Older age is associated with increased FNR; patients with thick, ulcerated lesions should be considered for increased nodal surveillance after negative SLNB given low NPV in this group.

Introduction Sentinel lymph node (SLN) biopsy is recommended for all patients with intermediate thickness melanomas. We sought to identify such patients at low risk of SLN positivity. Methods All patients with intermediate thickness melanomas (1.01–4 mm) undergoing SLN biopsy at a single institution from 1995–2011 were included in this retrospective cohort study. Univariate and multivariate logistic regression determined factors associated with a low risk of SLN positivity. Classification and regression tree (CART) analysis was used to stratify groups based on risk of positivity. Results Of the 952 study patients, 157 (16.5%) had a positive SLN. In the multivariate analysis, thickness <1.5 mm (OR= 0.29), age ≥60 (OR=0.69), present tumor infiltrating lymphocytes (TIL) (OR=0.60), absent lymphovascular invasion (LVI) (OR=0.46), and absent satellitosis (OR=0.44) were significantly associated with a low risk of SLN positivity. CART analysis identified thickness of 1.5 mm as being the primary cut point for risk of SLN metastasis. Patients with a thickness of <1.5 mm represented 36% of the total cohort and had a SLN positivity rate of 6.6% (95% CI=3.8–9.4%). In patients with melanomas <1.5 mm in thickness, the presence of additional low risk factors identified 257 patients (75% of patients with <1.5 mm melanomas) in which the rate of SLN positivity was <5%. Discussion Despite a SLN positivity rate of 16.5% overall, substantial heterogeneity of risk exists among patients with intermediate thickness melanoma. Most patients with melanoma between 1.01–1.5 mm have a risk of SLN positivity similar to that in patients with thin melanomas.

Gastrointestinal stromal tumors (GISTs) are the most common human sarcoma and can form along the entire gastrointestinal tract. Over the last 20 years, considerable advances have been made in our understanding of the biology of GISTs. The advent of tyrosine kinase inhibitors has provided effective medical therapy for the first time. In fact, given that GIST typically is driven by either a KIT or PDGFRA gene mutation, it has become a paradigm of targeted molecular therapy. In addition, diagnostic and surgical techniques have been refined. Here, the critical aspects of primary GISTs and how they are now managed with an integrated approach are summarized. Treatment plans are developed based on specific pathologic and molecular features of the tumor. The authors outline the general principles of therapy and highlight some of the nuances. Particular focus is given to diagnosis, surgical considerations, and the use of preoperative and postoperative tyrosine kinase inhibitors.

Type I interferons (IFN) are implicated in tumor immunogenicity and response to systemic therapy, but their interaction with oncogene signaling is not well understood. Here, we studied oncogenic KIT, which drives gastrointestinal stromal tumor (GIST), the most common sarcoma. Using mouse models of GIST, we found that KIT inhibition reduced type I IFN production and signaling, which downregulated tumor MHC class I expression. Absence of type I IFN signaling increased tumor size, in part due to CD8 + T-cell impairment. Oncogenic KIT was required for GIST type I IFN signal transduction via STAT1. In human GIST cell lines and surgical specimens, type I IFN signaling contributed to HLA class I expression and correlated with tumor immunogenicity. Augmenting the type I IFN response partially compensated for the immunosuppressive effects of KIT inhibition. Thus, KIT signaling contributes to type I IFN signaling while KIT inhibition attenuates tumor immunogenicity and is party rescued by innate immune stimulation.

Targeted therapy with a tyrosine kinase inhibitor (TKI) such as imatinib is effective in treating gastrointestinal stromal tumor (GIST), but it is rarely curative. Despite the presence of a robust immune CD8+ T-cell infiltrate, combining a TKI with immune checkpoint blockade (ICB) in advanced GIST has achieved only modest effects. To identify limitations imposed by imatinib on the antitumor immune response, we performed bulk RNA sequencing (RNAseq), single-cell RNAseq, and flow cytometry to phenotype CD8+ T-cell subsets in a genetically engineered mouse model of GIST. Imatinib reduced the frequency of effector CD8+ T cells and increased the frequency of naive CD8+ T cells within mouse GIST, which coincided with altered tumor chemokine production, CD8+ T-cell recruitment, and reduced CD8+ T-cell intracellular PI3K signaling. Imatinib also failed to induce intratumoral T-cell receptor (TCR) clonal expansion. Consistent with these findings, human GISTs sensitive to imatinib harbored fewer effector CD8+ T cells but more naïve CD8+ T cells. Combining an IL15 superagonist (IL15SA) with imatinib restored intratumoral effector CD8+ T-cell function and CD8+ T-cell intracellular PI3K signaling, resulting in greater tumor destruction. Combination therapy with IL15SA and ICB resulted in the greatest tumor killing and maintained an effector CD8+ T-cell population in the presence of imatinib. Our findings highlight the impact of oncogene inhibition on intratumoral CD8+ T cells and support the use of agonistic T-cell therapy during TKI and/or ICB administration.