human papilloma virus (HPV)-driven cancer, immune checkpoint blockade with anti-programmed cell death 1 (PD-1) antibodies produces tumor regression in only a minority of patients. Therapeutic HPV vaccines have produced strong immune responses to HPV-16, but vaccination alone has been ineffective for invasive cancer. OBJECTIVE To determine whether the efficacy of nivolumab, an anti-PD-1 immune checkpoint antibody, is amplified through treatment with ISA 101, a synthetic long-peptide HPV-16 vaccine inducing HPV-specific T cells, in patients with incurable HPV-16-positive cancer. DESIGN, SETTING, AND PARTICIPANTS In this single-arm, single-center phase 2 clinical trial, 24 patients with incurable HPV-16-positive cancer were enrolled from December 23, 2015, to December 12, 2016. Duration of follow-up for censored patients was 12.2 months through August 31, 2017. INTERVENTIONS The vaccine ISA101, 100 μg/peptide, was given subcutaneously on days 1, 22, and 50. Nivolumab, 3 mg/kg, was given intravenously every 2 weeks beginning day 8 for up to 1 year. MAIN OUTCOMES AND MEASURES Assessment of efficacy reflected in the overall response rate (per Response Evaluation Criteria in Solid Tumors, version 1.1). RESULTS Of the 24 patients (4 women and 20 men; 22 with oropharyngeal cancer; median age, 60 years [range, 36-73 years]), the overall response rate was 33% (8 patients; 90% CI, 19%-50%). Median duration of response was 10.3 months (95% CI, 10.3 months to inestimable). Five of 8 patients remain in response. Median progression-free survival was 2.7 months (95% CI, 2.5-9.4 months). Median overall survival was 17.5 months (95% CI, 17.5 months to inestimable). Grades 3 to 4 toxicity occurred in 2 patients (asymptomatic grade 3 transaminase level elevation in 1 patient and grade 4 lipase elevation in 1 patient), requiring discontinuation of nivolumab therapy. CONCLUSIONS AND RELEVANCE The overall response rate of 33% and median overall survival of 17.5 months is promising compared with PD-1 inhibition alone in similar patients. A randomized clinical trial to confirm the contribution of HPV-16 vaccination to tumoricidal effects of PD-1 inhibition is warranted for further study. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT02426892

Context Dexamethasone is often used to treat dyspnea in cancer patients but evidence is lacking. Objectives We determined the feasibility of conducting a randomized trial of dexamethasone in cancer patients, and estimated the efficacy of dexamethasone in the treatment of dyspnea. Methods In this double-blind, randomized, controlled trial, patients with dyspnea ≥4 were randomized to receive either dexamethasone 8 mg twice daily × four days then 4 mg twice daily × three days or placebo for seven days, followed by an open-label phase for seven days. We documented the changes in dyspnea (0-10 numeric rating scale [NRS]), spirometry measures, quality of life and toxicities. Results A total of 41 patients were randomized and 35 (85%) completed the blinded phase. Dexamethasone was associated with a significant reduction in dyspnea NRS of -1.9 (95% confidence interval [CI] -3.3 to -0.5, P=0.01) by day 4 and -1.8 (95% CI -3.2 to -0.3, P=0.02) by day 7. In contrast, placebo was associated with a reduction of -0.7 (95% CI -2.1 to 0.6, P=0.38) by day 4 and -1.3 (95% CI -2.4 to -0.2, P=0.03) by day 7. The between-arm difference was not statistically significant. Drowsiness improved with dexamethasone. Dexamethasone was well tolerated with no significant toxicities. Conclusion A double-blind, randomized, controlled trial of dexamethasone was feasible with a low attrition rate. Our preliminary data suggest that dexamethasone may be associated with rapid improvement in dyspnea and was well tolerated. Further studies are needed to confirm our findings.

BackgroundThe combination of ISA101, a human papilloma virus (HPV) 16 peptide vaccine, and nivolumab showed a promising response rate of 33% in patients with incurable HPV-16+ cancer. Here we report long-term clinical outcomes and immune correlates of response.MethodsPatients with advanced HPV-16+ cancer and less than two prior regimens for recurrence were enrolled to receive ISA101 (100 µg/peptide) on days 1, 22, and 50 and nivolumab 3 mg/kg every 2 weeks beginning day 8 for up to 1 year. Baseline tumor samples were stained with multiplex immunofluorescence for programmed death-ligand 1 (PD-L1), programmed cell death protein-1 (PD-1), CD3, CD8, CD68, and pan-cytokeratin in a single panel and scanned with the Vectra 3.0 multispectral microscope. Whole transcriptome analysis of baseline tumors was performed with Affymetrix Clariom D arrays. Differential gene expression analysis was performed on responders versus non-responders.ResultsTwenty-four patients were followed for a median of 46.5 months (95% CI, 46.0 months to not reached (NR)). The median duration of response was 11.2 months (95% CI, 8.51 months to NR); three out of eight (38%) patients with objective response were without progression at 3 years. The median and 3-year overall survival were 15.3 months (95% CI, 10.6 months to 27.2 months) and 12.5% (95% CI, 4.3% to 36%), respectively. The scores for activated T cells ((CD3+PD-1+)+(CD3+CD8+PD-1+)), activated cytotoxic T cells (CD3+CD8+PD-1+), and total macrophage ((CD68+PD-L1−)+(CD68+PD-L1+)) in tumor were directly correlated with clinical response (p<0.05) and depth of response with the two complete response patients having the highest degree of CD8+ T cells. Gene expression analysis revealed differential regulation of 357 genes (≥1.25 fold) in non-responders versus responders (p<0.05). Higher expression of immune response, inflammatory response and interferon-signaling pathway genes were correlated with clinical response (p<0.05).ConclusionsEfficacy of ISA101 and nivolumab remains promising in long-term follow-up. Increased infiltration by PD-1+ T cells and macrophages was predictive of response. Enrichment in gene sets associated with interferon-γ response and immune infiltration strongly predicted response to therapy. A randomized trial is ongoing to test this strategy and to further explore correlates of immune response with combined nivolumab and ISA101, versus nivolumab alone.Trial registration numberNCT02426892.

7047 Background: Tumor size is a known prognostic factor for early stage (I and II) NSCLC, but its significance in node positive or locally advanced NSCLC has not been determined. We sought to evaluate its prognostic value in early and locally advanced NSCLC and create a nomogram incorporating tumor size and other prognostic variables to predict survival. Methods: The SEER registry was queried for patients (pts) with NSCLC, aged 20-103 and diagnosed between 1998 and 2003. Pts with extra-pulmonary metastases or distant lymph node metastases were excluded. Tumor size was analyzed as a continuous variable. Other demographic variables included age, gender, race, histology, primary tumor extension, node status and primary treatment modality (surgery vs radiation). Log-rank test was performed to evaluate the relationship between these variables and overall survival (OS). Cox proportional hazard model was used to evaluate whether tumor size was an independent prognostic factor. Results: 52,287 eligible pts were divided into 16 subgroups based on primary tumor extension and node status. For example, in group 1, tumor was confined to one lung with no nodes involved; pts in group 12 had tumor invading the mediastinum (T4 by extent) and positive ipsilateral mediastinal nodes. Tumor size had a significant effect on OS in almost all groups after adjustment for age, sex, race, histology, node status, primary tumor extension and primary treatment modality. Our model incorporating tumor size had significantly better predictive accuracy (larger C index) than our alternative model not including this information (p<0.0001). We then developed a nomogram incorporating tumor size, age, gender, race, histology, nodule stage, and tumor extension with the intent to predict OS. In subsequent bootstrap verification, the predicted 2-year OS from the nomogram was almost identical to the actual observed 2-year OS with a very slim biases of estimates. Conclusions: Tumor size is an independent prognostic factor, including pts with node positive or locally advanced NSCLC. We successfully created a nomogram incorporating tumor size and other clinical variables to predict survival.

Erectile dysfunction (ED) has been identified as one of the most frequent chronic complications of diabetes mellitus (DM). The prevalence of ED is estimated to be about 67.4% in all DM cases worldwide. The pathophysiological process leading to ED involves endothelial, neurological, hormonal, and psychological factors. In DM, endothelial and neurological factors play a crucial role. Damages in the blood vessels and erectile tissue due to insulin resistance are the hallmark of ED in DM. The current treatments for ED include phosphodiesterase-5 inhibitors and penile prosthesis surgery. However, these treatments are limited in terms of just relieving the symptoms, but not resolving the cause of the problem. The use of stem cells for treating ED is currently being studied mostly in experimental animals. The stem cells used are derived from adipose tissue, bone, or human urine. Most of the studies observed an improvement in erectile quality in the experimental animals as well as an improvement in erectile tissue. However, research on stem cell therapy for ED in humans remains to be limited. Nevertheless, significant findings from studies using animal models indicate a potential use of stem cells in the treatment of ED.