HIPEC for gynaecological malignancies: A last update (Review).

Advanced-stage gynaecological cancer represents a clinical entity with challenging surgical treatment in an effort to optimize prognosis. Hyperthermic intraperitoneal chemotherapy (HIPEC) following cytoreductive surgery (CRS) has been reported as a method potentially eligible to improve prognosis. However, no definitive conclusions have yet been made on which types of cancer and which context HIPEC may actually have a beneficial impact. The present review discusses the efficacy and safety of HIPEC as a treatment option for patients with primary/recurrent ovarian, endometrial and cervix cancer, as well as peritoneal sarcomatosis. A literature search was conducted using MeSH terms for each topic in the PubMed database and supplemented with a manual search to retrieve additional articles eligible for inclusion/fulfilling the inclusion criteria. The implementation of HIPEC appears to be beneficial in terms of survival in patients with epithelial ovarian carcinoma (EOC) following neoadjuvant chemotherapy, as well as in patients with recurrent EOC. Statistical superiority is not justified by current studies regarding other gynaecological malignancies with peritoneal dissemination. Furthermore, as regards safety, HIPEC following CRS does not appear to significantly increase the mortality and morbidity rates compared to the use of CRS alone. The rationale for using HIPEC and CRS in the treatment of ovarian cancer, particularly in the neoadjuvant setting, as well as for recurrences, is adequately evidenced, with acceptable safety and post-operative complication rate profiles. Its current place in the multimodal strategy for patients with peritoneal metastases remains uncertain, however. Randomized clinical trials are warranted to further examine the use of HIPEC and establish the optimal regimen and temperature settings. The role of optimal cytoreduction and no residual disease, as well as the proper patient selection remain basic parameters for maximizing survival parameters.

Sarcoma Botryoides: Optimal Therapeutic Management and Prognosis of an Unfavorable Malignant Neoplasm of Female Children.

Embryonal rhabdomyosarcoma (ERMS) is a rare malignancy and occurs primarily in the first two decades of life. Botryoid rhabdomyosarcoma is an aggressive subtype of ERMS that often manifests in the genital tract of female infants and children. Due to its rarity, the optimal treatment approach has been a matter of debate. We conducted a search in the PubMed database and supplemented it with a manual search to retrieve additional papers eligible for inclusion. We retrieved 13 case reports and case series, from which we summarized that the current trend is to approach each patient with a personalized treatment plan. This consists of a combination of local debulking surgery and adjuvant or neoadjuvant chemotherapy (NACT). Effort is made in every approach to avoid radiation for the sake of preserving fertility. Radical surgeries and radiation still have a role to play in extensive disease and in cases of relapse. Despite the rarity and aggressiveness of this tumor, disease-free survival and overall prognosis is excellent, especially when it is diagnosed early, compared with other subtypes of rhabdomyosarcoma (RMS). We conclude that the practice of a multidisciplinary approach is appropriate, with favorable outcomes; however, larger-scale studies need to be organized to have a definite consensus on optimal management.

Diagnostic comparison of electrical impedance spectroscopy with colposcopy and HPV mRNA-testing in the prediction of CIN2+ women in Greece.

AIM: To compare the diagnostic parameters of electrical impedance spectroscopy (EIS) via ZedScan, a device that measures spectra to differentiate between normal and abnormal cervical tissues, when used as an adjunct to colposcopies in the diagnosis of HSILs/CIN2+ in Greek women with abnormal referral cytology toward colposcopy alone and HPV mRNA-testing. METHODS: This study analyzed 86 women, patients of the Colposcopy and Cervical Pathology Clinic of 2nd Obstetrics and Gynecology Department, Aristotle University of Thessaloniki at Hippokration General Hospital, between January 2022 and September 2022. During the visits, women were subjected to cytology, colposcopy alone and then with EIS/ZedScan and histological sampling. RESULTS: Common use of colposcopies and EIS/ZedScan allowed detecting an additional 14 cases of CIN2+ (16.2%) that colposcopy alone failed to report. EIS enhanced the sensitivity of colposcopy from 80.65% to 100% equal with that of HPV-mRNA test while retaining a high specificity (94.74%) which is much higher than specificity of HPV mRNA-testing (65.45%). EIS-assisted colposcopy had the highest value combination of positive and negative predictive values (96.15% and 100%) compared to colposcopy alone (100% and 75%) and HPV mRNA-testing (72.46% and 100%). CONCLUSIONS: Colposcopies performed with EIS/ZedScan demonstrated effectiveness in the diagnosing of CIN2+ leading to a significant increase in the number of CIN2+ that would have been missed if only colposcopy was applied especially in women with LSIL referral cytology. EIS/ZedScan seems to possess the ideal diagnostic threshold for sensitivity, specificity, and predictive values for CIN2+ compared to colposcopy alone and HPV mRNA-testing.

The expression and possible role of corticotropin-releasing hormone family peptides and their corresponding receptors in gynaecological malignancies and premalignant conditions: a systematic review.

The aim of this systematic review is to investigate the impact of corticotropin-releasing hormone (CRH) family peptides and their corresponding receptors on human physiology and disease onset, with a specific focus on gynaecological malignancies such as breast, endometrial, ovarian, vulvar, and cervical cancer. A comprehensive systematic review of 3 medical databases was conducted by 2 independent reviewers. We reviewed studies that explored the expression and role of CRH peptides in various aspects of cancer biology, in the context of breast, endometrial, ovarian, vulvar, and cervical cancer. Our findings reveal that CRH family peptides and their receptors, CRHR1 and CRHR2, are expressed in diverse gynaecological tissues, including cancer cells. Notably, we observed differential expression patterns among different gynaecological cancer types and stages, indicating potential associations with tumour aggressiveness and patient prognosis. Furthermore, CRH peptides were found to exert significant influences on critical cellular processes, such as cell proliferation, migration, invasion, and immune response, in gynaecological cancers. These findings highlight the multifaceted roles of CRH family peptides in gynaecological malignancies and emphasize the need for further research in this field. Therefore, understanding the mechanisms underlying the involvement of CRH family peptides in tumourigenesis may open new avenues for targeted therapeutic strategies in gynaecological malignancies.

Sentinel lymph node mapping in endometrial cancer to reduce surgical morbidity: always, sometimes, or never.

Introduction: Surgical staging of nodal status is of utmost significance to determine the stage of endometrial cancer and construct a targeted treatment plan. Systematic lymphadenectomy has for years been the procedure of choice for staging purposes, enabling thorough assessment of lymph nodes. Nevertheless, it is associated with increased morbidity and severe postoperative complications. In an attempt to avoid the disadvantages of lymphadenectomy, the use of sentinel lymph node (SLN) biopsy has been examined as an alternative staging procedure.The purpose of the present review is to summarize and provide up-to-date evidence about the role of SLN biopsy in the staging and management of endometrial cancer cases in the terms of optimal technique, efficacy, safety, and postoperative morbidity, as an alternative approach to regional lymphadenectomy. Material and methods: A thorough literature search was conducted in MEDLINE and SCOPUS to identify recent primary research and previous review articles that explore the use of SLN mapping as a staging procedure in patients with endometrial cancer. Results: There is increasing evidence that SLN mapping is efficient in identifying metastatic nodal disease without compromising oncological safety, achieving comparable or even superior detection rates to those of lymphadenectomy, when optimal technique and careful intraoperative nodal assessment are applied. Conclusions: Sentinel lymph node mapping can safely replace lymphadenectomy as an acceptable alternative staging method for endometrial cancer; however, future research might further strengthen this suggestion by resolving potential areas of doubt and debate, especially for high-risk endometrial cancer cases.

Objective and Subjective Appetite Assessment in Patients with Gynecological Cancer: A Pre- and Post-Operative Pilot Study.

Although appetite and its disorders have been implicated in disease progression and outcomes, ghrelin concentrations, an objective appetite measure, are rarely assessed in patients with gynecological malignancies. The present study aimed to assess changes in post-operative versus pre-operative appetite levels in patients with gynecological cancers scheduled for tumor removal surgery (N = 53). Acylated ghrelin concentrations were assessed as an objective appetite proxy, whereas the Council of Nutrition appetite questionnaire (CNAQ) was employed as a subjective appetite measure. Ghrelin concentrations were increased post-operatively (median: 12.1 pg/mL, IQR: 0.67 to 23.5, p-value = 0.001) but the perceived appetite of patients (CNAQ) remained unchanged (median: -1, IQR: -3 to 1). Tumor removal surgery decreased all anthropometric indices (body weight, body mass index, waist and hips circumferences, triceps skinfolds, body fat, fat mass and fat mass index, p-value ≤ 0.001 for all) and doubled the risk of malnutrition among patients. No difference was recorded in the change in participants' objective and subjective appetite when they were classified according to the tumor type. No correlation was observed between ghrelin concentrations and CNAQ score pre-operatively (Spearman's rho correlation coefficient = -0.181, p-value = 0.298) or post-operatively (Spearman's rho correlation coefficient = 0.071, p-value = 0.684). The observed post-operative rise in ghrelin concentrations is associated with body weight loss and consists of a possible defense mechanism of the human body, aiming to prolong survival.

Axillary lymph node dissection vs. sentinel node biopsy for early-stage clinically node-negative breast cancer: a systematic review and meta-analysis.

ΟBJECTIVE: This study aimed at comparing survival outcomes between systematic axillary lymph node dissection (ALND) vs sentinel lymph node and axillary lymph node dissection only if sentinel positive (SLN ± ALND) in early-stage, clinically node-negative breast cancer patients. ΜETHODS: A systematic review and meta-analysis adhered to PRISMA guidelines was performed. Included studies were prospective randomized controlled trials (RCTs) comparing survival outcomes of ALND vs. SLN ± ALND in early-stage, node-negative breast cancer patients. Patients enrolled were only those with tumor size lower than 4 cm, clinically negative nodes and treated with breast-conservative surgery. Primary endpoints were locoregional recurrence, overall death and cancer-related death. RESULTS: There were four studies included in the analysis, enrolling overall 2982 patients, of which 1494 in ALND arm and 1488 in the SLN ± ALND arm. No statistically significant difference was observed in locoregional recurrence, breast cancer-related death and overall death. Locoregional recurrence was observed in 2.8% (ALND) vs. 4.1% (SLND ± ALND), (RR 0.69, 95% CI 0.20-2.30). Overall death rate was 7.0% vs. 6.8% respectively, (RR 1.00, 95% CI 0.73-1.39, I2 = 28.7%). Breast cancer-related death was 3.6% vs. 3.5%, respectively (SLN ± ALND), (RR 1.11, 95% CI 0.70-1.78, I2 = 0%). No statistically significant difference was observed in any of secondary study outcomes. CONCLUSIONS: Systematic axillary axillary lymph node dissection provides no survival benefit compared with sentinel lymph node dissection for early-stage clinically node-negative breast cancer patients.

Neoadjuvant chemotherapy in advanced-stage ovarian cancer - state of the art.

Ovarian cancer represents the fifth cause of cancer death among women, carrying one of the worst prognoses among gynaecological malignancies. The need to achieve no residual disease after surgery in order to optimize prognosis of advanced-stage ovarian cancer introduced the idea of neoadjuvant chemotherapy. The present review aims to summarize current state-of-the-art evidence regarding the efficacy and safety of neoadjuvant chemotherapy as well as novel insights regarding the usage of modern therapeutic regimens in the context of neoadjuvant chemotherapy. The last decade has been characterized by the breakthrough scientific evidence that neoadjuvant chemotherapy followed by interval debulking surgery for advanced-stage ovarian cancer may be comparable to primary debulking surgery. Neoadjuvant chemotherapy followed by interval debulking surgery is an acceptable - if not preferable - therapeutic approach in advanced-staged ovarian cancer patients because it is associated with higher optimal debulking surgery, fewer complications, and non-inferior survival outcomes. The addition of bevacizumab to chemotherapy contributes significantly to survival outcomes without causing side effects that outbalance the benefits. Patients with recurrent high-grade serous ovarian cancer and a germline or breast cancer mutation should be offered maintenance olaparib after a response to platinum-based chemotherapy. Finally, the role of hyperthermic intraperitoneal chemotherapy in the context of neoadjuvant chemotherapy remains unjustified.

Diagnostic performance of HPV E6/E7 mRNA testing towards HPV-DNA testing and p16/Ki67 immunostaining as a biomarker of high-risk HPV recurrence in Greek women surgically treated for their cervical lesions.

AIM: To evaluate the diagnostic performance of E6/E7 HPV-mRNA overexpression towards HPV-DNA testing and p16/Ki67 immunocytochemistry in a post-op population to verify if this biomarker can be effectively used as indicator of successful cervical intraepithelial neoplasia (CIN) treatment. METHODS: Our study retrospectively analyzed 197 patients of our Colposcopy Clinic between January 2013 and September 2020 coming with an abnormal Pap smear suggestive for colposcopy, and after a series of follow-ups including liquid-based cytology (LBC) and punch-biopsy sampling, there were surgically treated. LBC was used for cytology and molecular analysis of the three HPV-related biomarkers. RESULTS: Six months after treatment, 93% of the HPV-mRNA-positive women became negative while this applied to only 80.2% of the HPV-DNA-positive women. HPV persistence was 6.9% at 6-12 months after treatment. The comparison among cytology, colposcopy, HPV-DNA test, and HPV-mRNA test after treatment revealed that the last one is the only with a strong correlation with actual severity (histology during treatment) (ρ = 0.345, p = 0.006) implying that clinical cases with more severe CIN may have higher chances of unsuccessful treatment. HPV-mRNA test had higher sensitivity (100%), specificity (96.88%), and positive predictive value (45.45%) for CIN2+ recurrent lesions when compared with HPV-DNA testing (80%, 82.81%, 10.81% respectively) and p16/Ki67 immunocytochemistry (80%, 95.83%, 33.33% respectively) while their negative predictive values were similar. CONCLUSIONS: E6/E7 mRNA detection has higher diagnostic values for the prediction of treatment failure compared with HPV-DNA testing and p16/Ki67 immunocytochemistry, and as an outcome could be used as predictive indicator of CIN-treatment status.

Tumor Genotyping and Homologous Recombination Repair Gene Variants in Patients With Epithelial Ovarian Cancer: Is Pathogenic Enough?

Our hypothesis was that the predictive accuracy of pathogenic variants in genes participating in the homologous recombination repair (HRR) system in patients with epithelial ovarian cancer (EOC) could be improved by considering additional next-generation sequencing (NGS) metrics. NGS genotyping was performed in tumor tissue, retrospectively and prospectively collected from patients with EOC, diagnosed from 8/1998 to 10/2016. Variants were considered clonal when variant allele frequencies corresponded to >25%. The primary endpoint was overall survival (OS). This study included 501 patients with EOC, predominantly with high-grade serous (75.2%) and advanced stage tumors (81.7%); median age was 58 years (22-84). Pathogenic and clonal pathogenic variants in HRR and/or TP53 genes were identified in 72.8% and 66.5% tumors, respectively. With a median follow-up of 123.9 months, the presence of either pathogenic or clonal pathogenic HRR-only variants was associated with longer OS compared to HRR/TP53 co-mutation (HR=0.54; 95% CI, 0.34-0.87, Wald's p=0.012 and HR=0.45; 95% CI, 0.27-0.78, Wald's p=0.004, respectively). However, only the presence of clonal HRR-only variants was independently associated with improved OS (HR=0.55; 95% CI, 0.32-0.94, p=0.030). Variant clonality and co-occuring TP53 variants affect the predictive value of HRR pathogenic variants for platinum agents in patients with EOC. CLINICAL TRIAL REGISTRATION: [ClinicalTrials.gov], identifier [NCT04716374].

Multisite Tumor Sampling Reveals Extensive Heterogeneity of Tumor and Host Immune Response in Ovarian Cancer.

BACKGROUND/AIM: Ovarian cancer (OVCA) is characterized by genomic/molecular intra-patient heterogeneity (IPH). Tissue histology and morphological features are surrogates of the underlying genomic/molecular contexture. We assessed the morphological IPH of OVCA tumor compartments and of lymphocytic infiltrates in multiple matched samples per patient. MATERIALS AND METHODS: We examined 294 hematoxylin & eosin (H&E) OVCA tumor whole sections from 70 treatment-naïve patients who had undergone cytoreductive surgery. We assessed morphological subtypes as immunoreactive (IR), solid - proliferative (SD), papilloglandular (PG), and mesenchymal transition (MT); subtype load per patient; stromal tumor-infiltrating lymphocyte (sTIL) density as average per sample; and, as maximal sTIL values (max-TILs) among all samples per patient, ovaries and implants. RESULTS: Among all 294 tumor sections, the most frequent primary morphological subtype was PG (n=150, 51.0%), followed by MT (71, 24.1%), SD (48, 16.3%) and IR (15, 5.1%). Subtype combinations were observed in 67/294 sections (22.8%) and IPH in 48/70 patients (68.6%). PG prevailed in ovaries (p<0.001), SD and MT in implants (p=0.023 and p<0.001, respectively). sTILs were higher in SD compared to non-SD (p=0.019) and lower in PG, respectively (p<0.001). sTIL density was higher in implants than in ovaries (p<0.001). Higher max-TILs were associated with stage IV disease (p=0.043), upper abdominal dissemination (p=0.024), endometrioid histology (p=0.013), and grade 3 tumors (p=0.021). Favorable prognosticators were higher max-TILs per patient (PFS, OS) and higher SD-load (PFS). CONCLUSION: Clinically relevant morphological and host immune-response IPH appear to be the norm in OVCA. This may complicate efforts to decipher sensitivity of the tumor to certain treatment modalities from a single pre-operative biopsy.

Severe euglycemic diabetic ketoacidosis of multifactorial etiology in a type 2 diabetic patient treated with empagliflozin: case report and literature review.

BACKGROUND: Sodium-glucose co-transporter-2 (SGLT-2) inhibitors are a relatively novel class of oral medications for the treatment of Type 2 DM with a generally acceptable safety profile. However, these agents have been associated with rare events of a serious and potentially life-threatening complication named euglycemic diabetic ketoacidosis (euDKA). euDKA is not identical with the typical diabetic ketoacidosis, as it often presents with serious metabolic acidosis but only mild to moderate glucose and anion gap elevation. CASE PRESENTATION: We report a case of a 51-year old female with Type 2 DM treated with an SGLT-2 inhibitor, developing severe metabolic acidosis with only mild blood glucose elevation after a routine surgery. A careful evaluation of involved factors led to the diagnosis of euDKA, followed by cautious application of simple therapeutic measures that resulted in complete restoration of acidosis and glycemic control in less than 48-h. CONCLUSIONS: Euglycemic ketoacidosis is a rare but rather serious complication of SGLT-2 inhibitors use, often with a multifactorial etiology. Its atypical presentation requires a high level of awareness by physicians as early recognition of this complication can quickly and safely restore acid-base balance.

Cervical Pathology Following HPV Vaccination in Greece: A 10-year HeCPA Observational Cohort Study.

BACKGROUND: In Greece the population-level impact of HPV vaccination is unknown due to lack of official registries. This study presents in a pragmatic frame the comparison of cervical pathology data between HPV-vaccinated and unvaccinated women referred for colposcopy. PATIENTS AND METHODS: This is an observational prospective cohort study performed in 7 academic Obstetrics and Gynaecology Departments across Greece between 2009-2019. Cases were women that had completed HPV vaccination before coitarche and were referred for colposcopy due to abnormal cytology. For each vaccinated woman an unvaccinated matched control was selected. RESULTS: A total of 849 women who had been vaccinated before coitarche and 849 unvaccinated controls were recruited. The combination of cytological, colposcopic and molecular findings necessitated treatment in only a single case among vaccinated (0.1%) and in 8.4% among unvaccinated. CONCLUSION: HPV vaccination at a proper age can markedly reduce development of severe cervical precancers and consequently the need for treatment, as well as their long-term related obstetrical morbidity.

Combined pelvic and para-aortic is superior to only pelvic lymphadenectomy in intermediate and high-risk endometrial cancer: a systematic review and meta-analysis.

BACKGROUND: Lymph node metastasis is a principal prognostic factor for the treatment of endometrial cancer. Added value of para-aortic lymphadenectomy to only pelvic lymphadenectomy for intermediate/high-risk endometrial cancer patients remains controversial. OBJECTIVE: A systematic review and meta-analysis was performed to assess the impact of combined pelvic and para-aortic lymph node dissection (PPALND) compared to only pelvic lymph node dissection (PLND) on survival outcomes of intermediate and/or high-risk patients. STUDY DESIGN: The systematic review and meta-analysis adhered to the PRISMA guidelines for meta-analyses of interventional studies. Pubmed, Scopus, EMBASE and Cochrane were searched up to April 20, 2018. Included studies were those comparing high-risk endometrial cancer patients that had performed pelvic and para-aortic lymph node dissection (PPALND) vs. only pelvic lymph node dissection (PLND) apart from standard procedure (total hysterectomy with bilateral salpingo-oophorectomy, TAHBSO). Primary outcomes of the study were overall survival and disease-free survival rates. Methodological quality of the included studies was assessed using the ROBINS-I tool. Overall quality of the evidence for the primary and secondary outcomes was evaluated as per GRADE guideline using the GRADE pro GD tool. RESULTS: There were 13 studies identified with 7349 patients included. All studies were retrospective observational as no RCTs or prospective studies adhering to inclusion criteria were retrieved. Combined pelvic and para-aortic lymphadenectomy was associated with 46% decreased risk for death (HR 0.54, 95% CI 0.35-0.83, I2 = 62.1%) and 49% decreased risk for recurrence (HR 0.51, 95% CI 0.28-0.93). It was also associated with increased 5-year OS rate (RR 1.13, 95% CI 1.04-0.24, I2 = 57.3%) and increased 5-year DFS rate (RR 1.23, 95% CI 1.14-1.31, I2 = 85.5) compared with only pelvic lymphadenectomy. CONCLUSION: Combined pelvic and para-aortic lymphadenectomy is associated with improved survival outcomes compared with only pelvic lymphadenectomy in women with intermediate/high-risk endometrial cancers. Further prospective studies should be performed.

A cohort retrospective study of high-risk HPV recurrence in Greek women after cervical lesion treatment through detection of viral E6/E7 mRNA expression.

PURPOSE: Our aim was to detect and evaluate potential alterations in the postoperative status of E6/E7 HPV mRNA in women treated for cervical intraepithelial lesions (CIN) and if so, to evaluate its potential use as a prognostic tool to identify patients with increased risk of treatment failure or recurrent disease. METHODS: Our study retrospectively analyzed 101 women with an abnormal Pap smear, or in some cases with histological reports or molecular analysis requiring colposcopic evaluation. Thin-prep cytological samples were collected before colposcopy and histology (when necessary). After treatment, all women were scheduled for colposcopy in six months. The cytological material was analyzed with CLART-2 HPV-DNA test and HPV-PROOFER E6/E7 mRNA test. RESULTS: Concerning demographics, no significant correlations were found for smoking, condom use or vaccination status. It seems that the only statistically significant correlation with actual severity came from the mRNA-test after treatment. This shows that clinical cases with more severe CIN may have higher chances of unsuccessful treatment. At the first post-op visit, 83.5% of HPV mRNA-positive women had a negative HPV mRNA-test while only 60.4% of HPV DNA-positive women became negative. There were 12 HPV-mRNA positive patients both before and after treatment, 3 of whom had a negative HPV DNA test, meaning that, if based only on HPV-DNA results, they would have been managed wrongly as successfully treated patients. Our study shows that E6/E7 mRNA detection has particularly high specificity and positive likelihood ratio for the prediction of treatment failure in comparison with HPV DNA-testing. CONCLUSIONS: E6/E7 mRNA overexpression seems to be a promising candidate as an indicator-biomarker to determine the success of treatment.

Human papilloma virus vaccination and attitudes towards contraception: a cross-sectional study.

Objective: Human papilloma virus (HPV) vaccination may result in misconceptions that encourage young women to adopt risky contraceptive practices. The purpose of this article was to investigate whether HPV vaccination status was associated with choice of contraceptive method and adoption of risky sexual behaviour. Methods: Vaccinated and non-vaccinated visitors to a university department paediatric and adolescent gynaecology clinic were asked to anonymously fill in a survey comprising questions on sociodemographic characteristics, sexual history, opinions on contraception and attitudes towards contraception. Results: A total of 191 women were studied, 75 (39.3%) of whom had received the HPV vaccination and 116 (60.7%) of whom had not. The main contraceptive methods used in both groups were male condom (46%), emergency contraception (14%) and coitus interruptus (12%). The vaccinated group was less religious and had better educated mothers compared with the non-vaccinated group (relative risk [RR] 0.64; 95% confidence interval [CI] 0.45, 0.93; p = .016 vs RR 1.91; 95% CI 1.01, 3.63; p = .027, respectively). They also had an earlier sexual debut (RR 1.94; 95% CI 1.06, 3.55; p = .015), agreed that vaccination increased the safety of sex (RR 1.45; 95% CI 1.02, 2.05; p = .039) and considered the HPV vaccine a prerequisite to initiation of a sexual relationship (RR 1.87; 95% CI 1.34, 2.63; p < .001). Conclusion: HPV vaccination did not affect sexual behaviour, attitudes to condom use or choice of contraceptive method.

Pathogenic BRCA1 mutations may be necessary but not sufficient for tissue genomic heterogeneity: Deep sequencing data from ovarian cancer patients.

BACKGROUND: Tissue genomic heterogeneity (t-HET) in patients with epithelial ovarian cancer (OVCA) is related to tissue plasticity, i.e., flexibility to adapt to adverse molecular environments. Here, we interrogated the presence and clinical relevance of OVCA t-HET. METHODS: We applied high-depth (>2000×) sequencing on 297 paraffin tissue samples (fallopian tubes, ovaries, intra-abdominal metastases) from 71 treatment-naïve patients who subsequently received first-line platinum-based chemotherapy. Based on tissue mutation patterns, we distinguished tissue genotypes into: no mutation (33/297 samples; 11.1%), stable (173; 58.2%) and unstable (91; 30.7%). We profiled genotypes per patient and assessed t-HET in 69 patients. Predicted pathogenic mutations refer to germline and/or tissues. RESULTS: Among all 71 patients, 46 (64.8%) had pathogenic BRCA1 mutations and 15 (21.7%) had BRCA1/2 disruption (i.e., pathogenic mutations with position-LOH). We classified 29 patients with t-HET (42%), all with pathogenic BRCA1; t-HET was observed in 64% with such mutations (p < 0.001). As opposed to non-t-HET, matched tissues in t-HET shared pathogenic BRCA1 (p < 0.001) but not BRCA2 and TP53. Germline BRCA1 mutations in tissues exhibited position-LOH; heterozygous status; or, partial loss of the inherited allele accompanied by additional clonal mutations. Patients with t-HET had worse outcome (log-rank p = 0.048 [progression-free]; p = 0.037 [overall survival]), including 12/15 patients with disrupted BRCA1/2 and 3 BRCA1 carriers with partial germline loss in tissues. CONCLUSIONS: Pathogenic BRCA1 mutations appear necessary but may not be sufficient for the establishment of t-HET. t-HET may be associated with worse outcome, including in patients with disrupted BRCA1/2, which is usually considered as a favourable marker. OVCA t-HET may need to be addressed for treatment decisions.

Mismatch repair deficiency and aberrations in the Notch and Hedgehog pathways are of prognostic value in patients with endometrial cancer.

The aim of this study was to investigate the prognostic value of the Hedgehog (Gli, Patched-1, Shh, Smo) and Notch (Jag1, Notch2, Notch3) pathway members, in comparison to a panel of proteins (ER, PgR, HER2/neu, Ki67, p53, p16, PTEN and MMR) previously suggested to be involved in the pathogenesis of endometrial cancer, in association with clinical outcome and standard clinicopathological characteristics. A total of 204 patients with histological diagnosis of endometrial cancer treated from 2004 to 2013 were included. The evaluation of protein expression was assessed by immunohistochemistry. Univariate analysis showed that higher Ki67 labeling, expression of PTEN, p16, Notch2 and Notch3 proteins, as well as MMR proficiency were associated with increased relapse and mortality rate. Additionally, Patched-1 protein expression was associated with worse DFS, while p53 overexpression was associated with worse OS. In multivariate analyses, patients with MMR proficient tumors had more than double risk for death than patients with MMR deficient (MMRd) tumors (adjusted HR = 2.19, 95% CI 1.05-4.58, p = 0.036). Jag1 positivity conferred reduced mortality risk (HR = 0.48, 95% CI 0.23-0.97, p = 0.042). However, as shown by hierarchical clustering, patients fared better when their tumors expressed high Jag1 protein in the absence of Notch2 and Notch3, while they fared worse when all three proteins were highly expressed. Patched-1 positivity conferred higher risk for relapse (HR = 2.04, 95% CI 1.05-3.96, p = 0.036). Aberrant expression of key components of the Notch and Hedgehog signaling pathways, as well as MMRd may serve as independent prognostic factors for recurrence and survival in patients with endometrial cancer.

Successful isthmo-neovagina anastomosis after Davydov's colpopoiesis in Mayer-Rokitansky-Küster-Hauser syndrome patients with a functional rudimentary uterine horn.

The aim of these case reports is to present the feasibility of isthmo-neovagina anastomosis after Davydov's colpopoiesis in patients with Mayer-Rokitansky-Küster-Hauser syndrome (MRKH) with a rudimentary uterine horn. Ten MRKH patients were treated surgically with laparoscopic Davydov's vaginoplasty between 2006 and 2012. Two of these patients were found to have a functional rudimentary uterine horn. These patients underwent a 2-step surgical intervention: (1) Davydov's colpopoiesis with a combined laparoscopic and perineal approach and (2) isthmo-neovagina anastomosis with laparotomy in the 2 cases with a uterine horn in a second surgical step 4 and 6 months after the initial procedure, respectively. The main outcome measures were the perioperative and postoperative details, the vaginal length during follow-up, the postoperative initiation of intercourse, and the postoperative menstrual function. Isthmo-neovagina anastomosis was uneventful, and there were no early postoperative complications. The mean hospitalization duration was 9.5 days. Anastomosis was successful in both patients. The mean follow-up was 42 months, and the mean vaginal length was measured 9.5 cm; both patients reported normal intercourse and normal menstrual function. Anatomic restoration of the genital tract in these patients appears to have been successful and led to functional menstruation and restitution of the patients' sex life.