Prophylactic Ureteral Stent Placement and Urinary Injury During Hysterectomy for Placenta Accreta Spectrum.

OBJECTIVE: To evaluate the association between prophylactic ureteral stent placement at the time of hysterectomy for placenta accreta spectrum and genitourinary injury. METHODS: We conducted a retrospective cohort study of patients with placenta accreta spectrum who underwent hysterectomy at two referral centers from 2001 to 2021. The exposure was prophylactic ureteral stent placement. The primary outcome, genitourinary injury, was a composite of bladder injury, ureteral injury, or vesicovaginal fistula. Secondary outcomes included components of the primary outcome. We evaluated differences between groups using χ 2 and t test. To evaluate differences in the primary outcome, we reported odds ratios (ORs) and adjusted odds ratios (aORs) using multivariable logistic regression analyses to control for potential confounding variables. We used a Cochran-Armitage χ 2 trend test to evaluate difference in stent use and injury over time. RESULTS: In total, 236 patients were included. Prophylactic ureteral stents were used in 156 surgeries (66%). Overall, genitourinary injury occurred less frequently in the stent group compared with the no stent group (28% vs 51%, OR 0.37, 95% CI 0.21-0.65). This association persisted after controlling for urgency of delivery, three or more prior cesarean deliveries, and whether a gynecologic oncologist was present (aOR 0.27, 95% CI 0.14-0.52). Unintentional bladder injury occurred less frequently in the stent group compared with the no stent group (13% vs 25%, P =.018), as did ureteral injury (2% vs 9%, P =.019). CONCLUSION: Prophylactic ureteral stent placement was associated with a decreased risk of genitourinary injury during hysterectomy for placenta accreta spectrum.

Antihypertensive medication use and ovarian cancer survival.

OBJECTIVE: Although experimental models suggest that use of beta-blockers, a common antihypertensive agent, may improve survival in ovarian cancer patients, results from clinical studies have been mixed. METHODS: We evaluated the associations of pre-diagnostic (n = 950) and post-diagnostic (n = 743) use of antihypertensive medications with survival among patients with invasive, epithelial ovarian cancer in the Nurses' Health Study (NHS; 1994-2016) and NHSII (2001-2017), with follow-up until 2018 and 2019, respectively. Cox proportional hazards models were used to estimate hazard ratios (HR) for ovarian cancer mortality according to antihypertensive medication use before and after diagnosis, considering multiple drug classes (beta-blockers, calcium-channel blockers, thiazide diuretics, angiotensin-converting enzyme [ACE] inhibitors). RESULTS: After adjusting for age, BMI, smoking status and tumor characteristics, pre-diagnostic use versus non-use of calcium-channel blockers was associated with higher ovarian cancer mortality (HR: 1.49; 95% CI: 1.13, 1.96), which was primarily due to polytherapy involving calcium-channel blockers (HR: 1.61; 95% CI: 1.15, 2.26). Pre-diagnostic use of beta-blockers, thiazide diuretics, or ACE inhibitors was not associated with ovarian cancer mortality. No association was observed for post-diagnostic antihypertensive medication use individually or in combination, except for lower mortality associated with polytherapy involving ACE inhibitors (HR: 0.53; 95% CI: 0.31, 0.91). CONCLUSION: Overall, we did not find clear relationships between antihypertensive medication use and ovarian cancer mortality. However, given the limitation of the data, we cannot determine whether the association may differ by type of beta-blockers. The reasons underlying the observed associations with pre-diagnostic calcium-channel blocker use and post-diagnostic ACE inhibitor use require further investigation.

Clinical significance of homologous recombination deficiency score testing in endometrial Cancer.

BACKGROUND: Homologous recombination deficiency (HRD) score is related to chemotherapy response in some cancers, but its role in endometrial cancer in not known. We determined frequency and clinical significance of alterations in the HR pathway in endometrial cancer. METHODS: 253 endometrioid endometrial adenocarcinoma (EEA) samples from two independent cohorts (discovery and replication) were tested for HRD score using the Myriad HRD assay, microsatellite instability (MSI) and tumor mutation burden (TMB) using a next generation sequencing assay. HRD scores were also generated on endometrial cancer cell lines and in vivo response to olaparib was assessed. RESULTS: ROC curves were employed to determine optimal cutoffs of HRD in relation to survival impact in endometrial cancer and a cutoff of HRD ≥ 4 was suggested for DFS using the discovery cohort. Patients from two independent cohorts with HRD score ≥ 4 trended toward worse survival as compared to those with HRD score < 4. Both cohorts were further separated into four groups according to molecular subtypes (TMB positive; MSI positive; HRD positive; all others). When grouped by molecular subtype, there was a significant difference between groups using an HRD ≥4 cutoff in the initial (p = 0.0024) and replication (p = 0.042) cohorts. The Hec1a model (HRD score = 19) was highly sensitive to olaparib in in vitro and in vivo experiments. CONCLUSIONS: High HRD score was associated with worse DFS in our patient cohort. These findings suggest that HRD score may have clinical utility in patients with advanced or recurrent endometrial cancer.

Molecular Analysis of Clinically Defined Subsets of High-Grade Serous Ovarian Cancer.

The diversity and heterogeneity within high-grade serous ovarian cancer (HGSC), which is the most lethal gynecologic malignancy, is not well understood. Here, we perform comprehensive multi-platform omics analyses, including integrated analysis, and immune monitoring on primary and metastatic sites from highly clinically annotated HGSC samples based on a laparoscopic triage algorithm from patients who underwent complete gross resection (R0) or received neoadjuvant chemotherapy (NACT) with excellent or poor response. We identify significant distinct molecular abnormalities and cellular changes and immune cell repertoire alterations between the groups, including a higher rate of NF1 copy number loss, and reduced chromothripsis-like patterns, higher levels of strong-binding neoantigens, and a higher number of infiltrated T cells in the R0 versus the NACT groups.

When Ovarian Cancer Is Not: Characterizing Nonovarian Cancer Pathology in a Laparoscopy-Based Triage System.

OBJECTIVE: Establishing an accurate histologic diagnosis is essential for determining the appropriate course of therapy for ovarian cancer. This study sought to investigate and describe nonovarian cancer pathologies discovered during the systematic laparoscopic workup of presumed advanced ovarian cancer. METHODS: A retrospective cohort of patients with presumed advanced ovarian cancer (based on elevated CA125 and/or imaging) presenting to our center without confirmed pathologic diagnosis were identified and characterized. Patients without ovarian cancer on final pathology were described and compared with those with confirmed epithelial ovarian cancer using standard statistical methods. RESULTS: Nonovarian cancer was found in 26 (7.1%) of 365 cases over 3.5 years of study, and included benign ovarian pathology, and metastatic uterine, breast, and gastrointestinal cancers. Most nonovarian cancer cases could not be diagnosed with percutaneous biopsy, and instead used diagnostic laparoscopy or assessment at the time of laparotomy for diagnosis (58%). No patient received inappropriate treatment. Nonovarian cancer cases were more likely to be nonwhite (P = 0.003), have a better Eastern Cooperative Oncology Group performance status (P < 0.001), and have a lower CA125 value (P < 0.001), and were less likely to have pleural effusions (P = 0.04). CONCLUSIONS: A systematic laparoscopic triage approach to advanced-stage ovarian cancer eliminates incorrect neoadjuvant chemotherapy administration and inappropriate laparotomy. This algorithm identified a population of women who are more likely to have nonovarian cancer pathology. Increasing screening efforts should be focused on conclusive diagnosis with the least invasive testing possible.

Defining Survivorship Trajectories Across Patients With Solid Tumors: An Evidence-Based Approach.

Importance: Survivorship involves a multidisciplinary approach to surveillance and management of comorbidities and secondary cancers, overseen by oncologists, surgeons, and primary care physicians. Optimal timing and coordination of care, however, is unclear and often based on arbitrary 5-year cutoffs. Objective: To determine high- and low-risk periods for all tumor types that could define when survivorship care might best be overseen by oncologists and when to transition to primary care physicians. Design, Setting, and Participants: In this pan-cancer, longitudinal, observational study, excess mortality hazard, calculated as an annualized mortality risk above a baseline population, was plotted over time. The time this hazard took to stabilize defined a high-risk period. The percent morality elevation above age- and sex-matched controls in the latter low-risk period was reported as a mortality gap. The US population-based Surveillance, Epidemiology, and End Results database defined the cancer population, and the US Census life tables defined controls. Incident cases of patients with cancer were separated into tumor types based on International Classification of Diseases for Oncology definitions. Exposures: Population-level data on incident cancer cases was compared with the general US population. Main Outcomes and Measures: Overall mortality and cause of death were reported on observed cancer cases. Results: A total of 2 317 185 patients (median age, 63 years; 49.8% female) with 66 primary tumor types were evaluated. High-risk surveillance period durations ranged from less than 1 year (breast, prostate, lip, ocular, and parathyroid cancers) up to 19 years (unspecified gastrointestinal cancers). The annualized mortality gap, representing the excess mortality in the stable period, ranged from a median 0.26% to 9.33% excess annual mortality (thyroid and hypopharyngeal cancer populations, respectively). Cluster analysis produced 6 risk cluster groups: group 1, with median survival of 16.2 (5th to 95th percentile range [PR], 10.7-40.2) years and median high-risk period of 2.5 (PR, 0-5.0) years; group 2, 8.3 (PR, 5.1-23.3) and 2.5 (PR, 4.0-8.0) years; group 3, 2.8 (PR, 1.4-3.7) and 7.0 (PR, 6.0-11.1) years; group 4, 1.6 (PR, 1.5-1.8) and 6.0 (PR, 5.1-11.4) years; group 5, 0.8 (PR, 0.5-1.2) and 0.8 (PR, 0.5-1.2) years; and group 6, 0.5 (PR, 0.4-0.8) and 12.0 (PR, 9.3-12.9) years, respectively. Subanalyses of selected tumor types in these groups revealed that stratifying on stage and histologic type can change the risk cluster and guidance for care. Conclusions and Relevance: These findings indicate that a standardized 5-year surveillance period is inadequate for some cancers while excessive for others. High-risk cancers require the most resources with the longest high-risk period, highest persistent baseline mortality risk, and longest period of primary cancer mortality, all arguing for longer follow-up with an oncologist in these cancers.

Macrophage depletion through colony stimulating factor 1 receptor pathway blockade overcomes adaptive resistance to anti-VEGF therapy.

Anti-angiogenesis therapy has shown clinical benefit in patients with high-grade serous ovarian cancer (HGSC), but adaptive resistance rapidly emerges. Thus, approaches to overcome such resistance are needed. We developed the setting of adaptive resistance to anti-VEGF therapy, and performed a series of in vivo experiments in both immune competent and nude mouse models. Given the pro-angiogenic properties of tumor-associated macrophages (TAMs) and the dominant role of CSF1R in macrophage function, we added CSF1R inhibitors following emergence of adaptive resistance to anti-VEGF antibody. Mice treated with a CSF1R inhibitor (AC708) after anti-VEGF antibody resistance had little to no measurable tumor burden upon completion of the experiment while those that did not receive a CSF1R inhibitor still had abundant tumor. To mimic clinically used regimens, mice were also treated with anti-VEGF antibody and paclitaxel until resistance emerged, and then a CSF1R inhibitor was added. The addition of a CSF1R inhibitor restored response to anti-angiogenesis therapy, resulting in 83% lower tumor burden compared to treatment with anti-VEGF antibody and paclitaxel alone. Collectively, our data demonstrate that the addition of a CSF1R inhibitor to anti-VEGF therapy and taxane chemotherapy results in robust anti-tumor effects.

Adrenergic-mediated increases in INHBA drive CAF phenotype and collagens.

Adrenergic signaling is known to promote tumor growth and metastasis, but the effects on tumor stroma are not well understood. An unbiased bioinformatics approach analyzing tumor samples from patients with known biobehavioral profiles identified a prominent stromal signature associated with cancer-associated fibroblasts (CAFs) in those with a high biobehavioral risk profile (high Center for Epidemiologic Studies Depression Scale [CES-D] score and low social support). In several models of epithelial ovarian cancer, daily restraint stress resulted in significantly increased CAF activation and was abrogated by a nonspecific ß-blocker. Adrenergic signaling-induced CAFs had significantly higher levels of collagen and extracellular matrix components than control tumors. Using a systems-based approach, we found INHBA production by cancer cells to induce CAFs. Ablating inhibin ß A decreased CAF phenotype both in vitro and in vivo. In preclinical models of breast and colon cancers, there were increased CAFs and collagens following daily restraint stress. In an independent data set of renal cell carcinoma patients, there was an association between high depression (CES-D) scores and elevated expression of ACTA2, collagens, and inhibin ß A. Collectively, our findings implicate adrenergic influences on tumor stroma as important drivers of CAFs and establish inhibin ß A as an important regulator of the CAF phenotype in ovarian cancer.

Platelets reduce anoikis and promote metastasis by activating YAP1 signaling.

Thrombocytosis is present in more than 30% of patients with solid malignancies and correlates with worsened patient survival. Tumor cell interaction with various cellular components of the tumor microenvironment including platelets is crucial for tumor growth and metastasis. Although it is known that platelets can infiltrate into tumor tissue, secrete pro-angiogenic and pro-tumorigenic factors and thereby increase tumor growth, the precise molecular interactions between platelets and metastatic cancer cells are not well understood. Here we demonstrate that platelets induce resistance to anoikis in vitro and are critical for metastasis in vivo. We further show that platelets activate RhoA-MYPT1-PP1-mediated YAP1 dephosphorylation and promote its nuclear translocation which induces a pro-survival gene expression signature and inhibits apoptosis. Reduction of YAP1 in cancer cells in vivo protects against thrombocytosis-induced increase in metastasis. Collectively, our results indicate that cancer cells depend on platelets to avoid anoikis and succeed in the metastatic process.Platelets have been associated with increased tumor growth and metastasis but the mechanistic details of this interaction are still unclear. Here the authors show that platelets improve anoikis resistance of cancer cells and increase metastasis by activating Yap through a RhoA/MYPT-PP1 pathway.

Metabolic Markers and Statistical Prediction of Serous Ovarian Cancer Aggressiveness by Ambient Ionization Mass Spectrometry Imaging.

Ovarian high-grade serous carcinoma (HGSC) results in the highest mortality among gynecological cancers, developing rapidly and aggressively. Dissimilarly, serous borderline ovarian tumors (BOT) can progress into low-grade serous carcinomas and have relatively indolent clinical behavior. The underlying biological differences between HGSC and BOT call for accurate diagnostic methodologies and tailored treatment options, and identification of molecular markers of aggressiveness could provide valuable biochemical insights and improve disease management. Here, we used desorption electrospray ionization (DESI) mass spectrometry (MS) to image and chemically characterize the metabolic profiles of HGSC, BOT, and normal ovarian tissue samples. DESI-MS imaging enabled clear visualization of fine papillary branches in serous BOT and allowed for characterization of spatial features of tumor heterogeneity such as adjacent necrosis and stroma in HGSC. Predictive markers of cancer aggressiveness were identified, including various free fatty acids, metabolites, and complex lipids such as ceramides, glycerophosphoglycerols, cardiolipins, and glycerophosphocholines. Classification models built from a total of 89,826 individual pixels, acquired in positive and negative ion modes from 78 different tissue samples, enabled diagnosis and prediction of HGSC and all tumor samples in comparison with normal tissues, with overall agreements of 96.4% and 96.2%, respectively. HGSC and BOT discrimination was achieved with an overall accuracy of 93.0%. Interestingly, our classification model allowed identification of three BOT samples presenting unusual histologic features that could be associated with the development of low-grade carcinomas. Our results suggest DESI-MS as a powerful approach for rapid serous ovarian cancer diagnosis based on altered metabolic signatures. Cancer Res; 77(11); 2903-13. ©2017 AACR.

Endometrial cancer after endometrial ablation vs medical management of abnormal uterine bleeding.

STUDY OBJECTIVE: To investigate whether endometrial ablation is associated with increased risk or delayed diagnosis of endometrial cancer compared with medical management of abnormal uterine bleeding. DESIGN: Multi-centered retrospective cohort study (Canadian Task Force classification II-2). SETTING: The study was performed using data from The Health Improvement Network, a representative population-based cohort of patients in 495 outpatient general practitioner practices in the United Kingdom. PATIENTS: Women aged >25 years with abnormal uterine bleeding diagnosed between June 1994 and September 2010. INTERVENTIONS: Endometrial ablation, medical management, or both. MEASUREMENTS AND MAIN RESULTS: A total of 234 721 women met study inclusion and exclusion criteria, 4776 of whom underwent endometrial ablation and the remaining 229 945 received medical management. Cox models compared endometrial cancer rates between ablation and medical management groups using hazard ratios. To investigate a possible diagnostic delay, the median time from bleeding diagnosis to endometrial cancer diagnosis in women in whom endometrial cancer developed was compared using the Mann-Whitney U test. All statistical tests were 2-tailed, with α = .05. During a median observation period of 4.07 years (interquartile range [IQR], 1.88-7.17), endometrial cancer developed in 3 women in the ablation group and 601 women in the medical management group (ablation hazard ratio, 0.45; 95% confidence interval, 0.15-1.40; p = .17). Median time to diagnosis was 237 in the ablation group, and 299 days in the medical management group (ablation IQR, 155-1350; medical management IQR, 144-1133.5; p = .99). Adjusted and sensitivity analyses did not change the results. CONCLUSIONS: No difference was observed in endometrial cancer rates, and there was no delay in diagnosis when comparing endometrial ablation vs medical management. Further studies are needed to investigate the effect of previous ablation exposure on histology or cancer stage at manifestation of endometrial cancer.