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Context.— In the early months of the response to the coronavirus disease 2019 (COVID-19) pandemic, the Johns Hopkins University School of Medicine (JHUSOM) (Baltimore, Maryland) leadership reached out to faculty to develop and implement virtual clinical clerkships after all in-person medical student clinical experiences were suspended. Objective.— To develop and implement a digital slide–based virtual surgical pathology (VSP) clinical elective to meet the demand for meaningful and robust virtual clinical electives in response to the temporary suspension of in-person clinical rotations at JHUSOM. Design.— The VSP elective was modeled after the in-person surgical pathology elective to include virtual previewing and sign-out with standardized cases supplemented by synchronous and asynchronous pathology educational content. Results.— Validation of existing Web communications technology and slide-scanning systems was performed by feasibility testing. Curriculum development included drafting of course objectives and syllabus, Blackboard course site design, electronic-lecture creation, communications with JHUSOM leadership, scheduling, and slide curation. Subjectively, the weekly schedule averaged 35 to 40 hours of asynchronous, synchronous, and independent content, approximately 10 to 11 hours of which were synchronous. As of February 2021, VSP has hosted 35 JHUSOM and 8 non-JHUSOM students, who have provided positive subjective and objective course feedback. Conclusions.— The Johns Hopkins VSP elective provided meaningful clinical experience to 43 students in a time of immense online education need. Added benefits of implementing VSP included increased medical student exposure to pathology as a medical specialty and demonstration of how digital slides have the potential to improve standardization of the pathology clerkship curriculum.

BACKGROUND Although aberrant glycosylation is recognized as a hallmark of cancer, glycosylation in clinical breast cancer (BC) metastasis has not yet been studied. While preclinical studies show that the glycocalyx coating of cancer cells is involved in adhesion, migration, and metastasis, glycosylation changes from primary tumor (PT) to various metastatic sites remain unknown in patients. METHODS We investigated N-glycosylation profiles in 17 metastatic BC patients from our rapid autopsy program. Primary breast tumor, lymph node metastases, multiple systemic metastases, and various normal tissue cores from each patient were arranged on unique single-patient tissue microarrays (TMAs). We performed mass spectrometry imaging (MSI) combined with extensive pathology annotation of these TMAs, which enabled spatially differentiated cell-based analysis of N-glycosylation patterns in metastatic BC. RESULTS N-glycan abundance increased during metastatic progression independent of BC subtype and treatment regimen, with high-mannose glycans most frequently elevated in BC metastases, followed by fucosylated and complex glycans. Bone metastasis, however, displayed increased core-fucosylation and decreased high-mannose glycans. Consistently, N-glycosylated proteins and N-glycan biosynthesis genes were differentially expressed during metastatic BC progression, with reduced expression of EpCAM and mannose-trimming enzymes and elevated N-glycan branching and sialylation enzymes in BC metastases versus PT. CONCLUSION We show for the first time in patients that N-glycosylation of breast cancer cells undergoing metastasis occurs in a metastatic site-specific manner, supporting the clinical importance of high-mannose, fucosylated, and complex N-glycans as future diagnostic markers and therapeutic targets in metastatic BC. FUNDING United States National Institutes of Health grants NIH R01CA213428, R01CA213492, T32CA193145, Dutch Province Limburg "LINK", European Union ERA-NET TRANSCAN2-643638.

We report an Xp11 translocation perivascular epithelioid cell tumor (PEComa) with a novel RBMX-TFE3 gene fusion, resulting from a paracentric X chromosome inversion, inv(X)(p11;q26). The neoplasm occurred in an otherwise healthy 12-year-old boy who presented with a large left renal mass with extension into the inferior vena cava. The patient was found to have multiple pulmonary metastases at diagnosis and died of disease 3 months later. The morphology (epithelioid clear cells with alveolar and nested architecture) and immunophenotype (TFE3 and HMB45 strongly positive; actin, desmin, and PAX8 negative) was typical of an Xp11 translocation PEComa; however, TFE3 rearrangement was initially not detected by routine TFE3 break-apart fluorescence in situ hybridization (FISH). Further RNA sequencing revealed a novel RBMX-TFE3 gene fusion, which was subsequently confirmed by fusion assay FISH, using custom design RBMX and TFE3 come-together probes. This report describes a novel TFE3 gene fusion partner, RBMX, in a pediatric renal PEComa patient associated with a fulminant clinical course. As documented in other intrachromosomal Xp11.2 inversions, such as fusions with NONO, RBM10, or GRIPAP1 genes, the TFE3 break-apart might be below the FISH resolution, resulting in a false negative result.

Context.— Like many medical specialties, pathology faces the ongoing challenge of effectively enriching diversity, equity, and inclusion within training programs and the field as a whole. This issue is furthered by a decline in US medical student interest in the field of pathology, possibly attributable to increasingly limited pathology exposure during medical school and medical student perceptions about careers in pathology. Objective.— To review the literature to identify the challenges to diversity, equity, and inclusion in pathology, with an emphasis on the pathology trainee pipeline. To evaluate the medical education literature from other medical specialties for diversity and inclusion–focused studies and initiatives, and determine the outcomes and/or approaches relevant for pathology training programs. Data Sources.— A literature review was completed by a search of the PubMed database, as well as a similar general Google search. Additional resources, including the Web sites of the Association of American Medical Colleges, the Electronic Residency Application Service, and the National Resident Matching Program, were used. Conclusions.— Many strategies exist to increase diversity and encourage an inclusive and equitable training environment, and many of these strategies may be applied to the field of pathology. Interventions such as increasing exposure to the field, using a holistic application review process, and addressing implicit biases have been shown to promote diversity, equity, and inclusion in many medical specialties. In addition, increasing access to elective and pipeline programs may help to bolster medical student interest in careers in pathology.

While essential to our understanding of solid tumor progression, the study of cell and tissue mechanics has yet to find traction in the clinic. Determining tissue stiffness, a mechanical property known to promote a malignant phenotypein vitroandin vivo, is not part of the standard algorithm for the diagnosis and treatment of breast cancer. Instead, clinicians routinely use mammograms to identify malignant lesions and radiographically dense breast tissue is associated with an increased risk of developing cancer. Whether breast density is related to tumor tissue stiffness, and what cellular and non-cellular components of the tumor contribute the most to its stiffness are not well understood. Through training of a deep learning network and mechanical measurements of fresh patient tissue, we create a bridge in understanding between clinical and mechanical markers. The automatic identification of cellular and extracellular features from hematoxylin and eosin (H&E)-stained slides reveals that global and local breast tissue stiffness best correlate with the percentage of straight collagen. Global breast tissue mechanics correlate weakly with the percentage of blood vessels and fibrotic tissue, and non-significantly with the percentage of fat, ducts, tumor cells, and wavy collagen in tissue. Importantly, the percentage of dense breast tissue does not directly correlate with tissue stiffness or straight collagen content.

Context.— Endosalpingiosis is a benign Müllerian inclusion that can mimic metastatic low-grade mammary carcinoma, particularly when encountered in axillary lymph nodes excised for breast cancer staging. Immunohistochemistry can be useful in histologically ambiguous cases, and a targeted immunopanel should include a marker of gynecologic tract origin and a marker of mammary origin. GATA3 is a sensitive immunomarker for breast carcinoma, but the immunoreactivity of GATA3 in endosalpingiosis has not been systematically evaluated. Objective.— To evaluate whether GATA3 immunohistochemistry could be used to differentiate endosalpingiosis from metastatic mammary carcinoma. Design.— Whole slide sections of 15 cases of endosalpingiosis involving nonneoplastic tissues were subjected to GATA3 immunohistochemistry. Nuclear GATA3 labeling was scored as percentage and intensity labeling, with any labeling considered positive; GATA3 labeling was recorded in all cells present in the sections. Results.— Half (47%, n = 7 of 15) of the endosalpingiosis cases involved lymph nodes (2 axillary, 5 pelvic) and half (53%, n = 8 of 15) involved pelvic organs or soft tissue (3 myometrial, 2 paratubal, 2 periadnexal soft tissue, and 1 pelvic sidewall). GATA3 immunohistochemistry was negative in all cases of endosalpingiosis, with intact, positive control labeling in lymphocytes. The benign fallopian tube epithelium present on the sections of paratubal endosalpingiosis displayed focal ( Conclusions.— These findings support the diagnostic utility of GATA3 immunohistochemistry and its use in a targeted immunopanel to resolve the differential diagnosis of metastatic low-grade mammary carcinoma (GATA3+) and nodal endosalpingiosis (GATA3−).

Objectives This study assessed historical and current gender, racial, and ethnic diversity trends within US pathology graduate medical education (GME) and the pathologist workforce. Methods Data from online, publicly available sources were assessed for significant differences in racial, ethnic, and sex distribution in pathology trainees, as well as pathologists in practice or on faculty, separately compared with the US population and then each other using binomial tests. Results Since 1995, female pathology resident representation has been increasing at a rate of 0.45% per year (95% confidence interval [CI], 0.29-0.61; P < .01), with pathology now having significantly more females (49.8%) compared to the total GME pool (45.4%; P < .0001). In contrast, there was no significant trend in the rate of change per year in black or American Indian, Alaskan Native, Native Hawaiian, and Pacific Islander (AI/AN/NH/PI) resident representation (P = .04 and .02). Since 1995, underrepresented minority (URM) faculty representation has increased by 0.03% per year (95% CI, 0.024-0.036; P < .01), with 7.6% URM faculty in 2018 (5.2% Hispanic, 2.2% black, 0.2% AI/AN/NH/PI). Conclusions This assessment of pathology trainee and physician workforce diversity highlights significant improvements in achieving trainee gender parity. However, there are persistent disparities in URM representation, with significant underrepresentation of URM pathologists compared with residents.

Metaplastic breast carcinoma (MBC) is a highly aggressive form of triple-negative cancer (TNBC), defined by the presence of metaplastic components of spindle, squamous, or sarcomatoid histology. The protein profiles underpinning the pathological subtypes and metastatic behavior of MBC are unknown. Using multiplex quantitative tandem mass tag-based proteomics we quantify 5798 proteins in MBC, TNBC, and normal breast from 27 patients. Comparing MBC and TNBC protein profiles we show MBC-specific increases related to epithelial-to-mesenchymal transition and extracellular matrix, and reduced metabolic pathways. MBC subtypes exhibit distinct upregulated profiles, including translation and ribosomal events in spindle, inflammation- and apical junction-related proteins in squamous, and extracellular matrix proteins in sarcomatoid subtypes. Comparison of the proteomes of human spindle MBC with mouse spindle (CCN6 knockout) MBC tumors reveals a shared spindle-specific signature of 17 upregulated proteins involved in translation and 19 downregulated proteins with roles in cell metabolism. These data identify potential subtype specific MBC biomarkers and therapeutic targets., Metaplastic breast carcinoma (MBC) is among the most aggressive subtypes of triple-negative breast cancer (TNBC) but the underlying proteome profiles are unknown. Here, the authors characterize the protein signatures of human MBC tissue samples and their relationship to TNBC and normal breast tissue.

Pathology interns face a steep learning curve as they transition from medical school to residency. Innovative teaching tools are needed to effectively and efficiently bridge this gap. We created four online learning modules geared toward pathology interns, for use at the beginning of the gastrointestinal pathology rotation at our institution. Our modules covered introductory esophageal, gastric, small bowel, and colonic pathology. Each module incorporated photomicrographs and annotated virtual slides, and included pre- and post-module assessment questions and a link to an anonymous survey. Twelve interns completed the modules between 9/20/2019 and 12/31/2021, including 80% of the 2020-2021 intern class. Significant improvement in performance was seen between the pre- and post-module questions for the stomach, small bowel, and colon modules (p 0.05 for all), with a trend toward improved performance with the esophageal module. Interns rated the modules highly and indicated that they would recommend the modules to their peers. While the modules were geared toward interns, due to the coronavirus-19 pandemic we expanded access to the modules to include medical students. Medical students also found the learning modules valuable and requested more modules in the future. We conclude that online learning modules are an effective tool for teaching pathology interns and are well-received by this group. Online modules can also be seamlessly incorporated into asynchronous medical student teaching.

Background Disseminated fungal infections are a known serious complication in individuals with cystic fibrosis (CF) following orthotopic lung transplantation. Aspergillus fumigatus and Scedosporium species are among the more common causes of invasive fungal infection in this population. However, it is also important for clinicians to be aware of other emerging fungal species which may require markedly different antifungal therapies. Case summary We describe the first laboratory-documented case of a fatal disseminated fungal infection caused by Rasamsonia aegroticola in a 21-year-old female CF patient status post-bilateral lung transplantation, which was only identified post-mortem. Molecular analysis revealed the presence of the identical Rasamsonia strains in the patient's respiratory cultures preceding transplantation. Discussion We propose that the patient's disseminated fungal disease and death occurred as a result of recrudescence of Rasamsonia infection from her native respiratory system in the setting of profound immunosuppression post-operatively. Since Rasamsonia species have been increasingly recovered from the respiratory tract of CF patients, we further review the literature on these fungi and discuss their association with invasive fungal infections in the CF lung transplant host. Conclusion Our report suggests Rasamsonia species may be important fungal pathogens that may have fatal consequences in immunosuppressed CF patients after solid organ transplantation.

Pathologists who enter the workforce must have a diverse skill set beyond that of clinical diagnostics alone. Anticipating this need, the Johns Hopkins Pathology Residency Program developed Special Expertise Tracks to enhance training in relevant subspecialty domains. Using a combination of discussions and surveys, we assessed: (1) our current resident curriculum; (2) perceived curricular strengths and needs; (3) resident career preferences and ultimate career paths; (4) perceived barriers to implementing an advanced elective curriculum; and (5) available departmental/institutional resources. Additionally, we utilized the Accreditation Council for Graduate Medical Education Pathology Milestones as a curricular guide. Six professional residency training Special Expertise Tracks were established: Education, Physician-Scientist Research, Informatics, Quality Improvement/Quality Assurance/Value-Based Care, Health Policy/Hospital Management and Global Health. After implementation in 2017, the Education track has had 4 residents complete the curriculum successfully; the Physician-Scientist Research track has had 2 residents and the Informatics and Global Health tracks have each had one resident successfully complete their respective curricula. Currently, 5 residents are pursuing the Education track, one is pursuing the Physician-Scientist Research track, one is pursuing the Informatics track, and 2 residents are pursuing the Global Health track. Five residents have completed long-term projects including developing several e-learning modules, an online free digital cytopathology atlas, peer-reviewed articles, book chapters, and books. The Johns Hopkins Pathology Resident Special Expertise Track program provides pathology residents an opportunity to gain meaningful experience and additional skills tailored to their individual career interests.

With 3.8% black trainees in 2012, pathology had significantly fewer trainees from groups underrepresented in medicine compared to other specialties. To address this, faculty in the Johns Hopkins Department of Pathology established an outreach program and funded rotation for students underrepresented in medicine and from disadvantaged groups. The aims were to increase exposure to the field and improve diversity, inclusion, and equity in pathology. A 1-month rotation for students underrepresented in medicine was established in 2013. Rotation schedules tailored to each rotator’s interests included resident conferences and individual faculty meetings. In 2016, a proactive outreach program was established. Faculty visited historically black medical schools and underrepresented in medicine student groups at other institutions, where they gave a “Careers in Pathology” presentation targeted to second- and third-year medical students. Faculty also attended underrepresented in medicine student conferences and participated in high school student programs to further expand the underrepresented in medicine pipeline into medicine and pathology. Since 2016, fourteen outreach presentations have been delivered. The number of rotators increased from 1 in 2013 to 18 in July 2019. Rotators self-identified as African, African American, Hispanic, and Native American. Most were second- to fourth-year medical students, and 1 was a pathology resident. Six rotators are currently pathology residents, and others are strongly considering applying to pathology. The outreach efforts account for the success of our rotation, which, in turn, has had a positive impact on interest in pathology. However, we recognize barriers to retention and intend to incorporate additional professional development activities to further address equity.

The evolution of modern anesthesia and surgical practices has been accompanied by enhanced supportive procedures in blood banking and transfusion medicine. There is increased focus on the preparation and the use of blood components including, but not limited to, preventing unnecessary type and screen/crossmatch orders, decreasing the time required to provide compatible red blood cells (RBCs), and reducing the waste of limited blood and personnel resources. The aim of this review is to help the anesthesiologist and surgical staff identify patients at highest risk for surgical bleeding. In addition, this review examines how anesthesia and transfusion medicine can efficiently and safely allocate blood components for surgical patients who require transfusions. The following databases were searched: PubMed, EMBASE, Google Scholar, and the Cochrane Library from January 1970 through March 2014. Subsequent reference searches of retrieved articles were also assessed. Several innovations have drastically changed the procedures by which blood is ordered, inventoried, and the speed in which blood is delivered for patient care. Before entering an operating room, patient blood management provides guidance to clinicians about when and how to treat preoperative anemia and intra- and postoperative strategies to limit the patient's exposure to blood components. Timely updates of the recommendations for blood orders (maximum surgical blood ordering schedule) have enhanced preoperative decision making regarding the appropriateness of the type and screen versus the type and crossmatch order. The updated maximum surgical blood ordering schedule reflects modern practices, such as laparoscopy, improved surgical techniques, and use of hemostatic agents resulting in a more streamlined process for ordering and obtaining RBCs. The electronic (computer) crossmatch and electronic remote blood issue have also dramatically reduced the amount of time required to obtain crossmatch-compatible RBCs when compared with the more traditional serologic crossmatch methods. These changes in blood banking methods have resulted in more efficient delivery of blood to surgical patients.