A genome-scale screen reveals context-dependent ovarian cancer sensitivity to miRNA overexpression.

Large-scale molecular annotation of epithelial ovarian cancer (EOC) indicates remarkable heterogeneity in the etiology of that disease. This diversity presents a significant obstacle against intervention target discovery. However, inactivation of miRNA biogenesis is commonly associated with advanced disease. Thus, restoration of miRNA activity may represent a common vulnerability among diverse EOC oncogenotypes. To test this, we employed genome-scale, gain-of-function, miRNA mimic toxicity screens in a large, diverse spectrum of EOC cell lines. We found that all cell lines responded to at least some miRNA mimics, but that the nature of the miRNA mimics provoking a response was highly selective within the panel. These selective toxicity profiles were leveraged to define modes of action and molecular response indicators for miRNA mimics with tumor-suppressive characteristics in vivo. A mechanistic principle emerging from this analysis was sensitivity of EOC to miRNA-mediated release of cell fate specification programs, loss of which may be a prerequisite for development of this disease.

Utility of routine cytology in detecting asymptomatic cervical cancer recurrence.

INTRODUCTION: The objective of this study was to examine the utility of routine cervical cytology after cervical cancer treatment. MATERIAL AND METHODS: We performed a retrospective study from 2004 to 2020, which identified 581 cervical cancer patients. Of the 581 patients, 233 were included in the analysis. The remaining 348 were excluded because of failure to enter the surveillance period, loss to follow-up, or treatment at an outside facility. The continuous data were summarized using the median and interquartile range for non-normally distributed data. The categorical data were summarized using frequencies and proportions. Comparisons between the categorical data were performed using the Fisher exact test. RESULTS: Of the 233 included patients, 78 (33.5%) had had ≥1 abnormal Papanicolaou (Pap) test during surveillance. Of these 78 patients, 22 (28.2%) underwent biopsy, with all biopsies negative for malignancy. Local recurrence was identified in 15 patients. Of these 15 patients, 14 (93.3%) were symptomatic at diagnosis, 7 (46.7%) had had visible disease on the physical examination, and 6 (40.0%) had normal cytology findings throughout surveillance. Only 1 case of local, asymptomatic cervical cancer recurrence was detected by Pap test alone. A subset analysis was performed to compare the rate of abnormal Pap tests between the radiation therapy and non-radiation therapy groups. Of the 233 patients, 154 (66.1%) underwent primary radiation therapy, 64 (41.6%) of whom had abnormal cytology during surveillance. Of 82 patients who did not undergo radiation therapy, only 14 (17.1%) had had abnormal cytology (P < 0.01). None of the patients in either group had underlying recurrent disease at the time of abnormal cytology. CONCLUSIONS: The results of our study show that routine Pap tests have limited clinical utility in the surveillance of cervical cancer recurrence. Consideration should be given to removing routine cytology from the surveillance recommendations.

Gastric type adenocarcinoma of the cervix presenting as ovarian neoplasm.

Gastric-type adenocarcinoma of the uterine cervix (GAS) is a rare subtype of mucinous adenocarcinoma, unrelated to HPV infection. It first appeared in the World Health Organization Classification of Tumours of Female Reproductive Organs in 2014. This report discusses a 50-year-old, Caucasian female who presented with new onset abdominal pain, distension, and diffuse ascites. CT scan revealed an ovarian neoplasm later diagnosed as GAS on surgical pathology. Immunohistological stains were positive for PAX8, CK7, CK20 (focally strong), CAIX (strong), CEA (patchy), MUC6 (strong), HNF1b, UBC, RNA, KOC (focal), and P53 (wild type). Tumor cells were negative for p16, PAX2, ER, low-risk 5 HPV, high-risk 18 HPV, and CDX2. The proliferative index (Ki-67) was 20%. The patient is scheduled to receive systemic chemotherapy of cisplatin, paclitaxel, and bevacizumab. Following chemotherapy, she will undergo external beam radiation and vaginal brachytherapy. The prevalence of GAS in the United States is currently unknown. Little is understood about the ideal treatment for this disease, and prognosis is very poor. As more cases are identified and reported, more targeted therapy be developed and trialed in these patients.

Tumor antigen acrosin binding protein normalizes mitotic spindle function to promote cancer cell proliferation.

Cancer cells manage to divide in the context of gross chromosomal abnormalities. These abnormalities can promote bypass of normal restraints on cell proliferation but at a cost of mitotic vulnerabilities that can be attacked by chemotherapy. Determining how cancer cells balance these issues may permit chemotherapeutic sensitivity to be leveraged more efficiently. From a pan-genomic small interfering RNA screen for modifiers of chemoresponsiveness, we identified the tumor antigen acrosin binding protein (ACRBP)/OY-TES-1 as a specifier of paclitaxel resistance. ACRBP expression is normally restricted to the testes but is detected in a wide variety of cancers, including most ovarian cancers. We found that ACRBP is both necessary and sufficient for paclitaxel resistance in ovarian cancer cell lines and ovarian tumor explants. Moreover, high ACRBP expression correlated with reduced survival time and faster relapse among ovarian cancer patients. We identified the mitotic spindle protein NuMA as an ACRBP-interacting protein that could account for the effects of ACRBP on paclitaxel sensitivity. In cancer cells, ACRBP restricted a NuMA-dependent abrogation of a mitotic spindle assembly that is otherwise pathologic. As a consequence, ACRBP depletion resulted in mitotic errors and reduced proliferative fitness that could be rescued by NuMA codepletion. We propose that the codependent relationship of ACRBP and NuMA in cancer cells reflects their passage through a selection bottleneck during tumor evolution, one which requires the acquisition of traits that normalize mitotic perturbations that originally drove the plasticity of a preneoplastic genome. The molecular definition of such traits as defined by the ACRBP-NuMA complex may represent conceptually ideal intervention targets based on the wide therapeutic windows they may offer.

Cost-effectiveness of routine vaginal cytology for endometrial cancer surveillance.

OBJECTIVE: To examine the cost-effectiveness of routine vaginal cytology in detecting asymptomatic isolated vaginal recurrence during post-treatment endometrial cancer surveillance. METHODS: All patients treated for endometrial cancer between 7/1/97 and 6/30/2005 were retrospectively identified from the tumor registry database. Clinico-pathologic characteristics and surveillance testing data were abstracted from medical records. The total number of Pap tests performed during surveillance or until the time of recurrence was calculated and charges associated with detecting asymptomatic isolated vaginal recurrence assigned based on 2005 Pap test costs adjusted retroactively using the consumer price index. RESULTS: Three hundred seventy-seven patients met inclusion criteria: FIGO Stage I=63.7%, Stage II=10.1%, Stage III=18.8%, Stage IV=7.4%. The median follow-up time was 30.4 months. A total of 2,134 Pap tests were collected during the study interval (median 5, mean 5.76 samples/patient). Endometrial cancer recurred in 61 patients (16.2%); 11 patients (2.9%) had an isolated vaginal recurrence. Seven isolated vaginal recurrences were detected by physical examination alone, and 2 were detected by interval computed tomography. An asymptomatic isolated vaginal recurrence was detected by routine vaginal cytology in 2 of 377 patients (0.5%). Detection of each asymptomatic vaginal recurrence required 1067 Pap tests, generating 44,049 US dollar in cumulative charges. CONCLUSIONS: As a surveillance test for endometrial cancer recurrence, routine vaginal cytology is costly, inefficient, and benefits less than 1% of patients. Elimination or reduction in the use of vaginal cytology for this purpose offers an opportunity for significant cost savings in gynecologic oncology health care expenditure.

Oestrogen augments the fetal ovine hypothalamus- pituitary-adrenal axis in response to hypotension.

In the fetal sheep, parturition is triggered by an increase in the activity of the fetal hypothalamus- pituitary-adrenal (HPA) axis which, in turn, augments the biosynthesis of oestrogen by the placenta. Parturition can be prevented or delayed by destruction of the paraventricular nucleus (PVN), pituitary or adrenal, or stimulated by infusions of adrenocorticotropin (ACTH) or glucocorticoids. We have previously reported that physiological increases in fetal plasma concentrations of oestradiol have a neuroendocrine effect to increase both basal and hypotension-stimulated ACTH secretion. The present study was performed to test the effect of oestradiol on the central baroreceptor and chemoreceptor reflex pathways. We used immunohistological techniques to identify various neuroanatomical regions which are activated by hypotension and, subsequently, those areas modified by oestrogen's action and baroreceptor and chemoreceptor denervation. We assessed cellular activation in these brain regions by immunostaining for Fos, the protein product of c-fos, an immediate early response gene. We found that oestradiol increased Fos abundance in nucleus tractus solitarius (NTS), rostral ventrolateral medulla (RVLM), and PVN, and augmented the increase in Fos in these regions in response to a 10 min period of brachiocephalic arterial occlusion (BCO). Carotid sinus denervation blocked the Fos response to BCO, but not to oestrogen alone, in these regions. In contrast, the hippocampus responded to BCO with increase Fos in intact fetuses, but did not respond to oestrogen treatment. None of the treatments altered Fos expression in cerebral cortex or in cerebellum. We conclude that oestradiol augments the activity of the central baroreceptor and chemoreceptor reflex pathways, and that it may influence fetal ACTH secretion via this site of action.