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Background Reducing the overuse of care that is proven to be of low value increases the quality and safety of care. We aimed to identify lessons for reducing low-value care by looking at: (1) The effects of eight de-implementation projects. (2) The barriers and facilitators that emerged. (3) The experiences with the different components of the projects.Methods We performed a process evaluation of eight multicentre projects aimed at reducing low-value care. We reported the quantitative outcomes of the eight projects on the volume of low-value care and performed a qualitative analysis of the project teams’ experiences and evaluations. A total of 40 hospitals and 198 general practitioners participated.Results Five out of eight projects resulted in a reduction of low-value care, ranging from 11.4% to 61.3%. The remaining three projects showed no effect. Six projects monitored balancing measures and observed no negative consequences of their strategy. The most important barriers were a lack of time, an inability to reassure the patient, a desire to meet the patient’s wishes, financial considerations and a discomfort with uncertainty. The most important facilitators were support among clinicians, knowledge of the harms of low-value care and a growing consciousness that more is not always better. Repeated education and feedback for clinicians, patient information material and organisational changes were valued components of the strategy.Conclusions Successfully reducing low-value care is possible in spite of the powerful barriers that oppose it. The projects managed to recruit many hospitals and general practices, with five of them achieving significant results without measuring negative consequences. Based on our findings, we offer practical recommendations for successfully reducing low-value care.

Objectives To examine general practitioners’ (GP) management of cholecystolithiasis and to evaluate persisting abdominal complaints in the years after the diagnosis.Design Retrospective analysis of registry data and a subset of individual medical records.Setting Seventeen primary care practices affiliated with the Radboudumc Practice Based Research Network in the Netherlands.Participants 633 patients with cholecystolithiasis diagnosed between 2012 and 2016.Primary and secondary outcome measures The primary outcome of this study was the healthcare utilisation of patients with cholecystolithiasis diagnosed by the GP in terms of referrals to secondary care, laboratory diagnostics, prescribed medication and the prevalence of concomitant abdominal-related diagnoses in a time interval of 3 years before and 3 years after diagnosis of cholecystolithiasis. For secondary outcomes, electronic medical records were studied from seven practices to assess emergency department visits, operation rates and repeat visits for persistent abdominal symptoms. We compared the non-referred group with the referred group.Results In 57% of patients, concomitant abdominal-related diagnoses were recorded besides the diagnosis cholecystolithiasis. In-depth analyses of 294 patients showed a referral rate of 79.3% (n=233); 62.9% (n=185) underwent cholecystectomy. After referral, 55.4% (129/233) returned to the GP for persistent abdominal symptoms. Patients returning after referral were more often treated for another abdominal-related diagnosis before cholecystolithiasis was recorded (51.9% vs 28.8%, p

Gastrointestinal angiodysplasias may cause anemia. Quality of life (QoL) is a valid patient reported outcome and improvement of QoL represents an important treatment goal. There is a paucity of data on the effect of angiodysplasias on QoL. Therefore, we aim to evaluate QoL and fatigue in angiodysplasia patients. We performed a cross-sectional patient-reported outcome study. We included patients with endoscopy proven angiodysplasias and measured QoL with Short Form-36 and level of fatigue using Multi Fatigue Inventory-20. We distinguished three subgroups of patients according to disease severity: 1) with treatment for angiodysplasias, 2) without treatment for angiodysplasias and 3) without recent hospital visits. The primary outcome was the physical component summary (PCS) score on the SF-36. Multivariate regression analysis were performed to correct for differences at baseline. A total of 144 patients completed the questionnaires (response rate = 62%; mean age 68 years; 65% men). Angiodysplasia patients have a significant lower PCS compared to the age-matched general population (respectively 41.0 vs. 43.3, p = 0.01). Disease severity is independently associated with a negative outcome on QoL (ß -4.6, 95% CI -7.8--1.3). Similarly patients score lower on multiple QoL subdomains, i.e. role limitations due to physical health problems (40.8 vs. 44.0, p

BACKGROUND:Approval of drugs in chronic hepatitis C is supported by registration trials. These trials might have limited generalizability through use of strict eligibility criteria. We compared effectiveness and safety of real world hepatitis C patients eligible and ineligible for registration trials. METHODS:We performed a nationwide, multicenter, retrospective cohort study of chronic hepatitis C patients treated in the real world. We applied a combined set of inclusion and exclusion criteria of registration trials to our cohort to determine eligibility. We compared effectiveness and safety in eligible vs. ineligible patients, and performed sensitivity analyses with strict criteria. Further, we used log binomial regression to assess relative risks of criteria on outcomes. RESULTS:In this cohort (n = 467) 47% of patients would have been ineligible for registration trials. Main exclusion criteria were related to hepatic decompensation and co-morbidity (cardiac disease, anemia, malignancy and neutropenia), and were associated with an increased risk for serious adverse events (RR 1.45-2.31). Ineligible patients developed significantly more serious adverse events than eligible patients (27% vs. 11%, p< 0.001). Effectiveness was decreased if strict criteria were used. CONCLUSIONS:Nearly half of real world hepatitis C patients would have been excluded from registration trials, and these patients are at increased risk to develop serious adverse events. Hepatic decompensation and co-morbidity were important exclusion criteria, and were related to toxicity. Therefore, new drugs should also be studied in these patients, to genuinely assess benefits and risk of therapy in the real world population.

Polycystic liver disease (PCLD) is an autosomal dominant disorder characterised by multiple fluid filled cysts in the liver. This rare disease is caused by heterozygous germline mutations in PRKCSH and SEC63. We previously found that, in patients with a PRKCSH mutation, over 76% of the cysts acquired a somatic 'second-hit' mutation in the wild type PRKCSH allele. We hypothesise that somatic second-hit mutations are a general mechanism of cyst formation in PCLD which also plays a role in PCLD patients carrying a SEC63 germline mutation. We collected cyst epithelial cells from 52 liver cysts from three different SEC63 patients using laser microdissection. DNA samples were sequenced to identify loss of heterozygosity (LOH) mutations and other somatic mutations in cyst epithelial DNA. We discovered somatic SEC63 mutations in patient 3 (1/14 cysts), but not in patient 1 and 2 (38 cysts). Upon review we found that the germline mutation of patient 1 and 2 (SEC63 c.1703_1705delAAG) was present in the same frequency in DNA samples from healthy controls, suggesting that this variant is not causative of PCLD. In conclusion, as somatic second-hit mutations also play a role in cyst formation in patients with a SEC63 germline mutation, this appears to be a general mechanism of cyst formation in PCLD.

BACKGROUND: Chronic pancreatitis (CP) is an inflammatory disease that in some patients leads to exocrine and endocrine dysfunction. In industrialized countries the most common aetiology is chronic alcohol abuse. Descriptions of associated genetic alterations in alcoholic CP are rare. However, a common PNPLA3 variant (p.I148M) is associated with the development of alcoholic liver cirrhosis (ALC). Since, alcoholic CP and ALC share the same aetiology PNPLA3 variant (p.I148M) possibly influences the development of alcoholic CP. METHODS: Using melting curve analysis we genotyped the variant in 1510 patients with pancreatitis or liver disease (961 German and Dutch alcoholic CP patients, 414 German patients with idiopathic or hereditary CP, and 135 patients with ALC). In addition, we included in total 2781 healthy controls in the study. RESULTS: The previously published overrepresentation of GG-genotype was replicated in our cohort of ALC (p-value

Heme oxygenase 1 (HMOX1) is the rate limiting enzyme in heme degradation and a key regulator of inflammatory processes. In animal models the course of pancreatitis was ameliorated by up-regulation of HMOX1 expression. Additionally, carbon monoxide released during heme breakdown inhibited proliferation of pancreatic stellate cells and might thereby prevent the development of chronic pancreatitis (CP). Transcription of HMOX1 in humans is influenced by a GT-repeat located in the promoter. As such, HMOX1 variants might be of importance in the pathogenesis of pancreatitis.The GT-repeat and SNP rs2071746 were investigated with fluorescence labelled primers and by melting curve analysis in 285 patients with acute pancreatitis, 208 patients with alcoholic CP, 207 patients with idiopathic/hereditary CP, 147 patients with alcoholic liver cirrhosis, and in 289 controls, respectively. GT-repeat analysis was extended to a total of 446 alcoholic CP patients. In addition, we performed DNA sequencing in 145 patients with alcoholic CP, 138 patients with idiopathic/hereditary CP, 147 patients with alcoholic liver cirrhosis, and 151 controls. Exon 3 screening was extended to additional patients and controls.S- and L-alleles of the GT-repeat, genotypes and alleles of SNP rs2071746 and non-synonymous variants detected by sequencing were found with similar frequencies in all groups.Although functional data implicate a potential influence of HMOX1 variants on the pathogenesis of pancreatitis, we did not find any association. As rare non-synonymous HMOX1 variants were found in patients and controls, it is rather unlikely that they will have functional consequences essential for pancreatitis development.

Abstract Background Nowadays, large benign lateral spreading lesions (LSLs) and sessile polyps in the colorectum are mostly resected by endoscopic mucosal resection (EMR). A major drawback of EMR is the polyp recurrence rate of up to 20%. Snare tip soft coagulation (STSC) is considered an effective technique to reduce recurrence rates. However, clinical trials on STSC have mainly been conducted in expert referral centers. In these studies, polyp recurrence was assessed optically, and additional adjunctive techniques were excluded. In the current trial, we will evaluate the efficacy and safety of STSC in daily practice, by allowing adjunctive techniques during EMR and the use of both optical and histological polyp recurrence to assess recurrences during follow-up. Methods The RESPECT study is a multicenter, parallel-group, international single blinded randomized controlled superiority trial performed in the Netherlands and Germany. A total of 306 patients undergoing piecemeal EMR for LSLs or sessile colorectal polyps sized 20–60 mm will be randomized during the procedure after endoscopic complete polyp resection to the intervention or control group. Post-EMR defects allocated to the intervention group will be treated with thermal ablation with STSC of the entire resection margin. Primary outcome will be polyp recurrence by optical and histological confirmation at the first surveillance colonoscopy after 6 months. Secondary outcomes include technical success and complication rates. Discussion The RESPECT study will evaluate if STSC is effective in reducing recurrence rates after piecemeal EMR of large colorectal lesions in daily clinical practice performed by expert and non-expert endoscopists. Moreover, endoscopists will be allowed to use adjunctive techniques to remove remaining adenomatous tissue during the procedure. Finally, adenomatous polyp recurrence during follow-up will be defined by histologic identification. Trial registration ClinicalTrials.gov NCT05121805. Registered on 16 November 2021. Start recruitment: 17 March 2022. Planned completion of recruitment: 31 April 2025.

Abstract Background Autoimmune hepatitis (AIH) is a rare, chronic inflammatory disease of the liver. The treatment goal is reaching complete biochemical response (CR), defined as the normalisation of aspartate and alanine aminotransferases and immunoglobulin gamma. Ongoing AIH activity can lead to fibrosis and (decompensated) cirrhosis. Incomplete biochemical response is the most important risk factor for liver transplantation or liver-related mortality. First-line treatment consists of a combination of azathioprine and prednisolone. If CR is not reached, tacrolimus (TAC) or mycophenolate mofetil (MMF) can be used as second-line therapy. Both products are registered for the prevention of graft rejection in solid organ transplant recipients. The aim of this study is to compare the effectiveness and safety of TAC and MMF as second-line treatment for AIH. Methods The TAILOR study is a phase IIIB, multicentre, open-label, parallel-group, randomised (1:1) controlled trial performed in large teaching and university hospitals in the Netherlands. We will enrol 86 patients with AIH who have not reached CR after at least 6 months of treatment with first-line therapy. Patients are randomised to TAC (0.07 mg/kg/day initially and adjusted by trough levels) or MMF (max 2000 mg/day), stratified by the presence of cirrhosis at inclusion. The primary endpoint is the difference in the proportion of patients reaching CR after 12 months. Secondary endpoints include the difference in the proportion of patients reaching CR after 6 months, adverse effects, difference in fibrogenesis, quality of life and cost-effectiveness. Discussion This is the first randomised controlled trial comparing two second-line therapies for AIH. Currently, second-line treatment is based on retrospective cohort studies. The rarity of AIH is the main issue in clinical research for alternative treatment options. The results of this trial can be implemented in existing international clinical guidelines. Trial registration ClinicalTrials.gov NCT05221411 . Retrospectively registered on 3 February 2022; EudraCT number 2021–003420-33. Prospectively registered on 16 June 2021.

Abstract Background Currently, the standard therapy for autoimmune hepatitis (AIH) consists of a combination of prednisolone and azathioprine. However, 15% of patients are intolerant to azathioprine which necessitates cessation of azathioprine or changes in therapy. In addition, not all patients achieve complete biochemical response (CR). Uncontrolled data indicate that mycophenolate mofetil (MMF) can induce CR in a majority of patients. Better understanding of first-line treatment and robust evidence from randomised clinical trials are needed. The aim of this study was to explore the potential benefits of MMF as compared to azathioprine, both combined with prednisolone, as induction therapy in a randomised controlled trial in patients with treatment-naive AIH. Methods CAMARO is a randomised (1:1), open-label, parallel-group, multicentre superiority trial. All patients with AIH are screened for eligibility. Seventy adult patients with AIH from fourteen centres in the Netherlands and Belgium will be randomised to receive MMF or azathioprine. Both treatment arms will start with prednisolone as induction therapy. The primary outcome is biochemical remission, defined as serum levels of alanine aminotransferase and immunoglobulin G below the upper limit of normal. Secondary outcomes include safety and tolerability of MMF and azathioprine, time to remission, changes in Model For End-Stage Liver Disease (MELD)-score, adverse events, and aspects of quality of life. The study period will last for 24 weeks. Discussion The CAMARO trial investigates whether treatment with MMF and prednisolone increases the proportion of patients in remission compared with azathioprine and prednisolone as the current standard treatment strategy. In addition, we reflect on the challenges of conducting a randomized trial in rare diseases. Trial registration EudraCT 2016-001038-91 . Prospectively registered on 18 April 2016. Graphical Abstract

Abstract Background People who use drugs (PWUD) are at high risk for hepatitis C virus (HCV) infection and its complications. Given the high prevalence rate of HCV in PWUD, the World Health Organization (WHO) emphasizes PWUD as a target population for HCV elimination. The introduction of pangenotypic direct acting antivirals (DAAs) greatly simplifies HCV treatment, which encourages integration of HCV treatment in primary care. Facilitating low threshold HCV care for PWUD by implementing decentralized models is crucial for HCV elimination. Aims With this study we aim to (1) eliminate 90% of identified HCV infections in Dutch addiction care, using a decentralized PWUD-HCV care model, and (2) identify facilitators and barriers for successful implementation of the model using interviews. Methods We will perform a multicenter mixed-method study on HCV treatment in addiction care. In a prospective observational study we will examine HCV-related outcomes in PWUD receiving HCV treatment as part of addiction care. The primary outcome is viral elimination, defined as percentage of identified HCV positive patients cured with DAAs. In parallel, we will perform a qualitative study to explore facilitators and barriers for implementation of fully decentralized HCV-PWUD care. We will interview addiction care professionals and board members about their experience with HCV-care as part of addiction care. Discussion This study will show effectiveness of integration of HCV care within addiction care, and provide insight in facilitators and barriers to implement integrated HCV-addiction care. The results will provide recommendations for implementation and maintenance of the decentralized HCV pathway, which can facilitate scaling-up to contribute to reaching WHO HCV elimination goals. Trial registration NCT05401136.

Abstract Background Polycystic liver disease (PLD) is an inherited disorder characterized by numerous cysts in the liver. Autosomal dominant polycystic kidney and liver disease (ADPKD and ADPLD, respectively) have been linked to pathogenic GANAB variants. GANAB encodes the α-subunit of glucosidase II (GIIα). Here, we report the identification of novel GANAB variants in an international cohort of patients with the primary phenotype of PLD using molecular inversion probe analysis. Results Five novel GANAB variants were identified in a cohort of 625 patients with ADPKD or ADPLD. In silico analysis revealed that these variants are likely to affect functionally important domains of glucosidase II α-subunit. Missense variant c.1835G>C p.(Arg612Pro) was predicted to disrupt the structure of the active site of the protein, likely reducing its activity. Frameshift variant c.687delT p.(Asp229Glufs*60) introduces a premature termination codon predicted to have no activity. Two nonsense variants (c.2509C>T; p.(Arg837*), and c.2656C>T; p.(Arg886*)) and splice variant c.2002+1G>C, which causes aberrant pre-mRNA splicing and affecting RNA processing, result in truncated proteins and are predicted to cause abnormal binding of α- and β-subunits of glucosidase II, thus affecting its enzymatic activity. Analysis of glucosidase II subunits in cell lines shows expression of a truncated GIIα protein in cells with c.687delT, c.2509C>T, c.2656C>T, and c.2002+1G>C variants. Incomplete colocalization of the subunits was present in cells with c.687delT or c.2002+1G>C variants. Other variants showed normal distribution of GIIα protein. Conclusions We identified five novel GANAB variants associated with PLD in both ADPKD and ADPLD patients supporting a common pathway in cystogenesis. These variants may lead to decreased or complete loss of enzymatic activity of glucosidase II which makes GANAB a candidate gene to be screened in patients with an unknown genetic background.

Abstract The European Reference Network for rare liver diseases (ERN RARE-LIVER) is a Europe-wide network of paediatric and adult hepatologists from expert centres in close collaboration with patient advocates from the various disease-areas covered in our ERN. The ERN is focused on providing more equitable care across Europe and creates a network of both medical specialists and patient experts in rare liver disease. This position paper summarizes the achievements of the first year and plots the route for the near future for ERN RARE-LIVER, as discussed during a strategy meeting that took place 27 and 28 February 2018 in Nijmegen, the Netherlands. ERN RARE-LIVER has established itself as a group with experts, hospitals and patients. One of the tools to improve communication is the clinical patient management system (CPMS) that allows access to expert consultation by European physicians confronted with a patient with rare liver disease. ERN RARE-LIVER will function as the platform to improve healthcare by initiating registries, foster research efforts and coordinate development of clinical guidelines in Europe.

Background: Age is an important and objective risk factor for upper gastrointestinal (GI) malignancy. The accuracy of various age limits to detect upper GI malignancy is unclear. Determination of this accuracy may aid in the decision to refer symptomatic patients for upper GI endoscopy. The aim of this analysis was to synthesize data on upper GI malignancy detection rates for various age limits worldwide through meta-analysis. Methods: We searched MEDLINE, EMBASE, and Web of Science in November 2018. Selection criteria included studies addressing malignant findings at upper GI endoscopy in a symptomatic population reporting age at time of diagnosis. Meta-analyses were conducted to derive continent-specific cancer detection rates. Results: A total of 33 studies including 346,641 patients across 21 countries fulfilled the inclusion criteria. To detect >80% of malignant cases all symptomatic patients over 40 years of age should be investigated in Africa, over 50 years of age in South America and Asia, and over 55 years of age in North America and Europe. Conclusion: This systematic review and meta-analysis provides data on intercontinental variation in age at time of upper GI malignancy diagnosis in symptomatic patients referred for upper GI endoscopy. Guideline recommendations for age-based selection should be tailored to local age-related detection rates.

Abstract Background Cholecystectomy is the preferred treatment for symptomatic cholecystolithiasis. However, persistent pain after cholecystectomy for symptomatic cholecystolithiasis is reported in up to 40% of patients. The aim of the SECURE trial is to compare the effectiveness of usual care with a restrictive strategy using a standardized work-up with stepwise selection for cholecystectomy in patients with gallstones and abdominal complaints. The SECURE trial is designed as a multicenter, randomized, parallel-arm, non-inferiority trial in patients with abdominal symptoms and ultrasound-proven gallstones or sludge. Randomization was performed to either usual care (standard practice, according to the physician’s knowledge and experience, and physician’s and patient’s preference) or a restrictive standardized strategy: treated with interval evaluation and stepwise selection for laparoscopic cholecystectomy based on fulfilment of pre-specified criteria. This article presents in detail the statistical analysis plan (SAP) of this trial and was submitted before outcomes were available to the investigators. Results The primary end point of this trial is defined as the proportion of patients being pain-free at 12 months’ follow-up. Pain will be assessed with the Izbicki Pain Score. Secondary endpoints will be the proportion of patients with complications due to gallstones or cholecystectomy, quality of life, the association between the patients’ symptoms and treatment, work performance, and cost-effectiveness. Discussion The data from the SECURE trial will provide evidence whether or not a restrictive strategy in patients with symptomatic cholecystolithiasis is associated with similar patient reported outcomes and a reduction in the number of cholecystectomies compared to usual care. The data from this trial will be analyzed according to this pre-specified SAP. Trial registration The Netherlands National Trial Register NTR4022. Registered on 5 June 2013.

Abstract Background Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) is the most common complication of ERCP and may run a severe course. Evidence suggests that vigorous periprocedural hydration can prevent PEP, but studies to date have significant methodological drawbacks. Importantly, evidence for its added value in patients already receiving prophylactic rectal non-steroidal anti-inflammatory drugs (NSAIDs) is lacking and the cost-effectiveness of the approach has not been investigated. We hypothesize that combination therapy of rectal NSAIDs and periprocedural hydration would significantly lower the incidence of post-ERCP pancreatitis compared to rectal NSAIDs alone in moderate- to high-risk patients undergoing ERCP. Methods The FLUYT trial is a multicenter, parallel group, open label, superiority randomized controlled trial. A total of 826 moderate- to high-risk patients undergoing ERCP that receive prophylactic rectal NSAIDs will be randomized to a control group (no fluids or normal saline with a maximum of 1.5 mL/kg/h and 3 L/24 h) or intervention group (lactated Ringer’s solution with 20 mL/kg over 60 min at start of ERCP, followed by 3 mL/kg/h for 8 h thereafter). The primary endpoint is the incidence of post-ERCP pancreatitis. Secondary endpoints include PEP severity, hydration-related complications, and cost-effectiveness. Discussion The FLUYT trial design, including hydration schedule, fluid type, and sample size, maximize its power of identifying a potential difference in post-ERCP pancreatitis incidence in patients receiving prophylactic rectal NSAIDs. Trial registration EudraCT: 2015-000829-37. Registered on 18 February 2015. ISRCTN: 13659155. Registered on 18 May 2015.

Abstract Background Little is known about determinants of quality of life (QoL) in autosomal dominant polycystic kidney disease (ADPKD). Recent studies suggest that QoL in ADPKD is determined by more factors than mere renal function. We investigated the effect of ADPKD on QoL and evaluated how Qol is affected by disease severity markers renal function, kidney volume and liver volume. Methods We performed a systematic review, meta-analysis and meta-regression analyses of cohort studies and randomized controlled trials investigating patient-reported QoL in adult patients with ADPKD not yet on dialysis. EMBASE, MEDLINE, and Web of Science were searched to August 2015 without language restrictions. Two investigators independently reviewed title, abstracts and full text of potentially relevant citations to determine eligibility. We compared pooled QoL summary scores of ADPKD patients using a random-effects meta-analytic model. These scores were compared with mean and age-corrected reference scores of the general population. In a meta-regression analysis, we investigated the univariate effect of renal function, kidney volume and liver volume on QoL. Results We included nine studies in meta-analysis including 1623 patients who completed the SF-36 questionnaire. Pooled physical (PCS) and mental component scores (MCS) of the SF-36 of individuals with ADPKD were lower than those of the reference population (45.7 vs. 50.0 and 47.8 vs. 50.0 points, both P

The rough endoplasmic reticulum (ER) of nucleated human cells has crucial functions in protein biogenesis, calcium (Ca2+) homeostasis, and signal transduction. Among the roughly one hundred components, which are involved in protein import and protein folding or assembly, two components stand out: The Sec61 complex and BiP. The Sec61 complex in the ER membrane represents the major entry point for precursor polypeptides into the membrane or lumen of the ER and provides a conduit for Ca2+ ions from the ER lumen to the cytosol. The second component, the Hsp70-type molecular chaperone immunoglobulin heavy chain binding protein, short BiP, plays central roles in protein folding and assembly (hence its name), protein import, cellular Ca2+ homeostasis, and various intracellular signal transduction pathways. For the purpose of this review, we focus on these two components, their relevant allosteric effectors and on the question of how their respective functional cycles are linked in order to reconcile the apparently contradictory features of the ER membrane, selective permeability for precursor polypeptides, and impermeability for Ca2+. The key issues are that the Sec61 complex exists in two conformations: An open and a closed state that are in a dynamic equilibrium with each other, and that BiP contributes to its gating in both directions in cooperation with different co-chaperones. While the open Sec61 complex forms an aqueous polypeptide-conducting- and transiently Ca2+-permeable channel, the closed complex is impermeable even to Ca2+. Therefore, we discuss the human hereditary and tumor diseases that are linked to Sec61 channel gating, termed Sec61-channelopathies, as disturbances of selective polypeptide-impermeability and/or aberrant Ca2+-permeability.

Background. Cholecystectomy does not relieve abdominal symptoms in up to 40% of patients. With 700,000 cholecystectomies performed in the US, annually, about 280,000 patients are left with symptoms, making this a serious problem. We performed a systematic review to determine the different etiologies of long-term postcholecystectomy symptoms with the aim to provide guidance for clinicians treating these patients. Methods. A systematic search of the literature was performed using MEDLINE, EMBASE, and Web of Science. Articles describing at least one possible etiology of long-term symptoms after a laparoscopic cholecystectomy were included in this review. Long-term symptoms were defined as abdominal symptoms that were present at least four weeks after cholecystectomy, either persistent or incident. The etiologies of persistent and incident symptoms after LC and the mechanism or hypothesis behind the etiologies are provided. If available, the prevalence of the discussed etiology is provided. Results. The search strategy identified 3320 articles of which 130 articles were included. Etiologies for persistent symptoms were residual and newly formed gallstones (41 studies, prevalence ranged from 0.2 to 23%), coexistent diseases (64 studies, prevalence 1-65%), and psychological distress (13 studies, no prevalence provided). Etiologies for incident symptoms were surgical complications (21 studies, prevalence 1-3%) and physiological changes (39 studies, prevalence 16-58%). Sphincter of Oddi dysfunction (SOD) was reported as an etiology for both persistent and incident symptoms (21 studies, prevalence 3-40%). Conclusion. Long-term postcholecystectomy symptoms vary amongst patients, arise from different etiologies, and require specific diagnostic and treatment strategies. Most symptoms after cholecystectomy seem to be caused by coexistent diseases and physiological changes due to cholecystectomy. The outcome of this research is summarized in a decision tree to give clinical guidance on the treatment of patients with symptoms after cholecystectomy.

Background: Somatostatin analogues (SAs) reduce liver volume and relief symptoms in polycystic liver disease (PLD). Its effect wears off after continuing therapy suggesting development of SA tolerance in patients on chronic therapy. We postulate that a drug holiday resensitizes the liver to its acute pharmacological effects. Therefore, this study examines the liver volume-reducing effect of SAs after a drug holiday. Methods: Patients were identified from the International PLD Registry and included in our analysis when (1) treated with SAs during two cycles separated by a drug holiday and (2) height-adjusted total liver volume (hTLV) was available at start and end of each cycle. For our primary outcome we compared the effect of SAs (in % per 6 months) on hTLV between the first and second treatment cycle. Results: In 34 patients, initial liver volume-reducing effect was similar to that after rechallenge [−2.6% per 6 months (interquartile range, −3.8–0.8) versus −1.6% per 6 months (interquartile range, −3.1–1.1), p = 0.510]. Cessation of treatment led to a rebound effect, but liver volume remained stable compared with the baseline with intermittent therapy in responders to SA [−0.6% (interquartile range, −7.4–5.7) after 46.5 months]. Conclusions: PLD patients treated with SAs benefit from retreatment after a drug holiday. The significant increase of liver volume after cessation of treatment complicates widespread use of a drug holiday as new treatment strategy. Our results contribute to a better understanding of the pharmacological effect of SAs and help to identify patients who might benefit.