A B S T R A C T PurposeThis phase II trial was designed to define the role of O 6 -benzylguanine (O 6 -BG) in restoring temozolomide sensitivity in patients with recurrent or progressive, temozolomide-resistant malignant glioma and to evaluate the safety of administering O 6 -BG in combination with temozolomide. Patients and MethodsPatients were accrued into two independent strata on the basis of histology: glioblastoma multiforme (GBM) and anaplastic glioma. Both temozolomide and O 6 -BG were administered on day 1 of a 28-day treatment cycle. Patients were administered a 1-hour O 6 -BG infusion at a dose of 120 mg/m 2 followed immediately by a 48-hour infusion at a dose of 30 mg/m 2 /d. Temozolomide was administered orally within 60 minutes of the end of the 1-hour O 6 -BG infusion at a dose of 472 mg/m 2 . The primary end point was objective response rate. Secondary end points included progression-free survival, overall survival, and safety. ResultsSixty-six of 67 patients who enrolled were treated with temozolomide and O 6 -BG. One of 34 patients (3%) with GBM (95% CI, 0.1% to 15%) and five of 32 assessable patients (16%) with anaplastic glioma (95% CI, 5% to 33%) were responders. The most commonly reported adverse events were grade 4 hematologic events experienced in 48% of the patients. ConclusionO 6 -BG when added to a 1-day dosing regimen of temozolomide was able to restore temozolomide sensitivity in patients with temozolomide-resistant anaplastic glioma, but there seemed to be no significant restoration of temozolomide sensitivity in patients with temozolomide-resistant GBM.

The vesicular monoamine transporter 2 (VMAT2) is localized primarily within the CNS and is responsible for transporting monoamines from the cytoplasm into secretory vesicles. Because reserpine (a VMAT inhibitor) can precipitate depressive-like symptoms in humans, we investigated whether Vmat2 heterozygous (HET) mice present with depressive-like behaviors. The mutants showed locomotor and rearing retardation in the open field and appeared anhedonic to 1 and 1.5% sucrose solutions. Immobility times for Vmat2 heterozygotes were prolonged in forced swim and imipramine normalized this behavior. HET animals also showed enhanced immobility in tail suspension and this response was alleviated by fluoxetine, reboxetine, and bupropion. Stimulated GTP␥S binding indicated that ␣ 2 -adrenergic receptors in HET hippocampus were more sensitive to UK 14,304 (5-bromo-N-(4,5-dihydro-1-H-imidazol-2-yl)-6-quinoxalinamine) stimulation than in wild type (WT) mice. In learned helplessness, mice were exposed to a shuttle box for 4 d or were given inescapable foot-shocks for the same time period. On day 5, all animals were tested in shock escape. Failure rates and the latency to escape were similar for WT and HET mice that were only pre-exposed to the test apparatus. In foot-shock groups, learned helplessness was more robust in heterozygotes than in WT controls. Basal secretion of serum corticosterone was not distinguished by genotype; however, corticosterone levels in mutants were more responsive to stress. Anxiety-like responses of WT and HET animals in the open field, light-dark exploration, zero maze, and novelty-suppressed feeding tests were indistinguishable. Collectively, these findings suggest that Vmat2 heterozygotes display a depressive-like phenotype that is devoid of anxiety-like behavior.

The current results indicate that NIFTP is a rare tumor if defined by strict criteria, that both the GEC and UPMC methods indicate abnormalities in NIFTP, and further independent study will be needed to better characterize the molecular and clinical characteristics of NIFTP. Cancer Cytopathol 2016;124:893-900. © 2016 American Cancer Society.

Purpose: This phase II trial was designed to define the efficacy of Gliadel wafers in combination with an infusion of O 6 -benzylguanine (O 6 -BG) that suppresses tumor O 6 -alkylguanine-DNA alkyltransferase (AGT) levels in patients with recurrent glioblastoma multiforme for 5 days and to evaluate the safety of this combination therapy. Experimental Design: This was a phase II, open-label, single center trial. On gross total resection of the tumor, up to eight Gliadel wafers were implanted. Bolus infusion of O 6 -BG was administered at 120 mg/m 2 over 1 hour on days 1, 3, and 5, along with a continuous infusion at 30 mg/m 2 /d. The primary end points were 6-month overall survival (OS) and safety, and the secondary end points were 1-year, 2-year, and median OS. Results: Fifty-two patients were accrued. The 6-month OS was 82% [95% confidence interval (95% CI), 72-93%]. The 1-and 2-year OS rates were 47% (95% CI, 35-63%) and 10% (95% CI, 3-32%), respectively. The median OS was 50.3 weeks (95% CI, 36

Social media in academics and research: 21st-century tools to turbocharge education, collaboration, and dissemination of research findings The near-ubiquitous use of smartphones and the rapid emergence of free, widely used, social media platforms have combined to turbocharge the dissemination of information at a scale and speed that would have been unimaginable just a few years ago. Increasingly, internet-savvy pathologists of all ages from every corner of the world are flipping the paradigm of traditional academia by posting educational content online free of charge, unencumbered by the limitations of traditional print media and educational conferences. These platforms are being used in innovative ways, not just to disseminate research findings, but also to create new knowledge through using them to empower research collaborations. In this review, we outline ways in which social media platforms, such as Twitter, Facebook, and YouTube, are being used by pathologists to enhance academic work and facilitate the dissemination of research. We outline key differences between the various platforms with respect to pathology academics and research, and describe key areas in which these platforms have already made an impact. These include rapid dissemination of research findings to a worldwide audience, live transnational discussion of journal articles and conference proceedings, intercontinental networking between pathologists for academic purposes, free education on a global scale at minimal or no cost, and research collaborations initiated on and facilitated by social media platforms. Finally, we provide practical tips for pathologists who wish to adopt these novel 21st-century technologies to enhance their academic endeavours.

BACKGROUND: Fine needle aspiration (FNA) is commonly used for the preoperative evaluation of salivary gland tumors.Tumor grade is a key factor influencing clinical management of salivary gland carcinomas (SGCs). To assess the ability to grade nonbasaloid SGCs in FNA specimens, an international panel of cytopathologists convened to review and score SGC cases. METHODS: The study cohort included 61 cases of primary SGC from the pathology archives of 3 tertiary medical centers. Cases from 2005 to 2016 were selected, scanned, and digitized. Nineteen cytopathologists blinded to the histologic diagnosis reviewed the digitized cytology slides and graded them as low, high, or indeterminate. The panelists' results were then compared to the tumor grades based on histopathologic examination of the corresponding resection specimens. RESULTS:All but 2 of the 19 (89.5%) expert panelists review more than 20 salivary gland FNAs per year; 16 (84.2%) of the panelists work at academic medical centers, and 13 (68.4%) have more than 10 years' experience. Participants had an overall accuracy of 89.4% in the grading of SGC cases, with 90.2% and 88.3% for low-and high-grade SGC, respectively. Acinic cell carcinoma and mucoepidermoid carcinoma had the highest degree of accuracy, while epithelial-myoepithelial carcinoma and salivary duct carcinoma had the lowest degree of accuracy. As expected, the intermediate-grade SGC cases showed the greatest variability (high-grade, 42.1%; low-grade, 37.5%, indeterminate, 20.4%). CONCLUSION: This study confirms the high accuracy of cytomorphologic grading of primary SGC by FNA as low-or high-grade. However, caution should be exercised when a grade cannot be confidently assigned. Cancer Cytopathol 2020;128:392-402.

This phase I clinical trial conducted with patients who had recurrent or progressive malignant glioma (MG) was designed to determine the maximum tolerated dose (MTD) and toxicity of three different 5-day dosing regimens of temozolomide (TMZ) in combination with O(6)-benzylguanine (O(6)-BG). Both TMZ and O(6)-BG were administered on days 1-5 of a 28-day treatment cycle. A bolus infusion of O(6)-BG was administered at 120 mg/m(2) over 1 h on days 1, 3, and 5, along with a continuous infusion of O(6)-BG at 30 mg/m(2)/day. TMZ was administered at the end of the first bolus infusion of O(6)-BG and then every 24 h for 5 days during the continuous infusion of O(6)-BG. Patients were accrued to one of three 5-day dosing regimens of TMZ. Twenty-nine patients were enrolled into this study. The dose-limiting toxicities (DLTs) were grade 4 neutropenia, leukopenia, and thrombocytopenia. The MTD for TMZ for the three different 5-day dosing schedules was determined as follows: schedule 1, 200 mg/m(2) on day 1 and 50 mg/m(2)/day on days 2-5; schedule 2, 50 mg/m(2)/day on days 1-5; and schedule 3, 50 mg/m(2)/day on days 1-5 while receiving pegfilgrastim. Thus, the 5-day TMZ dosing schedule that maximized the total dose of TMZ when combined with O(6)-BG was schedule 1. This study provides the foundation for a phase II trial of O(6)-BG in combination with a 5-day dosing schedule of TMZ in TMZ-resistant MG.

Background In a previous worldwide survey, the authors showed a drastic reduction in the number of cytological specimens processed during the coronavirus disease 2019 “lockdown” period along with an increase in malignancy rates. To assess the continued impact of the pandemic on cytological practices around the world, they undertook a second follow‐up worldwide survey collecting data from the post‐lockdown period (2020). Methods Participants were asked to provide data regarding their cytopathology activity during the first 12 weeks of their respective national post‐lockdown period (2020), which ranged from April 4 to October 31. Differences between the post‐lockdown period and the corresponding 2019 period were evaluated, and the authors specifically focused on rates of malignant diagnoses. Results A total of 29 respondents from 17 countries worldwide joined the survey. Overall, a lower number of cytological specimens (n = 236,352) were processed in comparison with the same period in 2019 (n = 321,466) for a relative reduction of 26.5%. The overall malignancy rate showed a statistically significant increase (12,442 [5.26%] vs 12,882 [4.01%]; P < .001) during the same time period. Similar results were obtained if both malignancy and suspicious for malignancy rates were considered together (15,759 [6.58%] vs 16,011 [4.98%]; P < .001). Conclusions The data showed a persistent reduction in the cytological specimen volume during the post‐lockdown period (2020). However, the relative increase in the cytological workload in the late part of the post‐lockdown is a promising finding of a slow return to normality.