Paul H. McClelland

A comprehensive framework for descriptive statistics and regression analysis that produces publication-ready tables and forest plots. Provides a unified interface from descriptive statistics through multivariable modeling, with support for linear models, generalized linear models, Cox proportional hazards, and mixed-effects models. Also includes univariable screening, multivariate regression, model comparison, and export to multiple formats including PDF, DOCX, PPTX, 'LaTeX', HTML, and RTF. Built on 'data.table' for computational efficiency.

Marker genes used for annotating major cell types in single cell RNA sequencing analysis.

Antibody panel used in co-detection by indexing (CODEX) multiplexed immunofluorescence tissue imaging.

Patient demographics, genetic, and histopathology characteristics.

Additional SRC-enriched markers from single cell RNA sequencing analysis.

Leading edge analysis following GSEA demonstrating enriched pathways associated with ECM remodeling between SRC and EP.

PURPOSE: Acral lentiginous melanoma is a subtype of cutaneous melanoma arising from palmar, plantar, or subungual skin. These tumors are characterized by aggressive biology, a low tumor mutational burden (TMB), and diminished sensitivity to immune checkpoint blockade. It is unknown whether adoptive cell transfer of tumor-infiltrating lymphocytes (ACT-TIL) has efficacy in patients with acral melanoma. METHODS: We analyzed prospectively collected data from 442 patients with metastatic cutaneous melanoma who were treated on clinical trials of ACT-TIL at a single institution between 1999 and 2018. Although blinded to treatment outcome and genomic data, we retrospectively identified patients who had acral subtype on the basis of clinicopathologic data available at the time of diagnosis. We then evaluated the ACT-TIL treatment outcomes of patients with acral melanoma and compared them with contemporaneously treated patients with nonacral melanoma. RESULTS: Out of 442 included patients, 30 (7%) had acral melanoma while 412 (93%) had nonacral melanoma. Cohorts had similar clinical characteristics, protocol enrollment, and treatment-related factors. The objective response rate to ACT-TIL in patients with acral and nonacral melanomas was 43% and 40%, respectively ( P = .87), with 3% and 16% having complete responses (CRs; P = .07). Median progression-free survival was 3.5 and 4.1 months ( P = .40) and median overall survival was 13 and 17 months ( P = .79), respectively. Acral melanomas had lower TMB and ultraviolet mutational signature scores than nonacral melanomas. CONCLUSION: ACT-TIL can mediate objective responses in patients with metastatic acral melanoma, and outcomes in patients with acral disease were unexpectedly comparable with those of contemporaneously treated patients with nonacral cutaneous melanoma. Further research is necessary to understand the immunologic basis of responses to ACT-TIL in acral melanoma and to increase the frequency of CRs.

Germline CDH1 loss-of-function mutations are causally linked to an increased lifetime risk of diffuse gastric cancer (DGC). Early, multifocal signet ring cell (SRC) lesions are ubiquitous among CDH1 variant carriers, yet only a subset of patients will develop advanced DGC. A multiomic analysis was performed to establish the molecular phenotype of early SRC lesions and how they differ from advanced DGC using 20 samples from human total gastrectomy specimens of germline CDH1 variant carriers. Spatial transcriptomic analysis demonstrated reduced CDH1 gene expression and increased expression of extracellular matrix remodeling in SRC lesions compared with unaffected adjacent gastric epithelium. Single-cell RNA sequencing revealed an SRC-enriched signature with markers REG1A, VIM, AQP5, PRR4, MUC6, and AGR2. Importantly, SRC lesions lacked alterations in known drivers of gastric cancer (TP53, ARID1A, and KRAS) and activation of associated signal transduction pathways. Advanced DGC demonstrated E-cadherin reexpression, somatic TP53 and ERBB3 mutations, and upregulated CTNNA1, MYC, and MET expression when compared with SRC lesions. Implications: The marked differences in the genomic and transcriptomic profiles of SRC lesions and advanced DGC support the consideration of SRC lesions as precancers in patients with germline CDH1 mutations.

Background Iatrogenic urinary injury (IUI) can lead to significant complications after colorectal surgery, especially when diagnosis is delayed. This study analyzes risk factors associated with IUI and delayed IUI among patients undergoing colorectal procedures. Methods Adults undergoing colorectal surgery between 2012 and 2021 were identified in the American College of Surgeons National Surgical Quality Improvement Program (NSQIP^®) database. Multivariable regression analysis was used to determine risk factors and outcomes associated with IUI and delayed IUI. Results Among 566,036 patients, 5836 patients (1.0%) had IUI after colorectal surgery, of whom 236 (4.0%) had delayed IUI. Multiple preoperative risk factors for IUI and delayed IUI were identified, with disseminated cancer [adjusted odds ratio (aOR) 1.4, 95% confidence interval (CI) 1.2–1.5; p < 0.001] and diverticular disease [aOR 1.1, 95% CI 1.0–1.2; p = 0.009] correlated with IUI and increased body mass index [aOR 1.6, 95% CI 1.2–2.1; p = 0.003] and ascites [aOR 5.6, 95% CI 2.1–15.4; p = 0.001] associated with delayed IUI. Laparoscopic approach was associated with decreased risk of IUI [aOR 0.4, 95% CI 0.4–0.5; p < 0.001] and increased risk of delayed IUI [aOR 1.8, 95% CI 1.4–2.5; p < 0.001]. Both IUI and delayed IUI were associated with significant postoperative morbidity, with severe multiorgan complications seen in delayed IUI. Conclusions While IUI occurs infrequently in colorectal surgery, unrecognized injuries can complicate repair and cause other negative postoperative outcomes. Patients with complex intra-abdominal pathology are at increased risk of IUI, and patients with large body habitus undergoing laparoscopic procedures are at increased risk of delayed IUI.