Implications of the Hippo Pathway Dysregulation in Uterine Leiomyosarcoma.

BACKGROUND/AIM: Uterine leiomyosarcomas (uLMS) are the most common mesenchymal tumors of the female genital tract. uLMS genetics encompass complex karyotypes with no specific molecular alterations. The Hippo pathway has been implicated in the pathogenesis of epithelioid hemangio-endotheliomas and endometrial sarcomas. Hippo pathway effectors are YAP1 and TAZ co-transcriptional factors. PATIENTS AND METHODS: We studied Hippo pathway in a series of 32 uLMS patients and its association with clinicopathological parameters. MATERIALS AND METHODS: Immunohistochemical analysis of YAP1 and TAZ proteins accompanied with fluorescent in situ hybridization study of YAP1 gene was performed in patient samples. Age, sex, tumor size, stage at the time of diagnosis and treatment have been analyzed. Overall survival (OS) was calculated from the time of diagnosis until death, loss of follow up or data cut-off. RESULTS: Hippo signaling was found to be dysregulated in 20 (62.5%) patients with uLMS. Regarding OS we detected a trend of Hippo deregulation, designating it as a positive prognostic factor. CONCLUSION: The Hippo pathway is implicated in uLMS oncogenesis, since nuclear expression of YAP1 was detected in 17 (53.1%) of the 32 patients with immunohistochemistry and YAP1 amplification was found in 8 (25%) patients.

The Prognostic Role of BRD4 Expression in High-Grade Serous Ovarian Cancer.

BACKGROUND: Bromodomain and extra-terminal (BET) domain proteins that bind to acetylated lysine residues of histones serve as the "readers" of DNA acetylation. BRD4 is the most thoroughly studied member of the BET family and regulates the expression of key oncogenes. BRD4 gene amplification has been identified in ovarian cancer (~18-19%) according to The Cancer Genome Atlas (TCGA) analysis. BET inhibitors are novel small molecules that displace BET proteins from acetylated histones and are currently tested in Phase I/II trials. We here aim to explore the prognostic role of the BRD4 gene and protein expression in the ascitic fluid of patients with advanced FIGO III/IV high-grade serous ovarian carcinoma (HGSC). METHODS: Ascitic fluid was obtained from 28 patients with advanced stage (FIGO III/IV) HGSC through diagnostic/therapeutic paracentesis or laparoscopy before the initiation of chemotherapy. An amount of ~200 mL of ascitic fluid was collected from each patient and peripheral blood mononuclear cells (PBMCs) were isolated. Each sample was evaluated for BRD4 and GAPDH gene expression through RT-qPCR and BRD4 protein levels through enzyme-linked immunosorbent assay (ELISA). The study protocol was approved by the Institutional Review Board of Alexandra University Hospital and the Committee on Ethics and Good Practice (CEGP) of the National and Kapodistrian University of Athens (NKUA). RESULTS: Low BRD4 gene expression was associated with worse prognosis at 12 months compared to intermediate/high expression (95% CI; 1.75-30.49; p = 0.008). The same association was observed at 24 months although this association was not statistically significant (95% CI; 0.96-9.2; p = 0.065). Progression-free survival was shorter in patients with low BRD4 gene expression at 12 months (5.6 months; 95% CI; 2.6-8.6) compared to intermediate/high expression (9.8 months; 95% CI; 8.3-11.3) (95% CI; 1.2-16.5; p = 0.03). The same association was confirmed at 24 months (6.9 months vs. 13.1 months) (95% CI; 1.1-8.6; p = 0.048). There was a trend for worse prognosis in patients with high BRD4 protein levels versus intermediate/low BRD4 protein expression both at 12 months (9.8 months vs. 7.6 months; p = 0.3) and at 24 months (14.2 months vs. 16.6 months; p = 0.56) although not statistically significant. Again, there was a trend for shorter PFS in patients with high BRD4 protein expression although not statistically significant both at 12 months (p = 0.29) and at 24 months (p = 0.47). CONCLUSIONS: There are contradictory data in the literature over the prognostic role of BRD4 gene expression in solid tumors. In our study, intermediate/high BRD4 gene expression was associated with a favorable prognosis in terms of overall survival and progression-free survival compared to low BRD4 gene expression.

The Impact of Positive Peritoneal Cytology on the Survival Rates of Early-Stage-Disease Endometrial Cancer Patients: Systematic Review and Meta-Analysis.

Background and Objectives: The impact of positive peritoneal cytology has been a matter of controversy in early-stage endometrial cancer for several years. The latest staging systems do not take into consideration its presence; however, emerging evidence about its potential harmful effect on patient survival outcomes suggests otherwise. In the present systematic review and meta-analysis, we sought to accumulate current evidence. Materials and Methods: Medline, Scopus, the Cochrane Central Register of Controlled Trials CENTRAL, Google Scholar and Clinicaltrials.gov databases were searched for relevant articles. Effect sizes were calculated in Rstudio using the meta function. A sensitivity analysis was carried out to evaluate the possibility of small-study effects and p-hacking. Trial sequential analysis was used to evaluate the adequacy of the sample size. The methodological quality of the included studies was assessed using the Newcastle-Ottawa scale. Results: Fifteen articles were finally included in the present systematic review that involved 19,255 women with early-stage endometrial cancer. The Newcastle-Ottawa scale indicated that the majority of included studies had a moderate risk of bias in their selection of participants, a moderate risk of bias in terms of the comparability of groups (positive peritoneal cytology vs. negative peritoneal cytology) and a low risk of bias concerning the assessment of the outcome. The results of the meta-analysis indicated that women with early-stage endometrial cancer and positive peritoneal cytology had significantly lower 5-year recurrence-free survival (RFS) (hazards ratio (HR) 0.26, 95% CI 0.09, 0.71). As a result of the decreased recurrence-free survival, patients with positive peritoneal cytology also exhibited reduced 5-year overall survival outcomes (HR 0.50, 95% CI 0.27, 0.92). The overall survival of the included patients was considerably higher among those that did not have positive peritoneal cytology (HR 12.76, 95% CI 2.78, 58.51). Conclusions: Positive peritoneal cytology seems to be a negative prognostic indicator of survival outcomes of patients with endometrial cancer. Considering the absence of data related to the molecular profile of patients, further research is needed to evaluate if this factor should be reinstituted in future staging systems.

Pre-treatment thrombocytosis and ovarian cancer survival: A meta-analysis.

An association between thrombocytosis and cancer progression and decreased survival has been observed for various forms of cancer. The aim of this study was to evaluate the impact of pre-treatment thrombocytosis on ovarian cancer survival. Medline, Scopus, Clinicaltrials.gov, Cochrane Central Register of Controlled Trials CENTRAL and Google Scholar were searched systematically for studies that compared survival outcomes of patients with ovarian cancer who had pre-treatment thrombocytosis with survival outcomes of patients with normal platelet counts. Fourteen articles were retrieved, with a total of 5414 patients with ovarian cancer. The methodological quality of included studies ranged between moderate and high. Patients with advanced stage disease were more likely to have pre-treatment thrombocytosis, and this was associated with lower rates of optimal debulking. Thrombocytosis was also associated with increased likelihood of recurrence of ovarian cancer [hazard ratio (HR) 2.01, 95 % confidence interval (CI) 1.34-3.01] and increased risk of death from ovarian cancer (HR 2.29, 95 % CI 1.35-3.90). The incidence of deep vein thrombosis was comparable in both groups (odds ratio 1.62, 95 % CI 0.48-5.46). Considering these findings, it is evident that pre-treatment thrombocytosis in patients with ovarian cancer is associated with increased risk of recurrence and death. Pre-treatment thrombocytosis is a potential sign of advanced stage disease, and may be predictive of suboptimal tumour debulking during surgery. Its association with other factors that affect survival, including platinum resistance and response to targeted therapy, remains poorly explored, although preliminary data suggest a potential correlation.

Chemotherapy response score as a predictor of survival in ovarian cancer patients.

OBJECTIVE: The chemotherapy response score (CRS) has been widely adopted as a predictive tool for ovarian cancer survival. In the present study, we seek to define differences in survival rates among patients grouped in the traditionally established three-tiered system and those who have not been offered debulking surgery. STUDY DESIGN: We designed a retrospective cohort study involving women treated with chemotherapy and offered interval or late debulking surgery for ovarian cancer. Twenty-eight women were not considered for a debulking procedure for various reasons. Of the 89 women who were finally offered interval debulking or late debulking surgery, 28 had a CRS 1 score, 34 had a CRS 2 score and 27 had a CRS 3 score. RESULTS: Significant differences were noted in the progression-free survival (PFS) and overall survival (OS) of patients based on the CRS stratification, although survival rates were considerably longer for all three groups compared to those of patients who were not offered surgery. Cox regression univariate analysis revealed that suboptimal debulking and CRS 1 or no surgery had a significant negative impact on PFS and OS rates. The binary stratification of CRS (CRS 1-2 vs CRS 3) revealed comparable differences in the PFS and OS to those in the groups that were stratified as platinum resistant and platinum sensitive. CONCLUSION: The chemotherapy response score is a significant determinant of ovarian cancer survival that helps evaluate the risk of early disease relapse and death and may soon be useful in guiding patient-tailored treatment.

Cardiovascular complications of ribociclib in breast cancer patients.

Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have unprecedentedly advanced hormone-dependent breast cancer treatment paradigm. In the metastatic setting, ribociclib has consistently demonstrated survival benefit in pre-, peri-, and postmenopausal patients, conjugating efficacy with health-related quality of life preservation. Accordingly, the emergence of cardiac and/or vascular adverse events related to this novel targeted agent is gaining significant interest. This narrative review provides an overview of the incidence and spectrum of cardiovascular toxicity, in both clinical trial framework and real-world evidence. The potential pathogenetic mechanism, along with the available diagnostic parameters including biomarkers, and proper management, are also summarized.

Microsatellite Instability Is Insufficiently Used as a Biomarker for Lynch Syndrome Testing in Clinical Practice.

PURPOSE: The pan-cancer presence of microsatellite instability (MSI)-positive tumors demonstrates its clinical utility as an agnostic biomarker for identifying immunotherapy-eligible patients. Additionally, MSI is a hallmark of Lynch syndrome (LS), the most prevalent cancer susceptibility syndrome among patients with colorectal and endometrial cancer. Therefore, MSI-high results should inform germline genetic testing for cancer-predisposing genes. However, in clinical practice, such analysis is frequently disregarded. METHODS: A next-generation sequencing (NGS)-based technique was used for MSI analysis in 4,553 patients with various tumor types. Upon request, somatic BRAF gene analysis was conducted. In addition, hereditary testing of cancer-associated genes was performed in MSI-high cases using a capture-based NGS protocol. MLH1 promoter methylation analysis was conducted retrospectively in patients with colorectal and endometrial cancer to further investigate the origin of MSI at the tumor level. RESULTS: The MSI positivity rate for the entire cohort was 5.27%. Endometrial, gastric, colorectal, urinary tract, and prostate cancers showed the highest proportion of MSI-high cases (15.69%, 8.54%, 7.40%, 4.55%, and 3.19%, respectively). A minority of 45 patients (22.73%) among the MSI-high cases underwent germline testing to determine whether the mismatch repair pathway deficiency was inherited. 24.44% of those who performed the genetic test carried a pathogenic variant in an LS-associated gene. Three MSI-high individuals had non-LS gene alterations, including BRCA1, BRCA2, and CDKN2A pathogenic variants, indicating the presence of non-LS-associated gene alterations among MSI-high patients. CONCLUSION: Although MSI analysis is routinely performed in clinical practice, as many as 77% of MSI-high patients do not undergo LS genetic testing, despite international guidelines strongly recommending it. BRAF and MLH1 methylation analysis could shed light on the somatic origin of MSI in 42.50% of the MSI-high patients; however, MLH1 analysis is barely ever requested in clinical practice.

Concordance between Three Homologous Recombination Deficiency (HRD) Assays in Patients with High-Grade Epithelial Ovarian Cancer.

Our aim was to evaluate the concordance between the Myriad MyChoice and two alternative homologous recombination deficiency (HRD) assays (AmoyDx HRD Focus NGS Panel and OncoScan™) in patients with epithelial ovarian cancer (EOC). Tissue samples from 50 patients with newly diagnosed EOC and known Myriad MyChoice HRD status were included. DNA aliquots from tumor samples, previously evaluated with Myriad MyChoice and centrally reassessed, were distributed to laboratories to assess their HRD status using the two platforms, after being blinded for the Myriad MyChoice CDx HRD status. The primary endpoint was the concordance between Myriad MyChoice and each alternative assay. Tumor samples were evaluated with an AmoyDx® HRD Focus Panel (n = 50) and with OncoScan™ (n = 43). Both platforms provided results for all tumors. Analysis showed that correlation was high for the Myriad MyChoice GI score and AmoyDx® HRD Focus Panel (r = 0.79) or OncoScan™ (r = 0.87) (continuous variable). The overall percent agreement (OPA) between Myriad MyChoice GI status (categorical variable) and each alternative assay was 83.3% (68.6-93.3%) with AmoyDx and 77.5% (61.5-89.2%) with OncoScan™. The OPA in HRD status between Myriad MyChoice and AmoyDx was 88.6% (75.4-96.2). False-positive rates were 31.6% (6/19) for AmoyDx GI status and 31.9% (7/22) for OncoScan™, while false-negative rates were 0% (0/28, AmoyDx) and 11.1% (2/18, OncoScan™) compared with the Myriad MyChoice GI status. While substantial concordance between Myriad MyChoice and alternative assays was demonstrated, prospective validation of the analytical performance and clinical relevance of these assays is warranted.

Spontaneous tumor lysis syndrome in patients with solid tumors: a scoping review of the literature.

No systematic synthesis of all cases of spontaneous tumor lysis syndrome (STLS) in adult patients with solid tumors is available to date. Herein, we aim to recognize specific STLS characteristics and parameters related to a worse prognosis. We conducted a systematic search for randomized controlled trials, cohorts, case-control studies, and case reports. The primary endpoints were death and the need for renal replacement therapy (RRT) due to STLS. We estimated crude odds ratios (ORs) with 95% confidence intervals (95%CI) via univariate binary logistic regression. We included one cohort of 9 patients and 66 case reports of 71 patients [lung cancer 15(21.1%)]. Regarding the case reports, most patients [61(87.1%)] had metastatic disease [liver 46(75.4%)], developed acute kidney injury [59(83.1%)], needed RRT [25(37.3%)], and died due to STLS [36(55.4%)]. Metastatic disease, especially in the liver [p = 0.035; OR (95%CI): 9.88 (1.09, 89.29)] or lungs [p = 0.024; 14.00 (1.37, 142.89)], was significantly associated with STLS-related death compared to no metastasis. Cases resulting in death had a significantly higher probability of receiving rasburicase monotherapy than receiving no urate-lowering agents [p = 0.034; 5.33 (1.09, 26.61)], or the allopurinol-rasburicase combination [p = 0.023; 7.47 (1.40, 39.84)]. Patients receiving allopurinol were less likely to need RRT compared to those not receiving it or those receiving rasburicase. In conclusion, current anecdotal evidence demonstrated that metastatic disease, especially in the liver and lungs, may be associated with STLS-related death compared to no metastatic status. Careful surveillance of high-risk cases within larger studies is essential to identify markers predicting morbidity or mortality.

Optimal Time Interval between Neoadjuvant Platinum-Based Chemotherapy and Interval Debulking Surgery in High-Grade Serous Ovarian Cancer.

BACKGROUND: There is limited data on the optimal time interval between the last dose of neoadjuvant chemotherapy (NACT) and interval debulking surgery (IDS) in high-grade serous ovarian carcinoma (HGSC). METHODS: We retrospectively identified patients with stage IIIC/IV HGSC who received NACT followed by IDS during a 15-year period (January 2003-December 2018) in our Institution. RESULTS: Overall, 115 patients with stage IIIC/IV HGSC were included. The median age of diagnosis was 62.7 years (IQR: 14.0). A total of 76.5% (88/115) of patients were diagnosed with IIIC HGSC and 23.5% (27/115) with IV HGSC. Median PFS was 15.7 months (95% CI: 13.0-18.5), and median OS was 44.7 months (95% CI: 38.8-50.5). Patients were categorized in groups according to the time interval from NACT to IDS: <4 weeks (group A); 4-5 weeks (group B); 5-6 weeks (group C); >6 weeks (group D). Patients with a time interval IDS to NACT ≥4 weeks had significantly shorter PFS (p = 0.004) and OS (p = 0.002). Median PFS was 26.6 months (95% CI: 24-29.2) for patients undergoing IDS <4 weeks after NACT vs. 14.4 months (95% CI: 12.6-16.2) for those undergoing IDS later (p = 0.004). Accordingly, median OS was 66.3 months (95% CI: 39.1-93.4) vs. 39.4 months (95% CI: 31.8-47.0) in the <4 week vs. >4 week time interval NACT to IDS groups (p = 0.002). On multivariate analysis, the short time interval (<4 weeks) from NACT to IDS was an independent factor of PFS (p = 0.004) and OS (p = 0.003). CONCLUSION: We have demonstrated that performing IDS within four weeks after NACT may be associated with better survival outcomes. Multidisciplinary coordination among ovarian cancer patients is required to avoid any unnecessary delays.

Metaplastic Carcinoma of the Breast: Case Series of a Single Institute and Review of the Literature.

Metaplastic carcinoma of the breast (MpBC) is a very rare and aggressive type of breast cancer. Data focusing on MpBC are limited. The aim of this study was to describe the clinicopathological features of MpBC and evaluate the prognosis of patients with MpBC. Eligible articles about MpBC were identified by searching CASES SERIES gov and the MEDLINE bibliographic database for the period of 1 January 2010 to 1 June 2021 with the keywords metaplastic breast cancer, mammary gland cancer, neoplasm, tumor, and metaplastic carcinoma. In this study, we also report 46 cases of MpBC stemming from our hospital. Survival rates, clinical behavior, and pathological characteristics were analyzed. Data from 205 patients were included for analysis. The mean age at diagnosis was 55 (14.7) years. The TNM stage at diagnosis was mostly stage II (58.5%) and most tumors were triple negative. The median overall survival was 66 (12-118) months, and the median disease-free survival was 56.8 (11-102) months. Multivariate Cox regression analysis revealed that surgical treatment was associated with decreased risk of death (hazard ratio 0.11, 95% confidence interval 0.02-0.54, p = 0.01) while advanced TNM stage was associated with increased risk of death (hazard ratio 1.5, 95% confidence interval 1.04-2.28, p = 0.03). Our results revealed that surgical treatment and TNM stage were the only independent risk factors related to patients' overall survival.

Chemotherapy Response Score in Ovarian Cancer Patients: An Overview of Its Clinical Utility.

The chemotherapy response score has been developed over the last few years as a predictive index of survival outcomes for patients with advanced-stage epithelial ovarian cancer undergoing interval debulking surgery. While its importance in predicting patients at risk of developing recurrences earlier seems to be important, its accuracy in determining patients with a shorter overall survival remains arbitrary. Moreover, standardization of the actual scoring system that was initially developed as a 6-tiered score and adopted as a 3-tiered score is still needed, as several studies suggest that a 2-tiered system is preferable. Given its actual importance in detecting patients with shorter progression-free survival, research should also focus on the actual predictive value of determining patients with platinum resistance, as a suboptimal patient response to standard neoadjuvant chemotherapy might help determine patients at risk of an earlier recurrence. In the present review, we summarize current knowledge retrieved from studies addressing outcomes related to the chemotherapy response score in epithelial ovarian cancer patients undergoing neoadjuvant chemotherapy and discuss differences in outcome reporting to help provide directions for further research.

Pembrolizumab in combination with bevacizumab and oral cyclophosphamide in heavily pre-treated platinum-resistant ovarian cancer.

OBJECTIVE: Immune checkpoint inhibitors have been widely implemented in the treatment of solid tumors. Combinations of immune checkpoint inhibitors with chemotherapy, anti-vascular endothelial growth factor (VEGF) compounds, and poly-adenosine diphosphate-ribose polymerase inhibitors (PARP) are under evaluation in ovarian cancer. We aim to explore the efficacy of pembrolizumab in combination with bevacizumab and oral cyclophosphamide in patients with recurrent epithelial ovarian cancer. METHODS: This was a retrospective study of all patients who received pembrolizumab in combination with bevacizumab and oral cyclophosphamide for recurrent platinum-resistant heavily pre-treated ovarian cancer in the Oncology Unit of Alexandra University Hospital from January 2021 to July 2022. RESULTS: Median age at diagnosis was 56 years (SD 9.2; range 37-72). All patients were diagnosed with high-grade serous ovarian carcinoma. Initial disease stage was International Federation of Gynecology and Obstetrics (FIGO) IIIC in most cases (11/15, 73%). Patients were heavily pre-treated with a median of six (range 4-9) prior lines of systemic therapy. All patients experienced disease progression on first-line platinum-based chemotherapy, and median progression-free survival on first-line treatment was 22 months (95% CI 10.6 to 33.4). Patients received a median of four cycles of pembrolizumab in combination with cyclophosphamide and bevacizumab (range 3-20). Overall response rate was 13% (2/15) and disease control rate was 33% (5/15) with two patients achieving partial response and three patients achieving stable disease. Median progression-free survival was 3.5 months (95% CI 1.3 to 5.7) and the 6-month progression-free survival rate was 20%. Treatment was well tolerated with no dose-limiting toxicities. CONCLUSION: We showed that the combination of pembrolizumab with bevacizumab and oral cyclophosphamide is an effective alternative in heavily pre-treated patients with ovarian cancer who have otherwise limited treatment options.

What to expect from paraneoplastic syndromes of the nervous system in uterine cancer: A review of the literature.

Neurological paraneoplastic syndromes are a rare subgroup of diseases commonly related to neuroendocrine tumors. However, they have been associated with uterine malignancies (sarcomas, endometrial carcinomas, and neuroendocrine cancers). Their presentation often correlates with a cancer diagnosis or cancer recurrence underlining their clinical significance. The most common neurological paraneoplastic syndrome in uterine cancer is cerebral degeneration with a comprehensive clinical presentation of pancerebral dysfunction. However, other neurological syndromes present with various symptoms leading to delayed diagnosis. Less common paraneoplastic neurological syndromes associated with uterine cancer are encephalitis, encephalomyelitis, subacute sensory neuropathy, sensory-motor neuropathy, dermatomyositis, cancer-associated retinopathy, opsoclonus, Guillain-Barre syndrome, necrotizing myopathy, and stiff-person syndrome. Herein, we reviewed published cases of neurological paraneoplastic syndromes in uterine cancer in order to raise awareness of these rare syndromes. We recorded patients' clinical presentation, antibodies detected, treatment, and clinical outcomes.

Digging into the NGS Information from a Large-Scale South European Population with Metastatic/Unresectable Pancreatic Ductal Adenocarcinoma: A Real-World Genomic Depiction.

Despite ongoing oncological advances, pancreatic ductal adenocarcinoma (PDAC) continues to have an extremely poor prognosis with limited targeted and immunotherapeutic options. Its genomic background has not been fully characterized yet in large-scale populations all over the world. Methods: Replicating a recent study from China, we collected tissue samples from consecutive Greek patients with pathologically-confirmed metastatic/unresectable PDAC and retrospectively investigated their genomic landscape using next generation sequencing (NGS). Findings: From a cohort of 409 patients, NGS analysis was successfully achieved in 400 cases (56.50% males, median age: 61.8 years). Consistent with a previous study, KRAS was the most frequently mutated gene in 81.50% of tested samples, followed by TP53 (50.75%), CDKN2 (8%), and SMAD4 (7.50%). BRCA1/2 variants with on-label indications were detected in 2%, and 87.50% carried a variant associated with off-label treatment (KRAS, ERBB2, STK11, or HRR-genes), while 3.5% of the alterations had unknown/preliminary-studied actionability (TP53/CDKN2A). Most of HRR-alterations were in intermediate- and low-risk genes (CHEK2, RAD50, RAD51, ATM, FANCA, FANCL, FANCC, BAP1), with controversial actionability: 8% harbored a somatic non-BRCA1/2 alteration, 6 cases had a high-risk alteration (PALB2, RAD51C), and one co-presented a PALB2/BRCA2 alteration. Elevated LOH was associated with HRR-mutated status and TP53 mutations while lowered LOH was associated with KRAS alterations. Including TMB/MSI data, the potential benefit from an NGS-oriented treatment was increased from 1.91% to 13.74% (high-MSI: 0.3%, TMB > 10 muts/MB: 12.78%). TMB was slightly increased in females (4.75 vs. 4.46 muts/MB) and in individuals with age > 60 (4.77 vs. 4.40 muts/MB). About 28.41% showed PD-L1 > 1% either in tumor or immune cells, 15.75% expressed PD-L1 ≥ 10%, and only 1.18% had PD-L1 ≥ 50%. This is the largest depiction of real-world genomic characteristics of European patients with PDAC, which offers some useful clinical and research insights.

Germline and somatic variants in ovarian carcinoma: A next-generation sequencing (NGS) analysis.

Background: Germline BRCA1/2 mutations are identified in 13-15% of ovarian cancers, while an additional 5-7% of ovarian cancers harbor somatic BRCA1/2 mutations. Beyond these mutations, germline or somatic aberrations in genes of the homologous recombination (HR) pathway such as RAD51B/C/D, PALB2, ATM, BRIP1 may confer an HR deficiency in up to 50% of ovarian tumors. Next-generation sequencing (NGS) is a high-throughput massive parallel sequencing method that enables the simultaneous detection of several mutations in entire genomes. Methods: We performed NGS analysis in 86 patients with ovarian cancer treated in the Oncology Department of Alexandra University Hospital in order to identify the molecular landscape of germline and somatic mutations in ovarian cancer. Results: The genes with the highest number of pathogenic somatic mutations in high grade serous carcinoma (HGSC) patients were TP53 [68%; 34/50] and BRCA1 [22%; 11/50] followed by somatic mutations in RB1 [2%; 1/50], NF1 [2%; 1/50], BRCA2 [2%; 1/50], AKT1 [2%; 1/50], RAD50 [2%; 1/50], PIK3CA [2%; 1/50] genes. Of note, the most common TP53 genetic polymorphism was c.524G>A p.Arg175His in exon 5. Variants of unknown significance (VUS) detected in HGSC included ROS1 [26%; 13/50], RAD50 [6%; 3/50], BRCA2 [6%; 3/50], NOTCH1 [6%; 3/50], TP53 [6%; 3/50], AR [6%; 3/50]. As for germline mutations, BRCA1 [8/30; 27%] and BRCA2 [4/30; 13%] were the most common genes bearing pathogenic alterations in HGSC, while VUS germline mutations commonly affected HRR-related genes, including ATM (c.7816A>G), BRIP (c.2327 C>A), CHEK2 (c.320-5T>A). Conclusion: Overall, genetic testing should be offered in most patients with ovarian cancer to identify mutations in HRR genes and determine the population that would be susceptible to poly ADP ribose polymerase (PARP) inhibitors.

Factors That Affect Survival Outcomes in Patients with Endometrial Clear Cell Carcinoma.

Background: Clear cell carcinoma (CCC) is a rare aggressive histologic subtype of endometrial cancer with a high relapse rate. In the present study, we sought to evaluate the prognostic factors of disease relapse and overall survival. Methods: We conducted retrospective cohort studies that included endometrial CCC patients treated at our institution. Predictive variables of survival outcomes were evaluated considering factors that determine the survival of patients with endometrioid carcinoma. Results: Fifty-five patients with a median age of 68 years and a median follow-up period of 31 months were included in the present study. Recurrence-free and overall survival rates did not differ among patients with early-stage and advanced-stage disease (RFS HR 1.51 (95% CI 0.63, 3.61), OS HR 1.36 (0.56, 3.31)). Patients with upper abdominal metastases had significantly shorter progression-free and overall survival intervals (log-rank < 0.001). The Gehan-Breslow-Wilcoxon analysis indicated worse survival rates for patients with advanced disease (p = 0.040); however, the log-rank test that gave equal weight to all time points did not reveal significant differences (log-rank = 0.576). Conclusion: Clear cell carcinoma is an aggressive histologic subtype of endometrial cancer that seems to be moderately affected by known predictors of survival rates in endometrioid carcinoma patients, except for the disease stage. Further research is needed to evaluate whether the molecular profiling of these patients may help predict survival outcomes.

Subarachnoid hemorrhage in a postpartum mother: A rare manifestation of an uncommon disease.

Subarachnoid hemorrhage, a potentially lethal medical emergency, represents an atypical clinical manifestation of gestational choriocarcinoma. We present the uncommon case of a 31-year-old primigravid female who presented with cerebral oncotic aneurysmal rupture, five weeks after vaginal delivery. Albeit the absence of neurological deficits after endovascular embolization, the patient was soon readmitted, complaining of fever, abdominal pain, and fetid lochia, all suggestive of puerperal endometritis. Upon a comprehensive diagnostic work-up, she was subsequently diagnosed with metastatic choriocarcinoma. Early initiation of multiagent chemotherapy, despite being in septic shock associated with Escherichia coli bacteremia, resulted in favorable prognosis.

Machine learning applications in gynecological cancer: A critical review.

Machine Learning (ML) represents a computer science capable of generating predictive models, by exposure to raw, training data, without being rigidly programmed. Over the last few years, ML has gained attention within the field of oncology, with considerable strides in both diagnostic, predictive, and prognostic spectrum of malignancies, but also as a catalyst of cancer research. In this review, we discuss the state of ML applications on gynecologic oncology and systematically address major technical and ethical concerns, with respect to their real-world medical practice translation. Undoubtedly, advances in ML will enable the analysis of large, rather complex, datasets for improved, cost-effective, and efficient clinical decisions.

Assessment of Postvaccination Neutralizing Antibodies Response against SARS-CoV-2 in Cancer Patients under Treatment with Targeted Agents.

The administration of a third dose of a vaccine against SARS-CoV-2 has increased protection against disease transmission and severity. However, the kinetics of neutralizing antibodies against the virus has been poorly studied in cancer patients under targeted therapies. Baseline characteristics and levels of neutralizing antibodies at specific timepoints after vaccination were compared between patients suffering from breast, ovarian or prostate cancer and healthy individuals. Breast cancer patients were treated with cyclin D kinase 4/6 inhibitors and hormonal therapy, ovarian cancer patients were treated with poly (ADP-ribose) polymerase inhibitors and prostate cancer patients were treated with an androgen receptor targeted agent. Levels of neutralizing antibodies were significantly lower in cancer patients compared to healthy individuals at all timepoints. Antibodies' titers declined over time in both groups but remained above protective levels (>50%) at 6 months after the administration of the second dose. The administration of a third dose increased neutralizing antibodies' levels in both groups. The titers of protective against SARS-CoV-2 antibodies wane over time and increase after a third dose in cancer patients under treatment.