Acute Radiation-Induced Hematopoietic Depletion Does Not Alter the Onset or Severity of Pneumonitis in Mice.

Survival from partial-body irradiation (PBI) may be limited by the development of the late lung injury response of pneumonitis. Herein we investigated the hypothesis that acute hematopoietic depletion alters the onset and severity of lung disease in a mouse model. To establish depletion, C3H/HeJ mice received 8 Gy PBI with shielding of only the tibiae, ankles and feet. One week after irradiation, blood lymphocyte and neutrophil counts were each significantly reduced (P < 0.04) in these mice compared to levels in untreated controls or in mice receiving 16 Gy to the whole thorax only. All 8 Gy PBI mice survived to the experimental end point of 16 weeks postirradiation. To determine whether the hematopoietic depletion affects lung disease, groups of mice received 8 Gy PBI plus 8 Gy whole-thorax irradiation (total lung dose of 16 Gy) or 16 Gy whole-thorax irradiation only. The weight loss, survival to onset of respiratory distress (P = 0.17) and pneumonitis score (P = 0.96) of mice that received 8 Gy PBI plus 8 Gy whole-thorax irradiation were not significantly different from those of mice receiving 16 Gy whole-thorax irradiation only. Mice in respiratory distress from PBI plus whole-thorax irradiation had significantly reduced (P = 0.02) blood monocyte counts compared to levels in distressed, whole-thorax irradiated mice, and symptomatic pneumonitis was associated with increased blood neutrophil counts (P = 0.04) relative to measures from irradiated, non-distressed mice. In conclusion, survivable acute hematopoietic depletion by partial-body irradiation did not alter the onset or severity of lethal pneumonitis in the C3H/HeJ mouse model.

Prognostic Nutritional Index Predicts Toxicity in Head and Neck Cancer Patients Treated with Definitive Radiotherapy in Association with Chemotherapy.

BACKGROUND: The Prognostic Nutritional Index (PNI) is a parameter of nutritional and inflammation status related to toxicity in cancer treatment. Since data for head and neck cancer are scanty, this study aims to investigate the association between PNI and acute and late toxicity for this malignancy. METHODS: A retrospective cohort of 179 head and neck cancer patients treated with definitive radiotherapy with induction/concurrent chemotherapy was followed-up (median follow-up: 38 months) for toxicity and vital status between 2010 and 2017. PNI was calculated according to Onodera formula and low/high PNI levels were defined according to median value. Odds ratio (OR) for acute toxicity were calculated through logistic regression model; hazard ratios (HR) for late toxicity and survival were calculated through the Cox proportional hazards model. RESULTS: median PNI was 50.0 (interquartile range: 45.5-53.5). Low PNI was associated with higher risk of weight loss > 10% during treatment (OR = 4.84, 95% CI: 1.73-13.53 for PNI < 50 versus PNI ≥ 50), which was in turn significantly associated with worse overall survival, and higher risk of late mucositis (HR = 1.84; 95% CI:1.09-3.12). PNI predicts acute weight loss >10% and late mucositis. CONCLUSIONS: PNI could help clinicians to identify patients undergoing radiotherapy who are at high risk of acute and late toxicity.

PEG-G-CSF and L-Citrulline Combination Therapy for Mitigating Skin Wound Combined Radiation Injury in a Mouse Model.

Radiation combined injury (RCI, radiation exposure coupled with other forms of injury, such as burn, wound, hemorrhage, blast, trauma and/or sepsis) comprises approximately 65% of injuries from a nuclear explosion, and greatly increases the risk of morbidity and mortality when compared to that of radiation injury alone. To date, no U.S. Food and Drug Administration (FDA)-approved countermeasures are available for RCI. Currently, three leukocyte growth factors (Neupogen®, Neulasta® and Leukine®) have been approved by the FDA for mitigating the hematopoietic acute radiation syndrome. However these granulocyte-colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) products have failed to increase 30-day survival of mice after RCI, suggesting a more complicated biological mechanism is in play for RCI than for radiation injury. In the current study, the mitigative efficacy of combination therapy using pegylated (PEG)-G-CSF (Neulasta) and -citrulline was evaluated in an RCI mouse model. L-citrulline is a neutral alpha-amino acid shown to improve vascular endothelial function in cardiovascular diseases. Three doses of PEG-G-CSF at 1 mg/kg, subcutaneously administered on days 1, 8 and 15 postirradiation, were supplemented with oral -citrulline (1 g/kg), once daily from day 1 to day 21 postirradiation. The combination treatment significantly improved the 30-day survival of mice after RCI from 15% (vehicle-treated) to 42%, and extended the median survival time by 4 days, as compared to vehicle controls. In addition, the combination therapy significantly increased body weight and bone marrow stem and progenitor cell clonogenicity in RCI mice, and accelerated recovery from RCI-induced intestinal injury, compared to animals treated with vehicle. Treatment with -citrulline alone also accelerated skin wound healing after RCI. In conclusion, these data indicate that the PEG-G-CSF and -citrulline combination therapy is a potentially effective countermeasure for mitigating RCI, likely by enhancing survival of the hematopoietic stem/progenitor cells and accelerating recovery from the RCI-induced intestinal injury and skin wounds.

Nutrition impact symptoms and weight loss in head and neck cancer during radiotherapy: a longitudinal study.

OBJECTIVE: Patients with head and neck cancer (HNC) receiving radiotherapy (RT) are at high risk of weight loss (WL) due to a variety of nutrition impact symptoms (NIS). This study aimed to describe the NIS through the Head and Neck patient Symptom Checklist and body weight over time and further explore the impact of NIS on WL in patients with HNC undergoing RT. METHODS: This was a prospective, longitudinal observational study. NIS and body weight of 117 participants were assessed at baseline, mid-treatment and post-treatment of RT. Generalised estimation equations (GEE) were used to conduct repeated measures analysis of NIS interference score and body weight at each time point and estimate the impact of NIS interference score on WL. RESULTS: All participants experienced a substantial increase in the mean number of NIS during RT, with each patient having eight to nine NIS at mid-treatment and post-treatment. Marked increases were noted in almost each NIS score during RT. Compared with their baseline body weight, 97 (82.9%) and 111 (94.9%) participants experienced WL at mid-treatment and post-treatment, with the mean WL of 2.55±1.70 kg and 5.31±3.18 kg, respectively. NIS of dry mouth (ß=-0.681, p=0.002, 95% CI -1.116 to -0.247), difficulty swallowing (ß=-0.410, p=0.001, 95% CI -0.651 to -0.169) and taste change (ß=-0.447, p=0.000, 95% CI -0.670 to -0.225) impacted WL significantly in GEE multivariate model. CONCLUSIONS: Patients with HNC experience a variety of NIS which have significant impact on WL during RT. Assessment of NIS, especially dry mouth, difficulty swallowing and taste change, should be given more considerable attention in the supportive care of patients with HNC.

The reliable predictors of severe weight loss during the radiotherapy of Head and Neck Cancer.

Side effects of severe weight loss during radiation therapy and its definitive risk factors are the significant complexities of cancer treatment. This study aimed to identify the reliable predictors of severe weight loss during three-dimensional conformal radiation therapy (3D-CRT) in head and neck cancer patients. Weight changes during radiotherapy were investigated on 87 patients. Tumor site, T-stage, BMI, age, smoking, treatment modality, and prior surgery were considered as effective factors. During the 3D-CRT, 78.7% of patients experienced weight loss (p<0.001). The risk of weight loss was higher in patients with cancer in the larynx and oral cavity. Severe weight loss (≥5% during the radiation course) was observed in 47.8% of patients. There was the highest risk of severe weight loss in patients undergoing chemoradiation therapy with previous surgical resection (83.3%). The incidence of severe weight loss in normal-weight patients compared to overweight patients was significant. Severe weight loss was more common at higher doses and in younger patients. BMI regardless of body composition is not a credible predictor. Advanced tumor stage and combined treatment modality in head and neck cancer patients which result in synergizing of treatment toxicities, can be used as the reliable risk factors of severe weight loss during radiotherapy.

El ejercicio y el adecuado control nutricional previenen la pérdida de peso durante la radioterapia en cáncer de cabeza y cuello: a propósito de un caso / Exercise and adequate nutritional control prevent weight loss during radiotherapy in head and neck cancer: a case report

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Multi-view radiomics and dosiomics analysis with machine learning for predicting acute-phase weight loss in lung cancer patients treated with radiotherapy.

We propose a multi-view data analysis approach using radiomics and dosiomics (R&D) texture features for predicting acute-phase weight loss (WL) in lung cancer radiotherapy. Baseline weight of 388 patients who underwent intensity modulated radiation therapy (IMRT) was measured between one month prior to and one week after the start of IMRT. Weight change between one week and two months after the commencement of IMRT was analyzed, and dichotomized at 5% WL. Each patient had a planning CT and contours of gross tumor volume (GTV) and esophagus (ESO). A total of 355 features including clinical parameter (CP), GTV and ESO (GTV&ESO) dose-volume histogram (DVH), GTV radiomics, and GTV&ESO dosiomics features were extracted. R&D features were categorized as first- (L1), second- (L2), higher-order (L3) statistics, and three combined groups, L1 + L2, L2 + L3 and L1 + L2 + L3. Multi-view texture analysis was performed to identify optimal R&D input features. In the training set (194 earlier patients), feature selection was performed using Boruta algorithm followed by collinearity removal based on variance inflation factor. Machine-learning models were developed using Laplacian kernel support vector machine (lpSVM), deep neural network (DNN) and their averaged ensemble classifiers. Prediction performance was tested on an independent test set (194 more recent patients), and compared among seven different input conditions: CP-only, DVH-only, R&D-only, DVH + CP, R&D + CP, R&D + DVH and R&D + DVH + CP. Combined GTV L1 + L2 + L3 radiomics and GTV&ESO L3 dosiomics were identified as optimal input features, which achieved the best performance with an ensemble classifier (AUC = 0.710), having statistically significantly higher predictability compared with DVH and/or CP features (p < 0.05). When this performance was compared to that with full R&D-only features which reflect traditional single-view data, there was a statistically significant difference (p < 0.05). Using optimized multi-view R&D input features is beneficial for predicting early WL in lung cancer radiotherapy, leading to improved performance compared to using conventional DVH and/or CP features.

Predictors of Weight Loss in Patients With Head and Neck Cancer Receiving Radiation or Concurrent Chemoradiation Treated at a Tertiary Cancer Center.

BACKGROUND: Radiation therapy (RT) has remained the mainstay treatment approach for head and neck cancers. Weight loss due to tumor or tumor-related factors remains a major health issue among head and neck cancer patients. METHODS: A total of 357 patients were identified for the study. Possible weight-loss predictors were determined in the patients undergoing RT based on the patient demographics, tumor site, and treatment characteristics. RESULTS: The mean age of patients was 52 years, whereas the median age was 51 years (range, 18-87). Two hundred and thirteen (66%) patients had oral cavity cancers, 43 (14%) had oropharyngeal cancer, 26 (8%) had hypopharyngeal cancer, 13 (6%) had larynx cancer, and 19 (6%) had other site involvement. A total of 192 patients received 3-dimensional conformal radiation therapy (3DCRT), whereas 127 patients received intensity modulated radiation therapy-image guided radiation therapy (IMRT-IGRT), 212 (66%) received concurrent chemotherapy, and 107 (34%) patients did not receive concurrent chemotherapy. A total of 127 (40%) of the patients gained weight during the first week of RT; on the other hand, maximum weight loss among patients was occurred during the third and fourth weeks of RT. CONCLUSION: Analysis by logistic regression determined there is significant weight loss (>10%) in patients receiving radical RT as compared with adjuvant RT. Better outcomes were observed in patients receiving RT by IMRT-IGRT technique as compared with 3DCRT technique.

Low-level laser therapy for weight reduction: a randomized pilot study.

Obesity and overweight is a global health crisis and novel methods of treatment are needed to address it. Low-level laser therapy (LLLT) is a currently available non-invasive procedure for lysing excess fat, but there is a lack of consensus exists on LLLT frequency and limited research from studies of LLLT. The purpose of this pilot study is to compare the effect of three of the most common LLLT frequencies on weight, waist circumference, body fat percentage, and quality of life. Sixty overweight (body mass index (BMI) 25-29.9 kg/m2) adult participants were randomized to 12 LLLT treatments: (1) three times weekly for 4 weeks, (2) twice weekly for 6 weeks, or (3) once weekly for 12 weeks. All participants attended an in-person visit at baseline and at weeks 4, 6, 12, and 26. Participants were recruited September 30, 2016 through to August 27, 2017. The majority of the 60 participants were female (90%) with an average age of 43.7 years (± 9.2 years). Most participants (98%) completed 10 or more of the 12 LLLT treatments. When comparing across treatment groups, the greatest reductions from baseline were observed in those assigned to twice weekly for 6 weeks in weight (1 ± 1.7 (±SD) kg by week 6), waist circumference (- 2.0 ± 3.2 in. by week 6 and - 1.5 ± 3.2 in. by week 26), body mass index (- 0.4 ± 0.6 kg/m2), and body fat mass (- 1.1 ± 1.6 kg). This group also had the most significant improvement from baseline in quality of life (+ 0.5 ± 0.8 by week 6), body satisfaction (+ 0.2 ± 0.4 by week 6 and week 26), and body appreciation (+ 0.2 ± 0.3 by week 6 and + 0.3 ± 0.3 by week 26). LLLT twice weekly for 6 weeks could be proposed as the optimal frequency and duration for the management of body weight. Trial registration: https://clinicaltrials.gov/ct2/show/NCT02877004. Registered August 24, 2016.

An explorative study on energy balance in patients with head and neck cancer.

Background: Involuntary body weight loss in head and neck cancer is common. Fundamental for weight loss is an energy imbalance where total energy expenditure exceeds energy intake.Aim: To map energy intake and parameters of energy expenditure at the start of and after radiotherapy, and their relation to weight change, body mass index, and immune markers in patients with head and neck cancer.Materials and Methods: Data from 20 patients on energy intake (24-hour dietary intake recalls), total energy expenditure (SenseWear Armband Pro3), resting energy expenditure (indirect calorimetry), body weight, body mass index, and immune markers in serum (C-reactive protein and Interleukin-6) were collected at the start of and after radiotherapy (median 8 mo, range 5-13).Results: No statistical significance was shown between the two measurement points for energy intake or for the different parameters of energy expenditure. Median values for energy balance were 0.93 and 0.96 for the start of treatment and follow-up, respectively. Twelve and 13 patients had a negative energy balance at the start of radiotherapy and at follow-up, respectively.Conclusion: A negative energy balance was seen for the majority of patients, which stresses the importance of nutritional treatment at the start of and after radiotherapy.

The changing landscape of head and neck cancer radiotherapy patients: is high-risk, prolonged feeding tube use indicative of on-treatment weight loss?

INTRODUCTION: Precision radiotherapy relies heavily on optimal weight management. Our group previously developed a risk stratification model for patients at risk of prolonged feeding tube (FT) intervention. The study objective was to assess on-treatment weight loss according to stratified risk of prolonged FT use. METHODS: One hundred and one (n = 101) definitive head and neck radiotherapy patients were included in this study. Patients were stratified into high risk (HRi: T-classification ≥ 3 with level 2 Nodal disease), high-intermediate risk (HIRi: T-classification ≥ 3 without level 2 Nodes) and low-intermediate risk (LIRi: T-classification < 3 with level 2 Nodes) of prolonged FT use. Demographic variables and on-treatment weight loss were evaluated according to risk status. RESULTS: Oropharyngeal carcinoma (OPC) was present in a larger proportion in the LIRi cohort (HRi: 71%, HIRi: 52%, LIRi: 81%, P = 0.008). LIRi patients were more likely to have human papilloma virus (HPV)-associated disease (88%, P = 0.001). Never/minimal smoking (P = 0.003), good performance status (P < 0.001), healthy BMI (P = 0.050) and no pre-existing dysphagia (P < 0.001) were predominant within the LIRi prognostic group. LIRi patients lost significantly more weight in total (HRi = 4.8% vs. LIRi = 8.2%, P = 0.002; HIRi = 5.2% vs. LIRi = 8.2%, P = 0.006) and when using a FT (HRi = 4.6% vs. LIRi = 8.8%, P < 0.001; HIRi = 5.3% vs. LIRi = 8.8%, P = 0.002). CONCLUSIONS: Patients identified as low-intermediate risk of prolonged, ≥25% FT use report significantly increased weight loss compared with patients at higher risk of FT use. This cohort is typical of the increasing number of patients presenting with HPV-associated OPC. Results of this study suggest we should closely observe such patients throughout treatment, to ensure optimal weight maintenance, facilitating precision radiotherapy.

Total body irradiation induced mouse small intestine senescence as a late effect.

Radiation can induce senescence in many organs and tissues; however, it is still unclear how radiation stimulates senescence in mouse small intestine. In this study, we use the bone marrow transplantation mouse model to explore the late effects of total body irradiation on small intestine. Our results showed that almost all of the body hairs of the irradiated mice were white (which is an indication of aging) 10 months after the exposure to radiation. Furthermore, compared with the age-matched control mice, there were more SA-ß-galactosidase (SA-ß-gal)-positive cells and an upregulation of p16 and p21 in 8 Gy-irradiated mice intestinal crypts, indicating that radiation induced senescence in the small intestine. Intestinal bacterial flora profile analysis showed that the diversity of the intestinal bacterial flora decreased in irradiated mice; in addition it showed that the principal components of the irradiated and control mice differed: there was increased abundance of Bacteroidia and a decreased abundance of Clostridia in irradiated mice. To explore the underlying mechanism, an RNA-sequence was executed; the results suggested that pancreatic secretion, and the digestion and absorption of proteins, carbohydrates, fats and vitamins were damaged in irradiated mice, which may be responsible for the body weight loss observed in irradiated mice. In summary, our study suggested that total body irradiation may induce senescence in the small intestine and damage the health status of the irradiated mice.

Patterns of failure, treatment outcomes and late toxicities of head and neck cancer in the current era of IMRT.

Intensity modulated radiotherapy (IMRT) in head and neck cancer allows sculpting of radiation dose to conform closely to target volumes and spare organs at risk. However, this may be offset by an increased risk of a geographical miss and reduction in survival outcomes. We reviewed the data from 5 prospective randomized controlled trials, one prospective phase II trial and 10 retrospective comparative series in terms of patterns of failure, treatment outcomes and late toxicities to determine any compromise in survival outcomes in favour of reduced late toxicity. Whilst there was some variablility in target volume delineation, radiation dose and technique, the published data consistently show reduced long term xerostomia (ranging from 0.5 to 87%) with IMRT compared to older radiation techniques. Some studies showed reduced incidence of >10% weight loss and grade ≥2 dysphagia with IMRT, and 2 studies reported higher rates of dysphagia with IMRT. Most studies demonstrated better, though non-significant, locoregional, disease-free and overall survival. The 4 studies that did demonstrate significantly better overall survival with IMRT were the largest cohorts with around 250 patients or greater. Standardization of target volume delineation, treatment verification protocols and outcome reporting will reduce heterogeneity and allow data to be pooled in order to be adequately powered for survival analyses.

The Prediction of Deterioration of Nutritional Status during Chemoradiation Therapy in Patients with Esophageal Cancer.

Patients with esophageal cancer are at high risk of developing malnutrition during neoadjuvant chemoradiation therapy (CRT), which in turn is associated with postoperative morbidity. The aim of the study is to explore whether parameters of a complete pre-treatment nutritional status may predict deterioration of nutritional status during CRT in patients with esophageal cancer. In this prospective cohort study, 101 patients with esophageal cancer treated with CRT were included. Data of patient characteristics, tumor classification, performance score, %weight change, body mass index, fat (free) mass index, phase angle, handgrip strength, energy- and protein intake, and use of (additional) dietary supplements were collected. A prediction model was constructed to identify predictive parameters for deterioration in nutritional status (defined as weight loss of >5% and/or decline in fat free mass of ≥1.4 kg) during CRT. Nutritional status deteriorated in 49 patients (49%) during CRT. The only predictor for deterioration in nutritional status was fat free mass index (OR 1.21 (90% CI: 1.03 - 1.42)). Patients with a higher fat free mass index are at increased risk of deterioration in nutrition status during CRT. Results suggest that all patients should be carefully supervised during CRT, regardless of their nutritional status before start of CRT.

Implications of weight loss for cancer patients receiving radiotherapy.

PURPOSE OF REVIEW: Cancer-associated weight loss is a common comorbid condition best described among patients with advanced malignancy receiving systemic therapy, but its relationship to patients undergoing radiation treatment is less well described. We review the interaction between cancer-associated weight loss and radiation treatment as well as its prognostic significance. RECENT FINDINGS: Multiple studies demonstrate a consistent detrimental effect of cancer-associated weight loss either existing prior to treatment or developing during radiotherapy. Emerging data suggest cancer-associated weight loss independently contributes to an aggressive malignant phenotype rather than simply reflecting a consequence of disease. Novel therapies are urgently needed to address the unmet burden of cancer-associated weight loss. SUMMARY: Consideration of cancer-associated weight loss is important among patients receiving radiotherapy. Further study will further characterize the relationship and identify targetable biologic mechanisms of cancer cachexia.

The effects of oral glutamine on clinical and survival outcomes of non-small cell lung cancer patients treated with chemoradiotherapy.

PURPOSE: To assess the efficacy of oral glutamine (Gln) supplementation on clinical and survival outcomes of patients with locally advanced non-small cell lung cancer (LA-NSCLC). MATERIALS/METHODS: Between 2010 and 2014, 122 stage III NSCLC patients were retrospectively analyzed. All patients received curative intent chemoradiotherapy (CRT). Prophylactic oral Gln powder was applied at a dose of 10 g tid. Effect of oral Gln supplementation in the prevention of severe (≥grade 2-3) acute radiation-induced esophagitis (ARE) and weight loss, and their relation with overall survival (OS) and disease-free survival (DFS) was measured. RESULTS: Median follow-up was 13.14 months (range; 1.97-55.36). Fifty-six (46%) patients had received oral Gln. Severe ARE was significantly lower in Gln-supplemented group (30% vs 70%; p = 0.002). Gln-free patients demonstrated a higher weight loss (p = 0.0001). In multivariate analysis hemoglobin (hb) level (<12 g/dL; p = 0.01) and nodal stage (N3; p = 0.01) were poor prognostic factors that affect OS; Weight loss (p = 0.06) and Gln-free (p = 0.05) reached nearly significant levels that poorly affect OS. Similarly, nodal stage (N3, p = 0.014) and Gln-free (p = 0.035) were poor prognostic factors that affect DFS. Weight loss (≥2%, p = 0.06) and hb level (<12 g/dL, p = 0.07) reached borderline significance that poorly affect DFS. Nodal stage (N3) was the only poor prognostic factor that affect OS and DFS in univariate analysis (p = 0.01, p = 0.009; respectively). CONCLUSION: Oral Gln supplementation significantly reduces grade 2-3 esophagitis and weight loss and also no negative impact on tumor control and survival outcomes in patients with LA-NSCLC.

A non-human primate model of radiation-induced cachexia.

Cachexia, or muscle wasting, is a serious health threat to victims of radiological accidents or patients receiving radiotherapy. Here, we propose a non-human primate (NHP) radiation-induced cachexia model based on clinical and molecular pathology findings. NHP exposed to potentially lethal partial-body irradiation developed symptoms of cachexia such as body weight loss in a time- and dose-dependent manner. Severe body weight loss as high as 20-25% was observed which was refractory to nutritional intervention. Radiographic imaging indicated that cachectic NHP lost as much as 50% of skeletal muscle. Histological analysis of muscle tissues showed abnormalities such as presence of central nuclei, inflammation, fatty replacement of skeletal muscle, and muscle fiber degeneration. Biochemical parameters such as hemoglobin and albumin levels decreased after radiation exposure. Levels of FBXO32 (Atrogin-1), ActRIIB and myostatin were significantly changed in the irradiated cachectic NHP compared to the non-irradiated NHP. Our data suggest NHP that have been exposed to high dose radiation manifest cachexia-like symptoms in a time- and dose-dependent manner. This model provides a unique opportunity to study the mechanism of radiation-induced cachexia and will aid in efficacy studies of mitigators of this disease.