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Sickness behavior induced by cisplatin chemotherapy and radiotherapy in a murine head and neck cancer model is associated with altered mitochondrial gene expression.

ABSTRACT: The present study was undertaken to explore the possible mechanisms of the behavioral alterations that develop in response to cancer and to cancer therapy. For this purpose we used a syngeneic heterotopic mouse model of human papilloma virus (HPV)-related head and neck cancer in which cancer therapy is curative. Mice implanted or not with HPV+ tumor cells were exposed to sham treatment or a regimen of cisplatin and radiotherapy (chemoradiation). Sickness was measured by body weight loss and reduced food intake. Motivation was measured by burrowing, a highly prevalent species specific behavior. Tumor-bearing mice showed a gradual decrease in burrowing over time and increased brain and liver inflammatory cytokine mRNA expression by 28 days post tumor implantation. Chemoradiation administered to healthy mice resulted in a mild decrease in burrowing, body weight, and food intake. Chemoradiation in tumor-bearing mice decreased tumor growth and abrogated liver and brain inflammation, but failed to attenuate burrowing deficits. PCR array analysis of selected hypoxia and mitochondrial genes revealed that both the tumor and chemoradiation altered the expression of genes involved in mitochondrial energy metabolism within the liver and brain and increased expression of genes related to HIF-1? signaling within the brain. The most prominent changes in brain mitochondrial genes were noted in tumor-bearing mice treated with chemoradiation. These findings indicate that targeting mitochondrial dysfunction following cancer and cancer therapy may be a strategy for prevention of cancer-related symptoms.

SUBMITTER: Vichaya EG

PROVIDER: S-EPMC4679574 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Sickness behavior induced by cisplatin chemotherapy and radiotherapy in a murine head and neck cancer model is associated with altered mitochondrial gene expression.

Vichaya Elisabeth G EG Molkentine Jessica M JM Vermeer Daniel W DW Walker Adam K AK Feng Rebekah R Holder Gerard G Luu Katherine K Mason Ryan M RM Saligan Leo L Heijnen Cobi J CJ Kavelaars Annemieke A Mason Kathy A KA Lee John H JH Dantzer Robert R

Behavioural brain research 20151022

The present study was undertaken to explore the possible mechanisms of the behavioral alterations that develop in response to cancer and to cancer therapy. For this purpose we used a syngeneic heterotopic mouse model of human papilloma virus (HPV)-related head and neck cancer in which cancer therapy is curative. Mice implanted or not with HPV+ tumor cells were exposed to sham treatment or a regimen of cisplatin and radiotherapy (chemoradiation). Sickness was measured by body weight loss and redu ...[more]

PMID: 26475509

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Project description:Importance:Accurate, accessible predictions of posttreatment hearing loss for patients with head and neck cancer prior to the initiation of treatment are a necessary part of informed patient decision-making. Objective:To develop a prediction model for postradiotherapy and/or post-cisplatin chemotherapy hearing loss for patients with head and neck cancer. Design, Setting, and Participants:A retrospective cohort study was conducted at a tertiary academic medical center among 242 patients (482 ears) with head and neck cancer who were treated with radiotherapy and/or cisplatin from October 1, 2014, to July 31, 2018, and had follow-up audiometric data available. Exposures:Radiotherapy and cisplatin chemotherapy. Main Outcomes and Measures:Patient hearing level, as measured by the mean of pure tone audiometry at 1, 2, and 4 kHz on completion of treatment. A multivariable mixed model for predicting the posttreatment pure tone average was developed using only information available to clinicians at the beginning of treatment. Results:A total of 242 patients (482 ears; 56 women and 186 men; mean [SD] age, 60 [10] years) were included in the analysis. All patients in the study received radiotherapy, and 105 (43.4%) received cisplatin chemotherapy. The mean (SD) total cumulative cisplatin dose was 298 (109) mg/m2. Patients' ears received a mean (SD) cochlear radiotherapy dose of 15 (13) Gy. The fixed-effects predictions from the predictive model agreed with 77% (95% CI, 73%-81%) of the variability in the posttreatment pure tone average. This predictive model also had a sensitivity of 80% and a specificity of 75% for predicting an observed posttreatment pure tone average greater than 35 dB (area under the receiver operating characteristic curve, 0.85). Conclusions and Relevance:To our knowledge, this study develops the first accurate prediction model of posttreatment hearing in patients with head and neck cancer that is feasible for use in the clinical setting before the initiation of treatment. This research confirms that exposure of the cochlea to cisplatin chemotherapy and radiotherapy is associated with hearing loss in patients with head and neck cancer. Finally, this research motivates future studies of ototoxic effects to better understand the adverse effects of head and neck cancer treatment.

Project description:BACKGROUND:The evolution of radiotherapy over recent decades has reintroduced the hypofractionation for many tumor sites with similar outcomes to those of conventional fractionated radiotherapy. The use of hypofractionation in locally advanced head and neck cancer (LAHNC) has been already used, however, its use has been restricted to only a few countries. The aim of this trial was to evaluate the safety and feasibility of moderate hypofractionated radiotherapy (HYP-RT) with concomitant cisplatin (CDDP). METHODS:This single-arm trial was designed to evaluate the safety and feasibility of HYP-RT with concomitant CDDP in LAHNC. Stage III and IV patients withnonmetastatic disease were enrolled. Patients were submitted to intensity modulatedradiation therapy, which comprised 55 Gy/20 fractions to the gross tumor and44-48 Gy/20 fractions to the areas of subclinical disease. Concomitant CDDPconsisted of 4 weekly cycles of 35 mg/m2. The primary endpoints were the treatment completion rate and acute toxicity. RESULTS:Twenty patients were enrolled from January 2015 to September 2016, and 12 (60%) were classified as unresectable. All patients completed the total dose of radiotherapy, and 19 patients (95%) received at least 3 of 4 cycles of chemotherapy. The median overall treatment time was 29 days (27-34). Grade 4 toxicity was reported twice (1 fatigue and 1 lymphopenia). The rates of grade 3 dermatitis and mucositis were 30% and 40%, respectively, with spontaneous resolution. Nasogastric tubes were offered to 15 patients (75%) during treatment; 4 patients (20%) needed feeding tubes after 2 months, and only 1 patient needed a feeding tube after 12 months. CONCLUSION:HYP-RT with concomitant CDDP was considered feasible for LAHNC, and the rate of acute toxicity was comparable to that of standard concomitant chemoradiation. A feeding tube was necessary for most patients during treatment. Further investigation of this strategy is warranted. TRIAL REGISTRATION:ClinicalTrials, NCT03194061 . Registered 21 Jun 2017 - Retrospectively registered.

Project description:ImportanceHearing loss affects up to 88% of patients undergoing head and neck cancer treatment; however, there are few validated models to predict this outcome. A predictive posttreatment model for hearing loss will allow clinicians and patients to make well-informed decisions about treatment with cisplatin-based chemotherapies and radiotherapy.ObjectiveTo validate a previously created predictive model for objective hearing outcomes and to assess barriers to using the prediction nomogram in general practice for patients newly diagnosed with head and neck cancer.Design, setting, and participantsThis cohort study includes an evaluation of 105 patients (208 ears) and interviews with 6 clinicians. The patients were treated at a high-volume tertiary care hospital. Patient participants were newly diagnosed with head and neck cancer and treated at Siteman Cancer Center from July 1, 2018, to December 31, 2019, with radiotherapy both with and without cisplatin-based chemotherapy. Additionally, the clinicians involved in the care of patients with head and neck cancer were interviewed to assess implementation strategies.ExposuresRadiotherapy with and without cisplatin-based chemotherapy.Main outcomes and measuresHearing defined by the audiometric pure-tone average of 1, 2, and 4 kHz.ResultsA total of 105 patients (208 ears; mean [SD] age, 61 [11] years; 82 men [78%]) were compared with the development cohort to assess the similarities and differences in case mix. All patients underwent radiation therapy, 50 (48%) received cisplatin-based chemotherapy, and 67 (64%) had a surgical resection. The mean (SD) cochlear dose of radiation was 13 (12) Gy, and the mean (SD) total cisplatin dose was 238 (83) mg/m2 for those undergoing cisplatin therapy. A calibration curve demonstrated that predicted and observed posttreatment pure-tone average were not significantly different. The model predicted a posttreatment pure-tone average greater than 35 dB (a common threshold for hearing aid consideration) with a sensitivity of 73% and specificity of 67% with an area under the curve of 0.71, showing good discrimination. Clinician interviews suggest the nomogram requires careful integration into patient counseling to clarify risks and benefits for treatment.Conclusions and relevanceThe findings of this cohort study confirm this model's ability to predict posttreatment hearing outcomes in a unique population of patients. This model has the potential to inform pretreatment counseling and posttreatment hearing evaluations for this patient population.

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Sickness behavior induced by cisplatin chemotherapy and radiotherapy in a murine head and neck cancer model is associated with altered mitochondrial gene expression.

Publications

Sickness behavior induced by cisplatin chemotherapy and radiotherapy in a murine head and neck cancer model is associated with altered mitochondrial gene expression.

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