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Adenocarcinoma is preceded by chronic atrophic gastritis, gastric intestinal metaplasia and dysplasia. Trefoil factor 3 (TFF3) is a peptide secreted by goblet cells, which is abundantly present in intestinal metaplasia.To evaluate the utility of serum TFF3 as a non-invasive biomarker for the diagnosis of intestinal metaplasia and gastric cancer.Single-center, cross-sectional study of 274 patients who consecutively underwent upper gastrointestinal endoscopy with gastric biopsies (updated Sydney system). TFF3 levels were measured in serum by a commercial ELISA kit. Patients with normal histology or chronic atrophic gastritis without intestinal metaplasia comprised the control group. In addition, 14 patients with invasive gastric cancer were included as a reference group. The association between TFF3 levels and intestinal metaplasia was assessed by logistic regression.Patients with intestinal metaplasia (n=110) had a higher median TFF3 level as compared to controls (n=164), 13.1 vs. 11.9ng/mL, respectively (p=0.024). Multivariable logistic regression showed a no significant association between TFF3 levels and intestinal metaplasia (OR=1.20; 95%CI: 0.87-1.65; p-trend=0.273). The gastric cancer group had a median TFF3 level of 20.5ng/mL, and a significant association was found (OR=3.26; 95%CI: 1.29-8.27; p-trend=0.013).Serum levels of TFF3 do not discriminate intestinal metaplasia in this high-risk Latin American population. Nevertheless, we confirmed an association between TFF3 levels and invasive gastric cancer.

Context.— The nature and associations of gallbladder (GB) “adenomyoma” (AM) remain controversial. Some studies have attributed up to 26% of GB carcinoma to AMs. Objective.— To examine the true frequency, clinicopathologic characteristics, and neoplastic changes in GB AM. Design.— Cholecystectomy cohorts analyzed were 1953 consecutive cases, prospectively with specific attention to AM; 2347 consecutive archival cases; 203 totally embedded GBs; 207 GBs with carcinoma; and archival search of institutions for all cases diagnosed as AM. Results.— Frequency of AM was 9.3% (19 of 203) in totally submitted cases but 3.3% (77 of 2347) in routinely sampled archival tissue. A total of 283 AMs were identified, with a female to male ratio = 1.9 (177:94) and mean size = 1.3 cm (range, 0.3–5.9). Most (96%, 203 of 210) were fundic, with formed nodular trabeculated submucosal thickening, and were difficult to appreciate from the mucosal surface. Four of 257 were multifocal (1.6%), and 3 of 257 (1.2%) were extensive (“adenomyomatosis”). Dilated glands (up to 14 mm), often radially converging to a point in the mucosa, were typical. Muscle was often minimal, confined to the upper segment. Nine of 225 (4%) revealed features of a duplication. No specific associations with inflammation, cholesterolosis, intestinal metaplasia, or thickening of the uninvolved GB wall were identified. Neoplastic change arising in AM was seen in 9.9% (28 of 283). Sixteen of 283 (5.6%) had mural intracholecystic neoplasm; 7 of 283 (2.5%) had flat-type high-grade dysplasia/carcinoma in situ. Thirteen of 283 cases had both AM and invasive carcinoma (4.6%), but in only 5 of 283 (1.8%), carcinoma was arising from AM (invasion was confined to AM, and dysplasia was predominantly in AM). Conclusions.— AMs have all the features of a malformative developmental lesion, and may not show a significant muscle component; (ie, the name “adeno-myoma” is partly a misnomer). While most are innocuous, some pathologies may arise in AMs, including intracholecystic neoplasms, flat-type high-grade dysplasia or carcinoma in situ and invasive carcinoma (1.8%, 5 of 283). It is recommended that gross examination of GBs include serial slicing of the fundus for AM detection and total submission if one is found.

© 2022, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.There are highly conflicting data on relative frequency (2–32%), prognosis, and management of pT1b-gallbladder carcinoma (GBC), with 5-year survival ranging from > 90% in East/Chile where cholecystectomy is regarded as curative, versus < 50% in the West, with radical operations post-cholecystectomy being recommended by guidelines. A total of 473 in situ and invasive extensively sampled GBCs from the USA (n = 225) and Chile (n = 248) were re-evaluated histopathologically per Western invasiveness criteria. 349 had invasive carcinoma, and only 24 were pT1. Seven cases previously staged as pT1b were re-classified as pT2. There were 19 cases (5% of all invasive GBCs) qualified as pT1b and most pT1b carcinomas were minute (< 1mm). One patient with extensive pTis at margins (but pT1b focus away from the margins) died of GBC at 27 months, two died of other causes, and the remainder were alive without disease (median follow-up 69.9 months; 5-year disease-specific survival, 92%). In conclusion, careful pathologic analysis of well-sampled cases reveals that only 5% of invasive GBCs are pT1b, with a 5-year disease-specific survival of > 90%, similar to findings in the East. This supports the inclusion of pT1b in the “early GBC” category, as is typically done in high-incidence regions. Pathologic mis-staging of pT2 as pT1 is not uncommon. Cases should not be classified as pT1b unless extensive, preferably total, sampling of the gallbladder to rule out a subtle pT2 is performed. Critical appraisal of the literature reveals that the Western guidelines are based on either SEER or mis-interpretation of stage IB cases as “pT1b.” Although the prognosis of pT1b-GBC is very good, additional surgery (radical cholecystectomy) may be indicated, and long-term surveillance of the biliary tract is warranted.

Background & Aims Gallbladder cancer (GBC) is the most common type of biliary tract cancer, but the molecular mechanisms involved in gallbladder carcinogenesis remain poorly understood. In this study, we applied integrative genomics approaches to characterise GBC and explore molecular subtypes associated with patient survival. Methods We profiled the mutational landscape of GBC tumours (whole-exome sequencing on 92, targeted sequencing on 98, in total 190 patients). In a subset (n = 45), we interrogated the matched transcriptomes, DNA methylomes, and somatic copy number alterations. We explored molecular subtypes identified through clustering tumours by genes whose expression was associated with survival in 47 tumours and validated subtypes on 34 publicly available GBC cases. Results Exome analysis revealed TP53 was the most mutated gene. The overall mutation rate was low (median 0.82 Mut/Mb). APOBEC-mediated mutational signatures were more common in tumours with higher mutational burden. Aflatoxin-related signatures tended to be highly clonal (present in ≥50% of cancer cells). Transcriptome-wide survival association analysis revealed a 95-gene signature that stratified all GBC patients into 3 subtypes that suggested an association with overall survival post-resection. The 2 poor-survival subtypes were associated with adverse clinicopathologic features (advanced stage, pN1, pM1), immunosuppressive micro-environments (myeloid-derived suppressor cell accumulation, extensive desmoplasia, hypoxia) and T cell dysfunction, whereas the good-survival subtype showed the opposite features. Conclusion These data suggest that the tumour micro-environment and immune profiles could play an important role in gallbladder carcinogenesis and should be evaluated in future clinical studies, along with mutational profiles. Lay summary Gallbladder cancer is highly fatal, and its causes are poorly understood. We evaluated gallbladder tumours to see if there were differences between tumours in genetic information such as DNA and RNA. We found evidence of aflatoxin exposure in these tumours, and immune cells surrounding the tumours were associated with survival.

Chile has high incidence rates of gallbladder cancer globally, particularly among Amerindian women, who also have a high prevalence of gallstones. We examined differences in inflammatory biomarkers between Mapuche and non-Mapuche women from the Chile Biliary Longitudinal Study, a cohort of women with ultrasound-detected gallstones. We randomly selected 200 Mapuche women frequency matched to non-Mapuche women on age and statin use Inflammatory biomarkers were analyzed using a multiplex assay and linear regression to assess associations of a priori markers (CCL20, CXCL10, IL-6, and IL-8) with ethnicity. Novel biomarkers were analyzed using exploratory factor analysis (EFA) and sufficient dimension reduction (SDR) to identify correlated marker groups, followed by linear regression to examine their association with ethnicity. The mean values of IL-8 were higher in Mapuche than non-Mapuche women (P = 0.04), while CCL20, CXCL10, and IL-6 did not differ significantly by ethnicity. EFA revealed two marker groups associated with ethnicity (P = 0.03 and P

Intracholecystic neoplasms (ICNs) (pyloric gland adenomas and intracholecystic papillary neoplasms, collectively also called intracholecystic papillary/tubular neoplasms) form multifocal, extensive proliferations on the gallbladder mucosa and have a high propensity for invasion (>50%). In this study, 19 examples of a poorly characterized phenomenon, mural papillary mucinous lesions that arise in adenomyomatous nodules and form localized ICNs, were analyzed. Two of these were identified in 1750 consecutive cholecystectomies reviewed specifically for this purpose, placing its incidence at 0.1%. Median age was 68 years. Unlike other gallbladder lesions, these were slightly more common in men (female/male=0.8), and 55% had documented cholelithiasis. All were characterized by a compact multilocular, demarcated, cystic lesion with papillary proliferations and mucinous epithelial lining. The lesions' architecture, distribution, location, and typical size were suggestive of evolution from an underlying adenomyomatous nodule. All had gastric/endocervical-like mucinous epithelium, but 5 also had a focal intestinal-like epithelium. Cytologic atypia was graded as 1 to 3 and defined as 1A: mucinous, without cytoarchitectural atypia (n=3), 1B: mild (n=7), 2: moderate (n=2), and 3: severe atypia (n=7, 3 of which also had invasive carcinoma, 16%). Background gallbladder mucosal involvement was absent in all but 2 cases, both of which had multifocal papillary mucosal nodules. In conclusion, these cases highlight a distinct clinicopathologic entity, that is, mural ICNs arising in adenomyomatous nodules, which, by essentially sparing the "main" mucosa, not displaying "field-effect/defect" phenomenon, and only rarely (16%) showing carcinomatous transformation, are analogous to pancreatic branch duct intraductal papillary mucinous neoplasms.

Gallbladder cancer (GBC) is a highly fatal cancer that can be cured through cholecystectomy if identified early. The presence of gallstones is the primary risk factor for GBC, but few people with gallstones develop GBC. A key question is what drives the development of GBC among persons with gallstones. We initiated the Chile Biliary Longitudinal Study (Chile BiLS) to address this question. From 2016 to 2019, Chile BiLS enrolled 4,726 women aged 50–74 years with ultrasound-detected gallstones from southern-central Chile, accounting for an estimated 36% of eligible women with gallstones in the study area. The median age was 59 years; 25% of the women were Amerindian (Mapuche), 60% were obese, 25% had diabetes, and 6% had cardiovascular disease. Participants will be followed for gallbladder dysplasia or cancer for 6 years. As of April 30, 2020, over 91% of those eligible completed the year 2 follow-up visit. Data being collected include epidemiologic and sociodemographic information, anthropometric measurements, blood pressure, and tooth counts. Biosamples being taken include baseline plasma, buffy coat, red blood cells, serum, blood clot from serum, and PAXgene whole blood (PreAnalytiX GmbH, Hombrechtikon, Switzerland). Complete gallbladder sampling is conducted for most participants undergoing cholecystectomy. The Chile BiLS cohort study will increase our understanding of GBC etiology and could identify potential risk stratification and early detection strategies in high-risk areas.

BackgroundDifferent perspectives exist regarding the clinicopathologic characteristics, biology and management of gallbladder polyps. Size is often used as the surrogate evidence of polyp behavior and size of ≥1cm is widely used as cholecystectomy indication. Most studies on this issue are based on the pathologic correlation of polyps clinically selected for resection, whereas, the data regarding the nature of polypoid lesions from pathology perspective -regardless of the cholecystectomy indication- is highly limited.MethodsIn this study, 4231 gallbladders -606 of which had gallbladder carcinoma- were reviewed carefully pathologically by the authors for polyps (defined as ≥2 mm). Separately, the cases that were diagnosed as "gallbladder polyps" in the surgical pathology databases were retrieved.Results643 polyps identified accordingly were re-evaluated histopathologically. Mean age of all patients was 55 years (range: 20-94); mean polyp size was 9 mm. Among these 643 polyps, 223 (34.6%) were neoplastic: I. Non-neoplastic polyps (n = 420; 65.4%) were smaller (mean: 4.1 mm), occurred in younger patients (mean: 52 years). This group consisted of fibromyoglandular polyps (n = 196) per the updated classification, cholesterol polyps (n = 166), polypoid pyloric gland metaplasia (n = 41) and inflammatory polyps (n = 17). II. Neoplastic polyps were larger (mean: 21 mm), detected in older patients (mean: 61 years) and consisted of intra-cholecystic neoplasms (WHO's "adenomas" and "intracholecystic papillary neoplasms", ≥1 cm; n = 120), their "incipient" version (ConclusionsApproximately a third of polypoid lesions in the cholecystectomies (regardless of the indication) prove to be neoplastic. The vast majority of (90%) of polyps ≥1 cm and virtually all of those ≥2 cm are neoplastic confirming the current impression that polyps ≥1 cm ought to be removed. However, this study also illustrates that 30% of the neoplastic polyps are

Context. Follicular cholecystitis (FC) is a poorly characterized entity. Objective. To determine its frequency/clinicopathologic associations. Design. A total of 2550 cholecystectomy specimens were examined. Two hundred three of these were consecutive routine cholecystectomies submitted entirely for microscopic examination to determine the relative frequency of incidental pathologies in gallbladders (GBs). The remainder had representative sampling. Underlying conditions were nonobstructive pathologies (1270 nonspecific cholecystitis), obstructive (62 distal biliary tract tumors, 35 primary sclerosing cholangitis, and 31 autoimmune pancreatitis), and neoplastic (n = 949). FC was defined as 3 distinct lymphoid follicles (LFs)/centimeter. Results. In the GBs totally submitted for microscopic examination, the true frequency of FC was found to be 2.5% (5/203), and in the representatively sampled group, it was 1.9%, with similar frequencies in nonobstructive, obstructive, and neoplastic cases (2.3%, 3.1%, and 1.3%, respectively, P = .77). When the 39 FC in nonneoplastic GBs contrasted with ordinary chronic cholecystitis, they were associated with older age (68 vs 49 years, P < .0001), similar gallstone frequency (68 vs 81%), female/male ratio (2.7 vs 2.6), and wall thickness (4 mm for both). None had lymphoma/parasites/ Salmonella infection. Of 17 cases who had undergone gastric biopsy, 5 had chronic gastritis (2 with Helicobacter pylori). Microscopically, the LFs were the main inflammatory process often with minimal intervening inflammation. IgG4-positive plasma cell density was low (Conclusions. Follicular cholecystitis is seen in 2% of cholecystectomies, typically in significantly older patients, suggesting a deranged immune response. A third of the patients reveal biopsy-proven gastritis. FC does not seem to be associated with autoimmunity, lymphoma, or obstructive pathologies.

Published data on survival of T2 gallbladder carcinoma (GBC) from different countries show a wide range of 5-year survival rates from 30-> 70%. Recently, studies have demonstrated substantial variation between countries in terms of their approach to sampling gallbladders, and furthermore, that pathologists from different continents apply highly variable criteria in determining stage of invasion in this organ. These findings raised the question of whether these variations in pathologic evaluation could account for the vastly different survival rates of T2 GBC reported in the literature. In this study, survival of 316 GBCs from three countries (Chile n = 137, South Korea n = 105, USA n = 74), all adequately sampled (with a minimum of five tumor sections examined) and histopathologically verified as pT2 (after consensus examination by expert pathologists from three continents), was analyzed. Chilean patients had a significantly worse prognosis based on 5-year all-cause mortality (HR: 1.89, 95% CI: 1.27-2.83, p = 0.002) and disease-specific mortality (HR: 2.41, 95% CI: 1.51-3.84, p < 0.001), compared to their South Korean counterparts, even when controlled for age and sex. Comparing the USA to South Korea, the survival differences in all-cause mortality (HR: 1.75, 95% CI: 1.12-2.75, p = 0.015) and disease-specific mortality (HR: 1.94, 95% CI: 1.14-3.31, p = 0.015) were also pronounced. The 3-year disease-specific survival rates in South Korea, the USA, and Chile were 75%, 65%, and 55%, respectively, the 5-year disease-specific survival rates were 60%, 50%, and 50%, respectively, and the overall 5-year survival rates were 55%, 45%, and 35%, respectively. In conclusion, the survival of true T2 GBC in properly classified cases is neither as good nor as bad as previously documented in the literature and shows notable geographic differences even in well-sampled cases with consensus histopathologic criteria. Future studies should focus on other potential reasons including biologic, etiopathogenetic, management-related, populational, or healthcare practice-related factors that may influence the survival differences of T2 GBC in different regions.

There is no systematic histopathologic analysis of non-neoplastic polyps in the gallbladder. In this study, in addition to a computer search for cases designated as "polyp," a systematic review of 2533 consecutive routinely sampled archival and 203 totally submitted prospective cholecystectomies were analyzed for >2 mm polyps (cut-off was based on radiologic sensitivity). A total of 447 non-neoplastic polyps were identified. The frequency was 3% in archival cases and 5% in totally submitted cases. Only 21 (5%) were >= 1 cm. The average age was 52 years, and the female to male ratio was 3.1. Two distinct categories were delineated: (1) injury-related polyps (n=273): (a) Fibro(myo)glandular polyps (n=214) were small (mean=0.4 cm), broad-based, often multiple (45%), almost always (98%) gallstone-associated, and were composed of a mixture of (myo)fibroblastic tissue/lobular glandular units with chronic cholecystitis. Dysplasia seen in 9% seemed to be secondary involvement. (b) Metaplastic pyloric glands forming polypoid collections (n=42). (c) Inflammatory-type polyps associated with acute/subacute injury (11 granulation tissue, 3 xanthogranulomatous, 3 lymphoid). (2) Cholesterol polyps (n=174) occurred in uninjured gallbladders, revealing a very thin stalk, edematous cores devoid of glands but with cholesterol-laden macrophages in 85%, and cholesterolosis in the uninvolved mucosa in 60%. Focal low-grade dysplasia was seen in 3%, always confined to the polyp, unaccompanied by carcinoma. In conclusion, non-neoplastic polyps are seen in 3% of cholecystectomies and are often small. Injury-related fibromyoglandular polyps are the most common. Cholesterol polyps have distinctive cauliflower architecture, often in a background of uninjured gallbladders with cholesterolosis and may lack the cholesterol-laden macrophages in the polyp itself. Although dysplastic changes can involve non-neoplastic polyps, they do not seem to be the cause of invasive carcinoma by themselves.

Gallbladder dysplasia can progress to cancer and may be associated with increased cancer risk at other biliary tract sites. Thus, its accurate identification is relevant both for etiologic understanding and for clinical purposes. Data on the frequency and distribution of gallbladder dysplasia are lacking due to limited gallbladder sampling and inability to visualize dysplasia grossly. An expert pathology group used consensus criteria to review 140 totally sampled consecutive cholecystectomy specimens from Chilean women. Three cases (2%) revealed incidental invasive carcinoma, all T2, along with high-grade dysplasia (HGD). The surface area covered by dysplasia or cancer in these cases was 9%, 37%, and 87%. Although the first longitudinal (“diagnostic”) section of the whole gallbladder captured HGD or cancer in all three cases, the deepest focus of invasive carcinoma was not present in this section. Fourteen additional cases (10%) had low-grade dysplasia (LGD), which was typically very focal (covering

Background Chile has one of the highest mortality rates by gastric cancer (GC) worldwide. Primary prevention of GC and detection of pre-neoplastic and early neoplastic lesions should be a national priority. Aim To assess the impact of the protocolization of endoscopy referral and the use of H. pylori stool antigen test (HPSA) in the management of dyspepsia to decrease the waiting list for endoscopy and increase the detection of gastric pre-neoplastic and early neoplastic lesions. Material and Methods We included all patients referred to the Endoscopy Unit of a regional hospital, from January 2015 to December 2017. We also included patients with known pre-neoplastic lesions and all those with first degree relatives with GC. We implemented protocols for referral of patients with dyspepsia considering the use of HPSA test, prioritizing to endoscopy those with a higher risk of GC. Results A total of 4,641 endoscopies and 2,631 HPSA tests were carried out. After the adoption of these protocols, we observed a 52% decrease in the waiting time for endoscopy. The GC detection rate in this period was 1.8 to 3.1 cases per 100 endoscopies. After the adoption of the protocols, we observed a significant increase in early GC detection rate (from none in 2015 to 13% in 2017, p = 0.03). Conclusions The protocolization of the referral for endoscopy associated with widespread use of HPSA test in the management of patients with dyspepsia, are successful strategies to decrease waiting lists for endoscopy and optimize the detection rate of pre-neoplastic lesions and early GC.

Most gallbladder cancer (GBC) cases arise in the context of gallstones, which cause inflammation, but few gallstone patients develop GBC. We explored inflammation/immune-related markers measured in bile and serum in GBC cases compared to gallstone patients to better understand how inflammatory patterns in these two conditions differ. We measured 65 immune-related markers in serum and bile from 41 GBC cases and 127 gallstone patients from Shanghai, China, and calculated age- and sex-adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) for GBC versus gallstones. We then focused on the markers that were significantly elevated in bile and serum to replicate the findings in serum from 35 GBC cases and 31 gallstone controls from Chile. Comparing the highest versus lowest quantile, 15 markers (23%) were elevated in both serum and bile from GBC versus gallstone patients in the Shanghai study (p

The PI3K/AKT/mTOR pathway plays a crucial role in the regulation of multiple cellular functions including cell growth, proliferation, metabolism and angiogenesis. Emerging evidence has shown that deregulation of this pathway has a role promoting gastric cancer (GC). The aim was to assess the expression of genes involved in this pathway by qPCR in 23 tumor and 23 non-tumor gastric mucosa samples from advanced GC patients, and in AGS, MKN28 and MKN45 gastric cancer cell lines. Results showed a slight overexpression of PIK3CA, PIK3CB, AKT1, MTOR, RPS6KB1, EIF4EBP1 and EIF4E genes, and a slightly decreased PTEN and TSC1 expression. In AGS, MKN28 and MKN45 cells a significant gene overexpression of PIK3CA, PIK3CB, AKT1, MTOR, RPS6KB1 and EIF4E, and a significant repression of PTEN gene expression were observed. Immunoblotting showed that PI3K-β, AKT, p-AKT, PTEN, mTOR, p-mTOR, P70S6K1, p-P70S6K1, 4E-BP1, p-4E-BP1, eIF4E and p-eIF4E proteins were present in cell lines at different levels, confirming activation of this pathway in vitro. This is the first time this extensive panel of 9 genes within PI3K/AKT/mTOR pathway has been studied in GC to clarify the biological role of this pathway in GC and develop new strategies for this malignancy.

Introduction Gallbladder adenocarcinoma (GBC) is a relatively rare malignancy with high mortality rate due to late stage discovery. At advanced-stages, there are limited treatment options, and most patients develop resistance to chemotherapy. Adapting the recent major advances in cancer immunotherapy specifically to GBC will require a deep understanding of the immune landscape. Our aim is to characterize Immune Checkpoint markers (IC), Tumor infiltrating Lymphocytes (TILs), and Myeloid cells (MCs), and associate them with cancer genomic alterations, clinic-pathological information, and patient survival. Methods We selected formalin-fixed and paraffin-embedded tumor tissues from surgically resected primary GBC (n=97 patients) without neoadjuvant therapy to construct a tissue microarray. Tumor samples were collected from two institutions (MD Anderson Cancer Center (MDACC), USA, n=53; Sotero del Rio Hospital (SRH), Chile, n=44). We performed immunohistochemistry with the following biomarkers: IC (PD-1, PD-L1, LAG-3, TIM-3, B7-H3, B7-H4, VISTA, ICOS, OX-40, IDO1), TILs (CD3, CD4, CD8, CD45RO, CD57, GZB, FOXP-3, CD20), and MCs (CD68, CD11b, CD14). The evaluation of PD-L1, B7-H3, B7-H4, and IDO1 was performed in malignant cells and scored as percentage of positive cells. The TILs and IC were scored as cell densities (n/mm2) using digital image analysis. Tumors were classified in 4 types based on PD-L1 expression and CD8 densities (cut-off median): I (PD-L1+/CD8high), II (PD-L1-/CD8low), III (PD-L1+/CD8low), and IV (PD-L1-/CD8high). Next Generation sequencing platform T200 was used to access genomic alterations in a subset of cases (n=58). Results Expression of PD-L1, B7-H3, B7-H4, and IDO1 (cutoff ≥1%) was 4, 12, 7, and 22 % respectively. From all tumors, 49% were type IV, 47% type II, 3% type I, and 1% type III. Comparing MDACC and SRH cohort, densities of CD3, CD4, TIM3, and PD-1 were higher in tumors from SRH (p Conclusions We characterize the immunological landscape of gallbladder adenocarcinoma. Most tumors were immune ignorant or tolerant (Type II or IV). Different genomic alterations may have distinct immune patterns. Citation Format: Fernando Cintra Lopes Carapeto, Luisa Maren Solis Soto, Wai Chin Foo, Wei Lu, Eduardo A. Vinuela Fawaz, Miguel A. Villaseca, Eduardo Alberto Vega Pizarro, Juan C. Araya, Ignacio I. Wistuba, Javle Milind, Pant Shubham, Lawrence Kwong. Immunological and mutational landscape of gallbladder adenocarcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2658.

Background Chile has one of the highest mortality rates by gastric cancer (GC) worldwide. Primary prevention of GC and detection of pre-neoplastic and early neoplastic lesions should be a national priority. Aim To assess the impact of the protocolization of endoscopy referral and the use of H. pylori stool antigen test (HPSA) in the management of dyspepsia to decrease the waiting list for endoscopy and increase the detection of gastric pre-neoplastic and early neoplastic lesions. Material and Methods We included all patients referred to the Endoscopy Unit of a regional hospital, from January 2015 to December 2017. We also included patients with known pre-neoplastic lesions and all those with first degree relatives with GC. We implemented protocols for referral of patients with dyspepsia considering the use of HPSA test, prioritizing to endoscopy those with a higher risk of GC. Results A total of 4,641 endoscopies and 2,631 HPSA tests were carried out. After the adoption of these protocols, we observed a 52% decrease in the waiting time for endoscopy. The GC detection rate in this period was 1.8 to 3.1 cases per 100 endoscopies. After the adoption of the protocols, we observed a significant increase in early GC detection rate (from none in 2015 to 13% in 2017, p = 0.03). Conclusions The protocolization of the referral for endoscopy associated with widespread use of HPSA test in the management of patients with dyspepsia, are successful strategies to decrease waiting lists for endoscopy and optimize the detection rate of pre-neoplastic lesions and early GC.

International audience; A new series of novel complexes of type cis-[Ru(CO)2Cl2(L)2], L = 2-phenyl-1,8-naphthyridine, 2-(4′-nitrophenyl)-1,8-naphthyridine, 2-(4′-bromophenyl)-1,8-naphthyridine, 2-(4′-methylphenyl)-1,8-naphthyridine, 2-(3′-methoxyphenyl)-1,8-naphthyridine, 2-(2′-methoxyphenyl)-1,8-naphthyridine and 2-(4′-methoxyphenyl)-1,8-naphthyridine have been successfully synthesized and characterized. We found that the complexes can be directly synthesized from [RuCl2(CO)2]2 with high yield. The crystallographic structures of complex cis-[RuCl2(CO)2(2-(4′-methoxyphenyl)-1,8-naphthyridine-κN8)2] and cis-[RuCl2(CO)2(2-(2′-methoxyphenyl)-1,8-naphthyridine-κN8)2] have been established by X-ray single crystal diffraction studies, which indicate an octahedral geometry with two 1,8-naphthyridine ligands coordinated to the metal in a N-monodentate fashion. The ruthenium(II) complexes have been studied as catalysts in the transfer hydrogenation of acetophenone. We found that complexes show moderate activities and a 100% selectivity. The best turnover frequency (390 h−1) is found for cis-[RuCl2(CO)2(2-(4′-methoxyphenyl)-1,8-naphthyridine-κN8)2] when the substrate/catalysis ratio was 1000/1. The catalytic conditions were optimized using different substrate/catalyst and base/catalyst ratios. © 2018

WOS: 000474496100006, PubMed: 31177317, Sarcomatoid carcinomas recently came into the spotlight through genetic profiling studies and also as a distinct model of epithelial-mesenchymal transition. The literature on sarcomatoid carcinomas of gallbladder is limited. In this study, 656 gallbladder carcinomas (GBC) were reviewed. Eleven (1.7%) with a sarcomatoid component were identified and analyzed in comparison with ordinary GBC (O-GBC). Patients included 9 females and 2 males (F/M = 4.5 vs. 3.9) with a mean age-at-diagnosis of 71 (vs. 64). The median tumor size was 4.6 cm (vs. 2.5; P = 0.01). Nine patients (84%) presented with advanced stage (pT3/4) tumor (vs. 48%). An adenocarcinoma component constituting 1-75% of the tumor was present in nine, and eight had surface dysplasia/CIS; either in situ or invasive carcinoma was present in all cases. An intracholecystic papillary-tubular neoplasm was identified in one. Seven showed pleomorphic-sarcomatoid pattern, and four showed subtle/bland elongated spindle cells. Three had an angiosarcomatoid pattern. Two had heterologous elements. One showed few osteoclast-like giant cells, only adjacent to osteoid. Immunohistochemically, vimentin, was positive in six of six; P53 expression was >60% in six of six, keratins in six of seven, and p63 in two of six. Actin, desmin, and S100 were negative. The median Ki67 index was 40%. In the follow-up, one died peri-operatively, eight died of disease within 3 to 8 months (vs. 26 months median survival for O-GBC), and two were alive at 9 and 15 months. The behavior overall was worse than ordinary adenocarcinomas in general but was not different when grade and stage were matched. In summary, sarcomatoid component is identified in < 2% of GBC. Unlike sarcomatoid carcinomas in the remainder of pancreatobiliary tract, these are seldom of the "osteoclastic" type and patients present with large/advanced stage tumors. Limited data suggests that these tumors are aggressive with rapid mortality unlike pancreatic osteoclastic ones which often have indolent behavior.

Although inflammation is central to gallbladder cancer (GBC) development and proliferation, no study has systematically investigated circulating inflammatory proteins and patient survival. We aimed to examine whether the circulating levels of inflammatory proteins is associated with all-cause mortality among such patients. We recruited 134 patients with newly diagnosed with GBC from 1997 to 2001 in a population-based study in Shanghai and an independent set of 35 patients from 2012 to 2013 in Chile. Cox proportional hazards regression models adjusted for covariates were used to evaluate the hazard ratios (HRs) for death by serum levels of 49 inflammatory proteins (quartiles). Of 49 evaluable proteins, eight were significantly associated with overall survival. Seven were associated with a poorer survival, while the highest levels of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) were associated with an increase in survival (HR = 0.26, 95% CI = 0.14, 0.47). No substantial difference in the magnitude of the association was observed between early- and late-stages of GBC. Of seven proteins, five were validated in the patients from Chile. Reducing inflammation and targeting pathways associated with increased survival might improve GBC outcomes. The potential for using a TRAIL-related anticancer drug for GBC treatment merits further investigation.

Background: To validate the BIRADS in mammography, the calculation of its predictive value in each center is required, as recommended by the American College of Radiology. Aim: To determine the predictive value of the BIRADS system in our center. Material and Methods: All ultrasound guided needle percutaneous biopsies, performed at our center between 2006 and 2010 were reviewed. Predictive value, sensitivity, specificity and diagnostic accuracy of BIRADS were calculated, with a confidence interval of 95%. Results: Of 1,313 biopsies available, 1,058 met the inclusion criteria. Fifty eight percent of biopsies were performed to women with mammographies classified as BIRADS 4 or 5. The presence of cancer in mammographies classified as BIRADS 0 was 4%. The prevalence of cancer for mammographies BIRADS 1, 2, 3, 4 and 5 were 0, 3, 2.7, 17.7 and 72.4% respectively. The positive and negative predictive values of BIRADS classification were 55 and 92 % respectively. Conclusions: In our institution BIRADS classification 4 and 5 has a high positive predictive value for detecting cancer as in developed countries.

Gastric cancer (GC) is the first cancer-related cause of death in Chile; however, no plan for GC early detection has been implemented in this country. The OLGA system characterizes gastritis from stages 0 to IV according to the risk of developing GC based on H. pylori infection, atrophy, metaplasia and GC. In this study, the performance of the OLGA system was evaluated in 485 Chilean patients receiving routine endoscopy to improve the detection of early GC or preneoplastic lesions. The results showed that OLGA scores, atrophy, metaplasia and GC increased significantly with age (p 0.001). Conversely, H. pylori infection was higher in younger groups (p 0.05). All gastric lesions were more frequent in men than women. The majority of patients with atrophy also had metaplasia (99%, p 0.0001). Patients with H. pylori infection had more gastric atrophy and metaplasia than those without infection (p 0.05). Of the 485 patients, 21 (4.3%) had GC, being 2.3 times more frequent among men than women and about 2/3 (14) were in OLGA stage ≥2. In addition, 19 (90%) GC patients had atrophy and 18 (85%) had metaplasia (p 0.001). In conclusion, the OLGA system facilitated the evaluation of GC precursor lesions particularly in patients with an OLGA score 2 between 45 and 56 years old, because this group showed atrophy and intestinal metaplasia more frequently. Therefore, biennial endoscopic surveillance of patients with an OLGA2 can be an important health policy in Chile for diagnosing GC in its early stages and reducing mortality over the next two decades.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Gallbladder cancer (GBC) is a highly fatal disease with poor prognosis and few therapeutic alternatives. Molecular profiling has revealed that the deregulation in the ERK/MAPK signaling pathway plays a crucial role in many disease and malignancies, including GBC. The aim of this study was to measure the expression of ERK1/2 and p-ERK1/2 in a population with high GBC-related mortality, such as the Chilean population, and characterize the protein expression of this ERK/MAPK pathway in seven GBC cell lines. Immunohistochemistry (IHC) for ERK1/2 and p-ERK1/2 was performed in 123 GBC tissues and 37 chronic cholecystitis (CC) tissues. In addition, protein expression analysis by western blot for ERK1/2, p-ERK1/2, EGFR, ERBB2 and ERBB3 were performed in seven GBC cell lines (GB-d1, G415, NOZ, OCUG-1, TGBC-1, TGBC-2 and TGBC-24). A higher ERK1/2 and p-ERK1/2 expression was found in GBC tissues compared to chronic cholecystitis (CC) tissues (P

WOS: 000394069800004 PubMed ID: 27666767 Signet ring cell carcinoma is an extremely rare type of gallbladder carcinoma: In the gastrointestinal system, carcinomas with single-cell or cord-like infiltration, previously called "diffuse-infiltrative" type or "signet ring cell," are now designated as "poorly cohesive cell" (PCC) type (regardless of with/without signet ring cells) in the World Health Organization 2010 classification. Six hundred twenty-eight primary invasive gallbladder carcinomas were reviewed for the PCC pattern. Twenty-four cases in which classical PCC pattern constituted greater than 50% of the tumor were included in the study. The mean age was 63 (range, 44-84) years. A strong female predominance was present (female/male ratio, 6.3 versus 3.9 for all gallbladder carcinomas). Most cases (79%) had advanced carcinoma (pT3+) in comparison with 51% of usual carcinomas (P < .01). All cases (100%) showed at least focal signet ring morphology (intracytoplasmic mucin), and this was predominant in 50%. Twelve cases (50%) demonstrated a focal invasive glandular component of the usual type. Overlying focal high-grade dysplasia was identified in 11 (46%). Due to block loss, immunohistochemistry could be performed in only 5 cases and revealed a profile similar to upper gastrointestinal carcinomas CK7++/CK20-+/CDX2+-/p53+. E-cadherin was decreased in the PCC component of all cases. The clinical course appeared to be more aggressive than ordinary gallbladder. carcinomas, with median survival of 3.3 months versus 11.8 months, which did not reach statistical significance (P = .06 by log-rank test). In conclusion, PCC carcinoma originating in the gallbladder should be kept in mind for the differential diagnosis of disseminated poorly differentiated carcinomas in the abdomen.

Background : Extracapsular lymph node involvement has a negative prognosis in malignant tumors. Aim : To assess the prognostic importance of extracapsular lymph node involvement in patients with gastric cancer with lymph node metastases. Material and Methods: Clinical and morphological features and survival of patients with gastric cancer and lymph node involvement operated between 1986 and 2003, were analyzed. Patients with and without extracapsular involvement were compared. Results : During the study period, 459 gastrect omies were performed, 312 patients (68%) had lymph node involvement and 144 (31%) had extracapsular involvement. Patients with and without extracapsular involvem ent were followed for a median of 10 (range 1 to 120) and 41 (range 1 to 193) months, respectively. Five years actuarial survival for patients with and without extracapsular involvement was 23 and 40% respectively. Extracapsular lymph node in volvement and level of wall infi ltration were identifi ed as prognostic factors using a multivariate analysis. Conclusions : Extracapsular lymph node involvement is an independent risk factor for mortality among patients with gastric cancer

Cryptococcosis is an invasive mycotic infection caused by Cryptococcus neoformans, an encapsulated, yeast-like fungus. It is considered an opportunist infection, since it mainly affects immunocompromised subjects. However there are isolated reports of the infection in immunocompetent subjects. Cryptococcal infection of intra-abdominal organs or tissues is extremely rare. We report a 21-year-old HIV positive male that, during the treatment of a meningeal cryptococcosis, presented a clinical picture of an acute abdomen suggesting acute appendicitis. The patient was operated, finding enlarged mesenteric lymph nodes forming conglomerates and a macroscopically normal appendix. The conglomerated lymph nodes and the appendix were excised. The pathological study of the surgical piece revealed an intra abdominal cryptococcal lymphadenitis and a normal appendix.

Resumen Fundamento y objetivo El silenciamiento genico mediado por la metilacion aberrante de la region promotora del acido desoxirribonucleico esta implicado en la inactivacion de genes involucrados en diversas vias metabolicas y se ha constituido en un marcador molecular util en el diagnostico, tratamiento y seguimiento de sujetos oncologicos. El objetivo de este trabajo es analizar los patrones de hipermetilacion genica en mujeres con tumores ginecologicos. Sujetos y metodo Se seleccionaron 115 mujeres con canceres ginecologicos: 22 mujeres con cancer de ovario (CO), 13 mujeres con cancer de endometrio (CE), 11 mujeres con cancer de cuello uterino y 69 mujeres con cancer de mama. Mediante prueba de metilacion especifica por reaccion en cadena de la polimerasa, se estudio el estado de metilacion de los genes CDNK2A ( p16 ), APC1A , FHIT , CDH1 y hMLH1 . Resultados Las frecuencias de metilacion genica para los genes CDNK2A ( p16 ), APC1A , FHIT , CDH1 y hMLH1 fueron del 29,2; 34; 60,4; 10,9, y 79,8%, respectivamente. El 70% de los casos presento al menos 2 genes metilados, es decir, un indice de metilacion superior a 0,4. La frecuencia de metilacion mas baja se observo en el CO, mientras que la frecuencia de metilacion mas alta se presento en el CE. Conclusiones Los resultados indican que la metilacion aberrante de la region promotora es un acontecimiento importante en la carcinogenesis de los tumores ginecologicos y que el patron de metilacion genica se asocia a la naturaleza tumoral. Estas caracteristicas particulares pueden entregar informacion relevante acerca de las principales vias metabolicas alteradas en cada tipo tumoral, informacion que sumada a estudios complementarios de perdida de expresion o de funcion representa una herramienta clinica para el tratamiento adecuado de la enfermedad.

Resumen Introduccion La glandula pineal es una glandula endocrina derivada del diencefalo y septada por derivados piales, por lo que su morfometria y celularidad pudieran quedar definidos durante los primeros anos de vida (proliferacion y apoptosis celulares). En la estroma de la glandula pineal se describen astrocitos derivados de la glia. Sin embargo, no se mencionan la presencia de celulas c-kit+ (CD-117). Objetivos Este trabajo plantea estudiar la morfometria y celularidad, y la presencia de celulas c-kit en la glandula pineal humana a distintas edades, permitiendo demostrar la presencia de celulas con actividad de proteincinasa III. Material y metodos Se obtuvieron glandulas pineales humanas de preparaciones anatomicas frescas: a) grupo 1, de 1 a 6 anos, n = 6; b) grupo 2, de 12 a 17 anos, n = 3; c) grupo 3, de 20 a 30 anos, n = 3, y d) grupo 4, de 35 anos de edad, n = 3. Las muestras fijadas en formol (pH, 7,2) durante 48 h se impregnaron en parafina, y se montaron en portaobjetos silanizados secciones de 5 μm. Las secciones, hematoxilina/eosina, se examinaron para la descripcion histologica y cuantificacion del diametro lobulillar (μm), area del nucleo de los pinealocitos (mm2) e inmunohistoquimica con uso de anticuerpos especificos para la identificacion de: c-kit (DAKO A4502), ki-67 y apaf-1 (Vector Co.). Resultados y discusion Se observaron cambios dinamicos en la morfometria y celularidad (pinealocitos) de la glandula pineal humana segun la edad, con un aumento en el tamano celular hacia la edad de adulto joven y de la proliferacion celular durante la adolescencia, en conjunto con una alta tasa de apoptosis inicial y su disminucion progresiva a traves de la vida. En recien nacidos las celulas c-kit+ no estan presentes. Sin embargo, en los grupos 2, 3 y 4, se encontraron celulas c-kit+, con un aumento en adolescentes y adultos jovenes. Las celulas se presentan como estructuras de nucleo eliptico fuertemente tenidas en el intersticio de la glandula. Aparentemente, la glandula pineal humana termina su desarrollo hacia la pubertad, con la aparicion de celulas c-kit, que podrian participar como focos de depolarizacion de membrana para la liberacion de melatonina. Paralelamente aparecen signos de degeneracion a traves de la presencia de estructuras calcareas calcificadas.

Gastric cancer (GC) is a deadly malignancy worldwide. In the past, it has been shown that cellular signaling pathway alterations play a crucial role in the development of GC. In particular, deregulation of the PI3K/AKT/mTOR pathway seems to affect multiple GC functions including growth, proliferation, metabolism, motility and angiogenesis. Targeting alterations in this pathway by microRNAs (miRNAs) represents a potential therapeutic strategy, especially in inhibitor-resistant tumors. The objective of this study was to evaluate the expression of 3 pre-selected miRNAs, miR-101-2, miR-125b-2 and miR-451a, in a series of primary GC tissues and matched non-GC tissues and in several GC-derived cell lines, and to subsequently evaluate the functional role of these miRNAs.Twenty-five primary GC samples, 25 matched non-GC samples and 3 GC-derived cell lines, i.e., AGS, MKN28 and MKN45, were included in this study. miRNA and target gene expression levels were assessed by quantitative RT-PCR and western blotting, respectively. Subsequently, cell viability, clone formation, cell death, migration and invasion assays were performed on AGS cells.miR-101-2, miR-125b-2 and miR-451a were found to be down-regulated in the primary GC tissues and the GC-derived cell lines tested. MiRNA mimic transfections significantly reduced cell viability and colony formation, increased cell death and reduced cell migration and invasion in AGS cells. We also found that exogenous expression of miR-101-2, miR-125b-2 and miR-451a decreased the expression of their putative targets MTOR, PIK3CB and TSC1, respectively.Our expression analyses and in vitro functional assays suggest that miR-101-2, miR-125b-2 and miR-451a act as potential tumor suppressors in primary GCs as well as in GC-derived AGS cells.

Gallbladder cancer (GBC) is a highly malignant tumor characterized by a poor response to chemotherapy and radiotherapy. We evaluated the in vitro and in vivo antitumor efficacy of mTOR inhibitors, rapamycin and WYE-354. In vitro assays showed WYE-354 significantly reduced cell viability, migration and invasion and phospho-P70S6K expression in GBC cells. Mice harboring subcutaneous gallbladder tumors, treated with WYE-354 or rapamycin, exhibited a significant reduction in tumor mass. A short-term treatment with a higher dose of WYE-354 decreased the tumor size by 68.6% and 52.4%, in mice harboring G-415 or TGBC-2TKB tumors, respectively, compared to the control group. By contrast, treatment with a prolonged-low-dose regime of rapamycin almost abrogated tumor growth, exhibiting 92.7% and 97.1% reduction in tumor size, respectively, compared to control mice. These results were accompanied by a greater decrease in the phosphorylation status of P70S6K and a lower cell proliferation Ki67 index, compared to WYE-354 treated mice, suggesting a more effective mTOR pathway inhibition. These findings provide a proof of concept for the use of rapamycin or WYE-354 as potentially good candidates to be studied in clinical trials in GBC patients.

The nutritional composition of the edible seaweeds Durvillaea antarctica (frond and stem) and dried Ulva lactuca was determined, including the soluble (SDF), insoluble (IDF) and total (TDF) dietary fiber content, amino acid and fatty acid profiles along with tocopherols and tocotrienols (pro-vitamin E). Results show that U. lactuca contained 60.5 ± 1.5%, and D. antarctica frond and stem 71.4 ± 1.5% and 56.4 ± 0.4% of TDF, respectively. Levels for the different amino acids ranged from 0.7 ± 0.1 to 1508.4 ± 9.5 (mg/100 g protein) in U. lactuca, from 0.2 ± 0.0 to 2019.9 ± 5.2 (mg/100 g protein) in D. antarctica (stem), and from 0.3 ± 0.0 to 1052.6 ± 2.9 (mg/100 g protein) in D. antarctica (leaves). In the three seaweeds, the most abundant fatty acid was C18:1ω9cis which in U. lactuca accounted for 27.42 ± 2.60%; in D. antarctica it was 25.36 ± 3.10% and 25.83 ± 2.52% in leaves and stem, respectively. In D. antarctica, γ-tocotrienol (651.7 ± 5.1 mg/kg), δ-tocopherol (245.9 ± 3.7 mg/kg) and α-tocopherol (179.4 ± 12.1 mg/kg) were determined in fronds, α-tocopherol (258.0 ± 7.2 mg/kg) was determined in stem. U. lactuca, showed a high γ-tocopherol level (963.5 ± 3.8 mg/kg).

Background : To determine the incidence and prevalence of salivary gland tumours in the province of Valparaíso, Chile. Material and Methods : Retrospective review of salivary gland tumours diagnosed between the years 2000 and 2011 from four local pathology services. Information on demographics and histopathology were retrieved from the medical records. Results : The study sample consisted of 279 salivary gland tumours. Prevalence and incidence rates per 100.000 persons were 15.4 and 2.51, respectively. Most of the neoplasms corresponded to benign tumours (70.3%). The most affected gland was the parotid gland. Pleomorphic adenoma was the most common benign tumour (53.8%) and mucoepidermoid carcinoma was the most common malignant tumour (7.2%). Conclusions : Salivary gland tumours are uncommon neoplasms that usually arise in the parotid gland. Pleomor- : Salivary gland tumours are uncommon neoplasms that usually arise in the parotid gland. Pleomorphic adenoma and mucoepidermoid carcinoma were the most common benign and malignant tumours reported in this series.

To validate the BIRADS in mammography, the calculation of its predictive value in each center is required, as recommended by the American College of Radiology.To determine the predictive value of the BIRADS system in our center.All ultrasound guided needle percutaneous biopsies, performed at our center between 2006 and 2010 were reviewed. Predictive value, sensitivity, specificity and diagnostic accuracy of BIRADS were calculated, with a confidence interval of 95%.Of 1,313 biopsies available, 1,058 met the inclusion criteria. Fifty eight percent of biopsies were performed to women with mammographies classified as BIRADS 4 or 5. The presence of cancer in mammographies classified as BIRADS 0 was 4%. The prevalence of cancer for mammographies BIRADS 1, 2, 3, 4 and 5 were 0, 3, 2.7, 17.7 and 72.4% respectively. The positive and negative predictive values of BIRADS classification were 55 and 92 % respectively.In our institution BIRADS classification 4 and 5 has a high positive predictive value for detecting cancer as in developed countries.

Background & Aims: Cancer of the gallbladder is the number one cause of cancer mortality in Chilean women. Incidence rates for this tumor vary widely on a worldwide basis, being approximately 30 times higher in high-risk than in low-risk populations, suggesting that environmental factors such as infectious microorganisms, carcinogens, and nutrition play a role in its pathogenesis. Because several Helicobacter sp. colonize the livers of animals and induce hepatitis, the aim of this study was to determine whether Helicobacter infection was associated with cholecystitis in humans. Methods: Bile or resected gallbladder tissue from 46 Chileans with chronic cholecystitis undergoing cholecystectomy were cultured for Helicobacter sp. and subjected to polymerase chain reaction (PCR) analysis using Helicobacter -specific 16S ribosomal RNA primers. Results: Recovery of Helicobacter sp. from frozen specimens was unsuccessful. However, by PCR analysis, 13 of 23 bile samples and 9 of 23 gallbladder tissues were positive for Helicobacter . Eight of the Helicobacter -specific PCR amplicons were sequenced and subjected to phylogenetic analysis. Five sequences represented strains of H. bilis , two strains of " Flexispira rappini " (ATCC 49317), and one strain of H. pullorum . Conclusions: These data support an association of bile-resistant Helicobacter sp. with gallbladder disease. Further studies are needed to ascertain whether similar Helicobacter sp. play a causative role in the development of gallbladder cancer. GASTROENTEROLOGY 1998;114:755-763

AIMS: To examine the relation between the expression of p53 protein and the chaperone heat shock protein (hsp)72/73 in a population at high risk for gastric carcinoma, using single and double immunohistochemistry, and to compare the expression of these two proteins with clinicopathological features. METHODS: Monoclonal antibodies were used to investigate the expression of p53 protein and hsp72/73 in 46 human gastric carcinomas. A double immunohistochemical technique was used in cases that showed p53/hsp72/73 coexpression. RESULTS: p53 immunoreactivity was present in 11 tumours (24%), and hsp72/73 immunostaining was observed in 22 cases (48%). p53 expression was observed as nuclear staining in tumoral cells. hsp72/73 expression was demonstrated mainly as cytoplasmic staining, but six tumours also showed focal weak nuclear staining. Seven cases showed p53 and hsp72/73 coexpression with immunoreactivity for both proteins in the same neoplastic cells, three of them with focal areas of nuclear coexpression. p53 expression was seen more frequently in cases that showed a high intensity (+ + +) of hsp72/73 staining. No significant association was observed between the expression of the two proteins and clinicopathological features. CONCLUSIONS: More than half of our cases may have some impairment in p53 protein growth suppressive function, as a result of p53 gene alterations or complex formation. The positive correlation between p53 expression and intensity of hsp72/73 supports the postulate of a p53 regulating function for the chaperone hsp72/73. A high intensity of hsp72/73 immunohistochemical staining could be used as an indirect marker of p53 gene abnormalities.

BACKGROUND Recent studies have suggested that the Epstein-Barr virus (EBV) is associated with leiomyosarcoma in children with human immunodeficiency virus (HIV) and in organ transplant recipients. To determine whether EBV is associated with leiomyosarcoma in HIV negative patients, the authors examined resected leiomyosarcomas for EBV and HIV. METHODS Twenty-four leiomyosarcomas were studied and their diagnosis confirmed on pathologic review. From these specimens DNA was isolated. Tumor samples were analyzed for EBV and HIV using a polymerase chain reaction (PCR) technique followed by gel electrophoresis and Southern blot analysis. DNA from an EBV-infected human Burkitt's lymphoma cell line and peripheral blood from an HIV positive patient were used as positive controls for the presence of EBV and HIV, respectively. Immunohistochemistry was performed using an antibody to Epstein-Barr nuclear antigen. RESULTS HIV was not present in any of the patients analyzed. EBV DNA was detected in tumor tissue; however, 80 cycles of PCR were used before EBV sequences were detected. Therefore, the data indicate that tumor tissue was not infected with EBV. The positive results observed after 80 cycles of PCR were likely due to infiltrating lymphocytes. Immunohistochemistry confirmed the lack of active or latent EBV infection in tumor cells. CONCLUSIONS The results indicate that EBV is not associated with sporadic leiomyosarcoma in HIV negative patients. Therefore, the biology of leiomyosarcoma associated with HIV may be substantially different from the more common sporadic form. Cancer 1997; 80:204-10. © 1997 American Cancer Society.

The general impression about gallbladder carcinomas is that they are uniformly fatal; however, for the early forms, an entirely different picture indicating a very good prognosis is evolving from the high-incidence regions. We subjected 190 early gallbladder carcinomas (EGBC), defined as carcinomas confined to and above the tunica muscularis (AJCC's Tis, T1a, and T1b), and identified in cholecystectomy specimens sampled entirely according to an established protocol, to detailed analysis. Average patient age was 57.9 years (29–95). In more than half of the cases (114/190; 60 %), the tumor was inapparent by gross examination. In 81 cases (42.6 %), carcinomatous epithelium abutted the muscularis, whereas 57.4 % (n = 109) were qualified as intramucosal with no overt contiguity with muscularis. Intraepithelial extension into Rokitansky–Aschoff sinuses (RAS) was found in 34 cases (17.8 %). At the time of data analysis, 171 patients (99 %) were alive. Overall actuarial survival was 92.3 % at 5 years and 90.4 % at 10 years. The 5- and 10-year actuarial survival rates of the intramucosal group (93.2 and 92.1 %, respectively) were not statistically different from that of the muscle-abutting group (89.7 % and 88.2 % ; p = 0.334). Patients with RAS involvement had a significantly shorter survival than those without (p

Correspondencia: Dr. Oscar Tapia E. Manuel Montt 112. Codigo Postal 478-1176. Temuco, Chile. otescalona@gmail.com y esplenomegalia de 21 cm (Figura 1). Se efectuo biopsia ganglionar que evidencio una linfoadenopatia granulomatosa no caseosa compatible con sarcoidosis. Se complemento estudio con niveles de enzima convertidora de angiotensina que resultaron elevados (271 U/L). Dado los hallazgos clinicos, de laboratorio e histopatologicos se diagnostico una sarcoidosis y realizo esplenectomia. El estudio macroscopico demostro un bazo de 19,8 cm de longitud mayor, de consistencia aumentada y levemente granular (Figura 2). El examen Mujer de 41 anos con historia de 8 meses de dolor en hemiabdomen izquierdo, baja de peso y compromiso del estado general. Al examen fisico se constataron adenopatias cervicales e inguinales y bazo acentuadamente aumentado de tamano. El hemograma demostro anemia normociticanormocromica, sin alteraciones de la serie blanca ni megacariocitica. La tomografia computada de cuello, torax y abdomen mostro ganglios linfaticos aumentados de tamano a nivel submandibular, yugular, mediastinico, axilar, retroperitoneal e inguinal

Scarce biological information exists about the importance of preneoplastic lesions in gallbladder cancer. The aim of this study was to estimate the time required for the sequence of dysplasia (DY) to carcinoma of the gallbladder.Eighty-four cases of DY, 60 cases of early carcinomas (ECs), 181 cases of advanced carcinomas (ACs), and 121 cases of metastatic (ME) gallbladder cancer were analyzed. Age was used as the main parameter. Statistical analysis was performed using analysis of variance and multiple regression analysis.Among all cases, the mean age of female patients was lower than the mean age of male patients (P = 0.001). A significant difference in mean age between sexes by specific type of lesion was also observed (P0.001). The mean age was 46.3 years (SD, 16) in the DY group, 57.5 years (SD, 16.7) in the EC group, 59 (SD, 13.7) in the AC group, and 61.1 (SD, 12.1) in the ME group. Multiple regression analysis showed statistically significant differences (r = 0.386; P0.001) in the mean age of patients with dysplastic lesions compared with the carcinoma group.According to these observations, the period required to progress from dysplasia to advanced gallbladder carcinoma would be around 15 years, observing a continuum in the progression of the lesions.

International audience; A series of novel complexes of the Ru(L)(2)(CO)(2) L = 2-(3' methoxyphenyl)-1,8-naphthyridine (complex 1), and type Ru(acac)(2)(L)(CO) with L = 2-(3' methoxyphenyl)-1,8-naphthyridine (complex 2), 2-(2'-bromophenyl)-1,8-naphthyridine (complex 3) and 2-phenyl-1,8-naphthyridine (complex 4) was synthesized and characterized. We found that the complexes 2, 3, and 4 can be directly synthesized from Ru-3(CO)(12). The complex Ru(acac)(2)(L)(CO) L = 2-(3' methoxyphenyl)-1,8-naphthyridine (2) was characterized by X-ray single crystal analysis which confirms the monodentate coordination mode of the 1,8-naphthyridine derivate and the cis arrangement of the acac ligands. Preliminary studies in transfer hydrogenation of acetophenone in the presence of 2-propanol show the good catalytic activity of complex 2 with 92% conversion. (C) 2012 Elsevier B.V. All rights reserved.