European multidisciplinary tumor boards support cross-border networking and increase treatment options for patients with rare gynecological tumors.

OBJECTIVE: To evaluate outcomes of European cross-border multidisciplinary tumor boards in terms of participation, adherence to treatment recommendations, and access to novel treatment strategies. METHODS: The European reference network for rare gynecological tumors (EURACAN G2 domain) aims to improve the diagnosis, management, and treatment of patients with these cancers. Cross-border multidisciplinary tumor boards were initiated to facilitate intercollegiate clinical discussions across Europe and increase patients' access to specialist treatment recommendations and clinical trials. All G2 healthcare providers were invited to participate in monthly multidisciplinary meetings. Patient data were collected using a standardized form and case summaries were distributed before each meeting. After each tumor board, a meeting summary with treatment recommendations was sent to all participants and the project manager at the coordinating center. The multidisciplinary tumor board format and outcomes were regularly discussed at G2 domain meetings. Anonymized clinical data and treatment recommendations were registered in a prospective database. For this report, clinical data were collected between November 2017 and December 2020 and follow-up data retrieved until May 2021. RESULTS: During the 3-year period, 31 multidisciplinary tumor boards were held with participants from 10 countries and 20 centers. 91 individual patients were discussed between one and six times for a total of 109 case discussions. Follow-up data were retrieved from 64 patients and 80 case discussions. Adherence to treatment recommendations was 99%. Multidisciplinary tumor board recommendations resulted in 11 patients getting access to off-label treatment and one patient being enrolled in a clinical trial in another European country. 14/91 patients were recommended for surveillance only when additional treatment had been considered locally. CONCLUSION: Cross-border multidisciplinary tumor boards enable networking and clinical collaboration between healthcare professionals in different countries. Surveillance strategies, off-label drug use, and increased participation in clinical trials are possible benefits to patients with rare gynecological tumors.

Incidence of and survival after surgical intervention for bowel obstruction in women with advanced ovarian cancer.

INTRODUCTION: Women with advanced ovarian cancer commonly present with peritoneal disease both at primary diagnosis and relapse, with risk of subsequent bowel obstruction. The aims of this study were to assess the cumulative incidence of and survival after intervention for bowel obstruction in women with advanced ovarian cancer, to identify factors predictive of survival and the extent to which the intended outcome of the intervention was achieved. MATERIAL AND METHODS: Women diagnosed with advanced ovarian cancer stages III and IV in 2009-2011 and 2014-2016 in the Stockholm-Gotland Region in Sweden were identified in the Swedish Quality Registry for Gynecologic Cancer. Through hospital records, types of intended and executed interventions for bowel obstruction were assessed, and as well as when in the course of oncologic treatment, the intervention was performed. Time from first intervention to death was analyzed with survival methodology and proportional hazard regression was used. RESULTS: Of 751 identified women, 108 had an intervention for bowel obstruction. Laparotomy was the most prevalent intervention and was used in 87% (94/108) of all women, with a success rate of 87% (82/94). An intervention for bowel obstruction was performed before or during first line treatment in 32% (35/108) with a cumulative incidence in the whole cohort of 14% (108/751, 95% confidence interval [CI] 11-16). Median survival after intervention for bowel obstruction was 4 months (95% CI 3-6). The hazard of death increased when the intervention was performed after completion of primary treatment (HR 4.46, 95% CI 1.61-12.29, P < 0.01), with a median survival of 3 months. In women subjected to radical surgery during primary treatment, the hazard of death after intervention for bowel obstruction decreased (hazard ratio [HR] 0.54, 95% CI 0.32-0.91, P = 0.02). CONCLUSIONS: Women with advanced ovarian cancer undergoing intervention for bowel obstruction have a dismal prognosis, regardless of which line of oncologic treatment the intervention was performed. In the majority of women an intervention for bowel obstruction was performed in a relapse situation with an even worse survival. Our findings emphasize the importance of a holistic approach in the decision-making before an intervention for bowel obstruction in women with advanced ovarian cancer.

Surgical Management of Gestational Trophoblastic Disease.

Background Gestational Trophoblastic Disease (GTD) is a rare pregnancy related condition consisting of premalignant and malignant forms arising from proliferation of trophoblastic cells. The malignant forms are collectively referred to as Gestational Trophoblastic Neoplasia (GTN) and are highly sensitive to chemotherapy. However, surgical procedures remain indispensable in the diagnosis and treatment of GTD. Objectives The aim of this review is to summarize surgical interventions in the treatment of GTD and GTN. We reviewed indications, efficacy, possible complications and oncological outcomes of surgery. Methods Three searches were performed in the databases of PubMed, Embase and the Cochrane Library to create an up-to-date overview of existing literature on the following subjects: 1. The role of primary hysterectomy in GTD and GTN 2. The role of second curettage in GTD and GTN 3. Fertility sparing surgery in GTN 4. Surgical management of metastases. Included articles originated from the time period 1952-2022. Articles written in English, Spanish and French were included. Outcomes Thirty-eight articles were found and selected. Surgical evacuation through suction curettage is most used and advised in the treatment of GTD. A second curettage could be beneficial in patients with low hCG levels and low FIGO scores. In women who have completed their families, primary hysterectomy might be considered as the risk of subsequent GTN is lower than after suction curettage. In case of the rare forms of GTN (Epithelioid Trophoblastic Tumor (ETT) or Placental Site Trophoblastic Tumor (PSTT)) surgical tumor resection remains the most important step in treatment. Data on fertility sparing surgery in GTN are scarce and this treatment should be considered experimental. Conclusion and Outlook Surgery remains an important part of treatment of GTD and is sometimes indispensable to achieve curation. Further collection of evidence is needed to determine treatment steps.

Fertility and pregnancy outcome in gestational trophoblastic disease.

The aim of this review is to provide an overview of existing literature and current knowledge on fertility rates and reproductive outcomes after gestational trophoblastic disease. A systematic literature search was performed to retrieve all available studies on fertility rates and reproductive outcomes after hydatidiform mole pregnancy, low-risk gestational trophoblastic neoplasia, high- and ultra-high-risk gestational trophoblastic neoplasia, and the rare placental site trophoblastic tumor and epithelioid trophoblastic tumor forms of gestational trophoblastic neoplasia. The effects of single-agent chemotherapy, multi-agent including high-dose chemotherapy, and immunotherapy on fertility, pregnancy wish, and pregnancy outcomes were evaluated and summarized. After treatment for gestational trophoblastic neoplasia, most, but not all, women want to achieve another pregnancy. Age and extent of therapy determine if there is a risk of loss of fertility. Single-agent treatment does not affect fertility and subsequent pregnancy outcome. Miscarriage occurs more often in women who conceive within 6 months of follow-up after chemotherapy. Multi-agent chemotherapy hastens the natural menopause by three years and commonly induces a temporary amenorrhea, but in young women rarely causes permanent ovarian failure or infertility. Subsequent pregnancies have a high chance of ending with live healthy babies. In contrast, high-dose chemotherapy typically induces permanent amenorrhea, and no pregnancies have been reported after high-dose chemotherapy for gestational trophoblastic neoplasia. Immunotherapy is promising and may give better outcomes than multiple schedules of chemotherapy or even high-dose chemotherapy. The first pregnancy after immunotherapy has recently been described. Data on fertility-sparing treatment in placental site trophoblastic tumor and epithelioid trophoblastic tumor are still scarce, and this option should be offered with caution. In general, patients with gestational trophoblastic neoplasia may be reassured about their future fertility and pregnancy outcome. Detailed registration of high-risk gestational trophoblastic neoplasia is still indispensable to obtain more complete data to better inform patients in the future.

Ultra-radical upfront surgery does not improve survival in women with advanced epithelial ovarian cancer; a natural experiment in a complete population.

OBJECTIVE: Ultra-radical surgery to achieve complete resection in advanced epithelial ovarian cancer (EOC) has been widely accepted without strong supporting data. Our objective was to assess overall survival after a structured shift to an ultra-radical upfront surgical treatment algorithm and to investigate changes in the distribution of primary treatments after this shift. PATIENTS AND METHODS: In this population-based cohort study, all women with suspected EOC in the Stockholm-Gotland region of Sweden reported to the Swedish Quality Registry for Gynecologic Cancer (SQRGC) and National Cancer Registry (NCR) were selected in two 3-year cohorts, based on year of diagnosis (before (cohort1) or after (cohort 2) change in surgical treatment algorithm) and followed for at least three years. 5-year overall survival (OS) in non-surgically and surgically treated women was analyzed. Moreover, proportional distribution of primary treatment was evaluated. RESULTS: 752 women were included in the final analysis (n = 364 and 388 in cohort 1 and 2 respectively) with a median follow-up of 29 and 27 months. The complete resection rate increased from 37 to 67% (p ≤ 0.001) as well as proportion non-surgically treated women, 24 to 33%. No improvement in OS was observed in non-surgically (HR 0.76 (95% CI, 0.58-1.01); p = 0.06) or surgically treated (HR 0.94 (95% CI, 0.75-1.18); p = 0.59) women, even when complete resection was achieved (HR 1.31 (95% CI, 0.89-1.92); p = 0.17). CONCLUSION: A shift to ultra-radical upfront surgery in EOC did not improve survival despite a significant increase in complete resection rate. Identifying the limitations of surgical treatment remains a challenge.

Surgery performed later in the week is associated with failure to achieve complete radical surgical resection in advanced ovarian cancer.

Background: The surgical treatment of advanced ovarian cancer aims to resect all visible tumor to no gross residual, these procedures are often extensive with need of prolonged attention to detail. Our objective was to investigate the association between week-day of surgery, time of year (season) when surgery was performed and non-radical surgery (surgical failure) in advanced ovarian cancer.Material and methods: Women diagnosed with primary invasive epithelial ovarian cancer in the Stockholm/Gotland Region, Sweden were identified in the regional Swedish Quality Registry of Gynecologic Cancer (SQRGC). Data of all women with International Federation of Gynecology and Obstetrics (FIGO) stages III and IV were validated against the National Cancer Registry. Women subjected to surgery with curative intent were selected and included in the analysis. Uni- and multivariable regression analyses were performed.Results: Out of 538 women identified in the SQRGC-string ovary between 2014 and 2016, 240 were eligible for analysis. In 29% of women, complete radical resection was not achieved. There was a significant trend of increased non-radical resection when surgery was performed from Monday through Thursday (p = .03). The adjusted odds of non-radical surgery increased if surgery was performed on Thursday rather than Monday (Odds Ratio (OR) 3.04, 95% Confidence Interval (CI) 1.05-8.79, p = .04). Surgery performed during summer compared to the rest of the year, did not significantly increase the adjusted odds of non-radical surgery (OR 1.92, 95% CI 0.91-4.07, p = .09).Conclusion: Complete surgical resection of tumor is one of the strongest prognostic factors for survival in advanced epithelial ovarian cancer. For this reason, advanced ovarian cancer surgery should be scheduled early in the week.

Cardiophrenic lymph node resection in advanced ovarian cancer: surgical outcomes, pre- and postoperative imaging.

OBJECTIVE: To evaluate the accuracy of preoperative imaging in the diagnosis of cardiophrenic lymph node (CPLN) metastases and to report perioperative outcomes after resection of CPLN at the time of cytoreductive surgery for advanced epithelial ovarian cancer (EOC). Furthermore, to assess clearance of CPLN by postoperative imaging. METHODS: All women with stage IIIC/IV EOC subjected to surgery at our institution from January 2014 to October 2016 were retrospectively identified from a database. Among these, women subjected to CPLN resection during surgery were identified. Pre- and postoperative computed tomography (CT) scans, pathology reports, surgical approach and outcomes were reviewed. RESULTS: One hundred and eighty women with stage IIIC/IV EOC subjected to surgery with curative intent were identified. Twenty-four (13%) of these women underwent CPLN resection. All had CT imaging suggestive of CPLN metastases. 20/24 (83%) had confirmed metastases upon final pathology. CPLN resection was associated with longer operation time, more often advanced upper abdominal surgery and more postoperative complications but there was no difference in days from surgery to initiation of chemotherapy. Postoperative CT was still indicative of CPLN metastases in 13/22 (59%) women despite resection with confirmative pathology. CONCLUSIONS: Resection of CPLN metastases is highly feasible without considerable added morbidity. Concern regarding surgical clearance is raised since postoperative imaging was indicative of metastases in the majority of women. The prognostic significance of stage IV disease based exclusively on CPLN metastases is unclear and any survival benefit from the procedure is yet to be determined.

Hydatidiform mole and subsequent pregnancy outcome: a population-based cohort study.

OBJECTIVE: The objective of the study was to investigate whether a history of hydatidiform mole (HM) is associated with an increased risk of adverse outcomes in subsequent pregnancies. STUDY DESIGN: This was a nationwide cohort study with data from population-based registers. The study population consisted of all children registered in the Swedish Medical Birth Register 1973-2009 (n = 3,730,825). Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated for adverse maternal and offspring pregnancy outcomes by maternal history of HM prior to the delivery, with children to women with no maternal history of HM as the reference. Risk estimates were adjusted for maternal age at delivery and maternal country of birth. RESULTS: A history of HM was not associated with an increased risk of adverse maternal outcomes in subsequent pregnancies (n = 5186). Women exposed to a molar pregnancy prior to the index birth were at an almost 25% increased risk of preterm birth (OR, 1.23; 95% CI, 1.06-1.43), whereas women with at least 1 birth between the HM and the index birth were at an increased risk of a large-for-gestational-age birth and stillbirth (OR, 1.35; 95% CI, 1.10-1.67 and OR, 1.81; 95% CI, 1.11-2.96, respectively). The risk of repeat mole was 0.4%. CONCLUSION: Women with a history of HM are at no increased risk of adverse maternal outcomes in subsequent pregnancies but have an increased risk of large-for-gestational-age birth, stillbirth, and preterm birth. However, in absolute terms, the risk of subsequent adverse offspring outcomes is very low.

Current clinical features of complete and partial hydatidiform mole in Sweden.

OBJECTIVE: To describe the current clinical presentation of complete (CHM) and partial (PHM) hydatidiform mole in a Swedish setting. STUDY DESIGN: A retrospective analysis of medical charts from 331 women with hydatidiform mole (HM) between 1991 and 2010 was performed. Demographics and clinical features were analyzed, and symptoms in women with CHM were compared to those from a historic group (1988 to 1993) from the New England Trophoblastic Disease Center. RESULTS: In women with CHM, bleeding was more common than in women with PHM (57% vs. 41%, p < 0.001) but significantly less common as compared to the historic group (84%). Women with CHM and PHM were diagnosed before the onset of symptoms in 32% and 53%, respectively, compared to the previously reported 10% (p < 0.001). There was a significantly higher proportion of women 240 years of age with CHM than with PHM (23% vs. 7%). Ultrasound predicted the molar diagnosis in 73% of CHMs and 35% of PHMs (p < 0.001). CONCLUSION: In our study a large proportion of molar pregnancies were asymptomatic at the time of diagnosis. This confirms earlier reports of the changing clinical presentation of HM and shows that this trend continues. Age, ultrasound findings and hCG levels can add valuable information.

The drug efficacy testing in 3D cultures platform identifies effective drugs for ovarian cancer patients.

Most patients with advanced ovarian cancer (OC) relapse and progress despite systemic therapy, pointing to the need for improved and tailored therapy options. Functional precision medicine can help to identify effective therapies for individual patients in a clinically relevant timeframe. Here, we present a scalable functional precision medicine platform: DET3Ct (Drug Efficacy Testing in 3D Cultures), where the response of patient cells to drugs and drug combinations are quantified with live-cell imaging. We demonstrate the delivery of individual drug sensitivity profiles in 20 samples from 16 patients with ovarian cancer in both 2D and 3D culture formats, achieving over 90% success rate in providing results six days after operation. In this cohort all patients received carboplatin. The carboplatin sensitivity scores were significantly different for patients with a progression free interval (PFI) less than or equal to 12 months and those with more than 12 months (p < 0.05). We find that the 3D culture format better retains proliferation and characteristics of the in vivo setting. Using the DET3Ct platform we evaluate 27 tailored combinations with results available 10 days after operation. Notably, carboplatin and A-1331852 (Bcl-xL inhibitor) showed an additive effect in four of eight OC samples tested, while afatinib and A-1331852 led to synergy in five of seven OC models. In conclusion, our 3D DET3Ct platform can rapidly define potential, clinically relevant data on efficacy of existing drugs in OC for precision medicine purposes, as well as provide insights on emerging drugs and drug combinations that warrant testing in clinical trials.

Differences in Administration of Methotrexate and Impact on Outcome in Low-Risk Gestational Trophoblastic Neoplasia.

Methotrexate (MTX) is frequently used as first-line treatment for low-risk gestational trophoblastic neoplasia (GTN). Intravenous and intramuscular (im) routes of administration are the most common methods, although oral administration is used by some Scandinavian centers. The primary aim of this study was to assess the impact of form of administration (im/oral) on resistance to methotrexate (MTX-R) treatment in low-risk GTN. Secondary aims were time to hCG normalization, rates of toxicity-induced treatment switch, and rates of complete remission and recurrence. In total, 170 women treated at Karolinska University Hospital in Sweden and Aarhus University Hospital in Denmark between 1994 and 2018 were included, of whom 107 were given im and 63 oral MTX. MTX-R developed in 35% and 54% in the im and oral groups, respectively (p = 0.01). There was no difference in days to hCG normalization (42 vs. 41 days, p = 0.50) for MTX-sensitive women. Toxicity-induced treatment switch was only seen in the im group. Complete remission was obtained in 99.1% and 100% (p = 0.44), and recurrence rate within one year was 2.8% and 1.6% (p = 0.29). The form of administration of MTX had a significant impact on development of MTX-R and treatment-associated toxicity, but does not affect rates of complete remission, recurrence or survival.

Choriocarcinoma following ovarian hydatidiform mole: a case report.

BACKGROUND: Ovarian ectopic pregnancies are uncommon, and a hydatidiform mole in this location is extremely rare but may later develop into a choriocarcinoma. CASE: A 49-year-old woman with a history of an ectopic pregnancy, lost to follow-up in spite of rising human chorionic gonadotropin (hCG) levels, presented three years later at the emergency ward with hemoptysis, vaginal bleeding and elevated serum hCG. Pulmonary and vaginal metastasis was found, and the diagnosis of a choriocarcinoma was confirmed. She received chemotherapy during a 6-month period and recovered successfully. Seven years later she is free of disease. Reevaluation of the histological specimen from the previous ectopic pregnancy confirmed an ovarian hydatidiform mole and the later development of choriocarcinoma which probably originated from this mole. CONCLUSION: The diagnosis of hydatidiform mole can be difficult, however, it may be crucial to the patient. Whenever a histopathologic examination of products of conception is performed, it is important that a hydatidiform mole can be ruled out, and that may require additional analysis such as immunohistochemistry and DNA ploidy. In cases in which a gestational trophoblastic disease is suspected, it is necessary to monitor serum hCG until values are negative.

Time-interval to adjuvant chemotherapy and postoperative management after upper abdominal surgical procedures in advanced ovarian cancer.

INTRODUCTION: In advanced epithelial ovarian cancer (EOC), longer time-interval from surgery to initiation of adjuvant chemotherapy (TITC) is associated with decreased survival. Adding upper abdominal surgical procedures (UAP) increases rates of both complete gross resection and postoperative complications in EOC. Our objective was to investigate the association of UAP and TITC. Moreover, if specific postoperative monitoring after the most prevalent UAP increases early detection and management of complications. MATERIAL AND METHODS: Women diagnosed with EOC 2014-2016 in the Stockholm/Gotland Region in Sweden were identified in the Swedish Quality Registry for Gynaecologic Cancer. The association between UAP and TITC was investigated by multivariable linear regression and adjusted for predefined confounders. The follow-up and detection of postoperative complications after diaphragm resection, splenectomy and cholecystectomy was examined. RESULTS: 240 women were selected for analysis. The TITC in women subjected to UAP was similar with a median of 30 days (p = 0.99). Moreover, despite a higher rate of postoperative and major complications (p < 0.001) and longer hospital stay (p < 0.001), in the adjusted analysis there was no association between UAP and prolonged TITC, with a mean difference of -2.27 days (95% Confidence Interval (CI), -5.99 to -1.45, p = 0.23). After the most prevalent UAP (diaphragm resection, splenectomy and cholecystectomy), eventual postoperative interventions were based on routine clinical management rather than procedure-specific postoperative surveillance. CONCLUSION: UAP does not prolong TITC despite an increased rate of postoperative complications and longer length of hospital stay. Clinical non-specific surveillance is sufficient to detect postoperative complications after the most prevalent UAP.

PFKFB3 Inhibition Sensitizes DNA Crosslinking Chemotherapies by Suppressing Fanconi Anemia Repair.

Replicative repair of interstrand crosslinks (ICL) generated by platinum chemotherapeutics is orchestrated by the Fanconi anemia (FA) repair pathway to ensure resolution of stalled replication forks and the maintenance of genomic integrity. Here, we identify novel regulation of FA repair by the cancer-associated glycolytic enzyme PFKFB3 that has functional consequences for replication-associated ICL repair and cancer cell survival. Inhibition of PFKFB3 displays a cancer-specific synergy with platinum compounds in blocking cell viability and restores sensitivity in treatment-resistant models. Notably, the synergies are associated with DNA-damage-induced chromatin association of PFKFB3 upon cancer transformation, which further increases upon platinum resistance. FA pathway activation triggers the PFKFB3 assembly into nuclear foci in an ATR- and FANCM-dependent manner. Blocking PFKFB3 activity disrupts the assembly of key FA repair factors and consequently prevents fork restart. This results in an incapacity to replicate cells to progress through S-phase, an accumulation of DNA damage in replicating cells, and fork collapse. We further validate PFKFB3-dependent regulation of FA repair in ex vivo cultures from cancer patients. Collectively, targeting PFKFB3 opens up therapeutic possibilities to improve the efficacy of ICL-inducing cancer treatments.

Co-evolution of matrisome and adaptive adhesion dynamics drives ovarian cancer chemoresistance.

Due to its dynamic nature, the evolution of cancer cell-extracellular matrix (ECM) crosstalk, critically affecting metastasis and treatment resistance, remains elusive. Our results show that platinum-chemotherapy itself enhances resistance by progressively changing the cancer cell-intrinsic adhesion signaling and cell-surrounding ECM. Examining ovarian high-grade serous carcinoma (HGSC) transcriptome and histology, we describe the fibrotic ECM heterogeneity at primary tumors and distinct metastatic sites, prior and after chemotherapy. Using cell models from systematic ECM screen to collagen-based 2D and 3D cultures, we demonstrate that both specific ECM substrates and stiffness increase resistance to platinum-mediated, apoptosis-inducing DNA damage via FAK and ß1 integrin-pMLC-YAP signaling. Among such substrates around metastatic HGSCs, COL6 was upregulated by chemotherapy and enhanced the resistance of relapse, but not treatment-naïve, HGSC organoids. These results identify matrix adhesion as an adaptive response, driving HGSC aggressiveness via co-evolving ECM composition and sensing, suggesting stromal and tumor strategies for ECM pathway targeting.

Adaptive RSK-EphA2-GPRC5A signaling switch triggers chemotherapy resistance in ovarian cancer.

Metastatic cancers commonly activate adaptive chemotherapy resistance, attributed to both microenvironment-dependent phenotypic plasticity and genetic characteristics of cancer cells. However, the contribution of chemotherapy itself to the non-genetic resistance mechanisms was long neglected. Using high-grade serous ovarian cancer (HGSC) patient material and cell lines, we describe here an unexpectedly robust cisplatin and carboplatin chemotherapy-induced ERK1/2-RSK1/2-EphA2-GPRC5A signaling switch associated with cancer cell intrinsic and acquired chemoresistance. Mechanistically, pharmacological inhibition or knockdown of RSK1/2 prevented oncogenic EphA2-S897 phosphorylation and EphA2-GPRC5A co-regulation, thereby facilitating a signaling shift to the canonical tumor-suppressive tyrosine phosphorylation and consequent downregulation of EphA2. In combination with platinum, RSK inhibitors effectively sensitized even the most platinum-resistant EphA2high , GPRC5Ahigh cells to the therapy-induced apoptosis. In HGSC patient tumors, this orphan receptor GPRC5A was expressed exclusively in cancer cells and associated with chemotherapy resistance and poor survival. Our results reveal a kinase signaling pathway uniquely activated by platinum to elicit adaptive resistance. They further identify GPRC5A as a marker for abysmal HGSC outcome and putative vulnerability of the chemo-resistant cells to RSK1/2-EphA2-pS897 pathway inhibition.

Thermal Proteome Profiling Identifies Oxidative-Dependent Inhibition of the Transcription of Major Oncogenes as a New Therapeutic Mechanism for Select Anticancer Compounds.

Identification of the molecular mechanism of action (MoA) of bioactive compounds is a crucial step for drug development but remains a challenging task despite recent advances in technology. In this study, we applied multidimensional proteomics, sensitivity correlation analysis, and transcriptomics to identify a common MoA for the anticancer compounds RITA, aminoflavone (AF), and oncrasin-1 (Onc-1). Global thermal proteome profiling revealed that the three compounds target mRNA processing and transcription, thereby attacking a cancer vulnerability, transcriptional addiction. This led to the preferential loss of expression of oncogenes involved in PDGF, EGFR, VEGF, insulin/IGF/MAPKK, FGF, Hedgehog, TGFß, and PI3K signaling pathways. Increased reactive oxygen species level in cancer cells was a prerequisite for targeting the mRNA transcription machinery, thus conferring cancer selectivity to these compounds. Furthermore, DNA repair factors involved in homologous recombination were among the most prominently repressed proteins. In cancer patient samples, RITA, AF, and Onc-1 sensitized to poly(ADP-ribose) polymerase inhibitors both in vitro and ex vivo These findings might pave a way for new synthetic lethal combination therapies.Significance: These findings highlight agents that target transcriptional addiction in cancer cells and suggest combination treatments that target RNA processing and DNA repair pathways simultaneously as effective cancer therapies.

Iliaco-enteric fistula after robot-assisted comprehensive surgical staging of endometrial cancer: a case report.

Fistula formation between bowel and blood-vessel is a very rare complication after intraabdominal surgery. We report a case of iliaco-enteric fistula following robot-assisted surgical staging of endometrial cancer. A 71-year-old woman subjected to comprehensive endometrial cancer staging presented with hematochezia 35 days postoperatively. A retroperitoneal right-sided abscess and an iliaco-enteric fistula was confirmed upon imaging. The patient received endovascular repair of the aneurysm in her right common iliac artery and the segments of the small bowel containing the fistula were resected via laparotomy. If a patient presents with new onset postoperative hematochezia after pelvic and/or paraaortic lymphadenectomy, fistulation between bowel and the major abdominal blood vessels should be part of the differential diagnoses.