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.

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.

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

Glucocorticoids are key components of the current standard-of-care regimens (e.g., R-CHOP, EPOCH-R, Hyper-CVAD) for treatment of B-cell malignancy. However, systemic glucocorticoid treatment is associated with several adverse events. CD19 displays restricted expression in normal B-cells and is up-regulated in B-cell malignancies. ABBV-319 is a CD19-targeting antibody-drug conjugate (ADC) engineered to reduce glucocorticoid-associated toxicities while possessing three distinct mechanisms of action (MOA) to increase therapeutic efficacy: (1) antibody-mediated delivery of glucocorticoid receptor modulator (GRM) payload to activate apoptosis, (2) inhibition of CD19 signaling, and (3) enhanced Fc-mediated effector function via afucosylation of the antibody backbone. ABBV-319 elicited potent GRM-driven anti-tumor activity against multiple malignant B-cell lines in vitro as well as in cell line-derived xenografts (CDXs) and patient-derived xenografts (PDXs) in vivo. Remarkably, a single-dose of ABBV-319 induced sustained tumor regression and enhanced anti-tumor activity compared to repeat dosing of systemic prednisolone at the maximum tolerated dose (MTD) in mice. The unconjugated CD19 monoclonal antibody (mAb) also displayed anti-proliferative activity on a subset of B-cell lymphoma cell lines through the inhibition of PI3K signaling. Moreover, afucosylation of the CD19 mAb enhanced Fc-mediated antibody-dependent cellular cytotoxicity (ADCC), and this activity was maintained after conjugation with GRM payloads. Notably, ABBV-319 displayed superior efficacy compared to afucosylated CD19 mAb in human CD34+ PBMC-engrafted NSG-tg(Hu-IL15) transgenic mice, demonstrating enhanced anti-tumor activity when multiple MOAs are enabled. ABBV-319 also showed durable anti-tumor activity across multiple B-cell lymphoma PDX models, including non-germinal center B-cell (GCB) DLBCL and relapsed lymphoma post R-CHOP treatment. Collectively, these data support the ongoing evaluation of ABBV-319 in Phase I clinical trial (NCT05512390).

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.

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.

The Impact of Hearing Loss and Its Treatment on Health-Related Quality of Life Utility: a Systematic Review with Meta-analysis.

BACKGROUND: Hearing loss significantly impacts health-related quality of life (QoL), yet the effects of current treatments on QoL utility remain uncertain. Our objective was to describe the impact of untreated and treated hearing loss on QoL utility to inform hearing healthcare policy. METHODS: We searched databases for articles published through 02/01/2021. Two independent reviewers screened for articles that reported elicitation of general QoL utility values for untreated and treated hearing loss health states. We extracted data and quality indicators from 62 studies that met the inclusion criteria. RESULTS: Included studies predominately used observational pre/post designs (61%), evaluated unilateral cochlear implantation (65%), administered the Health Utilities Index 3 (HUI3; 71%), and were conducted in Europe and North America (84%). In general, treatment of hearing loss improved post-treatment QoL utility when measured by most methods except the Euro-QoL 5 dimension (EQ-5D). In meta-analysis, hearing aids for adult mild-to-moderate hearing loss compared to no treatment significantly improved HUI3-estimated QoL utility (3 studies; mean change=0.11; 95% confidence interval (CI): 0.07 to 0.14) but did not impact EQ-5D-estimated QoL (3 studies; mean change=0.0; 95% CI: -0.03 to 0.04). Cochlear implants improved adult QoL utility 1-year post-implantation when measured by the HUI3 (7 studies; mean change=0.17; 95% CI: 0.11 to 0.23); however, pediatric VAS-estimated QoL utility was non-significant (4 studies; mean change=0.12; 95% CI: -0.02 to 0.25). The quality of included studies was limited by failure to report missingness of data and low survey response rates. Our study was limited by heterogeneous study populations and designs. FINDINGS: Treatment of hearing loss significantly improves QoL utility, and the HUI3 and VAS were most sensitive to improvements in hearing. Improved access to hearing healthcare should be prioritized. SYSTEMATIC REVIEW REGISTRATION: PROSPERO: CRD42021253314.

Integrating Mental and Social Health in Orthopaedic Practice: The Time Is Now.

Tremendous advances have been made in understanding the intimate relationships between physical, emotional, and social health. There is now a substantial body of evidence demonstrating that mental health and social health may have as much influence on patients' symptom intensity and level of capability-the key metrics of success in orthopaedic care-as pathophysiology. But as a specialty the focus remains mostly on biomedical management (which focuses on structural damage and technical solutions), rather than taking a biopsychosocial approach, which involves screening, measurement, and decision making that prioritizes mental and social health concerns. Failure to do so means orthopaedic surgeons fall short in delivering whole-person care. It is important to highlight the biopsychosocial model of health and healthcare; describe the evidence for mental and social health in orthopaedic practice; outline strategies to identify, measure, and manage psychological and social concerns; and provide frameworks to implement comprehensive models of orthopaedic care that promise to benefit patients, populations, and health systems.

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.

Pyrocarbon hemiarthroplasty of the shoulder: a systematic review and meta-analysis of clinical results.

BACKGROUND: Hemiarthroplasty is often considered in the setting of preserved glenoid cartilage given the high risk of revision associated with total shoulder arthroplasty. Pyrocarbon (PyC) has been used as an implant material that theoretically allows for formation of a neo-membrane that would act like cartilage to reduce glenoid wear. The purpose of this study was to evaluate the clinical outcomes, radiographic outcomes, revision rates, and complication rates in the existing literature on shoulder hemiarthroplasty using PyC. METHODS: The MEDLINE, Embase, and Scopus databases were searched for articles relating to shoulder hemiarthroplasty using the terms "pyrocarbon" or "pyrolytic carbon." Abstracts and articles were screened against predefined inclusion and exclusion criteria, with a minimum of 24 months' follow-up required. Data on patient demographic characteristics, clinical outcome scores, complications, revision rates, and radiographic findings were recorded. Where appropriate, meta-analysis was performed. RESULTS: Twelve studies were selected for final inclusion, with a total of 536 patients. Among the studies reporting preoperative and postoperative range of motion (ROM), an overall improvement in ROM was observed. The mean Constant score was 70.9 points postoperatively, with a mean improvement of 36.2 points (n = 359, 9 studies). Radiographically, 22.8% of patients (n = 536, 8 studies) had evidence of glenoid erosion, 10.4% had changes in implant positioning, and 9.9% had tuberosity thinning. In addition, 1.5% of patients had radiographic subacromial space reduction, whereas 0.7% had an increase in tuberosity thickness. Across all studies, there was an 8.6% complication rate, with the most common cause being glenoid erosion (2.6%, n = 14). There was an overall 7.7% revision rate (n = 41), with 63% of revisions (n = 26) undergoing conversion to reverse or total shoulder arthroplasty. CONCLUSION: PyC hemiarthroplasty shows overall improvements in ROM and patient-reported outcomes for patients. However, there remains concern for glenoid erosion on radiographic evaluation at minimum 2-year follow-up. Although preliminary studies have shown encouraging results, this systematic review emphasizes the need for longer-term follow-up studies with further radiographic evaluation of the severity of glenoid erosion and the association with functional outcomes and failure risk.

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.

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.

Regional Anesthesia Associated With Decreased Inpatient and Outpatient Opioid Demand in Tibial Plateau Fracture Surgery.

BACKGROUND: Regional anesthesia (RA) has been used to reduce pain and opioid usage in elective orthopedic surgery. The hypothesis of this study was that RA would be associated with decreased opioid demand in tibial plateau fracture surgery. METHODS: Inpatient opioid consumption and 90-day outpatient opioid prescribing in all patients ≥18 years of age undergoing tibial plateau fracture surgery from July 2013 to July 2018 (n = 264) at a single, level I trauma center were recorded. The presence or absence of perioperative RA was noted. Of 60 patients receiving RA, 52 underwent peripheral nerve blockade (PNB) with single-shot sciatic-popliteal (40.0%; n = 24), femoral (26.7%; n = 16), adductor canal (18.3%; n = 11), or fascia iliaca (1.7%; n = 1) block with ropivacaine. Ten patients received epidural analgesia (EA) with either single-shot spinal (11.7%; n = 7) blocks or continuous epidural (5.0%; n = 3). Additional baseline and treatment characteristics were recorded, including age, sex, race, body mass index (BMI), smoking, chronic opioid use, American Society of Anesthesiologists (ASA) score, injury mechanism, additional injuries, open injury, and additional inpatient surgery. Statistical models, including multivariable generalized linear models with propensity score weighting to adjust for baseline patient and treatment characteristics, were used to assess perioperative opioid demand with and without RA. RESULTS: RA was associated with reduced inpatient opioid usage from 0 to 24 hours postoperatively of approximately 5.2 oxycodone 5-mg equivalents (0.74 incident rate ratio [IRR]; 0.63-0.86 CI; P < .001) and from 24 to 48 hours postoperatively of approximately 2.9 oxycodone 5-mg equivalents (0.78 IRR; 0.64-0.95 CI; P = .014) but not at 48 to 72 hours postoperatively. From 1 month preoperatively to 2 weeks postoperatively, RA was associated with reduced outpatient opioid prescribing of approximately 24.0 oxycodone 5-mg equivalents (0.87; 0.75-0.99; P = .044) and from 1 month preoperatively to 90 days postoperatively of approximately 44.0 oxycodone 5-mg equivalents (0.83; 0.71-0.96; P = .011), although there was no significant difference from 1 month preoperatively to 6 weeks postoperatively. There were no cases of acute compartment syndrome in this cohort. CONCLUSIONS: In tibial plateau fracture surgery, RA was associated with reduced inpatient opioid consumption up to 48 hours postoperatively and reduced outpatient opioid demand up to 90 days postoperatively without an associated risk of acute compartment syndrome. RA should be considered for patients undergoing tibial plateau fracture fixation.

Regional anesthesia reduces inpatient and outpatient perioperative opioid demand in periarticular elbow surgery.

HYPOTHESIS: Regional anesthesia (RA) can be used to manage perioperative pain in the treatment of periarticular elbow fracture fixation. However, the opioid-sparing benefit is not well-characterized. The hypothesis of this study was that RA had reduced inpatient opioid consumption and outpatient opioid demand in patients who had undergone periarticular elbow fracture surgery. METHODS: This study retrospectively reviews inpatient opioid consumption and outpatient opioid demand in all patients aged ≥18 years at a single Level I trauma center undergoing fixation of periarticular elbow (distal humerus and proximal forearm) fracture surgery (n=418 patients). In addition to RA vs. no RA, additional patient and operative characteristics were recorded. Unadjusted and adjusted models were constructed to evaluate the impact of RA and other factors on inpatient opioid consumption and outpatient opioid demand. RESULTS: Adjusted models demonstrated decreases in inpatient opioid consumption postoperation in patients with RA (13.7 estimated oxycodone 5-mg equivalents or OEs without RA vs. 10.4 OEs with RA from 0 to 24 hours postoperation, P = .003; 12.3 vs. 9.2 OEs from 24 to 48 hours postoperation, P = .045). Estimated cumulative outpatient opioid demand differed significantly in patients with RA (166.1 vs. 132.1 OEs to 6 weeks, P = .002; and 181 vs. 138.6 OEs to 90 days, P < .001). DISCUSSION: In proximal forearm and distal humerus fracture surgery, RA was associated with decreased inpatient and outpatient opioid demand after adjusting for baseline patient and treatment characteristics. These results encourage utilization of perioperative RA to reduce opioid use.

Legislation Only Limiting Opioid Prescription Length Has Minimal Impact on Prescribing in Orthopaedic Trauma.

This study evaluates the efficacy of North Carolina's Strengthen Opioid Misuse Prevention (STOP) Act in reducing the volume and rate of 90-day perioperative opioid prescribing to patients ages 18 and older after orthopaedic trauma surgery. Patients undergoing fracture surgery from January 2017 to June 2017 (pre-STOP) were compared with patients undergoing fracture surgery from January 2018 to June 2018 (post-STOP). Adjusted analyses demonstrated that patients undergoing surgery after the STOP Act (n = 730) were prescribed significantly lower volume of opioids in the discharge to 2-week time frame and at the first postoperative prescription (7.3 and 5.8 fewer oxycodone, respectively). Otherwise, there were no significant differences between the two cohorts in adjusted volume or rates of 90-day opioid prescribing. The STOP act has had only a minor impact on early post-discharge opioid prescribing in patients undergoing fracture surgery. These findings question the efficacy of this type of legislation in combating opioid overprescribing in orthopaedic trauma. (Journal of Surgical Orthopaedic Advances 30(2):101-107, 2021).

P16 Expression in Primary Vulvar Extramammary Paget Disease.

P16 immunohistochemistry has been widely used in facilitating the diagnosis of human papillomavirus (HPV)-related usual type vulvar intraepithelial neoplasm. However, studies of p16 expression in primary vulvar extramammary Paget disease (EMPD) are limited. We assessed the p16 expression by immunohistochemistry in 40 cases of primary vulvar EMPD, including 34 cases of intraepithelial vulvar EMPD and 6 cases of invasive vulvar EMPD and correlated p16 expression patterns with disease progression. Overall, p16 expression was present in 36 cases (90%), including 20 cases (50%) with focal staining pattern and 16 cases (40%) with diffuse staining pattern. All 20 cases with focal p16 staining pattern were intraepithelial vulvar EMPD. Diffuse p16 staining pattern was present in 10/30 cases (33.3%) of intraepithelial EMPD and in 6/6 cases (100%) with invasive vulvar EMPD. Negative p16 staining was present in four intraepithelial EMPD cases. Using a highly sensitive RNA in situ hybridization method, we did not detect high-risk HPV in the selected 10 cases with diffuse p16 staining pattern, including 6 cases of intraepithelial EMPD and 4 cases of invasive EMPD. We also observed that intraepithelial EMPD had predominantly cytoplasmic p16 immunoreactivity, whereas nuclear p16 immunoreactivity was mainly seen in invasive EMPD components. Our study demonstrated that the p16 positive immunostaining was seen in the majority of primary vulvar EMPD which is not related to HPV infection. Therefore, knowing the overlapping p16 immunostaining patterns in vulvar EMPD and usual type vulvar intraepithelial neoplasm is important to render the correct diagnosis.

Cystic neutrophilic granulomatous mastitis: The Cleveland Clinic experience with diagnosis and management.

Granulomatous mastitis is an uncommon inflammatory disease that typically presents with painful breast lesions. Recent publications have brought to light a specific subset of granulomatous mastitis patients with a distinct histological pattern of disease termed, "cystic neutrophilic granulomatous mastitis" (CNGM). Although many cases of granulomatous lobular mastitis have been thought to be idiopathic, this rare subset of an uncommon disease has been linked to infections with Corynebacterium species. Herein, a cohort of CNGM patients from a large, tertiary care, North-American, academic medical center is presented. Correlative demographic, clinical, radiographic, pathologic, microbiologic, management, and outcomes data are provided. Collaborative communication between specialists to accurately diagnose and manage these patients is essential to decreasing potential morbidity.

Differential expression patterns of GATA3 in usual and differentiated types of vulvar intraepithelial neoplasia: potential diagnostic implications.

The two main precursors of vulvar squamous cell carcinoma, usual and differentiated vulvar intraepithelial neoplasia (VIN), have distinctive etiology, pathogenesis, and natural history. Usual type VIN is often associated with high-risk HPV and differentiated VIN has de novo p53 genetic alterations that are unrelated to HPV infection. GATA-binding protein 3 (GATA3) is a tumor suppressor that shows increased expression in several types of human malignancies including breast and bladder carcinomas. Little is known regarding the expression of GATA3 in vulvar squamous neoplasms. We have systematically examined the expression of GATA3 in 119 vulvar lesions and neoplasms including 20 cases of lichen sclerosus, 12 cases of lichen simplex chronicus, 30 cases of usual type VIN, 34 cases of differentiated VIN, and 23 cases of squamous cell carcinoma. Similar to adjacent non-neoplastic epidermis, moderate to strong GATA3 expression was retained in all cases of lichen sclerosus, lichen simplex chronicus, and usual type VIN. However, in comparison, the GATA3 immunostaining pattern in differentiated VIN was distinct. Partial/complete loss of GATA3 expression in the basal layer with or without loss in the parabasal layer was observed in 30/34 (88%) of differentiated VIN cases. Significant loss of GATA3 expression was also observed in all (7/7) squamous cell carcinomas associated with usual type VIN and in 13/16 (81%) of those associated with differentiated VIN. There was no significant correlation between loss of GATA3 expression and overexpression of p53 in differentiated VIN. Our study shows that loss of GATA3 expression is seen in the vast majority (87%) of vulvar squamous cell carcinomas. Downregulation of GATA3 may be an early event during tumorigenesis in differentiated VIN but not in HPV-related usual type VIN. Our data suggests that application of GATA3 immunohistochemistry along with p53 may be a useful tool in facilitating the accurate diagnosis of VIN.

Mucocele-like lesions diagnosed on breast core biopsy: Low risk of upgrade and subsequent carcinoma.

Mucocele-like lesions of the breast diagnosed on core biopsy are usually excised to exclude the possibility of partial sampling of an invasive mucinous carcinoma. The goal of this study was to correlate the pathologic and radiologic features of mucocele-like lesions to determine if excision is mandatory. Over a 16 year period we identified 32 patients with mucocele-like lesions diagnosed on 27 (84%) stereotactic and 5 (16%) ultrasound-guided core biopsies. The indications for core biopsy were: calcifications in 24 (75%), a mass in 7 (22%), and a mass with calcifications in 1 (3%). There were 22 (69%) mucocele-like lesions without atypia and 10 (31%) with atypical ductal hyperplasia or detached groups of atypical cells. Of the 22 mucocele-like lesions without atypia, 19 (86%) were excised: 15/19 (79%) were benign, 3/19 (16%) had atypical ductal hyperplasia and 1/19 (5%) had ductal carcinoma in situ. None of the patients with mucocele-like lesions without atypia were upgraded to invasive carcinoma. The single patient who was upgraded to low-grade ductal carcinoma in situ had a history of ductal carcinoma in situ in the same breast. Of the 10 patients with mucocele-like lesions with atypia, 9 (90%) were excised: 5/9 (56%) were benign, 1/9 (11%) had atypical ductal hyperplasia and 3/9 (33%) had invasive carcinoma. Of the patients with mucocele-like lesions with atypia who were upgraded to invasive carcinoma, one had a BIRADS 5 mass and discordant pathology and one had a history of Hodgkin lymphoma and mantle radiation. There were 24 patients with mucocele-like lesions with or without atypia who were not upgraded on excision, and none developed breast cancer after a median of 51 months (range 7-192). These findings indicate that mucocele-like lesions without atypia are unlikely to be upgraded on excision and are associated with a low risk for the subsequent development of carcinoma.

Primary cytoreductive surgery and adjuvant hormonal monotherapy in women with advanced low-grade serous ovarian carcinoma: Reducing overtreatment without compromising survival?

OBJECTIVES: Women with advanced-stage, low-grade serous ovarian carcinoma (LGSC) have low chemotherapy response rates and poor overall survival. Most LGSC tumors overexpress hormone receptors, which represent a potential treatment target. Our study objective was to determine the outcomes of patients with advanced-stage LGSC treated with primary cytoreductive surgery (CRS) and hormone therapy (HT). METHODS: A retrospective study was performed at two academic cancer centers. Patients with Stage II-IV LGSC underwent either primary or interval CRS followed by adjuvant HT between 2004 and 2016. Gynecologic pathologists reviewed all cases. Two-year progression-free (PFS) and overall survival (OS) were calculated. RESULTS: Twenty-seven patients were studied; primary CRS followed by HT were administered in 26, while 1 patient had neoadjuvant chemotherapy followed by CRS and HT. The median patient age was 47.5, and patients had Stage II (n=2), Stage IIIA (n=6), Stage IIIC (n=18), and Stage IV (n=1) disease. Optimal cytoreduction to no gross residual was achieved in 85.2%. Ninety six percent of tumors expressed estrogen receptors, while only 32% expressed progesterone receptors. Letrozole was administered post operatively in 55.5% cases, anastrozole in 37.1% and tamoxifen in 7.4%. After a median follow up of 41months, only 6 patients (22.2%) have developed a tumor recurrence and two patients have died of disease. Median PFS and OS have not yet been reached, but 2-year PFS and OS were 82.8% and 96.3%, respectively, and 3-year PFS and OS were 79.0% and 92.6%, respectively. CONCLUSIONS: Our series describes the initial experience with cytoreductive surgery and hormonal monotherapy for women with Stage II-IV primary ovarian LGSC. While surgery remains the mainstay of treatment, chemotherapy may not be necessary in patients with advanced-stage disease who receive adjuvant hormonal therapy. A cooperative group, Phase III trial is planned to define the optimal therapy for women with this ovarian carcinoma subtype.