Little is known regarding the early aspects of ovarian carcinogenesis. As a consequence, the identification of women at risk for the disease is based primarily on clinical grounds, with family ...history being the most important risk factor. In this review, we will discuss the various hypotheses regarding ovarian etiology and pathogenesis. In addition, we will discuss the epidemiology of ovarian cancer, including hereditary, reproductive, hormonal, inflammatory, dietary, surgical, and geographic factors that influence ovarian cancer risk.
We review post-infectious and post-vaccination neurological syndromes involving peripheral and central nervous system (CNS) and report an illustrative case of simultaneous occurrence of ...Guillain-Barré syndrome (GBS), confirmed by nerve conduction velocities, plus MRI-demonstrated transverse myelitis (TM) and acute encephalitis acute disseminated encephalomyelitis (ADEM+GBS) affecting a 24-year-old woman from Cúcuta, Colombia, who developed acute Zika virus (ZIKV) infection confirmed by serum reverse transcriptase-polymerase chain reaction (RT-PCR) and convalescent ZIKV IgG antibodies. With intensive care treatment, respiratory support, steroids, and intravenous immunoglobulin (IVIg), patient survived with residual flaccid paraparesis. She had preexisting immunity against Chikungunya virus (CHIKV) and Dengue virus (DENV) acquired before the arrival of ZIKV in Colombia. From reports in the Caribbean, Central and South America we review 19 cases of ZIKV-associated TM, encephalitis and ADEM occurring after a mean latent period of 10.5 days (range 1–96) post-infection. Although GBS and ADEM are usually considered post-infectious and associated with development of antibodies against peripheral nerve and CNS epitopes, we postulate that our case of ADEM+GBS is para-infectious, induced by acute ZIKV neurotropism boosted by active immunity against other arboviruses. Animal models of ZIKV demonstrated strong viral neurotropism enhanced by passive immunity with antibodies against arboviruses such as West Nile virus, CHIKV, or DENV. These considerations are relevant to prevent potential ZIKV vaccine-induced reactions involving central and peripheral nervous system.
•Zika virus (ZIKV) is a single-stranded RNA flavivirus with strong neurotropism.•In 2015–16 a ZIKV epidemic affected Pacific and Caribbean islands and the Americas.•Prenatal ZIKV infection caused microcephaly.•ZIKV caused Guillain-Barré syndrome, transverse myelitis and encephalomyelitis.•Previous arboviral infections enhance ZIKV neurotropism.
Recent data show that simvastatin (SIM) and metformin (MET) have anti-proliferative effects in endometrial cancer cells. The combination (MET+SIM) inhibits tumor growth and metastasis in prostate ...cancer cells which possess similar molecular alterations to many early endometrial cancers. We tested the hypothesis that the anti-proliferative effects of MET+SIM in endometrial cancer cells would be greater than the effects of each agent alone.
RL95-2, HEC1B, and Ishikawa endometrial cancer cell lines were treated with MET and/or SIM. Growth inhibition was measured by MTS cell proliferation assays. Apoptosis was evaluated by caspase-3, Annexin V, and TUNEL assays and by apoptosis markers (BAX, Bcl-2, Bim) using western blot. Bim was silenced using Bim siRNA to confirm this apoptotic pathway. Treatment effects on the mTOR pathway were investigated by western blot using antibodies to phosphorylated (phospho)-AMPK and phospho-S6.
MET+SIM synergistically inhibited growth in all three cell lines. The combination induced apoptosis as measured by TUNEL, Annexin V, and caspase-3 assays. Bim siRNA transfection abrogated this effect—silencing Bim in MET+SIM-treated RL95-2 cells rescued cell viability in MTS assays and reduced caspase-3 activity compared with control siRNA-transfected cells. Combination treatment upregulated phosphorylated AMPK and downregulated downstream phosphorylated S6, suggesting mTOR inhibition as a mechanism for these anti-proliferative effects.
MET+SIM treatment synergistically inhibits endometrial cancer cell viability. This may be mediated by apoptosis and mTOR pathway inhibition. Our results provide preclinical evidence that the combination of these well-tolerated drugs may warrant further clinical investigation for endometrial cancer treatment.
•Combination metformin and simvastatin treatment synergistically inhibited growth in three endometrial cancer cell lines.•This treatment combination demonstrated apoptosis induction and mTOR pathway inhibition in vitro.•Drug repurposing using this combination may warrant clinical investigation in endometrial cancer.
Recent evidence suggests that the fimbriated end of the fallopian tube harbors the precursor cells for many high-grade ovarian cancers, opening the door for development of better screening methods ...that directly assess the fallopian tube in women at risk for malignancy. Previously we have shown that the karyometric signature is abnormal in the fallopian tube epithelium in women at hereditary risk of ovarian cancer. In this study, we sought to determine whether the karyometric signature in serous tubal intraepithelial carcinoma (STIC) is significantly different from normal, and whether an abnormal karyometric signature can be detected in histologically normal tubal epithelial cells adjacent to STIC lesions.
The karyometric signature was measured in epithelial cells from the proximal and fimbriated portion of the fallopian tube in fallopian tube specimens removed from women at: 1) average risk for ovarian cancer undergoing surgery for benign gynecologic indications (n = 37), 2) hereditary risk of ovarian cancer (germline BRCA alterations) undergoing risk-reducing surgery (n = 44), and 3) diagnosed with fimbrial STICs (n = 17).
The karyometric signature in tubes with fimbrial STICs differed from that of tubes with benign histology. The degree of karyometric alteration increased with increasing proximity to fimbrial STICs, ranging from moderate in the proximal portion of the tube, to greatest in both normal appearing fimbrial cells near STICs as well as in fimbrial STIC lesions.
These data demonstrate an abnormal karyometric signature in STICs that may extend beyond the STIC, potentially providing an opportunity for early detection of fallopian tube neoplasia.
•Karyometric assessment reveals a signature that is abnormal in serous tubal intraepithelial carcinoma (STIC).•The abnormal karyometric signature extends to histologically normal fallopian tube epithelial cells beyond the STIC.•An abnormal karyometric signature in the fallopian tube has potential as a target for ovarian cancer screening.
Abstract Objectives Previously we have shown in endometrial cells that progesterone (P4) and calcitriol (CAL, 1,25(OH)2 D3 ) synergistically promote apoptosis and that progestins induce expression of ...the vitamin D receptor. In the current study we examined the progestin/vitamin D combination in ovarian cells and searched for other progestin-related effects on vitamin D metabolism that may underlie the novel interaction between progestins and vitamin D, including whether progestins inhibit CYP24A1 , the enzyme that renders CAL inactive. Methods We investigated the impact of P4 on CAL-induced CYP24A1 expression in cancer cell lines expressing progesterone receptors (PRs), OVCAR-5, OVCAR-3-PGR (PR-transfected OVCAR-3 ovarian line), and T47D-WT, T47D-A and T47D-B (breast lines expressing PRs or individual PR isoforms) or lines that do not express PRs (OVCAR-3 and T47D-Y). We examined CYP24A1 expression using RT-PCR and western blotting, and apoptosis by TUNEL. We also investigated P4 inhibition of Cyp24a1 in ovaries from CAL-treated mice. Results CAL treatment induced CYP24A1 expression. When co-treated with P4, cell lines expressing PRs showed marked inhibition of CYP24A1 expression (p < 0.001), along with increased apoptosis (p < 0.01); cells not expressing PRs did not. Mouse ovaries showed a significant reduction in CAL-induced Cyp24a1 mRNA (p < 0.001) and protein (p < 0.01) in response to P4. Conclusions We show for the first time that progestins and vitamin D synergistically reduce cell viability and induce apoptosis in ovarian cells and that progestins PR-dependently inhibit CAL-induced CYP24A1 , thus extending CAL activity. The combination of progestins and vitamin D deserves further consideration as a strategy for inhibiting ovarian carcinogenesis.
A concern of surgical oncologists has been to find a method to select patients for groin dissection in penile carcinomas considering the high morbidity of this procedure. A promising methodology, in ...the identification of early metastatic foci by the sentinel lymph node technique (initiated in Paraguay in the 1970s), was found, using a static anatomic approach, to be associated with a recurrence rate of 30%. Later, a dynamic method using radioactive tracers and peritumoral dye injection was introduced with an improvement in patients' outcome. Recurrences, however, remained high in most studies at a rate of about 15% to 20% except in few highly specialized centers with failure rates of 5%. The technical sophistication, lack of multicenter reproduction, and cost of dynamic sentinel node biopsies preclude their routine implementation in developing countries and other approaches are necessary. Because histologic grade, depth of tumor infiltration, and perineural invasion (PNI) are considered among the most important pathologic prognostic parameters in penile cancer, we devised a Prognostic Index combining these 3 factors. In this study, we are evaluating the incidence of nodal metastasis according to the Prognostic Index score. Pathologic materials from 193 patients with penectomy/circumcision and bilateral groin dissections for invasive squamous cell carcinoma were analyzed. The Prognostic Index (ranging from 2 to 7) consisted in the addition of numerical values given to histologic grade (1 to 3), deepest anatomic level involved by cancer (1 to 3), and presence of PNI (0 or 1). Histologic grades were defined as follows: grade 1, carcinomas with minimal to no atypias; grade 3, tumors showing any proportion of anaplastic cells; and grade 2, the remainder tumors. The anatomic levels and their numerical values were: in glans, lamina propria, 1; corpus spongiosum, 2; and corpus cavernosum, 3. In foreskin they were: lamina propria, 1; dartos, 2; and skin, 3. PNI was evaluated as follows: absence of PNI, 0; presence of PNI, 1. Penile intraepithelial neoplasia (carcinoma in situ), or index 1, was excluded from the study. Mean follow-up obtained in all patients was of 81 months. The distribution of cases and rate of metastasis according to index scores were: 2 (1 case), no metastasis; 3 (17 cases), no metastasis; 4 (35 cases), 20% of metastasis; 5 50 cases), 50% of metastasis; 6 (47 cases), 66% of metastasis; and 7 (43 cases), 79% of metastasis. On logistic regression analysis evaluating various pathologic factors, Prognostic Index scores were found as the best predictors of inguinal node metastasis and patients' survival. Inguinal node dissections might not be necessary for patients with low indices (2 and 3). Nodal dissections might be formally indicated for high-grade indexes (5 to 7). Patients with index 4 should be individually assessed for nodal dissection. If sentinel node biopsy cannot be performed for various reasons the Prognostic Index might represent a useful pathologic guide to the clinicians in the often difficult decision to perform an inguinal dissection or not.
Stroke is the major cause of vascular behavior and cognitive disorders worldwide. In developing countries, there is a dearth of information regarding the public health magnitude of stroke. The aim of ...the Fogarty-Mexico cohort was to assess the prevalence of vascular behavioral and cognitive disorders, ranging from mild vascular cognitive impairment (VCI) to vascular dementia (VaD), in a cohort of acute first-ever symptomatic stroke patients in Mexico.
A total of 165 consecutive, first-ever stroke patients admitted to the National Institute of Neurology and Neurosurgery in Mexico City, were included in the cohort. Patients were eligible if they had an ischemic stroke, primary intracerebral hemorrhage, or cerebral venous thrombosis (CVT). Stroke diagnosis required the presence of an acute focal deficit lasting more than 24 h, confirmed by a corresponding lesion on CT/MRI. Stroke severity was established with the NIH Stroke Scale. The pre-stroke functional status was determined by the IQCODE. Three months after the occurrence of stroke, 110 survivor patients returned for follow-up and were able to undergo functional outcome (modified Rankin scale, Barthel index), along with neurological, psychiatric, neuropsychological, laboratory, and imaging assessments. We compared depression, demographic, and clinical and imaging features between patients with and without dementia, and between patients with VCI and those with intact cognition.
Of the 110 patients (62% men, mean age 56 ± 17.8, education 7.7 ± 5.2 years) 93 (84%) had ischemic strokes, 14 (13%) intracerebral hemorrhage, and 3 (3%) CVT. The main risk factors were hypertension (50%), smoking (40%), hypercholesterolemia (29%), hyperhomocysteinemia (24%), and diabetes (22%). Clinical and neuropsychological evaluations demonstrated post-stroke depression in 56%, VCI in 41%, and VaD in 12%; 17% of the latter had pre-stroke functional impairment (IQCODE >3.5). Cognitive deficits included executive function in 69%, verbal memory in 49%, language in 38%, perception in 36%, and attention in 38%. Executive dysfunction occurred in 36% of non-demented subjects, 65% of them with mild-moderate deficits in daily living activities. Female gender (p ≤ 0.054), older age (mean age 65.6 years vs. 49.3, p < 0.001), diabetes (p ≤ 0.004), illiteracy and lower education (p ≤ 0.001), and PSD (p = 0.03) were significantly higher in VCI-VaD compared with cognitively intact post-stroke subjects. We could not demonstrate an association with lesion site and distribution of the cognitive deficits.
The Fogarty-Mexico cohort recruited relatively young acute stroke patients, compared with other Mexican stroke cohorts. PSD and VCI occurred frequently but prevalence of VaD (12%) was lower than expected. A high prevalence of treatable stroke risk factors suggests that preventive interventions are advisable.
Significance: Most cases of high-grade serous ovarian carcinoma originate as serous tubal intraepithelial carcinoma (STIC) lesions in the fallopian tube epithelium (FTE), enabling early endoscopic ...detection.
Aim: The cell-acquiring fallopian endoscope (CAFE) was built to meet requirements for locating potentially pathological tissue indicated by an alteration in autofluorescence or presence of a targeted fluorophore. A channel was included for directed scrape biopsy of cells from regions of interest.
Approach: Imaging resolution and fluorescence sensitivity were measured using a standard resolution target and fluorescence standards, respectively. A prototype was tested in ex vivo tissue, and collected cells were counted and processed.
Results: Measured imaging resolution was 88 μm at a 5-mm distance, and full field of view was ∼45 deg in air. Reflectance and fluorescence images in ex vivo porcine reproductive tracts were captured, and fit through human tracts was verified. Hemocytometry counts showed that on the order of 105 cells per scrape biopsy could be collected from ex vivo porcine tissue.
Conclusions: All requirements for viewing STIC in the FTE were met, and collected cell counts exceeded input requirements for relevant analyses. Our benchtop findings suggest the potential utility of the CAFE device for in vivo imaging and cell collection in future clinical trials.
Women undergoing premenopausal oophorectomy for a variety of reasons, including to reduce ovarian or breast cancer risk were evaluated for accelerated bone loss.
The Gynecologic Oncology Group ...(GOG)-0215 randomized phase-II trial of zoledronic acid was initiated to determine if postoophorectomy bisphosphonate therapy could prevent this bone loss. The study was closed after slow accrual prevented evaluation of the primary study endpoint. We analyzed changes in bone mineral density (BMD) among the 80 women randomized to the observation arm of this study, as measured 3, 9, and 18 months postenrollment.
The mean change in BMD from baseline to 18 months was -0.09 (95% CI, -0.12 to -0.07), -0.05 (95% CI, -0.07 to -0.03), and -0.06 (95% CI, -0.07 to -0.05) g/cm across the lumbar spine, right hip, and left hip, respectively. This represents a BMD decrease of -8.5% for the lumbar spine and -5.7% for both the right and left hips from baseline to 18 months' observation.
These results demonstrate that premenopausal women undergoing oophorectomy clearly experience bone loss, an adverse effect of oophorectomy, which requires attention and active management. BMD should be monitored postoophorectomy, and treated per standard practice guidelines. Future studies will be required to determine if early treatment can mitigate fracture risk, and to test promising therapeutic interventions and novel prevention strategies, such as increased physical activity or alternative medications, in randomized trials.
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