The Integrin LFA-1 Controls T Follicular Helper Cell Generation and Maintenance.

T follicular helper (Tfh) cells are a CD4+ T cell subset critical for long-lived humoral immunity. We hypothesized that integrins play a decisive role in Tfh cell biology. Here we show that Tfh cells expressed a highly active form of leukocyte function-associated antigen-1 (LFA-1) that was required for their survival within the germinal center niche. In addition, LFA-1 promoted expression of Bcl-6, a transcriptional repressor critical for Tfh cell differentiation, and inhibition of LFA-1 abolished Tfh cell generation and prevented protective humoral immunity to intestinal helminth infection. Furthermore, we demonstrated that expression of Talin-1, an adaptor protein that regulates LFA-1 affinity, dictated Tfh versus Th2 effector cell differentiation. Collectively, our results define unique functions for LFA-1 in the Tfh cell effector program and suggest that integrin activity is important in lineage decision-making events in the adaptive immune system.

Family Planning Experiences and Challenges of Mohs Fellowship Trainees.

BACKGROUND: There is a paucity of literature describing family planning challenges faced by Mohs fellows. OBJECTIVE: To characterize perceptions about and experiences with family planning, fertility, lactation, and parental leave and identify ways to support parental health and family planning for Mohs fellows. MATERIALS AND METHODS: A voluntary, anonymous survey was distributed to Mohs surgeons who recently completed fellowship. RESULTS: In total, 116 Mohs surgeons completed the survey. Their mean age was 34.5 years old, and more were female ( n = 81, 69.8%) than male ( n = 35, 30.2%). Most had children before completion of their Mohs training ( n = 73, 62.9%). The most significant barrier to having children during fellowship was "loss of education or training time." Over 20% ( n = 23) of respondents or their partner had experienced infertility. Half of the 20 respondents ( n = 10) who breastfed or pumped did not have a convenient place to do so. CONCLUSION: This study elucidates trainee perceptions and gaps in parental support for Mohs fellowship trainees. In addition, barriers to implementing a universal family planning policy in Mohs surgery are discussed.

Defining and quantifying histopathologic risk factors for regional and distant metastases in a large cohort of vulvar squamous cell carcinomas.

BACKGROUND: Vulvar squamous cell carcinoma (vSCC) is a rare tumor with a good prognosis when treated at a localized stage. However, once regional/distant metastasis occurs, vSCC can be rapidly fatal. Thus, it is important to identify tumor prognostic features so that high-risk cases can be prioritized for further diagnostic workup and treatment. OBJECTIVE: To estimate the risk of regional/distant metastasis at presentation and sentinel lymph node status for vSCC based on histopathologic characteristics. METHODS: A retrospective cohort study of 15,188 adult vSCC cases from the National Cancer Database diagnosed from 2012 to 2019. RESULTS: We provide specific estimates of the risk of clinically positive nodes and metastatic disease at presentation and sentinel lymph node positivity according to tumor size, moderate/poor tumor differentiation, and lymph-vascular invasion. These histopathologic factors were all significantly associated with the tested clinical outcomes in a multivariable analysis. Moderate (hazard ratio, 1.190; P < .001) and poor differentiation (hazard ratio, 1.204; P < .001) and lymph-vascular invasion (hazard ratio, 1.465; P < .001) were also associated with significantly poorer overall survival. LIMITATIONS: Data on disease-specific survival not available in the data set. CONCLUSIONS: We demonstrate the association of the histopathologic characteristics of vSCC with clinically important outcomes. These data may provide individualized information when discussing diagnostic/treatment recommendations, particularly regarding sentinel lymph node biopsy. These data may also guide future staging and risk stratification efforts for vSCC.

Gender Differences in Clinical Practice and Medicare Reimbursement Among Mohs Surgeons.

OBJECTIVE: To evaluate Medicare reimbursement and clinical activity between male and female dermatologic surgeons. MATERIALS AND METHODS: A retrospective review of the Medicare Provider Utilization and Payment data from 2018 was performed for all dermatologists performing MMS. Provider gender, place of service, number of services, and average payment per service was recorded for all relevant procedure codes. RESULTS: Women represented 31.5% of the 2,581 surgeons who performed MMS in 2018. Women were paid significantly less than men (mean difference, -$73,033). On average, women performed 123 fewer cases than their male counterparts. When surgeons were stratified by productivity, remuneration was the same. CONCLUSION: Remuneration from CMS was disparate between male and female dermatologic surgeons, which may be attributed to submission of fewer charges by women. Further efforts are necessary to better evaluate and address causes for this discrepancy, because greater parity of opportunity and pay would greatly benefit this subspecialty of dermatology.

Assessing Rates of Positive Surgical Margins After Standard Excision of Vulvar Melanomas.

BACKGROUND: Vulvar melanoma is a rare malignancy with frequent recurrence and poor prognosis. National guidelines recommend wide local excision of these tumors with allowances for narrower margins for anatomic and functional limitations, which are common on specialty sites. There is presently a lack of data of margin positivity after standard excision of vulvar melanomas. OBJECTIVE: We aim to evaluate the rate of positive margins after standard excision of vulvar melanomas. MATERIALS AND METHODS: Retrospective cohort study of surgically excised vulvar melanomas from the NCDB diagnosed from 2004 to 2019. RESULTS: We identified a total of 2,226 cases. Across surgical approaches and tumor stages, 17.2% (Standard Error [SE]: 0.8%) of cases had positive surgical margins. Among tumor stages, T4 tumors were most commonly excised with positive margins (22.9%, SE: 1.5%). On multivariable survival analysis, excision with positive margins was associated with significantly poorer survival (Hazard Ratio 1.299, p = .015). CONCLUSION: We find that positive margin rates after standard excision of vulvar malignancies are higher than for other specialty site melanomas. Our data suggest that use of surgical approaches with complete margin assessment may improve local control and functional outcomes for patients with vulvar melanoma as they have for patients with other specialty site melanomas.

Evaluating Rates of Positive Margins After Standard Excision of Cutaneous Adnexal Malignancies.

BACKGROUND: It is recommended to excise adnexal neoplasms with standard local excision or Mohs micrographic surgery (MMS), although many occur on high-risk sites such as the head and neck (H&N) and exhibit subclinical extension. Minimal evidence exists on the efficacy of standard excisions for these tumors. OBJECTIVE: To evaluate the rate of positive surgical margins after standard excision of adnexal tumors. METHODS: Retrospective cohort study of cutaneous adnexal malignancies from the National Cancer Database diagnosed from 2004 to 2019. RESULTS: The authors identified a total of 4,402 cases treated with standard excision. Tumors on the H&N were approximately twice as likely as those on the trunk and extremities (T&E) to be excised with positive margins (odds ratio 2.146, p < .001), with the highest estimated rate for eccrine adenocarcinoma (12.1%, SE: 2.3%). The subtype with the highest positive margin rate on the T&E was microcystic adnexal carcinoma (8.0%, SE: 2.9). Positive margins were associated with poorer overall survival on multivariable survival analysis (hazard ratio 1.299, p = .015). CONCLUSION: The authors present subtype- and site-specific positive margin rates for adnexal tumors treated with standard excision, which suggest that tumors on the H&N and some T&E subtypes, should be considered for MMS.

Applying Occam's Razor and Descending the Reconstructive Ladder: The Modified Cheek Advancement Flap for Reconstruction of Nasal Defects.

Nasal reconstruction has important functional and cosmetic considerations, as proper repair of nasal defects is necessary to maintain function of the nasal airway and to recreate the normal appearance of this central facial structure. Cheek advancement flaps provide matched, mobile, and highly vascularized tissue for the reconstruction of nasal defects, allowing for the concealment of incisions within natural creases in a one-stage approach. However, cheek advancement flaps are often underutilized for nasal reconstruction because of their difficulty in restoring nasal contour. We describe reconstruction of 19 nasal dorsal and sidewall defects 0.8 to 3 cm in size. We incorporated a periosteal anchoring suture to maintain/restore nasal contour and additionally removed a half standing cone inferior to the defect to prevent encroachment of the nasal ala or alar crease. All patients were evaluated at least 3 months postoperatively. In all patients, we were able to restore concavity of the nasofacial sulcus, preserve the biconvex nasal tips, prevent alar flaring and retraction, and conserve the alar groove. All patients had excellent functional and cosmetic outcomes. We believe this modified cheek advancement flap provides functionally and aesthetically superior results and can be considered as a first-line approach for repair of nasal dorsal and sidewall defects in subselected patients.

Potassium Concentrations in Transgender Women Using Spironolactone: A Retrospective Chart Review.

OBJECTIVE: To assess the incidence of hyperkalemia in transgender women using spironolactone. METHODS: This was a retrospective chart review of transgender women who received gender-affirming hormone therapy that included spironolactone between January 2000 and September 2018. Forty-four participants who had paired potassium concentrations documented and were on spironolactone were included and analyzed. Study outcomes included the incidence of hyperkalemia (serum potassium concentrations > 5.0 mmol/L), the relationship between the duration of treatment and degree of hyperkalemia, and difference between serum potassium concentrations at the beginning of spironolactone treatment versus last serum potassium concentrations. RESULTS: The median age of the participants was 36.5 years. The cohort was predominantly non-Hispanic White (32/44). No serum potassium concentration was >5.5 mmol/L, and all participants had serum creatinine level of <2 mg/dL. Median duration of treatment was 25 months (range 2-92 months) and 140 potassium measurements were available. The mean potassium concentration (3.87 mmol/L) before the initiation of spironolactone was lower than the mean potassium concentration (4.03 mmol/L) while on spironolactone (mean difference, 0.16 mmol/L, P = .013). The regression ß, that is, the average change in potassium concentration per 1 additional month of treatment duration, was -.001 (95% CI [-.004, .001]; P = .255) signifying no relation between treatment duration and spironolactone use. CONCLUSION: No participant had laboratory evidence of significant hyperkalemia (K > 5.5 mmol/L) after initiation of spironolactone. Frequent measurement of potassium concentrations might be unnecessary in transgender women taking spironolactone in patients with serum creatinine levels of <2 mg/dL.

Skin Cancers and Lung Transplant.

It is well known that solid-organ transplant recipients (SOTRs) have a 65- to 100-fold increase in the risk of developing skin cancer, namely, nonmelanoma skin cancers (NMSCs) such as cutaneous squamous cell carcinoma (cSCC) and basal cell carcinoma (BCC). In addition, these patients are also at increased risk for development of melanoma as well as other less common cutaneous malignancies (Merkel's cell carcinoma, Kaposi's sarcoma). SOTRs with NMSC (namely cSCC) are also at significantly increased risk of poor clinical outcomes including local recurrence, nodal and distant metastasis, and disease-specific death relative to patients who are not immunosuppressed. Increased surveillance and monitoring in patients at risk of aggressive disease and poor outcomes who are on immunosuppression is essential in patients with lung transplants given the high degree of immunosuppression. Increased awareness of risks, treatments, and management allows for improved outcomes in these patients. This article will provide an overview of the risk factors for the development of cutaneous malignancies in organ transplant recipients as well as a detailed discussion of various immunosuppressant and prophylactic medications used in this patient population that contribute to the risk of developing cutaneous malignancies, with an emphasis on NMSC (cSCC and BCC) in lung transplant recipients. Finally, this article includes a discussion on the clinical and dermatologic management of this high-risk immunosuppressed population including a review of topical and systemic agents for field therapy of actinic damage and chemoprevention of keratinocyte carcinomas. In addition, indications for additional treatment and preventive measures such as adjuvant radiation treatment after surgical management of cutaneous malignancies and potential modification of immunosuppressive medication regimens are discussed.

SERUM HORMONE CONCENTRATIONS IN TRANSGENDER INDIVIDUALS RECEIVING GENDER-AFFIRMING HORMONE THERAPY: A LONGITUDINAL RETROSPECTIVE COHORT STUDY.

OBJECTIVE: To examine the association of various gender-affirming hormone therapy regimens with blood sex hormone concentrations in transgender individuals. METHODS: This retrospective study included transgender people receiving gender-affirming hormone therapy between January 2000 and September 2018. Data on patient demographics, laboratory values, and hormone dose and frequency were collected. Nonparametric tests and linear regression analyses were used to identify factors associated with serum hormone concentrations. RESULTS: Overall, 196 subjects (134 transgender women and 62 transgender men), with a total of 941 clinical visits, were included in this study. Transgender men receiving transdermal testosterone had a significantly lower median concentration of serum total testosterone when compared with those receiving injectable preparations (326.0 ng/dL vs 524.5 ng/dL, respectively, P = .018). Serum total estradiol concentrations in the transgender women were higher in those receiving intramuscular estrogen compared with those receiving oral and transdermal estrogen (366.0 pg/mL vs 102.0 pg/mL vs 70.8 pg/mL, respectively, P < .001). A dose-dependent increase in the hormone levels was observed for oral estradiol (P < .001) and injectable testosterone (P = .018) but not for intramuscular and transdermal estradiol. Older age and a history of gonadectomy in both the transgender men and women were associated with significantly higher concentrations of serum gender-affirming sex hormones. CONCLUSION: In the transgender men, all routes and formulations of testosterone appeared to be equally effective in achieving concentrations in the male range. The intramuscular injections of estradiol resulted in the highest serum concentrations of estradiol, whereas transdermal estradiol resulted in the lowest concentration. There was positive relationship between both oral estradiol and injectable testosterone dose and serum sex hormone concentrations in transgender people receiving GAHT.

Current Research in Melanoma and Aggressive Nonmelanoma Skin Cancer.

There have been several significant advances in cancer treatment in the last decade that are applicable to the treatment of melanoma and advanced nonmelanoma skin cancers. Among these are the development of immune checkpoint inhibitors targeting the programmed death protein-1 (PD-1)/programmed death legand-1 (PDL-1) axis, as well as targeted inhibitors of the BRAF/MEK signaling cascade in melanoma, and the hedgehog signaling pathway in basal cell carcinoma (BCC). These immune-based and targeted therapies have dramatically changed the treatment options for locally advanced and metastatic melanoma, Merkel's cell carcinoma, cutaneous squamous cell carcinoma (cSCC), and BCC. In this article, we will briefly review the currently approved targeted and immunotherapy-based treatments for locally advanced and metastatic melanoma, Merkel's cell carcinoma, and cSCC and discuss various combinations of approved therapies, as well as emerging therapeutic candidates that are currently in clinical trials, including novel checkpoint inhibitors in development, intratumoral oncolytic agents (viral and nonviral), and various immune-based therapies such as toll-like receptor (TLR) agonists, adoptive T-cell therapy, T-cell costimulation, and innate immune cell therapy. For advanced BCC, we will discuss trials investigating the currently approved smoothened (SMO) inhibitors for neoadjuvant use, emerging SMO inhibitors in development, topical SMO inhibitors, alternative targets in the hedgehog signaling pathway, and the use of anti-PD-1 agents for advanced BCC both alone and in combination with SMO inhibitors.

IRF-8 regulates expansion of myeloid-derived suppressor cells and Foxp3+ regulatory T cells and modulates Th2 immune responses to gastrointestinal nematode infection.

Interferon regulatory factor-8 (IRF-8) is critical for Th1 cell differentiation and negatively regulates myeloid cell development including myeloid-derived suppressor cells (MDSC). MDSC expand during infection with various pathogens including the gastrointestinal (GI) nematode Heligmosomoides polygyrus bakeri (Hpb). We investigated if IRF-8 contributes to Th2 immunity to Hpb infection. Irf8 expression was down-regulated in MDSC from Hpb-infected C57BL/6 (B6) mice. IRF-8 deficient Irf8-/- and BXH-2 mice had significantly higher adult worm burdens than B6 mice after primary or challenge Hpb infection. During primary infection, MDSC expanded to a significantly greater extent in mesenteric lymph nodes (MLN) and spleens of Irf8-/- and BXH-2 than B6 mice. CD4+GATA3+ T cells numbers were comparable in MLN of infected B6 and IRF-8 deficient mice, but MLN cells from infected IRF-8 deficient mice secreted significantly less parasite-specific IL-4 ex vivo. The numbers of alternatively activated macrophages in MLN and serum levels of Hpb-specific IgG1 and IgE were also significantly less in infected Irf8-/- than B6 mice. The frequencies of antigen-experienced CD4+CD11ahiCD49dhi cells that were CD44hiCD62L- were similar in MLN of infected Irf8-/- and B6 mice, but the proportions of CD4+GATA3+ and CD4+IL-4+ T cells were lower in infected Irf8-/- mice. CD11b+Gr1+ cells from naïve or infected Irf8-/- mice suppressed CD4+ T cell proliferation and parasite-specific IL-4 secretion in vitro albeit less efficiently than B6 mice. Surprisingly, there were significantly more CD4+ T cells in infected Irf8-/- mice, with a higher frequency of CD4+CD25+Foxp3+ T (Tregs) cells and significantly higher numbers of Tregs than B6 mice. In vivo depletion of MDSC and/or Tregs in Irf8-/- mice did not affect adult worm burdens, but Treg depletion resulted in higher egg production and enhanced parasite-specific IL-5, IL-13, and IL-6 secretion ex vivo. Our data thus provide a previously unrecognized role for IRF-8 in Th2 immunity to a GI nematode.

Skin cancer in transplant recipients: Scientific retreat of the international immunosuppression and transplant skin cancer collaborative and skin care in organ transplant patients-Europe.

The International Immunosuppression and Transplant Skin Cancer Collaborative (ITSCC) is an organization of more than 500 physicians and scientists focused on the treatment of cutaneous malignancies following solid organ transplantation and in other forms of immunosuppression. It is well known that solid organ transplant recipients (SOTRs) have an approximate 100-fold increase in the risk of developing skin cancer with consensus guidelines recommending these patients be managed as high risk for local recurrence and metastasis associated with poor outcomes. In September 2018, ITSCC and its European counterpart, the Skin Care in Organ Transplant Patients-Europe (SCOPE), held their biennial scientific retreat in Essex, MA to discuss novel findings in the pathogenesis of cutaneous malignancy including new treatment and prevention strategies in this at-risk population for significant morbidity and mortality from their cutaneous disease. This meeting report is a summary of the novel findings discussed.

Stratification of Poor Outcomes for Cutaneous Squamous Cell Carcinoma in Immunosuppressed Patients Using the American Joint Committee on Cancer Eighth Edition and Brigham and Women's Hospital Staging Systems.

BACKGROUND: Staging systems for cutaneous squamous cell carcinoma (CSCC) include Brigham and Women's Hospital (BWH) and American Joint Committee on Cancer staging system, eighth edition (AJCC-8). OBJECTIVE: To evaluate and compare AJCC-8 and BWH staging systems for CSCC in immunosuppressed patients. MATERIALS AND METHODS: A retrospective cohort study of immunosuppressed patients diagnosed with primary CSCC from 2012 to 2016. The main end point was any poor outcome (PO), which included local recurrence, nodal metastasis, and disease-specific death. RESULTS: Fifty-eight immunosuppressed patients had 263 CSCCs. Fifty percent of tumors were AJCC-8 T1, 44.7% T2, and 4.8% T3. Fifty percent of tumors were BWH T1, 48.5% T2a, 1.3% T2b, and 0.4% T3. Risk of PO for AJCC-8 was 1.7%, 8.8%, and 36.4% for T1, T2, and T3, respectively (p < .01). Risk of PO for BWH was 1.8%, 9.9%, 33.3%, and 100.0% for T1, T2a, T2b, and T3, respectively (p < .01). Thirty-six percent of AJCC-8 T3/T4 tumors had POs compared with 5.1% in low T1/T2 stages (p = .002). Fifty percent of BWH T2b/T3 tumors had POs compared with 5.3% in low T1/T2a stages (p = .01). CONCLUSION: AJCC-8 and BWH staging systems stratify CSCC with similar distinctiveness, homogeneity, and monotonicity for immunosuppressed patients.

Expertise in Head and Neck Cutaneous Reconstructive Surgery.

BACKGROUND: The management of skin cancers has evolved with the development of Mohs micrographic surgery and a greater emphasis on surgical training within dermatology. It is unclear whether these changes have translated into innovations and contributions to the reconstructive literature. OBJECTIVE: To assess contributions from each medical specialty to the cutaneous head and neck oncologic reconstructive literature. METHODS: The authors conducted a systematic review of the head and neck reconstructive literature from 2000 through 2015 based on a priori search terms relating to suture technique, linear closure, advancement, rotation, transposition and interpolation flaps, and identified the specialty of the senior authors. RESULTS: The authors identified 74,871 articles, of which 1,319 were relevant. Under suture technique articles, the senior authors were primarily dermatologists (58.2%) and plastic surgeons (20.3%). Under linear closure, the authors were dermatologists (48.1%), plastic surgeons (22.2%), and otolaryngologists (20.4%). Under advancement and rotation flaps, the senior authors were plastic surgeons (40.5%, 38.9%), dermatologists (38.1%, 34.2%), and otolaryngologists (14.4%, 21.6%). Under transposition and interpolation flaps, the senior authors were plastic surgeons (47.3%, 39.4%), dermatologists (32.3%, 27.0%), and otolaryngologists (15.3%, 23.4%). CONCLUSION: The primary specialties contributing to the cutaneous head and neck reconstructive literature are plastic surgery, dermatology, and otolaryngology.