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PURPOSE: Anti-PD-1 therapy provides clinical benefit in 40-50% of patients with relapsed and/or metastatic head and neck squamous cell carcinoma (RM-HNSCC). Selection of anti- PD-1 therapy is typically based on patient PD-L1 immunohistochemistry (IHC) which has low specificity for predicting disease control. Therefore, there is a critical need for a clinical biomarker that will predict clinical benefit to anti-PD-1 treatment with high specificity. METHODS: Clinical treatment and outcomes data for 103 RM-HNSCC patients were paired with RNA-sequencing data from formalin-fixed patient samples. Using logistic regression methods, we developed a novel biomarker classifier based on expression patterns in the tumor immune microenvironment to predict disease control with monotherapy PD-1 inhibitors (pembrolizumab and nivolumab). The performance of the biomarker was internally validated using out-of-bag methods. RESULTS: The biomarker significantly predicted disease control (65% in predicted non-progressors vs. 17% in predicted progressors, p < 0.001) and was significantly correlated with overall survival (OS; p = 0.004). In addition, the biomarker outperformed PD-L1 IHC across numerous metrics including sensitivity (0.79 vs 0.64, respectively; p = 0.005) and specificity (0.70 vs 0.61, respectively; p = 0.009). CONCLUSION: This novel assay uses tumor immune microenvironment expression data to predict disease control and OS with high sensitivity and specificity in patients with RM-HNSCC treated with anti-PD-1 monotherapy.

PurposeProgrammed cell death-1 (PD-1) receptor inhibitors have shown efficacy in head and neck squamous cell carcinoma (HNSCC), but treatment failure or secondary resistance occurs in most patients. In preclinical murine carcinoma models, inhibition of Bruton's tyrosine kinase (BTK) induces myeloid cell reprogramming that subsequently bolsters CD8+ T cell responses, resulting in enhanced antitumor activity. This phase 2, multicenter, open-label, randomized study evaluated pembrolizumab (anti-PD-1 monoclonal antibody) plus acalabrutinib (BTK inhibitor) in recurrent or metastatic HNSCC.Patients and methodsPatients received pembrolizumab 200 mg intravenously every 3 weeks, alone or in combination with acalabrutinib 100 mg orally twice daily. Safety and overall response rate (ORR) were co-primary objectives. The secondary objectives were progression-free survival (PFS) and overall survival.ResultsSeventy-six patients were evaluated (pembrolizumab, n = 39; pembrolizumab + acalabrutinib, n = 37). Higher frequencies of grade 3-4 treatment-emergent adverse events (AE; 65% vs. 39%) and serious AEs (68% vs. 31%) were observed with combination therapy versus monotherapy. ORR was 18% with monotherapy versus 14% with combination therapy. Median PFS was 2.7 [95% confidence interval (CI), 1.4-6.8] months in the combination arm and 1.7 (95% CI, 1.4-4.0) months in the monotherapy arm. The study was terminated due to lack of clinical benefit with combination treatment. To assess how tumor immune contexture was affected by therapy in patients with pre- and post-treatment biopsies, spatial proteomic analyses were conducted that revealed a trend toward increased CD45+ leukocyte infiltration of tumors from baseline at day 43 with pembrolizumab (monotherapy, n = 5; combination, n = 2), which appeared to be higher in combination-treated patients; however, definitive conclusions could not be drawn due to limited sample size.ConclusionsDespite lack of clinical efficacy, immune subset analyse

PurposeProgrammed cell death-1 (PD-1) receptor inhibitors have shown efficacy in head and neck squamous cell carcinoma (HNSCC), but treatment failure or secondary resistance occurs in most patients. In preclinical murine carcinoma models, inhibition of Bruton's tyrosine kinase (BTK) induces myeloid cell reprogramming that subsequently bolsters CD8+ T cell responses, resulting in enhanced antitumor activity. This phase 2, multicenter, open-label, randomized study evaluated pembrolizumab (anti-PD-1 monoclonal antibody) plus acalabrutinib (BTK inhibitor) in recurrent or metastatic HNSCC.Patients and methodsPatients received pembrolizumab 200 mg intravenously every 3 weeks, alone or in combination with acalabrutinib 100 mg orally twice daily. Safety and overall response rate (ORR) were co-primary objectives. The secondary objectives were progression-free survival (PFS) and overall survival.ResultsSeventy-six patients were evaluated (pembrolizumab, n = 39; pembrolizumab + acalabrutinib, n = 37). Higher frequencies of grade 3-4 treatment-emergent adverse events (AE; 65% vs. 39%) and serious AEs (68% vs. 31%) were observed with combination therapy versus monotherapy. ORR was 18% with monotherapy versus 14% with combination therapy. Median PFS was 2.7 [95% confidence interval (CI), 1.4-6.8] months in the combination arm and 1.7 (95% CI, 1.4-4.0) months in the monotherapy arm. The study was terminated due to lack of clinical benefit with combination treatment. To assess how tumor immune contexture was affected by therapy in patients with pre- and post-treatment biopsies, spatial proteomic analyses were conducted that revealed a trend toward increased CD45+ leukocyte infiltration of tumors from baseline at day 43 with pembrolizumab (monotherapy, n = 5; combination, n = 2), which appeared to be higher in combination-treated patients; however, definitive conclusions could not be drawn due to limited sample size.ConclusionsDespite lack of clinical efficacy, immune subset analyse

Sitravatinib (MGCD516), a spectrum-selective receptor tyrosine kinase inhibitor targeting TAM (TYRO3, AXL, MERTK) and split kinase family receptors, has demonstrated preclinical anti-tumor activity and modulation of tumor microenvironment. This first-in-human phase 1/1b study included sitravatinib dose exploration and anti-tumor activity evaluation in selected patients with advanced solid tumors. Primary objectives included assessment of safety, pharmacokinetics and clinical activity of sitravatinib. Secondary objectives included identifying doses for further investigation and exploring molecular markers for patient selection. In phase 1, 32 patients received 10-200 mg, while phase 1b dose expansion comprised 161 patients (150 mg n = 99, 120 mg n = 62). Maximum tolerated dose was determined as 150 mg daily. Dose-limiting toxicity was reported in 4/28 evaluable phase 1 patients (three at 200 mg, one at 80 mg). In phase 1b, 120 mg was defined as the recommended dose due to tolerability. Treatment-related adverse events (TRAEs) were experienced by 174/193 patients (90.2%); grade ≥ 3 TRAEs in 103 patients (53.4%). Most common TRAEs were diarrhea, fatigue, hypertension and nausea; TRAEs led to treatment discontinuation in 26 patients (13.5%) and death in one patient. Sitravatinib was steadily absorbed and declined from plasma with a terminal elimination half-life of 42.1-51.5 h following oral administration. Overall objective response rate was 11.8% in phase 1b, 13.2% in patients with non-small cell lung cancer (NSCLC) and 4.2% in patients with NSCLC with prior checkpoint inhibitor experience. Sitravatinib demonstrated manageable safety and modest clinical activity in solid tumors. NCT02219711 (first posted August 14, 2014).

The NCCN Guidelines for Head and Neck (H&N) Cancers provide treatment recommendations for cancers of the lip, oral cavity, pharynx, larynx, ethmoid and maxillary sinuses, and salivary glands. Recommendations are also provided for occult primary of the H&N, and separate algorithms have been developed by the panel for very advanced H&N cancers. These NCCN Guidelines Insights summarize the panel's discussion and most recent recommendations regarding evaluation and treatment of nasopharyngeal carcinoma.

The NCCN Guidelines for Head and Neck (H&N) Cancers provide treatment recommendations for cancers of the lip, oral cavity, pharynx, larynx, ethmoid and maxillary sinuses, and salivary glands. Recommendations are also provided for occult primary of the H&N, and separate algorithms have been developed by the panel for very advanced H&N cancers. These NCCN Guidelines Insights summarize the panel's discussion and most recent recommendations regarding evaluation and treatment of nasopharyngeal carcinoma.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Head and Neck Cancers provide treatment recommendations for cancers of the lip, oral cavity, pharynx, larynx, ethmoid and maxillary sinuses, and salivary glands. Recommendations are also provided for occult primary of the head and neck (H&N), and separate algorithms have been developed by the panel for very advanced H&N cancers. These NCCN Guidelines Insights summarize the panel's discussion and most recent recommendations regarding the increase in human papillomavirus-associated oropharyngeal cancer and the availability of immunotherapy agents for treatment of patients with recurrent or metastatic H&N cancer.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Head and Neck Cancers provide treatment recommendations for cancers of the lip, oral cavity, pharynx, larynx, ethmoid and maxillary sinuses, and salivary glands. Recommendations are also provided for occult primary of the head and neck (H&N), and separate algorithms have been developed by the panel for very advanced H&N cancers. These NCCN Guidelines Insights summarize the panel's discussion and most recent recommendations regarding the increase in human papillomavirus-associated oropharyngeal cancer and the availability of immunotherapy agents for treatment of patients with recurrent or metastatic H&N cancer.

Background Cixutumumab (IMC-A12), a fully human immunoglobulin G1 (IgG1) monoclonal antibody, exerts preclinical activity in several sarcoma models and may be effective for the treatment of these tumours. Methods In this open-label, multicentre, phase 2 study, patients with previously treated advanced or metastatic rhabdomyosarcoma, leiomyosarcoma, adipocytic sarcoma, synovial sarcoma or Ewing family of tumours received intravenous cixutumumab (10 mg/kg) for 1 h every other week until disease progression or discontinuation. The primary end-point was the progression-free survival rate (PFR), defined as stable disease or better at 12 weeks. In each tier of disease histology, Simon's optimum 2-stage design was applied (PFR at 12 weeks P0 = 20%, P1 = 40%, α = 0.10, β = 0.10). Stage 1 enrolled 17 patients in each disease group/tier, with at least four patients with stable disease or better required at 12 weeks to proceed to stage 2. Results A total of 113 patients were enrolled; all tiers except adipocytic sarcoma were closed after stage 1 due to futility. The 12-week PFR was 12% for rhabdomyosarcoma (n = 17), 14% for leiomyosarcoma (n = 22), 32% for adipocytic sarcoma (n = 37), 18% for synovial sarcoma (n = 17) and 11% for Ewing family of tumours (n = 18). Median progression-free survival (weeks) was 6.1 for rhabdomyosarcoma, 6.0 for leiomyosarcoma, 12.1 for adipocytic sarcoma, 6.4 for synovial sarcoma and 6.4 for Ewing family of tumours. Among all patients, the most frequent treatment-emergent adverse events (AEs) were nausea (26%), fatigue (23%), diarrhoea (23%) and hyperglycaemia (20%). Conclusions Patients with adipocytic sarcoma may benefit from treatment with cixutumumab. Cixutumumab treatment was well tolerated, with limited gastrointestinal AEs, fatigue and hyperglycaemia. © 2013 Elsevier Ltd. All rights reserved., SCOPUS: ar.j, info:eu-repo/semantics/published

It has been experimentally determined by previous investigators that hydrodynamic forces can cause a centrifugal pump impeller to whirl in a volute. The present work was undertaken to develop a theoretical model of the interactions that occur between an impeller and a volute, and to identify the source of the hydrodynamic forces. Experiments were then conducted to test the predictions of the model. The theoretical analysis presents a quasi-one dimensional treatment of the flow in the volute and accounts for the disturbance at the impeller discharge that is caused by the volute. The model also considers the lack of perfect guidance through the blade passages. Extending this model allowed for the calculation of hydrodynamic force perturbations that result when the impeller whirls eccentrically in the volute. These force perturbations were shown to encourage, rather than dissipate the whirling motion. The predictions of the model gave reasonable comparisons with the experimental data obtained in this study. Further, it was experimentally observed that pressure forces acting on the front shroud of the impeller could have a major influence on the hydrodynamic force perturbations acting on an eccentrically positioned impeller.

It has been experimentally determined by previous investigators that hydrodynamic forces can cause a centrifugal pump impeller to whirl in a volute. The present work was undertaken to develop a theoretical model of the interactions that occur between an impeller and a volute, and to identify the source of the hydrodynamic forces. Experiments were then conducted to test the predictions of the model. The theoretical analysis presents a quasi-one dimensional treatment of the flow in the volute and accounts for the disturbance at the impeller discharge that is caused by the volute. The model also considers the lack of perfect guidance through the blade passages. Extending this model allowed for the calculation of hydrodynamic force perturbations that result when the impeller whirls eccentrically in the volute. These force perturbations were shown to encourage, rather than dissipate the whirling motion. The predictions of the model gave reasonable comparisons with the experimental data obtained in this study. Further, it was experimentally observed that pressure forces acting on the front shroud of the impeller could have a major influence on the hydrodynamic force perturbations acting on an eccentrically positioned impeller.

It has been experimentally determined by previous investigators that hydrodynamic forces can cause a centrifugal pump impeller to whirl in a volute. The present work was undertaken to develop a theoretical model of the interactions that occur between an impeller and a volute, and to identify the source of the hydrodynamic forces. Experiments were then conducted to test the predictions of the model. The theoretical analysis presents a quasi-one dimensional treatment of the flow in the volute and accounts for the disturbance at the impeller discharge that is caused by the volute. The model also considers the lack of perfect guidance through the blade passages. Extending this model allowed for the calculation of hydrodynamic force perturbations that result when the impeller whirls eccentrically in the volute. These force perturbations were shown to encourage, rather than dissipate the whirling motion. The predictions of the model gave reasonable comparisons with the experimental data obtained in this study. Further, it was experimentally observed that pressure forces acting on the front shroud of the impeller could have a major influence on the hydrodynamic force perturbations acting on an eccentrically positioned impeller.

Hydrodynamic interactions that occur between a centrifugal pump impeller and volute are experimentally and theoretically investigated. The theoretical analysis considers the inability of the blades to perfectly guide the flow through the impeller, and also includes a quasi-one dimensional treatment of the flow in the volute. The disturbance at the impeller discharge and the resulting forces are determined by the theoretical model. The model is then extended to obtain the hydrodynamic force perturbations that are caused by the impeller whirling eccentrically in the volute. Under many operating conditions, these force perturbations were found to be destablizing. Comparisons are made between the theoretical model and the experimental measurements of pressure distributions and radial forces on the impeller. The theoretical model yields fairly accurate predictions of the radial forces caused by the flow through the impeller. However, it was found that the pressure acting on the front shroud of the impeller has a substantial effect on the destablizing hydrodynamic forces.

Hydrodynamic interactions that occur between a centrifugal pump impeller and volute are experimentally and theoretically investigated. The theoretical analysis considers the inability of the blades to perfectly guide the flow through the impeller, and also includes a quasi-one dimensional treatment of the flow in the volute. The disturbance at the impeller discharge and the resulting forces are determined by the theoretical model. The model is then extended to obtain the hydrodynamic force perturbations that are caused by the impeller whirling eccentrically in the volute. Under many operating conditions, these force perturbations were found to be destablizing. Comparisons are made between the theoretical model and the experimental measurements of pressure distributions and radial forces on the impeller. The theoretical model yields fairly accurate predictions of the radial forces caused by the flow through the impeller. However, it was found that the pressure acting on the front shroud of the impeller has a substantial effect on the destablizing hydrodynamic forces.

Hydrodynamic interactions that occur between a centrifugal pump impeller and volute are experimentally and theoretically investigated. The theoretical analysis considers the inability of the blades to perfectly guide the flow through the impeller, and also includes a quasi-one dimensional treatment of the flow in the volute. The disturbance at the impeller discharge and the resulting forces are determined by the theoretical model. The model is then extended to obtain the hydrodynamic force perturbations that are caused by the impeller whirling eccentrically in the volute. Under many operating conditions, these force perturbations were found to be destablizing. Comparisons are made between the theoretical model and the experimental measurements of pressure distributions and radial forces on the impeller. The theoretical model yields fairly accurate predictions of the radial forces caused by the flow through the impeller. However, it was found that the pressure acting on the front shroud of the impeller has a substantial effect on the destablizing hydrodynamic forces.