Measurement of CYP1A2 and CYP3A4 activity by a simplified Geneva cocktail approach in a cohort of free-living individuals: a pilot study.

Introduction: The cytochrome P450 enzyme subfamilies, including CYP3A4 and CYP1A2, have a major role in metabolism of a range of drugs including several anti-cancer treatments. Many factors including environmental exposures, diet, diseaserelated systemic inflammation and certain genetic polymorphisms can impact the activity level of these enzymes. As a result, the net activity of each enzyme subfamily can vary widely between individuals and in the same individual over time. This variability has potential major implications for treatment efficacy and risk of drug toxicity, but currently no assays are available for routine use to guide clinical decision-making. Methods: To address this, a mass spectrometry-based method to measure activities of CYP3A4, CYP1A2 was adapted and tested in free-living participants. The assay results were compared with the predicted activity of each enzyme, based on a self-report tool capturing diet, medication, chronic disease state, and tobacco usage. In addition, a feasibility test was performed using a low-volume dried blood spots (DBS) on two different filter-paper supports, to determine if the same assay could be deployed without the need for repeated standard blood tests. Results: The results confirmed the methodology is safe and feasible to perform in free-living participants using midazolam and caffeine as test substrates for CYP3A4 and CYP1A2 respectively. Furthermore, though similar methods were previously shown to be compatible with the DBS format, the assay can also be performed successfully while incorporating glucuronidase treatment into the DBS approach. The measured CYP3A4 activity score varied 2.6-fold across participants and correlated with predicted activity score obtained with the self-report tool. The measured CYP1A2 activity varied 3.5-fold between participants but no correlation with predicted activity from the self-report tool was found. Discussion: The results confirm the wide variation in CYP activity between individuals and the important role of diet and other exposures in determining CYP3A4 activity. This methodology shows great potential and future cross-sectional and longitudinal studies using DBS are warranted to determine how best to use the assay results to guide drug treatments.

Chronic aryl hydrocarbon receptor activity phenocopies smoking-induced skeletal muscle impairment.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) patients exhibit skeletal muscle atrophy, denervation, and reduced mitochondrial oxidative capacity. Whilst chronic tobacco smoke exposure is implicated in COPD muscle impairment, the mechanisms involved are ambiguous. The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that activates detoxifying pathways with numerous exogenous ligands, including tobacco smoke. Whereas transient AHR activation is adaptive, chronic activation can be toxic. On this basis, we tested the hypothesis that chronic smoke-induced AHR activation causes adverse muscle impact. METHODS: We used clinical patient muscle samples, and in vitro (C2C12 myotubes) and in vivo models (mouse), to perform gene expression, mitochondrial function, muscle and neuromuscular junction morphology, and genetic manipulations (adeno-associated virus-mediated gene transfer). RESULTS: Sixteen weeks of tobacco smoke exposure in mice caused muscle atrophy, neuromuscular junction degeneration, and reduced oxidative capacity. Similarly, smoke exposure reprogrammed the muscle transcriptome, with down-regulation of mitochondrial and neuromuscular junction genes. In mouse and human patient specimens, smoke exposure increased muscle AHR signalling. Mechanistically, experiments in cultured myotubes demonstrated that smoke condensate activated the AHR, caused mitochondrial impairments, and induced an AHR-dependent myotube atrophy. Finally, to isolate the role of AHR activity, expression of a constitutively active AHR mutant without smoke exposure caused atrophy and mitochondrial impairments in cultured myotubes, and muscle atrophy and neuromuscular junction degeneration in mice. CONCLUSIONS: These results establish that chronic AHR activity, as occurs in smokers, phenocopies the atrophy, mitochondrial impairment, and neuromuscular junction degeneration caused by chronic tobacco smoke exposure.

Diagnostic criteria for cancer cachexia: reduced food intake and inflammation predict weight loss and survival in an international, multi-cohort analysis.

BACKGROUND: Cancer-associated weight loss (WL) associates with increased mortality. International consensus suggests that WL is driven by a variable combination of reduced food intake and/or altered metabolism, the latter often represented by the inflammatory biomarker C-reactive protein (CRP). We aggregated data from Canadian and European research studies to evaluate the associations of reduced food intake and CRP with cancer-associated WL (primary endpoint) and overall survival (OS, secondary endpoint). METHODS: The data set included a total of 12,253 patients at risk for cancer-associated WL. Patient-reported WL history (% in 6 months) and food intake (normal, moderately, or severely reduced) were measured in all patients; CRP (mg/L) and OS were measured in N = 4960 and N = 9952 patients, respectively. All measures were from a baseline assessment. Clinical variables potentially associated with WL and overall survival (OS) including age, sex, cancer diagnosis, disease stage, and performance status were evaluated using multinomial logistic regression MLR and Cox proportional hazards models, respectively. RESULTS: Patients had a mean weight change of -7.3% (±7.1), which was categorized as: ±2.4% (stable weight; 30.4%), 2.5-5.9% (19.7%), 6.0-10.0% (23.2%), 11.0-14.9% (12.0%), ≥15.0% (14.6%). Normal food intake, moderately, and severely reduced food intake occurred in 37.9%, 42.8%, and 19.4%, respectively. In MLR, severe WL (≥15%) (vs. stable weight) was more likely (P < 0.0001) if food intake was moderately [OR 6.28, 95% confidence interval (CI 5.28-7.47)] or severely reduced [OR 18.98 (95% CI 15.30-23.56)]. In subset analysis, adjusted for food intake, CRP was independently associated (P < 0.0001) with ≥15% WL [CRP 10-100 mg/L: OR 2.00, (95% CI 1.58-2.53)] and [CRP > 100 mg/L: OR 2.30 (95% CI 1.62-3.26)]. Diagnosis, stage, and performance status, but not age or sex, were significantly associated with WL. Median OS was 9.9 months (95% CI 9.5-10.3), with median follow-up of 39.7 months (95% CI 38.8-40.6). Moderately and severely reduced food intake and CRP independently predicted OS (P < 0.0001). CONCLUSIONS: Modelling WL as the dependent variable is an approach that can help to identify clinical features and biomarkers associated with WL. Here, we identify criterion values for food intake impairment and CRP that may improve the diagnosis and classification of cancer-associated cachexia.

Defining barriers to implementation of nutritional advice in patients with cachexia.

BACKGROUND: Cancer cachexia is a multidimensional wasting syndrome and a reduced dietary intake is both common and strongly correlated with degree of weight loss. Many patients with cachexia do not achieve recommended dietary intake even after nutritional counselling. Prior reports suggest this is likely due to barrier symptoms, but other potential contributory factors have not been studied in detail. METHODS: Dietitian-assigned barriers to successful nutritional intervention were recorded at each visit in all patients attending a multidisciplinary clinic for management of cancer cachexia. The barriers were grouped into 15 categories and classified as either symptom-related or not symptom-related. In addition, symptom scores, dietary intake, and weight change were recorded. RESULTS: Data on 94 new patients showed that 89% of patients had at least one major barrier. Four of the five most common barriers and 65% of all barriers identified were not symptom-related. Over sequential visits the specific barrier(s) in any one patient changed approximately 50% of the time. However, the presence of barriers did not render patients refractory to nutritional intervention and with intervention from the CNR-JGH team, mean dietary intake increased significantly. CONCLUSIONS: In advanced cancer patients with cachexia, non-symptom-related barriers to nutritional intervention are more common than symptom-related. Barriers are dynamic, and repeated careful evaluation over time is required to achieve optimal impact with nutritional intervention in cancer cachexia. Members of the multidisciplinary team need appropriate expertise to address the barriers identified and achieve optimal results with nutritional intervention.

Physiological culture conditions alter myotube morphology and responses to atrophy treatments: implications for in vitro research on muscle wasting.

Standard in vitro myotube culture conditions are nonphysiological and there is increasing evidence that this may distort adaptations to both catabolic and anabolic stimuli and hamper preclinical research into mechanisms and treatments for muscle atrophy in cancer and other chronic diseases. We tested a new model of myotube culture which mimics more accurately the basal conditions for muscle tissue in patients with chronic disease, such as cancer. Myotubes derived from C2C12 myoblasts, cultured under the modified conditions were thinner, more numerous, with more uniform morphology and an increased proportion of mature myotubes. Furthermore, modified conditions led to increased expression of mir-210-3p, genes related to slow-twitch, oxidative phenotype and resistance to commonly used experimental atrophy-inducing treatments. However, treatment with a combination of drugs used in anti-cancer treatment (doxorubicin and dexamethasone) under the modified culture conditions did lead to myotube atrophy which was only partially prevented by co-administration of curcumin. The results underline the importance and potential advantages of using physiological conditions for in vivo experiments investigating mechanisms of muscle atrophy and especially for preclinical screening of therapies for cancer-related muscle wasting.

Smoke-induced neuromuscular junction degeneration precedes the fibre type shift and atrophy in chronic obstructive pulmonary disease.

KEY POINTS: Chronic obstructive pulmonary disease (COPD) is largely caused by smoking, and patient limb muscle exhibits a fast fibre shift and atrophy. We show that this fast fibre shift is associated with type grouping, suggesting recurring cycles of denervation-reinnervation underlie the type shift. Compared to patients with normal fat-free mass index (FFMI), patients with low FFMI exhibited an exacerbated fibre type shift, marked accumulation of very small persistently denervated muscle fibres, and a blunted denervation-responsive transcript profile, suggesting failed denervation precipitates muscle atrophy in patients with low FFMI. Sixteen weeks of passive tobacco smoke exposure in mice caused neuromuscular junction degeneration, consistent with a key role for smoke exposure in initiating denervation in COPD. ABSTRACT: A neurological basis for the fast fibre shift and atrophy seen in limb muscle of patients with chronic obstructive pulmonary disease (COPD) has not been considered previously. The objective of our study was: (1) to determine if denervation contributes to fast fibre shift and muscle atrophy in COPD; and (2) to assess using a preclinical smoking mouse model whether chronic tobacco smoke (TS) exposure could initiate denervation by causing neuromuscular junction (NMJ) degeneration. Vastus lateralis muscle biopsies were obtained from severe COPD patients [n = 10 with low fat-free mass index (FFMI), 65 years; n = 15 normal FFMI, 65 years) and healthy age- and activity-matched non-smoker control subjects (CON; n = 11, 67 years), to evaluate morphological and transcriptional markers of denervation. To evaluate the potential for chronic TS exposure to initiate these changes, we examined NMJ morphology in male adult mice following 16 weeks of passive TS exposure. We observed a high proportion of grouped fast fibres and a denervation transcript profile in COPD patients, suggesting that motor unit remodelling drives the fast fibre type shift in COPD patient limb muscle. A further exacerbation of fast fibre grouping in patients with low FFMI, coupled with blunted reinnervation signals, accumulation of very small non-specific esterase hyperactive fibres and neural cell adhesion molecule-positive type I and type II fibres, suggests denervation-induced exhaustion of reinnervation contributes to muscle atrophy in COPD. Evidence from a smoking mouse model showed significant NMJ degeneration, suggesting that recurring denervation in COPD is probably caused by decades of chronic TS exposure.

Defining the role of dietary intake in determining weight change in patients with cancer cachexia.

BACKGROUND & AIMS: Weight loss is a cardinal feature of cachexia and is frequently associated with reduced food intake and anorexia. It is still unclear how much reduced food intake contributes to cancer-related weight loss and how effective increasing dietary energy and protein is in combating this weight loss. The relationship between weight change and both diet and change in dietary intake, was examined in patients with advanced stage cancer referred to a multidisciplinary clinic for management of cancer cachexia. METHODS: A retrospective study of data for each of the first three clinic visits for patients seen between 2009 and 2015. Data on weight change, dietary intake and change in dietary intake were compared. Regression analysis was used to determine independent explanatory factors for weight change, including the impact of appetite level and a marker of systemic inflammation. RESULTS: Of 405 eligible patients, 320 had data on dietary intake available. Dietary intake varied widely at baseline: 26.9% reported very poor diet and only 17% were consuming recommended levels of energy and protein. A highly significant positive correlation was found between dietary energy or protein intake and weight change, both before and after being seen in the clinic. Anorexia was also significantly correlated with weight loss at each clinic visit. However, there was no similar overall correlation between change in dietary intake and change in weight. CONCLUSIONS: Many patients with advanced cancer and weight loss are consuming diets that would likely be insufficient to maintain weight even in healthy individuals. Higher consumption of protein and energy correlates with greater weight gain, but it is impossible to predict the response to increased nutritional intake when patients are first assessed. There is a pressing need to improve understanding of factors that modulate metabolic responses to dietary intake in patients with cancer cachexia.

Does the presence of emphysema increase the risk of radiation pneumonitis in lung cancer patients?

Introduction: Radiotherapy (rt) plays an important role in the treatment of lung cancer. One of the most common comorbidities in patients with lung cancer is pulmonary emphysema. The literature offers conflicting data about whether emphysema increases the occurrence and severity of radiation pneumonitis (rp). As a result, whether high doses of rt (with curative intent) should be avoided in patients with emphysema is still unclear. Objective: We measured the documented incidence of rp in patients with and without emphysema who received curative radiation treatment. Methods: This retrospective cohort study considered patients in the lung cancer clinical database of the Peter Brojde Lung Cancer Centre. Data from the database has been used previously for research studies, including a recent publication about emphysema grading, based on the percentage of lung occupied by emphysema on computed tomography (ct) imaging. Results: Using previously published methods, chest ct imaging for 498 patients with lung cancer was scored for the presence of emphysema. The analysis considered 114 patients who received at least 30 Gy radiation. Of those 114 patients, 64 (56%) had emphysema, with approximately 23% having severe or very severe disease. The incidence of rp was 34.4% in patients with emphysema (n = 22) and 32.0% in patients with no emphysema (n = 16, p = 0.48). No difference in the incidence of rp was evident between patients with various grades of emphysema (p = 0.96). Similarly, no difference in the incidence of rp was evident between the two treatment protocols-that is, definitive rt 17 (37%) and combined chemotherapy-rt 21 (31%, p = 0.5). Conclusions: In our cohort, the presence of emphysema on chest ct imaging was not associated with an increased risk of rp. That finding suggests that patients with lung cancer and emphysema should be offered rt when clinically indicated. However, further prospective studies will be needed for confirmation.

Lung cancer care trajectory at a Canadian centre: an evaluation of how wait times affect clinical outcomes.

BACKGROUND: Lung cancer continues to be one of the most common cancers in Canada, with approximately 28,400 new cases diagnosed each year. Although timely care can contribute substantially to quality of life for patients, it remains unclear whether it also improves patient outcomes. In this work, we used a set of quality indicators that aim to describe the quality of care in lung cancer patients. We assessed adherence with existing guidelines for timeliness of lung cancer care and concordance with existing standards of treatment, and we examined the association between timeliness of care and lung cancer survival. METHODS: Patients with lung cancer diagnosed between 2010 and 2015 were identified from the Pulmonary Division Lung Cancer Registry at our centre. RESULTS: We demonstrated that the interdisciplinary pulmonary oncology service successfully treated most of its patients within the recommended wait times. However, there is still work to be done to decrease variation in wait time. Our results demonstrate a significant association between wait time and survival, supporting the need for clinicians to optimize the patient care trajectory. INTERPRETATION: It would be helpful for Canadian clinicians treating patients with lung cancer to have wait time guidelines for all treatment modalities, together with standard definitions for all time intervals. Any reductions in wait times should be balanced against the need for thorough investigation before initiating treatment. We believe that our unique model of care leads to an acceleration of diagnostic steps. Avoiding any delay associated with referral to a medical oncologist for treatment could be an acceptable strategy with respect to reducing wait time.

A multidisciplinary rehabilitation programme for cancer cachexia improves quality of life.

OBJECTIVES: Patients with cancer cachexia have severely impaired quality of life (QoL). Multidisciplinary, multimodal treatment approaches have potential for stabilising weight and correcting other features of this syndrome, but the impact on QoL is unknown. METHODS: A retrospective analysis of QoL in patients with advanced cancer, referred for the management of cachexia by a specialised multidisciplinary clinic (The McGill Cancer Nutrition Rehabilitation Program clinic at the Jewish General Hospital (CNR-JGH)). QoL was assessed at visits 1-3 using a dedicated QoL tool for cachexia, and the change in QoL was calculated for each patient. The correlation between clinical features and QoL at baseline and subsequent change in QoL was analysed, to determine what factors predict improvements in QoL during the CNR-JGH intervention. RESULTS: 374 patients assessed at visit 1 with mean weight loss of 10.2% over the preceding 6 months. Baseline QoL scores were severely impaired but clinically important improvements were observed over visits 1-3 to the CNR-JGH clinic. Improvements in QoL were not determined by baseline characteristics and were similar in all patient subgroups. However, those patients who gained weight and increased their 6 min walk test (6MWT) had the greatest improvements in QoL. CONCLUSIONS: Improving management of all facets of the cancer cachexia syndrome, including poor QoL, remains a priority. The multimodal approach to management of cancer cachexia offered by the CNR-JGH results in clinically important improvements in QoL. All patients who are able to receive this type of intervention have similar potential to improve their QoL, but the greatest benefits are seen in those who gain weight and improve their 6MWT.

Eccentric Ergometer Training Promotes Locomotor Muscle Strength but Not Mitochondrial Adaptation in Patients with Severe Chronic Obstructive Pulmonary Disease.

Eccentric ergometer training (EET) is increasingly being proposed as a therapeutic strategy to improve skeletal muscle strength in various cardiorespiratory diseases, due to the principle that lengthening muscle actions lead to high force-generating capacity at low cardiopulmonary load. One clinical population that may particularly benefit from this strategy is chronic obstructive pulmonary disease (COPD), as ventilatory constraints and locomotor muscle dysfunction often limit efficacy of conventional exercise rehabilitation in patients with severe disease. While the feasibility of EET for COPD has been established, the nature and extent of adaptation within COPD muscle is unknown. The aim of this study was therefore to characterize the locomotor muscle adaptations to EET in patients with severe COPD, and compare them with adaptations gained through conventional concentric ergometer training (CET). Male patients were randomized to either EET (n = 8) or CET (n = 7) for 10 weeks and matched for heart rate intensity. EET patients trained on average at a workload that was three times that of CET, at a lower perception of leg fatigue and dyspnea. EET led to increases in isometric peak strength and relative thigh mass (p < 0.01) whereas CET had no such effect. However, EET did not result in fiber hypertrophy, as morphometric analysis of muscle biopsies showed no increase in mean fiber cross-sectional area (p = 0.82), with variability in the direction and magnitude of fiber-type responses (20% increase in Type 1, p = 0.18; 4% decrease in Type 2a, p = 0.37) compared to CET (26% increase in Type 1, p = 0.04; 15% increase in Type 2a, p = 0.09). EET had no impact on mitochondrial adaptation, as revealed by lack of change in markers of mitochondrial biogenesis, content and respiration, which contrasted to improvements (p < 0.05) within CET muscle. While future study is needed to more definitively determine the effects of EET on fiber hypertrophy and associated underlying molecular signaling pathways in COPD locomotor muscle, our findings promote the implementation of this strategy to improve muscle strength. Furthermore, contrasting mitochondrial adaptations suggest evaluation of a sequential paradigm of eccentric followed by concentric cycling as a means of augmenting the training response and attenuating skeletal muscle dysfunction in patients with advanced COPD.

A comparison of the effects of medical Qigong and standard exercise therapy on symptoms and quality of life in patients with advanced cancer.

PURPOSE: Patients with advanced cancer frequently experience anxiety, depression and poor quality of life (QOL), as well as physical symptoms such as fatigue and weakness. Physical exercise has potential to help control these symptoms but the optimal training prescription is still not clear. We performed a study comparing medical Qigong (QG) and standard endurance and strength training (SET) in patients with advanced stage non-small cell lung (NSCLC) and gastrointestinal (GI) cancers. METHODS: A randomized, cross-over study was performed in patients with advanced NSCLC and GI cancers receiving or eligible for chemotherapy. Patients received supervised QG or SET twice-weekly for 6 weeks. Psychological functioning, QOL, symptoms and physical functioning were assessed before and after each intervention period. RESULTS: Nineteen patients completed both interventions. Comparing interventions revealed no difference between QG and SET on change in anxiety or depression scores or QOL. However, SET treatment was better at improving perceived strength (P = 0.05) and walking distance (P = 0.02). The order in which interventions were performed had a significant impact on the improvement in certain symptoms (sleep quality, breathlessness, P < 0.05), QOL (P = 0.01) and walking distance (P = 0.008). In all cases, the beneficial effects of the exercise interventions were markedly reduced during the second interval. CONCLUSIONS: QG and SET are equivalent in their impact on many aspects of psychological function in cancer patients. However, SET leads to greater improvements in exercise capacity and helps reduce some symptoms. The reduction in beneficial effect of SET on exercise function when offered as the second intervention is a new finding that warrants further study.

Failed upregulation of TFAM protein and mitochondrial DNA in oxidatively deficient fibers of chronic obstructive pulmonary disease locomotor muscle.

BACKGROUND: Low mitochondrial content and oxidative capacity are well-established features of locomotor muscle dysfunction, a prevalent and debilitating systemic occurrence in patients with chronic obstructive pulmonary disease (COPD). Although the exact cause is not firmly established, physical inactivity and oxidative stress are among the proposed underlying mechanisms. Here, we assess the impact of COPD pathophysiology on mitochondrial DNA (mtDNA) integrity, biogenesis, and cellular oxidative capacity in locomotor muscle of COPD patients and healthy controls. We hypothesized that the high oxidative stress environment of COPD muscle would yield a higher presence of deletion-containing mtDNA and oxidative-deficient fibers and impaired capacity for mitochondrial biogenesis. METHODS: Vastus lateralis biopsies were analyzed from 29 COPD patients and 19 healthy age-matched controls for the presence of mtDNA deletions, levels of oxidatively damaged DNA, mtDNA copy number, and regulators of mitochondrial biogenesis as well the proportion of oxidative-deficient fibers (detected histologically as cytochrome c oxidase-deficient, succinate dehydrogenase positive (COX(-)/SDH(+) )). Additionally, mtDNA copy number and mitochondrial transcription factor A (TFAM) content were measured in laser captured COX(-)SDH(+) and normal single fibers of both COPD and controls. RESULTS: Compared to controls, COPD muscle exhibited significantly higher levels of oxidatively damaged DNA (8-hydroxy-2-deoxyguanosine (8-OHdG) levels = 387 ± 41 vs. 258 ± 21 pg/mL) and higher prevalence of mtDNA deletions (74 vs. 15 % of subjects in each group), which was accompanied by a higher abundance of oxidative-deficient fibers (8.0 ± 2.1 vs. 1.5 ± 0.4 %). Interestingly, COPD patients with mtDNA deletions had higher levels of 8-OHdG (457 ± 46 pg/mL) and longer smoking history (66.3 ± 7.5 years) than patients without deletions (197 ± 29 pg/mL; 38.0 ± 7.3 years). Transcript levels of regulators of mitochondrial biogenesis and oxidative metabolism were upregulated in COPD compared to controls. However, single fiber analyses of COX(-)/SDH(+) and normal fibers exposed an impairment in mitochondrial biogenesis in COPD; in healthy controls, we detected a marked upregulation of mtDNA copy number and TFAM protein in COX(-)/SDH(+) compared to normal fibers, reflecting the expected compensatory attempt by the oxidative-deficient cells to increase energy levels; in contrast, they were similar between COX(-)/SDH(+) and normal fibers in COPD patients. Taken together, these findings suggest that although the signaling factors regulating mitochondrial biogenesis are increased in COPD muscle, impairment in the translation of these signals prevents the restoration of normal oxidative capacity. CONCLUSIONS: Single fiber analyses provide the first substantive evidence that low muscle oxidative capacity in COPD cannot be explained by physical inactivity alone and is likely driven by the disease pathophysiology.

Anthracycline-containing chemotherapy causes long-term impairment of mitochondrial respiration and increased reactive oxygen species release in skeletal muscle.

Anticancer treatments for childhood acute lymphoblastic leukaemia (ALL) are highly effective but are now implicated in causing impaired muscle function in long-term survivors. However, no comprehensive assessment of skeletal muscle mitochondrial functions in long-term survivors has been performed and the presence of persistent chemotherapy-induced skeletal muscle mitochondrial dysfunction remains a strong possibility. Non-tumour-bearing mice were treated with two drugs that have been used frequently in ALL treatment (doxorubicin and dexamethasone) for up to 4 cycles at 3-week intervals and euthanized 3 months after the 4th cycle. Treated animals had impaired growth and lower muscle mass as well as reduced mitochondrial respiration and increased reactive oxygen species production per unit oxygen consumption. Mitochondrial DNA content and protein levels of key mitochondrial membrane proteins and markers of mitochondrial biogenesis were unchanged, but protein levels of Parkin were reduced. This suggests a novel pattern of chemotherapy-induced mitochondrial dysfunction in skeletal muscle that persists because of an acquired defect in mitophagy signaling. The results could explain the observed functional impairments in adult survivors of childhood ALL and may also be relevant to long-term survivors of other cancers treated with similar regimes.

Diagnostic criteria for the classification of cancer-associated weight loss.

PURPOSE: Existing definitions of clinically important weight loss (WL) in patients with cancer are unclear and heterogeneous and do not consider current trends toward obesity. METHODS: Canadian and European patients with cancer (n = 8,160) formed a population-based data set. Body mass index (BMI) and percent WL (%WL) were recorded, and patients were observed prospectively until death. Data were entered into a multivariable analysis controlling for age, sex, cancer site, stage, and performance status. Relationships for BMI and %WL to overall survival were examined to develop a grading system. RESULTS: Mean overall %WL was -9.7% ± 8.4% and BMI was 24.4 ± 5.1 kg/m(2), and both %WL and BMI independently predicted survival (P < .01). Differences in survival were observed across five categories of BMI (< 20.0, 20.0 to 21.9, 22.0 to 24.9, 25.0 to 27.9, and ≥ 28.0 kg/m(2); P < .001) and five categories of %WL (-2.5% to -5.9%, -6.0% to -10.9%, -11.0% to -14.9%, ≥ -15.0%, and weight stable (± 2.4%); P < .001). A 5 × 5 matrix representing the five %WL categories within each of the five BMI categories was graded based on median survival and prognostic significance. Weight-stable patients with BMI ≥ 25.0 kg/m(2) (grade 0) had the longest survival (20.9 months; 95% CI, 17.9 to 23.9 months), and %WL values associated with lowered categories of BMI were related to shorter survival (P < .001), as follows: grade 1, 14.6 months (95% CI, 12.9 to 16.2 months); grade 2, 10.8 months (95% CI, 9.7 to 11.9 months); grade 3, 7.6 months (95% CI, 7.0 to 8.2 months); and grade 4, 4.3 months (95% CI, 4.1 to 4.6 months). Survival discrimination by grade was observed within specific cancers, stages, ages, and performance status and in an independent validation sample (n = 2,963). CONCLUSION: A robust grading system incorporating the independent prognostic significance of both BMI and %WL was developed.

The feasibility and acceptability of neuromuscular electrical stimulation to improve exercise performance in patients with advanced cancer: a pilot study.

BACKGROUND: To determine the feasibility and acceptability of lower limb neuromuscular electrical stimulation (NMES) as a home-based exercise therapy in patients with cancer who could not attend hospital-based exercise training. METHODS: A single-arm prospective pilot study of NMES, applied daily to both quadriceps muscles for six weeks. Participants were recruited from patients referred to a hospital-based multi-disciplinary supportive care team specializing in treatment of patients with nutritional depletion and functional decline. RESULTS: Of the 15 participants who underwent baseline testing, 10 (67%) completed the study and only one (7%) withdrew because of discomfort due to NMES treatment. 7/10 (70%) of participants used NMES at least three times a week for the duration of the study. Use of NMES did not lead to significant improvements in physical performance tests. CONCLUSIONS: NMES is a feasible and acceptable intervention for home use in patients with cancer, poor performance status and metastatic disease. However, whether NMES is an effective strategy to stabilize or improve physical performance in such patients is not proven.

Autophagy in locomotor muscles of patients with chronic obstructive pulmonary disease.

RATIONALE: Locomotor muscle atrophy develops in patients with chronic obstructive pulmonary disease (COPD) partly because of increased protein degradation by the ubiquitin-proteasome system. It is not known if autophagy also contributes to protein degradation. OBJECTIVES: To investigate whether autophagy is enhanced in locomotor muscles of stable patients with COPD, to quantify autophagy-related gene expression in these muscles, and to identify mechanisms of autophagy induction. METHODS: Muscle biopsies were obtained from two cohorts of control subjects and patients with COPD and the numbers of autophagosomes in the vastus lateralis and tibialis anterior muscles, the levels of LC3B protein lipidation, and the expression of autophagy-related genes were measured in the vastus lateralis muscle. To investigate potential pathways that might induce the activation of autophagy, measures were taken of protein kinase B (AKT), mTORC1, and AMPK pathway activation, transcription factor regulation, proteasome activation, and oxidative stress. MEASUREMENTS AND MAIN RESULTS: Autophagy is enhanced in the locomotor muscles of patients with COPD as shown by significantly higher numbers of autophagosomes in affected muscles as compared with control subjects. Autophagosome number inversely correlates with FEV1. In the vastus lateralis, LC3B protein lipidation is increased by COPD and the expression of autophagy-related gene expressions is up-regulated. LC3B lipidation inversely correlates with thigh cross-sectional area, FEV1, and FEV1/FVC ratio. Enhanced autophagy is associated with activation of the AMPK pathway and FOXO transcription factors, inhibition of the mTORC1 and AKT pathways, and the development of oxidative stress. CONCLUSIONS: Autophagy is significantly enhanced in locomotor muscles of stable patients with COPD. The degree of autophagy correlates with severity of muscle atrophy and lung function impairment.

The potential role for acupuncture in treating symptoms in patients with lung cancer: an observational longitudinal study.

BACKGROUND: Most lung cancer patients experience multiple symptoms related either to the disease or its treatment. The commonly reported symptoms are pain, depression, anxiety, nausea, and poor well-being. The aim of the present study was to evaluate the effect of acupuncture as a potential treatment modality in symptomatic lung cancer patients. METHODS: This prospective observational study enrolled 33 lung cancer patients from the Peter Brojde Lung Cancer Centre between August 2010 and May 2012. All patients received 45-minute sessions of acupuncture, 1-2 times weekly for a minimum of 4 sessions. Symptom severity was assessed using the Edmonton Symptom Assessment System (esas) before and after completion of acupuncture. RESULTS: The study cohort included 30 patients with non-small- cell lung cancer and 3 with small-cell lung cancer. Mean age was 62 years (range: 36-88 years); 17 of the patients were women. Most of the patients had advanced-stage cancer (73%) and good performance status (Eastern Cooperative Oncology Group 0-1: 88%). Of these patients, 67% received anticancer treatment (chemotherapy or radiotherapy, or both) with acupuncture. Of the remaining 10 patients, 8 received acupuncture after a complete surgical resection of their tumour, and because of their advanced age, 2 received acupuncture and best supportive care. The median number of acupuncture sessions was 7 (interquartile range: 4-13 sessions). Statistically significant improvements in pain, appetite, nausea, nervousness, and well-being were observed. A clinically important improvement (2 points on the esas) was reported by 61% of patients for pain and by 33% for well-being. A significant positive correlation between improved well-being and the number of acupuncture sessions was observed. This correlation remained significant even after controlling for treatment and narcotic use. Receiver operating characteristic analysis demonstrated that a minimum of 6 acupuncture sessions are required for a 70% chance of a clinically important improvement in well-being. CONCLUSIONS: The present study is the first to demonstrate that acupuncture may be an effective approach for improving symptoms-in particular, pain and well-being-in lung cancer patients. Acupuncture is a safe and minimally invasive procedure, and it is potentially useful even in patients undergoing anticancer treatment.

Systemic cancer therapy: achievements and challenges that lie ahead.

In the last half of the century, advances in the systemic therapy of cancer, including chemotherapy, hormonal therapy, targeted therapy, and immunotherapy have been responsible for improvements in cancer related mortality in developed countries even as the population continues to age. Although such advancements have yet to benefit all cancer types, systemic therapies have led to an improvement in overall survival in both the adjuvant and metastatic setting for many cancers. With the pressure to make therapies available as soon as possible, the side-effects of systemic therapies, in particular long-term side-effects are not very well characterized and understood. Increasingly, a number of cancer types are requiring long-term and even lifelong systemic therapy. This is true for both younger and older patients with cancer and has important implications for each subset. Younger patients have an overall greater expected life-span, and as a result may suffer a greater variety of treatment related complications in the long-term, whereas older patients may develop earlier side-effects as a result of their frailty. Because the incidence of cancer in the world will increase over the next several decades and there will be more people living with cancer, it is important to have an understanding of the potential side-effects of new systemic therapies. As an introductory article, in this review series, we begin by describing some of the major advances made in systemic cancer therapy along with some of their known side-effects and we also make an attempt to describe the future of systemic cancer therapy.