Ketogenic diet promotes tumor ferroptosis but induces relative corticosterone deficiency that accelerates cachexia.

Glucose dependency of cancer cells can be targeted with a high-fat, low-carbohydrate ketogenic diet (KD). However, in IL-6-producing cancers, suppression of the hepatic ketogenic potential hinders the utilization of KD as energy for the organism. In IL-6-associated murine models of cancer cachexia, we describe delayed tumor growth but accelerated cachexia onset and shortened survival in mice fed KD. Mechanistically, this uncoupling is a consequence of the biochemical interaction of two NADPH-dependent pathways. Within the tumor, increased lipid peroxidation and, consequently, saturation of the glutathione (GSH) system lead to the ferroptotic death of cancer cells. Systemically, redox imbalance and NADPH depletion impair corticosterone biosynthesis. Administration of dexamethasone, a potent glucocorticoid, increases food intake, normalizes glucose levels and utilization of nutritional substrates, delays cachexia onset, and extends the survival of tumor-bearing mice fed KD while preserving reduced tumor growth. Our study emphasizes the need to investigate the effects of systemic interventions on both the tumor and the host to accurately assess therapeutic potential. These findings may be relevant to clinical research efforts that investigate nutritional interventions such as KD in patients with cancer.

Ketogenic diet promotes tumor ferroptosis but induces relative corticosterone deficiency that accelerates cachexia.

The dependency of cancer cells on glucose can be targeted with high-fat low-carbohydrate ketogenic diet (KD). However, hepatic ketogenesis is suppressed in IL-6 producing cancers, which prevents the utilization of this nutrient source as energy for the organism. In two IL-6 associated murine models of cancer cachexia we describe delayed tumor growth but accelerated onset of cancer cachexia and shortened survival when mice are fed KD. Mechanistically, we find this uncoupling is a consequence of the biochemical interaction of two simultaneously occurring NADPH-dependent pathways. Within the tumor, increased production of lipid peroxidation products (LPPs) and, consequently, saturation of the glutathione (GSH) system leads to ferroptotic death of cancer cells. Systemically, redox imbalance and NADPH depletion impairs the biosynthesis of corticosterone, the main regulator of metabolic stress, in the adrenal glands. Administration of dexamethasone, a potent glucocorticoid, improves food intake, normalizes glucose homeostasis and utilization of nutritional substrates, delays onset of cancer cachexia and extends survival of tumor-bearing mice fed KD, while preserving reduced tumor growth. Our study highlights that the outcome of systemic interventions cannot necessarily be extrapolated from the effect on the tumor alone, but that they have to be investigated for anti-cancer and host effects. These findings may be relevant to clinical research efforts that investigate nutritional interventions such as KD in patients with cancer.

Does training therapists to manage benign paroxysmal positional vertigo in patients with acute traumatic brain injury reduce vestibular neurology referrals?

OBJECTIVE: Dizziness is common in patients with acute traumatic brain injury (aTBI). However, patients are not always managed by the ward team but instead are referred to a visiting vestibular neurology team or referred for outpatient follow-up. We aimed to ascertain whether training trauma ward therapists to manage a common form of post-traumatic dizziness (Benign paroxysmal positional vertigo [BPPV]) reduced referrals to a visiting vestibular neurology team. DESIGN: Referrals of patients with aTBI with complaints of dizziness to the visiting vestibular neurology team were audited from the Major Trauma Centre at Imperial College Healthcare NHS Foundation Trust, London, UK. Ward therapists subsequently received training on management of BPPV. Referrals to the vestibular neurology service were re-audited. Therapist confidence in assessing and treating BPPV was also assessed pre and post-training. RESULTS: Pre-training, referral rate to the visiting vestibular neurology service was eight patients per month. Following training, referrals to the vestibular neurology service reduced by 35%. Therapist confidence improved significantly following training. CONCLUSIONS: Training trauma ward therapists to manage BPPV reduced referrals to a visiting vestibular neurology service. Further research is necessary to assess implications for service and patient level parameters, such as length of stay and time to discharge.

CamGFR v2: A New Model for Estimating the Glomerular Filtration Rate from Standardized or Non-standardized Creatinine in Patients with Cancer.

PURPOSE: Management of patients with cancer, specifically carboplatin dosing, requires accurate knowledge of glomerular filtration rate (GFR). Direct measurement of GFR is resource limited. Available models for estimated GFR (eGFR) are optimized for patients without cancer and either isotope dilution mass spectrometry (IDMS)- or non-IDMS-standardized creatinine measurements. We present an eGFR model for patients with cancer compatible with both creatinine measurement methods. EXPERIMENTAL DESIGN: GFR measurements, biometrics, and IDMS- or non-IDMS-standardized creatinine values were collected for adult patients from three cancer centers. Using statistical modeling, an IDMS and non-IDMS creatinine-compatible eGFR model (CamGFR v2) was developed. Its performance was compared with that of the existing models Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), Modification of Diet in Renal Disease (MDRD), Full Age Spectrum (FAS), Lund-Malmö revised, and CamGFR v1, using statistics for bias, precision, accuracy, and clinical robustness. RESULTS: A total of 3,083 IDMS- and 4,612 non-IDMS-standardized creatinine measurements were obtained from 7,240 patients. IDMS-standardized creatinine values were lower than non-IDMS-standardized values in within-center comparisons (13.8% lower in Cambridge; P < 0.0001 and 19.3% lower in Manchester; P < 0.0001), and more consistent between centers. CamGFR v2 was the most accurate [root-mean-squared error for IDMS, 14.97 mL/minute (95% confidence interval, 13.84-16.13) and non-IDMS, 15.74 mL/minute (14.86-16.63)], most clinically robust [proportion with >20% error of calculated carboplatin dose for IDMS, 0.12 (0.09-0.14) and non-IDMS, 0.17 (0.15-0.2)], and least biased [median residual for IDMS, 0.73 mL/minute (-0.68 to 2.2) and non-IDMS, -0.43 mL/minute (-1.48 to 0.91)] eGFR model, particularly when eGFR was larger than 60 ml/minute. CONCLUSIONS: CamGFR v2 can utilize IDMS- and non-IDMS-standardized creatinine measurements and outperforms previous models. CamGFR v2 should be examined prospectively as a practice-changing standard of care for eGFR-based carboplatin dosing.

A comparative analysis of immune privilege in pregnancy and cancer in the context of checkpoint blockade immunotherapy.

Despite their abilities to elicit immune responses, both syngeneic tumors and the half-mismatched placenta grow in the host, unlike a tissue allograft that is aggressively rejected. This is because of local and systemic factors that contribute to the immunologic privilege of tumors and the placenta. Checkpoint blockade immunotherapies subvert this privilege, with spectacularly beneficial outcomes in subsets of patients with certain types of cancer. A challenge for the community of scientists and clinicians is to replicate these successes in pregnant patients with cancer, without harm to the placenta. Here we compare and contrast the immunology of cancers and the placenta, and suggest that immunotherapy for pregnant patients with cancer may be a reasonable option, but that this should be explored systematically.

Cancer Immunotherapy Trials Underutilize Immune Response Monitoring.

Immune-related radiological and biomarker monitoring in cancer immunotherapy trials permits interrogation of efficacy and reasons for therapeutic failure. We report the results from a cross-sectional analysis of response monitoring in 685 T-cell checkpoint-targeted cancer immunotherapy trials in solid malignancies, as registered on the U.S. National Institutes of Health trial registry by October 2016. Immune-related radiological response criteria were registered for only 25% of clinical trials. Only 38% of trials registered an exploratory immunological biomarker, and registration of immunological biomarkers has decreased over the last 15 years. We suggest that increasing the utilization of immune-related response monitoring across cancer immunotherapy trials will improve analysis of outcomes and facilitate translational efforts to extend the benefit of immunotherapy to a greater proportion of patients with cancer.

Connecting the Metabolic and Immune Responses to Cancer.

Separate research fields have advanced our understanding of, on the one hand, cancer immunology and, on the other hand, cachexia, the fatal tumor-induced wasting syndrome. A link between the host's immune and metabolic responses to cancer remained unexplored. Emerging work in preclinical models of colorectal and pancreatic cancer has unveiled tumor-induced reprogramming of liver metabolism in cachexia that leads to suppression of antitumor immunity and failure of immunotherapy. As research efforts in metabolism and immunology in cancer are rapidly expanding, it is timely to discuss the metabolic and immunological determinants of the cancer-host interaction. We also present the hypothesis that the convergence of host metabolism and antitumor immunity may offer a platform for biomarker-driven investigations of new combination therapies.

Does one size fit all? Assessing the preferences of older and younger people for attributes of quality of life.

PURPOSE: To systematically compare, via ranking and best worst tasks, the relative importance of key dimensions of quality of life for younger and older people. METHODS: A web-based survey was developed for administration to two Australia-wide community-based samples comprising younger people aged 18-64 years and older people aged 65 years and above. Respondents were asked to rank 12 quality of life dimensions. Respondents also completed a successive best worst task using the same 12 quality of life dimensions. RESULTS: The relative importance of the quality of life dimensions differed for younger and older person samples. For older people, the ability to be independent and to have control over their daily lives were particularly important for their overall quality of life whereas for younger people, mental health was considered most important. CONCLUSIONS: Many interventions accessed by older people in geriatric medicine and aged care sectors have a broader impact upon quality of life beyond health status. The findings from this study indicate that a focus on broader aspects of quality of life may also be consistent with the preferences of older people themselves as to what constitutes quality of life from their perspective.

An Empirical Comparison of the EQ-5D-5L, DEMQOL-U and DEMQOL-Proxy-U in a Post-Hospitalisation Population of Frail Older People Living in Residential Aged Care.

OBJECTIVE: To empirically compare the measurement properties of the DEMQOL-U and DEMQOL-Proxy-U instruments to the EQ-5D-5L and its proxy version (CEQ-5D-5L) in a population of frail older people living in residential aged care in the post-hospitalisation period following a hip fracture. METHODS: A battery of instruments to measure health-related quality of life (HRQoL), cognition, and clinical indicators of depression, pain and functioning were administered at baseline and repeated at 4 weeks' follow-up. Descriptive summary statistics were produced and psychometric analyses were conducted to assess the levels of agreement, convergent validity and known group validity between clinical indicators and HRQoL measures. RESULTS: There was a large divergence in mean (SD) utility scores at baseline for the EQ-5D-5L and DEMQOL-U [EQ-5D-5L mean 0.21 (0.19); DEMQOL-U mean 0.79 (0.14)]. At 4 weeks' follow-up, there was a marked improvement in EQ-5D-5L scores whereas DEMQOL-U scores had deteriorated. [EQ-5D-5L mean 0.45 (0.38); DEMQOL-U mean 0.58 (0.38)]. The EQ-5D and CEQ-5D-5L were more responsive to the physical recovery trajectory experienced by frail older people following surgery to repair a fractured hip, whereas the DEMQOL-U and DEMQOL-Proxy-U appeared more responsive to the changes in delirium and dementia symptoms often experienced by frail older people in this period. CONCLUSIONS: This study presents important insights into the HRQoL of a relatively under-researched population of post-hospitalisation frail older people in residential care. Further research should investigate the implications for economic evaluation of self-complete versus proxy assessment of HRQoL and the choice of preference-based instrument for the measurement and valuation of HRQoL in older people exhibiting cognitive decline, dementia and other co-morbidities.

Tumor-Induced IL-6 Reprograms Host Metabolism to Suppress Anti-tumor Immunity.

In patients with cancer, the wasting syndrome, cachexia, is associated with caloric deficiency. Here, we describe tumor-induced alterations of the host metabolic response to caloric deficiency that cause intratumoral immune suppression. In pre-cachectic mice with transplanted colorectal cancer or autochthonous pancreatic ductal adenocarcinoma (PDA), we find that IL-6 reduces the hepatic ketogenic potential through suppression of PPARalpha, the transcriptional master regulator of ketogenesis. When these mice are challenged with caloric deficiency, the resulting relative hypoketonemia triggers a marked rise in glucocorticoid levels. Multiple intratumoral immune pathways are suppressed by this hormonal stress response. Moreover, administering corticosterone to elevate plasma corticosterone to a level that is lower than that occurring in cachectic mice abolishes the response of mouse PDA to an immunotherapy that has advanced to clinical trials. Therefore, tumor-induced IL-6 impairs the ketogenic response to reduced caloric intake, resulting in a systemic metabolic stress response that blocks anti-cancer immunotherapy.