The Clinical Utility and Impact of Next Generation Sequencing in Gynecologic Cancers.

Next generation sequencing (NGS) has facilitated the identification of molecularly targeted therapies. However, clinical utility is an emerging challenge. Our objective was to identify the clinical utility of NGS testing in gynecologic cancers. A retrospective review of clinico-pathologic data was performed on 299 gynecological cancers where NGS testing had been performed to identify (1) recognition of actionable targets for therapy, (2) whether the therapy changed based on the findings, and (3) the impact on survival. High grade serous carcinoma was the most common tumor (52.5%). The number of genetic alterations ranged from 0 to 25 with a mean of 2.8/case. The most altered genes were TP53, PIK3CA, BRCA1 and BRCA2. Among 299 patients, 100 had actionable alterations (79 received a targeted treatment (Group1), 29 did not receive treatment (Group 2), and there were no actionable alterations in 199 (Group3). The death rate in groups 1, 2 and 3 was 54.4%, 42.8% and 50.2%, with an average survival of 18.6, 6.6 and 10.8 months, respectively (p = 0.002). In summary, NGS testing for gynecologic cancers detected 33.4% of actionable alterations with a high clinical action rate. Along with the high clinical utility of NGS, testing also seemed to improve survival for patients who received targeted treatment.

Grossly unremarkable cervix in endometrial carcinomas: lymphovascular space invasion and microcystic elongated and fragmented pattern may be associated with high incidence of cervical stromal involvement.

Accurate staging of endometrial carcinoma is crucial to optimize patients' care. A pivotal parameter that pathologists evaluate to guide staging is the presence of cervical stromal involvement. However, the standard protocol for adequate sampling of the cervix is lacking. A total of 71 grossly unremarkable cervices in hysterectomy specimens with endometrial carcinomas have been studied. Sixty-three (89.7%), five (7.0%), and three (4.2%) were FIGO stage I, II, and III, respectively. Of 71 (8.5%) cases, 6 cases had cervical stromal involvement, among which, 4 (67%) showed endometrioid carcinoma (EC), 1 case of serous carcinoma, and 1 carcinosarcoma. Microcystic elongated and fragmented (MELF) pattern was identified in 12 (16.9%) cases, among which 11 were EC. The presence of MELF pattern was associated with advanced age, deeper myometrial invasion, and advanced FIGO stage. Tumors with lower uterine segment involvement (5/6; 80%), lymphovascular space invasion (4/6; 67%), and MELF pattern (3/6; 50.0%) tended to have cervical stromal involvement. Thus, we provide evidence that the presence of these features in hysterectomy specimens from patients with endometrial carcinoma may warrant extended sampling of the cervix while submitting four representative sections (one section from each quadrant) seems adequate to evaluate for occult cervical stromal involvement in grossly unremarkable cervices in the absence of these features.

Diagnostic Utility and Significance of Performing Multistep Level Sections in Breast and Gynecologic Biopsy Specimens.

OBJECTIVES: The significance of performing multistep level sections, including preparation of unstained sections in breast and gynecologic biopsy specimens, has been studied. METHODS: Consecutive H&E-stained level sections of 785 atypical and malignant biopsy specimens were included. The diagnostic material was categorized into present, absent, increased in size, or depleted. If the multistep level sections helped in establishing the diagnosis after a nondiagnostic material or the tissue significantly increased in size, this was considered a positive impact. RESULTS: No effect and positive impact of performing multistep level sections were obtained in 84.8% and 15.2% by preparing a second level and 97.2% and 2.8% by preparing a third level, respectively. Eighteen (2.3%) of the diagnoses could have been missed without performing a second level, while 8 (1%) could have been missed without performing a third level. The intervening unstained sections were used in 27 of 785 (3.4%) of the cases. CONCLUSIONS: Staining two level sections with H&E significantly affected the diagnosis. However, preparing a third level did not improve the diagnosis. A universal protocol should be considered to standardize the handling of biopsy specimens among laboratories.

Vascular disease in cocaine addiction.

Cocaine, a powerful vasoconstrictor, induces immune responses including cytokine elevations. Chronic cocaine use is associated with functional brain impairments potentially mediated by vascular pathology. Although the Crack-Cocaine epidemic has declined, its vascular consequences are increasingly becoming evident among individuals with cocaine use disorder of that period, now aging. Paradoxically, during the period when prevention efforts could make a difference, this population receives psychosocial treatment at best. We review major postmortem and in vitro studies documenting cocaine-induced vascular toxicity. PubMed and Academic Search Complete were used with relevant terms. Findings consist of the major mechanisms of cocaine-induced vasoconstriction, endothelial dysfunction, and accelerated atherosclerosis, emphasizing acute, chronic, and secondary effects of cocaine. The etiology underlying cocaine's acute and chronic vascular effects is multifactorial, spanning hypertension, impaired homeostasis and platelet function, thrombosis, thromboembolism, and alterations in blood flow. Early detection of vascular disease in cocaine addiction by multimodality imaging is discussed. Treatment may be similar to indications in patients with traditional risk-factors, with few exceptions such as enhanced supportive care and use of benzodiazepines and phentolamine for sedation, and avoiding ß-blockers. Given the vascular toxicity cocaine induces, further compounded by smoking and alcohol comorbidity, and interacting with aging of the crack generation, there is a public health imperative to identify pre-symptomatic markers of vascular impairments in cocaine addiction and employ preventive treatment to reduce silent disease progression.