Cancer-field surgery for endometrial cancer by robotic peritoneal mesometrial resection and targeted compartmental lymphadenectomy (PMMR+TCL).

OBJECTIVE: Cancer-field surgery by peritoneal mesometrial resection and targeted compartmental lymphadenectomy (PMMR+TCL) for the treatment of endometrial cancer (EC) aims at optimal locoregional tumor control without the need for adjuvant radiotherapy. In a previous publication we could demonstrate the feasibility of the method and presented encouraging first oncologic data. METHODS: Following up our 2021 publication, we present data on the treatment of EC by PMMR+TCL in much larger cohort and with longer follow-up. RESULTS: One hundred and thirty-five patients with EC International Federation of Gynecology and Obstetrics (FIGO) I-IV (75.6% FIGO I) underwent cancer field surgery via PMMR+TCL for EC in the years 2016-2023. Mean follow-up in our cohort was 27.5 months (0, 83; 19.7). The procedure was feasible and safe with favorable intra-and postoperative complication rates. Even though 50.4% of patients had an indication for postoperative radiotherapy following national and international guidelines, the rate of postoperative irradiation administered was 10.4%. The overall recurrence rate was 8.1% and we observed 2 (1.5%) isolated locoregional recurrences. CONCLUSION: Our results confirm the feasibility and safety of PMMR+TCL in EC patients. Oncologic data are very encouraging and hint at a superior locoregional control without adjuvant irradiation. Larger studies with longer follow-up will be needed to confirm these results.

Sentinel Lymph node detection in endometrial cancer - Anatomical and scientific facts.

Anatomical and functional aspects of the lymphatic drainage of the uterine corpus in endometrial cancer are demonstrated. Main lymphatic pathway runs along the upper pelvic pathway from the uterine artery first line to the medial external iliac nodes, followed by the lateral external and common iliac node basin. The second important pathway runs along the ovarian vessels directly to the paraaortic nodes. Pathways may visualized best by injection of indocyanine green (ICG) into the uterus. In contrast to the upper pelvic pathway visualized by cervical injection, the paraaortic drainage can only be marked by corporal injection. Lymphatic drainage works downstream (peripheral to central, with respect to vascular valves) only. Clinically, pelvic sentinel node excision replaced systematic lymphadenectomy for diagnostic purposes and even paraaortic node staging can be omitted in most of pelvic node negative patients. For therapeutic purposes compartmental resection of the uterus together with its lymphovascular system and first line nodes "en bloc" could be an option as performed in peritoneal mesometrial resection/targeted compartmental lymphadenctomy (PMMR/TCL).

Peritoneal mesometrial resection with lymphadenectomy following prior hysterectomy in intermediate/high-risk endometrial cancer: feasibility and safety.

OBJECTIVE: Peritoneal mesometrial resection (PMMR) plus targeted compartmental lymphadenectomy (TCL) aims at removal of the locoregional cancer field in endometrial cancer (EC). Optimal locoregional control without adjuvant radiotherapy should be achieved concomitantly sparing systematic lymphadenectomy (LNE) for most of the patients. However, intermediate/high-risk EC is often definitely diagnosed postoperatively in simple hysterectomy specimen. Our aim was to evaluate feasibility and safety of a completing PMMR + TCL in patients following prior hysterectomy. METHODS: We evaluated data from 32 patients with intermediate/high-risk EC treated with PMMR + TCL or systematic pelvic and periaortic LNE following prior hysterectomy. Perioperative data on disease characteristics and morbidity were collected and patients were contacted for follow-up to determine the recurrence and survival status. RESULTS: We report data from 32 patients with a mean follow-up of 31.7 months. The recurrence rate was 12.5% (4/32) without any isolated locoregional recurrences. Only 21.9% of patients received adjuvant radiotherapy. Rates of intra- and postoperative complications were 6.3% and 18.8%, respectively. CONCLUSION: Our data suggest that robotic PMMR can be performed following prior hysterectomy when previously unknown risk factors arise, albeit with a moderate increase in morbidity. Moreover, despite a relevant reduction of adjuvant radiotherapy, follow-up data suggest an excellent locoregional control even without adjuvant radiotherapy.

Tumor cell cytoplasmic metallothionein expression associates with differential tumor immunogenicity and prognostic outcome in high-grade serous ovarian carcinoma.

Background: The underlying mechanism of high T-cell presence as a favorable prognostic factor in high-grade serous ovarian carcinoma (HGSOC) is not yet understood. In addition to immune cells, various cofactors are essential for immune processes. One of those are metallothioneins (MTs), metal-binding proteins comprising various isoforms. MTs play a role in tumor development and drug resistance. Moreover, MTs influence inflammatory processes by regulating zinc homeostasis. In particular, T-cell function and polarization are particularly susceptible to changes in zinc status. The aim of the present study was to investigate a possible role of MT-mediated immune response and its association with prognostic outcome in ovarian cancer. Methods: A retrospective study was conducted on a clinically well-characterized cohort of 24 patients with HGSOC treated at the University Hospital of Essen. Gene expression patterns for anti-cancer immunogenicity-related targets were performed using the NanoString nCounter platform for digital gene expression analysis with the appurtenant PanCancer Immune Profiling panel, consisting of 770 targets and 30 reference genes. Tumor-associated immunohistochemical MT protein expression was evaluated using a semi-quantitative four-tier Immunohistochemistry (IHC) scoring. Results: MT immunoexpression was detected in 43% (10/23) of all HGSOC samples. MT immunoexpression levels showed a significant association to survival, leading to prolonged progression-free and overall survival in positively stained tumors. Furthermore, T-cell receptor signaling gene signature showed a strong activation in MT-positive tumors. Activated downstream signaling cascades resulting in elevated interferon-gamma expression with a shift in the balance between T helper cells (TH1 and TH2) could be observed in the MT-positive subgroup. In addition, a higher expression pattern of perforin and several granzymes could be detected, overall suggestive of acute, targeted anti-cancer immune response in MT-positive samples. Conclusion: This is the first study combining broad, digital mRNA screening of anti-tumor immune response-associated genes and their relation to MT-I/II in ovarian cancer. MT overexpression is associated with molecular characteristics of an anti-cancer immune response and is a strong prognostic marker in ovarian HGSOC. The observed immune cell activation associated with tumor MT expression comprises but is not limited to T cells and natural killer cells.

Treatment and survival of patients with malignant ovarian sex cord-stromal cell tumours: An analysis of the Arbeitsgemeinschaft für Gynäkologische Onkologie (AGO) study group CORSETT database.

BACKGROUND: Malignant sex cord-stromal cell tumours (SCST) account for only 7% of ovarian malignancies. The Arbeitsgemeinschaft fuer Gynaekologische Onkologie (AGO) study group has established a clinicopathological database to provide an overview of the current treatment strategies and survival of SCST patients and to identify research needs. METHODS: Twenty centres provided mixed retro- and prospective data of patients with tumour specimens and second-opinion pathology review treated between 2000 and 2014. Descriptive analyses of treatment strategies, Kaplan-Meier curves and cox regression analyses were conducted. RESULTS: Two hundred and sixty-two SCST patients were included. One hundred and ninety-one Granulosa-cell tumour (GCT) and 17 Sertoli-Leydig cell tumour (SLCT) patients were stage I disease (>80%). Forty four GCT (18.7%) and two (8.3%) SLCT patients received adjuvant systemic treatment. After a median observation time of 78.2 months, 46% of all SCST patients experienced disease recurrence, treated predominantly with secondary debulking surgery (> 90%). Advanced FIGO stage, lymph node involvement and intra-operative capsule rupture were associated with disease recurrence on univariate analysis (all p < 0.05). Median OS time was not reached. DISCUSSION: In this analysis of SCST patients, adjuvant chemotherapy was unable to prevent disease recurrence. Despite high recurrence rates, overall survival rates were excellent.

Treatment strategies in patients with gynecological sarcoma: Results of the prospective intergroup real-world registry for gynecological sarcoma in Germany (REGSA-NOGGO RU1).

OBJECTIVE: Gynecological sarcomas account for 3% of all gynecological malignancies and are associated with a poor prognosis. Due to the rarity and heterogeneity of gynecological sarcomas there is still no consensus on optimal therapeutic strategies. This study's objective was to describe the treatment strategies used in patients with gynecological sarcomas in the primary course of disease. METHODS: The German prospective registry for gynecological sarcoma (REGSA) is the largest registry for gynecological sarcomas in Germany, Austria and Switzerland. Primary inclusion criteria for REGSA are histological diagnosis of sarcoma of the female genital tract, sarcoma of the breast or uterine smooth muscle tumors of uncertain malignant potential (STUMP). We evaluated data of the REGSA registry on therapeutic strategies used for primary treatment from August 2015 to February 2021. RESULTS: A total of 723 patients from 120 centers were included. Data on therapeutic strategies for primary treatment were available in 605 cases. Overall, 580 (95.9%) patients underwent primary surgery, 472 (81.4%) of whom underwent only hysterectomy. Morcellation was reported in 11.4% (n=54) of all hysterectomies. A total of 42.8% (n=202) had no further surgical interventions, whereas an additional salpingo-ophorectomy was performed in 54% (n=255) of patients. An additional lymphadenectomy was performed in 12.7% (n=60), an omentectomy in 9.5% (n=45) and intestinal resection in 6.1% (n=29) of all patients. Among 448 patients with available information, 21.4% (n=96) received chemo- or targeted therapies, more commonly as single-agent treatment than as drug combinations. Information about anti-hormonal treatment was available for 423 patients, among which 42 (9.9%) received anti-hormonal treatment, 23 (54.8%) of whom with low-grade endometrial stroma sarcomas. For radiotherapy, data of 437 patients were available, among which 29 (6.6%) patients underwent radiotherapy. CONCLUSION: Our study showed that treatment of patients with gynecologic sarcomas is heterogeneous. Further trials are needed along with more information on treatment modalities, therapy response and patient-reported outcomes to implement new treatment strategies.

Hysterectomy in benign conditions: a 20-year single-center retrospective on the development of surgical techniques.

INTRODUCTION: Minimally invasive (MI) surgery has long been established as a standard for hysterectomy in benign conditions. Robotic surgery is generally seen as equivalent to conventional laparoscopy in terms of patient outcome. However, robotics might facilitate an MI approach even in complex patients, rendering laparotomy unnecessary for almost all patients. MATERIALS AND METHODS: We identified 1939 patients who underwent hysterectomy for benign conditions between 2002 and 2020 at the University Hospital of Essen. Peri- and postoperative data as well as patient characteristics were collected retrospectively. RESULTS: Robotic surgery, implemented at our institution in 2010, was the most common approach (n = 771; 39.8%). 60.2% of all hysterectomies (1168/1938) were performed using MI techniques. However, there was a significant shift in the methods used for hysterectomy over time. While in 2002 51.4% of all hysterectomies were performed via an open abdominal approach, this percentage dropped to 1.4% in the year 2020. Accordingly, the use of MI approaches increased from 18.9% in 2002 to 98.6% in 2020. The introduction of robotic surgery in 2010 marked a significant shift towards more MI procedures. MI surgery resulted in shorter hospital stay and less postoperative complications compared to laparotomy. On a special note, our cohort includes the largest uterus myomatous uterus in the scientific literature with a specimen weight of 54.8 kg. CONCLUSION: Our data support the hypothesis that the implementation of robotic surgery leads to an improved capability to perform MI surgery and avoid laparotomy in almost all patients. The known benefits of MI surgery could be confirmed.

Detection of ESR1 Mutations in Primary Tumors and Plasma Cell-Free DNA in High-Grade Serous Ovarian Carcinoma Patients.

ESR1 mutations have been recently associated with resistance to endocrine therapy in metastatic breast cancer and their detection has led to the development and current evaluation of novel, highly promising therapeutic strategies. In ovarian cancer there have been just a few reports on the presence of ESR1 mutations. The aim of our study was to evaluate the frequency and the clinical relevance of ESR1 mutations in high-grade serous ovarian cancer (HGSOC). Drop-off droplet digital PCR (ddPCR) was first used to screen for ESR1 mutations in 60 primary tumors (FFPEs) from HGSOC patients and in 80 plasma cell-free DNA (cfDNA) samples from advanced and metastatic ovarian cancer patients. We further used our recently developed ESR1-NAPA assay to identify individual ESR1 mutations in drop-off ddPCR-positive samples. We report for the first time the presence of ESR1 mutations in 15% of FFPEs and in 13.8% of plasma cfDNA samples from advanced and metastatic ovarian cancer patients. To define the clinical significance of this finding, our results should be further validated in a large and well-defined cohort of ovarian cancer patients.

Single-center study for robotic-assisted laparoscopic sacropexies: a one-fits-all strategy for pelvic organ prolapse?

PURPOSE: Sarcopenia has been established as the "gold standard" for the treatment of pelvic organ prolapse (POP). Minimal invasive laparoscopy can help to reduce the risks of open access surgery. We compare the surgical results and outcomes of robotic-assisted sacropexies. METHODS: In this monocentric retrospective study we enrolled 49 patients operated on symptomatic POP. Patients were divided into two groups according to the type of robotic-assisted sacropexy: patients with a history of hysterectomy received robotic-assisted sacrocolpopexy (RSCP; n = 19), while patients with subtotal hysterectomy received robotic-assisted cervicosacropexy (RCSP; n = 30). Failure was defined as recurrence of the disease with a need for reoperation. Validated questionnaires (the Pelvic Floor Distress Inventory-20 (PFDI-20) and Pelvic Floor Impact Questionnaire-7 (PFIQ-7)), were used for evaluation of patients quality of life postoperatively. RESULTS: The comparison between RCSP versus RSCP showed that the latter is related to slightly but not significantly increased recurrence rates and a higher impact of POP symptoms on quality of life in long-term follow-up (p = 0.04). Perioperative data showed similar complication rates in both RSP types but shorter postoperative time of bladder catheterization in the case of RCSP (p = 0.008). CONCLUSIONS: The monocentric long-term data confirm that RSP is a safe and effective method of surgical POP treatment, regardless of the site of the anatomical compartment. In comparison to RSCP, RCSP is associated with a lower impact of POP symptoms on patients' quality of life with a tendency to slightly lower rates of POP recurrence.

CAF-Associated Paracrine Signaling Worsens Outcome and Potentially Contributes to Chemoresistance in Epithelial Ovarian Cancer.

Background: High-grade serous ovarian cancer (HGSOC) is the predominant and deadliest form of ovarian cancer. Some of its histological subtypes can be distinguished by frequent occurrence of cancer-associated myofibroblasts (CAFs) and desmoplastic stroma reaction (DSR). In this study, we want to explore the relationship between therapy outcome and the activity of CAF-associated signaling pathways in a homogeneous HGSOC patient collective. Furthermore, we want to validate these findings in a general Epithelial ovarian cancer (EOC) cohort. Methods: The investigation cohort consists of 24 HGSOC patients. All of them were treated with platinum-based components and clinical follow-up was available. The validation cohort was comprised of 303 patients. Sequencing data (whole transcriptome) and clinical data were extracted from The Cancer Genome Atlas (TCGA). RNA of HGSOC patients was isolated using a Maxwell RSC instrument and the appropriate RNA isolation kit. For digital expression analysis a custom-designed gene panel was employed. All genes were linked to various DSR- and CAF- associated pathways. Expression analysis was performed on the NanoString nCounter platform. Finally, data were explored using the R programming environment (v. 4.0.3). Result: In total, 15 CAF-associated genes were associated with patients' survival. More specifically, 6 genes (MMP13, CGA, EPHA3, PSMD9, PITX2, PHLPP1) were linked to poor therapy outcome. Though a variety of different pathways appeared to be associated with therapy failure, many were related to CAF paracrine signaling, including MAPK, Ras and TGF-ß pathways. Similar results were obtained from the validation cohort. Discussion: In this study, we could successfully link CAF-associated pathways, as shown by increased Ras, MAPK and PI3K-Akt signaling to therapy failure (chemotherapy) in HGSOC and EOCs in general. As platinum-based chemotherapy has been the state-of-the-art therapy to treat HGSOC for decades, it is necessary to unveil the reasons behind resistance developments and poor outcome. In this work, CAF-associated signaling is shown to compromise therapy response. In the validation cohort, CAF-associated signaling is also associated with therapy failure in general EOC, possibly hinting towards a conserved mechanism. Therefore, it may be helpful to stratify HGSOC patients for CAF activity and consider alternative treatment options.

Total mesometrial resection (TMMR) for cervical cancer FIGO IB-IIA: first results from the multicentric TMMR register study.

OBJECTIVE: The surgical concept of total mesometrial resection (TMMR) and therapeutic lymphadenectomy (tLNE) for the treatment of early cervical cancer is based on the ontogenetic cancer field model. Unicentric data show excellent locoregional control rates without adjuvant chemoradiation. However, there are so far no prospective, multicentric data supporting the method. METHODS: The multicentric TMMR register study was designed to answer the question whether the concept of TMMR+tLNE could be transferred to different centers and surgeons without compromising the outstanding oncologic results described in a unicentric setting. RESULTS: In 116 patients with cervical cancer stages IB-IIA, (International Federation of Gynecology and Obstetrics [FIGO] 2018), who underwent TMMR/tLNE, 25.0% were lymph node-positive. pT stages were pT1a in 3 patients (2.6%), pT1b1 in 82 (70.7%), pT1b2 in 18 (15.5%), pT2a in 4 (3.5%) and pT2b in 9 (7.8%). The overall recurrence rate was 7.8% in a median follow-up time of 24 months (6-80). Locoregional recurrences occurred in 6.0% of patients. One patient (0.9%) died from the disease during the observation period. CONCLUSION: These are the first multicentric data on the surgical concept of TMMR and tLNE for the treatment of cervical cancer FIGO IB-IIA. We were able to reproduce the excellent oncologic data described for the method albeit with a relatively short median observation time. A randomized controlled trial seems warranted to definitely establish TMMR+tLNE as the method of choice for the treatment of early cervical cancer. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01819077.

Association of Soluble B7-H4 and Circulating Tumor Cells in Blood of Advanced Epithelial Ovarian Cancer Patients.

INTRODUCTION: Epithelial ovarian cancer (EOC) is the deadliest gynecologic malignancy worldwide. Reliable predictive biomarkers are urgently needed to estimate the risk of relapse and to improve treatment management. Soluble immune-checkpoints in EOC are promising molecules serving as prognostic biomarkers accessible via liquid biopsy. We thus, aimed at elucidating the role of sB7-H4 in EOC. MATERIAL AND METHODS: We analyzed soluble serum B7-H4 (sB7-H4) using ELISA and circulating tumor cells (CTCs) in blood applying the AdnaTest OvarianCancer in 85 patients suffering from advanced EOC. Findings were correlated with clinical parameters as well as survival data. RESULTS: sB7-H4 was detectable in 14.1% patients, CTCs in 32.9% patients and simultaneous presence of CTCs and sB7-H4 was found in 7% patients, respectively. Although no association between sB7-H4 and CTC could be documented, each of them served as independent predictive factors for overall survival (OS). CONCLUSION: sB7-H4 and CTCs are independent prognostic biomarkers for impaired survival in EOC. As they are easily accessible via liquid biopsy, they may be of potential benefit for the prediction of therapy response and survival for EOC patients.

Accuracy of Ultrasonography and Magnetic Resonance Imaging for Preoperative Staging of Cervical Cancer-Analysis of Patients from the Prospective Study on Total Mesometrial Resection.

We aimed to evaluate the accuracy of ultrasonography with gynecologic examination performed by a gynecological oncologist and magnetic resonance imaging (MRI) interpreted by a radiologist for the local and regional staging of patients with early-stage cervical cancer. The study was a single-site sub-analysis of the multi-institutional prospective, observational Total Mesometrial Resection (TMMR) Register Study, which included all consecutive study patients from Gdynia Oncology Center. Imaging results were compared with pathology findings. A total of 58 consecutive patients were enrolled, and 50 underwent both ultrasonography and MRI. The accuracy of tumor detection and measurement errors was comparable across ultrasonography and MRI. There were no significant differences between ultrasonography and MRI in the accuracy of detecting parametrial involvement (92%, confidence interval (CI) 84-100% vs. 76%, CI 64-88%, p = 0.3), uterine corpus infiltration (94%, CI 87-100% vs. 86%, CI 76-96%, p = 0.3), and vaginal fornix involvement (96%, CI 91-100% vs. 76%, CI 64-88%, p = 0.3). The importance of uterine corpus involvement for the first-line lymph node metastases was presented in few cases. The accuracy of ultrasonography was higher than MRI for correctly predicting tumor stage: International Federation of Gynecology and Obstetrics (FIGO)-2018: 69%, CI 57-81% vs. 42%, CI 28-56%, p = 0.002, T (from TNM system): 79%, CI 69-90% vs. 52%, CI 38-66%, p = 0.0005, and ontogenetic tumor staging: 88%, CI 80-96% vs. 70%, CI 57-83%, p = 0.005. For patients with cervical cancer who are eligible for TMMR and therapeutic lymphadenectomy, the accuracy of ultrasonography performed by gynecological oncologists is not inferior to that of MRI interpreted by a radiologist for assessing specific local parameters, and is more accurate for local staging of the disease and is thus more clinically useful for planning adequate surgical treatment.

Image-Based Identification and Genomic Analysis of Single Circulating Tumor Cells in High Grade Serous Ovarian Cancer Patients.

In Ovarian Cancer (OC), the analysis of single circulating tumor cells (sCTCs) might help to investigate genetic tumor evolution during the course of treatment. Since common CTC identification features failed to reliably detect CTCs in OC, we here present a workflow for their detection and genomic analysis. Blood of 13 high-grade serous primary OC patients was analyzed, using negative immunomagnetic enrichment, followed by immunofluorescence staining and imaging for Hoechst, ERCC1, CD45, CD11b and cytokeratin (CK) and sCTC sorting with the DEPArrayTM NxT. The whole genome of single cells was amplified and profiled for copy number variation (CNV). We detected: Type A-cells, epithelial (Hoechstpos, ERCC1pos, CD45neg, CD11bpos, CKpos); Type B-cells, potentially epithelial (Hoechstpos, ERCC1pos, CD45neg, CD11bpos, CKneg) and Type C-cells, potentially mesenchymal (Hoechstpos, ERCC1pos, CD45neg, CD11bneg, CKneg). In total, we identified five (38.5%) patients harboring sCTCs with an altered CN profile, which were mainly Type A-cells (80%). In addition to inter-and intra-patient genomic heterogeneity, high numbers of Type B- and C-cells were identified in every patient with their aberrant character only confirmed in 6.25% and 4.76% of cases. Further identification markers and studies in the course of treatment are under way to expand sCTC analysis for the identification of tumor evolution in OC.

The effect of fertility-sparing surgery on sexuality and global quality of life in women with malignant ovarian germ cell and sex cord stromal tumors: an analysis of the CORSETT database of the AGO study group.

PURPOSE: Malignant ovarian germ cell (MOGCT) and sex cord stromal tumors (SCST) are ovarian neoplasms that affect disproportionally young women. Little is known about the impact of surgical and adjuvant management of these patient's sexual life. This study investigated the effect of fertility-sparing surgery on sexual activity and global quality of life (gQoL) in women with MOGCT and SCST. METHODS: CORSETT was an observational, multicenter, mixed retrospective/prospective cohort study of the AGO study group. Women of any age who had been diagnosed with MOGCTs and SCSTs between 2001 and 2011 were asked to complete the Sexual Activity Questionnaire (SAQ) and the EORTC QLQ-C30. RESULTS: In total, 355 patients were included. Of these, 152 patients with confirmed histological diagnosis had completed the questionnaires. A total of 106 patients were diagnosed with SCST and 46 with MOGCT. Totally, 83 women (55%) were sexually active. After fertility-sparing surgery, patients had a 2.6 fold higher probability for being sexually active than after non-fertility-conserving treatment (unadjusted odds ratio (OR) 2.6, p = 0.01). After adjustment for age, time since diagnosis, FIGO stage, histology and phase of disease, the OR dropped to 1.8 (p = 0.22). Of the sexually active patients, 35 (42%) reported high levels of discomfort during intercourse; 38% after fertility-sparing; and 58% after non-fertility-sparing surgery (adjusted OR 2.8, p = 0.18). Women with fertility-conserving treatment reported a significantly better global QoL (Fadj 2.1, 6.2 points difference, p = 0.03) but not more pleasure during intercourse than women without fertility-sparing surgery (Fadj 0.4, p = 0.52). CONCLUSION: Fertility preserving approaches should be offered to every patient, when oncologically acceptable.

Prognostic Significance of SLFN11 Methylation in Plasma Cell-Free DNA in Advanced High-Grade Serous Ovarian Cancer.

BACKGROUND: Epigenetic alterations in ctDNA are highly promising as a source of novel potential liquid biopsy biomarkers and comprise a very promising liquid biopsy approach in ovarian cancer, for early diagnosis, prognosis and response to treatment. METHODS: In the present study, we examined the methylation status of six gene promoters (BRCA1, CST6, MGMT, RASSF10, SLFN11 and USP44) in high-grade serous ovarian cancer (HGSOC). We evaluated the prognostic significance of DNA methylation of these six gene promoters in primary tumors (FFPEs) and plasma cfDNA samples from patients with early, advanced and metastatic HGSOC. RESULTS: We report for the first time that the DNA methylation of SLFN11 in plasma cfDNA was significantly correlated with worse PFS (p = 0.045) in advanced stage HGSOC. CONCLUSIONS: Our results strongly indicate that SLFN11 epigenetic inactivation could be a predictor of resistance to platinum drugs in ovarian cancer. Our results should be further validated in studies based on a larger cohort of patients, in order to further explore whether the DNA methylation of SLFN11 promoter could serve as a potential prognostic DNA methylation biomarker and a predictor of resistance to platinum-based chemotherapy in ovarian cancer.

Cancer field surgery in endometrial cancer: peritoneal mesometrial resection and targeted compartmental lymphadenectomy for locoregional control.

OBJECTIVE: Peritoneal mesometrial resection (PMMR) plus targeted compartmental lymphadenectomy (TCL) aims at removal of the locoregional cancer field in endometrial cancer (EC). Optimal locoregional control without adjuvant radiotherapy and acceptable surgical morbidity should be achieved concomitantly sparing systematic lymphadenectomy (LNE) for most of the patients. METHODS: We evaluated data from 132 patients treated for EC. Out of these, between January 2017 and June 2020 we performed robotic PMMR and TCL on 51 women. We present the first data of feasibility and safety of the procedure as well as preliminary oncological results. RESULTS: The 51 patients treated with robotic PMMR and TCL showed comparable morbidity to classic laparoscopic hysterectomy or PMMR without LNE. One intraoperative complication occurred. Postoperative complications grade 3 and higher occurred in 2 cases (3.9%). One of these (85 years old) experienced grade 5 following pulmonary embolism with lysis therapy. Fifteen patients (29.4%) could be spared complete LNE. The rate of adjuvant radiotherapy was 3.9% in our collective (n=2), compared to 39.2% of patients (n=20) eligible for irradiation according to international guidelines. In a mean follow-up time of 15 months (0-41), no locoregional recurrences were observed, although three patients showed distant relapse. CONCLUSIONS: Our data suggest that robotic PMMR and pelvic TCL can be performed regardless of BMI and comorbidities without a relevant increase in surgical morbidity. Moreover, despite a relevant reduction of adjuvant radiotherapy, first follow-up data hint at a favorable locoregional recurrence rate in the reported cohort.

The role of sentinel-node biopsy in ovarian cancer.

Lymph node involvement is an important prognostic factor in early and advanced epithelial ovarian cancer (EOC). However, to date there is no reliable method of detecting lymph node involvement, apart from surgical staging. Thus, pelvic and paraaortic lymphadenectomy (LNE) are still part of standard surgery of early ovarian cancer. There is conflicting evidence about the therapeutic value of systematic LNE in early EOC. Thus, the developmemt of a method to predict nodal status accurately, without extensive LNE, is the subject of ongoing research. Sentinel lymphadenectomy (SLN) has become a standard procedure in oncological surgery. However, SLN is not yet an established and widely accepted procedure for EOC. This review aimed at summarizing available evidence on its feasibility and reliability in EOC. Overall, evidence of SLN in early EOC is still scarce. So far, only small series of patients with a variety of tracers and injection sites were published. From the available literature, the most promising technique seems to be injection into the infundibulopelvic, as well as the proper ovarian ligament. Indocyanine green seems to be an excellent tracer for successful SLN of ovarian tumors, which can be used during laparoscopic or robotic surgery. The detection rates and true positive rates of studies support further investigation of the technique. Results from prospective studies, e.g. the ongoing SELLY trial, are necesssary to implement SLN into the standard treatment of early EOC.

Diphenhydramine increases the therapeutic window for platinum drugs by simultaneously sensitizing tumor cells and protecting normal cells.

Platinum-based compounds remain a well-established chemotherapy for cancer treatment despite their adverse effects which substantially restrict the therapeutic windows of the drugs. Both the cell type-specific toxicity and the clinical responsiveness of tumors have been associated with mechanisms that alter drug entry and export. We sought to identify pharmacological agents that promote cisplatin (CP) efficacy by augmenting the levels of drug-induced DNA lesions in malignant cells and simultaneously protecting normal tissues from accumulating such damage and from functional loss. Formation and persistence of platination products in the DNA of individual nuclei were measured in drug-exposed cell lines, in primary human tumor cells and in tissue sections using an immunocytochemical method. Using a mouse model of CP-induced toxicity, the antihistaminic drug diphenhydramine (DIPH) and two methylated derivatives decreased DNA platination in normal tissues and also ameliorated nephrotoxicity, ototoxicity, and neurotoxicity. In addition, DIPH sensitized multiple cancer cell types, particularly ovarian cancer cells, to CP by increasing intracellular uptake, DNA platination, and/or apoptosis in cell lines and in patient-derived primary tumor cells. Mechanistically, DIPH diminished transport capacity of CP efflux pumps MRP2, MRP3, and MRP5 particularly in its C2+C6 bimethylated form. Overall, we demonstrate that DIPH reduces side effects of platinum-based chemotherapy and simultaneously inhibits key mechanisms of platinum resistance. We propose that measuring DNA platination after ex vivo exposure may predict the responsiveness of individual tumors to DIPH-like modulators.

A randomized, double-blind, placebo-controlled phase 1b/2 study of ralimetinib, a p38 MAPK inhibitor, plus gemcitabine and carboplatin versus gemcitabine and carboplatin for women with recurrent platinum-sensitive ovarian cancer.

OBJECTIVE: This phase 1b/2 clinical trial (NCT01663857) evaluated the efficacy of ralimetinib in combination with gemcitabine (G) and carboplatin (C), followed by maintenance ralimetinib, for patients with recurrent platinum-sensitive epithelial ovarian cancer. METHODS: Phase 1b was to determine the recommended phase 2 dose (RP2D) of ralimetinib administered Q12H on Days 1-10 (q21d) in combination with G (1000 mg/m2, Days 3 and 10) and C (AUC 4, Day 3) for six cycles. In phase 2, patients were randomized double-blind 1:1 to ralimetinib (R)+GC or placebo (P)+GC, for six cycles, followed by ralimetinib 300 mg Q12H or placebo on Days 1-14, q28d. RESULTS: 118 patients received at least one dose of ralimetinib or placebo; eight in phase 1b and 110 in phase 2 (R+GC, N = 58; P+GC, N = 52). The RP2D for R+GC was 200 mg Q12H. The study met its primary objective of a statistically significant difference in PFS (median: R+GC, 10.3 mo vs. P+GC, 7.9 mo; hazard ratio [HR] = 0.773, P = 0.2464, against a two-sided false positive rate of 0.4). Secondary objectives were not statistically significant for median overall survival (R+GC, 29.2 mo vs. P+GC, 25.1 mo; HR = 0.827, P = 0.4686) or overall response rate (R+GC 46.6% vs. P+GC, 46.2%; P = 0.9667). The safety profile of R+GC therapy was mainly consistent with safety of the chemotherapy backbone alone. Grade 3/4 elevated alanine aminotransferase was more common in the ralimetinib arm. CONCLUSIONS: Addition of ralimetinib to GC resulted in a modest improvement in PFS.