Background/Purpose Concurrent chemoradiotherapy (CCRT) for squamous cell carcinoma of the head and neck (SCCHN) increases local tumor control, but at the expense of increased toxicity. We recently showed that several clinical/pre-treatment factors were associated with the occurrence of severe late toxicity. This study evaluates the potential relationship between radiation dose delivered to the pharyngeal wall and toxicity. Methods This was an analysis of long-term survivors from three previously reported RTOG trials of concurrent chemoradiotherapy for locally advanced SCCHN (RTOG 91–11; 97–03; and 99–14). Severe late toxicity was defined in this secondary analysis as chronic Grade 3–4 pharyngeal/laryngeal toxicity and/or requirement for a feeding tube ≥ 2 years after registration and/or potential treatment-related death (e.g. pneumonia) within 3 years. Radiation dosimetry (2-dimensional) analysis was performed centrally at RTOG Headquarters to estimate doses to four regions of interest along the pharyngeal wall (superior oropharynx, inferior oropharynx, superior hypopharynx, and inferior hypopharynx). Case-control analysis was performed, with a multivariate logistic regression model that included pre-treatment and treatment potential factors. Results A total of 154 patients were evaluable for this analysis, 71 cases (patients with severe late toxicities) and 83 controls; thus 46% of evaluable patients had a severe late toxicity. On multivariate analysis, significant variables correlated with the development of severe late toxicity; older age (odds ratio 1.062 per year; p = 0.0021) and radiation dose received by the inferior hypopharynx (odds ratio 1.023 per Gy; p=0.016). The subgroup of patients receiving < 60 Gy to the inferior hypopharynx had a 40% rate of severe late toxicity, compared with 56% for patients receiving > 60 Gy. Oropharyngeal dose was not associated with this outcome. Conclusions Severe late toxicity following CCRT is common in long term survivors. Age is the most significant factor, but hypopharyngeal dose also was associated.

BackgroundInvasive micropapillary carcinoma (IMPC) is an uncommon subtype of breast cancer. Previous studies of this subtype demonstrated a higher propensity for lymph node metastases as compared with invasive ductal carcinoma (IDC). The purpose of the present study was to determine the clinical characteristics, outcomes, and propensity for lymph node metastasis of patients with IMPC of the breast recorded in the National Cancer Database (NCDB).MethodsRecords of patients with IMPC diagnosed between 2004 and 2014 were retrieved from the NCDB. Log-rank test was performed to evaluate associations of clinical characteristics with overall survival (OS). Cox proportional hazards model was used to determine variables associated with OS.ResultsOverall, 2660 patients with IMPC met the selection criteria; the 5-year OS rate was 87.5% and 24.9% of patients had nodal involvement at presentation. Patients with ≥ 4 positive lymph nodes had shorter OS than node-negative patients, whereas patients with 1–3 positive nodes had similar OS to node-negative patients. Age < 65 years, receipt of radiotherapy, and estrogen receptor positivity were also associated with prolonged OS. The benefit of radiotherapy was limited to IMPC patients undergoing lumpectomy; there was no benefit for the patients undergoing mastectomy (regardless of nodal positivity/negativity).ConclusionsFavorable prognostic factors of IMPC patients included age < 65 years, < 4 positive lymph nodes, receipt of radiotherapy, and estrogen receptor positivity. The results presented herein suggest a survival benefit associated with radiotherapy in IMPC treatment, though this may be limited to the patients treated with lumpectomy.

Until recently, patients with relapsed Hodgkin's lymphoma after brentuximab vedotin (Bv) treatments had poor treatment outcomes. Checkpoint inhibitors such as nivolumab and pembrolizumab that bind to and inhibit programmed cell death protein-1 (PD-1), have demonstrated an overall response rate of 70% in Hodgkin's lymphoma patients; however, complete response is still low at 20% with median progression-free survival of 14 months. There are ongoing clinical studies to seek out synergistic combinations, with the goal of improving the complete response rates for the cure of Hodgkin's lymphoma. Although radiotherapy has a limited survival benefit in such refractory patients, several preclinical models and anecdotal clinical evidence have suggested that combining local tumor irradiation with checkpoint inhibitors can produce systemic regression of distant tumors, an abscopal effect. Most of these reported studies on the response with local conformal radiotherapy and checkpoint inhibitors in combination with the anti-cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) antibody-ipilimumab are in melanoma. Here we report in our case series that the checkpoint inhibitors that block CTLA4 and B7-homolog 1 (B7-H1) or PD-1 in preclinical radiotherapy models have shown an increased the rate of tumor regression. Our case series demonstrates that combining local irradiation with anti-PD-1 checkpoint blockade treatment is feasible and synergistic in refractory Hodgkin's lymphoma. Correlative studies also suggest that the expression of programmed death-ligand 1 (PD-L1), DNA damage response and mutational tumor burden can be used as potential biomarkers for treatment response.

Neuroendocrine (NE) differentiation in prostate cancer (PCa) is an aggressive phenotype associated with therapy resistance. The complete phenotype of these cells is poorly understood. Clinical classification is based predominantly on the expression of standard NE markers. We analyzed the phenotype of NE carcinoma of the prostate utilizing in vitro methods, in silico, and immunohistochemical analyses of human disease. Results LNCaP cells, subjected to a variety of stressors (0.1% (v/v) fetal bovine serum, cyclic AMP) induced a reproducible phenotype consistent with neuronal trans-differentiation. Cells developed long cytoplasmic processes resembling neurons. As expected, serum deprived cells had decreased expression in androgen receptor and prostate specific antigen. A significant increase in neuronal markers also was observed. Gene array analysis demonstrated that LNCaP cells subjected to low serum or cAMP showed statistically significant manifestation of a human brain gene expression signature. In an in silico experiment using human data, we identified that only hormone resistant metastatic prostate cancer showed enrichment of the “brain profile”. Gene ontology analysis demonstrated categories involved in neuronal differentiation. Three neuronal markers were validated in a large human tissue cohort. This study proposes that the later stages of PCa evolution involves neuronal trans-differentiation, which would enable PCa cells to acquire independence from the neural axis, critical in primary tumors.