Genomic landscapes of ovarian clear cell carcinoma from latin countries reveal aberrations linked to survival and progression.

BACKGROUND: Ovarian clear cell carcinomas (OCCCs) are rare, aggressive and chemoresistant tumors. Geographical and ethnic differences in the incidence of OCCC have been reported with a higher incidence in Asiatic countries. There is a paucity of information regarding OCCC in Latin America (LA) and other countries. METHODS: Here, we characterized two cohorts of 33 patients with OCCC from LA (24 from Brazil and 9 from Costa Rica) and a cohort of 27 patients from Spain. Genomic analysis was performed for 26 OCCC using the OncoScan platform. Tumors were classified according to their genomic landscapes into subgroups. Clinical parameters were related to the frequency of genomic aberrations. RESULTS: The median overall survival (OS) was not significantly different between the cohorts. Genomic landscapes were characterized by different homologous recombination deficiency (HRD) levels. No difference in the distribution of genomic landscapes profiles was detected between patients from the different cohorts. OCCCs with MYC-amplified tumors harboring a concomitant loss of a region in chromosome 13q12-q13 that includes the BRCA2 gene had the longest OS. In contrast, patients carrying a high number (> 30) of total copy number (CN) aberrations with no concomitant alterations in MYC and BRCA2 genes presented the shortest OS. Furthermore, amplification of the ASH1L gene was also associated with a shorter OS. Initial-stage OCCCs with early progression were characterized by gains in the JNK1 and MKL1 genes. CONCLUSIONS: Our results provide new data from understudied OCCC populations and reveal new potential markers for OCCCs.

Assessment of Health Risk and Presence of Metals in Water and Fish Samples from Doce River, Brazil, After Fundão Dam Collapse.

The rupture of the Fundão dam released about 50 million m3 of mining tailings in the Doce river basin. To assess the potential for environmental contamination and the risks of residual exposure of the human population generated by these tailings, water and fish samples from the Doce river were collected 25 days after the accident and analyzed the physicochemical parameters of the water and levels of metals by ICP-MS, in addition to the temporal variability of the concentration of these elements through other studies. This was the first study to carry out an assessment of the health risk associated with the consumption of fish contaminated by metals from the areas affected by the disaster. The values of turbidity (5460 NTU), electrical conductivity (74.8 µS cm-1), total dissolved solids (892 mg L-1) and total suspended solids (772 mg L-1) were above the maximum limit allowed by Brazilian legislation, due to the presence of large amounts of solid materials released after the dam rupture. The analysis of metals in water samples indicated high concentrations of Al (1,906.71 µg L-1), Mn (370.32 µg L-1), Fe (8,503.50 µg L-1) and Hg (34.25 µg L-1), while for the fish samples, only As (1,033.98 µg kg-1) and Hg (herbivorous: 505.32 µg kg-1; predatory: 1,184.09 µg kg-1) presented levels above those established by Brazilian legislation. The health risk assessment showed that the estimated daily intake for Hg was higher than the reference dose, reinforcing the need for monitoring the area affected by the disaster.

Genomic profiling of platinum-resistant ovarian cancer: The road into druggable targets.

Ovarian cancer is the most lethal gynecologic cancer. High-grade serous carcinoma (HGSC) is the most frequent histologic subtype and while it is a highly platinum-sensitive cancer at initial treatment, nearly 90 % of stage IIIC patients recur in 5 years and eventually become resistant to platinum treatment. Historically, the definition of platinum-resistant disease is based on the time interval between last platinum therapy and recurrence shorter than 6 months. Nowadays the use of sophisticated imaging techniques and serum markers to detect recurrence makes the accuracy of this clinical definition less clear and even more debatable as we begin to better understand the molecular landscape of HGSC and markers of platinum resistance and sensitivity. HGSC is characterized by a low frequency of recurrent mutations, great genomic instability with widespread copy number variations, universal TP53 mutations, and homologous recombination deficiency in more than 50 % of cases. Platinum agents form DNA adducts and intra- and inter-strand cross-links in the DNA. Most of DNA repair pathways are involved at some point in the repair of platinum induced DNA damaging, most notably homologous recombination, Fanconi Anemia, and nucleotide excision repair pathways. Mechanisms of platinum resistance are related mostly to the limitation of platinum-DNA adduct formation by changing cellular pharmacology, and to the prevention of cell death after DNA damage due to alterations in DNA repair pathways and cell cycle regulation. Understanding these mechanisms of sensitivity and resistance may help to define the utility of platinum re-challenge in each situation and guide new therapeutic opportunities. Moreover, the discovery of mechanisms of synthetic lethality related to alterations in DNA repair and cell cycle regulation pathways has opened up a new avenue for drug therapy in the last decade. In the present article, we review pathways involved in platinum-induced DNA damage repair and their relationship with genomic alterations present in HGSC. Moreover, we report new treatment strategies that are underway to target these alterations.

Clinical analysis of pathologic complete responders in advanced-stage ovarian cancer.

OBJECTIVE: To determine the clinical characteristics of patients who attained pathologic complete response (pCR) after neoadjuvant chemotherapy (NACT) and to identify specific predictive or prognostic factors associated with pCR. METHODS: Two distinct populations of patients who underwent NACT followed by interval tumor reductive surgery (TRS) were used in this retrospective study. The first contained 472 patients from a single institution. The second contained only pCR patients (67); those identified from population one, plus 44 obtained through collaborative institutions. Cox analysis and log-rank tests were performed to assess associations between clinical characteristics and pCR outcome, recurrence-free survival (RFS), and overall survival (OS). RESULTS: The median RFS and OS in our pCR-only population was 24.2 and 80.8 months, respectively, with a median follow-up time of 32.4 months. In our single institution population, 23 patients attained pCR (4.9%) and had longer RFS compared to non-pCR patients with viable microscopic, optimal, or suboptimal residual disease (24.3 vs. 12.1 vs. 11.6 vs. 9.6 months, p = 0.025, 0.012, 0.008, respectively), and longer OS compared to those with optimal or suboptimal residual disease (54.5 vs. 29.4 vs. 25.7 months, p = 0.027, 0.007, respectively). Patients were more than three-fold likely to attain pCR if their CA125 value was normal at the time of surgery (OR 3.54, 95% CI: 1.14-11.05, p = 0.029). CONCLUSIONS: Women with pCR after NACT have significantly longer RFS compared to those with residual viable tumor at the time of interval tumor-reductive surgery, and CA125 is plausible biomarker for identifying these extreme responders preoperatively.

Prognostic factors in locally advanced cervical cancer with pelvic lymph node metastasis.

OBJECTIVE: To evaluate the prognostic impact of clinical and pathological variables and patterns of recurrence in patients with locally advanced cervical cancer with pelvic lymph node involvement (stage IIIC1 according to the 2018 FIGO Staging System). METHODS: We retrospectively analyzed 62 patients with locally advanced cervical cancer treated with curative intent with radiotherapy associated with chemotherapy in AC Camargo Cancer Center from January 2007 to December 2018. RESULTS: Lymph node involvement was assessed by CT, MRI and positron emission tomography (PET)/CT in 28 (45.2%), 20 (32.3%) and 14 (22.6%) patients, respectively. The median tumor size was 5.0 cm and 72.6% of cases were squamous cell carcinomas. The median number of positive pelvic lymph nodes was three, and the median size of lymph nodes was 24 mm. Twenty-two (35.5%) patients had recurrence and 50% had only one site of recurrence. The sites of recurrence were pelvic, para-aortic and distant in 12 (19.4%), 6 (9.7%) and 16 (25.8%) patients, respectively. The 3 year overall and disease-free survival were 70.8% and 64.6%, respectively. Patients with adenocarcinoma had worse disease-free survival (HR 2.38; 95% CI 1.01 to 5.60; p=0.047) and overall survival (HR 2.99; 95% CI 1.14 to 7.75; p=0.025) compared with squamous cell carcinoma. In multivariate analysis, metastatic pelvic lymph node size of >2.5 cm (HR 4.38; 95% CI 1.65 to 11.6; p=0.003) and incomplete response to radiotherapy (HR 5.14; 95% CI 1.60 to 16.4; p=0.006) maintained the negative impact for overall survival. CONCLUSIONS: We found that pelvic lymph node size and incomplete response to radiotherapy negatively impact overall survival in patients with advanced cervical cancer with pelvic lymph node involvement. This finding may help to stratify risk in this group of patients.

Fusion Cell Markers in Circulating Tumor Cells from Patients with High-Grade Ovarian Serous Carcinoma.

Cancer is primarily a disease in which late diagnosis is linked to poor prognosis, and unfortunately, detection and management are still challenging. Circulating tumor cells (CTCs) are a potential resource to address this disease. Cell fusion, an event discovered recently in CTCs expressing carcinoma and leukocyte markers, occurs when ≥2 cells become a single entity (hybrid cell) after the merging of their plasma membranes. Cell fusion is still poorly understood despite continuous evaluations in in vitro/in vivo studies. Blood samples from 14 patients with high-grade serous ovarian cancer (A.C. Camargo Cancer Center, São Paulo, Brazil) were collected with the aim to analyze the CTCs/hybrid cells and their correlation to clinical outcome. The EDTA collected blood (6 mL) from patients was used to isolate/identify CTCs/hybrid cells by ISET. We used markers with possible correlation with the phenomenon of cell fusion, such as MC1-R, EpCAM and CD45, as well as CEN8 expression by CISH analysis. Samples were collected at three timepoints: baseline, after one month (first follow-up) and after three months (second follow-up) of treatment with olaparib (total sample = 38). Fourteen patients were included and in baseline and first follow-up all patients showed at least one CTC. We found expression of MC1-R, EpCAM and CD45 in cells (hybrid) in at least one of the collection moments. Membrane staining with CD45 was found in CTCs from the other cohort, from the other center, evaluated by the CellSearch® system. The presence of circulating tumor microemboli (CTM) in the first follow-up was associated with a poor recurrence-free survival (RFS) (5.2 vs. 12.2 months; p = 0.005). The MC1-R expression in CTM in the first and second follow-ups was associated with a shorter RFS (p = 0.005). CEN8 expression in CTCs was also related to shorter RFS (p = 0.035). Our study identified a high prevalence of CTCs in ovarian cancer patients, as well as hybrid cells. Both cell subtypes demonstrate utility in prognosis and in the assessment of response to treatment. In addition, the expression of MC1-R and EpCAM in hybrid cells brings new perspectives as a possible marker for this phenomenon in ovarian cancer.

Impact of Sentinel Node Mapping in Decreasing the Risk of Lymphocele in Endometrial Cancer.

OBJECTIVE: Due to the growing evidence of sentinel lymph node (SLN) mapping in endometrial cancer (EC), our aim was to evaluate the impact of SLN mapping and other clinical-pathological variables in the risk of developing lymphocele. METHODS: We retrospectively analyzed a series of patients with ECs who underwent lymph node staging with SLN mapping with or without systematic pelvic ± para-aortic lymphadenectomy from November 2012 to January 2020. The lymphocele diagnosis was performed by computed tomography or magnetic resonance imaging. RESULTS: Of 348 patients included, 178 underwent SLN mapping only and 170 underwent SLN mapping and systematic lymphadenectomy (46.5% pelvic only; 53.5% pelvic and para-aortic). Seventy-three (21%) patients had open surgery and 275 (79%) had a minimally invasive approach. After a median follow-up of 25.4 months, the overall prevalence of lymphocele was 8.6% (n = 30), with 29 cases in a pelvic location. Lymphocele was found in 3.4% (n = 6/178) of patients submitted to SLN mapping only, compared with 14.1% (n = 24/170) among those who underwent SLN with lymphadenectomy (p = 0.009). Among those patients with lymphocele, seven (23.3%) were symptomatic and five (16.6%) required drainage. All symptomatic cases occurred in lymphoceles larger than 4 cm (p = 0.001). Neither resected lymph node count nor the type of systematic lymphadenectomy were related to the presence of lymphocele. Systematic lymphadenectomy was the only factor that emerged as a risk factor for the presence of lymphocele in multivariate analysis (odds ratio 3.68, 95% confidence interval 1.39-9.79; p = 0.009). CONCLUSIONS: Our data suggest that SLN mapping independently decreases the risk of lymphocele formation compared with full lymphadenectomy in EC.

Impact of BRCA1/2 Mutations on the Efficacy of Secondary Cytoreductive Surgery.

BACKGROUND: Phase III trials evaluating the role of secondary cytoreductive surgery (SCS) in recurrent ovarian cancer have pointed to the importance of patient selection. Two studies showed conflicting results regarding the benefit of SCS in BRCA1/2 mutation carriers. Our aim was to evaluate the impact of SCS on recurrent ovarian cancer according to BRCA1/2 status. METHODS: All patients with ovarian carcinoma with platinum-sensitive recurrent disease and tested for BRCA1/2 germline mutations were included. Cox regression and log rank test were used to evaluate the impact of SCS on progression-free survival (PFS) and the influence of BRCA1/2 mutations on the effect of SCS. RESULTS: 127 patients were included, 45.6% were treated with SCS and chemotherapy and 54.3% treated with chemotherapy only. Patients treated with SCS were younger, presented better performance status, had lower CA125, and had a longer platinum-free interval. In multivariate analysis SCS was associated with longer PFS (HR 0.42, 95% CI 0.25-0.72, p = 0.002). BRCA1/2 mutations were found in 35 patients (27.5%), and 11.8% of patients were treated with PARP inhibitors. Although not statistically significant, both BRCA1/2 wild type patients (PFS: 21.6 vs 18.4 months; p = 0.114) and BRCA1/2 mutation carriers (PFS: 23.1 vs 18.2 months, p = 0.193) appeared to derive benefit from SCS. DISCUSSION: The present study suggests a benefit of SCS irrespective of BRCA1/2 status among patients mostly not treated with PARP inhibitor. Further data on post hoc analysis from the phase III trials are warranted to confirm whether BRCA1/2 mutated patients should be selected for SCS.

Predictive Factors for Residual Disease After Conization in Cervical Cancer.

OBJECTIVE: The aim of this study was to evaluate predictive factors for the presence of residual disease after conization followed by definitive surgery in cervical cancer, and suggest a margin distance threshold that could predict residual disease. METHODS: We retrospectively analyzed a series of 42 patients with early-stage cervical cancer who underwent primary conization before definitive surgical treatment from March 2009 to May 2020. All conization specimens were reviewed for endocervical, ectocervical, and radial margins. Cases with residual disease in magnetic resonance imaging before definitive surgery were excluded. RESULTS: Thirty-three (78.6%) patients underwent hysterectomies and 9 (21.4%) trachelectomies ± lymph node staging. Twelve (28.6%) cases were stage IA1, 5 (11.8%) cases were stage IA2, 13 (31%) cases were stage IB1, 11 (26.2%) cases were stage IB2, and 1 (2.4%) case was stage IIIC1 [International Federation of Gynecology and Obstetrics (FIGO) 2019]. We found residual disease in 17 (40.4%) surgical specimens. Of the 20 patients with negative margins, there were still 3 (15%) cases with residual disease. Conversely, residual disease was identified in 14 (63.6%) of the 22 patients with positive cone margins (p = 0.001). Tumor size [odds ratio (OR) 1.71, 95% confidence interval (CI) 1.02-1.33] and positive endocervical margin status (OR 33.6, 95% CI 3.85-293.3) were related to a higher risk of residual disease in multivariate analysis. Notably, all patients with tumors larger than 2 cm had residual disease, in contrast to 29.4% in lesions up to 2 cm (p = 0.002). CONCLUSION: We found that tumor size and positive margin were predictive factors for residual disease. We could not suggest a reliable minimum margin distance threshold that could predict residual disease.

Comparison of dose-dense vs. 3-weekly paclitaxel and carboplatin in the first-line treatment of ovarian cancer in a propensity score-matched cohort.

BACKGROUND: Benefit of carboplatin and dose-dense weekly paclitaxel (ddCT) in first line treatment of ovarian cancer patients has been different in Western and Asian studies. In the present study we compare progression-free survival (PFS) of ddCT to three-weekly carboplatin and paclitaxel (CT) in first-line treatment of ovarian carcinoma in a single institution in a Western population. MATERIALS AND METHODS: We conducted a retrospective review of medical records from patients with ovarian carcinoma treated in a tertiary cancer center from 2007 to 2018. All patients treated with ddCT or CT in the first-line setting were included. Patients who received first-line bevacizumab were not included. PFS and overall survival (OS) were compared in a propensity score-matched cohort to address selection bias. Patients were matched according to age, ECOG performance status, CA 125, FIGO stage, residual disease, and histological subtype, in a 1:2 ratio. RESULTS: Five hundred eighty-eight patients were eligible for propensity score matching, the final cohort consisted of 69 patients treated with ddCT and 138 CT group. Baseline characteristics were well-balanced. After a median follow-up of 65.1 months, median PFS was 29.3 vs 20.0 months, favouring ddCT treatment (p = 0.035). In the multivariate cox regression ddCT showed a 18% lower risk of progression (HR 0.82, 95% CI 0.68-0.99, p = 0.04). Overall survival data is immature, but suggested better outcomes for ddCT (not reached versus 78.8 months; p = 0.07). CONCLUSION: Our retrospective study has shown superior PFS of ddCT over CT regimen in first-line treatment of ovarian carcinoma in a Western population not treated with bevacizumab.

Pathological factors associated with non-sentinel lymph node metastasis in early stage cervical cancer.

OBJECTIVE: To analyze the predictive factors for non-sentinel lymph node (non-SLN) metastasis in early-stage cervical cancer. METHODS: We analyzed a series of 113 patients who underwent sentinel lymph node (SLN) mapping for cervical cancer. The SLNs were examined by immunohistochemistry (IHC) when the hematoxylin-eosin stain was negative. RESULTS: The overall bilateral detection rate was 81.5%, with a median of two SLNs resected. The study ultimately included 92 patients with SLNs that were mapped who had also undergone systematic pelvic lymph node dissection. Thirteen (14.1%) patients had positive SLNs, with a median of one positive SLN. Regarding the size of SLN metastasis, one (1.1%) had isolated tumor cells (ITC), seven (7.6%) had micrometastases, and five (5.4%) had macrometastases. Notably, 46.1% (6/13) had lymph node metastases detected only after IHC. Five (38.5%) cases had positive non-SLNs, with a median count of one positive lymph node. Parametrial invasion was the only risk factor for positive non-SLN (p = .045). Regarding the size of SLN metastasis, non-SLN involvement was present in the only case with ITC (1/1), 42.9% (3/7) of cases with micrometastases, and in 20% (1/5) with macrometastases. CONCLUSIONS: Our data suggest that parametrial invasion correlates with the risk of non-SLN metastasis in cervical cancer.

Size of Sentinel Node Metastasis Predicts Non-sentinel Node Involvement in Endometrial Cancer.

PURPOSE: To analyze the relationship between the size of metastatic sentinel lymph nodes (SLNs) and the risk of non-sentinel lymph node (non-SLN) metastasis in endometrial cancer. PATIENTS AND METHODS: From a total of 328 patients with endometrial cancer who underwent SLN mapping from January 2013 to April 2019, 142 patients also underwent systematic completion pelvic ± paraaortic node dissections, and they form the basis of this study. The SLNs were examined by immunohistochemistry (IHC) when the hematoxylin-eosin stain was negative. RESULTS: The median age was 60 years. The overall detection rate for SLNs was 87.5%, and bilateral SLNs were observed in 66.2%, with a median of 2 SLNs resected (range 1-8). Twenty-nine (20.4%) cases had positive SLNs, with a median of one positive SLN. Regarding the size of SLN metastasis, 5 (3.5%) cases had isolated tumor cells (ITCs), 13 (9.2%) had micrometastases, and 11 (7.7%) had macrometastases. Notably, 14/29 (48.3%) had node metastases that were detected after IHC. Eight (27.6%) patients had positive non-SLNs, with a median count of 7 positive nodes (range 2-23). Regarding the size of SLN metastasis, non-SLN involvement was not present in cases with ITC (0/5) but was present in 15.4% (2/13) of cases with micrometastases and 54.5% (6/11) of cases with macrometastases. The only risk factor for positive non-SLNs was the size of SLN metastasis. CONCLUSIONS: Our data suggest that size of SLN metastasis is associated with the risk of non-SLN metastasis. No patients with ITCs in SLNs had another metastatic lymph node in this study.

Adnexal Involvement in Endometrial Cancer: Prognostic Factors and Implications for Ovarian Preservation.

PURPOSE: To determine the risk factors related to adnexal involvement in endometrial cancer (EC) and its implications for ovarian preservation in young women. METHODS: We analyzed a series of 802 patients who were treated at AC Camargo Cancer Center from July 1991 to July 2017. Patients who had peritoneal or systemic dissemination (stage IV) were excluded. Chi square and Fisher's exact tests were used to analyze the correlations between categories and clinicopathological variables. Multivariate analysis was performed by logistic regression. RESULTS: Forty-nine (6.2%) patients had adnexal involvement-43 (5.4%) ovarian and 24 (2.9%) tubal. After excluding the 14 (28%) cases with suspicious findings, 788 subjects were analyzed and adnexal involvement found in 35 (4.4%) cases. Adnexal involvement was statistically related to non-endometrioid histologies (12.6% vs. 3.1%; p < 0.001), lymph node metastasis (17% vs. 2.6%; p < 0.001), histological grade 3 tumors (9.4% vs. 2.1%; p < 0.001), presence of LVSI (14.2% vs. 2.4%; p < 0.001), and deep myometrial invasion (≥ 50%) (10.8% vs. 3.5%; p < 0.001). Although age younger than 45 years had higher risk of adnexal involvement, it was not statistically significant (8.9% vs. 4.2%; p = 0.13). Seven (14.2%) patients with adnexal involvement were aged < 45 years, 3 of whom (42.8%) had suspicious adnexal masses that were detected before surgery. Notably, all patients aged < 45 years and with adnexal involvement had at least 1 risk factor, such as presence of LVSI, grade 3 disease, node metastasis, or deep myometrial invasion. No patient with clinically normal ovaries and aged under 45 years, with endometrioid grades 1 and 2, superficial myometrial invasion, or node negativity had adnexal involvement. CONCLUSIONS: Ovarian preservation may be considered for patients younger than 45 years old with low-risk EC (grades 1 and 2 tumors, absence of LVSI, and myometrial invasion < 50%).

Guidelines of the Brazilian Society of Oncologic Surgery for pelvic exenteration in the treatment of cervical cancer.

BACKGROUND AND OBJECTIVES: The primary treatment for locally advanced cases of cervical cancer is chemoradiation followed by high-dose brachytherapy. When this treatment fails, pelvic exenteration (PE) is an option in some cases. This study aimed to develop recommendations for the best management of patients with cervical cancer undergoing salvage PE. METHODS: A questionnaire was administered to all members of the Brazilian Society of Surgical Oncology. Of them, 68 surgeons participated in the study and were divided into 10 working groups. A literature review of studies retrieved from the National Library of Medicine database was carried out on topics chosen by the participants. These topics were indications for curative and palliative PE, preoperative and intraoperative evaluation of tumor resectability, access routes and surgical techniques, PE classification, urinary, vaginal, intestinal, and pelvic floor reconstructions, and postoperative follow-up. To define the level of evidence and strength of each recommendation, an adapted version of the Infectious Diseases Society of America Health Service rating system was used. RESULTS: Most conducts and management strategies reviewed were strongly recommended by the participants. CONCLUSIONS: Guidelines outlining strategies for PE in the treatment of persistent or relapsed cervical cancer were developed and are based on the best evidence available in the literature.

Genomic profiling in ovarian cancer retreated with platinum based chemotherapy presented homologous recombination deficiency and copy number imbalances of CCNE1 and RB1 genes.

BACKGROUND: Ovarian carcinomas presenting homologous recombination deficiency (HRD), which is observed in about 50% of cases, are more sensitive to platinum and PARP inhibitor therapies. Although platinum resistant disease has a low chance to be responsive to platinum-based chemotherapy, a set of patients is retreated with platinum and some of them are responsive. In this study, we evaluated copy number alterations, HR gene mutations and HR deficiency scores in ovarian cancer patients with prolonged platinum sensitivity. METHODS: In this retrospective study (2005 to 2014), we selected 31 patients with platinum resistant ovarian cancer retreated with platinum therapy. Copy number alterations and HR scores were evaluated using the OncoScan® FFPE platform in 15 cases. The mutational profile of 24 genes was investigated by targeted-NGS. RESULTS: The median values of the four HRD scores were higher in responders (LOH = 15, LST = 28, tAI = 33, CS = 84) compared with non-responders (LOH = 7.5, LST = 17.5, tAI = 23, CS = 47). Patients with high LOH, LST, tAI and CS scores had better response rates, although these differences were not statistically significant. Response rate to platinum retreatment was 22% in patients with CCNE1 gains and 83.5% in patients with no CCNE1 gains (p = 0.041). Furthermore, response rate was 54.5% in patients with RB1 loss and 25% in patients without RB1 loss (p = 0.569). Patients with CCNE1 gains showed a worse progression free survival (PFS = 11.1 months vs 3.7 months; p = 0.008) and a shorter overall survival (OS = 39.3 months vs 7.1 months; p = 0.007) in comparison with patients with no CCNE1 gains. Patients with RB1 loss had better PFS (9.0 months vs 2.6 months; p = 0.093) and OS (27.4 months vs 3.6 months; p = 0.025) compared with cases with no RB1 loss. Four tumor samples were BRCA mutated and tumor mutations were not associated with response to treatment. CONCLUSIONS: HR deficiency was found in 60% of our cases and HRD medium values were higher in responders than in non-responders. Despite the small number of patients tested, CCNE1 gain and RB1 loss discriminate patients with tumors extremely sensitive to platinum retreatment.

Prevalence of BRCA1 and BRCA2 pathogenic and likely pathogenic variants in non-selected ovarian carcinoma patients in Brazil.

BACKGROUND: BRCA1/2 pathogenic (P) and likely pathogenic (LP) germline variants are frequent among patients with ovarian carcinoma. However, these variants have not been extensively characterized in patients with ovarian cancer in Brazil. METHODS: In this retrospective study we evaluated clinical characteristics and BRCA1/2 genetic test results from patients with ovarian carcinoma who underwent genetic counseling at A.C.Camargo Cancer Center (Brazil) between 2015 and 2017 and had performed germline genetic testing of BRCA1/2 genes. RESULTS: Among 158 patients, 33 P and LP variants and were found (20.8%), 27 in BRCA1 and six in BRCA2, and six variants of unknown clinical significance (VUS). Thirteen percent of the patients did not have Multiplex Ligation-dependent Probe Amplification (MLPA) results. Three P variants in BRCA1 were found in more than one patient: c.5266dupC (p.Gln1756Profs*74), c.3331_3334delCAAG (p.Gln1111Asnfs5*), and c.211A > G (p.Arg71Gly). One LP variant in BRCA1 had not been previously described, c.4153_4154delCT (p.Leu1385Ilefs*5). Patients with previous diagnosis of breast cancer were carriers of P or LP variant in 8 of 12 cases (66.7%), and patients with a family history of ovarian or breast cancer in first- or second-degree relatives were carriers of P or LP variant in 26.7% of cases compared to 16.9% for patients without family history (p = 0.166). CONCLUSION: Prevalence of BRCA1/2 germline P and LP variants is slightly higher than previously described by the largest occidental studies, with a high prevalence of variant c.5266dupC (p.Gln1756Profs*74) in BRCA1 observed. Moreover, we identified a new LP variant.

Prognostic impact of platinum sensitivity in ovarian carcinoma patients with brain metastasis.

BACKGROUND: Brain metastasis (BM) is a rare event in ovarian cancer patients. The current prognostic scores that have been used for other tumors do not account for specific characteristics of ovarian cancer, such as platinum sensitivity. METHODS: This retrospective cohort study examined patients with ovarian carcinoma and BM who were treated at a single institution from January 2007 to December 2017. Clinical data on the diagnosis of BM and follow-up were collected. Cox regression was used to evaluate prognostic factors for overall survival (OS). RESULTS: Of 560 patients, 26 presented with BM. Eight patients were treated with surgery, 15 with whole-brain radiotherapy (RT), and 5 with stereotactic RT, and 4 patients received systemic treatment at the diagnosis of BM. The median OS was 10.8 months. The following factors were associated with OS: platinum-sensitive recurrence (HR 0.34, 95% CI 0.12-0.99; p = 0.049), higher number of previous treatment lines (HR 1.57, 95% CI 1.12-2.19; p = 0.008), ECOG performance status (HR 2.52, 95% CI 1.24-5.09; p = 0.010), and longer interval from initial diagnosis to BM (p = 0.025). Notably, the number of brain metastasis, the largest tumor size, and progression outside of the CNS were not related to survival. Platinum sensitivity was not associated with any of the classic prognostic factors in brain metastasis patients such as number or size of brain metastasis or disease progression outside the CNS strengthening the hypothesis of the importance of platinum sensitivity to the prognosis of ovarian cancer patients with BM. CONCLUSIONS: The factors related to the biological behavior of the ovarian cancer such as platinum sensitivity at the time of BM diagnosis, fewer number of previous treatment lines and interval from initial diagnosis were associated with survival in ovarian cancer patients with BM, while factors that are usually related to survival in BM in other cancers were not associated with survival in this cohort of ovarian cancer patients. The small number of patients did not allow us to exclude the prognostic role of these former factors that were not associated with survival in the present cohort.

[Year in review : geriatrics]. / Gériatrie.

In 2018, new recommendations about the prevention of falls and fractures emphasized the benefits from exercise and from multimodal prevention programs but did not endorse any more vitamin D supplementation for falls prevention. Results were contrasted for several studies testing exercise (negative) and cognitive training (mixed results) in the management of older patients suffering from neurocognitive disorders. The new direct oral anticoagulants are increasingly prescribed in older patients despite the paucity of data. New information has been released in 2018 from « real-world ¼ data that seem reassuring about their risk/benefit ratio in old-old patients, provided a careful prescription. Finally, the Mediterranean diet is still gaining credit with a new study showing its benefits in preventing frailty in community-dwelling older persons.

En 2018, l'intérêt de l'activité physique et des programmes de prévention multimodaux est confirmé pour la prévention des chutes, mais l'utilisation de la vitamine D dans cette indication est remise en question. Pour les pathologies neurocognitives, les résultats sont contrastés concernant l'activité physique, alors qu'une revue systématique confirme les bénéfices, certes modestes, de l'entraînement cognitif sur les performances cognitives et la qualité de vie des patients et de leurs proches. Les nouveaux anticoagulants sont de plus en plus largement utilisés chez les patients âgés malgré des données encore limitées, mais plusieurs études du « monde réel ¼ semblent confirmer leur bon rapport risques/bénéfices aussi chez ces patients. Le régime méditerranéen a le vent en poupe, une étude rapporte un bénéfice sur l'incidence de la fragilité.