The Silva pattern-based classification for HPV-associated endocervical adenocarcinoma: A single institution concordance study of trainees and gynecologic pathologists.

The Silva pattern-based classification of HPV-associated endocervical adenocarcinoma has become an integral part of the histologic assessment of these tumors. Unfortunately, the Silva system reproducibility has had mixed results in past studies, and clinical practice still favors the FIGO stage assessment in directing therapeutic interventions for patients. In our study, we aimed to assess our institution's concordance including not only gynecologic pathologists, but also pathology trainees through a series of 69 cases. The grouped total kappa concordance from all participants was 0.439 (Moderate), with an overall trainee kappa of 0.417 (moderate) and an overall pathologist kappa of 0.460 (moderate). Perfect concordance among all 10 study participants was seen in 8/69 cases (11.6 %), corresponding to 5/22 Pattern A cases (22.7 %), 0/16 Pattern B cases (0 %), and 3/31 Pattern C cases (9.7 %), with similar findings between trainees and pathologists when compared within their own cohorts. Recurrence was identified in 2 Pattern A cases, indicating a potential issue with limited excisional specimens which may not fully appreciate the true biologic aggressiveness of the lesions.

Learning from crowds for automated histopathological image segmentation.

Automated semantic segmentation of histopathological images is an essential task in Computational Pathology (CPATH). The main limitation of Deep Learning (DL) to address this task is the scarcity of expert annotations. Crowdsourcing (CR) has emerged as a promising solution to reduce the individual (expert) annotation cost by distributing the labeling effort among a group of (non-expert) annotators. Extracting knowledge in this scenario is challenging, as it involves noisy annotations. Jointly learning the underlying (expert) segmentation and the annotators' expertise is currently a commonly used approach. Unfortunately, this approach is frequently carried out by learning a different neural network for each annotator, which scales poorly when the number of annotators grows. For this reason, this strategy cannot be easily applied to real-world CPATH segmentation. This paper proposes a new family of methods for CR segmentation of histopathological images. Our approach consists of two coupled networks: a segmentation network (for learning the expert segmentation) and an annotator network (for learning the annotators' expertise). We propose to estimate the annotators' behavior with only one network that receives the annotator ID as input, achieving scalability on the number of annotators. Our family is composed of three different models for the annotator network. Within this family, we propose a novel modeling of the annotator network in the CR segmentation literature, which considers the global features of the image. We validate our methods on a real-world dataset of Triple Negative Breast Cancer images labeled by several medical students. Our new CR modeling achieves a Dice coefficient of 0.7827, outperforming the well-known STAPLE (0.7039) and being competitive with the supervised method with expert labels (0.7723). The code is available at https://github.com/wizmik12/CRowd_Seg.

From principles to practice: Implementation of entrustable professional activities (EPAs) for surgical pathology residency education in a large academic hospital.

Over the past decade, competency-based medical education (CBME) has gained momentum in the United States to develop trainees into independent and confident physicians by the end of their training. Entrustable professional activities (EPAs) are an established methodology for assessing trainee development through an outcomes-driven rather than a time-based model. While EPAs have been utilized as an assessment tool for CBME in Europe and Canada, their validation and implementation in some medical specialties has occurred more recently in the United States. Pediatrics was the first specialty in the US to conduct a large-scale UME-GME pilot. Pathology Residency EPAs were published in 2018; however, implementation in training programs has been slow. We have piloted EPAs in our residency program's surgical pathology rotation and propose a unique set of 4 surgical pathology EPAs to track trainee preparedness for independent practice.

A novel 6-day cycle surgical pathology rotation improves resident satisfaction and maintains Accreditation Council for Graduate Medical Education (ACGME) milestone performance.

Surgical pathology residency training in the United States lags behind other specialties in quality control and graduated responsibility to train independent pathologists capable of seamlessly entering practice after training. We observed that our traditional 3-day-cycle surgical pathology cycle (day 1-grossing; day 2 -biopsies/frozens/preview; day 3 - sign-out) consistently and negatively impacted resident education by reducing preview time, case follow-up, immunohistochemical stain (IHC) interpretation, and molecular study integration. We aimed to create a modern surgical pathology rotation that improved performance and outcomes. We innovated our rotation to enhance resident education and ensure graduated responsibility. A novel 6-day cycle was created composed of 2 grossing days, 1 frozens/biopsies/preview days, 2 dedicated sign-out days, and 1 frozens/biopsies/case completion day. Residents completed surveys before implementing the new rotation and 6 months after implementation to track self-assessment of Accreditation Council for Graduate Medical Education (ACGME) milestone performance and internal quality control metrics. Clinical Competency Committee (CCC) annual evaluations were assessed in paired PGY levels pre- and post-intervention. After implementation, there was a statistically significant improvement in self-assessment of levels 4 and 5 of ACGME milestones and improved satisfaction of quality metrics, including time for previewing, reviewing IHC, graduated responsibility, and perceived readiness for independent practice. CCC evaluations showed overall maintained performance levels, with trends towards improvements in junior resident classes. Our 6-day cycle adequately fulfills the current demands of our sizeable academic center's surgical pathology training and can be a model for pathology residencies looking to modernize their surgical pathology rotations and resident education.

Alloimmunization Against RBC Antigens Is Not Associated With Decreased Survival in Liver Transplant Recipients.

BACKGROUND: Improvement of liver transplantation (LT) outcomes requires better understanding of factors affecting survival. The presence of RBC alloantibodies (RBCAs) on survival in LT recipients was evaluated. METHODS: This study was a single-center, retrospective cohort study reviewing transfusion records and all-cause mortality between 2002 and 2021. RESULTS: Between 2002 and 2021, 2079 LTs were completed, 1,396 of which met inclusion criteria (1,305 RBCA negative; 91 RBCA positive [6.5%]). The cohorts were similar in age (mean [range], 55.8 [17-79] years vs 56.8 [25-73] years; P = .41, respectively) or sex (RBCA negative, 859 [65%] men and 446 [35%] women vs RBCA positive, 51 [56%] men and 40 [44%] women; P = .0684). Of 132 RBCAs detected, 10 were most common were to E (27.27%), Jka (15.91%), K (9.09%), C (8.33%), M (6.06%), D (5.3%), Fya (4.55%), e (2.27%), c (2.27%), and Jkb (2.27%). Twenty-seven patients (29.7%) had more than 1 RBCA; the most common combinations were C with Jka (7.4%) and E with Dia (7.4%). All-cause mortality was increased in men (men, 14.45 years vs women, 17.27 years; P = .0266) and patients 65 years of age and older (≥65 years of age, 10.21 years vs <64 years of age, 17.22 years; P < .0001). The presence of RBCA (≥1) did not affect all-cause mortality (RBCA negative, 14.17 years vs RBCA positive, 15.29 years; P = .4367). The top 5 causes of death were infection (11.9%), primary malignancy (solid) (10.8%), recurrent malignancy (10.5%), cardiovascular arrest (7.1%), and pulmonary insufficiency/respiratory failure (5.7%). CONCLUSIONS: Survival in RBCA-positive LT recipients is no different from that in RBCA-negative LT recipients.

Primary HPV-Associated Enteric-Type Adenocarcinoma of Vagina: A Case Report.

Primary enteric type adenocarcinomas of the vagina are extremely rare. We present a 63-year-old woman who had a polypoid mass localized to the distal vagina. The lesion was composed of a columnar glandular cell proliferation with focal cribriforming, reminiscent of tubular adenoma. Immunohistochemical stains were notable for expression of enteric markers (CDX2 and KRT20), as well as negativity for Mullerian markers (PAX8, ER, and PR), diffuse expression for p16, and positivity for high-risk HPV mRNA expression. Ultimately, a diagnosis of vaginal primary HPV-associated enteric type adenocarcinoma was rendered for this unusual lesion. To our knowledge, no prior cases of HPV-associated enteric type adenocarcinomas of the vagina have been described before.

Neuroblastoma Arising in an Immature Teratoma of the Ovary in a 13-Year-Old.

Somatic malignancies arising in mature teratomas are exceedingly rare entities and even more so are those arising in immature teratomas. Here, we present a unique case of a 13-year-old who initially underwent ovarian sparing cystectomy for a 7.7 cm left ovarian mass with a pre-operative diagnosis of mature cystic teratoma. Histologically, all 3 germ cell layers were present and immature neuroepithelial tubules were also identified. Subsequent sections revealed a nodular lesion composed of neuropil, neuroblasts with a spectrum of maturation, and Schwannian-type stroma. The neuroblasts were diffusely positive for PHOX2B. Neuroblastoma arising in an immature teratoma has only been described in the literature once previously in an adult patient.

Loss of dystrophin is common in uterine leiomyosarcoma: a potential biomarker for clinical application.

Uterine leiomyosarcoma (LMS) is a deadly disease with high rates of recurrence and a poor prognosis. Its tumorigenesis remains largely unknown, and no specific biomarkers can be used for the differential diagnosis of LMS from other mimics. Recent whole-genome studies revealed a loss of dystrophin is common in LMS, especially in uterine LMS. To investigate the expression pattern of dystrophin expression across different types of uterine smooth muscle tumors, immunohistochemistry was performed, including usual-type leiomyoma, fumarate hydratase-deficient leiomyoma, leiomyoma with bizarre nuclei, conventional LMS, and normal myometrium for this study. To further evaluate the genomic change in dystrophin gene region, whole-genome sequencing in 10 LMS cases were analyzed. Dystrophin expression was detected in 94% (45/48) of myometrium, 97% (34/35) of usual-type leiomyoma, 84% (26/31) of fumarate hydratase-deficient leiomyoma, 60% (12/20) of leiomyoma with bizarre nuclei, and 18% (6/34) of LMS. Loss of dystrophin expression was significantly different between benign and malignant tumors (LMS cases counted as malignant only) (p < 0.01). Of note, copy number loss in the dystrophin genomic region was found in all 10 cases of LMS. Additionally, patients with dystrophin-positive LMS tend to have a better overall survival than patients with dystrophin-negative LMS.

Video-Based Education Improves Sampling (Grossing) Confidence in Pathology Trainees.

CONTEXT.­: Pathology resident education has a steep learning curve. Specimen sampling (grossing) is a procedural task, and procedural fields add video materials to their curricula to familiarize trainees with procedure(s), reduce errors, and improve patient care. Our team applied this strategy to develop original in-house sampling videos for our program. OBJECTIVES.­: To evaluate the effect of in-house sampling videos on resident sampling confidence. DESIGN.­: Sampling videos covering all major organ systems (AMOS) were created for our postgraduate year 1 (PGY1) trainees. Videos were hosted on a Northwestern cloud server for on-demand access. Trainees completed 3 surveys (0, 6, 12 months) evaluating sampling confidence comparing those who used in-house videos as an educational supplement with those who did not use the videos. RESULTS.­: Sampling confidence significantly improved at 6 and 12 months (P < .001) across AMOS and PGY levels. When compared with those who did not use in-house sampling videos, trainees who supplemented their education with in-house sampling videos had significantly higher confidence ratings across AMOS and PGY levels at the start of the study (P < .001) and at 6 months (P = .004). Sampling confidence significantly improved for PGY1 trainees at 6 and 12 months (P < .001); for PGY2 and PGY3 trainees, confidence significantly improved at 6 months (P < .001). When evaluated by organ-specific analyses, sampling and teaching confidence improved across all organ systems and, except for the gastrointestinal system, reached significance at 12 months for all PGY levels. CONCLUSIONS.­: Sampling videos, when used as a supplement to the existing curriculum, significantly improved trainee confidence.

Soft, bioresorbable coolers for reversible conduction block of peripheral nerves.

Implantable devices capable of targeted and reversible blocking of peripheral nerve activity may provide alternatives to opioids for treating pain. Local cooling represents an attractive means for on-demand elimination of pain signals, but traditional technologies are limited by rigid, bulky form factors; imprecise cooling; and requirements for extraction surgeries. Here, we introduce soft, bioresorbable, microfluidic devices that enable delivery of focused, minimally invasive cooling power at arbitrary depths in living tissues with real-time temperature feedback control. Construction with water-soluble, biocompatible materials leads to dissolution and bioresorption as a mechanism to eliminate unnecessary device load and risk to the patient without additional surgeries. Multiweek in vivo trials demonstrate the ability to rapidly and precisely cool peripheral nerves to provide local, on-demand analgesia in rat models for neuropathic pain.

Validation of the Milan system for reporting salivary gland cytopathology: a single institution's 10-year experience.

INTRODUCTION: Fine needle aspiration cytology is often used for the initial diagnosis and management of patients with salivary gland tumors. Because of its global usage, a consensus classification schema was devised in 2018 to initiate universal reporting of salivary gland cytology specimens, termed the Milan system for reporting salivary gland cytopathology (MSRSGC) and composed of distinct diagnostic categories. Few retrospective studies have been undertaken to review the MSRSGC within institutions. MATERIALS AND METHODS: We analyzed salivary gland fine needle aspirations during a 10-year span from 2011 to 2021, categorized each cytology case to fit the MSRSGC, and subsequently reviewed the corresponding surgical resections, if indicated, to determine the rate of malignancy (ROM) and rate of neoplasia. RESULTS: Our ROM was higher (>10%) for the following MSRSGC categories: non-neoplastic, atypia of undetermined significance, and suspicious for malignancy. Also, our data correlated well with the following MSRSGC categories: nondiagnostic, neoplasm-benign, salivary gland neoplasm of uncertain malignant, and malignant. CONCLUSIONS: Although the data were indicative of the ROM for surgically resected salivary gland lesions, the ROM for non-neoplastic lesions could truly be lower given that most lesions in this category will not undergo surgical resection. Additionally, determination of the rate of neoplasia could a tool that could be used to further guide our clinical colleagues.

Anaplasia and multinucleation in metastases of oropharyngeal squamous cell carcinoma is associated with poorer outcomes.

INTRODUCTION: The presence of tumor cell anaplasia and multinucleation (A/M) in oropharyngeal squamous cell carcinoma (OPSCC) has recently been found to be associated with increased disease recurrence and poorer disease-specific survival, regardless of human papillomavirus status. We studied the detection of A/M in cytology specimens. MATERIALS AND METHODS: We performed a comprehensive data search for all patients with OPSCC diagnosed and treated at Northwestern Memorial Hospital between January 2013 and April 2020. All cytology and histopathologic slides were reviewed for the presence of A/M in patients with both surgical resection or biopsy specimens and fine needle aspiration cytology of a metastatic site. RESULTS: A total of 87 patients were identified with both surgical and cytology specimens available for review. A/M was identified in 21 cytology specimens and 14 surgical specimens. Cytologic A/M was seen in 11 of the 14 patients (78.5%) with corresponding histologic A/M and in 10 of the 73 patients (13.7%) without histologic A/M. Disease-specific survival was significantly worse for the patients with cytologic A/M regardless of the presence of histologic A/M (P = 0.0064) and for the patients with cytologic A/M only (P = 0.0271). In patients with p16-positive/human papillomavirus-associated carcinoma, disease-specific survival was significantly worse for the patients with both histologic and cytologic A/M (P = 0.0305). CONCLUSIONS: A/M can be reliably identified in cytology specimens among all the various stains and preparations, irrespective of the primary tumor histologic type. Identification of A/M on cytology specimens could indicate more aggressive clinical behavior and help guide patient management.

Circulating ACE2-expressing extracellular vesicles block broad strains of SARS-CoV-2.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the pandemic of the coronavirus induced disease 2019 (COVID-19) with evolving variants of concern. It remains urgent to identify novel approaches against broad strains of SARS-CoV-2, which infect host cells via the entry receptor angiotensin-converting enzyme 2 (ACE2). Herein, we report an increase in circulating extracellular vesicles (EVs) that express ACE2 (evACE2) in plasma of COVID-19 patients, which levels are associated with severe pathogenesis. Importantly, evACE2 isolated from human plasma or cells neutralizes SARS-CoV-2 infection by competing with cellular ACE2. Compared to vesicle-free recombinant human ACE2 (rhACE2), evACE2 shows a 135-fold higher potency in blocking the binding of the viral spike protein RBD, and a 60- to 80-fold higher efficacy in preventing infections by both pseudotyped and authentic SARS-CoV-2. Consistently, evACE2 protects the hACE2 transgenic mice from SARS-CoV-2-induced lung injury and mortality. Furthermore, evACE2 inhibits the infection of SARS-CoV-2 variants (α, ß, and δ) with equal or higher potency than for the wildtype strain, supporting a broad-spectrum antiviral mechanism of evACE2 for therapeutic development to block the infection of existing and future coronaviruses that use the ACE2 receptor.

Clinical Characteristics and Outcomes of Patients With COVID-19-Associated Acute Respiratory Distress Syndrome Who Underwent Lung Transplant.

Importance: Lung transplantation is a potentially lifesaving treatment for patients who are critically ill due to COVID-19-associated acute respiratory distress syndrome (ARDS), but there is limited information about the long-term outcome. Objective: To report the clinical characteristics and outcomes of patients who had COVID-19-associated ARDS and underwent a lung transplant at a single US hospital. Design, Setting, and Participants: Retrospective case series of 102 consecutive patients who underwent a lung transplant at Northwestern University Medical Center in Chicago, Illinois, between January 21, 2020, and September 30, 2021, including 30 patients who had COVID-19-associated ARDS. The date of final follow-up was November 15, 2021. Exposures: Lung transplant. Main Outcomes and Measures: Demographic, clinical, laboratory, and treatment data were collected and analyzed. Outcomes of lung transplant, including postoperative complications, intensive care unit and hospital length of stay, and survival, were recorded. Results: Among the 102 lung transplant recipients, 30 patients (median age, 53 years [range, 27 to 62]; 13 women [43%]) had COVID-19-associated ARDS and 72 patients (median age, 62 years [range, 22 to 74]; 32 women [44%]) had chronic end-stage lung disease without COVID-19. For lung transplant recipients with COVID-19 compared with those without COVID-19, the median lung allocation scores were 85.8 vs 46.7, the median time on the lung transplant waitlist was 11.5 vs 15 days, and preoperative venovenous extracorporeal membrane oxygenation (ECMO) was used in 56.7% vs 1.4%, respectively. During transplant, patients who had COVID-19-associated ARDS received transfusion of a median of 6.5 units of packed red blood cells vs 0 in those without COVID-19, 96.7% vs 62.5% underwent intraoperative venoarterial ECMO, and the median operative time was 8.5 vs 7.4 hours, respectively. Postoperatively, the rates of primary graft dysfunction (grades 1 to 3) within 72 hours were 70% in the COVID-19 cohort vs 20.8% in those without COVID-19, the median time receiving invasive mechanical ventilation was 6.5 vs 2.0 days, the median duration of intensive care unit stay was 18 vs 9 days, the median post-lung transplant hospitalization duration was 28.5 vs 16 days, and 13.3% vs 5.5% required permanent hemodialysis, respectively. None of the lung transplant recipients who had COVID-19-associated ARDS demonstrated antibody-mediated rejection compared with 12.5% in those without COVID-19. At follow-up, all 30 lung transplant recipients who had COVID-19-associated ARDS were alive (median follow-up, 351 days [IQR, 176-555] after transplant) vs 60 patients (83%) who were alive in the non-COVID-19 cohort (median follow-up, 488 days [IQR, 368-570] after lung transplant). Conclusions and Relevance: In this single-center case series of 102 consecutive patients who underwent a lung transplant between January 21, 2020, and September 30, 2021, survival was 100% in the 30 patients who had COVID-19-associated ARDS as of November 15, 2021.

Histopathology of SPINK-1 Hereditary Pancreatitis.

Hereditary pancreatitis is a rare form of recurrent acute pancreatitis that typically has an onset in early adulthood. We report a rare case of hereditary pancreatitis in an individual with a serine protease inhibitor Kazal type 1 (SPINK1) mutation. Histologically the pancreas showed features of chronic pancreatitis with variable fibrosis, acinar destruction, and prominent inspissated secretions within the pancreatic ducts. Additionally, focal areas of low-grade pancreatic intraepithelial neoplasia (PanIN) were present. Although the histopathology of common gene mutations resulting in hereditary pancreatitis have been well described, the histopathology of pancreatitis secondary to SPINK1 mutation has been described in only one previous study.

TLR10 suppresses the activation and differentiation of monocytes with effects on DC-mediated adaptive immune responses.

TLRs are important pattern-recognition receptors involved in the activation of innate immune responses against foreign pathogens. TLR10 is the only TLR family member without a known ligand, signaling pathway, or clear cellular function. Previous work has shown that TLR10 suppresses proinflammatory cytokine production in response to TLR agonists in a mixed human mononuclear cell population. We report that TLR10 is preferentially expressed on monocytes and suppresses proinflammatory cytokine production resulting from either TLR or CD40 stimulation. TLR10 engagement affects both the MAPK and Akt signaling pathways, leading to changes in the transcriptome of isolated human monocytes. Differentiation of monocytes into dendritic cells in the presence of an αTLR10 mAb reduced the expression of maturation markers and the induction of proinflammatory cytokines, again in response to either TLR or CD40 stimulation. Finally, in coculture experiments, TLR10 differentiated dendritic cells exhibited a decreased capacity to activate T cells as measured by IL-2 and IFN-γ production. These data demonstrate that TLR10 is a novel regulator of innate immune responses and of the differentiation of primary human monocytes into effective dendritic cells.