Gallbladder Obstruction Research Articles

The Role of the Gallbladder, the Intestinal Barrier and the Gut Microbiota in the Development of Food Allergies and Other Disorders.

The microbiota present in the gastrointestinal tract is involved in the development or prevention of food allergies and autoimmune disorders; these bacteria can enter the gallbladder and, depending on the species involved, can either be benign or cause significant diseases. Occlusion of the gallbladder, usually due to the presence of calculi blocking the bile duct, facilitates microbial infection and inflammation, which can be serious enough to require life-saving surgery. In addition, the biliary salts are secreted into the intestine and can affect the gut microbiota. The interaction between the gut microbiota, pathogenic organisms, and the human immune system can create intestinal dysbiosis, generating a variety of syndromes including the development of food allergies and autoimmune disorders. The intestinal microbiota can aggravate certain food allergies, which become severe when the integrity of the intestinal barrier is affected, allowing bacteria, or their metabolites, to cross the intestinal barrier and invade the bloodstream, affecting distal body organs. This article deals with health conditions and severe diseases that are either influenced by the gut flora or caused by gallbladder obstruction and inflammation, as well as putative treatments for those illnesses.

Clinical Outcomes after MRI Guided Stereotactic Body Radiotherapy for (Peri-) Pancreatic Tumors

<h3>Purpose/Objective(s)</h3> Radiotherapy treatment of pancreatic cancer can be challenging due to close relationship between the tumor and radiosensitive intestines and poor visibility of the upper abdomen with conventional treatment methods. In recent years, with the introduction of MR-guided radiotherapy (MRgRT) it became possible to deliver ablative doses to (peri-)pancreatic tumors. In this multicenter cohort study, we report clinical outcomes from our first cohort of patients with (peri-)pancreatic tumors with MR-guided stereotactic radiotherapy on a 1.5 T MR-Linac. <h3>Materials/Methods</h3> All patients with (peri-)pancreatic tumors treated on the 1.5 T Unity MR-Linac between April 2019 and January 2022 at two institutes. Symptoms were reported using clinician-reported outcome measurements defined by the Common Terminology Criteria for Adverse Events (CTCAE) version 5. Quality of life (QoL) was assessed with the EORTC QLQ-C30 questionnaire and evaluated with the Global Health status. Symptoms and QoL were assessed at baseline, and at three, six and twelve months after treatment. The Kaplan-Meier analysis was performed for the 6 months-, and 1-year survival. <h3>Results</h3> The baseline characteristics of 79 patients are summarized in Table 1. The most frequently delivered SBRT scheme was 40 Gy in 5 fractions of 8 Gy. Most frequently reported grade 3 symptoms at baseline, three months follow-up, six months, and twelve months were abdominal pain (0%, 13%, 3%, and 5%); anorexia (0%, 9%, 0%, and 0%); fatigue (0%, 5%, 6%, and 5%); nausea (0%, 5%, 0%, and 5%), and diarrhea (0%, 5%, 6%, and 5%). Other grade 3 toxicity at three months follow up occurred in 5% for malabsorption; 2% of patients for vomiting; 2% for gastroparesis; 2% for weight loss; 2% for portal hypertension and 2% for gallbladder obstruction. No treatment-related toxicities higher than grade 3 were observed in our cohort. The EORTC Global Health status was 71 at baseline (n=37), 70 after three months follow up (n=20), 65 after six months (n=12), and 67 after twelve months (n=6). From the treatment start with MRgRT, the cumulative 6 months- and 1-year survival was 88%, and 74%, respectively. <h3>Conclusion</h3> In this international prospective cohort of patients with (peri-)pancreatic tumors, we observed a low incidence of major treatment-related toxicity and a stable Global Health status at three months post MRgRT on a 1.5T MR-Linac.

Establishing the Gastroduodenal Maximum Tolerated Dose for Ablative 5-Fraction Stereotactic MR-guided Online Adaptive Radiation Therapy (SMART) in a Novel Swine Model

Daily variations in abdominal anatomy introduce significant uncertainty in estimating the maximum tolerated dose (MTD). We investigated the gastroduodenal toxicity using stereotactic MR-guided online adaptive radiotherapy (SMART) to precisely control the dose to a novel swine model that closely matches human physiology and can be maintained at 80 kg. We hypothesized for a cumulative SMART course of 50 Gy in 5 fractions to the pancreas, the duodenum MTD is significantly > 37 Gy to 0.5 cc (D0.5cc).A total of 18 WMSTM were included at 3 duodenal dose levels: 37 Gy (n = 12), 43.5 Gy (n = 3), and 50 Gy (n = 3) in 5 fractions. We defined MTD as: > 10% (≥2 of 12) WMSTM present with dose limiting toxicity (DLT). A DLT was defined as ≥ Grade 3 non-hematologic toxicity due to RT per NCI CTCAE v4.0. All WMSTM underwent SMART on a clinical MR-guided radiotherapy (MRgRT) LINAC, under ventilation at breath hold (BH). Plans were IMRT and prescribed 50 Gy/5 fractions to pancreatic head, while maintaining uniform dose level (37, 43.5, 50 Gy) to duodenal circumference at 3 cm inferior to pylorus sphincter, typical uniform irradiated range 3-9 cc based on duodenal diameter. Circumference approach was used to eliminate underestimation of cumulative D0.5cc. Duodenal hotspot was 1.03% of the dose level (37, 43.5, 50 Gy) to 2 cc, 1.05% to 0.1 cc. Gated BH delivery was performed with sagittal plane tracking of the duodenum at 4 frames per second. Toxicity monitoring occurred for 30 days post-RT. Fecal occult blood test (FOBT) was done during RT and toxicity monitoring. Endoscopy occurred 14 days post-RT. Gross pathology was obtained at time of necropsy, 30 days post-RT.For the 37 Gy level, 1 of 12 WMSTM presented with DLT-pinpoint ulcer with surface damage on gross pathology (30 days post-RT). No DLT for 2 of 3 WMSTM at the 43.5 Gy level. One WMSTM at the 43.5 Gy level perforated on endoscopy, potentially due duodenal wall degradation and unknown RT-induced DLT on gross exam of emergency necropsy. Endoscopy was eliminated for the 50 Gy level. DLT was found for 2 of 3 WMSTM at the 50 Gy level upon gross pathology at necropsy, with each subject having 2-3 visible ulcerations at level of RT. One WMSTM at the 50 Gy level had duodenal pre-ulcer erosion at necropsy. All three WMSTM at 50 Gy level had visibly damaged papilla at necropsy. Another WMSTM at the 50 Gy level had common bile duct blockage, gall bladder obstruction, and jaundice at necropsy. FOBT were negative for all 18 WMSTM at 14 days post-RT.A duodenum D0.5cc of 37 Gy in 5 fractions was found to be safe in a swine model for a 50 Gy SMART course to the pancreas, showing the duodenal MTD is > 37 Gy - an increase from the RTOG 1112 limit (i.e., 30 Gy). Our results translate to a recommended MTD in human subjects and can potentially allow for greater tumor dose escalation and survival outcomes in future pancreatic patients. We are currently pursuing an expansion cohort to evaluate the MTD at 43.5 Gy.

Phase I INSIGHT platform trial: Advanced safety and efficacy data from stratum D evaluating feasibility and safety of eftilagimod alpha (soluble LAG-3 protein) combined with avelumab in advanced solid tumors.

2518 Background: Stratum D of the INSIGHT platform trial evaluates s.c. eftilagimod alpha (efti, IMP321) combined with avelumab in advanced solid tumors. Efti is an MHC class II agonist which activates antigen-presenting cells followed by CD8 T-cell activation. Combination with PD-1/PD-L1 blockade aims at enhanced efficacy. Methods: This IIT platform trial consists of 5 strata: intratumoral (A) or intraperitoneal efti (B); s.c. efti with SOC (C) or with PD-L1 inhibition (D). Strat E is currently under development and starts soon with a new efti combination. This abstract focuses on preliminary data of Strat D. Patients (pts) received 800mg avelumab i.v. q2w along with s.c. efti: 6mg in cohort 1 (coh 1, 6 pts), 30mg in cohort 2 (coh 2, 6 pts). Primary endpoint: safety. Results: Recruitment has been completed with 12 pts (coh 1: gastric, gallbladder, colon cancer, pleural mesothelioma; coh 2: gastric, gastroesophageal, anal, rectum, cervix uteri). No dose limiting toxicities (DLTs) occurred. 10 serious adverse events (SAEs) were reported, none of them considered causally related (4 in 3 pts of coh 1 [1 acute renal insufficiency grade 5 in 1 pt, 2 preileus grade 3 in 1 pt, hearing impaired grade 4 in 1 pt] and 6 in 4 pts of coh 2 [1 anal hemorrhage and 1 gallbladder obstruction in 1 pt, 1 eye pain and 1 surgery to replace the feeding tube in 1 pt, each grade 3, 1 skin infection grade 2, 1 diffuse myocardial fibrosis grade 5]. 1 AE of special interest (AESI) possibly related with avelumab (sarcoidosis grade 1) occurred in coh 1. 2 pts completed max treatment duration with 24 cycles. In coh 1, 47 adverse events (AEs; grade 1-2, 29; grade 3, 14; grade 4, 3; grade 5, 1) occurred in 5 pts. Most common grade 1-2 AEs were nausea, pain in 33%, 33% of the pts. Most common grade 3 AEs were ileus, vomiting in 33%, 33% of the pts. 2 AEs grade 4 (hearing impaired, sepsis) and 1 AE grade 5 (acute renal insufficiency) were reported. All AEs grade 3-5 were considered causally unrelated. In coh 2, 51 adverse events (AEs; grade 1-2, 29; grade 3, 19; grade 4, 2; grade 5, 1) occurred in 5 pts. The most common grade 1-2 AE was hypothyroidism in 33% of the pts. 1 AE grade 5 (diffuse myocardial fibrosis) was reported. Only 1 AE grade 3-5 was considered causally related (urinary tract infection grade 3 related with avelumab). 5 pts showed partial response as best response (2 coh 1: colon, pleural mesothelioma; 3 coh 2: gastric, anal, cervical), 1 stable disease with clinical progression (coh 2) (all but one of these pts still alive), 5 disease progressions acc. to RECIST 1.1 (3 coh 1, 2 coh 2), 1 clinical progression (coh 1). Signals of activity were also observed in pre-treated MSS/PD-L1low pts. Conclusions: Combined treatment with avelumab 800mg and efti 6mg (coh 1) or 30 mg efti (coh 2) seems feasible and safe. No unexpected AEs occurred. Signals of efficacy with CPI combination were seen (DCR 50%). Clinical trial information: NCT03252938.

Abstract PS12-06: Phase II randomized trial of fulvestrant with or without enzalutamide in ER+/Her2- primary breast cancer (BC)

Abstract Background: Almost all ER+ breast cancers express androgen receptor (AR), but its function is uncertain. AR expression is associated with more indolent tumors, however high AR expression relative to ER is associated with endocrine resistance, and in the absence of estradiol or if ER function is blocked, preclinical data would suggest that AR can take over to signal cell survival and proliferation. This non-blinded randomized phase II trial of neoadjuvant fulvestrant with or without enzalutamide was performed in women with T2 or greater ER+/Her2- primary breast cancer. Methods: Eligible patients were women with ECOG 0-2, ER+/Her2- primary breast cancer cT2 or greater. A total of 4 months of therapy was given (fulvestrant 500 mg IM weeks 1, 3, 5, 9, and 13). Patients were randomized to receive enzalutamide 160 mg po daily on a continual basis for 16 weeks. Stratification factors were clinical node status (N0 vs N1/2) and T-stage (T2 vs T3/4). Surgery was planned for week 17. Fresh tumor biopsies were required at study entry and at ~4 weeks on therapy. Tissue, both fresh frozen and FFPE, was also obtained at time of surgery. The PEPI score at time of surgery was the primary endpoint for efficacy. The statistical design were parallel phase II trials with the experimental arm designed as a Simon 2-stage. The expectation for the control arm was a PEPI score of 0 in 16% and 32% for the combination arm. Additional enrollment of 12 patients would ensue if 4 or more achieved a PEPI score of 0 within the first 22 patients enrolled onto the combination arm. 27 patients would be enrolled into the fulvestrant alone arm. Results: The Simon 2-stage criteria were met and the trial continues to accrue up to 11 more evaluable patients. Thus far, 58 patients were consented of whom 50 were treated. Median age was 61.5 years (45-83); PS 0 (0-2). Among the 46 patients with information on AEs, there are 25 patients with Grade 2 AEs, including 5 with fatigue, 3 with headache, and 2 with hot flashes. There are 5 patients with grade 3 AEs including abdominal pain, gallbladder obstruction, ALT elevation, hyperglycemia, and hypertension. We also have 2 patients with grade 4 AEs , chest pain-cardiac and cardiac disorder-other. There is no grade 5 event. Paired samples at baseline and at 4 weeks are collected so far from 49 patients. 42 patients have completed surgery, while two patients have not undergone surgery. Conclusions: The combination of fulvestrant plus enzalutamide had manageable side effects. The trial is now in its extended stage since PEPI score = 0 was achieved in at least 4 of the first 22 patients on the combination arm. Extensive molecular studies of paired fresh biopsies from pretreatment and at 4 weeks are underway. These analyses and correlations with clinical outcome will be described. Citation Format: Anthony D Elias, Monica Fournier, Gregory A Vidal, Sharon Sams, Nicole Spoelsta, Peter Kabos, Jennifer R Diamond, Elena Shagisultanova, Anosheh Afghahi, Jose Mayordomo, Julia Wulfkuhle, Emanuel Petricoin, Lisa Carter, Kathryn Zolman, Stephanie Armstead, Alyse Winchester, Tessa McSpadden, Gloria Crawford, Virginia Borges, Dexiang Gao, Jennifer Richer. Phase II randomized trial of fulvestrant with or without enzalutamide in ER+/Her2- primary breast cancer (BC) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS12-06.

Pattern of gall stone (GS) size & number in 1263 otherwise normal Sudanese subjects & their impact in the development of gall bladder disease & complications at the National Centre of Gastroentrology & Hepatology in Sudan during the last 10 years

1263 cases of GS, examined by ultrasound to decide size & number of stones. Size of stones was categorized into sand, tiny(1-4 mm), small(4-1.0 cm), medium(11-20 mm), big(21-30 mm), large(>30 mm), mixed stones(variable sizes). Number of stones categorized into; single, 2 stones, 3 stones, few( 20) & packed(no GB free space). Females scored (74.4%) GS cases. Prevalence of GS significantly increased above the age of 30years. Single stone was the predominant stone (21.2%) followed by multiple (19.6%), least was packed stones(3.1%), number didn't increase significantly with age while size significantly increased with age. Commonest stone size in both sexes was small stone in (32.1%) of cases. Predominance of fine, big & variable GS in females in 81.6%, 85% & 83.7% in total cases respectively. GS with normal gall bladder constituted (55.3%), Acute cholycystitis, had the highest prevalence of (28%) among gall bladder disease, chronic cholycystitis (16.7%). Gall bladder disease had no correlation with stone size & number. Risk of Gall bladder obstruction was significantly increased with single gall stone. Total complications of pericholycystic fluid, empyema, perforation, gangrene, emphysema, pancreatitis, Mirrizi, fistula & mucocoele occured in (9.8%) of cases. The predominant complication was pancreatitis (36.3%) of total complications one third of which had additional pseudopancreatic cyst. Pancreatitis was exclusively related to stone size Conclusion: No correlation of GS size & number to sex, single gall stone was the most prevalent stone number & carried a higher risk of gall bladder obstruction & higher incidence of acute cholycystitis. Acute cholycystitis was the commonest gall bladder disease. Pancreatitis was the most prevalent complication related to Stones

Hepatic Portocholecystostomy

Approximately 20% of cases of biliary atresia do not involve the gallbladder, the cystic duct, and the common bile duct. In these cases, a hepatoportocholecystostomy (HPC) may be performed instead of the classical hepatoportoenterostomy (HPE). We reviewed our cohort to investigate the efficacy of HPC and the associated surgical complications and clinical problems. From 1984 to 2009, 97 patients underwent HPC in our institution. In the first 6 months of the postoperative period no patient presented with bacterial cholangitis. Nine patients had bile leakage, and 1 patient had a gallbladder obstruction. For these 10 patients, HPC was modified in HPE. Jaundice clearance was maintained after HPE, but 4 of the patients presented 1 or more cholangitis episodes. After 6 months, there were no cases of cholangitis recorded, 2 patients presented bile leakage and 4 patients experienced gallbladder obstruction. After 5 years of follow-up, 46% of the patients were jaundice free with their native liver and 29.4% were transplanted. In patients with biliary atresia with patent extrahepatic bile ducts, hepatoportocholecystomy is a good surgical technique that can prevent cholangitis. These results are counterbalanced by specific surgical complications that need to be known and looked for in the postoperative period.

Intraoperative cholangiography during cholecystectomy among hospitalized medicare beneficiaries with non-neoplastic biliary disease

BackgroundPrior studies of Medicare beneficiaries with both neoplastic and non-neoplastic indications for cholecystectomy demonstrated a reduced risk of common bile duct (CBD) injury when intraoperative cholangiography (IOC) was used. We sought to determine the association between IOC and CBD injury during inpatient cholecystectomy for non-neoplastic biliary disease and compare survival among those with or without CBD injury. MethodsRetrospective study of patients ≥66 who underwent inpatient cholecystectomy (2005–2010) for gallstones, cholecystitis, cholangitis, or gallbladder obstruction. The association between IOC and CBD injury was analyzed using multivariable logistic regression and survival after cholecystectomy was analyzed using multivariable Cox regression. ResultsAmong 472,367 patients who underwent cholecystectomy, 0.3% had a CBD injury. IOC was associated with increased CBD injury (adjusted OR 1.41[1.27–1.57]). CBD injury was associated with increased hazards of death (adjusted HR 1.37[1.25–1.51]). ConclusionsIOC in patients with non-neoplastic biliary disease was associated with increased odds of CBD injury. This likely reflects its selective use in patients at higher risk of CBD injury or as a confirmatory test when an injury is suspected.

Percutaneous Placement of Permanent Metallic Stents in the Cystic Duct to Treat Obstructive Cholecystitis

This report presents a series of five patients unsuitable for surgery who had nonretrievable self-expanding metallic stents deployed along the cystic duct as treatment for benign and malignant causes of gallbladder obstruction. Techniques are described for draining cholecystitis, removing gallstones, bypassing gallbladder obstructions, and inserting metallic stents across the cystic duct to restore permanent antegrade gallbladder drainage in acute and chronic cholecystitis. Symptoms resolved in all cases, and stents remained patent for as long as 22 months. This procedure may be an effective alternative to cholecystectomy or long-term gallbladder drainage for patients in inoperable condition.

Ultrasonography and magnetic resonance cholangiopancreatography correlation in patients with obstructive jaundice

Background: Obstructive jaundice is a condition caused by blockage of the flow of bile out of the liver. This results in an overflow of bile and its by-products into the blood and bile excretion from the body is incomplete. Ultrasound (USG) is used to evaluate patients for biliary stones and cholecystitis. It can detect cystic duct and neck of the gallbladder obstruction as well as distension and inflammation of the gallbladder. It can identify carcinoma of the gallbladder, which is highly malignant and metastasize quickly. Magnetic resonance cholangiopancreatography (MRCP) is a relatively new noninvasive diagnostic technique for direct visualization of the biliary ducts through images similar to those produced in endoscopic retrograde cholangiopancreatography and percutaneous transhepatic cholangiography. Objective: To highlight the role of ultrasonography and MRCP as preliminary investigation in patients with obstructive jaundice. Materials and Methods: Thirty patients with complaints of jaundice and clinico-pathological appearance of obstructive jaundice were included in the study. The patients had undergone sonography of abdomen in radiology department and then MRCP study was conducted. Data of patients matching inclusion criteria were recorded after getting informed consent. Result: Of 30 patients, 17 (56.66%) were females and 13 (43.33%) were males. Most common age group of patients was 51–60 years (23.3%) followed by 61–70 years (16.6%). Jaundice was the most frequent symptom (96%) followed by abdominal pain (86.66%). Common bile duct (CBD) was most commonly involved in 50% of cases followed by confluence of right and left hepatic duct and pancreas in 13.33%. Most common obstructive lesions in this study were congenital anomalies of CBD (choledochal cyst) in 30% cases followed by stone in CBD +/- CHD with or without stricture in 19.99% cases. In this study, of 30 cases, 16 (53.33%) were benign lesions and 14 (46.66%) were malignant. Among benign lesions, choledochal cyst was the most common (9/16; 56.25%), especially more among females. However, among malignant lesions, hilar cholangiocarcinoma was most common (5/14), especially among females. USG (30/30) was found to be equally good as MRCP (30/30) in detecting the presence and level of obstruction. In detecting the extent of obstruction, USG could not localize the distal extent of the lesion involving distal CBD (6/30) due to poor patient factors (obesity) and bowel gases. In assessing the cause of obstruction, MRCP (30/30) scored over USG. Conclusion: USG is a cost-effective, noninvasive, and nonionizing easily available preliminary investigation in the evaluation of obstructive jaundice but MRCP scores over USG for evaluation of small hepatic metastasis in the presence of pancreaticobiliary malignancies that may be missed with USG.

Pharmacokinetics of Valproic Acid in Guinea-pigs with Biliary Abnormality

To explore whether biliary cannulation, biliary obstruction or gall bladder obstruction could alter the disposition of valproic acid, guinea-pigs were subjected to common bile duct cannulation or ligation, gall bladder-neck ligation or sham surgery as a control. They were then given an intravenous (i.v.) dose of sodium valproate (50 mg kg-1) and the pharmacokinetics of valproic acid in each group were compared. In the cannulated group, significant decreases (P less than 0.05) in the area under the elimination curve (AUC), the volume of distribution at steady-state (Vdss) and the mean residence time (MRT) were observed. Significant increases (P less than 0.05) in the elimination rate constant (kz) and total clearance (CLtot) of valproic acid were noted. In the biliary obstructed guinea-pigs, the Vdss was significantly decreased (P less than 0.05). In the gall bladder obstructed guinea-pigs, there was a secondary peak of valproate plasma concentration, and the kz was significantly decreased. The biliary excretion of unchanged and conjugated valproic acid was 2.0 +/- 0.7 (s.e.m.) and 19.7 +/- 3.6 (s.e.m.)% of dose, respectively, and was almost completely reabsorbed in the enterohepatic recycling. Urinary excretion of unchanged and conjugated valproic acid, as well as non-conjugate metabolic clearance of valproic acid, were not significantly different among the four groups. The results suggest that the pharmacokinetics of valproic acid in guinea-pigs are particularly sensitive to interruption of the enterohepatic cycle. Biliary obstruction may elevate plasma concentrations owing to the decreased Vdss of valproic acid. Gall bladder obstruction may cause fluctuation of valproate plasma concentrations. The data indicate that the apparent total clearance of valproic acid is significantly less than the intrinsic clearance owing to enterohepatic recycling.

Surgical complications of Kawasaki disease

Four of 10 cases of Kawasaki disease (KD), mucocutaneous lymph node syndrome, seen from 1975 to 1980 had serious surgical complications. These included gallbladder obstruction, massive necrosis of gallbladder, liver, duodenum, jejunum, and necrosis of digits of both hands. Less serious necrosis of adrenals, testes, bladder, and stomach were seen. The operative mortality rate was 25%. The etiology is unknown. The average age was 2 yr. There was no sex preponderance. The essential lesion is an arteritis and periarteritis initially involving small arteries and later the medium and large vessels.

ARGYRISM FOLLOWING THE USE OF COLLARGOL

Since argyrism is a rare condition, a report of the following case, which came under my observation recently, may be of interest. We do not see the baneful effect of chronic silver poisoning, as did our forefathers, because we do not employ this metal internally so often as they did. There is nevertheless a danger to argyrism resulting from the prolonged use of the colloidal preparations of silver now in vogue, especially since the manufacturing houses advertise widely that these preparations are innocuous and vaunt their virtue to the skies. The patient was a young woman sent to me by her physician, with the request that she be operated on. In his letter he said that she had been suffering for years from gastrointestinal troubles, which he attributed to gall-bladder obstruction. The most noticeable thing about the patient was her complexion, which had a dark bluish hue, with bright glistening