IL7 in combination with radiotherapy stimulates a memory T-cell response to improve outcomes in HNSCC models.

Clinically approved head and neck squamous cell carcinoma (HNSCC) immunotherapies manipulate the immune checkpoint blockade (ICB) axis but have had limited success outside of recurrent/metastatic disease. Interleukin-7 (IL7) has been shown to be essential for effector T-cell survival, activation, and proliferation. Here, we show that IL7 in combination with radiotherapy (RT) is effective in activating CD8 + T-cells for reducing tumor growth. Our studies were conducted using both human papillomavirus related and unrelated orthotopic HNSCC murine models. Immune populations from the tumor, draining lymph nodes, and blood were compared between treatment groups and controls using flow cytometry, proteomics, immunofluorescence staining, and RNA sequencing. Treatment with RT and IL7 (RT + IL7) resulted in significant tumor growth reduction, high CD8 T-cell tumor infiltration, and increased proliferation of T-cell progenitors in the bone marrow. IL7 also expanded a memory-like subpopulation of CD8 T-cells. These results indicate that IL7 in combination with RT can serve as an effective immunotherapy strategy outside of the conventional ICB axis to drive the antitumor activity of CD8 T-cells.

The Ninth Industrial Fluid Properties Simulation Challenge.

The Ninth Industrial Fluid Properties Simulation Challenge aimed to test the ability of molecular modeling approaches to predict water/oil interfacial tension (IFT) at conditions of high temperature and pressure. In particular, the challenge featured water/oil IFT where the oil was n-dodecane, toluene, or a 50:50 n-dodecane/toluene blend at 1.825 MPa and temperatures in the range of 383 K to 443 K. Seven entries were received including approaches such as molecular dynamics (MD) and Monte Carlo (MC) simulations, COSMO-RS, and iSAFT, and they were judged by comparison to pendant drop tensiometer benchmark data. The quality of predictions varied among the entries between approximately 20 % and 70 % of the total points possible with the entries based on MD and MC having the highest scores in most cases. As is often the case in molecular modeling, predictions of the relative trends tended to be reliable even if the absolute values were not.

The Eighth Industrial Fluids Properties Simulation Challenge.

The goal of the eighth industrial fluid properties simulation challenge was to test the ability of molecular simulation methods to predict the adsorption of organic adsorbates in activated carbon materials. In particular, the eighth challenge focused on the adsorption of perfluorohexane in the activated carbon BAM-109. Entrants were challenged to predict the adsorption in the carbon at 273 K and relative pressures of 0.1, 0.3, and 0.6. The predictions were judged by comparison to a benchmark set of experimentally determined values. Overall good agreement and consistency were found between the predictions of most entrants.

Adsorption, X-ray Diffraction, Photoelectron, and Atomic Emission Spectroscopy Benchmark Studies for the Eighth Industrial Fluid Properties Simulation Challenge.

The primary goal of the eighth industrial fluid properties simulation challenge was to test the ability of molecular simulation methods to predict the adsorption of organic adsorbates in activated carbon materials. The challenge focused on the adsorption of perfluorohexane in the activated carbon standard BAM-P109 (Panne and Thünemann 2010). Entrants were challenged to predict the adsorption of perfluorohexane in the activated carbon at a temperature of 273 K and at relative pressures of 0.1, 0.3, and 0.6. The relative pressure (P/Po) is defined as that relative to the bulk saturation pressure predicted by the fluid model at a given temperature (273 K in this case). The predictions were judged by comparison to a set of experimentally determined values, which are published here for the first time and were not disclosed to the entrants prior to the challenge. Benchmark experimental studies, described herein, were also carried out and provided to entrants in order to aid in the development of new force fields and simulation methods to be employed in the challenge. These studies included argon, carbon dioxide, and water adsorption in the BAM-P109 activated carbon as well as X-ray diffraction, X-ray microtomography, photoelectron spectroscopy, and atomic emission spectroscopy studies of BAM-P109. Several concurrent studies were carried out for the BAM-P108 activated carbon (Panne and Thünemann 2010). These are included in the current manuscript for comparison.

Manipulating the EphB4-ephrinB2 axis to reduce metastasis in HNSCC.

The EphB4-ephrinB2 signaling axis has been heavily implicated in metastasis across numerous cancer types. Our emerging understanding of the dichotomous roles that EphB4 and ephrinB2 play in head and neck squamous cell carcinoma (HNSCC) poses a significant challenge to rational drug design. We find that EphB4 knockdown in cancer cells enhances metastasis in preclinical HNSCC models by augmenting immunosuppressive cells like T regulatory cells (Tregs) within the tumor microenvironment. EphB4 inhibition in cancer cells also amplifies their ability to metastasize through increased expression of genes associated with epithelial mesenchymal transition and hallmark pathways of metastasis. In contrast, vascular ephrinB2 knockout coupled with radiation therapy (RT) enhances anti-tumor immunity, reduces Treg accumulation into the tumor, and decreases metastasis. Notably, targeting the EphB4-ephrinB2 signaling axis with the engineered EphB4 ligands EFNB2-Fc-His and Fc-TNYL-RAW-GS reduces local tumor growth and distant metastasis in a preclinical model of HNSCC. Our data suggest that targeted inhibition of vascular ephrinB2 while avoiding inhibition of EphB4 in cancer cells could be a promising strategy to mitigate HNSCC metastasis.

Sensory nerve release of CGRP increases tumor growth in HNSCC by suppressing TILs.

BACKGROUND: Perineural invasion (PNI) and nerve density within the tumor microenvironment (TME) have long been associated with worse outcomes in head and neck squamous cell carcinoma (HNSCC). This prompted an investigation into how nerves within the tumor microenvironment affect the adaptive immune system and tumor growth. METHODS: We used RNA sequencing analysis of human tumor tissue from a recent HNSCC clinical trial, proteomics of human nerves from HNSCC patients, and syngeneic orthotopic murine models of HPV-unrelated HNSCC to investigate how sensory nerves modulate the adaptive immune system. FINDINGS: Calcitonin gene-related peptide (CGRP) directly inhibited CD8 T cell activity in vitro, and blocking sensory nerve function surgically, pharmacologically, or genetically increased CD8 and CD4 T cell activity in vivo. CONCLUSIONS: Our data support sensory nerves playing a role in accelerating tumor growth by directly acting on the adaptive immune system to decrease Th1 CD4 T cells and activated CD8 T cells in the TME. These data support further investigation into the role of sensory nerves in the TME of HNSCC and points toward the possible treatment efficacy of blocking sensory nerve function or specifically inhibiting CGRP release or activity within the TME to improve outcomes. FUNDING: 1R01DE028282-01, 1R01DE028529-01, 1P50CA261605-01 (to S.D.K.), 1R01CA284651-01 (to S.D.K.), and F31 DE029997 (to L.B.D.).

Defining high-risk elective contralateral neck radiation volumes for oropharynx cancer.

BACKGROUND: To define the location of the initial contralateral lymph node (LN) metastasis in patients with oropharynx cancer. METHODS: The location of the LN centroids from patients with oropharynx cancer and a single radiographically positive contralateral LN was defined. A clinical target volume (CTV) inclusive of all LN centroids was created, and its impact on dose to organs at risk was assessed. RESULTS: We identified 55 patients of which 49/55 had a single contralateral LN in level IIA, 4/55 in level III, 1/55 in level IIB, and 1/55 in the retropharynx. Mean radiation dose to the contralateral parotid gland was 15.1 and 21.0 Gy, (p <0.001) using the modeled high-risk elective CTV and a consensus CTV, respectively. CONCLUSIONS: We present a systematic approach for identifying the contralateral nodal regions at highest risk of harboring subclinical disease in patients with oropharynx cancer that warrants prospective clinical study.

Stereotactic radiosurgery and local control of brain metastases from triple-negative breast cancer.

OBJECTIVE: Stereotactic radiosurgery (SRS) is an effective treatment for intracranial metastatic disease, but its role in triple-negative breast cancer requires further study. Herein, the authors report overall survival (OS) and local tumor control in a multiinstitutional cohort with triple-negative breast cancer metastases treated with SRS. METHODS: Patients treated from 2010 to 2019 at 9 institutions were included in this retrospective study if they had biopsy-proven triple-negative breast cancer with intracranial metastatic lesions treated with SRS. Patients were excluded if they had undergone prior SRS, whole-brain radiation therapy, or resection of the metastatic lesions. A retrospective chart review was conducted to determine OS, local control, and treatment efficacy. RESULTS: Sixty-eight patients with 315 treated lesions were assessed. Patients had a median Karnofsky Performance Status of 80 (IQR 70-90) and age of 57 years (IQR 48-67 years). Most treated patients had 5 or fewer intracranial lesions, with 34% of patients having a single lesion. Treated lesions were small, having a median volume owf 0.11 cm3 (IQR 0.03-0.60 cm3). Patients were treated with a median margin dose of 18 Gy (IQR 18-20 Gy) to the median 71% isodose line (IQR 50%-84%). Overall, patients had a 1-year OS of 43% and 2-year OS of 20%. Most patients (88%) were followed until death, by which time local tumor progression had occurred in only 7% of cases. Furthermore, 76% of the lesions demonstrated regression. Tumor volume was correlated with local tumor progression (p = 0.012). SRS was very well tolerated, and only 3 patients (5%) developed symptomatic radiation necrosis. CONCLUSIONS: SRS is a safe and efficacious treatment for well-selected patients with triple-negative breast cancer, especially for those with a favorable performance status and small- to moderate-volume metastatic lesions.

TraPPE-UA force field for acrylates and Monte Carlo simulations for their mixtures with alkanes and alcohols.

An extension of the transferable potentials for phase equilibria-united atom (TraPPE-UA) force field to acrylate and methacrylate monomers is presented. New parameters were fit to the liquid density, normal boiling point, saturated vapor pressure, and (where experimentally available) critical constants of 1,3-butadiene, isoprene, methyl acrylate, and methyl methacrylate using Gibbs ensemble Monte Carlo simulations. Excellent agreement with experiment was obtained for the parametrization compounds and seven additional acrylate and methacrylate compounds, with average errors in liquid density and normal boiling point of approximately 1%. The TraPPE-UA force field also predicts accurate heats of vaporization at 298 K. In addition, Gibbs ensemble Monte Carlo simulations of binary vapor-liquid equilibria for the mixtures methyl acrylate/1-butanol and methyl acrylate/n-decane show that the TraPPE-UA acrylate force field performs well in mixtures with both polar and nonpolar molecules. These simulations also indicate structural microheterogeneity in the liquid phase of these mixtures.

Selectively sparing the submandibular gland when level Ib lymph nodes are included in the radiation target volume: An initial safety analysis of a novel planning objective.

BACKGROUND: Submandibular gland (SMG) metastases are extremely rare in head and neck cancer, even in the presence of level Ib lymph node (LN) involvement. In recent years, we have contoured the SMG and specifically attempted to limit its dose exposure even in patients in whom the level Ib LN station is targeted. This study reports our preliminary feasibility and safety experience with selective submandibular gland sparing. METHODS: Patients with squamous cell cancer (SCC) of the oral cavity or oropharynx with T1-2, N0-3, M0 disease in whom at least a single level Ib lymph node region was included in the target volume were identified. All patients were treated from 2009 to 2014 with definitive or postoperative IMRT with or without chemotherapy. Patients with recurrent disease, previous radiation or treated palliatively were excluded. RESULTS: A total of 174 patients met criteria for inclusion. Among the 185 level Ib LN stations that were deliberately targeted in the clinical treatment volume, 32 submandibular glands were contoured, excluded from the target volume and avoided during treatment planning. Mean dose to the spared SMG were reduced by 12% (66.6 Gy vs. 58.9 Gy, p < .001). None of these patients experienced any level 1b LN failures. CONCLUSION: Selective sparing of the submandibular gland when targeting the level 1b nodes in oral cavity and oropharynx cancer is feasible, reduces the mean dose to submandibular glands and does not result in increased level 1b nodal failure rates. Additional studies with larger cohorts are needed to validate this preliminary observation.

Clinical Factors Associated With Cost in Head and Neck Cancer: Implications for a Bundled Payment Model.

PURPOSE: To determine which factors influence cost in head and neck cancer (HNC) to inform the development of a bundled payment model (BPM). METHODS: Patients with stages 0 to IVB (by American Joint Commission on Cancer, 7th edition) HNC of various sites and histology treated definitively at a single tertiary care center during 2013 were included. Clinical variables and direct cost data were obtained, and their associations were investigated using χ2, t, Wilcoxon rank sum, and analysis of variance testing. Results were used to develop a BPM. RESULTS: One hundred fifty patients were included; 87% were white, 74% were men, 48% had oropharyngeal cancer, and 58% had stage IVA disease. Treatment consisted of surgery alone (17%), radiation alone (11%), surgery plus radiation (14%), chemoradiation (45%), and surgery plus chemoradiation (13%). On multivariable analysis, both increasing group stage and number of treatment modalities used were significantly associated with higher cost. Given that stage often dictates treatment, we developed three cost tiers that were based on overall treatment modality. Tier A, the least costly, consisted of single-modality therapy with either surgery alone or radiation alone (median cost divided by the median overall cost of treatment, 0.54; 25th to 75th percentile range, 0.29 to 1.02), followed by tier B, which consisted of bimodality therapy with either chemoradiation or surgery plus radiation (1.03; range, 0.81 to 1.35), followed by tier C, which consisted of trimodality therapy with surgery plus chemoradiation (1.43; range, 1.10 to 1.96). CONCLUSION: The number of treatment modalities required is the primary driver of cost in HNC. These data can simplify development of a comprehensive HNC BPM.

Application of the TraPPE Force Field for Predicting the Hildebrand Solubility Parameters of Organic Solvents and Monomer Units.

Configurational-bias Monte Carlo simulations in the isothermal-isobaric and Gibbs ensembles using the transferable potentials for phase equilibria (TraPPE) force field were carried out to compute the liquid densities, the Hildebrand solubility parameters, and the heats of vaporization for a set of 32 organic molecules with different functional groups at a temperature of 298.15 K. In addition, the heats of vaporization were determined at the normal boiling points of these compounds. Comparison to experimental data demonstrates that the TraPPE force field is significantly more accurate than predictions obtained from molecular dynamics simulations with the Dreiding force field [Belmares et al. J. Comput. Chem. 2004, 25, 1814] and an equation of state approach [Stefanis et al. Fluid Phase Equil. 2006, 240, 144]. For the TraPPE force field, the mean unsigned percent errors for liquid density, the Hildebrand solubility parameter, and the heat of vaporization at 298.15 K are 1.3, 3.3, and 4.5%, respectively.