IUPHAR ECR review: Cancer-related anorexia-cachexia in cancer patients: Pathophysiology and treatment.

Cancer-related anorexia-cachexia (CRAC) comprises one of the most common syndromes of advanced cancer patients. The prevalence of CRAC increases from 50% to 80% before death. CRAC is associated not only with impaired quality of life in patients and family members but also with shorter survival. The management of CRAC is a great challenge in clinical practice. There are no definite practice guidelines yet for the prevention and treatment of CRAC. A multimodal strategy is the most effective way to treat anorexia-cachexia. Numerous medications have been suggested and used in clinical trials, while others are still being studied on experimental animals. These medications include branched-chain amino acids, eicosapentaenoic acid, thalidomide, cytokine inhibitors, steroids, antiserotoninergic medications, and appetite stimulants. The benefits of supportive care interventions and the advancement of exciting new pharmacological medicines for anorexia-cachexia are becoming more widely recognized. Health care professionals need to be aware of the psychosocial and biological effects of anorexia-cachexia, even though knowledge of the underlying molecular causes of the disorder has advanced significantly.

Appetite Loss and Anorexia of Aging in Clinical Care: An ICFSR Task Force Report.

Appetite loss/anorexia of aging is a highly prevalent and burdensome geriatric syndrome that strongly impairs the quality of life of older adults. Loss of appetite is associated with several clinical conditions, including comorbidities and other geriatric syndromes, such as frailty. Despite its importance, appetite loss has been under-evaluated and, consequently, under-diagnosed and under-treated in routine clinical care. The International Conference on Frailty and Sarcopenia Research (ICFSR) Task Force met virtually on September 27th 2021 to debate issues related to appetite loss/anorexia of aging. In particular, topics related to the implementation and management of appetite loss in at-risk older adult populations, energy balance during aging, and the design of future clinical trials on this topic were discussed. Future actions in this field should focus on the systematic assessment of appetite in the care pathway of older people, such as the Integrated Care for Older People (ICOPE) program recommended by the World Health Organization. Moreover, clinical care should move from the assessment to the treatment of appetite loss/anorexia. Researchers continue to pursue their efforts to find out effective pharmacologic and non-pharmacologic interventions with a favorable risk/benefit ratio.

At the heart of the interoception network: Influence of the parasubthalamic nucleus on autonomic functions and motivated behaviors.

The parasubthalamic nucleus (PSTN), a small nucleus located on the lateral edge of the posterior hypothalamus, has emerged in recent years as a highly interconnected node within the network of brain regions sensing and regulating autonomic function and homeostatic needs. Furthermore, the strong integration of the PSTN with extended amygdala circuits makes it ideally positioned to serve as an interface between interoception and emotions. While PSTN neurons are mostly glutamatergic, some of them also express neuropeptides that have been associated with stress-related affective and motivational dysfunction, including substance P, corticotropin-releasing factor, and pituitary adenylate-cyclase activating polypeptide. PSTN neurons respond to food ingestion and anorectic signals, as well as to arousing and distressing stimuli. Functional manipulation of defined pathways demonstrated that the PSTN serves as a central hub in multiple physiologically relevant networks and is notably implicated in appetite suppression, conditioned taste aversion, place avoidance, impulsive action, and fear-induced thermoregulation. We also discuss the putative role of the PSTN in interoceptive dysfunction and negative urgency. This review aims to synthesize the burgeoning preclinical literature dedicated to the PSTN and to stimulate interest in further investigating its influence on physiology and behavior.

Calcitonin gene related peptide α is dispensable for many danger-related motivational responses.

Calcitonin gene related peptide (CGRP) expressing neurons in the parabrachial nucleus have been shown to encode danger. Through projections to the amygdala and other forebrain structures, they regulate food intake and trigger adaptive behaviors in response to threats like inflammation, intoxication, tumors and pain. Despite the fact that this danger-encoding neuronal population has been defined based on its CGRP expression, it is not clear if CGRP is critical for its function. It is also not clear if CGRP in other neuronal structures is involved in danger-encoding. To examine the role of CGRP in danger-related motivational responses, we used male and female mice lacking αCGRP, which is the main form of CGRP in the brain. These mice had no, or only very weak, CGRP expression. Despite this, they did not behave differently compared to wildtype mice when they were tested for a battery of danger-related responses known to be mediated by CGRP neurons in the parabrachial nucleus. Mice lacking αCGRP and wildtype mice showed similar inflammation-induced anorexia, conditioned taste aversion, aversion to thermal pain and pain-induced escape behavior, although it should be pointed out that the study was not powered to detect any possible differences that were minor or sex-specific. Collectively, our findings suggest that αCGRP is not necessary for many threat-related responses, including some that are known to be mediated by CGRP neurons in the parabrachial nucleus.

Activity-Based Anorexia Induces Browning of Adipose Tissue Independent of Hypothalamic AMPK.

Anorexia nervosa (AN) is an eating disorder leading to malnutrition and, ultimately, to energy wasting and cachexia. Rodents develop activity-based anorexia (ABA) when simultaneously exposed to a restricted feeding schedule and allowed free access to running wheels. These conditions lead to a life-threatening reduction in body weight, resembling AN in human patients. Here, we investigate the effect of ABA on whole body energy homeostasis at different housing temperatures. Our data show that ABA rats develop hyperactivity and hypophagia, which account for a massive body weight loss and muscle cachexia, as well as reduced uncoupling protein 1 (UCP1) expression in brown adipose tissue (BAT), but increased browning of white adipose tissue (WAT). Increased housing temperature reverses not only the hyperactivity and weight loss of animals exposed to the ABA model, but also hypothermia and loss of body and muscle mass. Notably, despite the major metabolic impact of ABA, none of the changes observed are associated to changes in key hypothalamic pathways modulating energy metabolism, such as AMP-activated protein kinase (AMPK) or endoplasmic reticulum (ER) stress. Overall, this evidence indicates that although temperature control may account for an improvement of AN, key hypothalamic pathways regulating thermogenesis, such as AMPK and ER stress, are unlikely involved in later stages of the pathophysiology of this devastating disease.

Emotional imagination of negative situations: Functional neuroimaging in anorexia and bulimia.

AIM: The present study aims to extend the knowledge of the neural correlates of emotion processing in first episode subjects affected by anorexia nervosa (AN) or bulimia nervosa (BN). We applied an emotional distress paradigm targeting negative emotions thought to be relevant for interpersonal difficulties and therapeutic resistance mechanisms. METHODS: The current study applied to 44 female participants with newly diagnosed AN or BN and 20 matched controls a neuroimaging paradigm eliciting affective responses. The measurements also included an extensive assessment comprising clinical scales, neuropsychological tests, measures of emotion processing and empathy. RESULTS: AN and BN did not differ from controls in terms of emotional response, emotion matching, self-reported empathy and cognitive performance. However, eating disorder and psychopathological clinical scores, as well as alexithymia levels, were increased in AN and BN. On a neural level, no significant group differences emerged, even when focusing on a region of interest selected a priori: the amygdala. Some interesting findings put in relation the hippocampal activity with the level of Body Dissatisfaction of the participants, the relative importance of the key nodes for the common network in the decoding of different emotions (BN = right amygdala, AN = anterior cingulate area), and the qualitative profile of the deactivations. CONCLUSIONS: Our data do not support the hypothesis that participants with AN or BN display reduced emotional responsiveness. However, peculiar characteristics in emotion processing could be associated to the three different groups. Therefore, relational difficulties in eating disorders, as well as therapeutic resistance, could be not secondary to a simple difficulty in feeling and identifying basic negative emotions in AN and BN participants.

Effectiveness of Oral Nutritional Supplements on Older People with Anorexia: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Nutrition plays an important role in maintaining the overall health of older people. Inadequate intake may lead to impaired body function, higher morbidity, and mortality. Oral nutritional supplements (ONS) showed positive effect on the nutritional status of the elderly; however, systematic evidence is currently lacking on the effect of ONS on the elderly with anorexia. AIMS: The current systematic review and meta-analysis included randomized controlled trial (RCT) articles to investigate the effectiveness of ONS on the main aspects of anorexia of aging (AA). METHODS: By using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method, researchers independently searched PubMed/MEDLINE, EMBASE, CINAHL, PsycINFO, the Cochrane Library, China National Knowledge Infrastructure (CNKI) and other gray literature resources for publications that met the inclusion criteria by October 2020. The Cochrane Risk of Bias Tools were used for quality assessment. The inverse-variance method was used for the fixed model (FM) while the DerSimonian-Laird method was used for the random model (RM). Respective 95% confidence intervals (95% CIs), mean difference (MD) or standardized mean difference (SMD) was used for indices in terms of effect size (ES). RESULTS: 2497 records were found through the systematic search, while 17 RCTs (n = 1204) were included, with a mean age of 81.9 years (range: 74-87 years). Supplementation occurred in the morning, mid-day, and evening, while the times varied from one to three times a day. The results of meta-analysis showed that, generally, ONS had a positive effect on the overall appetite, MD = 0.18, 95% CI (0.03, 0.33), p = 0.02, and consumption, MD = 1.43, 95% CI (0.01, 2.86), p = 0.05; but not significant in terms of other aspects of appetite: hunger, p = 0.73; fullness, p = 0.60; desire to eat, p = 0.80; preoccupation, p = 0.15. Additionally, it showed an increase in the overall energy intake, SMD = 0.46, 95% CI (0.29, 0.63), p < 0.001, in protein intake, SMD = 0.59, 95% CI (0.16, 1.02), p = 0.007, and in fat intake, MD = 3.47, 95% CI (1.98, 4.97), p < 0.001, while no positive effect was found on carbohydrates intake, p = 0.06. Significance differences were also found in the body weight, SMD = 0.53, 95% CI (0.41, 0.65), p < 0.001, and body mass index (BMI), MD = 0.53, 95% CI (0.12, 0.95), p = 0.01. Moreover, subgroup analyses were conducted according to the nutrient density with no positive results showed except for the low-density ONS on overall energy intake. CONCLUSIONS: The results of the present study indicated that ONS had beneficial effects on overall appetite, energy intake, body weight and BMI.

Potential intestinal infection and faecal-oral transmission of SARS-CoV-2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread to more than 200 countries and regions globally. SARS-CoV-2 is thought to spread mainly through respiratory droplets and close contact. However, reports have shown that a notable proportion of patients with coronavirus disease 2019 (COVID-19) develop gastrointestinal symptoms and nearly half of patients confirmed to have COVID-19 have shown detectable SARS-CoV-2 RNA in their faecal samples. Moreover, SARS-CoV-2 infection reportedly alters intestinal microbiota, which correlated with the expression of inflammatory factors. Furthermore, multiple in vitro and in vivo animal studies have provided direct evidence of intestinal infection by SARS-CoV-2. These lines of evidence highlight the nature of SARS-CoV-2 gastrointestinal infection and its potential faecal-oral transmission. Here, we summarize the current findings on the gastrointestinal manifestations of COVID-19 and its possible mechanisms. We also discuss how SARS-CoV-2 gastrointestinal infection might occur and the current evidence and future studies needed to establish the occurrence of faecal-oral transmission.

Appetite problem in cancer patients: Pathophysiology, diagnosis, and treatment.

AIM: This study aims to review the current evidence regarding appetite problem in cancer patients, mainly focusing on pathophysiology, diagnosis, and treatment. INTRODUCTION: Anorexia is the common symptom of malnutrition in cancer patients. Recently, the understanding of the pathophysiological mechanism of the appetite problem in cancer patients has been increasing that give impact to rigorous research to find the therapies for improving appetite in cancer patients. DISCUSSION: The development of anorexia in cancer patients is a complex process that involves many cytokines, receptors, chemical mediators/substances, hormones, and peptides. Growth and differentiation factor-15 (GDF-15) and toll-like receptor (TLR-4) have recently been found to be implicated in the pathogenesis of anorexia. To help diagnose the appetite problem in cancer patients, several questionnaires can be used, starting from well-known questionnaires such as Functional Assessment of Anorexia Cachexia Therapy (FAACT), Visual Analog Scale (VAS), European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ30). Several drugs with different mechanisms of action have been studied to help in improving appetite in cancer patients. New repurposed agents such as anamorelin, mirtazapine, thalidomide, and eicosapentaenoic acid (EPA) have shown a beneficial effect in improving appetite and quality of life in cancer patients, however more phase 3 clinical trial studies is still needed. CONCLUSION: The pathophysiology of appetite problems in cancer patients is a complex process that involves many factors. Several drugs that target those factors have been studied, however more phase 3 clinical trial studies are needed to confirm the findings from previous studies.

Cystic Dumbbell-Shaped C1 Schwannoma with Intracranial Extension and Hydrocephalus.

BACKGROUND: Schwannomas at the craniocervical junction commonly originate from the lower cranial nerves or C1 and C2 nerves. To date, very few cases of C1 schwannomas have been described in the literature, and the majority involve either the intra- or the extradural compartment, but not both. To our knowledge, this report documents the first case of a dumbbell-shaped C1 schwannoma that encompassed both intra- and extradural compartments and was accompanied by hydrocephalus. CASE DESCRIPTION: The patient was admitted to our hospital, where magnetic resonance imaging revealed a tumor at the craniocervical junction, extending from the C1 level of the right first cervical vertebra into the cerebellopontine angle with 2 giant cysts. We removed the tumor by performing a midline posterior craniectomy and cervical laminectomy. Intraoperatively, the tumor was found to originate from the right C1 posterior root. The pathological diagnosis was of a schwannoma. The patient was subsequently discharged without any neurologic deficits. CONCLUSIONS: To our knowledge, we present the first case of a dumbbell-shaped C1 schwannoma with intracranial extensions and accompanying hydrocephalus. The tumor had spread inside and outside the dura, but was safely removed. Our findings in this case emphasize that to achieve safe resection, detailed case-specific preoperative consideration is essential.

Primary Adrenal Lymphoma: Two Case Series From China.

Objective: Primary adrenal lymphoma (PAL) is a rare form of adrenal mass. We summarize our experience in its clinical presentation, biochemical indexes, radiological features, pathological information, therapy regimens, and outcomes. Methods: This was an institutional review board-approved retrospective review of medical records and surgical pathology specimens of patients with a diagnosis of PAL at the Chinese People's Liberation Army General Hospital and the First Affiliate Hospital of Xiamen University between July 2007 and July 2017. Results: Twenty-six patients were identified. The mean age at presentation was 60.84 ± 13.14 years with a male-to-female ratio of 2.25:1 (18:8). The most common presenting symptoms were loss of appetite (65%, 17/26), weight loss (62%, 16/26), abdominal pain (58%, 15/26), and fatigue (58%, 15/26). The levels of lactate dehydrogenase (75%, 15/20), ß2-microglobulin (100%, 10/10), C-reactive protein (82%, 14/17), and ferritin (88%, 7/8) and the erythrocyte sedimentation rate (83%, 10/12) were elevated. Bilateral involvement was seen in 21 of 26 patients (81%); 12 of 19 evaluated patients with bilateral lesions (63%) were confirmed to have adrenal insufficiency. On computed tomography (CT), the mean tumor diameter was 7.31 ± 3.35 cm and the median Hounsfield density was 37.0 HU (range: 31.0-45.0 HU); 67% (10/15) and 27% (4/15) of lesions presented with mild and moderate enhancement after injection of contrast medium. 18F-fluorodeoxyglucose positron emission tomography (FDG PET)-CT revealed not only an adrenal tumor but also extra-adrenal lesions. Diffuse large B-cell lymphoma (DLBCL) was the most common phenotype (92%, 24/26). Ninety-two percent (24/26) of patients received chemotherapy while 8% (2/26) received unilateral adrenalectomy plus chemotherapy. The prognosis of PAL was poor, with a general survival time of 7.20 ± 5.18 months. Conclusion: PAL is a rare disease. The clinical characteristics of PAL include loss of appetite and weight loss. Endocrine evaluation should be performed to determine whether patients have adrenal insufficiency, especially patients with bilateral lesions. FDG-PET appears to be more accurate than other imaging modalities in revealing extra-adrenal sites. Better therapy is required to improve the poor prognosis of PAL.

Using real patients in e-learning: case-based online training in child and adolescent psychiatry.

Objectives: In undergraduate medical education and in the subject of child and adolescent psychiatry, examining young patients face-to-face is a key element of teaching. With the abrupt shutdown of face-to-face teaching caused by the SARS-CoV-2 pandemic, a case-based online training program integrating audio and video of real patients was developed. Methods: The blended learning platform CaseTrain guides medical students in their final year through real child-psychiatric patient cases, such as anorexia, autism, or attention deficit disorder, through presentation of video and audio of real patients and parents. The teaching format complements lectures on child psychiatric topics, comprising asynchronous elements (self-study using the digital material) as well as synchronous elements (web-conferences with a specialist). Learning objectives for students were set to develop knowledge of the spectra of psychiatric disorders that affect children and to recognize approaches how to assess and manage common psychiatric problems of childhood and adolescence. Results: The feedback from medical students through oral and written evaluation was positive. They appreciated getting to know 'real-world patients' in times of such a pandemic, to learn explorative techniques from role models, and to be in close contact with the supervising specialist. In consequence of critical feedback on the length of some video sequences, these training units will undergo revision. Conclusions: Case-based online training may continue to be a useful option in a post-pandemic future as integral part of medical education, complementing face-to-face lectures and training in (child) psychiatry.

Focus on uncommon symptoms of COVID-19: Potential reason for spread of infection.

Focus on uncommon symptoms of COVID-19: Potential reason for spread of infection.

Atypical manifestations of COVID-19 in general practice: a case of gastrointestinal symptoms.

During the previous months, we have seen the rapid pandemic spread of SARS-CoV-2. Despite being considered a respiratory virus, it has become clear that other clinical presentations are possible and some of these are quite frequent. In this paper, a case of a man in his late 70s showing atypical symptoms in general practice is presented. Apart from fever, the patient complained of diarrhoea, borborygmus, loss of appetite and nausea. He developed no respiratory symptoms during his disease. Due to his symptoms, malignant disease was suspected, and he was referred for further testing which revealed typical COVID-19 findings on a chest CT scan. The occurrence of atypical symptoms is discussed, including the importance of recognising these in an ongoing pandemic.

Claims of anomalously long fasting: An assessment of the evidence from investigated cases.

BACKGROUND: Throughout history and to the present day, there have been reports of people claiming inedia, i.e., an anomalous long-term abstinence from food or from food and fluid. Some were isolated and monitored and their abstinences confirmed. This raises the question of whether there may be an anomaly with wide implications that science has overlooked. On the other hand, there have been cases of exposed fraud. The reports on the studies are scattered and it can be difficult to judge their rigor and the strength and implications of their evidence. A critical evaluation seems useful. OBJECTIVES: The objectives were to obtain an overview of investigated cases of claimed inedia, to assess the anomaly of the claims and study results, to assess the quality of the studies, and to identify deception methods to inform future safeguards. METHOD: I developed criteria for differentiating normal from anomalous nutrition and fasting and for assessing the quality of inedia studies. Studies found through a systematic search were then assessed and the features of cases of fraud extracted. RESULTS: 47 eligible investigations of 38 claimants were found. Out of the 38 cases, results were assessed as (seemingly) anomalous in 11, with nine cases of monitored food and fluid deprivation ranging from 14 to 68 days (median 28 days), and two cases of food deprivation for 365 and 411 days. In 17 cases, anomaly was assessed as not confirmed due to issues with study design or reporting. Fraud was established in 10 cases. Deception methods were creative. Post-1900 studies were also assessed for quality. Quality was not considered adequate in any. CONCLUSIONS: I consider the evidential status of inedia unconfirmed as no assessed study had both anomalous findings and impeccable quality. However, quality was often downgraded due to reporting issues and it cannot be concluded in reverse that all claimants with anomalous results were able to deceive the investigators. The results of many studies are curious and demand further research. The conducted analysis provides guidance for improving rigor and transparency in future studies.

Histone Methylation of H3K4 Involved in the Anorexia of Carnivorous Mandarin Fish (Siniperca chuatsi) After Feeding on a Carbohydrate-Rich Diet.

Food intake of carnivorous fish decreases after feeding on a carbohydrate-rich diet. However, the molecular mechanism underlying the anorexia caused by high-carbohydrate diets has remained elusive. We domesticated the mandarin fish to feed on carbohydrate-rich (8%) diets. After 61 days of feeding, several fish (Group A) fed well on artificial diets during the whole feeding period; the other fish (Group B) fed well on artificial diets at the beginning of the feeding period, with their food intake then decreasing to half (anorexia) and then to zero for 5 days; and, finally, a negative control (Group C) fed on live prey fish throughout the experimental process. The plasma glucose was significantly higher in the mandarin fish of Group B than in those of Group A, whereas levels of hepatic glycogen and plasma triglyceride were significantly lower. Using transcriptome sequencing, we investigated the differentially expressed genes between Groups A and B and excluded the genes that were not differentially expressed between Groups A and C. The activation of mTOR and Jak/STAT pathways were found in the mandarin fish with anorexia, which was consistent with the higher expression levels of pepck and pomc genes. We found a higher expression of histone methyltransferase setd1b gene and an increased histone H3 tri-methylated at lysine 4 (H3K4me3) in the fish of Group B. Furthermore, using ChIP assay and inhibitor treatment, we found that the up-regulated H3K4me3 could activate pepck expression, which might have contributed to the hyperglycemia and anorexia in the mandarin fish that fed on carbohydrate-rich diets. Our study initially indicated a link between histone methylation and pepck expression, which might be a novel regulatory mechanism of fish who are fed a carbohydrate-rich diet.

Clinical characteristics of coronavirus disease (COVID-19) patients with gastrointestinal symptoms: A report of 164 cases.

Objective: To explore the clinical characteristics of Coronavirus Disease (COVID-19) patients with gastrointestinal symptoms. Methods: The clinical data of 164 COVID-19 patients with gastrointestinal symptoms were extracted and analysed retrospectively. Results: In total, 505 COVID-19 patients were divided into two groups: those with gastrointestinal symptoms (G group) and those without gastrointestinal symptoms (NG group). Common gastrointestinal symptoms included inappetence, diarrhoea, nausea, abdominal pain, and vomiting. Significantly higher proportions of patients with fever, dizziness, myalgia, and fatigue were noted in group G than in group NG. Compared with patients without fever, there was a significant difference between G group and NG group in moderate fever or above, while there was no significant difference between the two groups in low fever. The laboratory results showed that patients in the G group had significantly higher C-reactive protein, lactate dehydrogenase, and α-hydroxybutyrate dehydrogenase levels than those in the NG group. Moreover, the proportion of patients with severe pneumonia was significantly higher in the G group than in the NG group. Conclusion: In Wuhan, the proportion of COVID-19 patients who experience gastrointestinal symptoms is relatively high. Patients who experience gastrointestinal symptoms are more likely to suffer from severe pneumonia, which may help clinicians identify patients at high risk of COVID-19 and thus reduce the incidence of this condition.