Faculty Bibliography

BACKGROUND:As the incidence of frontal fibrosing alopecia (FFA) continues to rise, there is a need for an optimal treatment algorithm for FFA. OBJECTIVE:To produce an international consensus statement on the treatment modalities and prognostic indicators of FFA. METHODS:Sixty-nine hair experts from six continents were invited to participate in a three-round Delphi process. The final stage was held as a virtual meeting facilitated via Zoom. The consensus threshold was set at ≥66%. RESULTS:Of 365 questions, expert consensus was achieved in 204 (56%) questions following completion of the three rounds. Three additional questions were included at the final meeting. The category with the strongest consensus agreement was disease monitoring (9; 100%). Questions pertaining to physical therapies achieved the least category consensus (15; 40%), followed by systemic therapy (45; 43%). LIMITATIONS/CONCLUSIONS:The study lacked sufficient representation from Africa and South America. CONCLUSION/CONCLUSIONS:SOFFIA highlights areas of agreement and disagreement among experts. Robust research is warranted to provide evidence-based treatment recommendations.

Lymphatic vessels activate anti-tumor immune surveillance and support metastasis. Whether there are distinct lymphatic phenotypes that govern immunity and metastasis remains unclear. Here we reveal that cytotoxic immunity normalizes lymphatic function and uncouples immune and metastatic potential. We demonstrate that intratumoral lymphatic vessel density negatively correlates with cytotoxic immunity and that IFNγ reprograms the intratumoral lymphatic state. Lymphatic deletion of Ifngr1 expanded the intratumoral lymphatic network and drove the emergence of a tip-like state that promotes lymph node metastasis but not dendritic cell migration or response to immune checkpoint blockade (ICB). Mechanistically, IFNγ restrains proliferation and cell state programs through inhibition of mitochondrial respiration. Lymphatic-specific inhibition of mitochondrial complex III restrained the intratumoral tip-like state, blocked metastasis, and enhanced the response to ICB. Our data reveal that IFNγ induces a metabolic and phenotypic switch in tumor-associated lymphatic vessels that blocks regional metastasis and reinforces immune surveillance.

BACKGROUND:Penile cancer is a rare malignancy, the most common subtype of which is squamous cell carcinoma (SCC). Organ-sparing surgery (OSS) is the first-line treatment for early-stage tumors given the quality-of-life impairments of penectomy. However, the rarity of penile SCC has made the large-scale study of the efficacy of surgical approaches difficult. OBJECTIVE:To evaluate the rates of positive margins with the surgical approaches for penile SCC. METHODS:Retrospective cohort study of adult patients with excised penile SCC from the National Cancer Database diagnosed from 2004 to 2019. RESULTS:We found that treatment of penile SCC with OSS resulted in a positive margin rate of 18.8% (SE: 0.7%) versus 9.7% (SE: 0.4%) with partial penectomy and was associated with twice the odds of a positive margin compared with partial penectomy (odds ratio 2.312; p < .001). Positive margins were associated with poorer overall survival on multivariable analysis (hazard ratio 1.528; p < .01). CONCLUSION/CONCLUSIONS:OSS for penile SCC results in high rates of positive margins, which are associated with poorer overall survival. Use of margin-controlled surgery may improve local control for these tumors while minimizing functional damage to an anatomically sensitive organ, allowing for the most optimal quality-of-life outcomes.

BACKGROUND:Immunosuppression is associated with a higher risk of developing cutaneous squamous cell carcinoma and more aggressive tumors, but its role as an independent predictor of poor outcomes remains unclear. OBJECTIVE:To determine whether immunosuppression independently predicts poor outcomes in cutaneous squamous cell carcinoma. METHODS:This was a retrospective cohort study with pooled data from 12 international centers. Demographics, immunosuppression status, tumor characteristics, treatment, and outcomes were collected. Univariable and multivariable marginal Fine and Gray competing risk analyses were performed. Subgroup multivariable analyses were performed on the organ transplant and chronic lymphocytic leukemia cohorts. RESULTS:A total of 11,930 patients with 18,760 tumors (14,766 in immunocompetent and 3,994 in immunosuppressed) were included. Immunosuppressed patients had a higher prevalence of high-risk tumor features and poor disease outcomes. On multivariable analysis, immunosuppression was independently associated with local recurrence, distant metastasis, disease-specific death, and major poor outcomes. Organ transplantation was predictive of local recurrence, distant metastasis, and disease-specific death, whereas chronic lymphocytic leukemia independently predicted local recurrence, disease-specific death, and major poor outcomes. LIMITATIONS/CONCLUSIONS:Retrospective design, potential for data heterogeneity. CONCLUSIONS:Immunosuppression is an independent risk factor for major poor outcomes in cutaneous squamous cell carcinoma and should be included in risk nomograms.

Signaling interactions between the dermal papilla (DP) and neighboring stem cells in the hair germ (HGSCs) and bulge (BuSCs) regulate new follicle growth in the hair cycle. To study these interactions, the three populations had been profiled together by now-outdated microarrays or separately by bulk RNA-sequencing. Recent single-cell transcriptomics established signatures of DP, BuSCs and HGSCs, but low detection sensitivity limited the depth of gene expression discovery. Here, we define the transcriptomes of DP, BuSCs, HGSCs, epidermal, follicle and dermal fibroblast cells-after flow-sorting each population from four neighboring mouse back skin regions-to gain deeper insights into the unique gene expression programs of SCs and their instructive niche. With cross-comparisons of 56 whole-transcriptome measurements, we classify cell type-specific molecular signatures of enriched genes with unprecedented sensitivity. Joint analysis with signatures from 15 leading studies published in the last 20 years revealed many previously undescribed DP, BuSC and HGSC genes in mouse and human counterparts. With ligand-receptor mapping and CellChat analyses we then uncover comprehensive cell-cell communication insights. Finally, we provide a new installment of our Hair-Gel repository along with numerous signature and other gene tables for easy exploration of gene expression in hair follicle SCs and their niche.

PURPOSE/OBJECTIVE:Patients with stage II and resected stage III melanomas have variable clinical outcomes, evidence of underlying biological differences in tumors and/or the patients themselves, beyond stage. The approval of adjuvant immunotherapy for stage IIB/C and resected stage III/IV disease (and adjuvant targeted therapy for resected stage III disease), has created a pressing need to develop biomarkers to accurately distinguish patients at low- versus high-risk for recurrence and death from melanoma. MicroRNAs (miRNAs) are promising biomarkers because of their stability in tissues/fluids and their demonstrated functional and prognostic roles in melanoma. We hypothesized that miRNA expression could be integrated into prognostic models that would more accurately classify 5-year survival outcomes than clinical factors alone. PATIENTS AND METHODS/METHODS:Using a Nanostring miRNA Expression Assay, we analyzed 715 primary melanomas from patients with stage II or stage III disease within the InterMEL consortium, and examined associations between miRNA expression and melanoma-specific death. RESULTS:When integrated into clinical prognostic models for 5-year melanoma-specific survival, miRNA signatures improved the area under the receiver operating characteristic curve (AUC) for stage II patients from 0.71 for a 'clinical factors-only' model to 0.81 for a 'clinical plus miRNA' model in an independent test set, an improvement of 0.10 with 95% CI (0.03, 0.19). The improvement was more modest for stage III patients that were included in the analysis. CONCLUSIONS:Incorporating miRNA expression in primary melanomas may enhance the accuracy of clinical prognostic models, and potentially aid the selection of melanoma patients for adjuvant treatment and clinical trials.