Endometrial Cancer in a Family With RAD51D Gene Mutation.

RAD51 complex plays an important role in homologous recombination deficiency and germline mutations have a well-documented association with breast and tubo-ovarian carcinoma, as well as serous-type endometrial carcinoma. We report a family of French Canadian ancestry with a germline mutation in RAD51D and two sisters presenting with endometrial carcinoma, endometrioid-type. The risk factors for endometrial adenocarcinoma, endometrioid-type are discussed in the context of the RAD51-associated carcinomas described to date.

National pilot of entrustable professional activities in pathology residency training.

Entrustable professional activities (EPAs) are observable clinical skills and/or procedures that have been introduced into medical education at the student and resident levels in most specialties to determine readiness to advance into residency or independent practice, respectively. This publication describes the process and outcomes of a pilot study looking at the feasibility of using two anatomic pathology and two clinical pathology EPAs in pathology residency in 6 pathology residency programs that volunteered for the study. Faculty development on EPAs and their assessment was provided to pilot program faculty, and EPA assessment tools were developed and used by the pilot programs. Pre- and post-study surveys were given to participating residents, faculty, and program directors to gauge baseline practices and to gather feedback on the EPA implementation experience. Results demonstrated overall good feasibility in implementing EPAs. Faculty acceptance of EPAs varied and was less than that of program directors. Residents reported a significant increase in the frequency with which faculty provided formative assessments that included specific examples of performance and specific ways to improve, as well as increased frequency with which faculty provided summative assessments that included specific ways to improve. EPAs offered the most benefit in setting clear expectations for performance of each task, for providing more specific feedback to residents, and in increasing Program director's understanding of resident strengths abilities and weaknesses.

Leveraging faculty development to support validation of entrustable professional activities assessment tools in anatomic and clinical pathology training.

Entrustable professional activities (EPAs) are observable activities that define the practice of medicine and provide a framework of evaluation that has been incorporated into US medical school curricula in both undergraduate and graduate medical education. This manuscript describes the development of an entrustment scale and formative and summative evaluations for pathology EPAs, outlines a process for faculty development that was employed in a pilot study implementing two Anatomic Pathology and two Clinical Pathology EPAs in volunteer pathology residency programs, and provides initial validation data for the proposed pathology entrustment scales. Prior to implementation, faculty development was necessary to train faculty on the entrustment scale for each given activity. A "train the trainer" model used performance dimension training and frame of reference training to train key faculty at each institution. The session utilized vignettes to practice determination of entrustment ratings and development of feedback for trainees as to strengths and weaknesses in the performance of these activities. Validity of the entrustment scale is discussed using the Messick framework, based on concepts of content, response process, and internal structure. This model of entrustment scales, formative and summative assessments, and faculty development can be utilized for any pathology EPA and provides a roadmap for programs to design and implement EPA assessments into pathology residency training.

Continued Positive Job Search Experience for New Pathologists Seeking First Employment During the COVID-19 Pandemic (2020-2022).

CONTEXT.­: As pathologists retire and leave the field, it is critical to accurately capture employment trends for new-in-practice pathologists. There is always interest in the job market for newly graduated pathology trainees and prospective pathology trainees, but it is unclear how the COVID-19 pandemic may have affected the job search experience. OBJECTIVE.­: To provide an update on trends gleaned from a survey of pathology graduates' job search experiences during the COVID-19 pandemic. DESIGN.­: We analyzed data from an annual job search survey sent by the College of American Pathologists Graduate Medical Education Committee between 2020 and 2022 to College of American Pathologists junior members and fellows in practice 3 years or less actively looking for a nonfellowship position. Various indicators of the job search experience were compared year to year and with the data previously published 2017 to 2019 and 2012 to 2016. RESULTS.­: Analysis revealed continued positive trends between the 2020 to 2022 data and the data from 2017 to 2019 and 2012 to 2016. This includes continued ease in finding positions, continued availability of jobs in the subspecialty of choice, continued satisfaction with the positions accepted, and, notably, higher starting salaries. CONCLUSIONS.­: Despite the many challenges of the COVID-19 pandemic, job market trends for newly graduated pathology trainees continue to be favorable with respect to multiple indicators compared with 2 prior periods, 2017 to 2019 and 2012 to 2016.

Factors influencing US osteopathic medical students to choose pathology as a specialty.

The decline in the number of US allopathic (Medical Doctor or M.D.) medical students matching to pathology residency has been a topic of much discussion at national pathology professional society meetings and in recent publications. A recent survey of fourth-year allopathic medicals students was conducted to better understand the rationale behind students' interest or lack thereof in pathology as a specialty. This study utilizes a similar survey tool gauging osteopathic (Doctor of Osteopathy or D.O.) student knowledge and interest in pathology, and offers insight into a possible growth market for the specialty. Similar to allopathic students, osteopathic students noted that clinical or research opportunities in pathology during medical school, autopsy observation/participation, and participation in pathology interest groups correlated with a greater likelihood of selecting pathology as a specialty. However, some key differences in osteopathic medical school curricular elements including microscope use, gross pathology specimen demonstrations, case-based learning by pathologists, exposure to pathology during other rotations, awareness of a pathology interest group, as well as an overall understanding of the everyday work of a pathologist were noted. Experiential exposure to pathology, and direct mentorship from pathologists may present an opportunity for pathology professional organizations, and pathology residency programs to partner with osteopathic medical schools to increase interest in the field, and aid in pipeline development.

Feasibility of an Entrustable Professional Activity for Pathology Resident Frozen Section Training.

Entrustable professional activities are an intuitive form of workplace-based assessment that can support competency-based medical education. Many entrustable professional activities have been written and published, but few studies describe the feasibility or implementation of entrustable professional activities in graduate medical education. The frozen section entrustable professional activit was introduced into the pathology residency training at the University of Vermont for postgraduate year 1 at the start of their training in frozen section. The feasibility of the entrustable professional activit was evaluated based on 3 criteria: (a) utilization, (b) support of frozen section training, and (c) generating data to support entrustment decision about residents' readiness to take call. The entrustable professional activit was well utilized and satisfactory to residents, faculty, pathologists' assistants, and Clinical Competency Committee members. Most members of the Clinical Competency Committee agreed they had sufficient data and noted higher confidence in assessing resident readiness to take call with the addition of entrustable professional activit to the residents' assessment portfolio. Residents did not endorse it helped them prepare for call; however, the interruption to frozen section training due to the COVID-19 pandemic was a significant contributing factor. The frozen section entrustable professional activit is a feasible addition to pathology resident training based on utilization, support of training, and generation of data to support entrustment decisions for graduated responsibilities. The implementation and integration of the entrustable professional activit into pathology training at our institution is described with discussion of adjustments for future use.

Selective vs Complete Sampling in Hysterectomy Specimens Performed for Atypical Hyperplasia.

OBJECTIVES: Atypical hyperplasia of the endometrium is a significant risk factor for uterine endometrioid carcinoma (EC) and an indication for hysterectomy. Standard sampling of these specimens includes evaluation of the entire endometrium to identify possible EC. We evaluated a method of selective sampling in an effort to balance resource utilization with diagnostic accuracy in the detection of EC. METHODS: Histologic diagnoses based on selective sampling (exclusion of every other block of endometrium) were compared with the original diagnosis based on complete sampling. RESULTS: Double-blinded review of these cases using selective sampling detected EC in 92% of hysterectomies, including all high-grade/high-stage carcinomas. Selective sampling had an 82% agreement with the original diagnoses, with most discordant diagnoses attributable to interobserver variability. Adjusting for interobserver variability increased diagnostic agreement between selective and complete sampling to 96%. CONCLUSIONS: Selective sampling is a feasible method to save time and resources while maintaining diagnostic accuracy.

Glutamine Synthetase Immunoreactivity in Peritumoral Hyperplasia in Liver: Case Report of a Metastatic Paraganglioma With Focal Nodular Hyperplasia-Like Changes and Review of an Additional 54 Liver Masses.

OBJECTIVES: Focal nodular hyperplasia (FNH) and peritumoral hyperplasia in the liver exhibit increased immunoreactivity for glutamine synthetase (GS). We observed FNH-like changes with map-like GS staining surrounding a metastatic paraganglioma and sought to determine how often such changes occur around primary and metastatic liver lesions. METHODS: We performed GS immunohistochemistry in liver cases of 20 metastatic neuroendocrine carcinomas (NECs), 21 metastatic colon carcinomas (CCs), seven hepatocellular carcinomas (HCCs), and six FNHs and assessed lesions for size, degree of fibrosis (scored 1-3), and peritumoral hyperplasia. RESULTS: Most NEC or CC cases had few peritumoral hyperplastic features. Three NECs, two CCs, and one HCC (13%) had patchy GS staining at the periphery of the lesions. One CC case had both histologic and immunohistochemical peritumoral hyperplasia. CONCLUSIONS: Peritumoral hyperplasia or FNH-like changes are uncommon findings around primary or metastatic lesions in the liver. GS immunohistochemistry assists in distinguishing true peritumoral hyperplasia from mass effect.

Molecular diagnosis of Actinomadura madurae infection by 16S rRNA deep sequencing.

Next-generation DNA sequencing can be used to catalog individual organisms within complex, polymicrobial specimens. Here, we utilized deep sequencing of 16S rRNA to implicate Actinomadura madurae as the cause of mycetoma in a diabetic patient when culture and conventional molecular methods were overwhelmed by overgrowth of other organisms.

Spermatid head retention as a marker of 2,5-hexanedione-induced testicular toxicity in the rat.

Histopathological analysis is a basic methodology for assessing testicular injury after exposure to candidate therapeutics or toxicants. One possible injury response in rat testis is the failure of step 19 spermatids to spermiate. Such spermatids are transported toward the basement membrane, where they are retained for degradation by Sertoli cells. In control rats, these retained spermatid heads (RSH) were observed at Stages IX-XII. Exposure to the Sertoli cell toxicant, 2,5-hexanedione (HD), for eighteen days at 0.08%-1.0% in drinking water resulted in a dose-dependent increase in the number of RSH at Stages IX-XII (no observed effect level [NOEL], 0.14%). To explore the dynamics of spermatid head retention, rats were treated with 0.33% or 1% HD for various durations and RSH were assessed across all stages. After 0.33% HD exposure for eighteen days, there were more RSH present in Stage IX-XII tubules compared to control. Numbers of RSH dropped back to control levels after four weeks of recovery after the eighteen-day exposure. Exposure of rats to 1% HD for eighteen days resulted in markedly elevated numbers of RSH at Stages IX-II/III. There was no evidence of other histopathological alterations. These data identify RSH as a sensitive histopathological marker of testicular toxicity for subacute HD exposure.

Dose-dependent effects of sertoli cell toxicants 2,5-hexanedione, carbendazim, and mono-(2-ethylhexyl) phthalate in adult rat testis.

Sertoli cells are the primary cellular target for a number of pharmaceutical and environmental testicular toxicants, including 2,5-hexanedione, carbendazim, and mono-(2-ethylhexyl) phthalate. Exposure to these individual compounds can result in impaired Sertoli cell function and subsequent germ cell loss. The loss of testicular function is marked by histopathological changes in seminiferous tubule diameter, seminiferous epithelial sloughing, vacuolization, spermatid head retention, germ cell apoptosis, and altered microtubule assembly. The present study investigates dose-response relationships for these classic Sertoli cell toxicants using histopathology endpoints. Understanding the relationship between the Sertoli cell toxicant dose and its histopathologic manifestations will help establish the sensitivity of these endpoints as markers of testicular injury. The results indicate that no single histopathology endpoint was sensitive on its own in identifying altered testicular morphology resulting from toxicant exposure. However, when multiple endpoints were combined dose-response relationships could be associated with incremental alterations in histopathology. The data generated from these experiments will be useful in further investigating the effects of Sertoli cell toxicant exposure in animal toxicity studies. In addition, this work is fundamental to a planned investigation of the histopathologic and gene expression changes associated with testicular toxicant co-exposures, which may occur both occupationally and environmentally.

Time-dependent changes in post-mortem testis histopathology in the rat.

To clarify the contribution of spontaneous or autolytic post-mortem changes to testis histopathology, the testes of adult rats were examined after animals were left at room temperature for 12, 24, 36, and 48 hours postmortem (n = 2 for all time points except 0 hours postmortem, where n = 3). A progressive decrease in testis weight and seminiferous tubule diameter was observed, as well as detachment of the seminiferous epithelium from the basement membrane. As early as 12 hours postmortem, there was observable clumping and margination of chromatin in Leydig cells, Sertoli cells, spermatogonia, spermatocytes, and step 7-10 spermatids; extensive disintegration of Sertoli cells and residual bodies by 24 hours postmortem; and TUNEL positivity of Leydig cells (by 36 hours postmortem) and step 19 spermatids (at 48 hours postmortem). These findings will aid in ensuring proficient histopathological analysis of testes in toxicity studies.

Telomerase-mediated lifespan extension of human bronchial cells does not affect hexavalent chromium-induced cytotoxicity or genotoxicity.

Hexavalent chromium (Cr(VI)) is a metal of increasing public health concern, as exposure to it is widespread and it is a well-established cause of human bronchial carcinomas and fibrosarcomas. The water-insoluble Cr(VI) salts are potent carcinogens compared to the water soluble salts; yet the genotoxic mechanisms of both may be mediated by soluble Cr(VI) ions. Currently, these mechanisms are poorly understood. Emerging evidence suggests that initial cell culture models used to study the general toxicity of Cr(VI) may be suboptimal for investigating mechanisms specific to human bronchial cells. Accordingly, we have developed a new model system of human bronchial cells by introducing hTERT, the catalytic subunit of human telomerase, into primary human bronchial fibroblasts (PHBF). We have isolated a stable, clonally derived cell line, WHTBF-6, that demonstrate reconstitution of telomerase activity and maintenance of telomere lengths with increasing culture age. WHTBF-6 has been characterized as having an extended in vitro lifespan, a normal growth rate, a normal diploid karyotype that is maintained over time, and exhibits serum-dependent contact-inhibited anchorage-dependent growth. Moreover, we find that both particulate and soluble hexavalent chromium induce a pattern and degree of cytotoxicity and clastogenicity in WHTBF-6 that is similar to the parental PHBF cells. Because telomerase does not compromise growth or the response to Cr(VI), our results indicate that this is an excellent system for studying the mechanisms of Cr(VI) and potentially other carcinogens implicated in the development of lung cancer.