Hedgehog pathway inhibitors for locally advanced and metastatic basal cell carcinoma: A real-world single-center retrospective review.

Basal cell carcinoma (BCC) is highly curable by surgical excision or radiation. In rare cases, BCC can be locally destructive or difficult to surgically remove. Hedgehog inhibition (HHI) with vismodegib or sonidegib induces a 50-60% response rate. Long-term toxicity includes muscle spasms and weight loss leading to dose decreases. This retrospective chart review also investigates the impact of CoQ10 and calcium supplementation in patients treated with HHI drugs at a single academic medical center from 2012 to 2022. We reviewed the charts of adult patients diagnosed with locally advanced or metastatic BCC treated with vismodegib or sonidegib primarily for progression-free survival (PFS). Secondary objectives included overall survival, BCC-specific survival, time to and reasons for discontinuation, overall response rate, safety and tolerability, use of CoQ10 and calcium supplements, and insurance coverage. Of 55 patients assessable for outcome, 34 (61.8%) had an overall clinical benefit, with 25 (45.4%) having a complete response and 9 (16.3%) a partial response. Stable disease was seen in 14 (25.4%) and 7 (12.7%) progressed. Of the 34 patients who responded to treatment, 9 recurred. Patients who were rechallenged with HHI could respond again. The median overall BCC-specific survival rate at 5 years is 89%. Dose reductions or discontinuations for vismodegib and sonidegib occurred in 59% versus 24% of cases, or 30% versus 9% of cases, respectively. With CoQ10 and calcium supplementation, only 17% required a dose reduction versus 42% without. HHI is highly effective for treating advanced BCC but may require dosing decreases. Sonidegib was better tolerated than vismodegib. CoQ10 and calcium supplementation can effectively prevent muscle spasms.

Necrosis of the Ear Following Skin Cancer Resection.

We report 2 patients who underwent Mohs micrographic surgery (MMS) and operative closure on the ear. Both cases were complicated by necrosis resulting in the formation of auricular defects. These cases highlight the importance of the auricular vasculature and the associated watershed regions during operative planning for MMS as well as the complications that can arise with vascular compromise. This case report also provides a review of the auricular vasculature with special attention to these vulnerable watershed regions.

Reproducible Histopathologic Features in Cases of Basal Cell Carcinoma With Neuroendocrine Expression: A Clinicopathologic Study of 24 Cases With a Potential Diagnostic Pitfall.

ABSTRACT: Basal cell carcinomas (BCCs) are common malignancies that usually show clear histomorphologic features, but in certain instances, it can display different patterns of differentiation leading to potential diagnostic confusion. BCCs with neuroendocrine differentiation/expression have been mentioned only briefly in the literature. In this study, we present cases of BCCs with neuroendocrine differentiation/expression that demonstrate reproducible histopathological features. Twenty-four cases were included in the study. All tumors showed conventional histopathologic features that are seen in BCCs, but in addition, all the tumors showed large, hyperchromatic, pleomorphic, mononuclear, and multinucleate cells with intracytoplasmic inclusions and intranuclear cytoplasmic invaginations, with rare cases showing stippled nuclei (salt-and-pepper appearance). These histologic features were somewhat concerning for a neuroendocrine carcinoma; thus, immunohistochemistry studies were performed in all cases at the time of diagnosis. By immunohistochemistry, all tumors showed expression of neuroendocrine markers. CD56 was expressed in all cases 24/24, chromogranin was positive in 17/24 cases, and synaptophysin 8/24 was positive in cases. This study confirms a subset of histopathologic features that are present in cases of BCC that are associated with neuroendocrine expression that can potentially be interpreted differently and can create a diagnostic pitfall. Neuroendocrine expression in BCCs is yet uncertain, and further studies are required to fully understand this phenomenon. To avoid diagnostic pitfalls, dermatopathologists must be aware of these unusual histopathologic features and aberrant immunostaining in such tumors; hence, it is advised to perform a thorough histologic inspection.

Multiple Plantar Poromas in a Stem Cell Transplant Patient.

Poromatosis, or the formation of multiple eccrine poromas, is associated with chronic immunosuppression, lymphoproliferative neoplasms, and stem cell transplantation, though the etiology and clinical significance remain poorly understood. Eccrine poromas are asymptomatic, may appear years after treatment, and overlap morphologically with other diagnoses, particularly human papillomavirus-associated verrucae, to which immunosuppressed patients may be predisposed and commonly occur in similar sites. We report a 47-year-old female on chronic immunosuppression who developed multiple plantar eccrine poromas three years after achieving acute myeloid leukemia (AML) remission following treatment with chemotherapy, total body irradiation, and allogenic stem cell transplantation. We propose that early recognition, timely treatment, and regular follow-up skin examinations are necessary in the setting of multiple poromas to reduce the risk of malignancy and avoid delays in diagnosis.

Apparent darkening of scalp hair related to pili multigemini Following dabrafenib and trametinib.

The combination of dabrafenib and trametinib is an important immunotherapy option for patients with BRAF V600 mutation-positive melanoma. This regimen has been reported to cause cutaneous eruptions. However, hair dysmorphology is not a reported side effect to these or any other medications to date. Herein, we highlight a case of pili multigemini formation in a patient with stage IV melanoma receiving treatment with dabrafenib and trametinib and the corresponding clinical findings.

Improved patient access and outcomes with the integration of an eConsult program (teledermatology) within a large academic medical center.

BACKGROUND: Insurance, racial, and socioeconomic health disparities continue to pose significant challenges for access to dermatologic care. Studies applying teledermatology to increase access to underinsured individuals and ethnic minorities are limited. OBJECTIVE: To determine how the implementation of a teledermatology program affects access to health care and patient outcomes. METHODS: A cross-sectional evaluation was performed of all ambulatory dermatology referrals and electronic dermatology consultations (eConsults) at Ohio State University within a 25-month period. RESULTS: Compared with ambulatory referrals, eConsults served more nonwhite patients (612 of 1698 [36.0%] vs 4040 of 16,073 [25.1%]; P < .001) and more Medicaid enrollees (459 of 1698 patients [27.0%] vs 3266 of 16,073 [20.3%]; P < .001). In addition, ambulatory referral patients were significantly less likely to attend their scheduled appointment compared with eConsult patients, as either "no-shows" (246 of 2526 [9.7%] vs 3 of 62 [4.8%]) or cancellations (742 of 2526 [29.4%] vs 8 of 62 [12.9%]; P = .003). There were fewer median days to extirpation for eConsult patients compared with ambulatory referral patients (interquartile range; 80.7 ± 79.8 vs 116.9 ± 86.6 days; P = .004). CONCLUSION: Integrating dermatologic care through a telemedicine system can result in improved access for underserved patients through improved efficiency outcomes.

A Retrospective Analysis Comparing the New Standardized Letter of Recommendation in Dermatology with the Classic Narrative Letter of Recommendation.

Background: In an effort to avoid numerous problems associated with narrative letters of recommendation, a dermatology standardized letter of recommendation was utilized in the 2014-2015 resident application cycle. Objective: A comparison of the standardized letter of recommendation and narrative letters of recommendation from a single institution and application cycle to determine if the standardized letter of recommendation met its original goals of efficiency, applicant stratification, and validity. Methods: Eight dermatologists assessed all standardized letters of recommendation/narrative letters of recommendation pairs received during the 2014-2015 application cycle. Five readers repeated the analysis two months later. Each letter of recommendation was evaluated based on a seven question survey. Letter analysis and survey completion for each letter was timed. Results: Compared to the narrative letters of recommendation, the standardized letter of recommendation is easier to interpret (p<0.0001), has less exaggeration of applicants' positive traits (p<0.001), and has higher inter-rater and intrarater reliability for determining applicant traits including personality, reliability, work-ethic, and global score. Standardized letters of recommendation are also faster to interpret (p<0.0001) and provide more information about the writer's background or writer-applicant relationship than narrative letters of recommendation (p<0.001). Limitations: This study was completed at a single institution. Conclusions: The standardized letter of recommendation appears to be meeting its initial goals of 1) efficiency, 2) applicant stratification, and 3) validity. (J Clin Aesthet Dermatol. 2016;9(9):36-2.).

Cutaneous malignancies of the perineum.

This review discusses multiple cutaneous malignancies that can present on the perineum. Although all of these neoplasms are uncommon, a focus will be on the more common neoplasms including extramammary Paget disease, basal cell carcinoma, squamous cell carcinoma, and melanoma. Other more rare entities discussed are superficial leiomyosarcoma, giant solitary trichoepithelioma, and cutaneous endometriosis.

Lymphangioma circumscriptum of the vulva in a patient with Noonan syndrome.

Lymphangioma circumscriptum (LC) results from the development of abnormal lymphatic vasculature and is characterized by the presence of grouped vesicles filled with clear or colored fluid. Vulvar localization is uncommon. Abnormalities of the lymphatic system, such as lymphedema and cystic hygroma, are well-known features of genetic disorders such as Noonan syndrome (NS) and Turner syndrome. We report the case of a patient with NS who presented with LC of the vulva. We also discuss the expanding spectrum of clinical anomalies associated with the presentation of NS.

Evaluation of the value of frozen tissue section used as "gold standard" for immunohistochemistry.

To examine the use of acetone- or ethanol-fixed frozen tissue sections as the "gold standard" for immunohistochemical analysis, we evaluated frozen sections with various conditions of fixation and antigen retrieval (AR). Fresh human tissues were frozen in OCT. An adjacent tissue block was fixed in 10% neutral buffered formalin (NBF) and paraffin embedded (FFPE). Frozen sections were fixed by 6 protocols: acetone, ethanol, NBF (2 durations), and NBF + calcium chloride (2 durations). AR was used for all NBF-fixed sections. More than half of the antibodies (16/26 [62%]) showed immunohistochemical results indistinguishable between acetone- and NBF-fixed sections; 8 (31%) showed better immunohistochemical signals following NBF and AR; 2 gave better immunohistochemical results for acetone-fixed sections. Most cytoplasmic proteins (10/13) showed comparable immunohistochemical signals between acetone- and NBF-fixed sections. For nuclear proteins, NBF-fixed sections gave better immunohistochemical signals than did acetone-fixed sections. In most cases, NBF yielded stronger signals with less background and better morphology. The data do not support the use of acetone-fixed frozen tissue sections as the gold standard for immunohistochemical analysis. In evaluating new antibodies, a combination of acetone- and NBF-fixed frozen sections should be used, although in practice, FFPE tissue sections may serve as the standard for most antigens for immunohistochemical analysis.

ErbB-2 induces the cyclin D1 gene in prostate epithelial cells in vitro and in vivo.

The receptor tyrosine kinase ErbB-2 plays an important role in the regulation of growth factor-induced signal transduction cascades in the epithelium, and ErbB-2 is frequently overexpressed in epithelial tumors. Our previous studies on clinical prostate cancer specimens indicated that ErbB-2 expression was increased in patients undergoing hormone ablation therapy. We had also shown that the critical cell cycle regulatory gene cyclin D1 and its promoter were targets of proliferative signaling in prostate cancer cell lines, and that cyclin D1 was required for ErbB-2-induced mammary tumorigenesis. In the current studies, we found that increased ErbB-2 membrane expression correlated with increased nuclear cyclin D1 staining in clinical prostate cancer specimens, and that expression of ErbB-2 was capable of inducing cell cycle progression in human prostate cancer cell lines. We further showed that ErbB-2 induced the cyclin D1 promoter in DU145 cells, and that small interfering RNA knockdown of cyclin D1 protein levels blocked a significant proportion of the heregulin-induced cell cycle progression in LNCaP cells. Probasin promoter-targeted expression of an activated ErbB-2 isoform induced cyclin D1 expression in the mouse prostate, commensurate with prostate intraepithelial neoplasia. Together, these in vitro and in vivo studies identify cyclin D1 as a critical downstream target of ErbB-2 in the prostate epithelium, both of which are possible therapeutic targets for cancer intervention. Furthermore, our novel mouse model provides a useful platform for ongoing in vivo investigations of ErbB-2 signaling in the prostate epithelium.

Expression of stress response protein Grp78 is associated with the development of castration-resistant prostate cancer.

BACKGROUND: Induction of molecular chaperone Grp78 (78-kDa glucose-regulated protein) occurs in stress conditions that often characterize tumor microenvironments. We investigated the role of Grp78 in prostate cancer progression and the development of castration resistance, where cancer cells continue to survive despite the stress of an androgen-starved environment. EXPERIMENTAL DESIGN: Immunohistochemistry was done to examine Grp78 expression in 219 prostate cancers from patients with pathologic stage T3N0M0 disease [androgen ablation naive (untreated) and androgen ablation exposed (treated)] and castration-resistant prostate cancer. Classification of tumors was based on intensity of Grp78 cytoplasmic immunoreactivity and percentage of immunoreactive tumor cells. The associations of Grp78 expression with prostate cancer recurrence (clinical and/or serum prostate-specific antigen) and survival were examined in the untreated stage T3N0M0 group. Grp78 expression was also analyzed in the androgen-dependent LNCaP and castration-resistant C42B cell lines. RESULTS: The percentage of tumor cells expressing Grp78 was strongly associated with castration-resistant status (P = 0.005). Increased Grp78 expression was consistently associated with greater risk of prostate cancer recurrence and worse overall survival in patients who had not undergone prior hormonal manipulation. Grp78 expression was also increased in the castration-resistant LNCaP-derived cell line C42B and in LNCaP cells grown in androgen-deprived conditions compared with LNCaP cells grown in androgen-rich media. CONCLUSION: Our findings show that up-regulation of Grp78 is associated with the development of castration resistance, possibly in part by augmenting cell survival as previously suggested, and may serve as an important prognostic indicator of recurrence in a subset of patients with T3N0M0 disease.

Role of coordinated molecular alterations in the development of androgen-independent prostate cancer: an in vitro model that corroborates clinical observations.

OBJECTIVE: To investigate the role of potential downstream targets of HER-2/neu, including the cell-cycle regulator p27, proliferation-associated protein Ki-67, apoptosis inhibitor Bcl-2, and signal-transduction molecule Akt (which is associated with cell survival), as the development of androgen-independent prostate cancer (AIPC) in patients who are initially responsive to androgen-ablation therapy (AAT) is a significant clinical problem. PATIENTS AND METHODS: Earlier studies showed that high levels of HER-2/neu tyrosine kinase receptor expression as assessed by immunohistochemistry were significantly associated with the development of AIPC, and we hypothesised that HER-2/neu overexpression provides an alternative proliferative stimulus upon androgen depletion. We established a unique clinical model system, comprising patients who received no AAT, or who had preoperative AAT, or those with advanced tumours resistant to AAT. To test our hypothesis in vitro, we stably transfected full-length HER-2/neu cDNA in androgen-responsive LNCaP cells and examined the effects of HER-2/neu overexpression on cell proliferation, apoptosis, androgen-receptor activation, and Akt phosphorylation upon androgen deprivation by using immunohistochemistry and Western blot technique. RESULTS: p27 expression was initially induced on exposure to AAT, and significantly decreased in AIPC (P < 0.001). There was also a significant increase in the Ki-67 index in AIPC (P = 0.001). Elevated Bcl-2 expression was closely associated with AAT (P = 0.002), suggesting that Bcl-2 expression is induced on initial exposure to AAT. Further, Bcl-2 expression was highest in hormone-resistant cancers (P < 0.001). Using the HER-2/neu transfected cell-line model, we confirmed the mechanistic basis of the clinical observations which elucidate the pathway leading to HER-2/neu-mediated androgen independence. On androgen deprivation, the HER-2/neu transfected cells had higher proliferation rates, lower G1 arrest, inhibited p27 up-regulation, a lower apoptotic index, and higher Bcl-2, prostate-specific antigen and phosphorylated Akt expression than the mock-transfected LNCaP cells. CONCLUSION: This study suggests that prostate cancer cells undergo a series of coordinated changes after exposure to AAT, which eventually result in the development of androgen independence. Further, in support of previous results, it appears that a major factor in this process is the induction of HER-2/neu overexpression, which occurs after initial exposure to AAT. HER-2/neu may contribute to the development of androgen independence through: (i) maintaining cell proliferation; (ii) inhibiting apoptosis; and/or (iii) inducing AR activation in a ligand-independent fashion. These effects may be mediated, at least in part, through activation of the PI3K/Akt pathway.