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Acute pancreatitis can range from a mild, self-limiting disease requiring no more than supportive care, to severe disease with life-threatening complications. With the goal of providing a recommendation framework for clinicians to manage acute pancreatitis, and to contribute to improvements in national health care, the Korean Pancreatobiliary Association (KPBA) established the Korean guidelines for acute pancreatitis management in 2013. However, many challenging issues exist which often lead to differences in clinical practices. In addition, with newly obtained evidence regarding acute pancreatitis, there have been great changes in recent knowledge and information regarding this disorder. Therefore, the KPBA committee underwent an extensive revision of the guidelines. The revised guidelines were developed using the Delphi method, and the main topics of the guidelines include the following: diagnosis, severity assessment, initial treatment, nutritional support, convalescent treatment, and the treatment of local complications and necrotizing pancreatitis. Specific recommendations are presented, along with the evidence levels and recommendation grades.
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Background/Aims@#A previous history of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) is a risk factor for PEP, suggesting that there may be a genetic predisposition to PEP. However, nothing is known about this yet. The aim of this study was to identify genetic variations associated with PEP. @*Methods@#A cohort of high-risk PEP patients was queried from December 2016 to January 2019. For each PEP case, two propensity score-matched controls were selected. Whole exome sequencing was performed using blood samples. Genetic variants reported to be related to pancreatitis were identified. To discover genetic variants that predispose to PEP, a logistic regression analysis with clinical adjustment was performed. Gene-wise analyses were also conducted. @*Results@#Totals of 25 PEP patients and 50 matched controls were enrolled. Among the genetic variants reported to be associated with pancreatitis, only CASR rs1042636 was identified, and it showed no significant difference between the case and control groups. A total of 54,269 non-synonymous variants from 14,313 genes was identified. Logistic regression analysis of these variants showed that the IRF2BP1 rs60158447 GC genotype was significantly associated with the occurrence of PEP (odds ratio 2.248, FDR q value = 0.005). Gene-wise analyses did not show any significant results. @*Conclusions@#This study found that the IRF2BP1 gene variant was significantly associated with PEP. This genetic variant is a highly targeted PEP risk factor candidate and can be used for screening high-risk PEP groups before ERCP through future validation. (ClinicalTrials.gov no. NCT02928718)
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Biliary stent removal can cause hemobilia due to injury to the adjacent vessel, but it is rarely reported. If significant hemobilia occurs during stent removal, samesession covered self-expandable metal stent (CSEMS) insertion may be useful as a rescue or bridge therapy before angiography. Here, we report two cases of lifethreatening hemobilia following stent removal successfully treated by CSEMS. The first case was a Klatskin tumor bismuth type IV patient who required biliary stenting for resolving malignant biliary obstruction. The second case was a hepatocellular carcinoma patient who had undergone multiple transarterial chemoembolization and required biliary stents for liver abscess. In this situation, inserting a CSEMS at a higher level than the expected bleeding site and recognizing stenting as a temporary therapy with its limitations are important. Also, it is crucial to consider pre-procedural imaging in high-risk patients, and perform post-procedural imaging to evaluate for ongoing bleeding or vascular abnormalities.
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Background/Aims@#The combinatorial effects of prophylactic methods for postendoscopic retrograde cholangiopancreatography pancreatitis (PEP) in patients with risk factors remain unclear. In this network meta-analysis, we compared the efficacy of various prophylactic strategies to decrease the risk of PEP among patients with risk factors. @*Methods@#A systematic review was performed to identify randomized controlled trials from PubMed, Embase, and the Cochrane Library through July 2021. We used frequentist network meta-analysis to compare the rates of PEP among patients who received prophylactic treatments as follows: class A, rectal nonsteroidal anti-inflammatory drugs; class B, prophylactic pancreatic stent; class C, aggressive hydration; or control, no prophylaxis or active control. We selected those studies that included patients with risk factors for PEP. @*Results@#We identified 19 trials, comprising 4,328 participants. Class ABC (odds ratio [OR], 0.08; 95% confidence interval [CI], 0.03 to 0.24), class AC (OR, 0.10; 95% CI, 0.02 to 0.47), class AB (OR, 0.12; 95% CI, 0.05 to 0.26), class BC (OR, 0.13; 95% CI, 0.04 to 0.41), class A (OR, 0.16; 95% CI, 0.05 to 0.50), and class B (OR, 0.26; 95% CI, 0.14 to 0.46), were associated with a reduced risk of PEP as compared to that of the control. The most effective prophylaxis was ABC (0.87), followed by AC (0.68), AB (0.65), BC (0.56), A (0.49), and B (0.24) according to P-score. @*Conclusions@#The results of this network meta-analysis suggest that the more prophylactic methods are employed, the better the outcomes. It appears that for patients with risk factors, we need to prevent PEP through the use of these well proven combination strategies.
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Background/Aims@#Three-dimensional cultures of human pancreatic cancer tissue also known as “organoids” have largely been developed from surgical specimens. Given that most patients present with locally advanced and/or metastatic disease, such organoids are not representative of the majority of patients. Therefore, we used endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) to collect pancreatic cancer tissues from patients with advanced pancreatic cancer to create organoids, and evaluated their utility in pancreatic cancer research. @*Methods@#Single-pass EUS-FNA samplings were employed to obtain the tissue for organoid generation. After establishment of the organoid, we compared the core biopsy tissues with organoids using hematoxylin and eosin staining, and performed whole exome sequencing (WES) to detect mutational variants. Furthermore, we compared patient outcome with the organoid drug response to determine the potential utility of the clinical application of such organoid-based assays. @*Results@#Organoids were successfully generated in 14 of 20 tumors (70%) and were able to be passaged greater than 5 times in 12 of 20 tumors (60%). Among them, we selected eight pairs of organoid and core biopsy tissues for detailed analyses. They showed similar patterns in hematoxylin and eosin staining. WES revealed mutations in KRAS, TP53, CDKN2A, SMAD4, BRCA1, and BRCA2 which were 93% homologous, and the mean nonreference discordance rate was 5.47%. We observed moderate drug response correlations between the organoids and clinical outcomes in patients who underwent FOLFIRINOX chemotherapy. @*Conclusions@#The established organoids from EUS-FNA core biopsies can be used for a suitable model system for pancreatic cancer research
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A lumen-apposing metal stent (LAMS) is a saddle-shaped stent with large flanges at both ends, thereby preventing stent migration and helping with approximation of the adjacent structures. We report the case of a 25-year-old female with remnant choledochal cyst which was successfully treated with LAMS after initial treatment failure with a plastic stent. Although complete excision of the cyst is the definite treatment of choledochal cysts, endoscopic ultrasonography-guided cystoduodenostomy can be considered in cases wherein surgery is not feasible and dysplasia is not present. LAMS may be preferred to plastic stents for effective resolution of remnant choledochal cyst and prevention of ascending infection.
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Background/Aims@#Endoscopic ultrasonography (EUS) provides high-resolution images and is superior to computed tomography (CT) scan in diagnosing small pancreatic ductal adenocarcinoma (PDAC). As a result, the use of EUS for early detection of PDAC has attracted attention. This study aimed to identify the clinical and radiological characteristics of patients with PDAC diagnosed by EUS but not found on CT scan. @*Methods@#The medical records of patients diagnosed with PDAC at 12 tertiary referral centers in Korea from January 2003 to April 2019 were reviewed. This study included patients with pancreatic masses not clearly observed on CT scan but identified on EUS. The clinical characteristics and radiological features of the patients were analyzed, and survival analysis was performed. @*Results@#A total of 83 patients were enrolled. The most common abnormal CT findings other than a definite mass was pancreatic duct dilatation, which was identified in 61 patients (73.5%). All but four patients underwent surgery. The final pathologic stages were as follows: IA (n=31, 39.2%), IB (n=8, 10.1%), IIA (n=20, 25.3%), IIB (n=17, 21.5%), III (n=2, 2.5%), and IV (n=1, 1.4%). The 5-year survival rate of these patients was 50.6% (95% confidence interval, 38.8% to 66.7%). Elevated liver function testing and R1 resection emerged as significant predictors of mortality in the multivariable Cox regression analysis. @*Conclusions@#This multicenter study demonstrated favorable long-term prognosis in patients with PDAC diagnosed by EUS but indeterminate on CT scan. EUS should be considered for patients with suspected PDAC but indeterminate on CT scan.
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Acute pancreatitis can range from a mild, self-limiting disease that requires no more than supportive care to severe disease with life-threatening complications. Therefore, to provide a framework for clinicians to manage acute pancreatitis and to improve national health care, the Korean Pancreatobiliary Association (KPBA) established the first Korean guideline for the management of acute pancreatitis in 2013. However, many challenging issues exist, which sometimes lead to differences in practice between clinicians. Taking together the recent dramatic changes of latest knowledge and evidence newly obtained, the committee of the KPBA decided to perform an extensive revision of the guidelines. These revised guidelines were developed by using mainly Delphi methods, and the main topics of these guidelines fall under the following topics: 1) diagnosis, 2) severity assessment, 3) initial treatment, nutritional support, and convalescent treatment, 4) the treatment of local complication and necrotizing pancreatitis. The specific recommendations are presented with the quality of evidence and classification of recommendations.
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The severity of acute pancreatitis (AP) is classified into mild, moderately severe, and severe, considering the presence and duration of organ failure and local complications. Since patients with AP show a large difference in mortality and morbidity according to AP severity, evaluation of the severity of patients with AP in the early stage is important for predicting the prognosis and determining treatment plans including transfer to the intensive care unit or advanced facilities. In order to evaluate the initial severity of AP, it is necessary to confirm the presence of organ failure and objective evaluation using imaging or clinical examinations. In this guideline, it is recommended that evaluation using various severity indices such as bedside index for severity in acute pancreatitis (BISAP), systemic inflammatory response syndrome (SIRS), and acute physiology and chronic health evaluation (APACHE)-II scores be considered.
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Common bile duct (CBD) stones are prevalent in 11% to 21% of patients with gallstones and can cause various clinical manifestations, from biliary colic to biliary sepsis. The treatment of choice is endoscopic retrograde cholangiopancreatography, but approximately 5% to 10% of CBD stones are difficult to remove using these conventional endoscopic methods. Although percutaneous transhepatic cholangioscopy and lithotripsy can be used as an alternative, it can be technically demanding and risky if the intrahepatic duct is not dilated. We report a case of a large CBD stone that was successfully removed using percutaneous transcholecystic cholangioscopy.
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Post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP) is one of the most burdensome adverse events, occurs in about 3 to 15 percent of patients after the procedure. Various and extensive attempts have been made to find proper prophylaxis for PEP. Nowadays, pharmacologic agents consist one of the pivotal axis for prophylaxis for PEP. In this review article, we tried to overview pharmacologic prophylaxis including non-steroidal anti-inflammatory drugs, aggressive hydration, protease inhibitors, exocrine pancreatic secretion inhibitors, and nitrates from recent updated results of randomized controlled studies and key meta-analyses.
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Background/Aims@#Although many studies have reported the promising effect of neoadjuvant treatment for borderline resectable pancreatic cancer (BRPC) to increase resectability, only a few studies have recommended the use of first-line chemotherapeutic agents as neoadjuvant treatment for BRPC. The current study compared clinical outcomes between gemcitabine and FOLFIRINOX (5-fluorouracil, leucovorin, oxaliplatin, and irinotecan) in patients with BRPC. @*Methods@#In this single-center retrospective study, 100 BRPC patients treated with neoadjuvant chemotherapy and resection from 2008 to 2018 were reviewed. Clinical outcomes included overall survival, resectability, and recurrence patterns after gemcitabine or FOLFIRINOX treatment. @*Results@#For neoadjuvant chemotherapy, gemcitabine was administered to 34 patients and FOLFIRINOX to 66. Neoadjuvant radiotherapy was administered to 27 patients (79.4%) treated with gemcitabine and 19 (28.8%) treated with FOLFIRINOX (p<0.001). The 2- and 5-year survival rates (YSRs) were significantly higher after FOLFIRINOX (2YSR, 72.2%; 5YSR, 46.0%) than after gemcitabine (2YSR, 58.4%; 5YSR, 19.1%; p=0.041). The margin negative rate was comparable (gemcitabine, 94.1%; FOLFIRINOX, 92.4%; p=0.753), and the tumor size change in percentage showed only a marginal difference (gemcitabine, 20.5%; FOLFIRINOX, 29.0%; p=0.069). Notably, the metastatic recurrence rate was significantly lower in the FOLFIRINOX group (n=20, 52.6%) than in the gemcitabine group (n=22, 78.6%; p=0.001). The rate of adverse events after chemotherapy was significantly higher with FOLFIRINOX than with gemcitabine (43.9%, 20.6%, respectively; p=0.037). @*Conclusions@#FOLFIRINOX provided more clinical and oncological benefit than gemcitabine, with significantly higher overall survival and lower cumulative recurrence rates in BRPC. However, since FOLFIRINOX causes more adverse effects, the regimen should be individualized based on patient’s general condition and clinical status.
ABSTRACT
Post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP) is one of the most burdensome adverse events, occurs in about 3 to 15 percent of patients after the procedure. Various and extensive attempts have been made to find proper prophylaxis for PEP. Nowadays, pharmacologic agents consist one of the pivotal axis for prophylaxis for PEP. In this review article, we tried to overview pharmacologic prophylaxis including non-steroidal anti-inflammatory drugs, aggressive hydration, protease inhibitors, exocrine pancreatic secretion inhibitors, and nitrates from recent updated results of randomized controlled studies and key meta-analyses.
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Background/Aims@#There has been growing evidence on the utility of neoadjuvant FOLFIRINOX in borderline resectable (BR) or locally advanced (LA) pancreatic cancer. However, factors predicting survival in these patients remain to be identified, and we aimed to identify these prognostic factors. @*Methods@#Between January 2013 and April 2017, patients with BR or LA pancreatic cancer who received FOLFIRINOX as their initial treatment were identified. Demographic data and clinical outcomes, including the chemotherapy response, conversion to resection, and survival, were reviewed. @*Results@#A total of 117 patients with BR (n=39) or LA (n=78) pancreatic cancer were included. Of these patients, 29 (24.8%) underwent curative surgery, and R0 resection was achieved in 21 patients (72.4%). The median progression-free survival and overall survival time of all patients were 11.6 and 19.0 months, respectively. In resected patients, the median relapse-free survival and overall survival times were 14.8 and 28.6 months, respectively. In the multivariate Cox model, the lowest level of serum carbohydrate antigen 19-9 (CA 19-9) and resection after FOLFIRINOX were independent factors for improved overall survival. In the subgroup analysis of patients with initial 18 F-fluorodeoxyglucose-positron emission tomography (FDG-PET) images, the maximum standardized uptake value (SUVmax) of the pancreatic mass was also shown as an independent factor for improved overall survival. @*Conclusions@#In patients with BR or LA pancreatic cancer, FOLFIRINOX is a valuable neoadjuvant treatment that enables curative surgery in approximately one-quarter of patients and significantly improves overall survival. In these patients, the prognosis can be estimated using the lowest level of serum CA 19-9, operative status, and initial FDG-PET SUVmax.
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Background/Aims@#Cholangiocarcinoma (CCA) is a rare but aggressive disease with a poor survival. Recent trials have shown improved survival with intraductal radiofrequency ablation (RFA) therapy. We performed a systematic review with meta-analysis to determine the survival benefit of endoscopic RFA for unresectable extrahepatic CCA with malignant biliary obstruction (MBO). @*Methods@#A systematic search from 1970 to 2020 was performed in MEDLINE, EMBASE, Cochrane Library, and ClinicalTrials. gov. We selected eligible studies reporting relative risks, hazard ratios (HRs), or odds ratios, adjusted by controlling for confounding factors of survival rate and stent patency duration, among patients with extrahepatic CCA with MBO treated with RFA with stent insertion or stent insertion only. @*Results@#A total of eight trials (three randomized and five nonrandomized) with a total of 420 patients were included in the metaanalysis. Pooled overall survival analysis favored RFA treatment with stent insertion (HR, 0.47; 95% confidence interval [CI], 0.34– 0.64; I2=47%; p=0.09); however, no significant difference was found in the duration of stent patency between the groups (HR, 0.79; 95% CI, 0.57–1.09; I2=7%; p=0.36). @*Conclusions@#RFA therapy with stent insertion may confer a survival benefit compared with stent insertion only in patients with CCA and MBO.
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Background/Aims@#Although many studies have reported the promising effect of neoadjuvant treatment for borderline resectable pancreatic cancer (BRPC) to increase resectability, only a few studies have recommended the use of first-line chemotherapeutic agents as neoadjuvant treatment for BRPC. The current study compared clinical outcomes between gemcitabine and FOLFIRINOX (5-fluorouracil, leucovorin, oxaliplatin, and irinotecan) in patients with BRPC. @*Methods@#In this single-center retrospective study, 100 BRPC patients treated with neoadjuvant chemotherapy and resection from 2008 to 2018 were reviewed. Clinical outcomes included overall survival, resectability, and recurrence patterns after gemcitabine or FOLFIRINOX treatment. @*Results@#For neoadjuvant chemotherapy, gemcitabine was administered to 34 patients and FOLFIRINOX to 66. Neoadjuvant radiotherapy was administered to 27 patients (79.4%) treated with gemcitabine and 19 (28.8%) treated with FOLFIRINOX (p<0.001). The 2- and 5-year survival rates (YSRs) were significantly higher after FOLFIRINOX (2YSR, 72.2%; 5YSR, 46.0%) than after gemcitabine (2YSR, 58.4%; 5YSR, 19.1%; p=0.041). The margin negative rate was comparable (gemcitabine, 94.1%; FOLFIRINOX, 92.4%; p=0.753), and the tumor size change in percentage showed only a marginal difference (gemcitabine, 20.5%; FOLFIRINOX, 29.0%; p=0.069). Notably, the metastatic recurrence rate was significantly lower in the FOLFIRINOX group (n=20, 52.6%) than in the gemcitabine group (n=22, 78.6%; p=0.001). The rate of adverse events after chemotherapy was significantly higher with FOLFIRINOX than with gemcitabine (43.9%, 20.6%, respectively; p=0.037). @*Conclusions@#FOLFIRINOX provided more clinical and oncological benefit than gemcitabine, with significantly higher overall survival and lower cumulative recurrence rates in BRPC. However, since FOLFIRINOX causes more adverse effects, the regimen should be individualized based on patient’s general condition and clinical status.
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Eosinophilia occurs commonly in many diseases including allergic diseases and helminthic infections. Toxocariasis has been suggested as one cause of eosinophilia. The present study was undertaken to examine the prevalence of toxocariasis in patients with eosinophilia and to identify the risk factors for toxocariasis. This prospective cohort study recruited a total of 81 patients with eosinophilia (34 males and 47 females) who visited the outpatient clinic at Seoul National University Hospital from January 2017 to February 2018 and agreed to participate in this study. The prevalence of toxocariasis was examined by T. canis-specific ELISA, and the various risk factors for toxocariasis were evaluated by a questionnaire survey. Among 81 patients with eosinophilia, 18 were positive for anti-T. canis antibodies (22.2%); 88.9% were male (16/18) and 11.1% were female (2/18). Multivariate statistical analysis revealed that males (OR 21.876, 95% CI: 1.667-287.144) with a history of consuming the raw meat or livers of animals (OR 5.899, 95% CI: 1.004-34.669) and a heavy alcohol-drinking habit (OR 8.767, 95% CI: 1.018-75.497) were at higher risk of toxocariasis in patients with eosinophilia. Toxocariasis should be considered a potential cause of eosinophilia when the patient has a history of eating the raw meat or livers of animals in Korea. A single course of albendazole is recommended to reduce the migration of Toxocara larvae in serologically positive cases with eosinophilia.
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Background@#Complicated acute pyelonephritis (APN) is a life-threatening condition that requires immediate intervention. This study examined the characteristics of APN occurring as a complication of ureteral stone. @*Methods@#We retrospectively reviewed 85 patients diagnosed with APN complicated by ureteral stone between December 2006 and July 2017 at our institution. Patients with concomitant renal stone, multiple ureteral stones, ureteral strictures, ureteral cancer, and urogenital anomalies, including vesicoureteral reflux were excluded. Clinical characteristics including age, sex, underlying disease, medical history, stone characteristics, initial laboratory data, and the procedure used to correct urinary obstruction were summarized, and the risk factors associated with sepsis and septic shock were analyzed. @*Results@#Sepsis was diagnosed at initial presentation in 62 patients, 17 of whom suffered from septic shock. Disease-related death did not occur in any patient. Previous history of stone (P = 0.015), leukocytosis (P < 0.001), elevated C-reactive protein levels (P = 0.006), and low albumin (P = 0.038) were significant risk factors for progression to sepsis. The absence of hypertension (P = 0.047), thrombocytopenia (P = 0.006), decreased erythrocyte sedimentation rate (ESR) (P = 0.003), elevated blood urea nitrogen (P = 0.016), and positive blood culture (P= 0.018) were significant predictors for progression to septic shock.Multivariate analysis revealed that previous history of stone (P = 0.015) was an independent risk factor for sepsis, while the absence of hypertension (P = 0.047), thrombocytopenia (P= 0.013), and decreased ESR (P = 0.009) were risk factors for shock. @*Conclusion@#The risk factors associated with the progression from APN to sepsis differed from those associated with the progression from sepsis to septic shock. Various factors should be considered while selecting treatment options based on the severity of APN associated with ureteral stone. It should be managed with aggressive treatment and close observation, especially in the presence of risk factors.
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PURPOSE: The purpose of this study was to compare health-related quality of life (HRQoL) of disease-free prostate (PC), kidney (KC), and bladder cancer (BC) survivors with that of the general population. MATERIALS AND METHODS: Our study included 331 urological cancer (UC) survivors (114 PC, 108 KC, and 109 BC) aged ≥ 50 years disease-free for at least 1 year after surgery. The control group included 1,177 subjects without a history of cancer. The HRQoL was assessed using the European Organization for Research and Treatment of Cancer QLQ-C30, the Duke-UNC Functional Social Support Questionnaire, and the Patient Health Questionnaire-9. RESULTS: There was no significant difference between the groups in terms of any of the functioning sub-scales and symptoms, except significantly lower social functioning observed in BC survivors than that observed in KC survivors. Although the three groups of UC survivors showed essentially similar functioning sub-scales and symptoms when compared to the general population, PC and BC survivors showed significantly lower social functioning and a lower appetite than that observed in controls. KC survivors showed lower physical functioning, as well as higher pain and dyspnea. Although all three groups of UC survivors reported higher financial difficulties, they also reported higher perceived social support than that reported by the non-cancer control group. No statistically significant difference was observed in terms of depressive symptoms between each group of UC survivors and the general population. CONCLUSION: Disease-free survivors of the three major types of UCs showed generally similar HRQoL compared to the general population, as well as compared to each other.
Subject(s)
Humans , Appetite , Depression , Dyspnea , Kidney Neoplasms , Kidney , Prostate , Prostatic Neoplasms , Quality of Life , Survivors , Urinary Bladder Neoplasms , Urinary Bladder , Urologic NeoplasmsABSTRACT
BACKGROUND/AIMS: Gallstone disease (GSD) is a common gastrointestinal disorder. Clinical epidemiological studies revealed that alcohol consumption has a preventive effect on the development of GSD. This study aimed to evaluate the relative risks of drinking for GSD development and investigate the dose-response relationships. METHODS: A systematic search of the MEDLINE, EMBASE, and Cochrane Library databases for studies published up to 2018 was performed. All studies that satisfied the following eligibility criteria were included: patients with GSD with or without cholecystitis; and cohort or case-control studies investigating the association between alcohol consumption and GSD development. RESULTS: Sixteen case-control studies including 24,401 gallstone cases and 76,185 controls, and eight cohort studies with 14,693 GSD cases among 2,432,471 person-years were enrolled. Alcohol consumption presented a decreased overall risk of GSD (pooled relative ratio [RR], 0.84; 95% confidence interval [CI], 0.79 to 0.89; p=0.02). Subgroup analyses according to drinking levels indicated a gradual risk reduction for GSD compared to nondrinkers (light: RR, 0.96; 95% CI, 0.94 to 0.99; p=0.75; moderate: RR, 0.80; 95% CI, 0.75 to 0.85; p=0.27; high: RR, 0.66; 95% CI, 0.56 to 0.79; p < 0.01). A nonlinear risk reduction was observed in a dose-response meta-analysis of all the studies (n=14, p < 0.01 for nonlinearity). CONCLUSIONS: In this systematic review with meta-analysis, alcohol consumption could decrease the risk of GSD, and the dose-response analysis revealed a dose-dependent linear risk reduction and a weakened linear trend between alcohol consumption levels less than and greater than 28 g/day.