The NCCN Soft Tissue Sarcoma Guidelines include a subsection about treatment recommendations for gastrointestinal stromal tumors (GISTs). The standard of practice rapidly changed after the introduction of effective molecularly targeted therapy (such as imatinib and sunitinib) for GIST. Because of these changes, NCCN organized a multidisciplinary panel composed of experts in the fields of medical oncology, molecular diagnostics, pathology, radiation oncology, and surgery to discuss the optimal approach for the care of patients with GIST at all stages of the disease. The GIST Task Force is composed of NCCN faculty and other key experts from the United States, Europe, and Australia. The Task Force met for the first time in October 2003 and again in December 2006 with the purpose of expanding on the existing NCCN guidelines for gastrointestinal sarcomas and identifying areas of future research to optimize our understanding and treatment of GIST. (JNCCN 2007;5[Suppl 2]:S1–S29)

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Structured Abstract Objective To examine the association between extent of surgery and overall survival (OS) in a large contemporary cohort of patients with papillary thyroid cancer (PTC). Background Guidelines recommend total thyroidectomy for PTC tumors >1 cm based on older data demonstrating an OS advantage for total thyroidectomy over lobectomy. Methods Adult patients with PTC tumors 1.0–4.0 cm undergoing thyroidectomy in the National Cancer Database, 1998–2006, were included. Cox proportional hazards models were applied to measure the association between extent of surgery and OS while adjusting for patient demographic and clinical factors, including comorbidities, extrathyroidal extension, multifocality, nodal and distant metastases, and radioiodine treatment. Results Among 61,775 PTC patients, 54,926 underwent total thyroidectomy and 6,849 lobectomy. Compared to lobectomy, total thyroidectomy patients had more nodal (7% vs. 27%), extrathyroidal (5% vs.16%), and multifocal disease (29% vs. 44%), all p<0.001. Median follow-up was 82 months (60–179 months). After multivariable adjustment, OS was similar for total thyroidectomy vs. lobectomy in patients with tumors 1.0–4.0 cm (HR 0.96 [0.84–1.09], p=0.54), and when stratified by tumor size: 1.0–2.0 cm (HR 1.05 [0.88–1.26], p=0.61) and 2.1–4.0 cm (HR 0.89 [0.73–1.07], p=0.21). Older age, male gender, black race, lower income, tumor size, and presence of nodal or distant metastases were independently associated with compromised survival (p<0.0001). Conclusions Current guidelines suggest total thyroidectomy for PTC tumors >1 cm. However, we did not observe a survival advantage associated with total thyroidectomy compared to lobectomy. These findings call into question whether tumor size should be an absolute indication for total thyroidectomy.

The β-catenin signaling pathway has been demonstrated to promote the development of a tolerogenic dendritic cell (DC) population capable of driving regulatory T-cell (Treg) differentiation. Further studies have implicated tolerogenic DCs in promoting carcinogenesis in preclinical models. The molecular mechanisms underlying the establishment of immune tolerance by this DC population are poorly understood, and the methods by which developing cancers can co-opt this pathway to subvert immune surveillance are currently unknown. This work demonstrates that melanoma-derived Wnt5a ligand upregulates the durable expression and activity of the indoleamine 2,3-dioxygenase-1 (IDO) enzyme by local DCs in a manner that depends upon the β-catenin signaling pathway. These data indicate that Wnt5a-conditioned DCs promote the differentiation of Tregs in an IDO-dependent manner, and that this process serves to suppress melanoma immune surveillance. We further show that the genetic silencing of the PORCN membrane–bound O-acyl transferase, which is necessary for melanoma Wnt ligand secretion, enhances antitumor T-cell immunity, and that the pharmacologic inhibition of this enzyme synergistically suppresses melanoma progression when combined with anti–CTLA-4 antibody therapy. Finally, our data suggest that β-catenin signaling activity, based on a target gene expression profile that includes IDO in human sentinel lymph node–derived DCs, is associated with melanoma disease burden and diminished progression-free survival. This work implicates the Wnt–β-catenin signaling pathway as a novel therapeutic target in the melanoma immune microenvironment and demonstrates the potential impact of manipulating DC function as a strategy for optimizing tumor immunotherapy.