The hormonal form of vitamin D, 1,25-dihydroxyvitamin D3, acting through its cognate nuclear receptor (vitamin D3 receptor, VDR) will induce myeloid leukemic cell lines to terminally differentiate into monocytes/macrophages. Because VDR acts by transcriptionally regulating responsive genes in a ligand-dependent manner, we sought target genes of the receptor that initiate the differentiation process in response to ligand. We screened a cDNA library prepared from the myelomonocytic U937 cell line with probes generated from either 1,25-dihydroxyvitamin D3-treated or untreated cells. We report here that a candidate clone that hybridized differentially is the Cdk inhibitor p21 war1' cn, l. Furthermore, we show that p21 is transcriptionally induced by 1,25-dihydroxvitamin D 3 in a VDR-dependent, but not p53-dependent, manner, and we identify a functional vitamin D response element in the p21 promoter. Transient overexpression of p21 and/or the related Cdk inhibitor p27 in U937 cells in the absence of 1,25-dihydroxvitamin D3 results in the cell-surface expression of monocyte/macrophage-specific markers, suggesting that ligand-modulated transcriptional induction of the p21 gene facilitates the induced differentiation of this monoblastic cell line. We believe that this is the first report demonstrating that the ectopic overexpression of a Cdk inhibitor such as p21 or p27 directly leads to a terminal differentiation program.

This novel transoral robotic surgery treatment regimen offers disease control, survival, and safety commensurate with standard treatments and an unexpected beneficial outcome of gastrostomy dependency rates that are markedly lower than those reported with standard nonsurgical therapies.

Anti-tumor immunity is driven by self vs. non-self discrimination. Many immunotherapeutic approaches to cancer have taken advantage of tumor neoantigens derived from somatic mutations. Here, we demonstrate that gene fusions are a source of immunogenic neoantigens that can mediate responses to immunotherapy. We identified an exceptional responder with metastatic head and neck cancer who experienced a complete response to immune checkpoint inhibitor therapy, despite a low mutational load and minimal pre-treatment immune infiltration in the tumor. Using whole genome sequencing (WGS) and RNA sequencing (RNA-seq), we identified a novel gene fusion, and demonstrated that it produces a neoantigen that can specifically elicit a host cytotoxic T cell response. In a cohort of head and neck tumors with low mutation burden, minimal immune infiltration, and prevalent gene fusions, we also identified gene fusion-derived neoantigens that generate cytotoxic T cell responses. Finally, analyzing additional datasets of fusion-positive cancers, including checkpoint inhibitor-treated tumors, we found evidence of immune surveillance resulting in negative selective pressure against gene fusion-derived neoantigens. These findings highlight an important class of tumor-specific antigens, and have implications for targeting gene fusion events in cancers that would otherwise be less poised for response to immunotherapy, including cancers with low mutational load and minimal immune infiltration.

TORS as a primary surgical modality, followed by adjuvant therapy as indicated, offers disease control in both HPV-negative and HPV-positive groups. We believe that multi-institutional studies are warranted to further evaluate this novel approach for patients who are HPV negative and HPV positive.

Background There has been increasing interest in primary surgical treatment of patients with early T classification (T1–T2) oropharyngeal squamous cell carcinoma (OPSCC), with the stated goal of de-escalating or avoiding adjuvant treatment. We sought to determine the degree to which this interest has translated into changes in practice patterns, and the rates of adverse post-operative pathologic features. Methods Patients with T1–T2 OPSCC in the National Cancer Database (NCDB) treated from 2004–2013 were categorized as receiving primary surgical or primary radiation-based treatment. Trends in treatment selection and factors related to selection of primary surgery were examined. The rates of adverse pathologic features including positive margins, extracapsular spread (ECS), and advanced T and N stage following surgery were analyzed. Results Of 8,768 patients with T1–T2 OPSCC, 68% received primary surgical treatment, increasing from 56% in 2004 to 82% in 2013 (p<0.0001). The highest versus lowest volume hospitals treated 78% versus 59% of patients with primary surgery (O.R. 2.23 C.I. 1.55–3.22, p<0.0001). Higher nodal stage predicted lower rates of primary surgery, but the majority of patients with clinical N2/N3 disease underwent primary surgery. Among surgical patients, positive margins were present in 24% and ECS in 25%. Positive margins decreased over time (p<0.0001) and were seen less often at high volume centers (p<0.0001). Among candidates for single modality therapy (clinical T1–T2/N0–N1), 33% had positive margins and/or ECS, and 47% had at least one adverse feature (T3–T4, N2–N3, positive margins, and/or ECS). Conclusion Primary surgical treatment for early T-stage OPSCC has become more widespread.