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Smoking, Alcohol, and Biliary Tract Cancer Risk: A Pooling Project of 26 Prospective Studies
Abstract Background Tobacco and alcohol are well-established risk factors for numerous cancers, yet their relationship to biliary tract cancers remains unclear. Methods We pooled data from 26 prospective studies to evaluate associations of cigarette smoking and alcohol consumption with biliary tract cancer risk. Study-specific hazard ratios (HRs) and 95% confidence intervals (CIs) for associations with smoking and alcohol consumption were calculated. Random-effects meta-analysis produced summary estimates. All statistical tests were two-sided. Results Over a period of 38 369 156 person-years of follow-up, 1391 gallbladder, 758 intrahepatic bile duct, 1208 extrahepatic bile duct, and 623 ampulla of Vater cancer cases were identified. Ever, former, and current smoking were associated with increased extrahepatic bile duct and ampulla of Vater cancers risk (eg, current vs never smokers HR = 1.69, 95% CI = 1.34 to 2.13 and 2.22, 95% CI = 1.69 to 2.92, respectively), with dose-response effects for smoking pack-years, duration, and intensity (all Ptrend < .01). Current smoking and smoking intensity were also associated with intrahepatic bile duct cancer (eg, >40 cigarettes per day vs never smokers HR = 2.15, 95 % CI = 1.15 to 4.00; Ptrend = .001). No convincing association was observed between smoking and gallbladder cancer. Alcohol consumption was only associated with intrahepatic bile duct cancer, with increased risk for individuals consuming five or more vs zero drinks per day (HR = 2.35, 95%CI = 1.46 to 3.78; Ptrend = .04). There was evidence of statistical heterogeneity among several cancer sites, particularly between gallbladder cancer and the other biliary tract cancers. Conclusions Smoking appears to increase the risk of developing all biliary tract cancers except gallbladder cancer. Alcohol may increase the risk of intrahepatic bile duct cancer. Findings highlight etiologic heterogeneity across the biliary tract.
Radiation and Risk of Liver, Biliary Tract, and Pancreatic Cancers among Atomic Bomb Survivors in Hiroshima and Nagasaki: 1958–2009
The Life Span Study (LSS) of atomic bomb survivors has consistently demonstrated significant excess radiation-related risks of liver cancer since the first cancer incidence report. Here, we present updated information on radiation risks of liver, biliary tract and pancreatic cancers based on 11 additional years of follow-up since the last report, from 1958 to 2009. The current analyses used improved individual radiation doses and accounted for the effects of alcohol consumption, smoking and body mass index. The study participants included 105,444 LSS participants with known individual radiation dose and no known history of cancer at the start of follow-up. Cases were the first primary incident cancers of the liver (including intrahepatic bile duct), biliary tract (gallbladder and other and unspecified parts of biliary tract) or pancreas identified through linkage with population-based cancer registries in Hiroshima and Nagasaki. Poisson regression methods were used to estimate excess relative risks (ERRs) and excess absolute risks (EARs) associated with DS02R1 doses for liver (liver and biliary tract cancers) or pancreas (pancreatic cancer). We identified 2,016 incident liver cancer cases during the follow-up period. Radiation dose was significantly associated with liver cancer risk (ERR per Gy: 0.53, 95% CI: 0.23 to 0.89; EAR per 10,000 person-year Gy: 5.32, 95% CI: 2.49 to 8.51). There was no evidence for curvature in the radiation dose response (P=0.344). ERRs by age-at-exposure categories were significantly increased among those who were exposed at 0–9, 10–19 and 20–29 years, but not significantly increased after age 30 years, although there was no statistical evidence of heterogeneity in these ERRs (P = 0.378). The radiation ERRs were not affected by adjustment for smoking, alcohol consumption or body mass index. As in previously reported studies, radiation dose was not associated with risk of biliary tract cancer (ERR per Gy: –0.02, 95% CI: –0.25 to 0.30). Radiation dose was associated with a nonsignificant increase in pancreatic cancer risk (ERR per Gy: 0.38, 95% CI: <0 to 0.83). The increased risk was statistically significant among women (ERR per Gy: 0.70, 95% CI: 0.12 to 1.45), but not among men.
Impact of Intraluminal Brachytherapy on Survival Outcome for Radiation Therapy for Unresectable Biliary Tract Cancer: A Propensity-Score Matched-Pair Analysis
Purpose: To determine whether adding intraluminal brachytherapy (ILBT) to definitive radiation therapy (RT) for unresectable biliary tract cancer has a positive impact on survival outcome. Methods and Materials: The original cohort comprised 209 patients, including 153 who underwent external beam RT (EBRT) alone and 56 who received both ILBT and EBRT. By matching propensity scores, 56 pairs (112 patients) consisting of 1 patient with and 1 patient without ILBT were selected. They were well balanced in terms of sex, age, performance status, clinical stage, jaundice, and addition of chemotherapy. The impact of ILBT on overall survival (OS), disease-specific survival (DSS), and local control (LC) was investigated. Results: The 2-year OS rates were 31% for the ILBT+ group and 40% for theILBT– group (P=.862). The 2-year DSS rates were 42% for the ILBT+ group and 41% for the ILBT– group (P=.288). The 2-year LC rates were 65% for the ILBT+ group and 35% for the ILBT– group (P=.094). Three of the 4 sensitivity analyses showed a significantly better LC for the ILBT+ group (P=.010, .025, .049), and another showed a marginally better LC (P=.068), and none of the sensitivity analyses showed any statistically significant differences in OS or DSS. Conclusions: In the treatment for unresectable biliary tract cancer, the addition of ILBT to RT has no impact on OS or DSS but is associated with better LC. Therefore, the role of ILBT should be addressed by other measures than survival benefit, for example, by less toxicity, prolonged biliary tract patency decreasing the need for further palliative interventions, or patient quality of life.
Obesity is associated with biliary tract cancer mortality and incidence: A pooled analysis of 21 cohort studies in the Asia Cohort Consortium
Abstract Body fatness is considered a probable risk factor for biliary tract cancer (BTC), whereas cholelithiasis is an established factor. Nevertheless, although obesity is an established risk factor for cholelithiasis, previous studies of the association of body mass index (BMI) and BTC did not take the effect of cholelithiasis fully into account. To better understand the effect of BMI on BTC, we conducted a pooled analysis using population‐based cohort studies in Asians. In total, 905 530 subjects from 21 cohort studies participating in the Asia Cohort Consortium were included. BMI was categorized into four groups: underweight (<18.5 kg/m 2 ); normal (18.5‐22.9 kg/m 2 ); overweight (23‐24.9 kg/m 2 ); and obese (25+ kg/m 2 ). The association between BMI and BTC incidence and mortality was assessed using hazard ratios (HR) and 95% confidence intervals (CIs) by Cox regression models with shared frailty. Mediation analysis was used to decompose the association into a direct and an indirect (mediated) effect. Compared to normal BMI, high BMI was associated with BTC mortality (HR 1.19 [CI 1.02‐1.38] for males, HR 1.30 [1.14‐1.49] for females). Cholelithiasis had significant interaction with BMI on BTC risk. BMI was associated with BTC risk directly and through cholelithiasis in females, whereas the association was unclear in males. When cholelithiasis was present, BMI was not associated with BTC death in either males or females. BMI was associated with BTC death among females without cholelithiasis. This study suggests BMI is associated with BTC mortality in Asians. Cholelithiasis appears to contribute to the association; and moreover, obesity appears to increase BTC risk without cholelithiasis.
Is Antibiotic Prophylaxis for Percutaneous Radiofrequency Ablation (RFA) of Primary Liver Tumors Necessary? Results From a Single-Center Experience
PurposeThe purpose of this study was to evaluate need for antibiotic prophylaxis for radiofrequency ablation (RFA) of liver tumors in patients with no significant co-existing risk factors for infection.Materials and MethodsFrom January 2004 to September 2013, 83 patients underwent 123 percutaneous RFA procedures for total of 152 hepatocellular carcinoma (HCC) lesions. None of the patients had pre-existing biliary enteric anastomosis (BEA) or any biliary tract abnormality predisposing to ascending biliary infection or uncontrolled diabetes mellitus. No pre- or post-procedure antibiotic prophylaxis was provided for 121 procedures. Data for potential risk factors were reviewed retrospectively and analyzed for the frequency of infectious complications, including abscess formation.ResultsOne patient (1/121 (0.8 %) RFA sessions) developed a large segment 5 liver abscess/infected biloma communicating with the gallbladder 7 weeks after the procedure, successfully treated over 10 weeks with IV and PO antibiotic therapy and percutaneous catheter drainage. This patient did not receive any antibiotics prior to RFA. During the procedure, there was inadvertent placement of RFA probe tines into the gallbladder. No other infectious complications were documented.ConclusionThese data suggest that the routine use of prophylactic antibiotics for liver RFA is not necessary in majority of the patients undergoing liver ablation for HCC and could be limited to patients with high-risk factors such as the presence of BEA or other biliary abnormalities, uncontrolled diabetes mellitus, and large centrally located tumors in close proximity to central bile ducts. Larger randomized studies are needed to confirm this hypothesis.
Improved Accuracy of Percutaneous Biopsy Using “Cross and Push” Technique for Patients Suspected with Malignant Biliary Strictures
PurposeVarious methods have been used to sample biliary strictures, including percutaneous fine-needle aspiration biopsy, intraluminal biliary washings, and cytological analysis of drained bile. However, none of these methods has proven to be particularly sensitive in the diagnosis of biliary tract malignancy. We report improved diagnostic accuracy using a modified technique for percutaneous transluminal biopsy in patients with this disease.Materials and MethodsFifty-two patients with obstructive jaundice due to a biliary stricture underwent transluminal forceps biopsy with a modified “cross and push” technique with the use of a flexible biopsy forceps kit commonly used for cardiac biopsies. The modification entailed crossing the stricture with a 0.038-in. wire leading all the way down into the duodenum. A standard or long sheath was subsequently advanced up to the stricture over the wire. A Cook 5.2-Fr biopsy forceps was introduced alongside the wire and the cup was opened upon exiting the sheath. With the biopsy forceps open, within the stricture the sheath was used to push and advance the biopsy cup into the stricture before the cup was closed and the sample obtained. The data were analysed retrospectively.ResultsWe report the outcomes of this modified technique used on 52 consecutive patients with obstructive jaundice secondary to a biliary stricture. The sensitivity and accuracy were 93.3 and 94.2 %, respectively. There was one procedure-related late complication.ConclusionWe propose that the modified “cross and push” technique is a feasible, safe, and more accurate option over the standard technique for sampling strictures of the biliary tree.
Bile acid-induced necrosis in primary human hepatocytes and in patients with obstructive cholestasis
Accumulation of bile acids is a major mediator of cholestatic liver injury. Recent studies indicate bile acid composition between humans and rodents is dramatically different, as humans have a higher percent of glycine conjugated bile acids and increased chenodeoxycholate content, which increases the hydrophobicity index of bile acids. This increase may lead to direct toxicity that kills hepatocytes, and promotes inflammation. To address this issue, this study assessed how pathophysiological concentrations of bile acids measured in cholestatic patients affected primary human hepatocytes. Individual bile acid levels were determined in serum and bile by UPLC/QTOFMS in patients with extrahepatic cholestasis with, or without, concurrent increases in serum transaminases. Bile acid levels increased in serum of patients with liver injury, while biliary levels decreased, implicating infarction of the biliary tracts. To assess bile acid-induced toxicity in man, primary human hepatocytes were treated with relevant concentrations, derived from patient data, of the model bile acid glycochenodeoxycholic acid (GCDC). Treatment with GCDC resulted in necrosis with no increase in apoptotic parameters. This was recapitulated by treatment with biliary bile acid concentrations, but not serum concentrations. Marked elevations in serum full-length cytokeratin-18, high mobility group box 1 protein (HMGB1), and acetylated HMGB1 confirmed inflammatory necrosis in injured patients; only modest elevations in caspase-cleaved cytokeratin-18 were observed. These data suggest human hepatocytes are more resistant to human-relevant bile acids than rodent hepatocytes, and die through necrosis when exposed to bile acids. These mechanisms of cholestasis in humans are fundamentally different to mechanisms observed in rodent models. - Highlights: • Cholestatic liver injury is due to cytoplasmic bile acid accumulation in hepatocytes. • Primary human hepatocytes are resistant to BA-induced injury compared to rodents. • Primary human hepatocytes largely undergo necrosis in response to BA toxicity. • Cholestatic liver injury in vivo is predominantly necrotic with minor apoptosis. • Rodent models of bile acid toxicity may not recapitulate the injury in man.
The hepatoduodenal ligament revisited: cross-sectional imaging spectrum of non-neoplastic conditions
Introduction: The hepatoduodenal ligament is frequently involved by conditions affecting the portal triad and surrounding structures, including a vast array of non-neoplastic conditions. Due its unique location between the retroperitoneum and the peritoneal space, the hepatoduodenal ligament is also targeted by inflammatory conditions involving the retroperitoneum and the liver. Finally, the presence of lymphatics and of the biliary tracts makes the hepatoduodenal ligament a route of spread for a variety of infections. The purpose of this pictorial essay is twofold: to review the cross-sectional radiological anatomy and variants of the structures within the hepatoduodenal ligament, and to illustrate the non-neoplastic conditions that may arise within the hepatoduodenal ligament. Conclusion: Familiarity with these specific entities and their cross-sectional imaging findings is fundamental for a more accurate diagnosis.
Outcomes in patients ≥ 80 years with a diagnosis of a hepatopancreaticobiliary (HPB) malignancy
Older patients are underrepresented in oncological clinical trials. The incidence of hepatopancreaticobiliary (HPB) malignancies is higher in older patients, but data on outcomes are lacking. This study assessed patient outcomes in those < 80 and ≥ 80 years with a HPB malignancy seen at a tertiary referral centre, The Christie NHS Foundation Trust. Data on patients with a HPB malignancy were collected retrospectively between 2012 and 2017 via on-line case-note review. Survival was calculated using the Kaplan–Meier method and prognostic factors using log-rank analysis. Of 1421 patients, 10% were ≥ 80 years. Of patients < 80 and ≥ 80 years, 56% and 57% had pancreas cancer, 39% and 36% biliary tract cancer, and 5% and 7% had hepatocellular carcinoma, respectively. Amongst patients ≥ 80 years, 75% had an Eastern Cooperative Oncology Group performance status (ECOG PS) 0–2. Patients ≥ 80 years had higher rates of comorbidity; 28% received systemic anti-cancer therapy (SACT), compared with 62% of patients < 80 years. Best supportive care (BSC) was instituted in 44% of older patients, compared with 13% in those < 80 years. Of patients ≥ 80 years who received SACT, 82% received monotherapy. Median overall survival (OS) for patients receiving palliative SACT was 10.07 months (95% CI 8.89–11.08) and 10.10 months (95% CI 6.30–12.30) in patients < 80 and ≥ 80 years, respectively, p 0.41; ECOG PS (p < 0.001) was prognostic for OS in older patients but Adult Comorbidity Evaluation-27 comorbidity score (p = 0.07, when comparing groups of ACE score ≤ 1 and > 1) was not. Baseline factors were similar in both age cohorts, but more comorbidities were present in older patients. Older patients were less likely to receive SACT, but when they did, they had an equivalent benefit in OS to younger patients.
Long non-coding RNA EPIC1 promotes cholangiocarcinoma cell growth
Highlights: • Lnc-EPIC1 expression is elevated in cholangiocarcinoma tissues, compared to adjacent tissues. • Lnc-EPIC1 promotes CCA cancer cell growth. • MYC directly interacts with Lnc-EPIC1 in CCA cancer cells. Cholangiocarcinoma (CCA) is the as the most frequently observed biliary tract malignancy, which has low survival rate in addition to constrained treatment options. However, the fundamental molecular mechanism underlying malignant progression of CCA is quite ambiguous. Recent studies reported that long non-coding RNA (lncRNA) might play critical roles in regulating chemo-resistant of multiple types of cancer. In this study, our results indicate that the LncRNA-EPIC1 expression were significantly increased in cholangiocarcinoma tissues, compared to adjacent normal tissues. And also, its expression also increased in several CCA cancer cell lines than that in human normal immortalized cholangiocyte cell. Loss-and-gain of Lnc-EPIC1 contributes to the CCA cell growth, colony formation, cell apoptosis and also cell cycle. Myc has been reported to directly interact with Lnc-EPIC1 in several cancer cells. Myc targets, including Cyclin A/D and CDK9 were downregulated by Lnc-EPIC1 siRNA. Myc knockout also suppresses the CCA cell growth, colony formation and cell apoptosis. However, Lnc-EPIC1 knockdown failed to enhance the Myc-KO-induced suppression of CCA tumor progression. RNA immunoprecipitation (RIP) results showed the direct interaction between Lnc-EPIC1 and Myc. Taken together, our results show that Lnc-EPIC1 promotes CCA cancer progression by targeting Myc.
Transhepatic Tract Embolisation After Biliary Intervention Using n-Butyl Cyanoacrylate and Autologous Blood: A Retrospective Analysis of 42 Patients
Purpose: We evaluated the safety and efficacy of transhepatic tract embolisation after a biliary intervention using n-butyl cyanoacrylate (NBCA) and autologous blood. Materials and Methods: Between January 2017 and December 2018, 42 consecutive patients (mean age: 71 ± 15 years, 24 men) with malignant (n = 26) or benign (n = 16) biliary obstructions underwent percutaneous biliary intervention followed by tract embolisation within 2 weeks. Forty-six transhepatic tracts (4 bilateral) in 42 patients were embolised using a NBCA and lipiodol mixtures (1:1–1:2 ratios) after intraductal infusion of peripherally obtained autologous blood. The indwelling catheter diameters were 8.5–14 Fr. The median interval between percutaneous biliary drainage and tract embolisation was 10 days (range 3–14 days). Glue-cast formation via fluoroscopy and immediate complications were reviewed retrospectively in medical records. Follow-up data (median: 135, range 11–720 days) including computed tomography (CT) images (n = 17) were evaluated for delayed complications and glue-cast formation. Results: Successful glue-cast formations were achieved in all 46 tracts. No patients experienced haemorrhage, and only one patient had external bile leakage. Eight patients complained of abdominal pain (numerical scale ≤ 5) immediately after embolisation, which was controlled by analgesics. Two patients had transient fever. Segmental (n = 11) or sub-segmental (n = 6) glue-cast patterns were identified along the transhepatic tract by follow-up CT. No biliary obstructions were caused by inadvertent glue spread. Fragmented glue was detected outside the stent in one patient. Conclusion: Transhepatic parenchymal tract embolisation with NBCA and autologous blood is a safe and feasible method for preventing bile leakage. Level of Evidence: Level 4, Case Series.
Pathology effects at radiation doses below those causing increased mortality
Mortality data from experiments conducted at the Argonne National Laboratory (ANL) on the long-term effects of external whole-body irradiation on B6CF(1) mice were used to investigate radiation-induced effects at intermediate doses of (60)Co gamma rays or fission-spectrum neutrons either delivered as a single exposure or protracted over 60 once-weekly exposures. Kaplan-Meier analyses were used to identify the lowest dose in the ANL data (within radiation quality, pattern of exposure, and sex) at which radiation-induced mortality caused by primary tumors could be detected (approximately 1-2 Gy for gamma rays and 10-15 cGy for neutrons). Doses at and below these levels were then examined for radiation-induced shifts in the spectrum of pathology detected at death. To do this, specific pathology events were pooled into larger assemblages based on whether they were cancer, cardiovascular disease or non-neoplastic diseases detected within the lungs and pleura, liver and biliary tract, reproductive organs, or urinary tract. Cancer and cardiovascular disease were further subdivided into categories based on whether they caused death, contributed to death, or were simply observed at death. Counts of how often events falling within each of these combined pathology categories occurred within a mouse were then used as predictor variables in logistic regression to determine whether irradiated mice could be distinguished from control mice. Increased pathology burdens were detected in irradiated mice at doses lower than those causing detectable shifts in mortality-22 cGy for gamma rays and 2 cGy for neutrons. These findings suggest that (1) models based on mortality data alone may underestimate radiation effects, (2) radiation may have adverse health consequences (i.e. elevated health risks) even when mortality risks are not detected, and (3) radiation-induced pathologies other than cancer do occur, and they involve multiple organ systems.
Functional disorders of the stomach
Gastroenterologists frequently encounter patients who report vague epigastric discomforts or sensations of fullness, bloating, and distention in the upper abdomen. The discomfort is neither burning in character nor severe in intensity; there is no nocturnal pain. The epigastric location of discomfort and lack of radiation may help to exclude biliary tract and pancreatic diseases. Nausea may be present, but there is little or no vomiting. After these patients ingest liquids or solid foods, the symptoms of easy filling or early satiety and increasing discomfort and nausea are almost always present. The patient may only report "indigestion," but a specific chief complaint, such as pain, discomfort, nausea, or bloating may be elicited with further inquiries. Solid foods usually provoke more symptoms than do liquids. Symptoms of early satiety, nausea, bloating, and abdominal discomfort may culminate in the vomiting of undigested food. These vague upper gastrointestinal (GI) symptoms have been termed "dyspepsia." When peptic diseases of the stomach are excluded, the symptom complex has been called "nonulcer" dyspepsia, a vague syndrome with symptoms attributed to stomach dysfunction. Nonulcer dyspepsia has been reviewed recently. Such symptoms, commonly attributed to a "functional" disorder, are very common in clinical practice, with an incidence of 30% of patients. In this review, we will discuss an approach to the evaluation and treatment of patients with symptoms of nausea, early satiety, bloating, and vague epigastric discomfort--dyspeptic symptoms associated with functional stomach disorders. We will review the anatomy and motility of the stomach and suggest potential neuromuscular malfunctions of the stomach that may result in epigastric symptoms. The potential role of stress and other brain-gut interactions, which may underlie these symptoms, will also be reviewed.
Hepatic Tract Plug-Embolisation After Biliary Stenting. Is It Worthwhile?
PurposePTC and stenting procedures are associated with significant risks including life-threatening haemorrhage, sepsis, renal failure and high mortality rates. PTC tract closure methods are utilised to reduce haemorrhagic complications despite little evidence to support their use. The current study assesses the incidence of haemorrhagic complications following PTC and stenting procedures, both prior to and following the introduction of a dedicated expanding gelatin foam-targeted embolisation liver tract closure technique.Materials and MethodsHaemorrhagic complications were retrospectively identified in patients undergoing PTC procedures both prior to (subgroup 1) and following (subgroup 2) the introduction of a dedicated targeted liver tract closure method between 9/11/2010 and 10/08/2012 in a single tertiary referral centre. Mean blood Hb decrease following PTC was established in subgroups 1 and 2. Kaplan–Meier life-table analysis was performed to compare survival outcomes between subgroups using the log-rank test.ResultsHaemorrhagic complications were significantly reduced following the introduction of the targeted PTC tract closure method [(12 vs. 3 % of subgroups 1 (n = 101) and 2 (n = 92), respectively (p = 0.027)]. Mean blood Hb decrease following PTC was 1.40 versus 0.68 g/dL in subgroups 1 and 2, respectively (p = 0.069). 30-day mortality was 14 and 12 % in subgroups 1 and 2, respectively. 50 % of the entire cohort had died by 174 days post-PTC.ConclusionIntroduction of liver tract embolisation significantly reduced haemorrhagic complications in our patient cohort. Utilisation of this method has the potential to reduce the morbidity and mortality burden associated with post-PTC haemorrhage by preventing bleeding from the liver access tract.
Long-Term Efficacy of Percutaneous Internal Plastic Stent Placement for Non-anastomotic Biliary Stenosis After Liver Transplantation
PurposeWe aimed to evaluate the long-term efficacy of percutaneous management of non-anastomotic biliary stenosis after liver transplantation, using plastic internal biliary stents.Materials and MethodsThis study included 35 cases (28 men, 7 women; mean age: 52.09 ± 8.13 years, range 34–68) in 33 patients who needed repeated interventional procedures because of biliary strictures. After classification of the biliary strictures, we inserted percutaneous biliary plastic stents through the T-tube or percutaneous transhepatic biliary drainage tracts. Stents were exchanged according to percutaneous methods at regular 2- to 6-month intervals. The stents were removed if the condition improved, as observed on cholangiogram as well as based on clinical findings. The median patient follow-up period after initial diagnosis and treatment was 6.04 years (range 0.29–9.95 years). We assessed treatment success rate and patient and graft survival times.ResultsDuring the follow-up period, 14 patients (14/33, 42.42 %) were successfully treated and were tube-free. The median tube-free time, time without a stent, was 4.13 years (range 1.00–9.01). In contrast, internal plastic stents remained in 9 patients (9/33, 27.27 %) until the last follow-up. These patients had acceptable hepatic function. Among the remaining 10 patients, 3 (3/33, 9.09 %) were lost to regular follow-up and the other 7 (7/33, 21.21 %) patients died. The overall graft loss rate was 20.0 % (7/35). The median time from initial treatment to graft loss was 1.84 years (range 0.42–4.25).ConclusionsPercutaneous plastic stents placement is technically feasible and clinically useful in patients with multiple biliary stenoses following liver transplantation.
Toxicokinetics and toxicity of atorvastatin in dogs
HMG-CoA reductase inhibitors (e.g., statins) are an important clinical option to lower cholesterol and treat co-morbidities. Atorvastatin is the most prescribed statin and has obtained generic status. We recently had a clinical development program evaluating a combination of atorvastatin with a GPR119 agonist as a treatment for dyslipidemia, where toxicological evaluations in dogs were completed. There were several challenges related to selecting doses for atorvastatin, including understanding the dose–exposure relationship from different drug forms used by the innovator in their general toxicology studies, bioanalytical assays that did not separate and quantify parent from metabolites, and high variability in the systemic exposures following oral dosing. The studies in this report characterized the toxicokinetics and toxicity of atorvastatin in the dog for up to 13-weeks. Overall, there were no notable differences in the toxicokinetics of atorvastatin or the two active hydroxylated metabolites between the sexes at Week 13. However, systemic exposures were markedly lower at Week 13 compared to that observed at Week 4, suggesting induction of metabolism or reduced absorption from the gastrointestinal tract following oral dosing. Changes in laboratory chemistries included increased liver enzyme levels and lower cholesterol levels. Histopathologic evaluation revealed multifocal minimal to slight hemorrhages in the submucosa of the gallbladder; all findings were reversible. The information from these studies along with the existing clinical experience with atorvastatin can be used to design robust toxicology studies in dogs and reduce animal use. - Highlights: • Atorvastatin is given to reduce cholesterol and is available as a generic drug. • Co-dosing of multiple products to treat hypercholesterolemia is increasing. • This work characterized the toxicokinetics and toxicity of atorvastatin in dogs. • The toxicokinetics of two hydroxylated metabolites were determined. • Recommendations on the dose–exposure relationship in dog are provided.
Magnetic resonance cholangiopancreatography using optimized integrated combination with parallel imaging and compressed sensing technique
Purpose: To assess the combined parallel imaging (PI) and optimized integrated compressed sensing technique (prototype Compressed SENSE) for magnetic resonance cholangiopancreatography (MRCP) compared with conventional MRCP. Methods: This prospective study was approved by our Institutional Review Board, and all patients provided written informed consent. A total of 56 consecutive patients (27 men and 29 women; mean age 67.2 years) underwent breath-hold three-dimensional (3D) MRCP with PI alone (BH-MRCP; acquisition time, 23 s), respiratory-triggered 3D MRCP with PI alone (RT-MRCP; 201 s) and respiratory-triggered 3D MRCP with Compressed SENSE (RT-MRCPcs; 45 s). Relative duct-to-periductal contrast ratios (RCs) of the pancreaticobiliary ducts were calculated for quantitative image analyses. Two radiologists graded the visibility of the pancreaticobiliary ducts, pancreatic cystic lesion, motion artifact, and overall image quality using a five-point rating scale for qualitative image analyses. Theses qualitative and quantitative measurements were then compared among the three sequences. Results: RCs of the common bile duct, right hepatic duct (RHD), left hepatic duct (LHD), and main pancreatic duct at the pancreatic head, body, and tail segments, were significantly higher RT-MRCP, followed by RT-MRCPcs and BH-MRCP (P < 0.001). The visibility of the peripheral RHD and LHD was slightly better in RT-MRCP than in RT-MRCPcs and BH-MRCP (P < 0.001). The visibility of other pancreaticobiliary ducts, pancreatic cystic lesion, motion artifact, and overall image quality were almost comparable among three sequences. Conclusion: The acquisition time was markedly reduced in RT-MRCPcs compared with conventional RT-MRCP while there were significant differences in both quantitative and qualitative analyses, the differences were small enough that the reduced acquisition time makes up for it.