Andrew D. Ray

Objective: To determine whether physical activity modulates adiposity-driven immune suppression in the lung and tumor microenvironment to restore antitumor immunity. Background: Obesity is associated with immune dysfunction that supports lung cancer progression, namely reduced cytotoxic T-cell activity and expansion of suppressor populations. These alterations extend to the lung, the site of new and metastatic tumors. Although exercise improves metabolic and inflammatory profiles, its impact on adiposity-associated immune dysregulation in these compartments remains unclear. Methods: Obese and lean mice were implanted with Lewis lung carcinomas under sedentary conditions or with exercise wheel access. Exercise effects on the tumor and infiltrating leukocytes were assessed by RNA sequencing and flow cytometry. The lungs of obese and lean tumor-naïve mice with and without exercise were also characterized by flow, as were bronchoalveolar lavage samples from patients (n = 73) stratified by total fat area and physical activity with multivariable adjustments. Results: Obese mice allowed voluntary exercise displayed less profound enhancement of Tregs and potentially suppressive myeloid cells and fewer CD8⁺ T-cell deficits in the tumor and lung. These mice displayed significant delays in tumor growth, while muted effects were seen in lean mice. Transcriptomic modulation consistent with altered vascular and metabolic programs was also evident in active obese mice. In human bronchoalveolar lavage, physical activity was also linked to reductions in Programmed Death receptor 1⁺ Tregs and suppressive myeloid cells enhanced by adiposity. Conclusions: Exercise may reverse adiposity-associated immune suppression in the lung and tumor microenvironments to complement lung cancer interception and treatment strategies.

Background: Non-Hodgkin lymphoma is a commonly treated with allogeneic hematopoietic stem cell transplant (allo-HSCT), leading to severe weakness and impaired function. Dynamic body weight support systems (DBWS) are a promising rehabilitation tool for enhancing early mobilization in deconditioned patients. Purpose: Evaluate the integration of DBWS into the rehabilitation plan of a patient recovering from a prolonged ICU stay post-allo HSCT, focusing on mobility and functional recovery. Case Description: A 55-year-old male, two years post-allo HSCT for cutaneous T-cell lymphoma, was hospitalized for 14 weeks due to respiratory distress from pneumonia and lung GVHD, resulting in severe deconditioning. DBWS was introduced during week 9 of hospitalization after conventional physical therapy including but not limited to bed mobility, transfers, ambulation, stairs, seated and standing therapeutic exercise and balance. Over 19 DBWS sessions, the patient advanced from ambulating 4.88 meters with 50% body weight support and maximal assistance ×2 to ambulating independently with a front-wheeled walker. Weekly work output improved from 993 joules in week 9 to 10,441 joules in week 14. Outcomes: KPS improved from 20 at admission to 60 at discharge. He also achieved independence in bed mobility and required minimal assistance for transfers and ambulation. Conclusions: Integrating DBWS with conventional therapy facilitated significant functional recovery in a patient post-allo HSCT. Further studies are needed to assess its broader applicability in oncology rehabilitation.

Background: Patients with head and neck cancer (HNC) receiving radiation therapy (RT) are at increased risk for symptoms of oral mucositis (OM), opioid use, and declines in physical function, outcomes that contribute to increased morbidity and mortality. The study objective was to determine the effects of respiratory muscle training (RMT) on OM and opioid use, as well as functional performance in patients with HNC receiving RT with or without concurrent chemotherapy (CCRT). Methods: Patients aged ≥ 18 years of age with stage I to IV HNC being treated with RT or CCRT receiving a home-based respiratory muscle training (RMT) (n = 20) were compared to a 5:1 matched historical group (n = 100) who did not receive RMT. RMT was delivered using the commercially available Power Lung AireStream device (Houston, TX) via a standardized home-based inspiratory and expiratory muscle-training program requiring ~ 20–30 min/day, five days per week, with a progressively increasing workload. Primary endpoints collected from all patients included changes in OM symptoms and use of opioids for pain control following start of RT. Secondary outcomes collected on RMT patients included respiratory muscle strength and functional performance (Six-Minute Walk Test, 6MWT; Short Physical Performance Battery, SPPB). All measures were assessed before and within 1–2 weeks following a standard 7-week RT regimen. Results: RMT reduced the impact of self-reported swallowing soreness (p = 0.032), eating soreness (p = 0.036), and opioid use (p = 0.015). RMT maintained inspiratory muscle strength (+ 0.6 ± 18 cmH2O, p = 0.87), expiratory muscle strength (+ 0.7 ± 12.7 cmH2O, p = 0.197), and improved the 6MWT (+ 20 ± 39.9 m, p = 0.025), with no change in the SPPB total score (p = 0.262). Conclusions: RMT is a low-cost intervention that is easy to perform among patients undergoing RT/RTCC for HNC and is likely to reduce OM pain/symptoms and opioid, as well as to preserve respiratory muscle strength and physical function during cancer treatment. Trial registration: Not applicable. This was a matched retrospective cohort study not registered as it was a nonrandomized trial with a historical control group.

Introduction: Cigarette smoking is an important risk factor in the development of dyspnea. Programs designed to strengthen the respiratory muscles can improve dyspnea in people with or without lung disease. As a first step in understanding the feasibility of offering a respiratory muscle...

Background: Patients with head and neck cancer (HNC) undergoing radiation therapy (RT) often experience sleep disturbances that may contribute to oral mucositis (OM) and quality of life (QOL). Methods: Patients with HNC treated with RT at a single institution were examined. Sleep questionnaires were given on the first day of RT to assess for insomnia and obstructive sleep apnea (OSA). Patient-reported QOL and oral mucositis were assessed during RT. Associations between insomnia and OSA with QOL were assessed using the Mann–Whitney U test. Linear mixed models assessed associations with OM. Results: Among 87 patients, 34 patients (39%) had subthreshold or greater insomnia and 47 patients (54%) screened positive for OSA. Upon RT completion, patients with subthreshold or greater insomnia had worse physical function (p = 0.005), fatigue (p = 0.01), insomnia (p < 0.001), and sticky saliva (p = 0.002). Patients screening positive for OSA had worse physical function (p = 0.01), sticky saliva (p = 0.02), fatigue (p = 0.007), insomnia (p = 0.009), and pain (p = 0.005). Upon linear mixed model evaluation, subthreshold or greater insomnia (p = 0.01) and positive OSA screen (p = 0.002) were associated with worse OM. Conclusion: Insomnia and OSA are highly prevalent in patients with HNC undergoing RT. These sleep disturbances are associated with worse QOL and OM during treatment.

Background: Skeletal muscle indices have been associated with improved peri-operative outcomes after surgical resection of non-small-cell lung cancer (NSCLC). However, it is unclear if these indices can predict long term cancer specific outcomes. Methods: NSCLC patients undergoing lobectomy at our institute between 2009–2015 were included in this analysis (N = 492). Preoperative CT scans were used to quantify skeletal muscle index (SMI) at L4 using sliceOmatic software. Cox proportional modelling was performed for overall (OS) and recurrence free survival (RFS). Results: For all patients, median SMI was 45.7 cm²/m² (IQR, 40–53.8). SMI was negatively associated with age (R = -0.2; p < 0.05) and positively associated with BMI (R = 0.46; P < 0.05). No association with either OS or RFS was seen with univariate cox modelling. However, multivariable modelling for SMI with patient age, gender, race, smoking status, DLCO and FEV₁ (% predicted), American Society of Anesthesiology (ASA) score, tumor histology and stage, and postoperative neoadjuvant therapy showed improved OS (HR = 0.97; P = 0.0005) and RFS (HR = 0.97; P = 0.01) with SMI. Using sex specific median SMI as cutoff, a lower SMI was associated with poor OS (HR = 1.65, P = 0.001) and RFS (HR = 1.47, P = 0.03). Conclusions: SMI is associated with improved outcomes after resection of NSCLC. Further studies are needed to understand the biological basis of this observation. This study provides additional rationale for designing and implementation of rehabilitation trials after surgical resection, to gain durable oncologic benefit.

Background: Given the role of systematic inflammation in cancer progression, lymphocyte-monocyte ratio (LMR) from peripheral blood has been suggested as a biomarker to assess the extent of inflammation in several solid malignancies. However, the role of LMR as a prognostic factor in head and neck cancer was unclear in several meta-analyses, and there is a paucity of literature including patients in North America. We performed an observational cohort study to evaluate the association of LMR with survival outcomes in North American patients with head and neck cancer.Methods: A single-institution, retrospective database was queried for patients with non-metastatic head and neck cancer who underwent definitive chemoradiation from June 2007 to April 2021 at the Roswell Park Comprehensive Cancer Center. Primary endpoints were overall survival (OS) and cancer-specific survival (CSS). The association of LMR with OS and CSS was examined using nonlinear Cox proportional hazard model using restricted cubic splines (RCS). Cox multivariable analysis (MVA) and Kaplan–Meier method were used to analyze OS and CSS. Pre-radiation LMR was then stratified into high and low based on its median value. Propensity scored matching was used to reduce the selection bias.Results: A total of 476 patients met our criteria. Median follow up was 45.3 months (interquartile range 22.8–74.0). The nonlinear Cox regression model showed that low LMR was associated with worse OS and CSS in a continuous fashion without plateau for both OS and CSS. On Cox MVA, higher LMR as a continuous variable was associated with improved OS (adjusted hazard ratio [aHR] 0,90, 95% confidence interval [CI] 0.82–0.99,p = 0.03) and CSS (aHR 0.83, 95% CI 0.72–0.95,p = 0.009). The median value of LMR was 3.8. After propensity score matching, a total of 186 pairs were matched. Lower LMR than 3.8 remained to be associated with worse OS (HR 1.59, 95% CI 1.12–2.26,p = 0.009) and CSS (HR 1.68, 95% CI 1.08–2.63,p = 0.02).Conclusion: Low LMR, both as a continuous variable and dichotomized variable, was associated with worse OS and CSS. Further studies would be warranted to evaluate the role of such prognostic marker to tailor interventions.

Background Head and neck cancer (HNC) and its treatment are associated with muscle weakness and considerable long-term comorbidity. The goal of this study was to determine whether skeletal muscle density (SMD) as quantified from pretreatment computed tomography (CT) scans will correlate with measures of function and strength prior to treatment in physical function in HNC patients. Patients and methods A cross-sectional analysis was conducted on 90 HNC patients. SMD (myosteatosis vs. normal) was calculated from pretreatment CT scans using SliceOmatic software. Pretreatment physical function was assessed via handgrip strength (HGS), the timed up and go test (TUG), and the short physical performance battery (SPPB). Demographic, cancer, and social characteristics were also collected as confounders. Linear regression models assessed the association between myosteatosis and measures of physical function. Results The 90 patients were predominately White, male, former smokers with an average BMI of 28.7 ± 5.7 kg/m². Among men, adjusted models indicate, as compared to those with normal muscle density, the total SPPB score of those with myosteatosis was 1.57 points lower (p = 0.0008), HGS was 0.85 kg lower (p = 0.73), and TUG took 1.34 s longer (p = 0.03). There were no differences in women. Conclusion Myosteatosis is associated with physical function prior to treatment in HNC patients. Larger studies are needed to examine the importance of exercise programs prior to and during treatment to build lean mass and improve long-term prognosis in HNC.

Maintaining adequate amounts of physical activity is a critical component of survivorship care for women with breast cancer. Increased physical activity is associated with increases in well-being, quality of life, and longevity, but women with cancer face unique, cancer-related factors that might affect physical activity. Consistent with the Competing Neurobehavioral Decision Systems model of decision making, we proposed to decrease delay discounting and increase physical activity by stimulating the executive function system via high-frequency repetitive transcranial magnetic stimulation (HF rTMS) of the left dorsolateral prefrontal cortex (LDLPFC). This randomized, sham-controlled, double-blinded trial examined the feasibility and potential efficacy of this approach to increase physical activity in breast cancer survivors. We hypothesized that active rTMS would significantly increase the mean number of steps per day and decrease delay discounting. Participants (n = 30) were primarily middle-aged (M = 53.7, SD = 7.9) and white with a mean BMI and body mass indices below 40. Indicators of feasibility and limited efficacy testing were positive. Although repeated-measures ANOVA revealed no significant changes in delay discounting, generalized estimating equations (GEE) found that participants in the active condition increased their mean daily steps by 400 steps per day, while those in the sham condition decreased this by nearly 600 steps per day. These findings indicate that the continued investigation of HF rTMS for increasing physical activity among women with breast cancer is justified.