Retained PAX2 expression associated with DNA mismatch repair deficiency in endometrial endometrioid adenocarcinoma.

AIMS: Loss of expression of tumour suppressor PAX2 and MMR deficiency (dMMR) has been frequently seen in endometrial endometrioid adenocarcinoma (EEC). However, the relationship between PAX2 expression and MMR status is unknown. METHODS AND RESULTS: We studied the PAX2 expression and examined its association with MMR status at the protein and genetic levels in 180 cases of EEC. Overall, total loss of PAX2 expression was found in about 70%, while retained PAX2 expression was seen in 30% of EEC. Among 125 cases with loss of PAX2, 68.8% were found in EECs with pMMR, while 31.2% were seen in those with dMMR. Among 55 cases of EECs with retained PAX2 expression, 92.7% were EECs with dMMR and 7.3% were those with pMMR (P < 0.001). While dMMR cases with MLH1 hypermethylation show almost equal retained or loss of PAX2 expression (52% versus 48%), dMMR with genetic alterations had significantly more retained PAX2 expression than loss of PAX2 (92.3% versus 7.7%), regardless of somatic or germline mutations. Loss of PAX2 was observed in 97.3% of dMMR with MLH1 hypermethylation compared to 2.7% of dMMR with genetic alterations (P < 0.001). Aggressive features such as higher tumour grades (FIGO 2-3) and advanced clinical stage (T2-T4) were significantly more frequently seen in dMMR with retained PAX2 expression, compared those to pMMR with loss of PAX2 expression. CONCLUSION: Our study demonstrates a close correlation between retained PAX2 expression and dMMR in EEC. The molecular mechanism and clinical significance linking these two pathways in EEC remains to be unravelled.

Validation Study of the Newly Proposed Refined Diagnostic Criteria for Malignant Phyllodes Tumor With 136 Borderline and Malignant Phyllodes Tumor Cases.

The World Health Organization (WHO) diagnostic criteria for malignant phyllodes tumor (MPT) may miss a significant number of MPTs with metastatic potential. New refined diagnostic criteria (Refined Criteria) for MPT were recently proposed. The aim of this study is to validate the Refined Criteria. This validation study included 136 borderline (borderline phyllodes tumor [BoPT]) and MPT cases that were not included in the initial study. We evaluated tumor classifications based on both the Refined Criteria and the WHO criteria. The Refined Criteria defines MPT when these criteria are met (1) stromal overgrowth with ≥ 1 feature(s) of marked stromal cellularity, marked stromal cytologic atypia, or ≥10 mitoses per 10 high-power fields (10 mitoses/10 HPFs) or (2) marked stromal cellularity with ≥1 feature(s) of marked stromal cytologic atypia, ≥10 mitoses/10 HPFs or permeative border. The WHO criteria require all 5 morphologic features (stromal overgrowth, permeative border, marked stromal cellularity, marked stromal cytologic atypia, and ≥10 mitoses/10 HPFs) for an MPT diagnosis. Using the Refined Criteria, none of the 61 BoPTs developed metastasis and 40.0% of the 75 MPTs developed metastases; local recurrence was seen in 11.5% BoPTs and 25.3% MPTs. Using the WHO criteria, 9.6% of the 94 BoPTs developed metastases and 50.0% of the 42 MPTs developed metastases; 14.9% of the BoPTs had local recurrence and 28.6% of the MPTs had local recurrence. Nine (30.0%) of the 30 tumors that developed distant metastases were diagnosed as BoPTs by the WHO criteria. When we combined the 75 MPTs from this validation cohort with the 65 MPT cases from the published data using the Refined Criteria, 50 (35.7%) of the 140 MPTs developed metastases, whereas 8 cases with metastases were <5 cm. In the univariate analysis with log-rank test, stromal overgrowth, marked stromal cellularity, marked stromal cytologic atypia, ≥10 mitoses/10 HPFs, presence of heterologous components other than liposarcomatous component, and presence of stromal necrosis were significantly associated with the risk of metastasis (all with P < 0.05). In multivariate analysis with Cox proportional hazard regression, stromal overgrowth and marked stromal cellularity were significantly associated with metastasis (both with P < 0.001). The Refined Criteria are superior to the WHO criteria in predicting the clinical outcomes of BoPTs and MPTs. Using the Refined Criteria, 35.7% of 140 patients with MPT developed metastases, whereas none (0%) of the patients with BoPT developed metastases. Patients with MPT have a high metastatic rate; these patients may benefit from systemic chemotherapy or targeted therapies. In contrast, patients with BoPT may be managed with complete local excision alone without chemotherapy.

Breast Cancer With HER2 Immunohistochemical Score 2 and Average HER2 Signals/Cell 6 or More and HER2/CEP17 Ratio Less Than 2 ('ISH Group 3'): A Multiinstitutional Cohort Analysis Emphasizing Outcome and Molecular Subtype.

Breast cancer (BC) with average human epidermal growth factor receptor 2 (HER2) signals/cell ≥6 and HER2/chromosome enumeration probe 17 (CEP17) ratio <2 (in situ hybridization [ISH] group 3) is very rare, accounting for 0.4% to 3.0% of cases sent for the dual-probe ISH assay. Although such patients are currently eligible for treatment with HER2-targeted therapy, their characteristics and outcomes remain poorly understood. Sixty-two BCs with equivocal HER2 immunohistochemical score (2+) and reflex ISH group 3 results were identified across 4 institutions. Available clinicopathologic characteristics, MammaPrint and BluePrint molecular results, and follow-up information were retrospectively analyzed. Most BCs with HER2 equivocal immunohistochemical and ISH group 3 results were histologic grade 2 or 3 (100%), estrogen receptor (ER) positive (90.3%), with an average HER2 signals/cell of 7.3. Molecular profiles revealed that 80% (16/20) of tumors were luminal subtypes, and HER2 molecular subtype was identified in 10% of tumors (2/20). Twelve (19.4%) out of 62 patients developed local recurrence and/or distant metastasis with a median follow-up of 50 months. One (10%) of 10 patients achieved pathologic complete response after neoadjuvant chemotherapy. Forty-nine (79%) out of 62 patients completed anti-HER2 agents, and exploratory analysis showed no statistically significant difference in disease outcomes between patients who completed anti-HER2 treatment and those who did not. Univariate analysis revealed advanced clinical stage, and ER/progesterone receptor negativity was associated with unfavorable disease outcomes, and exploratory multivariate analysis demonstrated that clinical stage was the most significant factor associated with disease outcomes in the studied population. These findings increase our understanding of this rare, but clinically important HER2 category. Large-scale prospective randomized studies are needed to further evaluate the role of perioperative HER2-targeted therapy in this patient population.

ABBV-319: a CD19-targeting glucocorticoid receptor modulator antibody-drug conjugate therapy for B-cell malignancies.

ABSTRACT: Glucocorticoids are key components of the standard-of-care treatment regimens for B-cell malignancy. However, systemic glucocorticoid treatment is associated with several adverse events. ABBV-319 is a CD19-targeting antibody-drug conjugate engineered to reduce glucocorticoid-associated toxicities while possessing 3 distinct mechanisms of action (MOA) to increase therapeutic efficacy: (1) antibody-mediated delivery of a glucocorticoid receptor modulator (GRM) payload to activate apoptosis, (2) inhibition of CD19 signaling, and (3) enhanced fragment crystallizable (Fc)-mediated effector function via afucosylation of the antibody backbone. ABBV-319 elicited potent GRM-driven antitumor activity against multiple malignant B-cell lines in vitro, as well as in cell line-derived xenografts and patient-derived xenografts (PDXs) in vivo. Remarkably, a single dose of ABBV-319 induced sustained tumor regression and enhanced antitumor activity compared with repeated dosing of systemic prednisolone at the maximum tolerated dose in mice. The unconjugated CD19 monoclonal antibody (mAb) also displayed antiproliferative activity in a subset of B-cell lymphoma cell lines through the inhibition of phosphoinositide 3-kinase signaling. Moreover, afucosylation of CD19 mAb enhanced Fc-mediated antibody-dependent cellular cytotoxicity. Notably, ABBV-319 displayed superior efficacy compared with afucosylated CD19 mAb in human CD34+ peripheral blood mononuclear cell-engrafted NSG-Tg(Hu-IL15) transgenic mice, demonstrating enhanced antitumor activity when multiple MOAs are enabled. ABBV-319 also showed durable antitumor activity across multiple B-cell lymphoma PDX models, including nongerminal center B-cell diffuse large B-cell lymphoma and relapsed lymphoma after R-CHOP treatment. Collectively, these data support the ongoing evaluation of ABBV-319 in a phase 1 clinical trial.

Ventral Hernia Reconstruction with GORE ENFORM Biomaterial.

Introduction: Ventral hernia repair (VHR) is one of the most common surgeries performed in the United States. Degradable mesh is the recommended choice for patients presenting with high-risk co-morbidities or increased risk for infection. GORE® ENFORM BiomaterialTM is a biosynthetic degradable mesh that has recently been approved for use in ventral hernia reconstruction with no reports of its clinical outcomes. Methods: This study was a single surgeon case series. Patients were included in the study if they underwent VHR with GORE® ENFORM BiomaterialTM. The decision to use GORE® ENFORM BiomaterialTM was the senior surgeon's decision based on the patient's center for disease control classification. Patient comorbidities, hernia characteristics, postoperative hernia recurrence, and surgical site occurrences (SSOs) were collected at in-patient follow-up appointments and chart review. Patients were asked to complete preoperative and postoperative patient-reported outcomes (PROs) using the Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Intensity short form 3a and the hernia-specific quality of life (HerQLes) survey. Results: A total of 15 patients were included in this study. The average length of follow-up was 315 days. Postoperatively, 26.7% of patients had an SSO with 4 surgical site infections. Two patients required an operative washout with mesh removal. One patient experienced hernia recurrence. Eight of the 15 patients completed preoperative and postoperative PROs. Conclusion: This is the first clinical study to report the outcomes of ventral hernia repair using ENFORM mesh. These results show that Enform mesh is an option to consider in complex ventral hernia reconstruction.

Introduction: La réparation d'une hernie ventrale (RHV) est l'une des opérations les plus fréquentes aux États-Unis. Le treillis dégradable est le choix recommandé pour les patients ayant des affections connexes à haut risque ou qui sont vulnérables aux infections. Le biomatériau GORE® ENFORM est un treillis biosynthétique dégradable qui a récemment été approuvé pour la reconstruction des hernies ventrales et dont les résultats cliniques n'ont fait l'objet d'aucun rapport. Méthodologie : La présente étude était constituée d'une série de cas réalisée par un seul chirurgien. Les patients étaient inclus dans l'étude s'ils avaient subi une RHV à l'aide de biomatériau GORE® ENFORM. Le chirurgien en chef prenait la décision d'utiliser ce biomatériau d'après la classification du contrôle des maladies au centre du patient. Les chercheurs ont colligé les affections connexes du patient, les caractéristiques de la hernie, les récurrences de hernie postopératoire et les occurrences au foyer de l'opération (OFO) lors des rendez-vous de suivi et de l'examen des dossiers. Les patients ont été invités à préciser leurs résultats préopératoires et postopératoires (RPP) au moyen du formulaire court 3a sur l'intensité de la douleur tiré du système d'information des mesures de résultats déclarés par le patient (PROMIS) et du sondage sur la qualité de vie propre à la hernie (HerQLes). Résultats : Au total, 15 patients ont participé à l'étude et ont été suivis pendant une durée moyenne de 315 jours. Après l'opération, 26,7% des patients ont présenté une OFO ainsi que quatre infections au foyer de l'opération. Deux patients ont eu besoin d'un lessivage opératoire et du retrait du treillis. Un patient a subi une récurrence de la hernie. Huit des 15 patients ont rempli les RDP avant et après l'opération. Conclusion : Il s'agit de la première étude clinique à déclarer les résultats cliniques de la réparation d'une hernie ventrale à l'aide du treillis ENFORM. Ces résultats démontrent que le treillis Enform peut être envisagé pour la reconstruction d'une hernie ventrale complexe.

Identifying Barriers Faced by Applicants without a Home Residency Program when Matching into Plastic Surgery.

Background Applying into plastic surgery (PS) is competitive. Lacking a home residency program (HRP) is another barrier. Our goal is to characterize challenges faced by PS applicants without HRPs and identify solutions. Methods Surveys were designed for current integrated PS residents and applicants in the 2022 Match without HRPs. Surveys were distributed electronically. Only U.S. allopathic graduate responses were included. Results Of 182 individuals surveyed, 74 responded (39%, 33 residents, 41 applicants). Sixty-six percent reported feeling disadvantaged due to lack of an HRP. Seventy-six percent of applicants successfully matched. Of these, 48% felt they required academic time off (research year) versus 10% of unmatched applicants. Ninety-seven percent of matched applicants identified a mentor versus 40% of unmatched applicants ( p < 0.05). Matched applicants identified mentors through research (29%) and cold calling/emailing (25%). Matched versus unmatched applicants utilized the following resources: senior students (74 vs. 10%, p < 0.05) and social media (52 vs. 10%, p < 0.05). Among residents, 16 had PS divisions (48%). Thirty-six percent with divisions felt they had opportunities to explore PS, compared with 12% without divisions. Residents without divisions felt disadvantaged in finding research (94 vs. 65%, p < 0.05), delayed in deciding on PS (50 vs. 28%), and obtaining mentors (44 vs. 35%) and letters of recommendation (31 vs. 24%). Conclusion PS residents and applicants without HRPs reported feeling disadvantaged when matching. The data suggest that access to departments or divisions assists in matching. We identified that external outreach and research were successful strategies to obtain mentorship. To increase awareness for unaffiliated applicants, we should increase networking opportunities during local, regional, and national meetings.

p300 is an obligate integrator of combinatorial transcription factor inputs.

Transcription coactivators are proteins or protein complexes that mediate transcription factor (TF) function. However, they lack DNA-binding capacity, prompting the question of how they engage target loci. Three non-exclusive hypotheses have been posited: coactivators are recruited by complexing with TFs, by binding histones through epigenetic reader domains, or by partitioning into condensates through their extensive intrinsically disordered regions. Using p300 as a prototypical coactivator, we systematically mutated its annotated domains and show by single-molecule tracking in live U2OS cells that coactivator-chromatin binding depends entirely on combinatorial binding of multiple TF-interaction domains. Furthermore, we demonstrate that acetyltransferase activity opposes p300-chromatin association and that the N-terminal TF-interaction domains regulate that activity. Single TF-interaction domains are insufficient for chromatin binding and regulation of catalytic activity, implying a principle that we speculate could broadly apply to eukaryotic gene regulation: a TF must act in coordination with other TFs to recruit coactivator activity.

Solitary Fibrous Tumor of Breast and Axilla: Clinicopathological Profile of Five Tumors With Comparison of Risk Stratification Models.

Introduction: Solitary fibrous tumor (SFT) is a fibroblastic tumor with malignant potential that is underpinned by a recurrent inv12(q13q13)-derived NAB2::STAT6 fusion. Breast and axilla are uncommon locations for this entity. Methods: Records of two academic institutions were electronically searched for breast and axillary SFTs. Clinical and pathologic data were reviewed. Literature review for breast or axillary SFTs was performed. Present study and previously reported tumors were stratified using five SFT risk models: original and modified Demicco metastatic risk, Salas local recurrence risk, Salas metastatic risk, and Thompson local recurrence risk. Results: Five patients with breast or axillary SFT were identified. Median age was 49 years, and median follow-up (available for four patients) was 82 months. Three patients showed no evidence of disease, and one developed recurrence. Literature review identified 58 patients with breast or axillary SFT. Median age was 54 years, and median follow-up (available for 35 patients) was 24 months. Thirty-one patients showed no evidence of disease, three developed recurrence, and one developed metastasis. Original and modified Demicco models and Thompson model showed the highest sensitivity; original and modified Demicco models and Salas metastatic risk model demonstrated the highest specificity. Kaplan-Meier models were used to assess recurrence-free probability (RFP). Original and modified Demicco models predicted RFP when stratified by "low risk" and "moderate/intermediate and high risk" tumor, though sample size was small. Conclusions: While many SFTs of breast and axilla remain indolent, a subset may develop recurrence and rarely metastasize. The modified Demicco risk model demonstrated optimal performance characteristics.

Comprehensive Clinical-Pathologic Assessment of Malignant Phyllodes Tumors: Proposing Refined Diagnostic Criteria.

The latest World Health Organization classification of breast tumors recommends diagnosing malignant phyllodes tumors (MPTs) when all 5 morphologic features are present: permeative borders, marked stromal cellularity, marked stromal cytologic atypia, ≥10 mitoses per 10 high-power fields (HPF), and stromal overgrowth. We assessed the performance of this recommendation to capture MPTs and features predictive of distant metastasis in a multi-institutional retrospective study. Of 65 MPTs, most cases had at least focally permeative borders (58, 89%), with marked stromal cellularity in 40 (61.5%), marked atypia in 38 (58.5%), ≥10 mitoses per 10 HPF in 50 (77%), and stromal overgrowth in 56 (86%). Distant metastases were observed in 20 (31%) patients (median follow-up 24.5 mo, 1 to 204). Only 13 of 65 (20%) cases had all 5 morphologic features, while only 7 of 20 (35%) cases with distant metastases had all 5 features. In univariate analysis, only marked stromal atypia ( P =0.004) and cellularity ( P =0.017) were associated with decreased distant metastasis-free survival. In multivariate Cox regression, the combination of stromal overgrowth, marked stromal cellularity, and atypia (C-index 0.721, 95% CI: 0.578, 0.863) was associated with decreased distant metastasis-free survival. The current World Health Organization recommendation will miss a significant number of MPTs with distant metastases. We propose refined diagnostic criteria for MPTs: (1) stromal overgrowth combined with ≥1 feature(s) (marked cellularity, marked atypia, or ≥10 mitoses per 10 HPF), or (2) in the absence of stromal overgrowth, marked cellularity combined with ≥1 feature(s) (permeative borders, marked atypia, or ≥10 mitoses per 10 HPF).

Mendelian randomization analysis revealed potential metabolic causal factors for breast cancer.

Observational studies showed that metabolic phenotypes were associated with the risk of developing breast cancer (BC). However, those results are inconsistent regarding the magnitude of the association, particularly by subtypes of breast cancer. Furthermore, the mechanisms of the association remain unclear. We performed two-sample Mendelian randomization (MR) analyses to evaluate the causal effect of metabolic risk factors on breast cancer in the European population. Assessed individually using MR, body mass index (BMI) (odds ratio [OR] 0.94, 95% Confidence interval [CI] 0.90-0.98, P = 0.007), high-density lipoprotein cholesterol (HDL-C) (OR 1.10, 95% CI 1.07-1.13, P = 6.10 × 10-11) and triglycerides (TG) (OR 0.92, 95% CI 0.90-0.96, P = 1.58 × 10-6) were causally related to breast cancer risk. In multivariable MR, only HDL-C (OR 1.08; 95% CI 1.02-1.14; P = 0.02) retained a robust effect, suggesting that the genetic association between BMI, HDL-C and TG with breast cancer risk in univariable analysis was explained via HDL-C. These findings suggest a possible causal role of HDL-C in breast cancer etiology.

Management of Complex Hand and Wrist Ligament Injuries.

Ligamentous injuries in the hand and wrist are often underdiagnosed and can present with significant functional limitations if there is untimely recognition of injury. Adequate repair or reconstruction is critical in restoring joint stability and mobility. The purpose of this review is to provide an overview of the metacarpophalangeal joint, scapholunate interosseous ligament (SLIL), and non-SLIL carpal ligament anatomy, diagnosis, imaging, treatment consideration and options, as well as surgical techniques encompassing repair, reconstruction, and fusion.

p300 Is an Obligate Integrator of Combinatorial Transcription Factor Inputs.

Transcription coactivators are proteins or protein complexes that mediate transcription factor (TF) function. However, they lack DNA binding capacity, prompting the question of how they engage target loci. Three non-exclusive hypotheses have been posited: coactivators are recruited by complexing with TFs, by binding histones through epigenetic reader domains, or by partitioning into phase-separated compartments through their extensive intrinsically disordered regions (IDRs). Using p300 as a prototypical coactivator, we systematically mutated its annotated domains and show by single-molecule tracking in live cells that coactivator-chromatin binding depends entirely on combinatorial binding of multiple TF-interaction domains. Furthermore, we demonstrate that acetyltransferase activity negatively impacts p300-chromatin association and that the N-terminal TF-interaction domains regulate that activity. Single TF-interaction domains are insufficient for both chromatin binding and regulation of catalytic activity, implying a principle that could broadly inform eukaryotic gene regulation: a TF must act in coordination with other TFs to recruit coactivator activity.

Association Between Hospital Monopoly Status, Patient Socioeconomic Disadvantage, and Total Joint Arthroplasty Price Disclosure.

INTRODUCTION: In recent years, healthcare institutions and regulatory bodies have enacted cost transparency mandates for routine interventions such as total hip arthroplasty and total knee arthroplasty. However, disclosure rates remain low. This study examined the effect of financial characteristics of hospitals and the socioeconomic status of patients on price disclosure. METHODS: Hospitals conducting total hip arthroplasty/total knee arthroplasty, their quality ratings, and procedural volumes were identified using the Leapfrog Hospital Survey and linked to procedure-specific prices. Financial performance and the Area Deprivation Index (ADI) were used to correlate disclosure rates with hospital and patient characteristics. Hospital financial, operational, and patient summary statistics were compared by price-disclosure status using two-sample t -tests for continuous variables and Pearson chi-square test for categorical variables. The association between total joint arthroplasty price disclosure and hospital ADI was further evaluated using modified Poisson regression. RESULTS: A total of 1,425 hospitals certified by the Centers for Medicare & Medicaid Services were identified in the United States. 50.5% (n = 721) of hospitals had no published payer-specific price information. Hospitals in an area of higher socioeconomic disadvantage were more likely to disclose prices of total joint arthroplasty (incidence rate ratio = 0.966, 95% CI: 0.937 to 0.995, P = 0.024). Hospitals that were considered monopolies or were for-profit were less likely to disclose prices (IRR = 1.15, 95% CI: 1.030 to 1.280, P = 0.01; IRR = 1.256, 95% CI: 0.986 to 1.526, P = 0.038, respectively). When accounting for both ADI and monopoly status, hospitals with patients who had a higher ADI were more likely to disclose costs for a total joint arthroplasty, whereas for-profit hospitals or hospitals considered monopolies in their HSA were less likely to disclose prices. DISCUSSION: For nonmonopoly hospitals, a higher ADI correlated with a higher likelihood of price disclosure. However, for monopoly hospitals, there was no significant association between ADI and price disclosure. LEVEL OF EVIDENCE: II.

Closed reduction of nasoseptal fractures: key concepts for predictable results.

Nasal complex injuries are the most common facial fracture encountered in the trauma population. Multiple surgical techniques for treatment of these fractures have been described with varying results. The goal of this study was to review the efficacy of closed reduction of nasal and septal fractures using a technique based upon several key concepts. We reviewed the records of patients who had undergone isolated nasal and/or septal fractures with closed reduction at our institution between January 2013 and November 2021. Inclusion criteria consisted of preoperative CT imaging, surgical treatment within fourteen days of initial injury, and follow up of at least one year. All patients were treated under general or deep sedation. The same surgical technique was applied with closed reduction of the septum and nasal bones with internal and external postoperative splints. Of the 232 records initially reviewed, 103 met inclusion criteria. Four patients had undergone revision septorhinoplasty (3.9%). Mean (range) follow up was 2.7 (1-8.2) years. Three patients had undergone revision nasal repair due to persistent airflow obstruction with complete resolution of symptoms after revision. The other patient received multiple revisions at another institution as a result of their dissatisfaction with cosmesis without improvement. Closed reduction of nasal and septal fractures can be a highly successful procedure and yield predictable results, limiting the need for post-traumatic open septorhinoplastic surgery. Five critical concepts of nasal fracture repair can help surgeons achieve predictable functional and cosmetic results: selection, timing, anaesthesia, reduction, and support.

Creation of an asynchronous faculty development curriculum on well-written narrative assessments that avoid bias.

BACKGROUND: The COVID-19 pandemic in parallel with concerns about bias in grading resulted in many medical schools adopting pass/fail clinical grading and relying solely on narrative assessments. However, narratives often contain bias and lack specificity. The purpose of this project was to develop asynchronous faculty development to rapidly educate/re-educate > 2000 clinical faculty spread across geographic sites and clinical disciplines on components of a well-written narrative and methods to minimize bias in the assessment of students. METHODS: We describe creation, implementation, and pilot data outcomes for an asynchronous faculty development curriculum created by a committee of volunteer learners and faculty. After reviewing the literature on the presence and impact of bias in clinical rotations and ways to mitigate bias in written narrative assessments, the committee developed a web-based curriculum using multimedia learning theory and principles of adult learning. Just-in-time supplemental materials accompanied the curriculum. The Dean added completion of the module by 90% of clinical faculty to the department chairperson's annual education metric. Module completion was tracked in a learning management system, including time spent in the module and the answer to a single text entry question about intended changes in behavior. Thematic analysis of the text entry question with grounded theory and inductive processing was used to define themes of how faculty anticipate future teaching and assessment as a result of this curricula. OUTCOMES: Between January 1, 2021, and December 1, 2021, 2166 individuals completed the online module; 1820 spent between 5 and 90 min on the module, with a median time of 17 min and an average time of 20.2 min. 15/16 clinical departments achieved completion by 90% or more faculty. Major themes included: changing the wording of future narratives, changing content in future narratives, and focusing on efforts to change how faculty teach and lead teams, including efforts to minimize bias. CONCLUSIONS: We developed a faculty development curriculum on mitigating bias in written narratives with high rates of faculty participation. Inclusion of this module as part of the chair's education performance metric likely impacted participation. Nevertheless, time spent in the module suggests that faculty engaged with the material. Other institutions could easily adapt this curriculum with provided materials.

Low-grade adenosquamous carcinoma of the breast: a clinical, morphological and immunohistochemical analysis of 25 patients.

AIMS: Due to its rarity and non-specific clinical and pathological features, low-grade adenosquamous carcinoma (LGASC) of the breast continues to pose diagnostic challenges. Unlike other triple-negative breast carcinomas, LGASC tends to have an indolent clinical behaviour. It is essential to recognise this lesion for accurate diagnosis and appropriate management. METHODS AND RESULTS: Twenty-five cases of LGASC were identified in our archives and collaborating institutes. Cases of LGASC with dominant coexisting other type carcinomas were excluded. We studied the clinical presentation, morphological features, patterns of the commonly used immunohistochemical stains and follow-up. In our cohort, LGASC was commonly located at the outer aspect of the breast and associated with intraductal papilloma. The morphology of LGASC is characterised by infiltrating small glands and nests with variable squamous differentiation. We also found cuffing desmoplastic (fibrolamellar) stromal change in 75% of patients and peripheral lymphocytic aggregates in 87.5% of patients. P63 and smooth muscle myosin (SMM) were the most common myoepithelial markers used to assist in diagnosis. P63 often stained peripheral tumour cells surrounding invasive glands (circumferential staining in 80% of the cases), mimicking myoepithelial cells. It also stained the small nests with squamous differentiation. However, SMM was negative in 63% of the cases. The vast majority of our cases were triple-negative; only a few had focal and weak expressions of ER and PR. One patient who did not have excision developed lymph node metastasis. Most patients underwent excision or mastectomy with negative margins as surgical treatment; there were no recurrences or metastases in these patients with clinical follow-ups up to 108 months. CONCLUSIONS: LGASC has some unique, although not entirely specific, morphological features and immunohistochemical staining patterns. Fibrolamellar stromal change, peripheral lymphocytic aggregates and variable staining of p63 and SMM are valuable features to facilitate the diagnosis.

Biased precursor ingression underlies the center-to-pole pattern of male sex determination in mouse.

During mammalian development, gonadal sex determination results from the commitment of bipotential supporting cells to Sertoli or granulosa cell fates. Typically, this decision is coordinated across the gonad to ensure commitment to a single organ fate. When unified commitment fails in an XY mouse, an ovotestis forms in which supporting cells in the center of the gonad typically develop as Sertoli cells, while supporting cells in the poles develop as granulosa cells. This central bias for Sertoli cell fate was thought to result from the initial expression of the drivers of Sertoli cell fate, SRY and/or SOX9, in the central domain, followed by paracrine expansion to the poles. However, we show here that the earliest cells expressing SRY and SOX9 are widely distributed across the gonad. In addition, Sertoli cell fate does not spread among supporting cells through paracrine relay. Instead, we uncover a center-biased pattern of supporting cell precursor ingression that occurs in both sexes and results in increased supporting cell density in the central domain. Our findings prompt a new model of gonad patterning in which a density-dependent organizing principle dominates Sertoli cell fate stabilization.

Regional anesthesia improves inpatient but not outpatient opioid demand in tibial shaft fracture surgery.

BACKGROUND: Patients undergoing operative treatment of tibial shaft fractures have considerable pain largely managed with opioids. Regional anesthesia (RA) has been increasingly used to reduce perioperative opioid use. METHODS: This was a retrospective study of 426 patients that underwent operative treatment of tibial shaft fractures with and without RA. Inpatient opioid consumption and 90-day outpatient opioid demand were measured. RESULTS: RA significantly decreased inpatient opioid consumption for 48 h post-operatively (p = 0.008). Neither inpatient use after 48 h nor outpatient opioid demand differed in patients with RA (p > 0.05). CONCLUSIONS: RA may help with inpatient pain control and reduce opioid use in tibial shaft fracture. LEVEL OF EVIDENCE: Level III, retrospective, therapeutic cohort study.

Consequences and Predictors of Prolonged Tissue Expander Duration in Breast Reconstruction.

BACKGROUND: Tissue expanders (TEs) are temporary devices used in breast reconstruction, which are generally removed within 1 year. There is a paucity of data regarding the potential consequences when TEs have longer indwelling times. Thus, we aim to determine whether prolonged TE implantation length is associated with TE-related complications. METHODS: This is a single-center retrospective review of patients who underwent TE placement for breast reconstruction from 2015 to 2021. Complications were compared between patients who had a TE for >1 year and <1 year. Univariate and multivariate regressions were used to evaluate predictors of TE complications. RESULTS: A total of 582 patients underwent TE placement and 12.2% had the expander for >1 year. Adjuvant chemoradiation, body mass index (BMI), overall stage, and diabetes predicted the duration of TE placement (p ≤ 0.006). Rate of return to the operating room was higher in patients who had TEs in place >1 year (22.5 vs 6.1%, p < 0.001). On multivariate regression, prolonged TE duration predicted an infection requiring antibiotics, readmission, and reoperation (p < 0.001). Reasons for longer indwelling times included need for additional chemoradiation (79.4%), TE infections (12.7%), and requesting a break from surgery (6.3%). CONCLUSION: Indwelling TEs for >1 year are associated with higher rates of infection, readmission, and reoperation even when controlling for adjuvant chemoradiation. Patients with diabetes, a higher BMI, advanced cancer stage, and those requiring adjuvant chemoradiation should be advised they may require a TE for a longer time interval prior to final reconstruction.

Variations in Incidence of Trigger Finger and Response to Corticosteroid Injection after Aromatase Inhibitor Therapy for Breast Cancer.

BACKGROUND: Aromatase inhibitors (AIs), such as letrozole and anastrozole, have been demonstrated to have significant musculoskeletal symptoms in patients. The purpose of this study was to evaluate the effect of specific AI medications on the incidence of trigger finger and independent factors affecting treatment outcomes within this population. METHODS: A retrospective chart review was performed at the authors' institution between the years 2014 and 2018 in patients with the diagnosis of breast cancer. This cohort was then sorted based on receiving medication regimens, trigger finger diagnosis, steroid injections, and need for surgical release of trigger finger. RESULTS: A total of 15,144 patients were included for initial review. The overall rate of trigger finger diagnosis was 2.75% in the entire breast cancer population and 4.5% for patients receiving AI therapy. Patients taking letrozole and anastrozole had an increased odds ratio of 2.0 and 1.7, respectively, for developing trigger finger. Patients who switched between letrozole and anastrozole during treatment had a higher rate of failed steroid injection treatment (45.2% versus 23.5%; P = 0.021). Among patients receiving AI treatment diagnosed with trigger finger, diabetes and hemoglobin A1c level greater than 6.5 were associated with significantly increased rates of failed steroid therapy. CONCLUSIONS: Patients receiving AI therapy have an increased incidence of trigger finger. The outcomes of treatment are equivalent between AI and non-AI trigger finger populations. However, steroid therapy is more likely to fail in patients who require switching of regimens because of significant musculoskeletal symptoms. Poorly controlled diabetes was also an independent factor for compromised steroid treatment of trigger finger. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.