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Objective we investigate the prognostic role of pre-treatment ratio between Type 1 (M1) and Type 2 (M2) tumor-associated macrophages (TAMs) in locally advanced cervical cancer (LACC) patients treated with chemoradiation (CT/RT). Methods 84 consecutive LACC patients treated with cisplatin-based CT/RT for a total dose of 50.0 Gy, followed by radical surgery were analysed. Double-staining immunohistochemistry of CD163/p-STAT, CD68/pSTAT1, CD163/c-MAF, and CD68/c-MAF was performed on tumor samples taken at the time of diagnosis. TAMs with CD163+pSTAT1+, or CD68+pSTAT1+ were defined M1; CD163+c-MAF+ or CD68+c-MAF+ defined the M2 phenotype. The number of M1 and M2 cells was counted at low magnification by evaluating for each case the same tumour area. The ratio between M1 and M2 (M1/M2) was finally calculated. Results At diagnosis, we observed a direct correlation between the number of circulating monocytes and of TAMs (p-value = 0.001). Patients with high M1/M2 experienced more frequently complete pathologic response (no residual tumor) to CT/RT, compared to cases with low M1/M2 (55.0% Vs 29.5%; p-value = 0.029). At multivariate analysis M1/M2 (OR = 2.067; p-value = 0.037) emerged as independent predictor of pathologic response to CT/RT. Women with high M1/M2 showed a longer 5-yrs Disease-free (67.2% Vs. 44.3%; p-value = 0.019), and 5-yrs Overall (69.3% Vs. 46.9%; p-value = 0.037) survival, compared to cases with low M1/M2. The presence of a high M1/M2 ratio was independently associated with an unfavourable survival outcome in multivariate analysis. Conclusions polarisation of TAMs toward a M2 phenotype, as reflected by a lower M1/M2 ratio, is an independent predictor of poor response to CT/RT, and shorter survival in LACC.

OBJECTIVE: Massive parallel sequencing (MPS) is the new frontier for molecular diagnostics. Twenty-four papers regarding BRCA analysis were considered for reviewing all pipelines evaluated in this field. METHODS: Proposed here is an integrated MPS workflow able to successfully identify BRCA1/2 mutational status on 212 Italian ovarian cancer patients. The review of literature data is reported. RESULT: The pipeline can be routinely used as robust molecular diagnostic strategy, being highly sensitive and specific. CONCLUSION: Literature data report that efforts are being made in order to fully translate MPS-based BRCA1/2 gene assay into routine clinical diagnostics. However, this study highlights the need of an integrated MPS BRCA1/2 molecular workflow fulfilling the standardized requirements needed in the routine clinical laboratory practice.

Recurrence of disease represents a clinical challenge in cervical cancer patients, especially when all available treatment modalities have been used in the primary setting. The aim of this study was to analyze the patterns of recurrence and their association with clinical outcome in locally advanced cervical cancer (LACC) patients submitted to primary chemoradiation (CTRT) followed by radical surgery (RS).

To investigate the feasibility and determine the recommended pre-operative intensity-modulated radiotherapy (IMRT) dose of extended-field chemoradiation along with simultaneous integrated boost (SIB) dose escalation.

OBJECTIVE: To assess the feasibility of laparoscopic radical surgery in patients with locally advanced cervical cancer (LACC) who receive chemoradiation therapy (CT/RT). DESIGN: Prospective phase II study (Canadian Task Force classification II-1). INTERVENTION: Patients with LACC (FIGO stage IB2-III) were evaluated for accrual at the Gynecologic Oncology Unit of Catholic University, Rome/Campobasso. Neoadjuvant CT/RT included whole-pelvic irradiation (total dose, 45.0-50.4 Gy) combined with cisplatin and 5-fluorouracil. Objective response to treatment was evaluated according to Response Evaluation Criteria in Solid Tumors criteria. Laparoscopic radical hysterectomy (RH) plus pelvic and/or aortic lymphadenectomy was attempted within 6 to 8 weeks after CT/RT. The feasibility of laparoscopic RH, as well as the rate, pattern, and severity of early and late postoperative complications, were analyzed. RESULTS: Between January 2010 and October 2013, a total of 58 patients were enrolled into the study. After CT/RT, 23 patients (39.6%) underwent type B2 RH, 31 (53.4%) underwent type C1 RH, and 4 (6.9%) underwent type C2 RH. Pelvic lymphadenectomy was performed in all cases. Laparoscopic RH was feasible in 55 of 58 cases (feasibility rate, 94.8%). No intraoperative complications were recorded. During the observation period (median, 22 months; range, 5-50 months), there were 28 complications, of which only 21.4% were grade 2 complications and 14.3% were grade 3 complications. As of January 2015, disease recurrence was documented in 4 cases (6.9%). CONCLUSION: Total laparoscopic radical surgery is feasible in patients with LACC receiving preoperative CT/RT, providing perioperative outcomes comparable to those registered in early-stage disease.

Objective we investigate the prognostic role of pre-treatment ratio between Type 1 (M1) and Type 2 (M2) tumor-associated macrophages (TAMs) in locally advanced cervical cancer (LACC) patients treated with chemoradiation (CT/RT). Methods 84 consecutive LACC patients treated with cisplatin-based CT/RT for a total dose of 50.0 Gy, followed by radical surgery were analysed. Double-staining immunohistochemistry of CD163/p-STAT, CD68/pSTAT1, CD163/c-MAF, and CD68/c-MAF was performed on tumor samples taken at the time of diagnosis. TAMs with CD163+pSTAT1+, or CD68+pSTAT1+ were defined M1; CD163+c-MAF+ or CD68+c-MAF+ defined the M2 phenotype. The number of M1 and M2 cells was counted at low magnification by evaluating for each case the same tumour area. The ratio between M1 and M2 (M1/M2) was finally calculated. Results At diagnosis, we observed a direct correlation between the number of circulating monocytes and of TAMs (p-value = 0.001). Patients with high M1/M2 experienced more frequently complete pathologic response (no residual tumor) to CT/RT, compared to cases with low M1/M2 (55.0% Vs 29.5%; p-value = 0.029). At multivariate analysis M1/M2 (OR = 2.067; p-value = 0.037) emerged as independent predictor of pathologic response to CT/RT. Women with high M1/M2 showed a longer 5-yrs Disease-free (67.2% Vs. 44.3%; p-value = 0.019), and 5-yrs Overall (69.3% Vs. 46.9%; p-value = 0.037) survival, compared to cases with low M1/M2. The presence of a high M1/M2 ratio was independently associated with an unfavourable survival outcome in multivariate analysis. Conclusions polarisation of TAMs toward a M2 phenotype, as reflected by a lower M1/M2 ratio, is an independent predictor of poor response to CT/RT, and shorter survival in LACC.

Granulosa cell tumors (GCTs) are the most common estrogen-secreting ovarian tumors; perhaps due to the persistent hyperestrogenism, a wide spectrum of associated endometrial pathologies ranging from endometrial hyperplasia to carcinoma has been documented in patients with GCTs. The aim of this study is to evaluate the incidence of endometrial pathologies in a large series of GCT patients treated in MITO centers.

Recurrence of disease represents a clinical challenge in cervical cancer patients, especially when all available treatment modalities have been used in the primary setting. The aim of this study was to analyse the patterns of recurrence and their association with clinical outcome in locally advanced cervical cancer (LACC) patients submitted to primary chemoradiation (CTRT) followed by radical surgery (RS).

Objective: Chemoradiation-based neoadjuvant treatment followed by radical surgery is an alternative therapeutic strategy for locally advanced cervical cancer (LACC), but ultrasound variables used to predict partial response to neoadjuvant treatment are not well defined. Our goal was to analyze prospectively the potential role of transvaginal ultrasound in early prediction of partial pathological response, assessed in terms of residual disease at histology, in a large, single-institution series of LACC patients triaged to neoadjuvant treatment followed by radical surgery. Methods: Between October 2010 and June 2014, we screened 108 women with histologically documented LACC Stage IB2–IVA, of whom 88 were included in the final analysis. Tumor volume, three-dimensional (3D) power Doppler indices and contrast parameters were obtained before (baseline examination) and after 2 weeks of treatment. The pathological response was defined as complete (absence of any residual tumor after treatment) or partial (microscopic and/or macroscopic residual tumor at pathological examination). Complete-response and partial-response groups were compared and receiver–operating characteristics (ROC) curves were generated for ultrasound variables that were statistically significant on univariate analysis to evaluate their diagnostic ability to predict partial pathological response. Results: There was a complete pathological response to neoadjuvant therapy in 40 (45.5%) patients and a partial response in 48 (54.5%). At baseline examination, tumor volume did not differ between the two groups. However, after 2 weeks of neoadjuvant treatment, the tumor volume was significantly greater in patients with partial response than it was in those with complete response (P = 0.019). Among the 3D vascular indices, the vascularization index (VI) was significantly lower in the partial-response compared with the complete-response group, both before and after 2 weeks of treatment (P = 0.037 and P = 0.024, res

INTRODUCTION: In advanced epithelial ovarian cancer patients, the standard of care is primary debulking surgery, followed by first-line chemotherapy often with bevacizumab addiction. In this context, some experiences have shown that a comprehensive treatment approach to surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) could improve the prognosis. OBJECTIVE: This is a study aimed to explore the feasibility of primary debulking surgery and HIPEC upfront followed by first-line therapy with bevacizumab. STUDY DESIGN: Phase II monocentric, open label, non-randomised and single-arm study. Forty patients affected by advanced ovarian cancer submitted to primary debulking surgery with HIPEC were enrolled in the study. After surgery, all patients underwent systemic chemotherapy with bevacizumab addiction. RESULTS: Complete cytoreduction (RT = 0) was achieved in all cases. Treatment-related early complications were observed in 23 patients and in 15 cases were G1-G2. Major complications were reported in 8 patients. No postoperative death was recorded. Subsequent chemotherapy was administered in all cases. Median time between surgery and first cycle of chemotherapy was 42 days (range 30-76). Concomitant bevacizumab was administered in 34 patients (85%). Maintenance with bevacizumab was feasible in 33 patients (82.5%) and its withdrawal was necessary for 1 patient (2.5%) due to G3 hypertension. CONCLUSION: Our data suggest that HIPEC can be safely introduced in the upfront therapy of advanced ovarian cancer.

OBJECTIVE: To compare clinical outcomes of patients diagnosed with low-risk gestational trophoblastic neoplasia (GTN) receiving intramuscular methotrexate 50 mg total dose/day versus 1 mg/kg/day in a 8-day methotrexate/folinic acid (MTX/FA) regimen. METHODS: This retrospective, multicenter study included 176 patients: 99 (56%) receiving methotrexate 50 mg total dose/day on days 1, 3, 5, 7 alternated with FA 7,5 mg on days 2, 4, 6, 8, every 14 days (group A); and 77 patients (44%), receiving methotrexate 1 mg/kg/day on days 1, 3, 5, 7 alternated with FA 7,5 mg on days 2, 4, 6, 8, every 14 days (group B). Patients' characteristics and outcomes were compared by univariate analysis. RESULTS: Forty-five patients (25.6%) developed resistance to MTX and received a second-line treatment, 7 (4%) received a third-line treatment and 8 (4.5%) relapsed after initial remission. There was no difference between group A and B patients in the average number of chemotherapy cycles required to achieve remission (5.7 ± 2.6 vs 6.3 ± 2.3, p = 0.106). The 2 treatment groups showed comparable rates of MTX resistance (28.3% vs 22.1%, p = 0.387) and relapse (3% vs 6.5%, p = 0.300). There was no difference in the incidence of treatment toxicity of any CTCAE grade between group A and B patients (16.2% vs 15.2%, p = 0.999). Subgroup analysis stratifying patients by weight (<50 kg, ≥60 kg, ≥70 kg, ≥80 kg) confirmed these results. CONCLUSION: The 2 MTX schedules showed comparable efficacy in the treatment of low-risk GTN with an acceptable rate of toxicity.

Objective: To determine the diagnostic performance of two-dimensional (2D) ultrasound parameters, three-dimensional (3D) power Doppler and contrast-enhanced indices in detecting residual disease in locally advanced cervical cancer patients triaged to neoadjuvant treatment followed by radical surgery. Methods: Between October 2010 and June 2014, we screened 108 women with histologically documented locally advanced cervical cancer Stage IB2–IVA, of whom 88 were included in the final analysis. 2D ultrasound parameters, 3D power Doppler and contrast-ultrasound parameters were assessed 5 weeks after the end of neoadjuvant chemoradiation therapy. The pathological response was defined as complete (absence of any residual tumor after treatment) or partial (including microscopic and/or macroscopic residual tumor at pathology examination). The two response groups were compared and receiver–operating characteristics (ROC) curves generated to determine the best cut-off value of sonographic tumor diameter to predict residual disease. Histology was considered as reference. Results: Complete pathological response to chemoradiation was observed in 40 (45.5%) patients and partial response in 48 (54.5%). The presence of residual disease, as confirmed at pathology examination, was detected by 2D grayscale ultrasound with a sensitivity of 64.6% and specificity of 65%. Color Doppler examination in the cases with lesions visualized on grayscale imaging detected the presence of residual disease, confirmed at pathology, with a sensitivity of 87.1% and specificity of 21.4%. The best area under the ROC curve (0.817) was for the detection of pathological residual disease of at least 6 mm in diameter, using a cut-off value of 12 mm for the largest tumor diameter assessed using 2D grayscale ultrasound (sensitivity, 95%; specificity, 70.6%). Neither 3D vascular indices nor contrast-ultrasound parameters obtained for lesions suspected at ultrasound following chemoradiation differed significantly

Background: This study aims at evaluating the feasibility, surgical outcome and oncological results observed after robotic radical hysterectomy (RH) compared to laparoscopy for patients with early stage cervical cancer (ECC) patients. Methods: Between January 2010 and October 2016, 210 patients underwent RH for treatment of ECC: 70 underwent robotic approach (Cases), and 140 underwent laparoscopic approach (Controls). Results: There was no statistically significant difference between the two approaches with regard to clinical patient characteristics and in terms of extent of RH and rate of pelvic and aortic lymphadenectomy. Operative time was significantly longer in the robotic versus laparoscopic group (median = 243 min, range 90–612 versus median = 210 min, range 80–660; p value = 0.008). Conversion to laparotomy was necessary in 4 patients (1.9%) in the whole series. No difference was found in terms of intraoperative and postoperative complications between the two groups. Overall, during the observation period, 34 (16.2%) patients experienced any grade postoperative complications, and 21 (10.0%) had >G2 complications. The 3-yr DFS was 88.0% versus 84.0% in robotic and laparoscopic group, respectively (p value = 0.866). Central and/or lateral pelvic disease represented the most common site of relapse. The 3-yr OS was 90.8% in patients underwent robotic RH versus 94.0% in patients underwent laparoscopic RH (p value = 0.924). Conclusions: The present study shows the equivalence of robotic and laparoscopic approaches to radical surgery of ECC patients, in terms of perioperative and postoperative outcomes with equivalent survival figures, and thus the choice of approach can be tailored to the choice of patient and surgeon.

AIM: This study systematically reviews the recent literature on the role of definitive radiotherapy (RT) in the management of vaginal cancer (VC) and presents comprehensive data on clinical outcomes and toxicity. METHODS: The authors performed a literature search using PubMed (2007-2016) to identify all prospective and retrospective studies that have been published on RT in invasive VC. RESULTS: Of the 199 identified studies, 13 met the inclusion criteria. All studies had a retrospective design. Overall, 793 patients (median, 45; range, 26-138) were included. A high heterogeneity was found across studies in terms of RT techniques, assessment criteria, and reported outcomes. The majority of the patients were treated with a combination of external beam RT and brachytherapy (74.2%). Acute and late grade ≥3 toxicity rates ranged from 0.0% to 24.4% (median, 8.7%) and from 0.0% to 22.5% (median, 12.8%), respectively. The 5-year local control rates ranged between 39% and 79%. The 5-year overall survival ranged between 34% and 71.0% (median, 63.5%). Early stage of the disease (International Federation of Gynecology and Obstetrics stages I-II vs. III-IV), small tumor size (<4 cm), previous hysterectomy, high pretreatment/treatment hemoglobin levels (≥12/12.5 mg/dL), and patients' age <70 or <64 years were correlated with better clinical outcomes. CONCLUSION: Only retrospective studies, in a limited number, have been published on RT in VC in the past decade, with significant heterogeneity in terms of treatment characteristic and evaluation criteria. Clinical results were strongly influenced by tumor stage. Prospective randomized studies are needed to improve patients' outcomes, especially in advanced-stage disease.;23:1-10 IMPLICATIONS FOR PRACTICE: This study systematically reviews the recent literature on the role of definitive radiotherapy in the management of vaginal cancer and presents comprehensive data on clinical outcome and toxicity. The prognosis of patients is dism

BACKGROUND: to assess the feasibility of minimally invasive surgery in the management of lymph-nodal recurrences of gynecological cancers, in terms of surgical and oncological outcomes. METHODS: we retrospectively collected patients with isolated lymph-nodal recurrent disease of gynecological malignancies who underwent to minimally invasive lymphadenectomy at Catholic University of the Sacred Hearth in Rome (Italy), from January 2013 to November 2017. RESULTS: Forty patients were considered eligible (31 LPS, 9 Robot); 24 (60.0%) with an ovarian cancer, 8 (20.0%) with a cervical cancer and 8 (20.0%) with an endometrial cancer recurrence. The most frequent site of lymph-nodal recurrence was represented by the aortic region (47.5%), while 18 patients (45.0%) experiencing pelvic lymph-nodal recurrence, 2 (5.0%) both pelvic and aortic relapse, and only 1 (2.5%) had an hepato-celiac lymph node recurrence. No patient required a laparotomic conversion. Median operative time was 220 min, median EBL was 80 mL, and median post-operative hospital stay was 2 days. There were 2 (5.0%) intra-operative and 4 (10.0%) post-operative complications, of which 2 were grade 3. The median follow-up was 22.5 months, and during this time 15 patients showed another relapse with a median time to progression of 12 months. Seven women died because of the disease. The 2-year post-relapse disease-free survival (PR-DFS) was 54.7%, and the 2-year post-relapse overall survival (PR-OS) was 79.3%. CONCLUSIONS: In our experience minimally invasive surgery is a valid therapeutic approach in very select patients with localized lymph-nodal recurrence of gynecological cancers, with benefits about peri and post-operative morbidities and without compromising their oncological outcome.

AIM: To compare late toxicity after postoperative hypofractionated radiotherapy (RT) and standard fractionated RT in patients with early-stage breast carcinoma. METHODS: This retrospective study included 447 patients (Modulated Accelerated Radiotherapy [MARA-1]: 317 patients, and control group [CG]: 130 patients). In the CG, the whole breast received 50.4 Gy in 28 fractions (fx) using 3D-radiotherapy, plus a sequential electron boost (10 Gy in 4 fx) to tumor bed. In MARA-1 group, a forward-planned intensity-modulated radiotherapy technique with 40 Gy in 16 fx with a concomitant boost of 4 Gy to breast was used. The primary endpoint was to evaluate late toxicity, and secondary endpoints were acute toxicity, local control, and survival. ClinicalTrials.gov: NCT03461224. RESULTS: Median follow-up was 52 months (range: 3-115 months). Late skin and subcutaneous toxicity were acceptable: 5-year actuarial cumulative incidence of Grade (G) 3 late skin toxicity was 1.5% in CG and 0.0% in MARA-1. Five-year actuarial cumulative incidence of G3 late subcutaneous toxicity was 0.8% in CG and 0.3% in MARA-1. On multivariate analysis, tobacco smoking and planning target volume were associated with an increased risk of late G1 skin toxicity (HR: 2.15, 95% CI: 1.38-3.34 and HR: 1.12, 95% CI: 1.07-1.18, respectively), whereas patients with a larger planning target volume also showed an increased risk of G1 and G2 late subcutaneous toxicity (HR: 1.14, CI 95%: 1.08-1.20 and HR: 1.14, 95% CI: 1.01-1.28, respectively). MARA-1 patients also showed an increased risk of late G1 and G2 subcutaneous toxicity (HR: 2.35, 95% CI: 1.61-3.41 and HR: 3.07, 95% CI: 1.11-8.53, respectively) compared to CG. CONCLUSION: In this retrospective analysis, postoperative accelerated-hypofractionated RT for early-stage-breast carcinoma was associated with higher incidence of subcutaneous side effects. However, this increase was limited to G1-G2 toxicity. In the future, development of predictive models could hel

Purpose: The aim of this Phase II, non-randomized study was to assess activity and safety of neoadjuvant chemotherapy (NACT) before chemoradiation (CT/RT) followed by radical surgery (RS) in locally advanced cervical cancer (LACC) patients. Methods and materials: The primary end point was rate of pathologic complete response (pCR). FIGO Stage IB2-IVA patients were administered NACT chemotherapy (paclitaxel 80 mg/m2, carboplatin AUC 2), for 6 weeks, followed by Intensity Modulated Radiotherapy plus simultaneous boost (total dose of 50.4 Gy to CTV1, and 39.6 Gy to CTV2). Clinical response was assessed according to RECIST criteria. Responsive patients were triaged to RS. The regimen would be considered active if >20 pCRs were registered in 39 patients. Results: 45 patients were enrolled into the study; 25 patients (55.5%) were FIGO stage IIB, 9 cases (20.0%) had stage III disease. At work up, pelvic lymph node involvement was documented in 38 (84.4%) patients; pCR was documented in 18 out of 40 patients (45.0%). Grade 3–4 hematological toxicity after NACT occurred in 4 patients; CT/RT associated grade 3 toxicity was found in 7 patients. Early and late postoperative complications were detected in 16, and 11 cases, respectively. Three-year PFS and OS were 66.0% and 86.0%, respectively. Conclusions: NACT followed by CT/RT by IMRT and RS, is feasible and safe; failure to achieve the primary endpoint has to be recognized; however, enrollment of a higher rate of poor prognosis patients compared to historical data used to calculate sample size, could have resulted in reduced activity.

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Background: MITO-8 showed that prolonging platinum-free interval by introducing non-platinum-based chemotherapy (NPBC) does not improve prognosis of patients with partially platinum-sensitive recurrent ovarian cancer. Quality of life (QoL) was a secondary outcome. Patients and methods: Ovarian cancer patients recurring or progressing 6-12 months after previous platinum-based chemotherapy (PBC) were randomized to receive PBC or NPBC as first treatment. QoL was assessed at baseline, third and sixth cycles, with the EORTC C-30 and OV-28 questionnaires. Mean changes and best response were analysed. Progression-free survival, response rate, and toxicity are also reported for proper interpretation of data. All analyses were based on intentionto- treat. Results: Out of the 215 patients, 151 (70.2%) completed baseline questionnaire, balanced between the arms; thereafter, missing rate was higher in the NPBC arm. At mean change analysis, C30 scores were prevalently worse in the NPBC than PBC arm, statistical significance being attained for emotional functioning, global health status/QoL, fatigue, and dyspnoea (effect sizes ranging from 0.30 to 0.51). Conversely, as for OV28 scale, the other chemotherapy side-effects item was significantly worse with PBC at three and six cycles, with a larger effect size (0.70 and 0.54, respectively). At best response analysis, improvement of emotional functioning and pain and worsening of peripheral neuropathy and other chemotherapy side-effects were significantly more frequent in the PBC arm. Progression-free survival (median 9 versus 5 months, P=0.001) and objective response rate (51.6% versus 19.4%, P=0.0001) were significantly better with PBC. Allergy, blood cell count, alopecia, nausea, musculoskeletal, and neurological side-effects were more frequent and severe with PBC; hand-foot skin reaction, rash/ desquamation, mucositis, and vascular events were more frequent with NPBC. Conclusion: MITO-8 QoL analysis shows that deterioration of so

BRCA1/2 screening in Hereditary Breast and Ovarian Syndrome (HBOC) is an essential step for effective patients’ management. Next-Generation Sequencing (NGS) can rapidly provide high throughput and reliable information about the qualitative and quantitative status of tumor-associated genes. Straightforwardly, bioinformatics methods play a key role in molecular diagnostics pipelines. BRCA1/2 genes were evaluated with our NGS workflow, coupled with Multiplex Amplicon Quantification (MAQ) and Multiplex Ligation-dependent Probe Amplification (MLPA) assays. Variant calling was performed on Amplicon Suite, while Copy Number Variant (CNV) prediction by in house and commercial CNV tools, before confirmatory MAQ/MLPA testing. The germline profile of BRCA genes revealed a unique HBOC pattern. Although variant calling analysis pinpointed heterozygote and homozygote polymorphisms on BRCA1 and BRCA2, respectively, the CNV predicted by our script suggested two conflicting interpretations: BRCA1 duplication and/or BRCA2 deletion. Our commercial software reported a BRCA1 duplication, in contrast with variant calling results. Finally, the MAQ/MLPA assays assessed a whole BRCA2 copy loss. In silico CNV analysis is a time and cost-saving procedure to powerfully identify possible Large Rearrangements using robust and efficient NGS pipelines. Our layout shows as bioinformatics algorithms alone cannot completely and correctly identify whole BRCA1/2 deletions/duplications. In particular, the complete deletion of an entire gene, like in our case, cannot be solved without alternative strategies as MLPA/MAQ. These findings support the crucial role of bioinformatics in deciphering pitfalls within NGS data analysis.

Study Objective: To investigate the feasibility, safety, and short-term outcomes of robotic surgery (RS) for gynecologic oncologic indications (cervical, endometrial, and ovarian cancer) in elderly patients, especially women age 65 to 74 years (elderly group [EG]) compared with women age ≥75 years (very elderly group [VEG]). Design: Retrospective cohort study (Canadian Task Force classification II-2). Setting: Catholic University of the Sacred Heart, Rome, Italy. Patients: Between May 2013 and April 2017, 204 elderly and very elderly patients underwent RS procedures for gynecologic malignancies. Results: The median age was 71 years (range, 65-74 years) in the EG and 77 years (range, 75-87 years) in the VEG. The incidence of cardiovascular disease was higher in the VEG (p = .038). The EG and VEG were comparable in terms of operative time, blood loss, and need for blood transfusion. Almost all (98.5%) of the patients underwent total/radical hysterectomy, 109 patients (55.6% of the EG vs 48.3% of the VEG) underwent pelvic lymphadenectomy, and 19 patients (10.5% of the EG vs 6.7% of the VEG) underwent aortic lymphadenectomy. A total of 7 (3.4%) conversions to open surgery were registered. Only 3 patients required postoperative intensive care unit admission. The median length of hospital stay was 2 days in each group. A total of 11 patients (5.6%) had early postoperative complications. Four patients (2.8%) in the EG and 2 patients (3.3%) in the VEG experienced grade ≥2 complications. At the time of analysis, median follow-up was 18 months (range, 6-55 months). Eleven patients (5.6%) experienced disease relapse, 2 (1%) died of disease, and 3 (1.5%) died of cardiovascular disease. Conclusions: This study demonstrates the feasibility, safety, and good short-term outcomes of RS in elderly and very elderly gynecologic cancer patients. No patient can be considered too old for a minimally invasive robotic approach, but a multidisciplinary approach is the best management p

ACKGROUND: Carboplatin plus paclitaxel administered every 3 weeks is standard first-line chemotherapy for patients with advanced ovarian cancer. A weekly paclitaxel schedule combined with carboplatin every 3 weeks prolonged progression-free survival and overall survival in a Japanese phase 3 trial. The aim of our study was to assess whether a weekly schedule of carboplatin plus paclitaxel is more effective than the same drugs given every 3 weeks. METHODS: We did a multicentre, randomised, phase 3 study at 67 institutions in Italy and France. Women with FIGO stage IC-IV ovarian cancer, an ECOG performance status of 2 or lower, and who had never received chemotherapy were randomly allocated in a 1:1 ratio to receive either carboplatin (AUC 6 mg/mL per min) plus paclitaxel (175 mg/m(2)) every 3 weeks for six cycles or carboplatin (AUC 2 mg/mL per min) plus paclitaxel (60 mg/m(2)) every week for 18 weeks. Randomisation was done by computer-based minimisation, stratified by centre, residual disease after surgery, and ECOG performance status. The study was not blinded. Coprimary endpoints were progression-free survival and quality of life (assessed by the Functional Assessment of Cancer Therapy Ovarian Trial Outcome Index [FACT-O/TOI] score), and analysis was by modified intention to treat. This report presents the final analysis. The study is registered with ClinicalTrials.gov, number NCT00660842. FINDINGS: 822 patients were enrolled into the study between Nov 20, 2008, and March 1, 2012; 12 withdrew their consent immediately after randomisation and were excluded, and 810 were eligible for analysis. 404 women were allocated treatment every 3 weeks and 406 were assigned to the weekly schedule. After median follow-up of 22·3 months (IQR 16·2-30·9), 449 progression-free survival events were recorded. Median progression-free survival was 17·3 months (95% CI 15·2-20·2) in patients assigned to treatment every 3 weeks, versus 18·3 months (16·8-20·9) in women allocated to the we

We investigated the correlation of pathologic response and immunohistochemically assessed expression of survivin protein in 71 patients with locally advanced cervical cancer treated with chemoradiation (CT/RT) followed by radical surgery. The prognostic role of survivin expression was also evaluated. Immunohistochemical analysis of survivin expression was carried out using the polyclonal rabbit antisurvivin antibody. Cytoplasmic survivin immunoreaction was observed in 69 (97.2%) of 71 cases and nuclear staining in 7 (9.8%) of 71 women. Median cytoplasmic survivin expression was 160 (range, 0-280), and higher levels were observed in patients with residual disease (≥3 mm) in the cervix (survivin level, 160 versus 120; P = .016) and in women with metastatic lymph nodes (survivin levels, 160 versus 150; P = .032). No differences were documented in the distribution of patients with positive nuclear staining, according to clinicopathological variables. In multivariate analysis, cytoplasmic survivin expression emerged as an independent predictor of residual cervical disease and lymph node status after CT/RT. During a follow-up period of 83 months (range, 8-175 months), recurrences occurred in 24 (33.8%) women, and all patients died of disease. Women with high cytoplasmic survivin experienced shorter disease-free survival compared with patients with low levels (5-year disease-free survival, 80.8% versus 55.3%; P = .033). Only a trend was observed for greater overall survival in patients with high expression (5-year overall survival, 81.0% versus 55.3%; P = .069). No survival differences were documented for nuclear survivin status. The immunohistochemically assessed survivin cytoplasmic levels at diagnosis represent a reliable and easily assessable tool to predict response to CT/RT in patients with locally advanced cervical cancer.

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From the dualistic classification that divides endometrial cancer (EC) into two types with distinct underlying molecular profiling, histopathology and clinical behavior, arises a deeper understanding of the carcinogenesis pathways. EC treatment comprises different and multimodal therapeutic approaches, such as chemotherapy, radiation therapy or combinations of novel drugs; however, few of these regimens have truly improved progression-free or survival rates in advanced and metastatic settings.

Optimally, secondary cytoreduction is acknowledged as a valid option in terms of oncologic outcome for patients with platinum-sensitive recurrent ovarian cancer. In cases of localized relapse, a laparoscopic approach has been attempted at various institutions, but studies on its role for this subset of patients still are limited. This report describes the authors' experience using laparoscopic secondary cytoreduction for patients with localized recurrent ovarian cancer. The results from a retrospective analysis of a prospective case series are reported.

Much attention has been recently focused on the role of fertility-sparing surgery in patients with ovarian cancer. However, few data are currently available on the feasibility of conservative approaches in women with disease extending beyond the ovaries.

The aim of this multicenter, retrospective study was to evaluate the efficacy and safety of metronomic oral cyclophosphamide (MOC) in heavily treated, relapsed ovarian cancer (ROC) patients.

The aim of this study is to analyze the safety, adequacy, perioperative and survival figures in a large series of laparoscopic staging of patients with apparent early stage ovarian malignancies (ESOM).

This prospective, phase 2 study aimed at assessing the efficacy of accelerated fractionation radiation therapy by concomitant boosts (CBs) associated with chemoradiation therapy (CRT) of the whole pelvis, in improving the rate of pathological complete response (pCR) to treatment in patients with International Federation of Gynaecology and Obstetrics (FIGO) stage IB2-IVA locally advanced cervical cancer.

Among the pharmaceutical options available for treatment of ovarian cancer, attention has been increasingly focused on trabectedin (ET-743), a drug which displays a unique mechanism of action and has been shown to be active in several human malignancies. Currently, single agent trabectedin is approved for treatment of patients with advanced soft tissue sarcoma after failure of anthracyclines and ifosfamide, and in association with pegylated liposomal doxorubicin for treatment of patients with relapsed partially platinum-sensitive ovarian cancer. This review aims at summarizing the available evidence about the clinical role of trabectedin in the management of patients with epithelial ovarian cancer. Novel perspectives coming from a better understanding of trabectedin mechanisms of action and definition of patients subgroups likely susceptible to benefit of trabectedin treatment are also presented.

We provided a comprehensive analysis of rate, pattern, and severity of early and late postoperative complications in a very large, single-institution series of locally advanced cervical cancer (LACC) patients administered CT/RT plus radical surgery (RS).

INTRODUCTION: From the dualistic classification that divides endometrial cancer (EC) into two types with distinct underlying molecular profiling, histopathology and clinical behavior, arises a deeper understanding of the carcinogenesis pathways. EC treatment comprises different and multimodal therapeutic approaches, such as chemotherapy, radiation therapy or combinations of novel drugs; however, few of these regimens have truly improved progression-free or survival rates in advanced and metastatic settings. AREAS COVERED: We reviewed the main molecular pathways involved in EC carcinogenesis through a wide literature search of novel compounds that alone or in combination with traditional drugs have been investigated or are currently under investigation in randomized clinical trials. EXPERT OPINION: The molecular therapies mainly discussed in this review are potential therapeutic candidates for more effective and specific treatments. In the genomic era, a deeper knowledge about molecular characteristics of cancer provides the hope for the development of better therapeutic approaches. Targeting both genetic and epigenetic alterations, attacking tumor cells using cell-surface markers overexpressed in tumor tissue, reactivating antitumor immune responses and identifying predictive biomarkers represent the emerging strategies and the major challenges.

This article examines the cost-effectiveness of chemotherapy (gemcitabine) versus nanotherapy (PEGylated liposomal doxorubicin) in the treatment of ovarian cancer. Significant differences in costs were mainly due to the initial drug costs, which were €1285.28 in favor of chemotherapy. These costs were more than offset by hospitalization costs, which were €2670.21 in favor of the nanotherapy. The cost per quality-adjusted life week (QALW) for the nanotherapy was estimated to be €220.92/QALW for the base case and ranged from €170-318/QALW based on model assumptions. The clinical benefit associated with nanotherapy was achieved, yielding not only positive cost-effectiveness results, but also, surprisingly, financial savings. Although more studies are necessary, this first comprehensive analysis supports the further use of nanotherapy for ovarian cancer.

To present the interim results of a phase I trial on stereotactic radiosurgery (SRS) delivered using volumetric modulated arc therapy (VMAT) in patients with primary or metastatic tumours in different extracranial sites.

Among the pharmaceutical options available for treatment of ovarian cancer, attention has been increasingly focused on trabectedin (ET-743), a drug which displays a unique mechanism of action and has been shown to be active in several human malignancies. Currently, single agent trabectedin is approved for treatment of patients with advanced soft tissue sarcoma after failure of anthracyclines and ifosfamide, and in association with pegylated liposomal doxorubicin for treatment of patients with relapsed partially platinum-sensitive ovarian cancer. This review aims at summarizing the available evidence about the clinical role of trabectedin in the management of patients with epithelial ovarian cancer. Novel perspectives coming from a better understanding of trabectedin mechanisms of action and definition of patients subgroups likely susceptible to benefit of trabectedin treatment are also presented.

BACKGROUND: Optimally, secondary cytoreduction is acknowledged as a valid option in terms of oncologic outcome for patients with platinum-sensitive recurrent ovarian cancer. In cases of localized relapse, a laparoscopic approach has been attempted at various institutions, but studies on its role for this subset of patients still are limited. This report describes the authors' experience using laparoscopic secondary cytoreduction for patients with localized recurrent ovarian cancer. The results from a retrospective analysis of a prospective case series are reported. METHODS: Between October 2011 and May 2013, 29 patients with localized recurrent ovarian cancer were selected for a laparoscopic cytoreduction. Two conversions to laparotomy occurred. The analyzed outcome variables included stage and site of disease, type of surgical procedure, operative time, blood loss, length of hospital stay, complications, and oncologic outcome. RESULTS: The median operating time was 188 min. The median estimated blood loss was 150 mL, and the median hospital stay was 4 days. Complete debulking was achieved for 96.2% of the patients. No intraoperative complications occurred, and postoperative complications were noted in only one patient. The median disease-free survival time was 14 months. CONCLUSIONS: For selected patients, laparoscopy is a feasible and safe approach to optimal cytoreduction for patients with localized recurrent ovarian cancer.

OBJECTIVE: Evaluate the survival of patients who underwent pelvic exenteration (PE) with curative intent for primary persistent or recurrent cervical cancer. METHODS: We retrospectively investigated 167 consecutive patients, referred to the gynecological oncology units of 4 centers in Germany or Italy, who underwent PE. Data regarding surgery, histology, and oncologic outcomes were collected and statistically evaluated. Survival was determined from the day of exenteration until last follow-up or death. RESULTS: The median age was 51 years. Twenty-seven patients (16.2%) underwent PE owing to advanced primary tumors (group A), 34 patients (20.4%) underwent PE owing to persistent cancer after chemotherapy or chemoradiation (group B), and 106 patients (63.4%) underwent PE owing to recurrence (group C). The prevalent histologic type was squamous cell cancer. A complete tumor resection (R0), was achieved in 121 patients (72.5%). Forty-nine patients (29.3%) had pelvic lymph node metastases and 44 patients (26.3%) had pelvic sidewall involvement. Overall survival at the end of the study was 40.7%. The cumulative 5-year overall survival for the entire cohort was 38%. Resection margins, pelvic lymph node state, and sidewall involvement were independent prognostic factors in multivariate analysis. CONCLUSION: Pelvic exenteration is a valid therapeutic option for patients with locally advanced primary persistent or recurrent cervical cancer, with a long-term survival in 40% of the patients.

The aim of this retrospective study was to investigate the incidence of mesenteric lymph node (MLN) involvement, and its prognostic role in advanced ovarian cancer (OC).

The aim of the study was to prospectively, and longitudinally assess Quality of Life (QoL) and emotional distress in a large series of endometrial cancer (EC) patients.

Objective. To report dosimetric and acute toxicity data in prospectively enrolled high-intermediate risk endometrial cancer (HIR-EC) patients postoperatively irradiated by simultaneous integrated boost volumetric modulated arc therapy (SIB-VMAT). Methods. Thirty prospectively enrolled HIR-EC patients were postoperatively treated by SIB-VMAT. Target coverage, dose homogeneity, and sparing of organs at risk (OARs) were compared with corresponding data retrieved from an historical control (30 consecutive selected matched patients) treated by concomitant boost three-dimensional conformal radiotherapy (3D CRT CB) from a previously published study (ADA-I trial). All patients received 45 Gy on pelvic lymph nodes plus 10 Gy boost on the vaginal vault. Results. The SIB-VMAT technique produced more inhomogeneous plans than 3D CRT CB, but showed significantly better conformity index (CIs) for both PTVs. SIB-VMAT was associated with significant reduction in the irradiated small bowel (SB) volume compared with 3D CRT CB for all dose range > 10 Gy (e.g. V15: 163.5 cm(3) vs. 341.3 cm(3), p = 0.001 and V40: 43.8 cm(3) vs. 85.2 cm(3), p = 0.008). With regard to bladder and rectum, SIB-VMAT showed a significant sparing advantage at all dose levels with respect to 3D CRT CB retrieved plans. Moreover, overall OARs Dmean were significantly reduced by the SIB-VMAT (p = 0.001). According to CTCAE v.4.0, acute (within three months) GI toxicities were more frequent in 3D CRT CB versus SIB-VMAT (90.0% vs. 66.7%; p-value 0.028). Conclusions. Compared to data from a historical database of patients administered 3D CRT CB, SIB-VMAT significantly improves the dose conformity and sparing of OARs in HIR-EC patients undergoing postoperative radiotherapy. The improvement in terms of acute toxicity justifies further prospective clinical evaluation.

Clear cell adenocarcinoma (CCAC) of the uterine cervix is a rare variant of cervical adenocarcinoma accounting for approximately 4-9% of this disease. Given the rarity of this pathological entity, the optimal treatment management is far from being defined. Earlier evidence suggested that the prognosis of patients bearing cervical CCAC is worse than with other histotypes, thus making the investigation of multimodal treatment strategies clinically worthwhile. Herein, we report the first case of locally advanced, large size cervical CCAC in a young woman who was triaged to concomitant chemoradiotherapy followed by radical surgery and experienced a pathologically assessed optimal response to this multimodal approach

The aim of this multicenter, retrospective study was to evaluate the efficacy and the safety of single agent Trabectedin (ET-743, Yondelis) in very heavily treated, relapsed ovarian cancer (ROC) patients.

No abstract

This study aims at comparing the morbidity and oncologic outcomes in normal weight, overweight, and obese women with locally advanced cervical cancers (LACC) submitted to radical surgery after chemoradiation.

The aim of this study was to report early clinical experience in stereotactic body radiosurgery (SBRS) delivered using volumetric intensity modulated arc therapy (VMAT) in patients with primary or metastatic tumors in various extra-cranial body sites. Each enrolled subject was included in a different phase I study arm, depending on the tumor site and the disease stage (lung, liver, bone, metastatic), and sequentially assigned to a particular dose level. Technical feasibility and dosimetric results were investigated. The acute toxicity, tumor response and early local control were also studied. In total, 25 lesions in 20 consecutive patients (male/female, 11/9; median age, 67 years; age range, 47-86 years) were treated. Of these 25 lesions, 4 were primary or metastatic lung tumors, 6 were liver metastases, 8 were bone metastases and 7 were nodal metastases. The dose-volume constraints for organs at risk (OARs) were observed in 19 patients using a single-arc technique. Only in one patient were two arcs required. The treatment was performed without interruption or any other technical issues. The prescribed dose ranged from 12-26 Gy to the planning target volume (PTV). Delivery time ranged from 4 min to 9 min and 13 sec (median, 6 min and 6 sec). No incidence of grade 2-4 acute toxicity was recorded. The overall response rate was 48% (95% confidence interval (CI), 24.2-70.2) based on computed tomography (CT)/magnetic resonance imaging (MRI) and 89% (95% CI, 58.6-98.7) based on the positron emission tomography (PET) scan. SBRS delivered by means of VMAT allowed the required target coverage to be achieved while remaining within the normal tissue dose-volume constraints in the 20 consecutive patients. VMAT-SBRS resulted in adequate technical feasibility; the maximum tolerable dose has not yet been reached in any study arm.

PURPOSE: To compare the timing and pattern of recurrence in patients with advanced ovarian cancer (AOC) receiving primary debulking surgery (PDS) versus neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS). METHODS: We retrospectively evaluated a consecutive series of 175 stage IIIC-IV epithelial ovarian cancer patients, with diffuse peritoneal carcinomatosis documented at initial surgical exploration. Forty patients received complete PDS, and the remaining 135 were treated with NACT followed by IDS with absent residual tumor after surgery. RESULTS: No differences were observed in the distribution of clinical pathological characteristics at the time of diagnosis between the two groups. The median follow-up was 31 months (range 9-150 months). We observed 20 (50.0%) recurrences in the PDS group compared to 103 (76.3%) in the IDS group (p = 0.001). Duration of primary platinum-free interval (PFI) was shorter in IDS compared to PDS group (13 vs. 21 months, respectively; p = 0.014). A significantly higher percentage of patients in the IDS group experienced platinum-resistant recurrences (35.9 vs. 5.0%; p = 0.006) and carcinomatosis at the time of relapse (57.3 vs. 20.0%; p = 0.0021). Finally, in women with platinum-sensitive recurrence, we observed a shorter secondary PFI in the IDS compared to PDS group (p = 0.006). CONCLUSIONS: We documented a better behavior of recurrent disease in AOC patients with diffuse peritoneal carcinomatosis treated with complete PDS compared to women submitted to NACT followed by IDS with no residual tumor after surgery.

Background: To evaluate the feasibility and the predictive value of cone biopsy before performing radical hysterectomy in locally advanced cervical cancer patients showing complete clinical response to neo-adjuvant chemoradiation. Methods: Between March 2010 to March 2012 74 consecutive FIGO stage IIA2-IIB patients were submitted to neo-adjuvant chemoradiation. All complete clinical responder patients were enrolled in this pilot trial. Results: Fifty-seven out of 74 patients (77%) showed complete clinical response and were enrolled in the study. Forty-two out of 57 patients (74%) underwent successful pre-completion surgery cone biopsy with a median cone's tissue diameter of 24 mm (range 18-35). In 33 out of 42 patients (58%) a complete pathological response was found. In the remaining 5 (9%) and 4 (7%) a microscopic partial and partial response was found, respectively. All 33 cases (58%) with negative cone showed complete pathological response in the radical hysterectomy specimens. Patients with microscopic residual tumor foci in the cone showed negative residual cervical and paracervical tissue at definitive diagnosis, whereas in patients with partial response macroscopic residual disease in the surgical specimens was found. The negative predictive value of cone biopsy, MRI and PET/CT in the prediction of pathological status of the cervical and paracervical tissue was 100%, 79% and 79%, respectively (Table 2). Conclusions: In this study we observed that, in locally advanced cervical patients showing complete clinical response to neo-adjuvant chemoradiation, the cone biopsy feasibility was almost 75%, and that there is a complete pathological correspondence between cone and definitive pathology. (C) 2013 Elsevier Ltd. All rights reserved.