cancer Research ,endocrine system diseases ,Oncology ,Epithelial ovarian carcinoma ,NGS ,BRCA ,epithelial ovarian carcinoma ,female genital diseases and pregnancy complications - Abstract
The establishment of PARP inhibitors in the treatment of epithelial ovarian carcinoma (EOC) has prompt BRCA assessment at the time of diagnosis. We described our five years of experience of tumor BRCA testing, as part of a multidisciplinary workflow for the management of EOC patients. We used a BRCA next-generation sequencing (NGS) test for profiling formalin-fixed, paraffin-embedded (FFPE) EOCs of 762 consecutive patients, with a success rate of 99.7% and a median turnaround time of 12 days. We found 178 (23.4%) cases with pathogenic/likely pathogenic (P/LP) mutations, 74 (9.7%) cases with variants of uncertain significance and 508 (66.8%) wild type tumors. Among 174 patients without P/LP mutations and investigated with multiple-ligation probe-amplification analysis on peripheral blood, two (1.1%) were positive for large rearrangements. Patients with P/LP alterations and/or with positive family history were referred to genetic counselling. Comparing tumor and blood NGS test results of 256 patients, we obtained a tumor test negative predictive value of 100% and we defined 76% of P/LP alterations as germline and 24% as somatic variants. The proposed workflow may successfully identify EOC patients with BRCA1/2 alteration, guiding both therapeutic and risk assessment clinical decisions.
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- 2022
20. A novel algorithm to implement the molecular classification according to the new ESGO/ESTRO/ESP 2020 guidelines for endometrial cancer
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Ilaria Betella, Caterina Fumagalli, Paola Rafaniello Raviele, Gabriella Schivardi, Luigi Antonio De Vitis, Maria Teresa Achilarre, Alessia Aloisi, Annalisa Garbi, Matteo Maruccio, Vanna Zanagnolo, Giovanni Aletti, Elena Guerini-Rocco, Andrea Mariani, Angelo Maggioni, Massimo Barberis, Nicoletta Colombo, Francesco Multinu, Betella, I, Fumagalli, C, Rafaniello Raviele, P, Schivardi, G, De Vitis, L, Achilarre, M, Aloisi, A, Garbi, A, Maruccio, M, Zanagnolo, V, Aletti, G, Guerini-Rocco, E, Mariani, A, Maggioni, A, Barberis, M, Colombo, N, and Multinu, F
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Oncology ,Pathology ,Obstetrics and Gynecology ,Endometrial Neoplasm - Abstract
ObjectiveTo compare the risk class attribution withmolecular classification unknownto those withmolecular classification known,according to the European Society of Gynaecological Oncology/European Society for Radiotherapy and Oncology/European Society of Pathology (ESGO/ESTRO/ESP) 2020 guidelines on endometrial cancer, with a focus on risk group migration. Additionally, to evaluate the capability of a novel molecular analysis algorithm to reduce the number of required tests.MethodsWe conducted a retrospective study including all consecutive patients with endometrial cancer undergoing surgery and comprehensive molecular analyses between April 2019 and December 2021. Molecular analyses including immunohistochemistry for p53 and mismatch repair (MMR) proteins, and DNA sequencing for POLE exonuclease domain were performed to classify tumors as POLE-mutated (POLE), MMR-deficient (MMR-d), p53 abnormal (p53abn), or non-specific molecular profile (NSMP). The two risk classifications of the ESGO/ESTRO/ESP 2020 guidelines were compared to estimate the proportion of patients in which the molecular analysis was able to change the risk class attribution. We developed a novel algorithm where the molecular analyses are reserved only for patients in whom incorporation of the molecular classification could change the risk class attribution.ResultsA total of 278 patients were included. Molecular analyses were successful for all cases, identifying the four subgroups: 27 (9.7%) POLE, 77 (27.7%) MMR-d, 49 (17.6%) p53abn, and 125 (45.0%) NSMP. Comparison of risk class attribution between the two classification systems demonstrated discordance in the risk class assignment in 19 (6.8%, 95% CI 4.2% to 10.5%) cases. The application of our novel algorithm would have led to a reduction in the number of POLE sequencing tests by 67% (95% CI 61% to 73%) and a decrease of p53 immunohistochemistry by 27% (95% CI 22% to 33%), as compared with the application of molecular classification to all patients.ConclusionMolecular categorization of endometrial cancer allows the reallocation of a considerable proportion of patients in a different risk class. Furthermore, the application of our algorithm enables a reduction in the number of required tests without affecting the risk classification.
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- 2022
21. ESMO management and treatment adapted recommendations in the COVID-19 era: gynaecological malignancies
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Francesco Multinu, Cristiana Sessa, Nicoletta Colombo, Jonathan A. Ledermann, Eleonora Zaccarelli, Federica Tomao, Ilaria Betella, Antonio González-Martín, Ilaria Colombo, Maria Del Grande, Colombo, I, Zaccarelli, E, Del Grande, M, Tomao, F, Multinu, F, Betella, I, Ledermann, J, Gonzalez-Martin, A, Sessa, C, and Colombo, N
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medicine.medical_specialty ,Cancer Research ,Genital Neoplasms, Female ,cervical cancer ,Pneumonia, Viral ,Psychological intervention ,Uterine Cervical Neoplasms ,Context (language use) ,Comorbidity ,Review ,Disease ,Value-based priorities ,Medical Oncology ,lcsh:RC254-282 ,Betacoronavirus ,Endometrial cancer ,Ovarian cancer ,Health care ,Pandemic ,medicine ,Humans ,Intensive care medicine ,Pandemics ,Societies, Medical ,Ovarian Neoplasms ,Cervical cancer ,value-based priorities ,SARS-CoV-2 ,business.industry ,COVID-19 ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Endometrial Neoplasms ,Europe ,ovarian cancer ,Oncology ,Practice Guidelines as Topic ,endometrial cancer ,Female ,Coronavirus Infections ,business ,Delivery of Health Care - Abstract
The rapid spread of severe acute respiratory syndrome coronavirus 2 infection and its related disease (COVID-19) has required an immediate and coordinate healthcare response to face the worldwide emergency and define strategies to maintain the continuum of care for the non-COVID-19 diseases while protecting patients and healthcare providers. The dimension of the COVID-19 pandemic poses an unprecedented risk especially for the more vulnerable populations. To manage patients with cancer adequately, maintaining the highest quality of care, a definition of value-based priorities is necessary to define which interventions can be safely postponed without affecting patients’ outcome. The European Society for Medical Oncology (ESMO) has endorsed a tiered approach across three different levels of priority (high, medium, low) incorporating information on the value-based prioritisation and clinical cogency of the interventions that can be applied for different disease sites. Patients with gynaecological cancer are at particular risk of COVID-19 complications because of their age and prevalence of comorbidities. The definition of priority level should be based on tumour stage and histology, cancer-related symptoms or complications, aim (curative vs palliative) and magnitude of benefit of the oncological intervention, patients’ general condition and preferences. The decision-making process always needs to consider the disease-specific national and international guidelines and the local healthcare system and social resources, and a changing situation in relation to COVID-19 infection. These recommendations aim to provide guidance for the definition of deferrable and undeferrable interventions during the COVID-19 pandemic for ovarian, endometrial and cervical cancers within the context of the ESMO Clinical Practice Guidelines.
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- 2020
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22. Next-generation sequencing-based BRCA testing on cytological specimens from ovarian cancer ascites reveals high concordance with tumour tissue analysis
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Chiara Casadio, Massimo Barberis, Alessandra Rappa, Elena Guerini-Rocco, Caterina Fumagalli, Ilaria Betella, Nicoletta Colombo, Fumagalli, C, Rappa, A, Casadio, C, Betella, I, Colombo, N, Barberis, M, and Guerini-Rocco, E
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,endocrine system diseases ,Clinical Decision-Making ,DNA Mutational Analysis ,Gene mutation ,Poly(ADP-ribose) Polymerase Inhibitors ,Piperazines ,Pathology and Forensic Medicine ,Olaparib ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Breast cancer ,cytopathology ,Predictive Value of Tests ,Internal medicine ,Ascites ,molecular genetic ,medicine ,Biomarkers, Tumor ,Humans ,Genetic Predisposition to Disease ,ovarian tumour ,Cancer staging ,Tumor marker ,BRCA2 Protein ,Ovarian Neoplasms ,business.industry ,BRCA1 Protein ,Patient Selection ,High-Throughput Nucleotide Sequencing ,General Medicine ,medicine.disease ,030104 developmental biology ,Phenotype ,chemistry ,Cytopathology ,030220 oncology & carcinogenesis ,Mutation ,Feasibility Studies ,Phthalazines ,Female ,medicine.symptom ,Ovarian cancer ,business - Abstract
BackgroundWith the approval of the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib for newly diagnosed, breast cancer gene (BRCA)1/2 mutated, ovarian cancer women, the assessment of BRCA1/2 tumour status will be shortly required at the time of diagnosis.AimTo investigate the feasibility of next-generation sequencing (NGS)-based BRCA tumour test on cytological specimens from ovarian cancer ascites.MethodsWe evaluated the BRCA1/2 status on neoplastic ascites and corresponding tumour tissue of 11 patients with ovarian cancer, using the NGS ‘Oncomine BRCA Research Assay’.ResultsThe NGS-based BRCA test on cytological samples had a success rate of 100%, with 11 of 11 concordant BRCA1/2 results between ascites and tumour tissues analyses, including two wild type samples and nine cases harbouring somatic or germline variants.ConclusionBRCA test may be performed on ovarian cancer ascites, reproducing BRCA1/2 tumour status and representing a useful tool for clinical decision-making.
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- 2020
23. Tumor BRCA Test for Patients with Epithelial Ovarian Cancer: The Role of Molecular Pathology in the Era of PARP Inhibitor Therapy
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Giuseppe Viale, Mariarosaria Calvello, Loris Bernard, Nicoletta Colombo, Fedro A. Peccatori, Ilaria Betella, Bernardo Bonanni, Elena Guerini-Rocco, Massimo Barberis, Federica Tomao, Alessandra Rappa, Caterina Fumagalli, Fumagalli, C, Tomao, F, Betella, I, Rappa, A, Calvello, M, Bonanni, B, Bernard, L, Peccatori, F, Colombo, N, Viale, G, Barberis, M, and Guerini-Rocco, E
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,endocrine system diseases ,Somatic cell ,Concordance ,medicine.disease_cause ,lcsh:RC254-282 ,Article ,Germline ,Olaparib ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,BRCA1/2 ,Internal medicine ,Medicine ,skin and connective tissue diseases ,Mutation ,business.industry ,Molecular pathology ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,female genital diseases and pregnancy complications ,030104 developmental biology ,ovarian cancer ,chemistry ,next-generation sequencing ,030220 oncology & carcinogenesis ,PARP inhibitor ,brca1/2 ,business ,Ovarian cancer - Abstract
The PARP inhibitor olaparib has been approved in the maintenance setting of platinum-sensitive epithelial ovarian cancer patients with germline or somatic BRCA1/2 mutation. Therefore, the availability of a tumor BRCA test has become a clinical need. We report the results of the clinical implementation of a tumor BRCA test within the frame of an institutional workflow for the management of patients with nonmucinous and nonborderline epithelial ovarian cancer. In total, 223 patients with epithelial ovarian cancer were prospectively analyzed. BRCA1/2 status was evaluated on formalin-fixed, paraffin-embedded tumor specimens using next-generation sequencing technology. The tumor BRCA test had a success rate of 99.1% (221 of 223 successfully analyzed cases) and a median turnaround time of 17 calendar days. Among the 221 cases, BRCA1 or BRCA2 pathogenic/likely pathogenic mutations were found in 62 (28.1%) cases and variants of uncertain significance in 25 (11.3%) cases. The concordance rate between tumor BRCA test results and germline BRCA1/2 status was 87%, with five cases harboring pathogenic/likely pathogenic somatic-only mutations. The next-generation, sequencing-based tumor BRCA test showed a high success rate and a turnaround time compatible with clinical purposes. The tumor BRCA test could be implemented in a molecular diagnostic setting and it may guide the clinical management of patients with epithelial ovarian cancer.
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- 2019
24. Incidence of sentinel lymph node metastases in apparent early-stage endometrial cancer: a multicenter observational study.
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De Vitis LA, Fumagalli D, Schivardi G, Capasso I, Grcevich L, Multinu F, Cucinella G, Occhiali T, Betella I, Guillot BE, Pappalettera G, Shahi M, Fought AJ, McGree M, Reynolds E, Colombo N, Zanagnolo V, Aletti G, Langstraat C, Mariani A, and Glaser G
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- Humans, Female, Retrospective Studies, Middle Aged, Aged, Incidence, Adult, Aged, 80 and over, Neoplasm Micrometastasis pathology, Endometrial Neoplasms pathology, Endometrial Neoplasms surgery, Endometrial Neoplasms epidemiology, Lymphatic Metastasis, Sentinel Lymph Node Biopsy, Sentinel Lymph Node pathology, Sentinel Lymph Node surgery, Neoplasm Staging
- Abstract
Objective: Ultrastaging is accurate in detecting nodal metastases, but increases costs and may not be necessary in certain low-risk subgroups. In this study we examined the risk of nodal involvement detected by sentinel lymph node (SLN) biopsy in a large population of apparent early-stage endometrial cancer and stratified by histopathologic characteristics. Furthermore, we aimed to identify a subgroup in which ultrastaging may be omitted., Methods: We retrospectively included patients who underwent SLN (with bilateral mapping and no empty nodal packets on final pathology) ± systematic lymphadenectomy for apparent early-stage endometrial cancer at two referral cancer centers. Lymph node status was determined by SLN only, regardless of non-SLN findings. The incidence of macrometastasis, micrometastasis, and isolated tumor cells (ITC) was measured in the overall population and after stratification by histotype (endometrioid vs serous), myometrial invasion (none, <50%, ≥50%), and grade (G1, G2, G3)., Results: Bilateral SLN mapping was accomplished in 1570 patients: 1359 endometrioid and 211 non-endometrioid, of which 117 were serous. The incidence of macrometastasis, micrometastasis, and ITC was 3.8%, 3.4%, and 4.8%, respectively. In patients with endometrioid histology (n=1359) there were 2.9% macrometastases, 3.2% micrometastases, and 5.3% ITC. No macro/micrometastases and only one ITC were found in a subset of 274 patients with low-grade (G1-G2) endometrioid endometrial cancer without myometrial invasion (all <1%). The incidence of micro/macrometastasis was higher, 2.8%, in 708 patients with low-grade endometrioid endometrial cancer invading <50% of the myometrium. In patients with serous histology (n=117), the incidence of macrometastases, micrometastasis, and ITC was 11.1%, 6.0%, and 1.7%, respectively. For serous carcinoma without myometrial invasion (n=36), two patients had micrometastases for an incidence of 5.6%., Conclusions: Ultrastaging may be safely omitted in patients with low-grade endometrioid endometrial cancer without myometrial invasion. No other subgroups with a risk of nodal metastasis of less than 1% have been identified., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2024. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2024
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25. Clinicopathological characteristics of multiple-classifier endometrial cancers: a cohort study and systematic review.
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De Vitis LA, Schivardi G, Caruso G, Fumagalli C, Vacirca D, Achilarre MT, Aloisi A, Garbi A, Zanagnolo V, Aletti G, Guerini-Rocco E, Mariani A, Maggioni A, Barberis M, Bogani G, Colombo N, Multinu F, and Betella I
- Subjects
- Humans, Female, Cohort Studies, Mutation, Middle Aged, Aged, Poly-ADP-Ribose Binding Proteins genetics, DNA Polymerase II genetics, DNA Mismatch Repair, Endometrial Neoplasms pathology, Endometrial Neoplasms genetics, Tumor Suppressor Protein p53 genetics
- Abstract
Background: Endometrial cancers with more than one molecular feature- POLE mutations (POLEmut), mismatch repair protein deficiency (MMRd), p53 abnormality (p53abn)-are called 'multiple classifiers'., Objective: To describe our cohort of multiple classifiers and to report the results of a review on their incidence and the techniques used to identify them., Methods: Multiple classifiers identified at the European Institute of Oncology, Milan, between April 2019 and Decmber 2022, were included. Clinicopathological, molecular characteristics, and oncologic outcomes were summarized and compared between single and multiple classifiers sharing common features. Studies on molecular classification of endometrial cancer were searched in the PubMed Database to collect data on the incidence of multiple classifiers and the techniques used for classification., Results: Among 422 patients, 48 (11.4%) were multiple classifiers: 15 (3.6%) POLEmut-p53abn, 2 (0.5%) POLEmut-MMRd, 28 (6.6%) MMRd-p53abn, and 3 (0.7%) POLEmut-MMRd-p53abn. MMRd-p53abn and MMRd differed in histotype (non-endometrioid: 14.8% vs 2.0%, p=0.006), grade (high-grade: 55.6% vs 22.2%, p=0.001), and MMR proteins expression, whereas they differed from p53abn in histotype (non-endometrioid: 14.8% vs 50.0%, p=0.006). POLEmut-p53abn and POLEmut differed only in grade (high-grade: 66.7% vs 22.7%, p=0.008), while they differed from p53abn in age (56.1 vs 66.7 years, p=0.003), stage (advanced: 6.7% vs 53.4%, p=0.001), and histotype (non-endometrioid: 6.7% vs 50.0%, p=0.002). Two (7.1%) patients with MMRd-p53abn, 4 (4.0%) with MMRd, and 25 (34.3%) with p53abn had a recurrence. No recurrences were observed in POLEmut-p53abn and POLEmut. TP53 sequencing allowed the detection of additional 7 (18.9%) multiple classifiers with normal p53 immunostaining. The incidence of multiple classifiers ranged from 1.8% to 9.8% in 10 published studies including >100 patients. When only p53 immunohistochemistry was performed, the highest incidence was 3.9%., Conclusions: The characteristics of POLEmut-p53abn resembled those of POLEmut, whereas MMRd-p53abn appeared to be intermediate between MMRd and p53abn. The high proportion of multiple classifiers may be related to the methods used for molecular classification, which included both p53 immunohistochemistry and TP53 sequencing., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2024. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2024
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26. Dose-dense neoadjuvant chemotherapy before radical surgery in cervical cancer: a retrospective cohort study and systematic literature review.
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Caruso G, Bruni S, Lapresa M, De Vitis LA, Parma G, Minicucci V, Betella I, Schivardi G, Peccatori F, Lazzari R, Cliby W, Aletti GD, Zanagnolo V, Maggioni A, Colombo N, and Multinu F
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- Female, Humans, Retrospective Studies, Adult, Middle Aged, Carboplatin administration & dosage, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Neoplasm Staging, Chemotherapy, Adjuvant, Cohort Studies, Uterine Cervical Neoplasms pathology, Uterine Cervical Neoplasms therapy, Uterine Cervical Neoplasms drug therapy, Neoadjuvant Therapy, Hysterectomy, Paclitaxel administration & dosage
- Abstract
Objective: To evaluate the role of dose-dense neoadjuvant chemotherapy followed by radical hysterectomy in reducing adjuvant radiotherapy in International Federation of Gynecology and Obstetrics (FIGO) 2018 stage IB1-IB2/IIA1 cervical cancer with disrupted stromal ring and as an alternative to concurrent chemoradiotherapy in FIGO 2018 stages IB3/IIA2., Methods: This was a retrospective cohort study including patients with FIGO 2018 stage IB1-IIA2 cervical cancer undergoing dose-dense neoadjuvant chemotherapy at the European Institute of Oncology in Milan, Italy between July 2014 and December 2022. Weekly carboplatin (AUC2 or AUC2.7) plus paclitaxel (80 or 60 mg/m
2 , respectively) was administered for six to nine cycles. Radiological response was assessed by Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 criteria. The optimal pathological response was defined as residual tumor ≤3 mm. Kaplan-Meier curves were used to estimate survival rates. A systematic literature review on dose-dense neoadjuvant chemotherapy before surgery for cervical cancer was also performed., Results: A total of 63 patients with a median age of 42.8 years (IQR 35.3-47.9) were included: 39.7% stage IB-IB2/IIA1 and 60.3% stage IB3/IIA2. The radiological response was as follows: 81% objective response rate (17.5% complete and 63.5% partial), 17.5% stable disease, and 1.6% progressive disease. The operability rate was 92.1%. The optimal pathological response rate was 27.6%. Adjuvant radiotherapy was administered in 25.8% of cases. The median follow-up for patients who underwent radical hysterectomy was 49.7 months (IQR 16.8-67.7). The 5-year progression-free survival and overall survival were 79% (95% CI 0.63 to 0.88) and 92% (95% CI 0.80 to 0.97), respectively. Fifteen studies including 697 patients met the eligibility criteria for the systematic review. The objective response rate, operability rate, and adjuvant radiotherapy rate across studies ranged between 52.6% and 100%, 64% and 100%, and 4% and 70.6%, respectively., Conclusions: Dose-dense neoadjuvant chemotherapy before radical surgery could be a valid strategy to avoid radiotherapy in stage IB1-IIA2 cervical cancer, especially in young patients desiring to preserve overall quality of life. Prospective research is warranted to provide robust, high-quality evidence., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2024. No commercial re-use. See rights and permissions. Published by BMJ.)- Published
- 2024
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27. Letter to the editor-The new FIGO staging system for endometrial cancer: Is the paradigm shift clinically feasible?
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Betella I, De Vitis LA, Calidona C, Multinu F, and Colombo N
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- Female, Humans, Neoplasm Staging, Prognosis, Endometrial Neoplasms pathology
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- 2024
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28. Characteristics and outcomes of surgically staged multiple classifier endometrial cancer.
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Bogani G, Betella I, Multinu F, Casarin J, GhezzI F, Sorbi F, VizziellI G, Petrillo M, Cianci S, Berretta R, PaolinI B, FanfanI F, De Vitis L, Scambia G, Mariani A, Colombo N, and Raspagliesi F
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- Female, Humans, Retrospective Studies, Tumor Suppressor Protein p53 genetics, Endometrial Neoplasms genetics, Endometrial Neoplasms surgery
- Abstract
Objective: The growing adoption of molecular and genomic characterization is changing the current landscape of treatment of endometrial cancer patients. Using the surrogate molecular classification, endometrial cancer patients can be classified in four subgroups: POLE mutated (POLEmut), MMRd/MSI-H, p53 abnormal (p53abn), and no specific mutational profile (NSMP). However, some patients can harbor two or more molecular features (defined as multiple classifier). Since the rarity of this occurrence, evidence regarding multiple classifiers is still limited. Here, we described characteristics and outcomes of multiple classifiers., Methods: This is a multi-institutional retrospective study. Data of consecutive patients having 2 or more molecular features were collected. Survival was assessed using the Kaplan-Meier and Cox proportional hazard methods., Results: Charts of 72 multiple classifiers were reviewed. Median (range) follow-up was 9.8 (1.2, 37.5) months. Overall, 31 (43%) patients had POLEmut. Patients with POLEmut-MMRd/MSI-H, POLEmut-p53abn, and POLEmut-MMRd/MSI-H-p53abn were 6 (8.3%), 20 (27.8%), and 5 (6.9%), respectively. Among those 31 patients, no recurrence occurred within a median follow-up of 10.5 months (only seven (22.6%) patients had at least 2-year follow-up). The remaining 41 (56.9%) patients were diagnosed with tumors harboring both p53 and MMRd/MSI-H. Among them, four (9.8%) recurrences occurred at a median follow-up time of 8.9 months. Adjuvant therapy (other than vaginal brachytherapy) was administered in 5/31 (16%) and 25/41 (61%) patients with and without POLEmut, respectively (p < 0.001)., Conclusions: Multiple classifiers endometrial cancer with POLEmut are characterized by good prognosis even in case of presence of MMRd/MSI-H and/or p53abn. Additional studies with long-term follow-up are needed., Competing Interests: Declaration of competing interest None., (© 2023 Elsevier Ltd, BASO ∼ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)
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- 2024
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29. Microsatellite instability evaluation: which test to use for endometrial cancer?
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Rafaniello-Raviele P, Betella I, Rappa A, Vacirca D, Tolva G, Guerrieri-Gonzaga A, Bertario L, Barberis M, Bonanni B, and Marabelli M
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- Female, Humans, Microsatellite Instability, Reproducibility of Results, DNA Mismatch Repair genetics, Microsatellite Repeats, Endometrial Neoplasms diagnosis, Endometrial Neoplasms genetics, Colorectal Neoplasms genetics, Colorectal Neoplasms, Hereditary Nonpolyposis diagnosis, Colorectal Neoplasms, Hereditary Nonpolyposis genetics
- Abstract
Aims: Analysis of microsatellite instability (MSI) is strongly recommended in endometrial cancer (EC) and colorectal cancer to screen for Lynch syndrome, to predict prognosis and to determine optimal treatment and follow-up. In a large monoinstitutional series of ECs, we evaluated the reliability and accuracy of Idylla assay, a rapid, fully automated system to detect MSI, and we compared its performance with two routine reference methods., Methods: We evaluated MSI status in 174 formalin-fixed, paraffin-embedded EC tissue samples using immunohistochemistry (IHC) for mismatch repair (MMR) proteins and Idylla assay. Samples with discordant or equivocal results were analysed with a third technique, the Promega MSI kit., Results: Idylla MSI assay and IHC were highly concordant (overall agreement: 154/170=90.59%, 95% CI 85.26% to 94.12%). However, in four samples, MMR-IHC staining was equivocal; moreover, 16 cases showed discordant results, that is, MMR deficient using IHC and microsatellite stable using Idylla. These 20 samples were reanalysed using the MSI-Promega kit, which showed the same results of Idylla assay in 18/20 cases (overall agreement: 90%, 95% CI 69.90% to 97.21%)., Conclusions: Our results suggest that IHC is an efficient method to determine MMR status in ECs. However, the Idylla MSI assay is a rapid and reliable tool to define MSI status, and it could represent a valuable alternative to conventional MSI-PCR methods., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2023
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30. In-house testing for homologous recombination repair deficiency (HRD) testing in ovarian carcinoma: a feasibility study comparing AmoyDx HRD Focus panel with Myriad myChoiceCDx assay.
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Fumagalli C, Betella I, Ranghiero A, Guerini-Rocco E, Bonaldo G, Rappa A, Vacirca D, Colombo N, and Barberis M
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- Adenosine Diphosphate Ribose, BRCA1 Protein genetics, Carcinoma, Ovarian Epithelial diagnosis, Carcinoma, Ovarian Epithelial genetics, Feasibility Studies, Female, Formaldehyde, Genomic Instability, Humans, Recombinational DNA Repair genetics, Reproducibility of Results, BRCA2 Protein genetics, Ovarian Neoplasms diagnosis, Ovarian Neoplasms genetics, Ovarian Neoplasms pathology
- Abstract
Background: Homologous recombination repair (HRR) is the main mechanism of repair of DNA double-strand breaks. Its deficiency (HRD) is a common feature of epithelial ovarian cancers (EOCs). BRCA1/2 mutations and/or other aberrations in genes of HRR are well known causes of HRD and genomic instability. Poly ADP-ribose polymerase inhibitors (PARPi) have revolutionized the management of BRCA mutant EOCs and demonstrated activity in HRD tumor cells. Determining HRD status can provide informations on the magnitude of benefit for PARPi therapy. Myriad MyChoice CDx is a next generation sequencing- based in vitro diagnostic test that assesses the Genomic Instability Score (GIS) which is an algorithmic measurement of loss of heterozygosity, telomeric allelic imbalance, and large-scale state transitions using DNA isolated from formalin-fixed paraffin embedded tumor tissue specimens. However Myriad MyChoice CDx, is a centrally performed and costly assay, with no reimbursement scheduled, at least in Italy., Methods: In this report, we described our experience in performing the HRD Focus AmoyDx (Amoy Diagnostics Ltd, Xiamen, Fujian, China) on the same samples of EOCs evaluated with Myriad MyChoiceCDx assay., Results: The overall percent agreement between AmoyDx and Myriad was 87.8% (65 of 74 tumors tested). All the 36 AmoyDx negative cases were confirmed to be negative by Myriad (negative predictive value, 100%)., Conclusions: The concordance of the results with the gold standard Myriad MyChoice CDx assay suggest the feasibility and reliability of HRD testing in diagnostic laboratories with high-throughput NGS platforms and qualified personnel., (Copyright © 2022 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology.)
- Published
- 2022
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31. A novel algorithm to implement the molecular classification according to the new ESGO/ESTRO/ESP 2020 guidelines for endometrial cancer.
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Betella I, Fumagalli C, Rafaniello Raviele P, Schivardi G, De Vitis LA, Achilarre MT, Aloisi A, Garbi A, Maruccio M, Zanagnolo V, Aletti G, Guerini-Rocco E, Mariani A, Maggioni A, Barberis M, Colombo N, and Multinu F
- Abstract
Objective: To compare the risk class attribution with molecular classification unknown to those with molecular classification known, according to the European Society of Gynaecological Oncology/European Society for Radiotherapy and Oncology/European Society of Pathology (ESGO/ESTRO/ESP) 2020 guidelines on endometrial cancer, with a focus on risk group migration. Additionally, to evaluate the capability of a novel molecular analysis algorithm to reduce the number of required tests., Methods: We conducted a retrospective study including all consecutive patients with endometrial cancer undergoing surgery and comprehensive molecular analyses between April 2019 and December 2021. Molecular analyses including immunohistochemistry for p53 and mismatch repair (MMR) proteins, and DNA sequencing for POLE exonuclease domain were performed to classify tumors as POLE-mutated (POLE), MMR-deficient (MMR-d), p53 abnormal (p53abn), or non-specific molecular profile (NSMP). The two risk classifications of the ESGO/ESTRO/ESP 2020 guidelines were compared to estimate the proportion of patients in which the molecular analysis was able to change the risk class attribution. We developed a novel algorithm where the molecular analyses are reserved only for patients in whom incorporation of the molecular classification could change the risk class attribution., Results: A total of 278 patients were included. Molecular analyses were successful for all cases, identifying the four subgroups: 27 (9.7%) POLE, 77 (27.7%) MMR-d, 49 (17.6%) p53abn, and 125 (45.0%) NSMP. Comparison of risk class attribution between the two classification systems demonstrated discordance in the risk class assignment in 19 (6.8%, 95% CI 4.2% to 10.5%) cases. The application of our novel algorithm would have led to a reduction in the number of POLE sequencing tests by 67% (95% CI 61% to 73%) and a decrease of p53 immunohistochemistry by 27% (95% CI 22% to 33%), as compared with the application of molecular classification to all patients., Conclusion: Molecular categorization of endometrial cancer allows the reallocation of a considerable proportion of patients in a different risk class. Furthermore, the application of our algorithm enables a reduction in the number of required tests without affecting the risk classification., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2022. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2022
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32. Tumor BRCA Testing in Epithelial Ovarian Cancers: Past and Future-Five-Years' Single-Institution Experience of 762 Consecutive Patients.
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Fumagalli C, Betella I, Rappa A, di Giminiani M, Gaiano M, De Vitis LA, Zambetti B, Vacirca D, Multinu F, Venetis K, Colombo N, Barberis M, and Guerini Rocco E
- Abstract
The establishment of PARP inhibitors in the treatment of epithelial ovarian carcinoma (EOC) has prompt BRCA assessment at the time of diagnosis. We described our five years of experience of tumor BRCA testing, as part of a multidisciplinary workflow for the management of EOC patients. We used a BRCA next-generation sequencing (NGS) test for profiling formalin-fixed, paraffin-embedded (FFPE) EOCs of 762 consecutive patients, with a success rate of 99.7% and a median turnaround time of 12 days. We found 178 (23.4%) cases with pathogenic/likely pathogenic (P/LP) mutations, 74 (9.7%) cases with variants of uncertain significance and 508 (66.8%) wild type tumors. Among 174 patients without P/LP mutations and investigated with multiple-ligation probe-amplification analysis on peripheral blood, two (1.1%) were positive for large rearrangements. Patients with P/LP alterations and/or with positive family history were referred to genetic counselling. Comparing tumor and blood NGS test results of 256 patients, we obtained a tumor test negative predictive value of 100% and we defined 76% of P/LP alterations as germline and 24% as somatic variants. The proposed workflow may successfully identify EOC patients with BRCA1/2 alteration, guiding both therapeutic and risk assessment clinical decisions.
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- 2022
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33. Ovarian transposition in patients with cervical cancer prior to pelvic radiotherapy: a systematic review.
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Buonomo B, Multinu F, Casarin J, Betella I, Zanagnolo V, Aletti G, and Peccatori F
- Subjects
- Adult, Female, Humans, Middle Aged, Premenopause, Primary Ovarian Insufficiency prevention & control, Radiation Oncology methods, Fertility Preservation methods, Organ Sparing Treatments methods, Ovary surgery, Uterine Cervical Neoplasms radiotherapy
- Abstract
Ovarian transposition aims to minimize ovarian exposure and damage during pelvic radiotherapy. One or both ovaries are separated from the uterus and mobilized away from the area where the radiation will be administered. A review of the available literature was conducted to evaluate the efficacy and safety of ovarian transposition among pre-menopausal women diagnosed with cervical cancer and eligible for pelvic radiotherapy. Outcomes evaluated were ovarian function preservation and complication rates. We also searched for information on pregnancy/live birth rates after ovarian transposition. Our search yielded a total of 635 manuscripts, of which 33 were considered eligible. A total of 28 full texts were selected for the current review, including 1377 patients who underwent ovarian transposition. The median or mean follow-up ranged between 7 and 87 months. Ovarian function preservation after ovarian transposition and pelvic radiotherapy, with or without chemotherapy, was 61.7% (431/699 patients), ranging from 16.6% to 100%. A total of 12 studies reported on 117 complications, accounting for 8.5%. Ovarian metastases were described in 5 (0.4%). Data about fertility preservation after ovarian transposition are scarce and definitive conclusions cannot be drawn. Based on the available data, ovarian transposition could be performed on young patients with tumors smaller than 4 cm, and it should be avoided in those with bulky tumors. A risk/benefit assessment should be carefully evaluated by a multidisciplinary team, and the decision regarding ovarian transposition should be always guided by the values and informed preferences of the patient., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2021. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2021
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34. Oncologic Outcomes of Robotic Radical Hysterectomy (RRH) for Patients with Early-Stage Cervical Cancer: Experience at a Referral Cancer Center.
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Zanagnolo V, Baroni C, Achilarre MT, Aloisi A, Betella I, Bogliolo S, Garbi A, Maruccio M, Multinu F, Aletti G, and Maggioni A
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- Female, Humans, Hysterectomy, Laparoscopy, Neoplasm Recurrence, Local pathology, Neoplasm Recurrence, Local surgery, Neoplasm Staging, Referral and Consultation, Retrospective Studies, Survival Rate, Robotic Surgical Procedures, Uterine Cervical Neoplasms pathology, Uterine Cervical Neoplasms surgery
- Abstract
Purpose: To evaluate oncologic outcomes of early stage cervical cancer patients who underwent robotic radical hysterectomy (RRH) in a referral center, a retrospective analysis was performed., Methods: From January 2010 to December 2018, medical records of stage IA2-IIA1 cervical cancer patients, who underwent radical hysterectomy at our institute, were retrospectively reviewed. We focused our analysis on those who underwent RRH., Results: A total of 198 patients were included in the final analysis. Median follow up was 52 months. At last follow-up, 188 (94.9%) women were disease-free, 9 (4.5%) had died, and 1 (0.5%) was alive with recurrent disease. At 4.5 years, PFS was 93.1% (SE ± 2.1) and OS was 95.1% (SE ± 1.8). Stratified by tumor size, PFS for tumor < 2 cm versus tumor ≥ 2 cm was statistically different (96.8% ± 2.3 and 87.9% ± 4.1 respectively, p = 0.01), as well as OS (100% and 89.8% ± 40 respectively, p = 0.01).Stratified by evidence of tumor at time of robotic surgery, PFS was statistically different in women with no residual tumor after conisation versus those with residual disease (100% ± 2.5 and 90.8% ± 2.8 respectively, p = 0.04). A recurrence occurred in 11 patients (5.6%)., Conclusions: Based on our results, we could speculate that robotic approach, along with some technical precautions to avoid spillage, might be safe as primary treatment of early-stage cervical cancer, especially for tumor < 2 cm and in case of no evidence of disease at time of radical hysterectomy after previous conisation.
- Published
- 2021
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35. Corrigendum to 'Wnt signaling modulator DKK1 as an immunotherapeutic target in ovarian cancer' [Gynecologic Oncology 157 (2020) 765-774].
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Betella I, Turbitt WJ, Szul T, BinghaoWu, Martinez A, Katre A, Wall JA, Norian L, Birrer MJ, and Arend R
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- 2020
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36. ESMO management and treatment adapted recommendations in the COVID-19 era: gynaecological malignancies.
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Colombo I, Zaccarelli E, Del Grande M, Tomao F, Multinu F, Betella I, Ledermann JA, Gonzalez-Martin A, Sessa C, and Colombo N
- Subjects
- Betacoronavirus physiology, COVID-19, Comorbidity, Coronavirus Infections epidemiology, Coronavirus Infections virology, Delivery of Health Care statistics & numerical data, Delivery of Health Care trends, Endometrial Neoplasms diagnosis, Endometrial Neoplasms epidemiology, Endometrial Neoplasms therapy, Europe epidemiology, Female, Genital Neoplasms, Female diagnosis, Genital Neoplasms, Female epidemiology, Humans, Medical Oncology organization & administration, Ovarian Neoplasms diagnosis, Ovarian Neoplasms epidemiology, Ovarian Neoplasms therapy, Pandemics, Pneumonia, Viral epidemiology, Pneumonia, Viral virology, SARS-CoV-2, Societies, Medical, Uterine Cervical Neoplasms diagnosis, Uterine Cervical Neoplasms epidemiology, Uterine Cervical Neoplasms therapy, Coronavirus Infections therapy, Genital Neoplasms, Female therapy, Medical Oncology methods, Pneumonia, Viral therapy, Practice Guidelines as Topic
- Abstract
The rapid spread of severe acute respiratory syndrome coronavirus 2 infection and its related disease (COVID-19) has required an immediate and coordinate healthcare response to face the worldwide emergency and define strategies to maintain the continuum of care for the non-COVID-19 diseases while protecting patients and healthcare providers. The dimension of the COVID-19 pandemic poses an unprecedented risk especially for the more vulnerable populations. To manage patients with cancer adequately, maintaining the highest quality of care, a definition of value-based priorities is necessary to define which interventions can be safely postponed without affecting patients' outcome. The European Society for Medical Oncology (ESMO) has endorsed a tiered approach across three different levels of priority (high, medium, low) incorporating information on the value-based prioritisation and clinical cogency of the interventions that can be applied for different disease sites. Patients with gynaecological cancer are at particular risk of COVID-19 complications because of their age and prevalence of comorbidities. The definition of priority level should be based on tumour stage and histology, cancer-related symptoms or complications, aim (curative vs palliative) and magnitude of benefit of the oncological intervention, patients' general condition and preferences. The decision-making process always needs to consider the disease-specific national and international guidelines and the local healthcare system and social resources, and a changing situation in relation to COVID-19 infection. These recommendations aim to provide guidance for the definition of deferrable and undeferrable interventions during the COVID-19 pandemic for ovarian, endometrial and cervical cancers within the context of the ESMO Clinical Practice Guidelines., Competing Interests: Competing interests: These are the COI disclosure for each author. IC: travel grants from Tesaro. MDG: advisory board for AstraZeneca. JAL: Advisory Boards and lectures for Astra Zeneca; Clovis Oncology; GSK. Advisory Boards from MSD/Merck; Eisai; Artios; Amgen; Regeneron. Grants AstraZeneca; MSD/MerckAGM: lectures and/or advisory board for: Astra Zeneca, GSK, Clovis, Roche, Pharmamar, Immunogen, Genmab, Oncoinvent, MSD, Pfizer/Merck. NC: consulting, advisory services, speaking or writing engagements and public presentations for Roche, AstraZeneca, Pharmamar, Tesaro/GSK, Clovis, Advaxis, Pfizer, Takeda, Immunogen and Biocad. Financial support for clinical trials and research from Roche, Pharmamar, AstraZeneca., (© Author (s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.)
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- 2020
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37. Wnt signaling modulator DKK1 as an immunotherapeutic target in ovarian cancer.
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Betella I, Turbitt WJ, Szul T, Wu B, Martinez A, Katre A, Wall JA, Norian L, Birrer MJ, and Arend R
- Abstract
Objectives: Wnt pathway mutations are a hallmark of endometrioid and clear cell subtypes of epithelial ovarian carcinoma (EOC). However, no drugs targeting the Wnt pathway in EOC are FDA-approved. Dickkopf-related protein 1 (DKK1), a modulator of the Wnt pathway, has emerged as a promising therapeutic target. We aimed to examine the role of DKK1 and the effects of a monoclonal antibody against DKK1 (DKN-01) in vivo and in a murine model of ovarian cancer., Methods: We examined in vitro the role of DKK1 and the effects of DKK1 inhibition in EOC cell lines. We then studied in vivo the role of DKN-01 and DKK1 overexpression on tumor burden and anti-tumor immune cell populations using the ID8 syngeneic mouse model., Results: DKN-01 did not phenotypically alter ES2 cells in vitro; however, DKK1 inhibition promoted Wnt signaling. Tumor burden and immune populations were unchanged in ID8 challenged mice treated with mDKN01. Mice challenged with ID8 cells overexpressing DKK1 had tumor burden similar to controls (p = 0.175). However, the overexpression of DKK1 decreased CD45
+ leukocyte infiltration into the peritoneum (p = 0.008) and omentum (p = 0.032), reducing both natural killer (NK) and CD8 T cells, and reducing interferon-gamma (IFNγ) expression on activated CD8 T cells., Conclusions: Our results suggest that DKK1 inhibition does not affect tumor growth in the ID8 ovarian cancer model. DKK1 overexpression alters anti-tumor immune populations within the tumor microenvironment. Thus, our findings confirm DKK1 as a new therapeutic target in EOC and suggest that DKK1 inhibition may function best in a combinatorial, immune-modulatory therapy., Competing Interests: Declaration of competing interest The authors declare no conflict of interest with exceptions below. Dr. Birrer reported: Leap Therapeutics (grant); advisory board of Clovis Oncology, Merck, Genentech, Astra Zeneca, EMD, Pfizer, F. Hoffman-LA Roche, Bristol-Myers Squibb; consultant of Tesaro. Dr. Arend reported: advisory board of Clovis Oncology, Leap Therapeutics, Tesaro, Astra Zeneca., (Copyright © 2020 Elsevier Inc. All rights reserved.)- Published
- 2020
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38. Inhibition of the Wnt/β-catenin pathway enhances antitumor immunity in ovarian cancer.
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Doo DW, Meza-Perez S, Londoño AI, Goldsberry WN, Katre AA, Boone JD, Moore DJ, Hudson CT, Betella I, McCaw TR, Gangrade A, Bao R, Luke JJ, Yang ES, Birrer MJ, Starenki D, Cooper SJ, Buchsbaum DJ, Norian LA, Randall TD, and Arend RC
- Abstract
Background: The Wnt/β-catenin pathway is linked to tumorigenesis in a variety of tumors and promotes T cell exclusion and resistance to checkpoint inhibitors. We sought to determine whether a small molecule inhibitor of this pathway, WNT974, would impair tumor growth, affect gene expression patterns, and improve the immune response in human and murine ovarian cancer models., Methods: Human ovarian cancer cells were treated with WNT974 in vitro . RNAseq libraries were constructed and differences in gene expression patterns between responders and nonresponders were compared to The Cancer Genome Atlas (TCGA). Mice with subcutaneous or intraperitoneal ID8 ovarian cancer tumors were treated with WNT974, paclitaxel, combination, or control. Tumor growth and survival were measured. Flow cytometry and β-TCR repertoire analysis were used to determine the immune response., Results: Gene expression profiling revealed distinct signatures in responders and nonresponders, which strongly correlated with T cell infiltration patterns in the TCGA analysis of ovarian cancer. WNT974 inhibited tumor growth, prevented ascites formation, and prolonged survival in mouse models. WNT974 increased the ratio of CD8
+ T cells to T regulatory cells (Tregs) in tumors and enhanced the effector functions of infiltrating CD4+ and CD8+ T cells. Treatment also decreased the expression of inhibitory receptors on CD8+ T cells. Combining WNT974 with paclitaxel further reduced tumor growth, prolonged survival, and expanded the T cell repertoire., Conclusions: These findings suggest that inhibiting the Wnt/β-catenin pathway may have a potent immunomodulatory effect in the treatment of ovarian cancer, particularly when combined with paclitaxel., Competing Interests: Conflict of interest statement: JJL is a consultant to and receives clinical trial research support from Novartis. The remaining authors declare no potential conflicts of interest., (© The Author(s), 2020.)- Published
- 2020
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39. Next-generation sequencing-based BRCA testing on cytological specimens from ovarian cancer ascites reveals high concordance with tumour tissue analysis.
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Fumagalli C, Rappa A, Casadio C, Betella I, Colombo N, Barberis M, and Guerini-Rocco E
- Subjects
- Ascites pathology, Clinical Decision-Making, Feasibility Studies, Female, Genetic Predisposition to Disease, Humans, Mutation, Ovarian Neoplasms drug therapy, Ovarian Neoplasms pathology, Patient Selection, Phenotype, Phthalazines therapeutic use, Piperazines therapeutic use, Poly(ADP-ribose) Polymerase Inhibitors therapeutic use, Predictive Value of Tests, Ascites genetics, BRCA1 Protein genetics, BRCA2 Protein genetics, Biomarkers, Tumor genetics, DNA Mutational Analysis methods, High-Throughput Nucleotide Sequencing, Ovarian Neoplasms genetics
- Abstract
Background: With the approval of the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib for newly diagnosed, breast cancer gene (BRCA)1/2 mutated, ovarian cancer women, the assessment of BRCA1/2 tumour status will be shortly required at the time of diagnosis., Aim: To investigate the feasibility of next-generation sequencing (NGS)-based BRCA tumour test on cytological specimens from ovarian cancer ascites., Methods: We evaluated the BRCA1/2 status on neoplastic ascites and corresponding tumour tissue of 11 patients with ovarian cancer, using the NGS 'Oncomine BRCA Research Assay'., Results: The NGS-based BRCA test on cytological samples had a success rate of 100%, with 11 of 11 concordant BRCA1/2 results between ascites and tumour tissues analyses, including two wild type samples and nine cases harbouring somatic or germline variants., Conclusion: BRCA test may be performed on ovarian cancer ascites, reproducing BRCA1/2 tumour status and representing a useful tool for clinical decision-making., Competing Interests: Competing interests: CF received honoraria from Roche; EG-R received honoraria/advisory fee from Thermo Fisher Scientific, Roche, Novartis and AstraZeneca; and MB received honoraria from Thermo Fisher Scientific, Roche, BMS, MSD, and Biocartis., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2020
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40. Tumor BRCA Test for Patients with Epithelial Ovarian Cancer: The Role of Molecular Pathology in the Era of PARP Inhibitor Therapy.
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Fumagalli C, Tomao F, Betella I, Rappa A, Calvello M, Bonanni B, Bernard L, Peccatori F, Colombo N, Viale G, Barberis M, and Guerini-Rocco E
- Abstract
The PARP inhibitor olaparib has been approved in the maintenance setting of platinum-sensitive epithelial ovarian cancer patients with germline or somatic BRCA1/2 mutation. Therefore, the availability of a tumor BRCA test has become a clinical need. We report the results of the clinical implementation of a tumor BRCA test within the frame of an institutional workflow for the management of patients with nonmucinous and nonborderline epithelial ovarian cancer. In total, 223 patients with epithelial ovarian cancer were prospectively analyzed. BRCA1/2 status was evaluated on formalin-fixed, paraffin-embedded tumor specimens using next-generation sequencing technology. The tumor BRCA test had a success rate of 99.1% (221 of 223 successfully analyzed cases) and a median turnaround time of 17 calendar days. Among the 221 cases, BRCA1 or BRCA2 pathogenic/likely pathogenic mutations were found in 62 (28.1%) cases and variants of uncertain significance in 25 (11.3%) cases. The concordance rate between tumor BRCA test results and germline BRCA1/2 status was 87%, with five cases harboring pathogenic/likely pathogenic somatic-only mutations. The next-generation, sequencing-based tumor BRCA test showed a high success rate and a turnaround time compatible with clinical purposes. The tumor BRCA test could be implemented in a molecular diagnostic setting and it may guide the clinical management of patients with epithelial ovarian cancer., Competing Interests: E.G.-R. received honoraria/advisory fee from Thermofisher Scientific, Roche, Novartis, AstraZeneca, M.B. received honoraria from Thermofisher Scientific, Roche, BMS, MSD, Biocartis.
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- 2019
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41. Antibody-Drug Conjugate-Based Therapeutics: State of the Science.
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Birrer MJ, Moore KN, Betella I, and Bates RC
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- Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal chemistry, Antibodies, Monoclonal immunology, Clinical Trials as Topic, Humans, Immunoconjugates chemistry, Immunoconjugates immunology, Immunoconjugates pharmacokinetics, Neoplasms metabolism, Immunoconjugates administration & dosage, Neoplasms drug therapy
- Abstract
Antibody-drug conjugates (ADCs) are complex engineered therapeutics consisting of monoclonal antibodies, directed toward tumor-associated antigens, to which highly potent cytotoxic agents are attached using chemical linkers. This targeted drug delivery strategy couples the precision of the antibody targeting moiety with the cytocidal activity of the payload, which is generally too toxic on its own to be systemically administered. In this manner, ADCs confer a means to reduce off-target toxicities in patients by limiting the exposure of normal tissues to the payload, thus broadening the potential therapeutic window compared with traditional chemotherapy. The pace of ADC development is accelerating, with the number of investigational agents in human trials having more than tripled over the past 5 years, underscoring the enthusiasm for this transformative approach to cancer treatment. Here, we review the key structural elements of ADC design (antibody, linker, and payload), highlighting critical aspects and technological advances that have affected the clinical effectiveness of this class of biopharmaceuticals. The ADC field continues to evolve, including ongoing efforts aimed at improving target selection, developing payloads with varied mechanisms of action and increased potency, designing innovative bioconjugation strategies, as well as maximizing efficacy and tolerability in patients. An overview of the current clinical trial landscape is provided, with emphasis on the clinical experience of the four ADCs to have received regulatory approval to date, as well as additional promising candidates currently in late-stage clinical development in both solid tumor and hematological malignancies., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
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- 2019
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42. Is Targeting the Folate Receptor in Ovarian Cancer Coming of Age?
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Birrer MJ, Betella I, Martin LP, and Moore KN
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- Carcinoma, Ovarian Epithelial metabolism, Carcinoma, Ovarian Epithelial pathology, Clinical Trials as Topic, Female, Humans, Molecular Targeted Therapy, Prognosis, Antineoplastic Agents therapeutic use, Carcinoma, Ovarian Epithelial drug therapy, Folate Receptor 1 antagonists & inhibitors
- Abstract
Prognosis for women with epithelial ovarian cancer remains poor. One new molecular target in epithelial ovarian cancer is folate receptor alpha (FRα). This commentary discusses the characteristics that contribute to its attractiveness as a candidate for therapeutic intervention., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article.
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- 2019
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