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Gallbladder carcinoma is an uncommon malignancy with an overall 5-year survival of less than 5%. Gallbladder carcinoma has been strongly linked with cholelithiasis and chronic inflammation. Case reports and series have described cholecystitis with acute (neutrophilic) inflammation in association with gallbladder carcinoma, although a clear relationship to patient outcome has not been established. Our series included 8 cases of gallbladder carcinoma with high tumor-associated neutrophils (>25 per high power field) that were associated with shorter patient survival (Cox regression coefficient 6.2, p = 0.004) than age- and stage-matched controls. High tumor-associated neutrophils were not associated with gallbladder rupture/perforation or increased bacterial load measured by 16S PCR. Neutrophilic inflammation with gallbladder carcinoma correlates to shorter survival, independent of patient age and stage of carcinoma. The findings suggest that the degree of neutrophilic inflammation may have prognostic significance in specimens from patients with gallbladder carcinoma after cholecystectomy. Further studies with larger case numbers are needed to confirm and generalize these findings., (Copyright © 2021. Published by Elsevier Inc.)

Typhoid fever, caused primarily by Salmonella enterica serovar Typhi ( S Typhi), is a life-threatening systemic disease responsible for significant morbidity and mortality worldwide. Three to 5% of individuals infected with S Typhi become chronic carriers due to bacterial persistence in the gallbladder. We have demonstrated that Salmonella forms biofilms on gallstones to establish gallbladder carriage. However, an in-depth molecular understanding of chronic carriage in the gallbladder, from the perspective of both the pathogen and host, is poorly defined. To examine the dynamics of the gallbladder in response to Salmonella infection, we performed transcriptional profiling in the mouse gallbladder at early (7 days) and chronic (21 days) time points. Transcriptome sequencing (RNA-Seq) revealed a shift from a Th1 proinflammatory response at 7 days postinfection (dpi) toward an anti-inflammatory Th2 response by 21 dpi, characterized by increased levels of immunoglobulins and the Th2 master transcriptional regulator, GATA3. Additionally, bioinformatic analysis predicted the upstream regulation of characteristic Th2 markers, including interleukin-4 (IL-4) and Stat6. Immunohistochemistry and fluorescence-activated cell sorter (FACS) analysis confirmed a significant increase in lymphocytes, including T and B cells, at 21 dpi in mice with gallstones. Interestingly, the levels of Salmonella -specific CD4 T cells were 10-fold higher in the gallbladder of mice with gallstones at 21 dpi. We speculate that the biofilm state allows Salmonella to resist the initial onslaught of the Th1 inflammatory response, while yet undefined events influence a switch in the host immunity toward a more permissive type 2 response, enabling the establishment of chronic infection. IMPORTANCE The existence of chronic typhoid carriers has been in the public eye for over 100 years in part because of the publicity around Typhoid Mary. Additionally, it has been known for decades that the gallbladder is the main site of persistence and recently that gallstones play a key role. Despite this, very little is known about the physiological conditions that allow Salmonella enterica serovar Typhi to persist in the gallbladder. In this study, we analyze the transcriptional profile of the gallbladder in a mouse model of chronic carriage. We found a shift from an early proinflammatory immune response toward a later anti-inflammatory response, which could explain the stalemate that allows Salmonella persistence. Interestingly, we found a 10-fold increase in the number of Salmonella -specific T cells in mice with gallstones. This work moves us closer to understanding the mechanistic basis of chronic carriage, with a goal toward eradication of the disease., (Copyright © 2019 González et al.)

Background: Immune checkpoint inhibitors (ICIs) represent a promising novel class of cancer therapy, but immune-mediated adverse events can complicate ICI treatment. Acute cholecystitis in patients receiving ICI therapy has not been characterized. We aimed to describe the clinical features of patients who developed ICI-related cholecystitis., Methods: We evaluated a case series of patients at a tertiary cancer center who received ICI therapy and developed cholecystitis, diagnosed by clinical presentation and diagnostic imaging, during 2010-2018. Patients with a history of chronic cholecystitis or other etiologies of acute cholecystitis, such as cholelithiasis, were excluded. A chi-square test was used to compare the frequency of cholecystitis between ICI regimens. Kaplan-Meier and log rank analyses were used to compare survival between subgroups., Results: Of the 4253 patients who received ICIs in the study period, 25 (0.6%) patients developed suspected ICI-related cholecystitis. Alternatively, of the 31,426 cancer-matched patients who received non-ICI therapy, 72 (0.2%) developed acalculous cholecystitis (P < 0.001). Among the 25 included patients, the median time from ICI initiation to cholecystitis was 6 months (range, 0.1-31 months). Fifteen (60%) patients received an inhibitor of programmed death protein 1 (anti-PD-1) or of its ligand (anti-PD-L1) as a single agent, and 10 (40%) patients received an inhibitor of cytotoxic T-lymphocyte associated protein 4 (anti-CTLA-4) therapy alone or combined with anti-PD-1/L1. Anti-CTLA-4 monotherapy was associated with a higher risk of cholecystitis (P = 0.006). ICI therapy was discontinued in 20 patients, in three (12%) as a result of acute cholecystitis. Two (8%) patients developed sepsis, and four (16%) had perforation of the gallbladder wall. Five (20%) patients underwent surgical cholecystectomy, and eight (32%) underwent percutaneous drainage. Five (20%) patients were treated with steroids; two of them required surgery. Ten (40%) patients were able to restart ICI therapy. Patients who received a combination of anti-CTLA-4 and anti-PD-1/L1 had more complications of cholecystitis than did patients who received either agent alone (P = 0.03)., Conclusions: ICI treatment can result in a clinical condition similar to typical acute cholecystitis in a minority of patients. ICI-related cholecystitis should be managed in a similar fashion to typical cholecystitis. The efficacy of steroids for the treatment of ICI-related cholecystitis is unclear.

There is a well-established link between biliary tract cancers (BTC) and chronic inflammatory conditions such as primary sclerosing cholangitis, chronic cholecystitis, chronic cholelithiasis, liver fluke-associated infestations, and chronic viral hepatic infections. These associated risk factors highlight the potential for development of immune-modulatory agents in this poor-prognostic disease group with limited treatment options. Clinical trials have evaluated the role of immune cells, inflammatory biomarkers, vaccines, cytokines, adoptive cell therapy, and immune checkpoint inhibitors in patients with BTC. Although these have demonstrated the importance of the immune environment in BTC, currently none of the immune-based therapies have been approved for use in this disease group. The role of immunomodulatory agents is a developing field and has yet to find its way 'from bench to bedside' in BTC., (© 2018 S. Karger GmbH, Freiburg.)

A 47-year-old woman presented with a history of vague abdominal pain for several years, which worsened over the past 2 months, with pain more prominent in the right upper quadrant. She also had a history of peptic ulcer disease. The ultrasound scan of right upper quadrant revealed normal gallbladder and oesophagogastroduodenoscopy was unremarkable. A (99m)technetium labelled hepato iminodiacetic acid (HIDA) scan with cholecystokinin provocation demonstrated a decreased gallbladder ejection fraction (EF) of 32%. On this basis, the patient was diagnosed with biliary dyskinesia and underwent an elective laparoscopic cholecystectomy. Histopathological analysis revealed chronic cholecystitis with Cystoisospora belli identified in the gallbladder wall. Cystoisospora has been identified to cause an opportunistic acalculous cholecystitis among immunocompromised hosts, especially those with AIDS. This is the first case report of chronic cholecystitis due to C. belli in an immunocompetent patient., (2015 BMJ Publishing Group Ltd.)

Background: Cholecystitis is one of the major digestive diseases. Its prevalence is particularly high in some populations. Significant risk factors associated with cholecystitis include age, sex, obesity, diet, parity and type 2 diabetes., Objective: To determine the association between HLA-DRB1 and cholecystitis., Methods: This case-control study included forty Iraqi Arab patients who had cholecystitis with multiple calculi treated by cholecystectomy admitted in the surgical ward at Al-Kindy Teaching Hospital Baghdad between September -2013 to June -2014. The control group consisted of forty healthy volunteers among the staff of Al-Kindy College of Medicine. Control and cholecystitis patients groups were typed for identifying the DRB1* alleles using DNA-based methodology (PCR-SSOP)., Results: There was an increased frequency of HLA-DRB1*0301 in patients with cholecystitis compared with healthy controls (p=0.0442, odd ratio=4.1111, 95% CI: 1.0372-16.2949)., Conclusion: HLA-DRB1*0301, as a genetic factor, seems to have an association with cholecystitis.

Hyalinizing cholecystitis (HC) is a recently described rare subtype of chronic cholecystitis characterized by dense, paucicellular collagenous transmural fibrosis, which usually replaces the mucosa and muscularis propria. Immunoglobulin (Ig)G4-associated cholecystitis is also a newly described cholecystitis variant characterized by transmural or extramural lymphoplasmacytic inflammation, lymphoid follicles, storiform fibrosis, phlebitis, and increased tissue IgG4-positive plasma cells. We describe a case of cholecystitis in an elderly white man who harbored features of both HC and IgG4-associated cholecystitis. In retrospect, the patient also had a significantly elevated serum IgG4 level. To the best of our knowledge, an association between HC and IgG4-related disease has not been previously described in the literature. Although not entirely conclusive, our observations raise the possibility that some cases of HC represent the end stage of IgG4-related disease., (Copyright © 2015 Elsevier Inc. All rights reserved.)

An increased awareness of IgG4-related diseases has led to an escalation in the number of sites known to be involved by this fibroinflammatory disease. We report three cases of IgG4-related cholecystitis which were thought to represent biliary malignancies both clinically and radiographically. All three cases underwent surgery tailored towards presumed malignant neoplasms. Only following pathologic examination was the true nature of the disease identified. Recognition of the clinical, radiographic, and pathologic presentation of IgG4-related cholecystitis is essential for the consideration of this disease process prior to surgical management for suspected gallbladder malignancies. However, the pre-operative diagnosis remains challenging and extensive surgical intervention is often necessary given the distressing presentation of IgG4-related cholecystitis.

Recent studies have proposed nomenclatures of type 1 autoimmune pancreatitis (AIP) (IgG4-related pancreatitis), IgG4-related sclerosing cholangitis (IgG4-SC), IgG4-related cholecystitis, and IgG4-related hepatopathy as IgG4-related disease (IgG4-RD) in the hepato-bilio-pancreatic system. In IgG4-related hepatopathy, a novel concept of IgG4-related autoimmune hepatitis (AIH) with the same histopathological features as AIH has been proposed. Among organs involved in IgG4-RD, associations with pancreatic and biliary lesions are most frequently observed, supporting the novel concept of "biliary diseases with pancreatic counterparts." Targets of type 1 AIP and IgG4-SC may be periductal glands around the bile and pancreatic ducts. Based on genetic backgrounds, innate and acquired immunity, Th2-dominant immune status, regulatory T (Treg) or B cells, and complement activation via a classical pathway may be involved in the development of IgG4-RD. Although the role of IgG4 remains unclear in IgG4-RD, IgG4-production is upregulated by interleukin 10 from Treg cells and by B cell activating factor from monocytes/basophils with stimulation of toll-like receptors/nucleotide-binding oligomerization domain-like receptors. Based on these findings, we have proposed a hypothesis for the development of IgG4-RD in the hepato-bilio-pancreatic system. Further studies are necessary to clarify the pathogenic mechanism of IgG4-RD.

Application of ursodeoxycholic acid in a standard dosage for 3 months provided a positive effect in relation to the indexes of the immune system for patients with the cholesterosis of gall-bladder. It is shown that medicine assists renewal of T-cell immunity, renders positive influence on B-link and renewal of index of immunoregulation can be seen. Reliable increase of specific receptors to CD25, HLA-DR and high level of CD95 testifies about including of the scray reaction of organism under influence of ursodeoxycholic acid on the remaining high indexes of B-cell of immunity. At the initial indexes of lipid spectrum, corresponding to the norm, the efficiency of normalization of immunological changes is more considerable than at the higher level of general cholesterol of serum of blood.

IgG4-related sclerosing disease is an established disease entity with characteristic clinicopathological features. Recently, the association between IgG4-related sclerosing disease and the risk of malignancies has been suggested. IgG4-related autoimmune pancreatitis with pancreatic cancer has been reported. Further, a few cases of extraocular malignant lymphoma in patients with IgG4-related sclerosing disease have also been documented. Herein, we describe the first documented case of anaplastic large cell lymphoma (ALCL) following IgG4-related autoimmune pancreatitis and cholecystitis and diffuse large B-cell lymphoma (DLBCL). A 61-year-old Japanese male, with a past history of DLBCL, was detected with swelling of the pancreas and tumorous lesions in the gallbladder. Histopathological study of the resected gallbladder specimen revealed diffuse lymphoplasmacytic infiltration with fibrosclerosis in the entire gallbladder wall. Eosinophilic infiltration and obliterative phlebitis were also noted. Immunohistochemically, many IgG4-positive plasma cells had infiltrated into the lesion, and the ratio of IgG4/IgG-positive plasma cells was 71.6%. Accordingly, a diagnosis of IgG4-related cholecystitis was made. Seven months later, he presented with a painful tumor in his left parotid gland. Histopathological study demonstrated diffuse or cohesive sheet-like proliferation of large-sized lymphoid cells with rich slightly eosinophilic cytoplasm and irregular-shaped large nuclei. These lymphoid cells were positive for CD30, CD4, and cytotoxic markers, but negative for CD3 and ALK. Therefore, a diagnosis of ALK-negative ALCL was made. It has been suggested that the incidence of malignant lymphoma may be high in patients with IgG4-related sclerosing disease, therefore, intense medical follow-up is important in patients with this disorder.

Background and Aims: Gallbladder epithelial cells (GBEC) are exposed to high cholesterol concentrations in bile, and export cholesterol via an ATP-binding cassette (ABC) transporter-mediated pathway in vitro. These findings suggest that aberrant expression and/or function of ABC sterol transporters may be associated with cholesterol-related gallbladder diseases (CAGD). In this study, we investigated the relative levels of the sterol transporters ABCA1, ABCG5, and ABCG8 in human gallbladders in CAGD, and the relationship between ABCA1 and inflammation., Methods: Expression of ABCA1, ABCG5, and ABCG8 was evaluated in 31 gallbladders with CAGD and 6 normal gallbladders by western blotting and immunohistochemistry. RT-PCR was used to measure ABCA1 mRNA expression. To investigate the relationship between ABCA1 and inflammation, wWestern blots were performed on cultured dog GBEC treated with lipopolysaccharide (LPS) using an anti-ABCA1 antibody., Results: Immunohistochemistry showed ABCA1 to be localized predominantly to the basolateral membrane, while ABCG8 formed a diffuse intracellular pattern at the apical pole of human GBEC. ABCA1 and ABCG8 expression was more prominent in GBEC that were surrounded by cholesterol-laden macrophages. ABCA1 and ABCG8 expression was increased in gallbladders with CAGD. Western blots showed increased ABCA1, ABCG5, and ABCG8 expression in CAGD. ABCA1 mRNA levels were increased in all gallbladders with CAGD. LPS treatment of cultured dog GBEC enhanced ABCA1 expression., Conclusions: The sterol transporters ABCA1, ABCG5, and ABCG8 may play a role in the pathogenesis of human CAGD. Inflammation appears to be a key factor that increases ABCA1 expression and activity in the human gallbladder.

Background/aims: Chronic inflammation is a risk factor for gallbladder carcinoma. The molecular mechanisms linking inflammation and gallbladder carcinogenesis are incompletely understood. Toll-like receptors are involved in inflammatory response and play an important role in the innate immune system by initiating and directing immune response to pathogens. We tested the hypothesis that TLR4 participated in the development of gallbladder carcinoma through investigating the expression of TLR4 in chronic cholecystitis, gallbladder carcinoma and normal gallbladder., Methodology: The expression of TLR4 in 30 specimens of chronic calculous cholecystitis, 13 specimens of gallbladder adenocarcinoma and 10 specimens of normal gallbladder tissue was determined by immunohistochemistry, western blotting analysis and quantitative RT-PCR., Results: We showed that TLR4 was mostly localized to the glandular and luminal epithelium of gallbladder. TLR4 expression was lower in gallbladder carcinoma tissue than in chronic cholecystitis and normal gallbladder tissue, whereas the difference between chronic cholecystitis tissue and normal gallbladder tissue was not statistically significant., Conclusions: The expression of TLR4 may be closely associated with the course of gallbladder carcinoma.

Effectivity of detoxic preparation reamberin at complex treatment of the patients with acuting of chronic cholecystitis combined with chronic pancreatitis on background of HCV-infection was detected. It was set that before treatment took place increase "average molecules", lipid peroxidation products--malondialdehyde and dien conjugates and increase of circulatory immune complexes in serum. Including of reamberin provided to normalization clinical-biochemical indexes.

Purpose: Autoimmune pancreatitis (AIP) is the pancreatic manifestation of IgG4-associated systemic disease (ISD). Criteria for diagnosis of AIP include recognition of extra-pancreatic organ involvement. Because the diagnosis of AIP can be challenging, even for experts, it is important for clinicians to recognize other target organ damage in this disease. Typical gallbladder findings in AIP have been increasingly recognized. Because cholecystectomy is common in the community, the availability of previous tissue from the gallbladder can provide an important supportive clue in the diagnosis of AIP. The objective of this review is to examine the literature on common gallbladder pathology findings in AIP, and discuss their clinical utility., Results: Gallbladder involvement in AIP seems to be common. Transmural lymphoplasmacytic inflammatory infiltrates, extramural inflammatory nodules, the presence of tissue eosinophilia, phlebitis, and increased tissue IgG4 are all seen more frequently in the gallbladders of patients with AIP. These findings are not 100% specific, because some can be seen in primary sclerosing cholangitis and pancreatic adenocarcinoma., Conclusion: Cholecystectomy for the purpose of diagnosing AIP is not recommended. However, if gallbladder specimens from a previous cholecystectomy are available, an expert review of gallbladder slides with IgG4 immunostaining may help to provide additional criteria for diagnosis of autoimmune pancreatitis.

Purpose of Review: The spectrum of IgG4-related systemic disease (IgG4-RSD) continues to widen. At most of the sites involved by this condition, the clinical presentation can mimic neoplasm. Pathologic assessment of small biopsies can be critical to proper management. This review summarizes the histologic features of IgG4-RSD and the role of immunohistochemistry of IgG4 in the diagnosis., Recent Findings: The review period saw further expansion of the list of sites putatively involved by IgG4-RSD, with new, or more detailed, entries related to lung, lymph nodes, stomach, and thyroid. A tentative consensus was reached on the issue of subtypes of autoimmune pancreatitis. The role of immunohistochemistry for IgG4 as an adjunct to the diagnosis of IgG4-RSD was further clarified., Summary: Sclerosing lymphoplasmacytic inflammation at almost any site can represent a manifestation of IgG4-RSD. There are several histologic features that can suggest the diagnosis. Immunohistochemistry for IgG4 is a useful diagnostic test to further support the diagnosis.

Background: Gallbladder cancer (GBC) is the commonest gastrointestinal cancer in women of north India. Precursor epithelial lesions in GBC are known; however, the role of xanthogranulomatous (XG) inflammation in the pathogenesis of GBC is unknown., Aims: To analyze the role of precursor lesions in the pathogenesis of GBC we studied the immunohistochemical (IHC) expression of p53, carcino-embryonic antigen (CEA) and carbohydrate antigen 19.9 (CA-19.9) in GBC, chronic cholecystitis (CC), XG cholecystitis (XGC) and precursor lesions., Materials and Methods: The study included 51 GBC, 68 CC, 42 XGC and 10 normal gallbladders. All cases were evaluated for presence of precursor lesions and IHC was performed., Results: p53 immunoreactivity was found in 55% GBC, 32% of dysplasia with malignancy and in 14% of dysplasia with CC. Sixteen percent GBC had associated XG inflammation. Normal and metaplastic epithelium in CC and in XGC did not express p53. CEA expression was apical in normal and inflammatory GBs (CC, XGC), while cytoplasmic focal to diffuse positivity was seen in 82% GBC. CA-19.9 expression was seen in all cases of normal and inflammatory GBs; however, foci of antral metaplasia were negative. Seventy-five percent of GBC expressed CA-19.9; all negative cases were high-grade on histology., Conclusions: Altered CEA expression is seen in GBC as compared to normal and inflammatory gallbladders. Loss of expression of CA19.9 in antral metaplasia and poorly differentiated GBC may indicate that it is a marker of biliary differentiation. p53 over-expression seen in GBC and in dysplasia associated with malignancy and with CC suggests that p53 mutation and dysplasia are early events in the evolution of GBC. Epithelial metaplasia and XG inflammation are often associated with GBC but do not appear to play a role in its pathogenesis through the p53 pathway.

Aim: The purpose of this study was to investigate the expression of tumor-associated glycoprotein 72 (TAG-72) in primary gallbladder carcinoma (PGC) with an attempt to determine the potential usefulness of it in diagnostic and prognostic applications., Methods: Tissue samples from 118 patients with PGC, 30 patients with chronic cholecystitis, and 20 normal gallbladders were stained with anti-TAG-72 antibodies for immunohistochemical analysis. Then, the clinical outcome of the patients after a maximum follow-up of 5 years was determined in 110 out of 118 patients., Results: Clinicopathological characteristics of the carcinomas and clinical outcome of the patients were associated with the TAG-72 expression. TAG-72 was expressed more frequently in cancerous tissues of larger size, with lymph nodes metastasis, and with poor differentiation. Especially, a statistical association was found with more advanced UICC stages of the disease (55.77%, 65.38%, 92.86%, 93.75% and 100% in stages IA, IB, IIA, IIB, and III, respectively, p=0.02). Using a proportional hazard model, the survival rate of the patients with PGC expressing TAG-72 was significantly lower than the patients without TAG-72 expression (p<0.01), and including information of TAG-72 staining patterns within cancerous tissues along with clinical cancer staging may improve the accuracy of predicting patients' prognosis., Conclusion: These data suggest that TAG-72 expression is associated with clinicopathological parameters of aggressiveness in PGC. The detection of it combined with cancerous staging may increase the ability of investigators to predict the prognosis of patients with PGC.

Aims: Gallbladder involvement in autoimmune pancreatitis (AIP) is reported to be histologically similar to that seen in primary sclerosing cholangitis (PSC) and biliary obstruction secondary to pancreatic ductal adenocarcinoma (PDAC). The aim was to identify unique morphological and immunological features that could help distinguish gallbladders of AIP from those associated with PSC and PDACs., Methods and Results: Archival gallbladders from well-characterized individuals with AIP (n = 22), PSC (n = 13) and PDAC (n = 23) were examined. Quantitative immunohistochemical analysis for IgG and IgG4 plasma cells was performed and an IgG4/IgG ratio was derived. Dense extramural infiltrates were almost exclusively seen in AIP cases (41%), but seen in only 4% of PDAC-associated cases and 0% of PSC cases (P = 0.001). Phlebitis was more frequently noted in AIP cases (41%) (P = 0.03). Inflammatory nodules were almost exclusively seen in AIP (27%) (P = 0.04). AIP gallbladders showed higher IgG4/IgG ratios (P = 0.0001) than PDAC-associated and PSC gallbladders., Conclusions: The findings support our hypothesis that gallbladder involvement in AIP is a primary manifestation of this disease and not a secondary phenomenon related to biliary obstruction. In conjunction with imaging and serology, examination of the gallbladder could provide collaborative evidence of AIP. Evaluation of the gallbladder could also distinguish PSC from AIP-related cholangitis.

This review presents the latest information on new clinical and pathological syndrome in gastroenterology, forming the foundation of which is tissue infiltration of IgG4-positive plasma cells. Considered clinical variants of IgG4-associated diseases of the digestive system: IgG4-associated cholecystitis, holangita and autoimmune pancreatitis.

The article presented a rare clinical observation of 55 years old patient, long-suffering from gall bladder adenomiomatosis, for which the subsequent development was complicated by lymphocytoplasmocytic cholecystitis.

Objective: Serum IgG4 levels are frequently elevated in patients with autoimmune pancreatitis (AIP). AIP is sometimes associated with various extrapancreatic lesions. This study examined whether there is a correlation between serum IgG4 levels and associated extrapancreatic lesions in AIP patients., Methods: Serum IgG4 levels were measured in 40 AIP patients before therapy. In these patients, four associated extrapancreatic lesions (sclerosing cholangitis, sclerosing cholecystitis, sclerosing sialadenitis, and retroperitoneal fibrosis) and clinical factors, such as age, sex ratio, enlargement of the pancreas, and initial symptoms, were retrospectively assessed., Results: The mean serum IgG4 level of the 40 AIP patients was 411+/-448 mg/dl. On the basis of the receiver operator characteristic curve data, the optimal cutoff value for the serum IgG4 to distinguish between AIP patients with and without extrapancreatic lesions was 220 mg/dl; 18 (78%) of 23 patients whose serum IgG4 was more than or equal to 220 mg/dl had extrapancreatic lesions, whereas four (24%) of 17 patients whose serum IgG4 was less than 220 mg/dl had extrapancreatic lesions (P=0.0011). No significant differences between the two groups in age, sex, the frequency of pancreatic enlargement or obstructive jaundice, and associated sialadenitis, retroperitoneal fibrosis, and diabetes mellitus were identified. Sclerosing cholangitis and cholecystitis were more frequent in patients with serum IgG4 levels of more than or equal to 220 mg/dl than in those with a lower serum IgG4 level (P=0.0002 and 0.0204, respectively). The number of associated extrapancreatic lesions was significantly greater in patients with a high-serum IgG4 level., Conclusion: AIP patients with serum IgG4 levels of more than or equal to 220 mg/dl frequently have extrapancreatic lesions.

The levels of cytokines, immunoglobulins A, M, G, C3 and C4 complements, the number of E-rosette forming cells, and phagocytosis were determined in patients with chronic cholecystitis after they had received 7, 12, and 21 day courses of spa therapy at the Arshan Resort, Buryat Republic.

Background & Aims: The formation of cholesterol gallstones is a complex process involving contributions from genes and environmental factors. Although gallbladder inflammation is believed to be common during cholelithogenesis, the role of immunologic factors is unknown., Methods: The role of adaptive immunity in cholesterol cholelithogenesis was analyzed utilizing immunocompetent Helicobacter spp.-infected and -uninfected BALB/c and congenic immunodeficient Rag2(-/-) (Rag) mice. Lymphocyte transfer studies were performed to determine which cellular subset was responsible for cholesterol gallstone formation. Also, gallbladder inflammation was quantified to determine the nature of the inflammatory response associated with cholelilithogenesis., Results: When fed a lithogenic diet for 8 weeks, wild-type mice developed significantly more cholesterol gallstones (27%-80% prevalence) than Rag mice ( approximately 5%, P < .05). Helicobacter spp.-infected BALB/cJ mice displayed statistically significant increases in cholesterol gallstone prevalence compared with uninfected mice (81% vs. 39%; P < .05). Transfer of splenocytes or T lymphocytes to Rag2(-/-) mice increased stone prevalence markedly (26% and 40% respectively; P < .05), whereas transfer of B cells was not appreciably cholelithogenic (13%). The adaptive immune response increased the expression of gallbladder Muc genes and accumulation of mucin gel. In addition, T cells and cholesterol monohydrate crystals induced proinflammatory gene expression in the gallbladder, which likely contributes to gallbladder dysfunction., Conclusions: These studies indicate that T cells are critical in murine cholesterol cholelithogenesis. Furthermore, cholesterol monohydrate crystals induce expression of proinflammatory cytokines in a T-cell-dependent fashion. Acquired immunity and inflammation are likely to be crucial factors in cholesterol gallstone pathogenesis, rather then merely the result of cholelithogenesis.

Aim: The aim of the study was to perform a comparative analysis of proliferative and apoptotic activity as well as of microvascular density (MVD) in metaplasia, dysplasia and gallbladder carcinoma., Material and Method: There were investigated 10 cases of chronic cholecystitis associating premalignant lesions and 5 cases of gallbladder carcinoma developed on a chronic cholecystitis background. The immunohistochemical (IHC) staining was made using Ki-67, p53 and CD34 antibodies, and the streptavidin-biotin method. The semiquantitative analysis focused on the intensity of the IHC reaction for Ki-67 and p53 (on a scale from 0 to 4), the Ki-67 index and the percentage of p53 positive cell nuclei. The MVD was established on 5 representative fields as mean of the number of CD34 positive vessels., Results: Ki-67 was positive in all 10 chronic cholecystitis cases (100%) and in all 5 carcinoma cases (100%), which is explainable by the selection manner of chronic cholecystitis associating premalignant lesions and by the invasive pattern of the carcinomas. Ki-67 index rose from 10% in simple dysplastic lesions associated with chronic cholecystitis to 20% in severe dysplastic lesions associated with chronic cholecystitis up until 90% in carcinoma. In all chronic cholecystitis, p53 was negative for normal gallbladder epithelium, in metaplastic territories and in those with mild dysplasia. In the dysplastic areas present in chronic cholecystitis, the positive reaction of p53 rose from 20% (in moderate dysplasia) to 80% (in severe dysplasia). All carcinoma cases were p53 positive (100%), its expression varying from 30% in papillary areas and 30-50% in undifferentiated adenocarcinoma to 80-100% in well differentiated type. In chronic cholecystitis MVD was of 5-9 vessels / field in areas adjacent to pyloric metaplasia and 10-20 vessels / field in severe dysplastic areas. Gallbladder carcinoma cases presented a MVD of 15-30 vessels / field., Conclusions: The investigation of Ki-67, p53 and MVD brings important data regarding the carcinogenesis process in the gallbladder, initiated on the background of a chronic cholecystitis. The dynamics in the values for Ki-67, p53 and MDV followed from premalignant lesions to carcinoma sustains the hypothesis of the metaplasia-dysplasia-carcinoma sequence.

Background, Aims: The changes of different neuropeptide containing nerve elements might play a role in the pathogenesis of cholecystitis and the formation of gallstones, therefore the authors have investigated the density of the neuropeptide containing nerve fibres and immunocompetent cells in human gallbladder (control and cholecystitis)., Methods: The different neuropeptide containing nerve elements and immunocytes were detected by avidin-biotin-peroxidase (ABC) immunohistochemistry., Results: In the control gallbladder the density of the different neuropeptide containing nerve fibres showed different pattern in all layers. In the inflamed gallbladder the number of the vasoactive intestinal polypeptide (VIP) positive nerve fibres increased significantly, very dense immunoreactive (IR) nerve fibres were located mainly in the tunica mucosa just below the epithelial lining. The number of the VIP IR nerve cell bodies was also increased. However, the number of the substance P (SP) IR nerve fibres was decreased significantly in the cholecystitis. The number of the neuropeptide Y (NPY) nerve fibres showed no changes, while their distribution was altered compared to the control. In the inflamed area the number of immunocompetent cells was strongly increased (being granulocytes, lymphocytes, plasma cells and mast cells) and some of them were also immunoreactive for SP, calcitonin gene-related peptide (CGRP) and VIP. Close contacts were detected between IR nerve fibres and the immunocytes in several cases., Conclusions: During inflammation the changes of the neuropeptide containing nerve fibres might alter the function (causing dilation) of the gall bladder, the activated immunocytes can also synthesize neuropeptides (SP, CGRP, VIP), so the released materials (cytokines, chemokines, histamine, as well as neuropeptides) might act in an autocrine and/or paracrine way influencing the function of the organ and of the immune system.

Aim: To study the role of Fas and Fas ligand (FasL) in biological behaviors of gallbladder carcinoma, and their correlated action and mechanism in tumor escape., Methods: Streptavidin-biotin-peroxidase immunohistochemistry technique was used to study the expression of Fas and FasL protein in 26 gallbladder carcinoma tissues, 18 gallbladder adenoma tissues, 3 gallbladder dysplasia tissues and 20 chronic cholecystitis tissues. Apoptosis of the infiltrating lymphocytes in these tissues was studied by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) method. Expression of both proteins and apoptosis of the tumor infiltrating lymphocytes in cancer tissues of primary foci was compared with clinicopathological features of gallbladder carcinoma., Results: The positive rates of Fas were not significantly different among carcinoma, adenoma, dysplasia and chronic cholecystitis. The positive rate of FasL in carcinoma was significantly higher than that in chronic cholecystitis (chi(2) = 4.89, P<0.05). The apoptotic index (AI) in carcinoma was significantly higher than that in adenoma (t' = 4.19, P<0.01) and chronic cholecystitis (t' = 8.06, P<0.01). The AI was significantly lower in well-differentiated carcinoma and Nevin I-III carcinoma than that in poorly-differentiated carcinoma (t' = 2.63, P<0.05) and Nevin IV-V carcinoma (t' = 3.33, P<0.01). The confidence interval (CI) of infiltrating lymphocytes in adenoma, chronic cholecystitis, well-differentiated carcinoma and Nevin I-III carcinoma was very significantly lower than that in carcinoma (t' = 6.99, P<0.01), adenoma (t' = 3.66, P<0.01), poorly-differentiated carcinoma (t' = 5.31, P<0.01) and Nevin IV-V carcinoma (t' = 3.76, P<0.01), respectively. The CI of apoptosis of infiltrating lymphocytes in well-differentiated carcinoma was significantly lower than that in poorly-differentiated carcinoma (t = 2.52, P<0.05), and was not significantly lower in Nevin I-III carcinoma than in Nevin IV-V carcinoma (t = 1.42, P>0.05). Apoptosis of infiltrating lymphocytes was not discovered in adenoma and chronic cholecystitis., Conclusion: FasL expressed in gallbladder carcinoma cells permits tumor cells to escape from immune surveillance of organism by inducing apoptosis in infiltrating lymphocytes of carcinoma tissues. Up-regulation of FasL expression plays an important role in invasive depth, histological classification and metastasis of gallbladder carcinoma.

The aim of the study was to investigate pH and viscosity (h) of gall bladder contents during cholelithiasis and establishment of their correlation with bacterial and HBV infections. Seventy-eight patients undergone the planned cholecystectomy were investigated. 5 healthy persons (control group) were also involved into the study. In all cases the markers of HBV (Anti-HB core IgG, Anti-HB core IgM, HBsAg) in blood were detected, also bacteriological analysis of gall bladder tissue was performed. In 78 cases (I group) pH of gall bladder contents was measured, in 29 cases (II group), also viscosity of gall was studied. In the control group pH and viscosity were detected. Statistical analysis was performed using ANOVA method. Bacteriological study revealed presence of bacterial infection in gall bladder tissue in 34 cases (43,6%), in 30 patients Anti-HB core antibodies were found in the blood, in 13 cases (16,7%) coincidence of bacterial and HBV infection was documented. Mean indexes of pH and viscosity appeared to be significantly higher in the operated group (pH--7,30, h 2,1 mm(2)/sec), then in the control group (pH--6,74, h--1,34 mm(2)/sec); this indexes were highest in the infected patients. Thus, according to results of the study, changes of pH and viscosity of gall bladder contents could be considered as the useful indexes of initial stage of cholelithiasis and their values depend on the presence of bacterial or HBV infection of gall bladder.

We investigated the distribution of myofibroblasts and CD34-positive stromal cells in normal gallbladder and its pathological conditions (cholecystitis, n=25) using immunohistochemistry and in situ hybridization. In the wall of normal gallbladder, myofibroblasts were generally absent from all layers, but many CD34-positive stromal cells were observed in the connective tissue layer. In chronic cholecystitis with mild perimuscular fibrosis, a small to moderate number of myofibroblasts appeared in the mucosal layer. In chronic cholecystitis with marked perimuscular fibrosis, a small to large number of myofibroblasts appeared predominantly in the connective tissue layer, whereas the number of CD34-positive stromal cells decreased at the same location, although the number of myofibroblasts increased. In chronic cholecystitis with xanthogranulomatous foci, a small to large number of myofibroblasts were observed in the periphery of the xanthogranulomatous reaction and adjacent area. In contrast, CD34-positive stromal cells were completely absent or were limited to the area just around the xanthogranulomatous reaction. Induction of collagen type I and III mRNA was predominantly observed in the cytoplasm of myofibroblasts associated with the marked fibrosis, which consisted primarily of mature collagen fibers, and in the cytoplasm of myofibroblasts around the xanthogranulomatous reaction, respectively. Finally, myofibroblasts were observed in all subtypes. The increased number of myofibroblasts was most prominent in the connective tissue layer of chronic cholecystitis with marked perimuscular fibrosis or in the area adjacent to xanthogranulomatous foci of chronic cholecystitis. Under these conditions, CD34-positive stromal cells tended to disappear from the connective tissue layer, which exhibited an increase in myofibroblasts.

The laparoscopic approach is thought to reduce the postoperative immunologic and metabolic effects of an open operation. This study was designed with the aim of comparing the systemic immune response after laparoscopic and open cholecystectomy. Seventeen patients with gallbladder stones were assigned to undergo either a laparoscopic (n = 9) or open (n = 8) approach. The postoperative immune response was assessed by measuring the serum levels of soluble Fas (sFas), soluble L-selectin (sL-selectin), and transforming growth factor-beta1 (TGFbeta1) preoperatively and 2 hours, 1 day, and 2 days postoperatively. Both approaches resulted in a significant decrease in sFas levels 1 and 2 days postoperatively. The open approach evoked a transient increase in sL-selectin levels 2 hours postoperatively. Moreover, the open approach resulted in a persistent, significant increase in TGFbeta1 levels postoperatively. Comparison of open versus laparoscopic cholecystectomy has shown no significant difference in sFas level and a statistically significant increase of sL-selectin (within 2 hours) and TGFbeta levels after open surgery. Although both laparoscopic and open cholecystectomy evoked an alteration of the systemic immune response, our data showed that such immune response may be less after the laparoscopic approach.

The immune system state was studied up in dynamics in 100 patients with an acute cholecystitis, depending on the operative intervention method applied (the open or endoscopic one). The disease is accompanied by significant immunoperversion answer. Performance of laparoscopic cholecystectomy influences the organism immune system more sparely than open method.

The drug selena of the Novamed firm has been shown to be of high clinical, biochemical, and immunological effectiveness in a combined treatment of patients with chronic inflammatory diseases of the biliary system presenting with immunological disorders, that was evidenced by a sooner than in controls disappearance or alleviation of clinical manifestations of the disease, normalization of clinical indices for blood, ultrastructure of the immunocompetent cells, and by less time for the functional state of the liver to return to normal. It is suggested that the drug effect on the immune system might be mediated through normalization of lipid peroxidation and of the system for antioxidant defence.

Major surgery suppresses intracellular T-cell cytokine production. Laparoscopic surgery has been reported to have no effect on in vitro lymphocyte reactivity, but its effects on intracellular cytokine production are unknown. This study measured T-cell intracellular gamma-interferon, interleukin-4 (IL-4), and interleukin-10 (IL-10), along with serum interleukin-6 (IL-6) and cortisol levels, immediately before and 1 day after laparoscopic cholecystectomy in a cohort of six Air Force and veteran patients. Stimulated intracellular levels of gamma-interferon were slightly, but not significantly, elevated during the postoperative period in all T-cell subsets. There were no postoperative changes in stimulated IL-4 or IL-10 levels. Postoperative serum IL-6 levels, but not serum cortisol levels, were significantly elevated compared to preoperative values. In conclusion, laparoscopic surgery causes slight trauma but has no effect on T-cell intracellular interferon, IL-4, and IL-10 responses.

Background: Trauma, whether accidental or surgically induced, is known to cause significant modulation of the cell-mediated immune response. Minimal access surgery (MAS) has been shown to improve postoperative recovery and enhance rehabilitation. The degree of immunosuppression resulting from two MAS techniques was studied and compared by measuring the circulating T lymphocyte and natural killer (NK) cell subsets., Method: This investigation was a randomized prospective study of patients admitted to the Professorial Surgical Unit, Aberdeen Royal Infirmary for elective cholecystectomy. Two methods of MAS were studied-laparoscopy and minilaparotomy., Results: Laparoscopy was found to cause significantly less reduction in the number of cells expressing T lymphocyte phenotypic surface markers (CD2, CD3, CD8, CD4:CD8 ratio), activation markers (CD71 and HLA-DR), and NK cell subsets (CD11b, CD16, CD56 and CD57), when compared with the minilaparotomy technique., Conclusions: These data show that host defences are less suppressed after laparoscopic cholecystectomy, and this may have important implications for the use of laparoscopic techniques in major surgical resections, especially for malignant disease.

As many as 42 patients with chronic noncalculous cholecystitis who ranged from 18 to 36 years old were studied for the left ventricular systolic-and-diastolic function and for humoral immunity. Signs of left ventricular diastolic dysfunction were revealed as were increased levels of complement-fixing antibodies to the tissues of the gallbladder and myocardium. It is suggested that one of the pathogenetic mechanisms of the abnormal changes in the cardiac muscle might be immune factors for there is a similarity between antigenic determinants of the gallbladder and myocardium tissues antigen.

Aims: Transforming growth factor alpha (TGF-alpha), a protein structurally similar to epidermal growth factor (EGF), is implicated in the development of many human tumours. This study examines the expression of TGF-alpha in gallbladder and extrahepatic biliary tract tumours in which EGFR expression has been previously shown to be important., Methods: A monoclonal antibody to the TGF-alpha protein was used to investigate the immunohistochemical expression of TGF-alpha in carcinoma of the gallbladder (n = 13), common bile duct (CBD) (n = 6) and ampulla of Vater (n = 8). Tissues from cases of chronic cholecystitis (n = 11), gallbladder dysplasia (n = 3) and adenoma (n = 1), and ampullary carcinoma in situ (CIS) (n = 3) were used as non-malignant controls. These cases were previously studied for EGFR expression., Results: TGF-alpha overexpression, defined as intense immunoreactivity in more than two-thirds of cells immunostained for TGF-alpha, was present in most gallbladder carcinomas (n = 10; 77%) but with no significant differences in expression between different tumour grades. None of the cases of gallbladder dysplasia or chronic cholecystitis had strong TGF-alpha expression and this was significantly different from the carcinomas (P = 0.013 and P = 0.0001, respectively; chi 2 test), although a few cases of chronic cholecystitis showed weak (n = 4), moderate (n = 6) or no (n = 1) immunoreactivity. A few ampullary carcinomas (n = 2; 25%) and CIS (n = 1; 33%), and half of the CBD carcinomas (50%) had strong TGF-alpha immunoreactivity. There was correlation between TGF-alpha and EGFR immunoreactivity in the tumour cases (r = 0.70, r2 = 0.49, P = 0.0001; simple regression analysis), although the rate of EGFR immunoreactivity in CBD and ampullary carcinomas was somewhat higher than that of TGF-alpha. However, no statistically significant correlation between TGF-alpha expression with patient survival or tumour recurrence (r = 0.11, r2 = 0.012, P = 0.65; simple regression analysis) was found., Conclusions: Increased TGF-alpha expression occurs more frequently in gallbladder carcinoma than in gallbladder dysplasia, chronic cholecystitis, CBD or ampullary tumour, with no specific relationship to tumour grade, suggesting that TGF-alpha overexpression occurs early in the development of gallbladder cancers, and that biliary tract cancers have a different molecular origin. Correlation was found between TGF-alpha and EFGR expression in gallbladder and biliary tract tumours.

We present three cases of xanthogranulomatous cholecystitis (XGC) with an increased serum carbohydrate antigen 19-9 (CA19-9). All of the patients were elderly females and had gallstones lodged in the neck of the gallbladder. Preoperative serum CA19-9 levels were 709 U/ml, 87 U/ml, and 400 U/ml, respectively. A cholecystectomy with or without bile duct exploration was performed, and the histological diagnosis of XGC was made. Serum CA19-9 levels fell to normal levels in two patients who recovered uneventfully, but rose again in one patient who died of cholangitis. Clinicians must remember that XGC is a possible cause of increased serum CA19-9 levels.

The results of the clinical and laboratory study of the efficacy of the prophylactic and therapeutic use of cefodizime (modivid) in patients with chronic calculous cholecystitis and burns are presented. Expediency of the preoperative prophylactic use of the drug and its significance in the treatment of infectious complications of the burn disease were verified. The immunological investigation gave evidence of an increase of the phagocytosis functional activity when cefodizime (modivid) was used prophylactically in cholecystectomy.

The perioperative changes in epinephrin-, norepinephrine-, histamin-, C5a- and interleukin-6-levels were studied in 40 patients undergoing cholecystectomy for the diagnosis of acute cholecystitis. All relevant mediator levels could be determined in 38 patients. The outcome was not optimal in 16 of them (42%). In order to evaluate the predictive value of the mediators under investigation for the quality of the patients' outcome, a model based on the Bayes' theorem was developed. Using this model the outcome (optimal vs. not optimal) could be correctly predicted in 30 (79%) of our study patients. This kind of data analysis allows to define states of increased risk for a not optimal recovery based on biochemical parameters.

Among the investigated 27 gallbladders (GB) using immunofluorescent and histological methods 9 were nonaffected, 7--excised for an acute calculous cholecystitis and 11--for the destructive one. It was established, that the plasmocytes, producing immunoglobulins of main classes, play an important role in the immune defense of the GB mucosa. The stress and hyperfunctioning of the local immune homeostasis mechanisms were revealed in the acute calculous cholecystitis; in the destructive one--the local immune defense disorder, showing the essential lowering of the secretory immunoglobulin A (SIgA) level and the immunocytes-producers IgA quantity, the ratio between plasmocytes and immune complexes, which appear in the vessels wall and perivasal stroma of GB.