Welcome to this month's journal review podcast, covering key surgical dermatology and dermatologic oncology literature from the Journal of the American Academy of Dermatology, July twenty twenty-six. We have four articles on the docket today, spanning nail surgery analgesia, melanoma genomics, nail unit squamous cell carcinoma, and Mohs margins for melanoma in situ on the head and neck. Let's get into it.

Our first article is titled "A Novel Utilization of Liposomal Bupivacaine in Nail Procedures," by Camille Robinson, Minsoo Kim, Ruby Kwak, and Brian Morrison, from the University of Miami and University of Michigan.

The clinical question here is whether liposomal bupivacaine, an extended-release local anesthetic FDA-approved for postsurgical analgesia via infiltration or nerve block rather than as a primary intraoperative anesthetic, can improve postoperative pain control after nail procedures, an indication not previously studied in dermatology outside of Mohs surgery.

This was a retrospective cohort study, IRB-approved at University of Miami, of twenty-four patients undergoing nail procedures, twelve receiving liposomal bupivacaine admixed with zero-point-five percent bupivacaine, and twelve receiving zero-point-seven-five percent ropivacaine, both delivered via a two cc wing block. Procedures included nail matrix biopsy in seventeen patients, nail bed biopsy in five, and nail avulsion in two, performed by ten different physicians. Patients self-reported pain, sensation, numbness, and motor function on zero-to-ten scales by phone on postoperative days one through three, analyzed using linear mixed models with likelihood ratio testing.

Key findings: liposomal bupivacaine reduced pain by one-point-five points relative to ropivacaine, which did not reach statistical significance at p equals zero-point-zero-six-one, but this magnitude meets the published minimal clinically important difference of one-point-three to two points on an eleven-point numeric rating scale. Motor function was improved by one-point-seven points with liposomal bupivacaine, also not statistically significant at p equals zero-point-zero-seven-nine. There was no meaningful between-group difference in sensation, at p equals zero-point-eight-two, and numbness trended higher with liposomal bupivacaine by zero-point-seven-eight points, p equals zero-point-zero-eight-nine. No adverse events occurred in either group.

The evidence-based takeaway: this small pilot suggests liposomal bupivacaine may offer clinically meaningful pain reduction and preserved motor function after nail procedures without sacrificing sensation, but the study is underpowered, with all anesthetic-effect p-values above zero-point-zero-five. Limitations include the small sample of twenty-four, retrospective design, heterogeneous procedure types, ten different surgeons introducing technique variability, absence of a placebo arm, and no blinding. The authors themselves call for prospective, adequately powered trials before this can be considered practice-changing, but for surgeons already using liposomal bupivacaine off-label in nail surgery, this provides the first dermatology-specific data point supporting its use in this setting.

Our second article is "Driver Mutations and Tumor Mutational Burden Impact Stage Four Melanoma Survival," by Shaliz Aflatooni, Logan Hubbert, Monica Khadka, Lily Parker, Zoe Lipman, Rahul Mhaskar, Kenneth Tsai, and James Grichnik, from the University of South Florida and Moffitt Cancer Center.

The clinical question is whether specific driver gene mutations and tumor mutational burden are associated with differential survival in stage four melanoma, with implications for personalized management.

This was a retrospective, IRB-approved study of three hundred eighty-nine melanoma patients who underwent standardized one-hundred-seventy-gene sequencing between February twenty-eighteen and December twenty twenty-two. Patients were stratified by pathogenic mutations in GNAQ, GNA11, NRAS, BRAF, KIT, NF1, or wild type, with tumor mutational burden defined as total mutation count. Patients with incomplete data or non-melanoma death were excluded.

Key findings: overall survival differed significantly by mutated driver gene, p less than zero-point-zero-zero-one. Median time from stage four diagnosis to death across the cohort was one thousand five hundred twenty-four days. NF1-mutated tumors had the longest median survival at two thousand four hundred twenty-seven days, followed by BRAF at one thousand seven hundred forty-three days. Intermediate survival was seen with NRAS at one thousand five hundred six days and wild type at one thousand four hundred sixty-three days. GNAQ and GNA11 mutations had the shortest survival at four hundred sixty-nine days, and KIT mutations at nine hundred eighteen days. These differences held at five and ten years of follow-up, both p less than zero-point-zero-zero-one, and remained significant on Cox proportional hazards regression adjusting for tumor mutational burden, with a hazard ratio of zero-point-nine-seven-zero and ninety-five percent confidence interval of zero-point-nine-five-zero to zero-point-nine-nine-zero, as well as after adjusting for immunotherapy and molecular therapy use, and even after excluding GNAQ and GNA11 tumors entirely, p still less than zero-point-zero-zero-one.

Tumor mutational burden itself varied significantly by driver gene, p less than zero-point-zero-zero-one, with NF1 tumors showing the highest mean burden at twenty-eight-point-eight, standard deviation twenty-six-point-five, and GNAQ or GNA11 tumors the lowest at five-point-seven, standard deviation two-point-five. Higher tumor mutational burden correlated with better overall survival, p less than zero-point-zero-zero-one. TERT promoter mutations were also associated with higher tumor mutational burden, p less than zero-point-zero-zero-one. Immunotherapy use did not correlate with tumor mutational burden, p equals zero-point-six-nine, but did correlate with driver gene, p equals zero-point-zero-four, with BRAF-mutated tumors somewhat less likely to receive immunotherapy, at eighty-five percent. Response to immunotherapy correlated significantly with both driver gene, p equals zero-point-zero-zero-five, and tumor mutational burden, p less than zero-point-zero-zero-one.

Evidence-based takeaway: NF1 and BRAF V600E mutations are associated with improved stage four melanoma survival, while GNAQ, GNA11, and KIT mutations predict poorer outcomes, independent of tumor mutational burden and treatment type. This supports incorporating driver mutation profiling into prognostic counseling and personalized treatment planning for advanced melanoma. The principal limitation, acknowledged by the authors, is that survival patterns will shift as systemic therapies continue to evolve, so these associations should be interpreted within the treatment era studied.

Our third article is a commentary piece, "Highlights from JAAD Reviews: Cracking the Code on Nail Unit Squamous Cell Carcinoma," by Shari Lipner of Weill Cornell Medicine.

This piece synthesizes two recent publications on nail unit squamous cell carcinoma, or NSCC. The first, an expert panel review by Curtis and colleagues in JAAD Reviews, addresses epidemiology, human papillomavirus, or HPV, pathogenesis, and management. It reinforces that Mohs micrographic surgery is standard of care for NSCC, citing recurrence rates of three-point-six to ten percent, compared with twenty-five to fifty-six percent for conventional excision.

The second, a multinational retrospective study led by Lipner and colleagues, is described as the largest series to date, encompassing two hundred sixty-nine NSCCs in two hundred sixty-one patients. Mean diagnostic delay was three-point-one years, with frequent tumor localization to the thumb and index and middle fingers, potentially reflecting genital-digital HPV inoculation or cigarette holding.

Key clinically actionable findings center on predictors of invasion. Subungual ooze independently predicted invasive NSCC. Pain and nail plate loss were associated with invasive disease on univariate analysis. Conversely, koilocytosis was more common in in situ tumors, in periungual locations, and in younger patients. These findings align with a previously proposed two-subtype model distinguishing a blue-basaloid, HPV-driven, periungual, in situ phenotype from a pink-keratinizing, non-HPV, subungual, invasive phenotype.

Both papers reinforce genital-digital HPV transmission as a pathogenic mechanism. A separate study by Shimizu and colleagues found that twenty-four percent of HPV-related NSCC cases had a history of HPV disease elsewhere, and in the Lipner multicenter series, approximately ten percent of patients had a documented history of HPV-related disease at genital, cervical, perianal, or oropharyngeal sites. The practical implication is that clinicians should be asking NSCC patients about anogenital HPV history and offering examination or referral accordingly.

Limitations noted include reliance on koilocytosis rather than PCR confirmation for HPV status in some patients, introducing possible misclassification bias, undefined imaging criteria for bony invasion, limited recurrence data, and a near-absence of data in skin of color patients. Open questions include whether PCR testing for high-risk HPV subtypes pre- and post-surgery, or p16 immunohistochemistry of Mohs margins, could reduce recurrence, both of which remain unanswered but represent logical next steps for surgical practice.

Our fourth and final article is a JAAD Game Changers commentary by Jane Grant-Kels, covering the original study "Excision Margins for Melanoma In Situ on the Head and Neck: A Single-Center Ten-Year Retrospective Review of Treatment with Mohs Micrographic Surgery," originally authored by Jesalyn Tate, Andrew Matsumoto, Charlotte Greif, Jorena Lim, Rajiv Nijhawan, and Divya Srivastava.

The clinical question addressed is a long-debated one for our field: how wide a margin is actually required to clear melanoma in situ on the head and neck, and is the conventional five millimeter margin adequate.

This was a retrospective chart review of eight hundred forty-six melanoma in situ cases on the head and neck, comprising eight hundred seven primary and thirty-nine recurrent tumors, all treated with Mohs micrographic surgery, allowing precise determination of the margin required for histologic clearance in each case.

Key findings: only sixty-two percent of tumors were cleared with a five millimeter margin. Achieving a ninety-seven percent clearance rate required margins out to fifteen millimeters. Tumor location on the cheek and larger preoperative clinical size were both correlated with the need for margins greater than five millimeters.

Evidence-based takeaway for surgical practice: standard five millimeter margins are inadequate for a substantial proportion of head and neck melanoma in situ cases, particularly larger tumors and those located on the cheek. When Mohs micrographic surgery is not available or feasible, the commentary notes that excision margins of ten millimeters or more are often necessary for head and neck tumors to achieve equivalent clearance. Practically, this data supports more accurate preoperative patient counseling regarding expected defect size and reconstructive planning before definitive surgery, particularly for larger or cheek-located lesions where wide subclinical extension should be anticipated.

That closes out this month's four articles. In summary, we covered a pilot study suggesting a possible role for liposomal bupivacaine in post-nail-surgery analgesia pending larger trials, genomic data tying specific melanoma driver mutations to stage four survival outcomes independent of tumor mutational burden, a synthesis of nail unit squamous cell carcinoma diagnostics emphasizing HPV risk stratification and predictors of invasion, and Mohs-based margin data confirming that head and neck melanoma in situ frequently requires wider-than-standard excision margins for clearance. Thank you for listening, and we'll see you next month.