Determination of endometrial cancer molecular subtypes using a whole exome-sequencing based single-method approach.

AIM: Endometrial cancer (EC) is heterogeneous with respect to epidemiology, clinical course, histopathology and tumor biology. Recently, The Cancer Genome Atlas (TCGA) network has identified four molecular subtypes with distinct clinical courses by an integrated multi-omics approach. These subtypes are of critical importance in the clinical management of EC. However, determination of TCGA molecular subtypes requires a complex methodological approach that is resource intensive and difficult to implement in diagnostic routine procedures. In this context, Talhouk et al. reported the precise determination of modified subtypes based on molecular surrogates obtained by a two-method approach comprising immunohistochemistry and DNA-sequence analysis (Proactive Molecular Risk Classifier for Endometrial Cancer; ProMisE). In this study, we aimed to identify EC molecular subtypes in analogy to TCGA and ProMisE applying an innovative whole exome-sequencing (WES) based single-method approach. METHODS: WES was performed in a cohort comprising N = 114 EC patients. WES data were analyzed using the oncology treatment decision support software MH Guide (Molecular Health, Heidelberg, Germany) and EC molecular subtypes in analogy to TCGA and ProMisE were determined. Results from both classifications were compared regarding their prognostic values using overall survival and progression-free survival analyses. RESULTS: Applying a single-method WES-approach, EC molecular subtypes analogue to TCGA and ProMisE were identified in the study cohort. The surrogate marker-analogue classification precisely identified high-risk and low-risk EC, whereas the TCGA-analogue classification failed to obtain significant prognostic values in this regard. CONCLUSION: Our data demonstrate that determination of EC molecular subtypes analogue to TCGA and ProMisE is feasible by using a single-method WES approach. Within our EC cohort, prognostic implications were only reliably provided by applying the surrogate marker-analogue approach. Designation of molecular subtypes in EC will be increasingly important in routine clinical practice. Thus, the single-method WES approach provides an important simple tool to tailor therapeutic decisions in EC.

Anterior enterocele after cystectomy: case report and review of the literature.

PURPOSE: Anterior enterocele is a rare but potentially serious complication after cystectomy with heterogeneous treatment options. METHODS: Here we report on the management of a 71-year-old patient with recurrence of anterior enterocele after cystectomy and provide a systematic review of the literature using the PubMed/MEDLINE database. RESULTS: The 71-year-old patient with recurrence of anterior enterocele after cystectomy was successfully treated with colpocleisis and anterior colporrhaphy at the Department of Gynecology and Gynecological Oncology, University Hospital Bonn. The use of a synthetic mesh was not needed. At 16-month follow-up postoperatively, the patient was asymptomatic and had no signs of recurrence. n = 14 publications including n = 39 patients were identified for the systematic review including case reports and reviews. The median duration of developing an anterior enterocele after cystectomy was 9 months (range 3 months to 8 years). Patients had a median age of 71 years (range 44-84). In all cases, a surgical approach was described using a wide variety of surgical procedures. In total, 36% of all patients developed a recurrence with an average time period of 7 months after primary surgery. A rare complication represents a vaginal evisceration with the need of urgent surgery. Furthermore, the occurrence of a fistula is a possible long-term complication. CONCLUSION: Anterior enterocele after cystectomy is a rare complication requiring an individual and interdisciplinary treatment.

Optimized complete cytoreduction in ovarian cancer through intraoperative real-time tumor visualization by 5-ALA - a case report.

Introduction: Complete macroscopic cytoreduction represents the most important prognostic parameter for overall survival in ovarian cancer. This dogma remains tenacious despite significant improvements in adjuvant systemic treatment. Hence, optimization of surgical therapy is an overarching goal to improve patients' outcomes. In this context, intraoperative tumor-specific imaging might facilitate optimized cytoreduction. In neurosurgery, intraoperative 5-aminolevulinic acid (5-ALA) guided imaging is applied in clinical routine to assess surgical resection margins. Here, we report the case of a patient with ovarian cancer in whom intraoperative 5-ALA tumor visualization led to optimized complete cytoreduction. Objective: Intraoperative administration of 5-ALA led to improved complete cytoreduction by identification and resection of additional ovarian cancer tumor manifestations. Case: The 39-year-old patient, Jehovah`s witness, presented to our department with a left sided ovarian mass, suspicious of ovarian cancer, based on clinical examination, sonographic suspicious features and a CA12-5 elevation. The patient's medical history and family history was unremarkable. Preoperative CT imaging of the thorax and abdomen showed no pathology besides the adnexal mass. Surgery was performed by a midline laparotomy with hysterectomy, bilateral adnexectomy, pelvic peritonectomy, omentectomy, ureterolysis, diaphragm stripping, adhesiolysis and the collection of peritoneal and rectal samples. Intraoperative 5-ALA imaging using a dedicated excitation and detection loupe system (Reveal, DVI) led to tumor detection at the diaphragm, the omentum and the rectum that was not detectable by palpation and visualization using white light. The pathology results revealed that the 5-ALA positive samples (diaphragm, rectum and omentum) obtained by intraoperative 5-ALA were positive for ovarian cancer. Conclusion: Intraoperative administration of 5-ALA represents a promising approach to improve complete cytoreduction in ovarian cancer surgery thereby improving clinical outcomes. Hence, further research and clinical trials are required to investigate the potential of intraoperative 5-ALA imaging in ovarian cancer debulking surgery and its impact on long-term clinical outcomes.

Intraoperative Utilization of Indocyanine Green (ICG) Dye for the Assessment of Ovarian Perfusion-Case Report and Review of the Literature.

The assessment of ovarian perfusion after detorsion is crucial in the surgical management of patients with ovarian torsion. In current routine clinical practice, the surgical decision (preservation of the ovary versus oophorectomy) is based on the subjective impression of the surgeon. Intraoperative indocyanine green (ICG) angiography has been shown to sufficiently reflect tissue perfusion with a potential impact on the surgical procedure. Currently, there are only sparse data available on the utilization of ICG in the surgical treatment of ovarian torsion. Here, we describe the successful intraoperative use of ICG in a 17-year-old female patient with ovarian torsion who underwent ovary-preserving surgery. Further, a systematic literature review was performed. Based on the data available to date, the use of ICG in the surgical treatment of ovarian torsion is feasible and safe. The extent to which this might reduce the necessity for oophorectomy has to be evaluated in further investigations.

Determination of the Cancer Genome Atlas (TCGA) Endometrial Cancer Molecular Subtypes Using the Variant Interpretation and Clinical Decision Support Software MH Guide.

BACKGROUND: The Cancer Genome Atlas (TCGA) network (United States National Cancer Institute) identified four molecular endometrial cancer (EC) subtypes using an extensive multi-method approach. The aim of this study was to determine the four TCGA EC molecular subtypes using a single-method whole-exome sequencing (WES)-based approach provided by MH Guide (Molecular Health, Heidelberg, Germany). METHODS: WES and clinical data of n = 232 EC patients were obtained from TCGA. The four TCGA EC molecular subtypes designated as (i) Mutated Polymerase ε (POLE), (ii) Microsatellite Instability (MSI), (iii) Copy Number (CN) low and, (iv) CN-high were determined using the MH Guide software. The prognostic value of the subtypes determined by MH Guide were compared with the TCGA classification. RESULTS: Analysis of WES data using the MH Guide software led to the precise identification of the four EC molecular subtypes analogous to the TCGA classification. Both approaches displayed high concordance in terms of prognostic significance. CONCLUSIONS: The multi-method-based TCGA EC molecular subtypes can reliably be reproduced by the single-method-based MH Guide approach. The easy-to-implement single-method MH Guide approach represents a promising diagnostic tool.

Analysis of the cervical microbiome in women from the German national cervical cancer screening program.

PURPOSE: Cervical cancer (CC) is caused by a persistent high-risk human papillomavirus (hrHPV) infection. The cervico-vaginal microbiome may influence the development of (pre)cancer lesions. Aim of the study was (i) to evaluate the new CC screening program in Germany for the detection of high-grade CC precursor lesions, and (ii) to elucidate the role of the cervico-vaginal microbiome and its potential impact on cervical dysplasia. METHODS: The microbiome of 310 patients referred to colposcopy was determined by amplicon sequencing and correlated with clinicopathological parameters. RESULTS: Most patients were referred for colposcopy due to a positive hrHPV result in two consecutive years combined with a normal PAP smear. In 2.1% of these cases, a CIN III lesion was detected. There was a significant positive association between the PAP stage and Lactobacillus vaginalis colonization and between the severity of CC precursor lesions and Ureaplasma parvum. CONCLUSION: In our cohort, the new cervical cancer screening program resulted in a low rate of additional CIN III detected. It is questionable whether these cases were only identified earlier with additional HPV testing before the appearance of cytological abnormalities, or the new screening program will truly increase the detection rate of CIN III in the long run. Colonization with U. parvum was associated with histological dysplastic lesions. Whether targeted therapy of this pathogen or optimization of the microbiome prevents dysplasia remains speculative.

Programmed Cell Death Ligand-1 (PDL-1) Correlates With Tumor Infiltration by Immune Cells and Represents a Promising Target for Immunotherapy in Endometrial Cancer.

BACKGROUND/AIM: Endometrial carcinoma (EC) is one of the most common gynecological cancers in the Western Hemisphere. Nevertheless, there are not enough appropriate treatment options, especially for advanced stages. The immune checkpoint blockade represents a promising alternative to established cancer therapies by suppressing the immune-inhibitory activity of the immune checkpoint factors programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1). In the present study, we characterized the clinical relevance of the biomarker PD-L1 expression in terms of its prognostic capabilities in EC. PATIENTS AND METHODS: Tumor tissue samples from 87 EC patients were retrospectively analyzed by immunohistochemistry (PD-L1, p16, estrogen receptor, progesterone receptor, HER2/neu, Ki-67, CD3, CD20, CD68). RESULTS: A total of 17.3% of EC patients were PD-L1 positive. PD-L1 status did not represent a suitable prognostic marker in EC, but correlated with T3/T4stage, positive lymph node status, p16 expression, and absence of estrogen and progesterone receptor. PD-L1 positive tissues showed increased infiltration with lymphocytes, monocytes, and macrophages, although not statistically significant in every case. CONCLUSION: In EC, PD-L1 expression has no prognostic significance, but correlates with other oncogenic factors and indicates increased infiltration of the tumor with immune cells. Thus, PD-1/PD-L1 immunecheckpoint blockade seems to be very promising, at least in a subset of EC patients.

[Treatment of HIV in Pregnancy - Progress Over One Decade]. / Behandlung von HIV in der Schwangerschaft ­ Entwicklung über eine Dekade.

INTRODUCTION: Worldwide, 37 million people are infected with HIV; more than 50% are women. Currently, MTCT (mother-to-child transmission) can be reduced to<1%. The intention of the present study was to analyze the development of (1) the course of pregnancy of HIV-infected women, (2) the mode of delivery and (3) the post-exposure prophylaxis of the newborn over the last decade. METHODOLOGY: In this retrospective study, data from HIV-infected women who between 2005 and 2016 received care at the HIV outpatient department and gave birth at the Department of Obstetrics at University Hospital Bonn was analyzed. Furthermore, neonatal data was collected and HIV-MTCT was evaluated. RESULTS: In the 2005-2016 study period, 87 pregnancies in 61 women were identified. Seventy babies were born alive at the Department of Obstetrics, University Hospital Bonn. 53% of these women were of African origin. The median of CD4+ cell count was 510 cells/ml (IQR 444); however, 32 women (52%) had more than 500 cells/ml. During the antenatal period, the HI viral load had been suppressed completely in 77% of women (<50 HIV-1-RNA copies/ml) and was<400 HIV-1-RNA copies/ml in 92% of women. The elective cesarean section rate fell significantly from 77% in the years 2005-2011 to 58% in 2012-2016. The proportion of deliveries after 37 weeks of gestation increased markedly from 60% to 69% after 2012. Additionally, while between 2005-2011 the birth weight of 78% of the newborns was between the 10th and 90th percentile, this proportion increased to 92% after 2012. Fifty-four of 70 newborns (77%) were classified as having low to normal HIV transmission risk. A vertical HIV transmission from mother to child did not occur (0/70). CONCLUSIONS: Between 2005 and 2016 no vertical HIV transmission from mother to child occurred (0/70). Due to the change in treatment strategy, the elective cesarean section rate fell significantly as well the rate of premature births. An optimal interdisciplinary collaboration builds the basis for successful treatment of HIV in pregnancy.

Pravastatin for prevention of HELLP syndrome: A case report.

RATIONALE: Pravastatin has emerged for prevention and treatment of preeclampsia; no reports are available on pravastatin and HELLP (hemolysis, elevated liver enzymes and low platelets) syndrome. PATIENT CONCERNS: The first pregnancy necessitated termination of pregnancy at gestational age (GA) 20+5 for HELLP. Intrauterine fetal death at GA 22+5 occurred in the second pregnancy, whilst on temporizing management of HELLP. DIAGNOSES: Severe, recurrent early-onset HELLP syndrome. INTERVENTIONS: In her fourth pregnancy, pravastatin was commenced at GA 13. OUTCOMES: The course of pregnancy was uncomplicated, and a healthy, appropriate for gestational age fetus was delivered at term. LESSONS: Pravastatin may be effective in prevention of HELLP. The hepatic uptake may be of particular advantage.

Comparison of balloon kyphoplasty with the new Kiva® VCF system for the treatment of vertebral compression fractures.

BACKGROUND: Vertebral compression fractures are common among the elderly, which is conditioned by osteoporosis. They cause back pain and limit the patient's activities. The Kiva® VCF Treatment System is a new device to treat vertebral compression fractures. Compared to other methods, the utilization of the Kiva System reduces the risk for complications and delivers improvements in back pain reduction and functionality. OBJECTIVES: Evaluation of safety and effectiveness of the Kiva System in comparison to balloon kyphoplasty on the basis of matched pairs. METHODS: 52 patients (47 - 89 years, 68 fractures) were treated with balloon kyphoplasty or with the new Kiva System. Back pain and impairment of motility were assessed preoperatively and 6 months postoperatively, with the Visual Analog Scale (VAS) and Oswestry Disability Index (ODI). The operation time and cement extravasation were recorded. Control radiographs were evaluated for new fractures and vertebral heights. RESULTS: Mean VAS values in both groups improved from preoperatively 87.6 ± 12.8 and 83.1 ± 14.9 to 10.8 ± 20.8 and 24.6 ± 11.0 6 months after the treatment. The improvement after 6 months in the Kiva group was significantly better than in the balloon kyphoplasty group (P < 0.0001). Mean ODI scores in both groups also improved from 68.7% ± 15.8% in the Kiva group and 80.6% ± 8.6% in the balloon kyphoplasty group preoperatively to 24.8 ± 18.6% and 33.2 ± 6.3% 6 months after treatment. The mean operation time for the Kiva group was 12.7 ± 3.7 minutes per vertebra and cement leakage occurred in 6 patients. The mean operation time for the balloon kyphoplasty group was 34.1 ± 7.0 minutes per vertebra and cement leakage occurred in 8 patients. Anterior and mid vertebral height in the Kiva group increased from preoperatively 21.06 ± 7.44 mm and 18.36 ± 5.64 mm to postoperatively 22.41 ± 7.14 mm and 20.41 ± 6.00 mm. Anterior and mid vertebral height in the balloon kyphoplasty group increased from preoperatively 21.68 ± 2.06 mm and 21.97 ± 1.78 mm to postoperatively 25.09 ± 2.54 mm and 25.29 ± 2.10 mm. Vertebral height restoration could be therefore maintained with both procedures for 6 months. In the Kiva group 2 cases of nonadjacent fractures and one case of adjacent fractures were observed. In the balloon kyphoplasty group 9 cases of adjacent, as well as 5 cases of nonadjacent, fractures were observed. In the Kiva group significant fewer fractures occurred. LIMITATIONS: The study includes only 26 patients for each procedure, which were compared on the basis of matched pairs. CONCLUSION: The Kiva System appears to be a safe and effective procedure for the treatment of vertebral compression fractures. Six months after treatment with the Kiva System, better VAS values than the values after the treatment with balloon kyphoplasty were recorded. Reduction in functional impairment was as successful as it was after balloon kyphoplasty. Vertebral height restoration was observed in both groups, which was sustained for 6 months. The risk of cement extravasation during the Kiva Treatment is nearly the same as in balloon kyphoplasty; however, it requires a shorter operation time and produces less new fractures.