Effects of Peptide Receptor Radiotherapy in Patients with Advanced Paraganglioma and Pheochromocytoma: A Nation-Wide Cohort Study.

INTRODUCTION: Pheochromocytomas and paragangliomas are rare neuroendocrine tumours that originate from chromaffin cells within the adrenal medulla or extra-adrenal sympathetic ganglia. Management of disseminated or metastatic pheochromocytomas and paragangliomas continues to pose challenges and relies on limited evidence. METHOD: In this study, we report retrospective data on median overall survival (OS) and median progression-free survival (PFS) for all Danish patients treated with peptide receptor radionuclide therapy (PRRT) with 177Lu-Dotatate or 90Y-Dotatate over the past 15 years. One standard treatment of PRRT consisted of 4 consecutive cycles with 8-14-week intervals. RESULTS: We included 28 patients; 10 were diagnosed with pheochromocytoma and 18 with paraganglioma. Median age at first PRRT was 47 (IQR 15-76) years. The median follow-up time was 31 (IQR 17-37) months. Eight patients died during follow-up. Median OS was 72 months, and 5-year survival was 65% with no difference between pheochromocytoma and paraganglioma. Patients with germline mutations had better survival than patients without mutations (p = 0.041). Median PFS after the first cycle of PRRT was 30 months. For patients who previously received systemic treatment, the median PFS was 19 months, compared with 32 months for patients with no previous systemic treatment (p = 0.083). CONCLUSIONS: The median OS of around 6 years and median PFS of around 2.5 years found in this study are comparable to those reported in previous studies employing PRRT. Based on historical data, the efficacy of PRRT may be superior to 131I-MIBG therapy, and targeted therapy with sunitinib and PRRT might therefore be considered as first-line treatment in this patient group.

Case of primary low-grade neuroendocrine carcinoma of the skin.

A man presents a 4 mm skin tumour at his general practitioner. The tumour is removed on the suspicion of a dermatofibroma. Important differential diagnoses are sebaceous neoplasms, melanomas, Merkel cell carcinomas and large cell neuroendocrine carcinoma, and metastases of neuroendocrine neoplasms from the gut or lung. Immunohistochemical staining excluded sebaceous neoplasm, melanoma and Merkel cell carcinoma, however, was positive for multiple neuroendocrine markers. Relevant scans showed no signs of a primary tumour anywhere else. The final diagnosis was a primary low-grade neuroendocrine carcinoma of the skin. At 30 months follow-up, there was no sign of recurrence.

The role of N-terminal pro-brain natriuretic peptide, chromogranin A, and 5-hydroxyindoleacetic acid in screening for carcinoid heart disease.

Carcinoid heart disease (CHD) is a serious complication for patients with neuroendocrine tumors (NETs), and early detection is crucial. We aimed to investigate N-terminal pro-brain natriuretic peptide (NT-proBNP), chromogranin A (CgA), and plasma 5-hydroxyindoleacetic acid (P-5-HIAA) as a screening tool for detection of CHD. We prospectively included patients with disseminated small intestinal NETs (SI-NETs) and performed transthoracic echocardiography (TTE), questionnaires, and biochemical assessment of NT-proBNP, CgA, and P-5-HIAA. The presence and severity of CHD was assessed using a scoring system based on echocardiographic characteristics. A total of 93 patients were included in the final analysis. Fifteen (16%) were diagnosed with CHD. The median NT-proBNP (219 ng/L vs. 124 ng/L, p = .05), CgA (3930 pmol/L vs. 256 pmoL/L, p < .0001), and P-5-HIAA (1160 nmol/L vs. 210 nmoL/L, p < .0001) were significantly higher in patients with CHD compared to non-CHD patients. For NT-proBNP, the area under the receiver operating characteristic (AUROC) curve for detection of CHD was 0.67 (95% CI: 0.50-0.84), and at a 260 ng/L cutoff level, the sensitivity and specificity were 46% and 79%. For CgA, the AUROC was 0.91 (95% CI: 0.84-0.97), and at a cutoff level of 598 pmol/L, the sensitivity and specificity were 100% and 69%. For P-5-HIAA, the AUROC was 0.89 (95% CI: 0.80-0.98), and at a cutoff level of 752 nmol/L, the sensitivity and specificity were 92% and 85%. In conclusion, CgA and P-5-HIAA proved excellent markers of CHD while NT-proBNP lacked the required diagnostic accuracy to be used as a screening tool.

Local disease control after stereotactic body radiotherapy in patients with neuroendocrine neoplasms: a cohort study.

BACKGROUND: Neuroendocrine neoplasms represent a diverse group of malignancies. Anatomic origin, histology and aggressiveness vary extensively, from low-grade tumours with an indolent prognosis to highly aggressive conditions with poor outcome. Surgery, with a curative intent, is the standard of treatment when possible. Other treatment regimens include local treatment, or systemic therapy. The role of radiotherapy in treating neuroendocrine neoplasms is not yet established, but studies indicate that a high rate of local control can be achieved by high-dose radiotherapy. Stereotactic body radiotherapy (SBRT) is high dose of radiation delivered to a small volume. We aimed to investigate the one-year local control rate of SBRT in patients with neuroendocrine neoplasms. MATERIAL AND METHODS: Patients with neuroendocrine neoplasms treated with SBRT between 2003 and 2021 were retrospectively identified. Patient characteristics and SBRT-details were collected by review of patient records and the radiotherapy planning charts. All types except for small cell lung cancer and brain metastases were allowed. The prescribed dose was 45-67.8 Gy in three fractions. Progression, both within the target-site and in other sites, was determined based on existing imaging reports. One-year local control rate and systemic control rate was calculated. Descriptive analyses of local response duration, progression-free survival and overall survival were performed. RESULTS: Twenty-one patients were included. The one-year local control rate was 94%. Four of the patients had local progression. All patients receiving SBRT towards their primary tumour (n = 11) had a bronchopulmonary neuroendocrine neoplasm, and a one-year local control rate of 100%. In patients treated at a metastatic target, 80% developed systemic progression but the local control remained high. CONCLUSION: Our study suggests that SBRT may offer a feasible and effective treatment of neuroendocrine neoplasms in selected cases. SBRT provides long-term local stability and may be useful in treating patients with localised disease not fit for surgery.

Nordic 2023 guidelines for the diagnosis and treatment of lung neuroendocrine neoplasms.

Lung neuroendocrine neoplasms (NEN) are a heterogeneous population of neoplasms with different pathology, clinical behavior, and prognosis compared to the more common lung cancers. The diagnostic work-up and treatment of patients with lung- NEN has undergone major recent advances and new methods are currently being introduced into the clinic. These Nordic guidelines summarize and update the Nordic Neuroendocrine Tumor Group's current view on how to diagnose and treat lung NEN-patients and are meant to be useful in the daily practice for clinicians handling these patients. This review reflects our view of the current state of the art of diagnosis and treatment of patients with lung-NEN. Small cell lung carcinoma (SCLC) is not included in these guidelines.

Reduced 3-year risk of hospital admission and mortality after 12-week resistance training of cirrhosis patients: A follow-up of a randomized clinical trial.

BACKGROUND AND AIM: Physical activity confers health benefits in many diseases but remains almost unstudied for cirrhosis. We investigated whether a period of resistance training affects the subsequent long-term risk of hospitalization or mortality among patients with cirrhosis. METHODS: The study includes 39 participants with cirrhosis Child-Pugh class A/B who participated in a prior clinical trial randomized to either resistance training three times per week for 12 weeks or a control group. We gathered data through medical records from trial entry and the following 3 years. The outcomes were time to first hospitalization and all-cause mortality. We used regression models to examine the associations between trial groups and outcomes, adjusting for Child-Pugh class, age, gender, and comorbidity. RESULTS: Nine patients who trained and 15 controls were hospitalized, resulting in a lower risk of first hospitalization in the training group (adjusted subdistribution hazard ratio of 0.40, 95% confidence interval [CI] [0.17, 0.92]; P = 0.03). One patient who trained and six controls died, resulting in a lower all-cause mortality in the training group (adjusted hazard ratio of 0.06, 95% CI [0.01, 0.66]; P = 0.02). CONCLUSION: Twelve weeks of resistance training was associated with a reduced risk of first hospitalization and mortality among patients with cirrhosis Child-Pugh class A/B 3 years after trial entry. The mechanisms of this effect are not identified, and larger studies are warranted.

Fatigue and quality of life in patients with neuroendocrine neoplasia.

INTRODUCTION: Neuroendocrine Neoplasms (NEN) are rare tumours arising in the gastro-intestinal tract or lungs. Poor health related quality of life (HRQoL) is associated with the carcinoid syndrome (CS), but fatigue is also important. We aimed to quantify HRQoL and fatigue in out-patients with NEN. METHODS: In a cross-sectional study, we included 231 patients with NEN (G1-G3). We used pre-validated questionnaires MFI-20, EQ-5D-5L and 85% responded. We collected clinical, biochemical, imaging, and pathology data from Electronic Patient files. Normative values for fatigue and HRQoL were derived from background populations. RESULTS: Median age was 68 years (range 21-91) and 52% were male. Patients with NEN reported more fatigue and worse HRQoL compared to the background population (p < .05). Cured patients reported higher HRQoL than patients with current disease, and patients with high grade neoplasms (G2-G3) reported more anxiety and depression compared to patients with low grade G1 disease (p < .05). The CS resulted in a 9% relative loss in Quality Adjusted Life Years compared to patients without CS. (p < .05). More than 50% of patients with CS reported problems with usual activities, pain/discomfort, and anxiety/depression. Overall, 36% of patients with NEN were fatigued and 92% of these had psychological fatigue. Younger patients (<65 years) experienced more fatigue than older patients (p < .05). CONCLUSION: Patients with NEN report significantly lower HRQoL and more fatigue compared to the background population. Especially, patients with CS had pain, discomfort, anxiety, and depression and a relative reduction in HRQoL. However, compared to other cancer types, patients with NEN experience less fatigue.

Association between fibrosis markers and kidney function following peptide receptor radionuclide therapy in patients with neuroendocrine tumours.

Peptide receptor radionuclide therapy (PRRT) is a treatment for neuroendocrine tumours (NET). Renal impairment is a known side effect due to kidney fibrosis. We investigated the association between novel specific fibrosis markers and kidney function following PRRT. We included 38 patients who had all finished PRRT. In serum and urine, we analysed levels of three different fibrosis markers, PRO-C6 (type VI collagen formation), PRO-C3 (type III collagen formation) and C3M (type III collagen degradation). We determined kidney function by the 51Cr-EDTA plasma clearance. We used Wilcoxon rank sum test and Spearman's rank correlation to evaluate the association between the fibrosis markers and kidney function. We included 38 NET patients, 25 small-intestinal NET, 6 pancreatic NET, 2 pulmonary NET and 5 other types of NET. Median age was 69 years (IQR: 61-73). Median time from last PRRT to inclusion was 8 months (IQR: 3-20). We found significantly increased levels of serum PRO-C6 (p = .007) and urinary PRO-C6 (p = .033) and significantly decreased levels of urinary C3M (p = .035) in patients with impaired kidney function. Further, we observed a negative association between serum PRO-C6 and kidney function (rho = -0.33, p = .04) and a positive association between urinary C3M and kidney function (rho = 0.37, p = .02). We showed an association between the three fibrosis markers, serum PRO-C6, urinary PRO-C6 and urinary C3M and kidney function. These markers may help to improve the understanding of potential pathological tissue turnover and potentially improve monitoring of kidney function after PRRT in NET patients.

Predicting Progression, Recurrence, and Survival in Pancreatic Neuroendocrine Tumors: A Single Center Analysis of 174 Patients.

Introduction: The European Neuroendocrine Tumor Society, ENETS, reports variables of prognostic significance in pancreatic neuroendocrine tumors (PNET). However, studies have short follow-ups, and the optimal treatment remains controversial. We aimed to determine overall survival (OS), progression-free survival (PFS) after conservative treatment, and recurrence-free survival (RFS) after surgery and further to find predictors of aggressive PNET behavior to support treatment decisions. Methods: 174 patients with PNET treated at Aarhus University Hospital from 2011 to 2021 were included in a retrospective cohort study. Patients were divided into surgically resected (SUR, n=91) and medically or conservatively treated (MED, n=83). Variables were tested in univariate and multivariate survival analysis. Median follow-up time was 3.4 years in the MED group and 4.5 years in the SUR group. Results: The 5-year OS was 95% and 65% for the SUR and MED groups, respectively. The 5-year RFS in the SUR group was 80% whereas the 5-year PFS in the MED group was 41%. Larger tumor size, Ki67 index, tumor grade, and stage were predictive of shorter OS, RFS, and PFS. Further, chromogranin A was a predictor of OS. Larger tumor size was associated with higher stage and grade. Only 1 of 28 patients with stage 1 disease and size ≤2 cm developed progression on a watch-and-wait strategy during a median follow-up of 36 months. Conclusion: This study supported the ENETS staging and grading system to be useful to predict OS, PFS, and RFS in PNET. Further, our data support that small, localized, low-grade PNETS can be followed with active surveillance.

Prognosis of Patients with Bronchopulmonary Neuroendocrine Neoplasms in a Tertiary Neuroendocrine Tumor Centre of Excellence.

INTRODUCTION: The European Neuroendocrine Tumor Society (ENETS) reports variables of prognostic significance in bronchopulmonary neuroendocrine neoplasms (BP-NENs). The aim of this study was to investigate prognostic factors, recurrence-free survival (RFS), and overall survival (OS) for patients with typical carcinoid (TC), atypical carcinoid (AC), and large-cell neuroendocrine carcinoma (LCNEC). Current follow-up practices vary as the evidence is sparse, and we aimed to explore the relevance of routine bronchoscopy in follow-up. METHODS: This was a cohort study of 208 patients with BP-NENs followed at Aarhus University Hospital in 2008-2019. RFS and OS were determined using the Kaplan-Meier method for the variables such as primary tumor, primary treatment, smoking status, gender, and histological subtypes. RESULTS: The study included 153 patients with TC, 29 with AC, and 26 with LCNEC. Median follow-up was 48 months. The majority of patients (n = 191) received surgical resection, of which 22 (11%) recurred over time. Seventeen patients had nonsurgical treatment, of which 10 (59%) progressed. The 5-year OS rate was 86% for operated and 9% for nonoperated patients (p < 0.05). Patients with TC had a 5-year OS of 90% compared with 63% and 39% for AC and LCNEC, respectively. As for prognostic factors, nonsmokers did not secure a significant difference in OS compared with current/previous smokers (p = 0.51). In the follow-up period, only 2 (9%) of the 22 recurrences were found on a routine bronchoscopy. Both of these recurrences were also found by diagnostic imaging. CONCLUSIONS: Surgical treatment, especially, and diagnosis of TC were associated with a good prognosis. Furthermore, our data did not support routine bronchoscopy as part of a follow-up program for bronchial carcinoids.

von Hippel-Lindau disease: Updated guideline for diagnosis and surveillance.

von Hippel Lindau disease (vHL) is caused by a hereditary predisposition to multiple neoplasms, especially hemangioblastomas in the retina and CNS, renal cell carcinomas (RCC), pheochromocytomas, neuroendocrine pancreatic tumours (PNET) and endolymphatic sac tumours. Evidence based approaches are needed to ensure an optimal clinical care, while minimizing the burden for the patients and their families. This guideline is based on evidence from the international vHL literature and extensive research of geno- and phenotypic characteristics, disease progression and surveillance effect in the national Danish vHL cohort. We included the views and preferences of the Danish vHL patients, ensured consensus among Danish experts and compared with international recommendations. RECOMMENDATIONS: vHL can be diagnosed on clinical criteria, only; however, in most cases the diagnosis can be supported by identification of a pathogenic or likely pathogenic variant in VHL. Surveillance should be initiated in childhood in persons with, or at risk of, vHL, and include regular examination of the retina, CNS, inner ear, kidneys, neuroendocrine glands, and pancreas. Treatment of vHL manifestations should be planned to optimize the chance of cure, without unnecessary sequelae. Most manifestations are currently treated by surgery. However, belzutifan, that targets HIF-2α was recently approved by the U.S. Food and Drug Administration (FDA) for adult patients with vHL-associated RCC, CNS hemangioblastomas, or PNETs, not requiring immediate surgery. Diagnostics, surveillance, and treatment of vHL can be undertaken successfully by experts collaborating in multidisciplinary teams. Systematic registration, collaboration with patient organisations, and research are fundamental for the continuous improvement of clinical care and optimization of outcome with minimal patient inconvenience.

Low cerebral energy metabolism in hepatic encephalopathy reflects low neuronal energy demand. Role of ammonia-induced increased GABAergic tone.

Hepatic encephalopathy (HE) is a frequent and devastating but generally reversible neuropsychiatric complication secondary to chronic and acute liver failure. During HE, brain energy metabolism is markedly reduced and it remains unclear whether this is due to external or internal energy supply limitations, or secondary to depressed neuronal cellular functions - and if so, which mechanisms that are in play. The extent of deteriorated cerebral function correlates to blood ammonia levels but the metabolic link to ammonia is not clear. Early studies suggested that high levels of ammonia inhibited key tricarboxylic acid (TCA) cycle enzymes thus limiting mitochondrial energy production and oxygen consumption; however, later studies by us and others showed that this is not the case in vivo. Here, based on a series of translational studies from our group, we advocate the view that the low cerebral energy metabolism of HE is likely to be caused by neuronal metabolic depression due to an elevated GABAergic tone rather than by restricted energy availability. The increased GABAergic tone seems to be secondary to synthesis of large amounts of glutamine in astrocytes for detoxification of ammonia with the glutamine acting as a precursor for elevated neuronal synthesis of vesicular GABA.

First-generation somatostatin ligand receptor treatment in a pregnant patient with a neuroendocrine tumor with liver metastases.

SUMMARY: This rare case describes the course of a pregnancy in a patient with a disseminated small intestinal neuroendocrine tumor. The patient received treatment with first-generation somatostatin ligand receptor (SLR) every 4 weeks and had stable disease for several years before her pregnancy. First-generation SLR treatment was initially paused after detection of the pregnancy. During pregnancy, the patient experienced moderate gastro-intestinal discomfort and fatigue, which was considered predominantly pregnancy related. However, since symptoms could be linked to the patient's cancer, treatment was resumed after the first trimester. Chromogranin-A measurements remained stable throughout pregnancy and was paralleled by the absence of diarrhea and only minor flushing. She gave birth by elective caesarean section in week 37 to a healthy baby. Subsequent follow up imaging immediately after and 10 months postpartum showed no disease progression. The safety profile of SLR treatment during pregnancy in the context of disseminated neuroendocrine tumors (NET) is discussed. LEARNING POINTS: Neuroendocrine neoplasms (NEN) are rare cancers often occurring in the gastro-intestinal tract or lungs. Many patients with NEN live for several years with disseminated disease. SLR treatment has been given to pregnant patients before; often patients with acromegaly. Pregnancies are reported uneventful. This patient completed an uneventful pregnancy while receiving SLR treatment for disseminated neuroendocrine disease and gave birth to a healthy baby. More research regarding long term effects and safety signals of SLR treatment during pregnancy are much needed.

Nordic guidelines 2021 for diagnosis and treatment of gastroenteropancreatic neuroendocrine neoplasms.

BACKGROUND: The diagnostic work-up and treatment of patients with gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) has undergone major advances and new methods are introduced. Furthermore, an update of the WHO classification has resulted in a new nomenclature for GEP-NEN that is implemented in the clinic. AIM: These Nordic guidelines summarise the Nordic Neuroendocrine Tumour Group's current view on how to diagnose and treat GEP-NEN patients and aims to be useful in the daily practice for clinicians.

Resistance Training Increases Muscle Strength and Muscle Size in Patients With Liver Cirrhosis.

BACKGROUND & AIMS: Cirrhosis is often complicated by reduced muscle mass and strength, which limits the ability to perform daily activities and affects quality of life. Resistance training can increase muscle strength and mass in elderly and chronically ill patients. We performed a randomized controlled trial to investigate whether resistance training increases muscle strength and size in patients with compensated cirrhosis. METHODS: We performed a prospective study of 39 patients with cirrhosis (Child-Pugh class A or B) seen at an outpatient clinic in Denmark from January 2015 through March 2017. Participants protein intake and activity levels were registered daily. Participants were randomly assigned (1:1) to a group that performed 36 1-hour sessions of physical exercise (supervised progressive resistance training for 1 hour, 3 times weekly for 12 weeks) or a control group (no change in daily activity level). Maximal muscle strength was measured as the peak torque in isokinetic knee extension and muscle size was measured as the cross-sectional area of the quadriceps muscle, assessed by magnetic resonance imaging of the thigh. RESULTS: The exercise group increased their muscle strength by 13% (from a mean 119 Nm to 134 Nm)-an 11 Nm greater gain in mean strength than that of the control group (P = .05). The exercise group increased their quadriceps cross-sectional area by 10% (from a mean 58.5 cm2 to 64.6 cm2)-a 4.4 cm2 greater gain than that of the control group (P < .01). The exercise group had significant increases in whole-body lean mass and body cell mass, and significant increases in 6-minute walking distance and the mental component summary of the short form-36 questionnaire. Adverse events were minor and equal between groups. CONCLUSIONS: In a randomized trial of patients with compensated cirrhosis, we found that 12 weeks of supervised progressive resistance training increased muscle strength and size and had beneficial effects on general performance measures, compared with patients who did not change their daily activity routine (control subjects). ClinicalTrials.gov no: NCT02343653.

Prospective Study of Chromogranin A as a Predictor of Progression in Patients with Pancreatic, Small-Intestinal, and Unknown Primary Neuroendocrine Tumors.

BACKGROUND: Retrospective studies are conflicting but most of them report that an increase in plasma chromogranin A (CgA) predicts tumor progression in neuroendocrine tumor (NET) patients. Prospectively, we investigated if a change in plasma CgA is associated with tumor burden changes in NET patients with disseminated disease. METHODS: We included 239 patients treated at 5 NET centers from December 2010 to December 2013. CgA was measured within 6 weeks of a CT or MRI in a patient undergoing at least 2 scan examinations performed over a period of 1-24 months. In a post hoc analysis, CgA measured 3-6 months prior to the CT/MRI was analyzed. Changes in tumor size were evaluated by RECIST1.1. A 25% change in CgA was chosen to discriminate between increased, decreased, or unchanged levels. RESULTS: In 671 events (2 CT/MRI scans and 2 corresponding CgA measurements), we found a weak positive correlation between the RECIST 1.1 responses and change in plasma CgA from baseline (Spearman's rank correlation coefficient: 0.15; p < 0.05). Of 304 events in the post hoc analysis, 58 showed progression, 228 showed stable disease, and 18 showed regression, with a median change in CgA of 19% (IQR: 57 to -20%), -12% (23 to -38%), and -73% (-55 to -83%), respectively. The correlation coefficient for all sites was 0.17 (p = 0.003), and it was 0.16 (p = 0.07), 0.18 (p = 0.04), and 0.20 (p = 0.21) for small-intestinal (n = 137), pancreatic (n = 123), and unknown primary NET (n = 40), respectively. In the 58 patients showing tumor progression, the sensitivity and specificity of an increased CgA concentration were 36 and 82%, respectively, with positive and negative predictive values of 32 and 85%. CONCLUSIONS: In this prospective study of gastroenteropancreatic NET patients, we observed only a weak association between a change in plasma CgA and changes in tumor burden. CgA as a single biomarker was thus inadequate to predict tumor progression.

Use of biologically based complementary medicines in patients with neuroendocrine tumors.

Background: Biologically based complementary medicines (BB-CMs) are popular in patients with cancer. However, there are only limited data for BB-CMs in patients with neuroendocrine tumors (NET). We aimed to identify the prevalence and type of BB-CM use and the association to the nutritional risk score (NRS-2002) in NET patients. Methods: We performed a cross-sectional questionnaire study in NET outpatients at the Department of Hepatology and Gastroenterology at Aarhus University Hospital. The nutritional risk was determined by the NRS-2002. Results: We included 186 patients (51% women, median age 66 years). Sixty-six percent were regular BB-CM users. Forty-two percent used at least two supplements. The most popular BB-CMs were vitamin and mineral supplements (47%), calcium and vitamin D (34%). One-third used non-vitamin non-mineral supplements such as fish oil, herbs, Ginger, Q-10, garlic and probiotics. The use of BB-CMs was associated with female gender (48% vs. 37%, p < .05). Intake was significantly more frequent among patients with an NRS score ≥ 3, (60% vs. 76%) and in patients with change in performance status (58% vs. 76%), (p < .05, all). Patients reporting dietary changes used BB-CMs more frequently than patients without dietary changes (61% vs. 77%) (p < .05). Conclusions: In our study, 66% percent of NET patients use BB-CM and 42% used two or more supplements. Vitamins with and without herbal ingredients, minerals, calcium, vitamin D, and fish oil were the most popular supplements. The use of BB-CMs was associated with an NRS score ≥ 3, change in dietary intake, female gender, and change in ECOG performance status.

Cognitive impairment after liver transplantation: residual hepatic encephalopathy or posttransplant encephalopathy?

Liver transplantation (LT) represents the definitive treatment for end-stage liver disease. Cognitive impairment following LT is frequent, referred to as postliver transplant encephalopathy (PLTE). LT removes the underlying chronic liver disease, and until recently hepatic encephalopathy (HE) was assumed to be fully reversible after LT. However, increasing evidence indicates that some degree of cognitive impairment may be present after LT. To which extent PLTE reflects cognitive impairment caused by residual HE (RHE) or the combined effect of other factors affecting brain function before, during, and after LT is not clarified. None of the available psychometric and neurophysiological tests used for detecting HE is shown to be able to distinguish between etiologies. The available, mostly retrospective, clinical studies indicate a high prevalence of abnormal psychometric tests after LT, and not all seem to recover completely. The patients with earlier HE show the most marked improvements, suggesting that the clinical picture of the early PLTE, in fact, represents RHE. Other early post-LT etiologies for PLTE comprise cerebral ischemia, critical illness encephalopathy, and immunosuppressive therapy. Late-onset etiologies comprise diabetes and hypertension, among others. PLTE regardless of etiology is a worrying issue and needs more attention in the form of mechanistic research, development of diagnostic/discriminative tools, and standardized prospective clinical studies.

Cerebral water content mapping in cirrhosis patients with and without manifest HE.

Hepatic encephalopathy (HE) is a frequent and debilitating complication of cirrhosis and its pathogenesis is not definitively clarified. Recent hypotheses focus on the possible existence of low-grade cerebral edema due to accumulation of osmolytes secondary to hyperammonemia. In the present study we investigated increases in cerebral water content by a novel magnetic resonance impedance (MRI) technique in cirrhosis patients with and without clinically manifest HE. We used a 3 T MRI technique for quantitative cerebral water content mapping in nine cirrhosis patients with an episode of overt HE, ten cirrhosis patients who never suffered from HE, and ten healthy aged-matched controls. We tested for differences between groups by statistical non-parametric mapping (SnPM) for a voxel-based spatial evaluation. The patients with HE had significantly higher water content in white matter than the cirrhosis patients (0.6%), who in turn, had significantly higher content than the controls (1.7%). Although the global gray matter water content did not differ between the groups, the patients with HE had markedly higher thalamic water content than patients who never experienced HE (6.0% higher). We found increased white matter water content in cirrhosis patients, predominantly in those with manifest HE. This confirms the presence of increasing degrees of low-grade edema with exacerbation of pathology. The thalamic edema in manifest HE may lead to compromised basal ganglia-thalamo-cortical circuits, in accordance with the major clinical symptoms of HE. The identification of the thalamus as particularly inflicted in manifest HE is potentially relevant to the pathophysiology of HE.

Diabetes does not increase infection risk or mortality following an infection in patients with cirrhosis and ascites.

Both cirrhosis and diabetes are established risk factors for infections. However, it remains uncertain whether diabetes adds to the risk of infections in patients with cirrhosis who are already at high risk of infections, or increases the mortality following an infection. To answer these questions, we followed a cohort of trial participants with cirrhosis and ascites for 1 year to compare the incidence of infections and post-infection mortality between those with or without diabetes. METHODS: We used Cox regression to estimate the hazard ratio (HR) of any infection, adjusting for confounding by patient age, gender, MELD score, albumin, use of proton pump inhibitors and lactulose, cirrhosis aetiology, and severity of ascites. Further, we analysed the mortality after infection. RESULTS: Among 1,198 patients with cirrhosis and ascites, diabetics (n = 289, 24%) were more likely than non-diabetics (n = 909, 76%) to be old and male, to have low platelets, and to use lactulose. At inclusion, similar proportions of diabetic and non-diabetic patients were taking a quinolone antibiotic (13% vs. 12%) and they had similar median MELD scores (14 vs. 15). During the follow-up, 446 patients had an infection. Diabetes did not increase the HR of infections (adjusted HR 1.08; 95% CI 0.87-1.35). Further, diabetes did not increase the mortality following an infection (adjusted HR 0.93; 95% CI 0.64-1.35). CONCLUSIONS: In patients with cirrhosis and ascites, diabetes did not increase infection risk or mortality after infection. The immune incompetence of each disease did not appear to be additive. In clinical terms, this means that particular attention to infections is not indicated in patients with cirrhosis and diabetes. LAY SUMMARY: Cirrhosis and diabetes are chronic diseases that weaken the immune system and increase the risk of infections, but it is unknown whether their combined effects exceed the effect of cirrhosis alone. We showed that the risk of infections was the same in patients with cirrhosis, ascites and diabetes as in patients with cirrhosis and ascites alone. Thus, their combined effects do not exceed the effect of cirrhosis alone.