High concordance of molecular subtyping between pre-surgical biopsy and surgical resection specimen (matched-pair analysis) in patients with vulvar squamous cell carcinoma using p16- and p53-immunostaining.

OBJECTIVE: Vulvar squamous cell carcinoma (VSCC) can be stratified into three molecular subtypes based on the immunoexpression of p16 and p53: HPV-independent p53-abnormal (p53abn) (most common, biologically aggressive), HPV-associated, with p16-overexpression (second most common, prognostically more favourable) and more recently recognised HPV-independent p53-wildtype (p53wt) (rarest subtype, prognostically intermediate). Our aim was to determine whether molecular subtypes can be reliably identified in pre-operative biopsies and whether these correspond to the subsequent vulvectomy specimen. METHODS: Matched-paired pre-surgical biopsies and subsequent resection specimen of 57 patients with VSCC were analysed for the immunohistochemical expression of p16 and p53 by performing a three-tiered molecular subtyping to test the accuracy rate. RESULTS: Most cases 36/57 (63.2%) belonged to the HPV-independent (p53-abn) molecular subtype, followed by HPV-associated 17/57 (29.8%) and HPV-independent (p53wt) 4/57 (7.0%). The overall accuracy rate on biopsy was 91.2% (52/57): 97.3% for p53-abnormal, 94.1% for p16-overexpression and 50% for p16-neg/p53-wt VSCC. Incorrect interpretation of immunohistochemical p53 staining pattern was the reason for discordant results in molecular subtyping in all five cases. In one case there was an underestimation of p53 pattern (wildtype instead of abnormal/aberrant) and in one case an overestimation of the p53 staining pattern (abnormal/aberrant instead of wildtype). In 3/5 there was a "double positive" staining result (p16 overexpression and abnormal/aberrant p53 staining pattern). In that cases additional molecular workup is required for correct molecular subtyping, resulting in an overall need for molecular examination of 3/57 (3.5%). CONCLUSIONS: Compared to the final resections specimen, the three-tiered molecular classification of VSCC can be determined on pre-surgical biopsies with a high accuracy rate. This enables more precise surgical planning, prediction of the response to (chemo) radiation, selection of targeted therapies and planning of the optimal follow-up strategy for patients in the age of personalised medicine.

Human Papilloma Virus-Independent/p53abnormal Keratinizing Squamous Cell Carcinoma of the Uterine Cervix Associated With Uterine Prolapse.

Knowledge about the morphologic and molecular characteristics of cervical squamous cell carcinomas (CSCCs) associated with uterine prolapse is very limited. Detailed histopathological and immunohistochemical (p16, p53, and cytokeratin 17), as well as molecular evaluation for human papillomavirus (HPV)-DNA and p53-mutational analyses in 4 consecutive CSCCs associated with uterine prolapse with definition of a hitherto not well-described HPV-independent/p53abnormal precursor lesion (HPV-independent cervical intraepithelial neoplasia [CIN; differentiated CIN]) and molecular tumorigenetic pathway. Cases diagnosed within 7 years with a mean age of 75 (range: 69-83) years and a mean tumor size of 7.3 cm (range: 5.2-9.4 cm). All patients presented with locally advanced disease, and 1 woman died of the disease within 4, and another within 14 months of follow-up. All CSCCs and their adjacent precursor lesions were negative for p16, with aberrant p53-expression and diffuse and strong staining for cytokeratin 17. Both the CSCCs and their precursors were negative for HPV-DNA but harbored a TP53 mutation. The precursor lesions were characterized by epithelial thickening with superficial keratinization, and the presence of basal and parabasal keratinocytes with mitotic figures beyond the basal layer, thus showing features similar to those seen in differentiated types of vulvar intraepithelial lesions (vulvar intraepithelial neoplasia [VIN] syn. HPV-independent/p53abn VIN), suggesting the terminology of differentiated CIN or HPV-independent/p53abn CIN. An HPV-independent pathogenetic pathway with a p53-alteration was identified for these cases. CSCC associated with uterine prolapse represents HPV-independent tumors harboring a TP53 mutation. For the first time, a precursor lesion of HPV-independent CSCC of the uterine cervix is described with a differentiated VIN-like morphology, and a separate tumorigenic pathway defined.

Incidence and predictors for chemotherapy modifications and their impact on the outcome of ovarian cancer patients.

PURPOSE: Chemotherapy (CTX) is an important part of the treatment strategy of stage II-IV ovarian cancer. CTX modifications, such as delays, dose reductions or premature terminations might have a negative impact on overall survival (OS) and progression free survival (PFS). The goal of this study was to determine the incidence and predictors of CTX modifications and their influence on survival. METHODS: An observational retrospective cohort analysis of 192 ovarian cancer patients who were treated at the Department of Obstetrics and Gynaecology, Technical University Munich, Germany, according to international guidelines was performed including from 2009 to 2013. A potential association between patient and disease characteristics and CTX modifications was tested with multivariate logistic regression. OS and PFS were estimated by Kaplan-Meier analysis. RESULTS: 44.8% (86/192) received a modification of CTX. 34 (17.7%) women discontinued CTX prematurely, 17 (8.9%) underwent a dose reduction, 16 (8.3%) experienced a CTX delay and 10 (5.2%) had both a delay and a dose modification. In nine (4.7%) patients, the dose needed to be divided. Leukopenia (p < 0.001) and anaemia (p = 0.003) were significantly more common in patients with CTX modifications. Significant predictors for CTX modifications were a history of thrombosis or embolism (p < 0.001) and residual tumour postoperatively (p = 0.003). Patients with CTX modifications showed a significantly lower OS as well as PFS (p < 0.001), even after adjustment for prognostic factors such as age, body-mass-index, residual tumour, histology, FIGO stage and grading (p = 0.005 for OS and p = 0.001 for PFS). CONCLUSION: CTX modifications have a negative impact on survival. Significant predictors for such modifications are a history of thrombosis or embolism and the presence of residual postoperative tumour. Further studies are needed to avoid CTX modifications and to improve survival of ovarian cancer patients.

Intracavitary brachytherapy with additional Heyman capsules in the treatment of cervical cancer.

PURPOSE: Brachytherapy is a mandatory component of primary radiochemotherapy in cervical cancer. The dose can be applied with a traditional intracavitary approach (IC alone) or with multiple catheter brachytherapy to optimize dose distribution in an individual concept. We therefore evaluated whether the utilization of a tandem-ring applicator plus additional intracavitary applicators (add IC) provides an advantage over the traditional IC alone approach, as this method is less time consuming and less invasive compared to a combined intracavitary/interstitial brachytherapy. METHODS: Twenty three procedures of intracavitary brachytherapy for cervical cancer with additional intracavitary applicators performed in seven patients treated between 2016 and 2018 in our institution were included in this study. Plans were optimized for D90 HR-CTV with and without the utilization of the additional applicators and compared by statistical analysis. RESULTS: D90 for HR-CTV was 5.71 Gy (±1.17 Gy) for fractions optimized with add IC approach and 5.29 Gy (±1.24 Gy) for fractions without additional applicators (p < 0.01). This translates to a calculated mean EQD2 HR-CTV D90 of 80.72 Gy (±8.34 Gy) compared to 77.84 Gy (±8.49 Gy) after external beam therapy and four fractions of brachytherapy for add IC and IC alone, respectively (p < 0.01). The predictive value of improved coverage of HR-CTV in the first fraction was high. CONCLUSION: In a subgroup of cases, the addition of intracavitary Heyman capsules can be an alternative to interstitial brachytherapy to improve the plan quality compared to standard IC alone brachytherapy. The benefit from the addition of applicators in the first fraction is predictive for the following fractions.

First experiences with PET-MRI/CT in radiotherapy planning for cervical cancer.

PURPOSE: PET-CT has recently been included in the NCCN staging recommendations for cervical cancer stages II-IV and is already routinely applied to radiotherapy planning for other malignancies, as it is expected to provide higher accuracy for the detection of areas with tumor cell spread. In this study, we report on our first experiences of PET-based radiotherapy planning for cervical cancer. METHODS: 19 patients with cervical cancer that underwent pre-therapeutic PET imaging treated at our institution between January 2016 and April 2019 were included in the study. Information on the primary tumor, lymph node involvement, metastatic spread and changes in the radiotherapy procedure based on the PET findings are described. RESULTS: A previously unknown primary tumor extension that was detected by PET imaging in one patient. In patients who underwent a PET before the systematic pelvic and paraaortic lymphonodectomy (n = 2), PET was false negative for pelvic lymph node metastases in 50%. In patients who underwent a PET after the systematic LNE (n = 13), additional lymph node metastases were detected in seven patients (53.80%). Distant metastases were suspected in three patients (15.7%) based on PET imaging. The suspicion was confirmed in one patient (peritoneal spread) and excluded in two patients (supra-diaphragmatic lymph nodes). In 13 patients (68.4%), RT procedures were altered due to findings in PET imaging. CONCLUSION: PET-based radiochemotherapy planning may improve control rates by identifying areas of tumor cell spread eligible for dose escalation. False positivity, however, should be excluded in patients with findings that lead to major modifications of the therapeutic strategy.

The immunologic tumor microenvironment in endometrioid endometrial cancer in the morphomolecular context: mutual correlations and prognostic impact depending on molecular alterations.

OBJECTIVE: POLE-mutant, microsatellite-instable (MSI), p53-mutant and non-specific molecular profile (NSMP) are TCGA-defined molecular subgroups of endometrial cancer (EC). Hypothesizing that morphology and tumor immunology might differ depending on molecular background concerning composition and prognostic impact, we aimed to comprehensively interconnect morphologic, immunologic and molecular data. METHODS: TCGA-defined molecular groups were determined by immunohistochemistry and sequencing in n = 142 endometrioid EC. WHO-defined histopathological grading was performed. The immunologic microenvironment (iTME) was characterised by the quantification of intraepithelial and stromal populations of tumor-infiltrating lymphocytes (TIL: overall T-cells; T-Killer cells; regulatory T-cells (Treg)). Immunologic parameters were correlated with WHO-grading, TCGA-subgroups and prognosis. RESULTS: High density TIL were significantly more frequent in high-grade (G3) compared to low-grade (G1/2) EC in the whole cohort and in the subgroup of POLE-wildtype-/microsatellite-stable-EC. MSI was associated with high-level TIL-infiltration when taking into account the type of mismatch repair defect (MLH1/PMS2; MSH2/MSH6). Prognostic impact of biomarkers depended on molecular subgroups: In p53-mutant EC, Treg were independently prognostic, in NSMP, the unique independently prognostic biomarker was WHO-grading. CONCLUSIONS: EC morphology and immunology differ depending on genetics. Our study delineated two molecularly distinct subgroups of immunogenic EC characterized by high-density TIL-infiltration: MSI EC and high-grade POLE-wildtype/microsatellite-stable-EC. Prognostic impact of TIL-populations relied on TCGA-subgroups indicating specific roles for TIL depending on molecular background. In NSMP, histopathological grading was the only prognostic biomarker demonstrating the relevance of WHO-grading in an era of molecular subtyping.

An easy way to determine bone mineral density and predict pelvic insufficiency fractures in patients treated with radiotherapy for cervical cancer.

PURPOSE: The aim of this study was to investigate whether bone mineral density (BMD) as measured in planning computed tomographies (CTs) by a new method is a risk factor for pelvic insufficiency fractures (PIF) after radio(chemo)therapy (R(C)T) for cervical cancer. METHODS: 62 patients with cervical cancer who received definitive or adjuvant radio(chemo)therapy between 2013 and 2017 were reviewed. The PIF were detected on follow-up magntic resonance imaging (MRI). The MRI of the PIF patients was registered to the planning CT and the PIF contoured. On the contralateral side of the fracture, a mirrored structure of the fracture was generated (mPIF). For the whole sacral bone, three lumbar vertebrae, the first and second sacral vertebrae, and the PIF, we analyzed the BMD (mg/cm3), V50Gy, Dmean, and Dmax. RESULTS: Out of 62 patients, 6 (9.7%) had a fracture. Two out of the 6 patients had a bilateral fracture with only one of them being symptomatic. PIF patients showed a significantly lower BMD in the sacral and the lumbar vertebrae (p < 0.05). The BMD of the contoured PIF, however, when comparing to the mPIF, did not reach significance (p < 0.49). The difference of the V50Gy of the sacrum in the PIF group compared to the other (OTH) patients, i.e. those without PIF, did not reach significance. CONCLUSION: The dose does not seem to have a relevant impact on the incidence of PIF in our patients. One of the predisposing factors for developing PIF after radiotherapy seems to be the low BMD. We presented an easy method to assess the BMD in planning CTs.

Lifestyle modifications after the diagnosis of gynecological cancer.

BACKGROUND: The influence of lifestyle factors on the quality of life, incidence and tumor recurrence has been evaluated in several studies and is gaining increasing importance in cancer research. However, the extent of the influence of such lifestyle factors on the quality of life of cancer patients remains largely unclear, as does the number of patients actually pursuing these lifestyle changes. The purpose of this study was to examine the prevalence and predictors of lifestyle changes in patients with gynecological cancer. METHODS: The survey consisted of a pseudonymous questionnaire that was conducted from January to May 2014 via a telephone interview with 141 patients with a gynaecological malignancy who had undergone surgery at our Department of Gynaecology and Obstetrics. Lifestyle factors (diet, physical activity, stress level, alcohol and nicotine consumption) prior to and after the diagnosis of cancer were evaluated. RESULTS: 89% (n = 125) of the patients reported lifestyle changes after being diagnosed with cancer. There was a significant association between the implementation of lifestyle changes and age as well as the use of complementary medicine. Nutrition: 66% of the patients (n = 93) consumed more fruit and vegetables and 65% ate less meat (n = 92). Physical activity: 37% (n = 52) reported no change in their exercise routine, 36% (n = 51) described a decrease, 27% (n = 38) an increase in their physical activity. Subjective feeling of stress: 77% of the patients (n = 108) described a reduction in their perceived level of stress. Nicotine consumption: 63% (n = 12) of the 19 patients who were smokers at the time of the diagnosis quit or reduced smoking thereafter. Alcohol consumption: 47% (n = 61/129) of the patients reduced their alcohol consumption. CONCLUSIONS: Most of the patients from our study group implemented lifestyle changes after being diagnosed with cancer. Prospective randomized trials are needed in order to determine the benefit of lifestyle changes (physical activity, dietary habits and stress reduction) for cancer survivors. The potential impact of lifestyle on the quality of life and the trajectory of the disease should be discussed with all oncological patients.

Demand for integrative medicine among women with breast and gynecological cancer: a multicenter cross-sectional study in Southern and Northern Germany.

PURPOSE: The aim of this multicenter cross-sectional study was to analyze a cohort of breast (BC) and gynecological cancer (GC) patients regarding their interest in, perception of and demand for integrative therapeutic health approaches. METHODS: BC and GC patients were surveyed at their first integrative clinic visit using validated standardized questionnaires. Treatment goals and potential differences between the two groups were evaluated. RESULTS: 340 patients (272 BC, 68 GC) participated in the study. The overall interest in IM was 95.3% and correlated with older age, recent chemotherapy, and higher education. A total of 89.4% were using integrative methods at the time of enrolment, primarily exercise therapy (57.5%), and vitamin supplementation (51.4%). The major short-term goal of the BC patients was a side-effects reduction of conventional therapy (70.4%); the major long-term goal was the delay of a potential tumor progression (69.3%). In the GC group, major short-term and long-term goals were slowing tumor progression (73.1% and 79.1%) and prolonging survival (70.1% and 80.6%). GC patients were significantly more impaired by the side-effects of conventional treatment than BC patients [pain (p = 0.006), obstipation (< 0.005)]. CONCLUSION: Our data demonstrate a high overall interest in and use of IM in BC and GC patients. This supports the need for specialized IM counseling and the implementation of integrative treatments into conventional oncological treatment regimes in both patient groups. Primary tumor site, cancer diagnosis, treatment phase, and side effects had a relevant impact on the demand for IM in our study population.

TP53 germline mutations in the context of families with hereditary breast and ovarian cancer: a clinical challenge.

PURPOSE: TP53germline (g) mutations, associated with the Li-Fraumeni syndrome (LFS), have rarely been reported in the context of hereditary breast and ovarian cancer (HBOC). The prevalence and cancer risks in this target group are unknown and counseling remains challenging. Notably an extensive high-risk surveillance program is implemented, which evokes substantial psychological discomfort. Emphasizing the lack of consensus about clinical implications, we aim to further characterize TP53g mutations in HBOC families. METHODS: Next-generation sequencing was conducted on 1876 breast cancer (BC) patients who fulfilled the inclusion criteria for HBOC. RESULTS: (Likely) pathogenic variants in TP53 gene were present in 0.6% of the BC cohort with higher occurrence in early onset BC < 36 years. (1.1%) and bilateral vs. unilateral BC (1.1% vs. 0.3%). Two out of eleven patients with a (likely) pathogenic TP53g variant (c.542G > A; c.375G > A) did not comply with classic LFS/Chompret criteria. Albeit located in the DNA-binding domain of the p53-protein and therefore revealing no difference to LFS-related variants, they only displayed a medium transactivity reduction constituting a retainment of wildtype-like anti-proliferative functionality. CONCLUSION: Among our cohort of HBOC families, we were able to describe a clinical subgroup, which is distinct from the classic LFS-families. Strikingly, two families did not adhere to the LFS criteria, and functional analysis revealed a reduced impact on TP53 activity, which may suit to the attenuated phenotype. This is an approach that could be useful in developing individualized screening efforts for TP53g mutation carrier in HBOC families. Due to the low incidence, national/international cooperation is necessary to further explore clinical implications. This might allow providing directions for clinical recommendations in the future.

[Reporting and handling of lymphonodectomy specimens in gynecologic malignancies and sentinel lymph nodes]. / Leitlinienbasierte Aufarbeitung und Befundung von Lymphonodektomiepräparaten und Sentinel-Lymphknoten gynäkologischer Malignome.

The handling and reporting of resected lymph nodes in gynecologic cancer follows the recommendations of the German national guidelines and the recommendations of the International Collaboration of Cancer Reporting (ICCR) and the International Society of Gynecologic Pathologists (ISGyP). The definitions of micrometastases and isolated tumor cells are in accordance with the definition of the UICC (Union Internationale Contre le Cancer) and TNM system. Both findings must be reported as part of the pathology report and final tumor classification. It is mandatory to examine all excised lymph nodes with complete processing of all nodes up to 0.3 cm and slicing of all larger nodes in 0.2-cm wide intervals with complete processing of all lamellae. The amount of the resected lymph nodes in correlation to positive nodes, the metric dimension of the largest lymph node metastasis per lymph node region, and the presence of extracapsular extension of the lymph node deposits must be part of the pathology report. The handling and cutting of sentinel lymph nodes are similar to nonsentinel nodes. Within frozen section analyses and final processing from paraffin-embedded sentinel nodes, all nodes should be examined by three-step sections with an interval of about 200 µm. In cases of negative sentinel nodes on H&E staining, immunohistochemical ultrastaging should be performed.

Intrapartum PRSA: a new method to predict fetal acidosis?-a case-control study.

PURPOSE: Phase-rectified signal averaging method (PRSA) represents an analysis method which applied on fetal cardiotocography (CTG) allows the quantification of the speed of fetal heart rate changes. By calculating the average deceleration capacity (ADC) an assessment of the fetal autonomic nervous system (ANS) is possible. The objective of this study was to test its ability to predict perinatal acidosis. METHODS: A case-control study was performed at a University Hospital in Munich. All intrapartum CTG heart rate tracings saved during a 7-year period were considered for analysis. All neonates born with an umbilical arterial blood pH ≤ 7.10 were considered as cases. Controls were defined as healthy fetuses born with a pH ≥ 7.25. The main matching criteria were gestational age at delivery, parity, birth mode, and birth weight percentile. Exclusion criteria were a planned caesarean section, fetal malformations, and multiple pregnancies. ADC and STV were then calculated during the last 60, the last 45, and the last 30 min intervals prior to delivery. RESULTS: Of all stored birth CTG recordings, 227 cases met the inclusion criteria and were studied. ADC was significantly higher in fetuses born with acidemia (4.85 bpm ± 3.0) compared to controls (3.36 bpm ± 2.2). The area under ROC curve was 0.659 (95% CI 0.608-0.710) for ADC and 0.566 (0.512-0.620) for STV (p = 0.013). CONCLUSIONS: This study confirms that the assessment of ADC using PRSA represents a good additional tool for the prediction of acute fetal acidosis during delivery.

Cystic Adenomyoma in Pregnancy: A Case Report.

Cystic adenomyomas (CA) are rare. They primarily affect adolescents and young women in their fertile years. Therefore, fertility and pregnancy outcome are of pivotal relevance in this patient collective. Apart from the guidelines of the European Society of Human Reproduction and Embryology (ESHRE) on the management of endometriosis in general, there are no specific treatment recommendations for CA and, as far as our research shows, no data illustrating the behavior of a CA over the course of pregnancy. Thus, we report the case of a 32-year-old 1-gravida, 1-para, preconceptionally diagnosed with a CA by ultrasound. After thoroughly discussing further treatment options, the decision was made to opt for a more conservative approach and not perform surgery before attempting a next pregnancy. The patient conceived spontaneously and sonographic monitoring of the CA throughout pregnancy showed complete regression of the cystic component during the second trimester. A healthy baby was delivered at term by an uncomplicated elective cesarean section. Following a review of the literature and taking into account the course of our case, we propose the feasibility of a conservative, non-surgical approach in women with a CA and the desire to conceive.

Do PET-positive supradiaphragmatic lymph nodes predict overall survival or the success of primary surgery in patients with advanced ovarian cancer?

OBJECTIVES: Compared to conventional computed tomography (CT), fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) detects higher rates of lymph node and distant metastases in patients with ovarian cancer. However, FDG-PET/CT is not routinely performed during preoperative work-up. Therefore, we investigated the prognostic value of preoperative FDG-PET/CT in advanced epithelial ovarian cancer (EOC) and its predictive value for surgical resection in patients with no residual disease. The potential significance of PET-positive supradiaphragmatic lymph nodes (SDLNs) for these parameters was evaluated. METHODS: All patients with FIGO IIA-IVB EOC diagnosed between March 2014 and January 2021 at our certified gynaecological cancer centre, who underwent FDG PET/CT before primary surgery were retrospectively included. RESULTS: Fifty-three consecutive patients were included in the study. Eighteen (34 %) patients had PET-positive SDLNs. We could not demonstrate a significant correlation between PET-positive SDLNs and median overall survival (OS; SDLN-positive: 58.76 months, SDLN-negative: 60.76 months; p = 0.137) or intra- or perioperative outcomes. CONCLUSIONS: FDG PET/CT has a higher detection rate for SDLNs in patients with ovarian cancer than CT has, as described in the literature. Moreover, PET-positive SDLNs failed to predict intraoperative outcomes or overall survival.

Recurrent Pelvic Organ Prolapse after Sacrocolpopexy-A Surgical Challenge.

Background: Repeat sacrocolpopexy (reSCP) for recurrent pelvic organ prolapse (POP) is a rare and complex condition with little understanding of how to manage. Most authors recommend complete reSCP regardless of the underlying cause of the failure. This retrospective cohort study presents our management workflow and how to systematically approach this challenging situation. Methods: From 2017 to 2021, we analyzed all women undergoing surgery for recurrent POP after sacrocolpopexy at our tertiary referral hospital at the department of urogynecology. Preoperatively, all women underwent a structured work-up consisting of answering the validated German female pelvic floor questionnaires, a clinical examination utilizing the POP-Q staging system according to the International Continence Society (ICS), and a pelvic floor ultrasound. The surgical management was based on the preoperative findings and was adapted individually during surgery if indicated according to the estimated underlying problem for recurrence. Results: In total, 377 women underwent a primary laparoscopic sacrocolpopexy. However, ten women presented with a symptomatic recurrent prolapse requiring further surgical intervention. A reSCP was performed in eight women, including two with additional laparoscopic paravaginal repair to correct the displaced mesh placement at initial surgery. A vaginal correction was indicated in two women with an isolated posterior compartment prolapse. The analysis demonstrates that reSCP has a low intraoperative complication rate and high subjective and objective success rates. Conclusions: We could demonstrate that individualized reSCP after initial SCP is a challenging yet feasible and safe treatment option, but there may be suitable alternatives. If women undergo pre- and intraoperative standardized problem-oriented examinations, we can often identify the cause of the recurrent prolapse. Tailored surgery must be subsequently performed.

Mucinous cystadenoma and benign mesonephric-like proliferation in the ovary - Further evidence for clonal relationship.

Mesonephric-like adenocarcinomas rarely occur in the uterus and the ovary. Benign mesonephric-like (ML) proliferations and hyperplasia have been described solely within the ovary. Pathogenetic data are very limited. We report a case with microscopic focus of benign ML-proliferation in association with mucinous cystadenoma in the ovary. The immunophenotype was distinct (mucinous tumor: focal weak nuclear positivity for PAX-8, CK 7, patchy cytoplasmic positivity for p16 and negativity for estrogen receptor, CD 10, TTF-1, p53 wildtype; mesonephric component: diffusely positive for PAX-8, CK 7, luminal CD 10, TTF-1, focal staining for estrogen receptor, patchy cytoplasmic for p16, p53 wildtype). On NGS-analysis there was clonal mutation of KRAS p.G12C. The data provide additional evidence for the concept of transdifferentiation (Müllerian tissue representing Wolffian/mesonephric features on histology and immunostaining) within the pathogenesis of mesonephric proliferation of the female genital tract and demonstrate the clonal relationship between these distinct morphologic components.

[Molecular classification of endometrial carcinoma-a short summary for clinical use]. / Molekulare Klassifikation des Endometriumkarzinoms ­ ein kurzer Überblick.

BACKGROUND: Histopathological examination is still the backbone for the diagnosis and treatment decision making in endometrial carcinoma (EC). The binary classification of EC into type 1 (mostly endometrioid) and type 2 (mostly serous), although still helpful, showed overlapping clinical, morphological and molecular features and was not very prognostic discriminatory for all subtypes of EC. METHODS: Analysing the most recent studies dealing with the molecular classification of EC and the recommendations of the German S3-guidelines for EC. RESULTS AND CONCLUSION: Based on the comprehensive molecular study of The Cancer Genome Atlas Project (TCGA) four distinct molecular subtypes have been identified: EC with POLE mutation (POLEmut), with loss of mismatch repair proteins (MMR deficiency; dMMR), or with TP53 mutation (p53mut) and without any of these alterations, termed NSMP (no specific molecular profile). The molecular classification of EC presents a morphomolecular approach, based on histopathological evaluation (tumor diagnosis, subtyping, grading), immunohistochemistry (MMR, p53) and molecular analyses for POLE. The incorporation of this molecular classification is recommended for clinical use by the World Health Organisation (WHO) as well as many national guidelines and international societies. Due to the heterogeneity of NSMP-EC, which is the largest molecular group, additional research is indicated to further characterise these tumors.

The influence of the menstrual cycle and hormonal contraceptives on cardiorespiratory fitness in physically active women: A systematic review and meta-analysis.

Objective: To systematically review and summarize the existing evidence related to the influence of the menstrual cycle (MC) and hormonal contraceptive (HC) use on V˙O2max in physically active women. Methods: This systematic review and meta-analysis conforms to the PRISMA statement guidelines. Four (sub-)meta-analyses were performed. Two focused on longitudinal studies examining the same women several times to compare the V˙O2max during the different menstrual phases or oral contraceptive (OC) use and withdrawal. Two meta-analyses examined if there is a difference in V˙O2max between OC users and normally menstruating women by analyzing cross-sectional studies assigning physically active women to one of these two groups as well as intervention-based studies (cross-over studies, randomized controlled trials considering only the data of the intervention group) comparing women intra-individually with and without OCs. Results: Nine of the included studies (107 women) evaluated the influence of the MC, five studies (69 women) the impact of OCs on V˙O2max, and six studies investigated both topics (88 women). A mean difference of V˙O2max -0.03 ml/kg/min (95%CI -1.06 to 1.01) between the early follicular and luteal menstrual phase was observed. Between the active and inactive phases of OCs, a mean difference of -0.11 ml/kg/min (95%CI -2.32 to 2.10) was found. The inter-individual comparison of naturally menstruating women and OC users showed a mean difference in V˙O2max of 0.23 ml/kg/min (95% CI -2.33 to 2.79) in favor of OC use. The intra-individual comparison of the same women showed a mean decrease in V˙O2max of -0.84 ml/kg/min (95% CI -2.38 to 0.70) after a new start with OCs. Conclusions: Our meta-analyses showed no effects of the MC or the OCs on V˙O2max. More high-quality studies are needed determining the MC phases more precisely, including OCs with the current standard formulations and comparing the influence of different progestins.

Mesonephric-like adenocarcinoma of the female genital tract: possible role of KRAS-targeted treatment-detailed molecular analysis of a case series and review of the literature for targetable somatic KRAS-mutations.

PURPOSE: Mesonephric-like adenocarcinomas (MLA) of the female genital tract represent a rare and relatively recently described neoplasm exhibiting characteristic morphologic and immunohistochemical findings commonly associated with a KRAS-mutation. Most cases display an aggressive clinical behavior, but knowledge about treatment approaches is limited, especially for targeting KRAS. METHODS: We report a series of eight cases with a detailed molecular analysis for KRAS. These cases as well as the data of previously published cases with detailed information regarding KRAS-mutational events were reviewed for a potential targeted approach and its prognostic impact. RESULTS: Both the uterine and ovarian MLA harbor a somatic KRAS-mutation in about 85% of the reported cases, affecting the hotspot codons 12 and 13. 15.7% of the endometrial and 15.6% of ovarian MLA are wild type for KRAS. A p.G12A-alteration was seen in 5.6% (5/89) of the endometrial and in 6.2% (2/32) of the ovarian tumors, for p.G12C in 7.9% and 6.2%, for p.G12D in 32.6% and 34.5% and for p.G12V in 36% and 37.5%, respectively. Very limited data are available regarding the prognostic impact of different mutational sites within the KRAS-gene without significant prognostic impact. CONCLUSION: Because of a specific p.G12C-KRAS somatic mutation, only the minority of MLA (7.9% with uterine and 6.2% with ovarian primary) are potentially targetable by sotarasib in that rare but aggressive subtype of adenocarcinoma of the female genital tract. Until now, the different location of a somatic KRAS-mutation is of no prognostic impact.