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Background Endometrial cancer studies have led to a number of well-defined but mechanistically unconnected genetic and environmental risk factors. One of the emerging modulators between environmental triggers and genetic expression is the microbiome. We set out to inquire about the composition of the uterine microbiome and its putative role in endometrial cancer. Methods We undertook a study of the microbiome in samples taken from different locations along the female reproductive tract in patients with endometrial cancer ( n  = 17), patients with endometrial hyperplasia (endometrial cancer precursor, n  = 4), and patients afflicted with benign uterine conditions ( n  = 10). Vaginal, cervical, Fallopian, ovarian, peritoneal, and urine samples were collected aseptically both in the operating room and the pathology laboratory. DNA extraction was followed by amplification and high-throughput next generation sequencing (MiSeq) of the 16S rDNA V3-V5 region to identify the microbiota present. Microbiota data were summarized using both α-diversity to reflect species richness and evenness within bacterial populations and β-diversity to reflect the shared diversity between bacterial populations. Statistical significance was determined through the use of multiple testing, including the generalized mixed-effects model. Results The microbiome sequencing (16S rDNA V3-V5 region) revealed that the microbiomes of all organs (vagina, cervix, Fallopian tubes, and ovaries) are significantly correlated ( p  < 0.001) and that there is a structural microbiome shift in the cancer and hyperplasia cases, distinguishable from the benign cases ( p  = 0.01). Several taxa were found to be significantly enriched in samples belonging to the endometrial cancer cohort: Firmicutes ( Anaerostipes , ph2 , Dialister , Peptoniphilus , 1–68 , Ruminococcus , and Anaerotruncus ), Spirochaetes ( Treponema ), Actinobacteria ( Atopobium ), Bacteroidetes ( Bacteroides and Porphyromonas ), and Proteobacteria ( Arthrospira ). Of particular relevance, the simultaneous presence of Atopobium vaginae and an uncultured representative of the Porphyromonas sp. (99 % match to P. somerae ) were found to be associated with disease status, especially if combined with a high vaginal pH (>4.5). Conclusions Our results suggest that the detection of A. vaginae and the identified Porphyromonas sp. in the gynecologic tract combined with a high vaginal pH is statistically associated with the presence of endometrial cancer. Given the documented association of the identified microorganisms with other pathologies, these findings raise the possibility of a microbiome role in the manifestation, etiology, or progression of endometrial cancer that should be further investigated.

Ovarian cancer (OC) is the second most common gynecological malignancy and the fifth leading cause of death due to cancer in women in the United States mainly due to the late-stage diagnosis of this cancer. It is, therefore, critical to identify potential indicators to aid in early detection and diagnosis of this disease. We investigated the microbiome associated with OC and its potential role in detection, progression as well as prognosis of the disease. We identified a distinct OC microbiome with general enrichment of several microbial taxa, including Dialister , Corynebacterium , Prevotella , and Peptoniphilus in the OC cohort in all body sites excluding stool and omentum which were not sampled from the benign cohort. These taxa were, however, depleted in the advanced-stage and high-grade OC patients compared to early-stage and low-grade OC patients suggestive of decrease accumulation in advanced disease and could serve as potential indicators for early detection of OC. Similarly, we also observed the accumulation of these mainly pathogenic taxa in OC patients with adverse treatment outcomes compared to those without events and could also serve as potential indicators for predicting patients’ responses to treatment. These findings provide important insights into the potential use of the microbiome as indicators in (1) early detection of and screening for OC and (2) predicting patients’ response to treatment. Given the limited number of patients enrolled in the study, these results would need to be further investigated and confirmed in a larger study.

ObjectiveTo compare the risk class attribution with molecular classification unknown to those with molecular classification known, according to the European Society of Gynaecological Oncology/European Society for Radiotherapy and Oncology/European Society of Pathology (ESGO/ESTRO/ESP) 2020 guidelines on endometrial cancer, with a focus on risk group migration. Additionally, to evaluate the capability of a novel molecular analysis algorithm to reduce the number of required tests.MethodsWe conducted a retrospective study including all consecutive patients with endometrial cancer undergoing surgery and comprehensive molecular analyses between April 2019 and December 2021. Molecular analyses including immunohistochemistry for p53 and mismatch repair (MMR) proteins, and DNA sequencing for POLE exonuclease domain were performed to classify tumors as POLE-mutated (POLE), MMR-deficient (MMR-d), p53 abnormal (p53abn), or non-specific molecular profile (NSMP). The two risk classifications of the ESGO/ESTRO/ESP 2020 guidelines were compared to estimate the proportion of patients in which the molecular analysis was able to change the risk class attribution. We developed a novel algorithm where the molecular analyses are reserved only for patients in whom incorporation of the molecular classification could change the risk class attribution.ResultsA total of 278 patients were included. Molecular analyses were successful for all cases, identifying the four subgroups: 27 (9.7%) POLE, 77 (27.7%) MMR-d, 49 (17.6%) p53abn, and 125 (45.0%) NSMP. Comparison of risk class attribution between the two classification systems demonstrated discordance in the risk class assignment in 19 (6.8%, 95% CI 4.2% to 10.5%) cases. The application of our novel algorithm would have led to a reduction in the number of POLE sequencing tests by 67% (95% CI 61% to 73%) and a decrease of p53 immunohistochemistry by 27% (95% CI 22% to 33%), as compared with the application of molecular classification to all patients.ConclusionMolecular categorization of endometrial cancer allows the reallocation of a considerable proportion of patients in a different risk class. Furthermore, the application of our algorithm enables a reduction in the number of required tests without affecting the risk classification.

ObjectiveThe prognostic significance of isolated tumor cells (≤0.2 mm) in sentinel lymph nodes (SLNs) of endometrial cancer patients is still unclear. Our aim was to assess the prognostic value of isolated tumor cells in patients with low risk endometrial cancer who underwent SLN biopsy and did not receive adjuvant therapy. Outcomes were compared with node negative patients.MethodsPatients with SLNs–isolated tumor cells between 2013 and 2019 were identified from 15 centers worldwide, while SLN negative patients were identified from Mayo Clinic, Rochester, between 2013 and 2018. Only low risk patients (stage IA, endometrioid histology, grade 1 or 2) who did not receive any adjuvant therapy were included. Primary outcomes were recurrence free, non-vaginal recurrence free, and overall survival, evaluated with Kaplan–Meier methods.Results494 patients (42 isolated tumor cells and 452 node negative) were included. There were 21 (4.3%) recurrences (5 SLNs–isolated tumor cells, 16 node negative); recurrence was vaginal in six patients (1 isolated tumor cells, 5 node negative), and non-vaginal in 15 (4 isolated tumor cells, 11 node negative). Median follow-up among those without recurrence was 2.3 years (interquartile range (IQR) 1.1–3.0) and 2.6 years (IQR 0.6–4.2) in the SLN–isolated tumor cell and node negative patients, respectively. The presence of SLNs-isolated tumor cells, lymphovascular space invasion, and International Federation of Obstetrics and Gynecology (FIGO) grade 2 were significant risk factors for recurrence on univariate analysis. SLN–isolated tumor cell patients had worse recurrence free survival (p<0.01) and non-vaginal recurrence free survival (p<0.01) compared with node negative patients. Similar results were observed in the subgroup of patients without lymphovascular space invasion (n=480). There was no difference in overall survival between the two cohorts in the full sample and the subset excluding patients with lymphovascular space invasion.ConclusionsPatients with SLNs–isolated tumor cells and low risk profile, without adjuvant therapy, had a significantly worse recurrence free survival compared with node negative patients with similar risk factors, after adjusting for grade and excluding patients with lymphovascular space invasion. However, the presence of SLNs–isolated tumor cells was not associated with worse overall survival.

ObjectiveAdult granulosa cell tumors represent less than 5% of all ovarian malignancies. The aim of this study was to analyze the clinicopathological parameters and their impact on progression-free and overall survival.MethodsPatients with primary adult granulosa cell tumors treated in three international referral centers between July 1999 and December 2018 were included. The following data were anonymously exported from the prospective database: age at diagnosis, International Federation of Gynecology and Obstetrics (FIGO) stage, adjuvant therapy, surgical procedures, progression-free survival, and overall survival. Descriptive statistical analysis regarding tumor and treatment characteristics was performed. Survival analyses included Kaplan–Meier functions and Cox proportional hazard ratios (HR).ResultsA total of 168 patients with primary adult granulosa cell tumors were included. Median age was 50 years (range 13–82). With regard to stage distribution, 54.2% (n=91) of patients were FIGO stage IA, 1.2% (n=2) were stage IB, 26.8% (n=45) were stage IC, and 17.9% (n=30) were FIGO stage II–IV. 66.7% (n=112) of patients underwent surgical restaging, of whom 17.9% (n=20) were moved to a higher stage. In addition, 36 (21.4%) patients underwent fertility-sparing surgery. After a median follow-up of 61 months (range 0–209), 10.7% of patients (n=18) had recurrent disease and 4.8% (n=8) died of disease. Five-year progression-free survival was 86.1% and estimated overall survival was 95.7%. Five-year progression-free survival was worse for patients with advanced stages (FIGO stage IA/B vs IC: HR 5.09 (95% CI 1.53 to 16.9); FIGO stage IA/B vs II–IV: HR 5.62 (95% CI 1.58 to 19.9)). Nineteen patients receiving adjuvant chemotherapy had lower estimated 5-year progression-free survival compared with patients not receiving chemotherapy (49.7% vs 91.1%, p<0.001; HR 9.15 (95% CI 3.62 to 23.1)).ConclusionThe prognosis of patients with primary adult granulosa cell tumors is mainly determined by FIGO stage. The outcome of patients with FIGO stage IC is comparable to those with advanced stages. Fertility-sparing surgery seems to be a safe procedure in stage IA. Our data do not support the use of adjuvant chemotherapy in early and advanced stages of adult granulosa cell tumors.

PurposeTo evaluate oncologic outcomes of early stage cervical cancer patients who underwent robotic radical hysterectomy (RRH) in a referral center, a retrospective analysis was performed.MethodsFrom January 2010 to December 2018, medical records of stage IA2–IIA1 cervical cancer patients, who underwent radical hysterectomy at our institute, were retrospectively reviewed. We focused our analysis on those who underwent RRH.ResultsA total of 198 patients were included in the final analysis. Median follow up was 52 months. At last follow-up, 188 (94.9%) women were disease-free, 9 (4.5%) had died, and 1 (0.5%) was alive with recurrent disease. At 4.5 years, PFS was 93.1% (SE ± 2.1) and OS was 95.1% (SE ± 1.8). Stratified by tumor size, PFS for tumor < 2 cm versus tumor ≥ 2 cm was statistically different (96.8% ± 2.3 and 87.9% ± 4.1 respectively, p = 0.01), as well as OS (100% and 89.8% ± 40 respectively, p = 0.01).Stratified by evidence of tumor at time of robotic surgery, PFS was statistically different in women with no residual tumor after conisation versus those with residual disease (100% ± 2.5 and 90.8% ± 2.8 respectively, p = 0.04). A recurrence occurred in 11 patients (5.6%).ConclusionsBased on our results, we could speculate that robotic approach, along with some technical precautions to avoid spillage, might be safe as primary treatment of early-stage cervical cancer, especially for tumor < 2 cm and in case of no evidence of disease at time of radical hysterectomy after previous conisation.

There are no reliable blood biomarkers for monitoring endometrial cancer patients in the current clinical practice. Circulating tumor DNA (ctDNA) is emerging as a promising non-invasive method to measure tumor burden, define prognosis and monitor disease status in many solid cancers. In this pilot study, we investigated if unique tumor-specific DNA junctions can be used to detect ctDNA levels in patients with endometrial cancer. Chromosomal rearrangements in primary tumors of eleven patients with high-grade or advanced stage endometrial cancer were determined by whole-genome Mate-Pair sequencing. Identified unique tumor-specific junctions were evaluated in pre- and six-week post-surgery patient plasma using individualized quantitative polymerase chain reaction (qPCR) assays. The relationship between clinicopathological features and detection of ctDNA was investigated. CtDNA was detected in 60% (6/10) of cases pre-surgery and in 27% (3/11) post-surgery. The detection of ctDNA pre-surgery was consistent with clinical indicators of aggressive disease such as advanced stage (80% - 4/5), lymphatic spread of disease (100% - 3/3), serous histology (80% - 4/5), deep myometrial invasion (100% - 3/3), lympho-vascular space invasion (75% - 3/4). All patients in which ctDNA was detected post-surgically had type II endometrial cancer. This pilot study demonstrates the feasibility of using personalized tumor-specific junction panels for detecting ctDNA in the plasma of endometrial cancer patients. Larger studies and longer follow-up are needed to validate the potential association between pre-surgical ctDNA detection and the presence of cancers with aggressive pathologic tumor characteristics or advanced stage observed in this study.

ObjectiveTo explore the factors influencing adoption of the sentinel lymph node (SLN) technique for endometrial cancer staging among gynecologic oncologists.MethodsA self-administered, web-based survey was sent via email (April 20 through May 21, 2017) to all members of European Society of Gynecologic Oncologists, International Gynecologic Cancer Society, and Society of Gynecologic Oncologists. Surgical and pathologic practices related to SLN and reasons for not adopting this technique were investigated.ResultsOverall, 489 attending physicians or consultants in gynecologic oncology from 69 countries responded: 201 (41.1%), 118 (24.1%), and 117 (23.9%) from Europe, the USA, and other countries, respectively (10.8% did not report a country). SLN was adopted by 246 (50.3%) respondents, with 93.1% injecting the cervix and 62.6 % using indocyanine green dye. The National Comprehensive Cancer Network SLN algorithm was followed by 160 (65.0%) respondents (USA 74.4%, Europe 55.4%, other countries 71.4%). However, 66.7% completed a backup lymphadenectomy in high-risk patients. When SLN biopsy revealed isolated tumor cells, 13.8% of respondents recommended adjuvant therapy. This percentage increased to 52% if micrometastases were detected. Among the 243 not adopting SLN, 50.2% cited lack of evidence and 45.3% stated that inadequate instrumentation fueled their decisions.ConclusionsSLN with a cervical injection is gaining widespread acceptance for staging of endometrial cancer among gynecologic oncologists worldwide. Standardization of the surgical approach with the National Comprehensive Care Network algorithm is applied by most users. Management of isolated tumor cells and the role of backup lymphadenectomy for ‘high-risk’ cases remain areas of investigation.

The genomic DNA input for stool samples utilized for microbiome composition has not been determined. In this study, we determined the reliable threshold level under which conclusions drawn from the data may be compromised. We also determined the type of microbial bias introduced by less-than-ideal genomic input. Variability in representation of microbial communities can be caused by differences in microbial composition or artifacts introduced at sample collection or processing. Alterations in community representation introduced by variations in starting DNA concentrations have not been systematically investigated in stool samples. The goal of this study was to evaluate the effect of the genomic DNA (gDNA) concentration in the resulting 16S rRNA gene library composition and compare its effect to other sample processing variables in homogenized human fecal material. Compared to a gDNA input of 1 ng/μl, inputs of ≤1.6 × 10 −3 ng/μl resulted in a marked decrease in the concentration of the 16S rRNA gene amplicon ( P < 0.001). Low gDNA concentrations (≤1.6 × 10 −3 ng/μl) were also associated with a decrease ( P < 0.001) in the number of operational taxonomic units and significant divergence in β-diversity profiles (unweighted UniFrac distance, P < 0.001), as characterized by an overestimation of Proteobacteria and underestimation of Firmicutes . Even a gDNA concentration of 4 × 10 −2 ng/μl showed a significant impact on the β-diversity profile (unweighted UniFrac distance, P = 0.03). Overall, the gDNA concentration explained 22.4% to 38.1% of the microbiota variation based on various β-diversity measures ( P < 0.001). By comparison, the DNA extraction methods and PCR volumes tested did not significantly affect the microbial composition profile, and the PCR cycling method explained less than 3.7% of the microbiota variation (weighted UniFrac distance, P = 0.03). The 16S rRNA gene yield and the microbial community representation of human homogenized stool samples are significantly altered by gDNA template concentrations of ≤1.6 × 10 −3 ng/μl. In addition, data from studies with a gDNA input of ≤4 × 10 −2 ng/μl should be interpreted with caution. IMPORTANCE The genomic DNA input for stool samples utilized for microbiome composition has not been determined. In this study, we determined the reliable threshold level under which conclusions drawn from the data may be compromised. We also determined the type of microbial bias introduced by less-than-ideal genomic input.