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OBJECTIVE: Environmental hazards and heightened neighborhood social vulnerability coexist and disproportionately affect minoritized populations. We investigated associations between adverse environmental burden concentrated in areas with high social vulnerability with care fragmentation (missed appointments, Emergency Department (ED) visits and hospitalizations) and social needs (e.g., food and housing insecurity) among individuals with rheumatic conditions. METHODS: We identified adults receiving care in a Massachusetts multihospital system with >2 rheumatic disease codes and complete street addresses. Geocoded addresses were linked to the CDC/ATSDR Social-Environmental Ranking (SER), which combines census tract social vulnerability variables (e.g., socioeconomic status) with environmental hazards (e.g., air and water pollution). Social needs were from self-reported surveys. Multilevel, multinomial regression models estimated associations between SER quartiles, care fragmentation, and social need burden, accounting for demographics and comorbidities. RESULTS: Among 16,856 individuals with rheumatic conditions, 70% were female, 6% were Black, 82% were White, and 7% resided in the highest combined social vulnerability and environmental burden (SER Quartile 4) areas. Among 7,083 with social needs data, 19% experienced >1 challenge. Individuals in SER Quartile 4 areas (vs. Quartile 1), had 2.02 (95% CI 1.67-2.46) times greater odds of >4 care fragmentation occurrences (vs. 0) and 2.37 (95% CI 1.73-3.25) times greater odds of >2 social needs (vs. 0). CONCLUSIONS: Residence in areas of high combined adverse environmental burden and social vulnerability was associated with significantly greater odds of care fragmentation and social needs. Addressing structural factors and emerging environmental threats contributing to these adverse exposures is essential to reduce rheumatic disease care inequities.

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BACKGROUND: Recurrence score (RS) based on a 21-gene genomic assay is frequently used to estimate risk of distant recurrence for choice of adjuvant chemotherapy in breast cancer. It remains unclear whether RS is an independent prognostic factor for breast cancer-specific survival (BCSS) and overall survival (OS) in the TAILORx trial population. METHODS: We evaluated the association of RS with BCSS and OS plus recurrence-free interval (RFI) and invasive disease-free survival (DFS) using multivariable Cox proportional hazards regression analysis, adjusting for clinicopathologic measures, in 8,916 patients with hormone receptor-positive, HER2-negative, node-negative breast cancer. Likelihood ratio (LR) test was used to assess the relative amount of prognostic information provided by RS to BCSS, OS, RFI, and DFS, comparatively. RESULTS: Event rates for BCSS, OS, RFI, and DFS were 1.7%, 5.2%, 5.6%, and 12.6%, respectively, by up to 11.6 years of follow-up. Compared with low-range RS (0-10), patients with midrange (11-25) and high-range (26-100) RS had inferior BCSS (adjusted hazard ratio [aHR], 5.12 [95% CI, 2.09-16.92] and 8.03 [95% CI, 2.91-28.47], respectively) and RFI (aHR, 1.68 [95% CI, 1.23-2.36] and 3.05 [95% CI, 2.02-4.67], respectively), independent of clinicopathologic factors. High-range score was associated with an increased risk of DFS (aHR, 1.56 [95% CI, 1.20-2.04]) but not significantly associated with OS (aHR, 1.44 [95% CI, 0.95-2.18]). Midrange score was associated with neither DFS (aHR, 1.15 [95% CI, 0.96-1.38]) nor OS (HR 1.14 [95% CI, 0.87-1.52]). LR-χ2 values were 83.0 and 65.1 for RFI and BCSS, respectively, and 17.5 and 33.6 for OS and DFS, respectively (P<.0001). CONCLUSIONS: RS is an independent measure for BCSS and recurrence prognoses relative to OS in early-stage breast cancer. It carries more prognostic information for breast cancer-specific outcomes.

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BACKGROUND: Ten-eleven-translocation (TET) 2 is a member of the TET family of proteins (TET1-3). DNMT1 gene deletion confers resistance to DNA methyltransferase (DNMT) inhibitors in colorectal, breast, and ovarian cancer cells. Currently, the effect of DNMT1 gene status on TET2 phenotype following DNMT inhibitor treatment is unclear in human malignancies. METHODS: Human colorectal carcinoma HCT116 cells (DNMT+/+) and their isogenic DNMT1 knockout (DNMT1-/-) counterpart were treated with DNMT inhibitors. Expression of TET2 and tumor suppressor (p16ink4A and p15ink4B) proteins were examined by Western blot. Apoptosis and CDKN2A promoter demethylation following drug treatment were detected by Annexin-V apoptosis assay and methylation-specific PCR. RESULTS: TET2 expression was robustly increased in DNMT1-/- cells by 0.5 µM and 5 µM decitabine and azacitidine treatment. Augmentation of TET2 expression was accompanied by re-expression of p16ink4A and p15ink4B proteins and CDKN2A promoter demethylation. TET2 upregulation and tumor suppressor re-expression were associated with resistance conferred by DNMT1 deletion. Treatment with 5-aza-4'-thio-2'-deoxycytidine at a low 0.5 µM dose only upregulated TET2 and reduced CDKN2A promoter methylation, and re-expression of p16ink4A in DNMT1-/- cells. DNMT inhibitors showed minimal effects on TET2 upregulation and re-expression of tumor suppressor proteins in cells with intact DNMT1. CONCLUSIONS: DNMT1 gene deletion made cancer cells prone to TET2 upregulation and activation of tumor suppressor expression upon DNMT inhibitor challenge. TET2 augmentation is concomitant with resistance to DNMT inhibitors in a DNMT1-deleted state.

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Hidradenitis suppurativa (HS) is a painful chronic skin condition of apocrine gland regions. This retrospective cohort study aimed to assess the impact of hormonal contraception type on HS disease control in adult women. In total, 160 patients were included, with the majority identifying as Black or African American (73.1%). Multivariate logistic regression showed that oestrogen-progesterone users were 3.14 times more likely to experience stable or improved HS than progesterone-only users (adjusted odds ratio 3.14, 95% CI 1.18-8.35; P = 0.02). Further investigation is needed to elucidate the antiandrogenic mechanisms affecting HS symptom response to hormonal contraceptives.

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Role of DNA damage and demethylation on anticancer activity of DNA methyltransferase inhibitors (DNMTi) remains undefined. We report the effects of DNMT1 gene deletion/disruption (DNMT1-/-) on anticancer activity of a class of DNMTi in vitro, in vivo and in human cancers. The gene deletion markedly attenuated cytotoxicity and growth inhibition mediated by decitabine, azacitidine and 5-aza-4'-thio-2'-deoxycytidine (aza-T-dCyd) in colon and breast cancer cells. The drugs induced DNA damage that concurred with DNMT1 inhibition, subsequent G2/M cell-cycle arrest and apoptosis, and upregulated p21 in DNMT1+/+ versus DNMT1-/- status, with aza-T-dCyd the most potent. Tumor growth and DNMT1 were significantly inhibited, and p21 was upmodulated in mice bearing HCT116 DNMT1+/+ xenograft and bladder PDX tumors. DNMT1 gene deletion occurred in ~ 9% human colon cancers and other cancer types at varying degrees. Decitabine and azacitidine demethylated CDKN2A/CDKN2B genes in DNMT1+/+ and DNMT1-/- conditions and increased histone-H3 acetylation with re-expression of p16INK4A/p15INK4B in DNMT1-/- state. Thus, DNMT1 deletion confers resistance to DNMTi, and their anti-cancer activity is determined by DNA damage effects. Patients with DNMT1 gene deletions may not respond to DNMTi treatment.

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Dermatology residents have 3 years to master core competencies related to the delivery of patient care, preservation of medical professionalism, and responsible use of health care; however, it is crucial for residents to recognize other things outside of their formal curriculum that are equally vital to their training. Over the years, we have observed residents and now offer our own perspectives. We have collectively observed five extracurricular aspects commonly overlooked by dermatology residents that are important to their education and future practice. (SKINmed. 2022;20:123-125).

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The role of lymph node involvement and tumor size in metastatic disease including breast cancer is unclear. Here, nodal metastasis and T stage on the risk of mortality were investigated in de novo metastatic breast cancer population (35812 patients) in the Surveillance, Epidemiology, and End Results (SEER) Program database in the United States. We found an association between all-cause mortality and regional node involvement (adjusted hazard ratio [HR] = 1.45, 95% confidence interval [CI] 1.36-1.55, p < 0.0001) or T stage (HR = 1.20, 95% CI 1.14-1.25, p < 0.0001), independent of known clinicopathologic measurements. Number of positive nodes, and size and chest wall involvement of the breast tumors exhibited similar significance for breast cancer-specific mortality in the population (p < 0.0001 each), and all-cause mortality in hormone receptor (HR)-positive/HER2-negative (HR+/HER2-), HR+/HER2+, HR-/HER2+ and triple-negative metastatic breast cancer subtypes. Thus, nodal involvement and T stage are independent risk factors for mortality in the population of de novo metastatic breast cancer.

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BACKGROUND: Challenges remain on the selection of patients who potentially respond to a class of drugs that target epigenetics for cancer treatment. This study aims to investigate TET2/DNMT3A mutations and antitumor activity of a novel epigenetic agent in multiple human cancer cell lines and animal models. METHODS: Seventeen cancer cell lines and multiple xenograft models bearing representative human solid tumors were subjected to 4'-thio-2'-deoxycytidine (T-dCyd) or control treatment. Gene mutations in cell lines were examined by whole exome and/or Sanger sequencing. Specific gene expression was measured in cells and xenograft tumor samples by Western blotting and immunohistochemistry. TET2/DNMT3A mutation status in 47,571 human tumor samples was analyzed at cBioPortal for Cancer Genomics. RESULTS: Cell survival was significantly inhibited by T-dCyd in breast BT549, lung NCI-H23, melanoma SKMEL5 and renal ACHN cancer lines harboring deleterious TET2 and nonsynonymous DNMT3A mutations compared to 13 lines without such mutation pattern (P = 0.007). The treatment upregulated p21 and induced cell cycle arrest in NCI-H23 cells, and dramatically inhibited their xenograft tumor growth versus wildtype models. T-dCyd administrations led to a significant p21 increase and near eradication of tumor cells in the double-mutant xenografts by histological evaluation. TET2/DNMT3A was co-mutated in human lung, breast, skin and kidney cancers and frequently in angioimmunoblastic and peripheral T cell lymphomas and several types of leukemia. CONCLUSIONS: Cell and animal models with concurrent mutations in TET2 and DNMT3A were sensitive to T-dCyd treatment. The mutations were detectable in human solid tumors and frequently occur in some hematological malignancies.

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Importance: It is not well understood whether prognostic factors in breast cancer are affected by specific treatment and vary by clinical outcome type compared with untreated patients. Objective: To identify independent clinical and molecular measurements associated with overall survival (OS) and recurrence-free survival (RFS) by homogeneous treatment in women with breast cancer. Design, Setting, and Participants: This prognostic study included 956 patients diagnosed with invasive breast cancer from hospital centers across 4 geographical regions of the United States who participated in the accreditation program of the Commission on Cancer of the American College of Surgeons from 1985 to 1997. The duration of follow-up ranged from 1 to 282 months. The study analysis was conducted from June 10, 2019, to March 18, 2020. Main Outcomes and Measures: Analysis of OS and RFS in patients who underwent chemotherapy, radiotherapy, or endocrine therapy alone compared with no systemic or locoregional therapy. Cox proportional hazards regression models were used to estimate independent performance and 95% CI of age, tumor size, number of positive nodes (nodal status), tumor grades 2 and 3, p53 status, estrogen receptor (ER) status, and ERBB2 (formerly HER2) status. Results: Among 956 participants, median age was 61 (range, 25-96) years. Age (adjusted hazard ratio [AHR], 2.24; 95% CI, 1.27-3.94; P = .01) and high grade (AHR, 2.05; 95% CI, 1.09-3.86; P = .02), in addition to nodal status and tumor size, were independently associated with OS and RFS, respectively, in untreated patients. p53 status (AHR, 2.11; 95% CI, 1.07-4.18; P = .03) and ER status (AHR, 0.46; 95% CI, 0.23-0.92; P = .03) were associated with higher and lower risks of death, respectively, whereas nodal status (AHR, 1.13; 95% CI, 1.06-1.20; P < .005), high grade (AHR, 4.01; 95% CI, 1.51-10.70; P = .01), and ERBB2 positivity (AHR, 2.67; 95% CI, 1.25-5.70; P = .01) were associated with the risk of recurrence after endocrine therapy. Tumor size (AHR for OS, 2.76 [95% CI, 1.79-4.31; P < .005]; AHR for RFS, 2.27 [95% CI, 1.23-4.18; P = .01]) and ERBB2 status (AHR for OS, 5.35 [95% CI, 1.31-21.98; P = .02]; AHR for RFS, 6.05 [95% CI, 1.48-24.78; P = .01]) were independently associated with radiotherapy outcomes, and nodal status was significantly associated with chemotherapy outcomes (AHR for OS, 1.06 [95% CI, 1.02-1.09; P < .005]; AHR for RFS, 1.05 [95% CI, 1.01-1.09; P = .01]). Conclusions and Relevance: In this study, independent prognostic factors were associated with specific treatment and weighted by the outcome category with reference to untreated patients within biological and clinical contexts.

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A common complication of acne vulgaris is clinically significant scarring, which can greatly impact patient quality of life. While treatment options have included microneedling, the recent addition of platelet-rich plasma (PRP) to this regimen has led to an increased popularity of combination treatment. Here, we offer backgrounds on microneedling and PRP therapies and review the literature on combination treatment for acne scars.

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The increased use of monoclonal antibodies that target the immune checkpoint T cell receptor programmed death-1 (PD1) to treat numerous solid tumors has led to several reports describing associated cutaneous adverse events. Although lichenoid reactions have been well described, we propose that PD1 inhibitor-induced inverse lichenoid eruption (PILE) is a distinct variant. We describe two patients who presented with nearly identical deeply erythematous, malodorous, eroded anogenital plaques with focal crusting. Diagnosis of PILE was established given the biopsy findings and temporal association with PD1 inhibitor therapy. Treatment with clobetasol ointment was successful without necessitating discontinuation of immunotherapy. The findings were consistent with the only other previously published case of inverse lichenoid eruption in the groin secondary to PD1 inhibitors.

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OBJECTIVES: Preoperative decision-making for differentiating malignant from benign lesions in the gallbladder remains challenging. We aimed to create a diagnostic nomogram to identify gallbladder cancer (GBC), especially for incidental GBC (IGBC), before surgical resection. METHODS: A total of 587 consecutive patients with pathologically confirmed gallbladder lesions from a hospital were randomly assigned to a training cohort (70%) and an internal validation cohort (30%), with 287 patients from other centers as an external validation cohort. Radiological features were developed by the least absolute shrinkage and selection operator logistic regression model. Significant radiological features and independent clinical factors, identified by multivariate analyses, were used to construct a nomogram. RESULTS: A diagnostic nomogram was established by age, CA19.9, and 6 radiological features. The values of area under the curve in the internal and external validation cohorts were up to 0.91 and 0.89, respectively. The calibration curves for probability of GBC showed optimal agreement between nomogram prediction and actual observation. Compared with previous methods, it demonstrated superior sensitivity (91.5%) and accuracy (85.1%) in the diagnosis of GBC. The accuracy using the nomogram was significantly higher in GBC groups compared with that by radiologists in the training cohort (P < 0.001) and similarly in each cohort. Notably, most of the IGBC, which were misdiagnosed as benign lesions, were successfully identified using this nomogram. DISCUSSION: A novel nomogram provides a powerful tool for detecting the presence of cancer in gallbladder masses, with an increase in accuracy and sensitivity. It demonstrates an unprecedented potential for IGBC identification.

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B-cell lymphoblastic lymphoma (B-LBL) is a malignant neoplasm of immature B cells that accounts for only 10% of all cases of lymphoblastic lymphoma. Most commonly, B-LBL presents as bony lesions, but in rare cases, the disease manifests cutaneously. We present a case of simultaneous cutaneous and systemic presentation of B-LBL in an otherwise healthy 28-year-old man in which the lymphoblastic infiltrate stained positive for CD79a, Tdt, CD10, and CD20. A diagnosis of cutaneous B-LBL was made, and systemic work-up revealed widespread involvement of the skin, bone, and lymph nodes. Review of all currently described cases of cutaneous B-LBL with or without systemic involvement revealed that the most frequently positive tumor markers were CD79a (92.3%), Tdt (90.6%), and CD10 (83.3%). Systemic involvement of B-LBL was found in nearly half of all cases with cutaneous presentation.

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