H2A.Z overexpression suppresses senescence and chemosensitivity in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most intractable and devastating malignant tumors. Epigenetic modifications such as DNA methylation and histone modification regulate tumor initiation and progression. However, the contribution of histone variants in PDAC is unknown. Here, we demonstrated that the histone variant H2A.Z is highly expressed in PDAC cell lines and PDAC patients and that its overexpression correlates with poor prognosis. Moreover, all three H2A.Z isoforms (H2A.Z.1, H2A.Z.2.1, and H2A.Z.2.2) are highly expressed in PDAC cell lines and PDAC patients. Knockdown of these H2A.Z isoforms in PDAC cell lines induces a senescent phenotype, cell cycle arrest in phase G2/M, increased expression of cyclin-dependent kinase inhibitor CDKN2A/p16, SA-ß-galactosidase activity and interleukin 8 production. Transcriptome analysis of H2A.Z-depleted PDAC cells showed altered gene expression in fatty acid biosynthesis pathways and those that regulate cell cycle and DNA damage repair. Importantly, depletion of H2A.Z isoforms reduces the tumor size in a mouse xenograft model in vivo and sensitizes PDAC cells to gemcitabine. Overexpression of H2A.Z.1 and H2A.Z.2.1 more than H2A.Z.2.2 partially restores the oncogenic phenotype. Therefore, our data suggest that overexpression of H2A.Z isoforms enables cells to overcome the oncoprotective barrier associated with senescence, favoring PDAC tumor grow and chemoresistance. These results make H2A.Z a potential candidate as a diagnostic biomarker and therapeutic target for PDAC.

Obstructive cholangiopathy patient caused by cytomegalovirus and Kaposi sarcoma in a person living with HIV and hepatitis C.

We present the case of a 28-year-old man with recently-diagnosed human immunodeficiency virus and hepatitis C virus infection. He developed obstructive cholangiopathy secondary to cytomegalovirus and Kaposi sarcoma, both diagnosed by endoscopic retrograde cholangiopancreatography and biopsies. He received antiretroviral therapy, chemotherapy and valganciclovir with full recovery.

The fourth Mexican consensus on Helicobacter pylori. / IV consenso mexicano sobre Helicobacter pylori.

Important advances have been made since the last Mexican consensus on the diagnosis and treatment of Helicobacter pylori (H. pylori) infection was published in 2007. Therefore, the Asociación Mexicana de Gastroenterología summoned 20 experts to produce "The Fourth Mexican Consensus on Helicobacter pylori". From February to June 2017, 4 working groups were organized, a literature review was performed, and 3 voting rounds were carried out, resulting in the formulation of 32 statements for discussion and consensus. From the ensuing recommendations, it was striking that Mexico is a country with an intermediate-to-low risk for gastric cancer, despite having a high prevalence of H. pylori infection. It was also corroborated that peptic ulcer disease, premalignant lesions, and histories of gastric cancer and mucosa-associated lymphoid tissue lymphoma should be considered clear indications for eradication. The relation of H. pylori to dyspeptic symptoms continues to be controversial. Eradication triple therapy with amoxicillin, clarithromycin, and a proton pump inhibitor should no longer be considered first-line treatment, with the following 2 options proposed to take its place: quadruple therapy with bismuth (proton pump inhibitor, bismuth subcitrate, tetracycline, and metronidazole) and quadruple therapy without bismuth (proton pump inhibitor, amoxicillin, clarithromycin, and metronidazole). The need for antimicrobial sensitivity testing when 2 eradication treatments have failed was also established. Finally, the promotion of educational campaigns on the diagnosis and treatment of H. pylori for both primary care physicians and the general population were proposed.

[The value of targeted biopsies with endoscopic magnification and narrow band image vs. chromoendoscopy for the diagnosis of gastric metaplasia]. / Valor de la biopsia dirigida con magnificación endoscópica más imagen de banda estrecha vs. Cromoendoscopia para el diagnóstico de metaplasia gástrica.

INTRODUCTION: Endoscopy is the better test to detect premalignant lesions, but its main problem is the sampling error. OBJECTIVES: To evaluate the diagnostic usefulness of endoscopic biopsies using narrow band imaging (NBI) vs. chromoendoscopy for diagnosing gastric intestinal metaplasia. METHODS: Forty one patients were studied with conventional endoscopy, NBI magnification endoscopy and chromoendoscopy (3% acetic acid, 0.6% indigo carmine) for examination of gastric antrum. Biopsies were taken randomly from the antrum, body and incisura angularis. Additional biopsies were taken from areas with villous or crypt pattern according to NBI and chromoendoscopy examination (targeted biopsies). RESULTS: 240 biopsies were taken, 205 randomized biopsies and 35 targeted biopsies. Intestinal metaplasia was found in 25 randomized biopsies and 9 directed samples (12% vs. 25.7%). The NBI and chromoendoscopy had sensitivity of 70% vs. 77%, specificity of 97% vs. 98%, with diagnostic accuracy of 96% vs. 97%, respectively. Random biopsies and targeted biopsies had a sensitivity of 91% vs. 74%, specificity of 51% vs. 95%, and diagnostic accuracy of 93% vs. 86%, respectively. The intra-observer variability showed a k value of 0.86 (range 0.74 to 0.99). CONCLUSION: Targeted biopsies are more specific than random biopsies to detect gastric intestinal metaplasia. NBI and chromoendoscopy may be used similarly to guide biopsies.

[Concordance between pathologists in the diagnosis of gastric atrophy according with the OLGA system]. / Concordancia en el diagnóstico de atrofia gástrica entre patólogos según el sistema OLGA.

BACKGROUND: The intestinal gastric cancer is preceded by a sequence of pathological changes whose link is mucosal atrophy. The modified Sydney system for atrophy is a parameter not reproducible among pathologists. AIM: To know the interobserver variability using the OLGA system (Operative Link on Gastritis Assessment). METHODS: We selected 116 histologic slides. Sixty cases of both types of atrophy and 56 without atrophy were included. Three general pathologists, interested in gastrointestinal biopsies independently review the slides and established a diagnosis. For statistical analyses we employed singles frequencies in order to describe the individual diagnosis and the kappa test for evaluate the concordance between 2 and 4 observers with 2 and 3 categories. RESULTS: The global concordance has a kappa index of 0.48 (IC 95% 0.4-0.57). When we compared two pathologists the kappa index varies from 0.82(IC 95% 0.73-0.91) to 0.36 (IC 95% 0.22-0.5). The consensus among three pathologists was achieved in 25 out 30 slides in the metaplastic variety and 11 out 30 for the non-metaplastic type. The concordance for the atrophy scale has a kappa index between 0.2 and 0.5. CONCLUSION: The problematic atrophic evaluation with the Sydney system justify every effort to improve the interobserver evaluation. The OLGA system seems reproducible, although laborious,it requires a careful application, but with daily practice it could be applied easier. The clinician acceptation becomes crucial.

Antimicrobial resistance and characterization of Helicobacter pylori strains isolated from Mexican adults with clinical outcome.

Eradication of Helicobacter pylori infection in Mexico is of great importance due to the elevated seroprevalence, however, there is yet very little information about antibiotic resistance rates in H. pylori isolates in our country. We analyzed susceptibility to three antimicrobials used in therapy of 49 H. pylori strains isolated from patients with active chronic gastritis, active chronic gastritis with lymphoid follicles, intestinal metaplasia and gastric cancer. All isolated strains were susceptible to amoxicillin, 28 (58%) were resistant to metronidazole and 2 (4%) were resistant to both clarithromycin and metronidazole. Sequence analysis of the 23S rRNA of the two clarithromycin-resistant strains showed the A2142G mutation in one and A2143G and T2182C mutations in the other. Metronidazole resistance was associated with cagA negative strains with a frequency of 82% (9/11). No significant correlation was found between vacA s/m alleles and metronidazole resistance.

[Early gastric carcinoma. Analysis of 21 cases]. / Carcinoma gástrico incipiente. Análisis de 21 casos.

BACKGROUND: Early gastric carcinoma (EGC) is defined as a neoplasm confined to the mucosa and submucosa regardless of the presence of metastasis. This lesion is found in approximately 3% of cases in Mexico. The aim of this study is to describe our experience with EGC, emphasizing early detection as the most useful method to decrease mortality. METHODS: Retrospective review of records of patients with EGC treated at an oncologic referral center over a 12-years period. RESULTS: Twenty-one cases of EGC were retrieved. Mean age was 58.1 years (range, 33 to 84). Twelve were women and nine, men. Lymph node or distant metastasis were not found. Overall 5-year survival was 66.4%. Twenty patients underwent radical gastrectomy and only one underwent wedge resection of the gastric wall. Two patients (9.5%) presented recurrence and cancer-related death. Mean follow-up was 8.3 years. CONCLUSION: The prognosis of EGC in our hospital is lower than in countries other than Mexico and this lesion is found with low frequency. Increasing the detection EGC is the best method to reduce GC-related mortality.

Pathological disorders of the gastric mucosa surrounding carcinomas and primary lymphomas.

OBJECTIVE: Gastritis, intestinal metaplasia, atrophy, and dysplasia are disorders that frequently precede the full development of gastric adenocarcinoma. On the other hand, primary gastric lymphomas seem to arise from mucosa-associated lymphoid tissue. It is well accepted that these histological changes are caused by Helicobacter pylori infection. The objective of this study is to determine the frequency and characteristics of epithelial and lymphoid tissue disorders of the gastric mucosa surrounding primary carcinomas and lymphomas. METHODS: We studied 111 gastrectomies from patients harboring primary adenocarcinomas (30 intestinal and 30 diffuse type) and 51 gastric lymphomas. For comparative purposes, we analized 86 stomachs from patients who died of diseases other than gastric malignancies. Histopathological disorders of the gastric mucosa adjacent to primary neoplasms such as atrophy, intestinal metaplasia, and dysplasia were recorded. Lymphoid follicles were classified in two groups, with or without expansion. Expansion was characterized by increased size, irregular borders, enlarged marginal zone, and expanded germinal centers. Differences were statistically evaluated with chi2 and Fisher exact tests, odds ratio, and relative risk, with 95% CI. p values <0.05 were considered statistically significant. RESULTS: Most intestinal-type adenocarcinomas showed atrophy (76.6%) and intestinal metaplasia (86.6%) and less frequently, dysplasia (23.3%), in the surrounding gastric mucosa. Expansive lymphoid follicles were more frequent among lymphomas than in adenocarcinomas (56.8% vs 25%); however, a high percentage of lymphomas were also associated with atrophy (50.9%), intestinal metaplasia (62.7%), and rarely dysplasia (11.8%). On the contrary, diffuse-type adenocarcinoma displayed less frequently atrophy (33%), intestinal metaplasia (50%), and dysplasia (3%). Gastric mucosa from patients without any gastric neoplasia was almost normal (84%), whereas the remaining 16% showed, both or alone, atrophy and intestinal metaplasia. CONCLUSION: Histopathological disorders of the gastric mucosa are not specific for any neoplasm, but intestinal-type adenocarcinomas frequently showed atrophy, intestinal metaplasia, and not uncommonly, dysplasia of the surrounding non-neoplastic gastric mucosa. Diffuse-type adenocarcinomas did not frequently show such lesions. Primary lymphomas displayed expansive lymphoid follicles and also a high percentage of atrophy and intestinal metaplasia of the surrounding gastric mucosa. The presence of intestinal metaplasia, atrophy, and lymphoid follicles with expansion in endoscopic biopsies could suggest a higher suceptibility for the development of gastric intestinal-type adenocarcinoma or gastric lymphoma. Patients harboring such histopathological changes must receive eradication therapy against H. pylori and probably closer follow-up.

Screening markers for chronic atrophic gastritis in Chiapas, Mexico.

Intestinal-type gastric adenocarcinomas usually are preceded by chronic atrophic gastritis. Studies of gastric cancer prevention often rely on identification of this condition. In a clinical trial, we sought to determine the best serological screening method for chronic atrophic gastritis and compared our findings to the published literature. Test characteristics of potential screening tests (antibodies to Helicobacter pyloni or CagA, elevated gastrin, low pepsinogen, increased age) alone or in combination were examined among consecutive subjects enrolled in a study of H. pylori and preneoplastic gastric lesions in Chiapas, Mexico; 70% had chronic atrophic gastritis. English-language articles concerning screening for chronic atrophic gastritis were also reviewed. Sensitivity for chronic atrophic gastritis was highest for antibodies to H. pylori (92%) or CagA, or gastrin levels >25 ng/l (both 83%). Specificity, however, was low for these tests (18, 41, and 22%, respectively). Pepsinogen levels were highly specific but insensitive markers of chronic atrophic gastritis (for pepsinogen I <25 microg/l, sensitivity was 6% and specificity was 100%; for pepsinogen I:pepsinogen II ratio <2.5, sensitivity was 14% and specificity was 96%). Combinations of markers did not improve test characteristics. Screening test characteristics from the literature varied widely and did not consistently identify a good screening strategy. In this study, CagA antibodies alone had the best combination of test characteristics for chronic atrophic gastritis screening. However, no screening test was both highly sensitive and highly specific for chronic atrophic gastritis.

Histologic changes of the gastric mucosa associated with primary gastric lymphoma in endoscopic biopsy specimens.

CONTEXT: Recently, we have observed intestinal metaplasia, atrophy, and dysplasia in the mucosa adjacent to primary gastric lymphoma (PGL) in gastrectomy specimens. OBJECTIVE: To determine the frequency and type of epithelial disorders at the histopathologic level in the mucosa adjacent to PGL in endoscopic specimens. DESIGN: We studied 54 endoscopic biopsies from patients harboring PGL. We searched for the following morphologic changes in the gastric mucosa: intestinal metaplasia; atrophy; dysplasia; epithelial erosion; and atypical regeneration of the glandular epithelium. Other nonepithelial findings such as lymphoid follicles, Helicobacter pylori, and lymphoma grade, were also recorded. For comparative purposes, 50 endoscopic biopsies with gastric adenocarcinoma and 50 biopsies with chronic gastritis associated with H pylori infection were also studied. RESULTS: The 54 biopsies included 28 (52%) low-grade and 26 (48%) high-grade PGLs. We found intestinal metaplasia in 32 biopsies (59%), atrophy in 20 biopsies (37%), dysplasia in 2 biopsies (4%), erosion of the epithelium in 33 biopsies (61%), and atypical regenerative changes of the glandular epithelium in 10 biopsies (19%). Lymphoid follicles were found in 21 biopsies (39%), and H pylori was demonstrated in 31 biopsies (57%). When groups were compared, the frequency of epithelial changes in biopsies from patients with PGL and adenocarcinoma was similar. Intestinal metaplasia or atrophy were present in only 10% of biopsies from patients with gastritis, and dysplastic glands were not identified. CONCLUSIONS: Biopsies from patients with PGL showed chronic damage of the gastric mucosa at diagnosis, including precancerous conditions. Intestinal metaplasia and atrophy were among the most frequent disorders, but dysplasia was also occasionally present. Endoscopists and pathologists must be acquainted with such changes and look for them in the initial biopsy, as well in subsequent samples. This practice is particularly important when reviewing biopsies from patients with low-grade mucosa-associated lymphoid tissue (MALT)-lymphomas who are eligible for eradication treatment for H pylori.

Increasing frequency of gastric lymphoma in two national institutes of health in Mexico.

BACKGROUND: Some studies performed in developed countries with caucasian population have suggested an increase in the frequency of primary gastric lymphoma (PGL) in the past two decades. OBJECTIVE: To establish the frequency of PGL in two National Institutes of Health in Mexico in an interval of 18 years. METHODS: We reviewed 1,854 gastric malignant neoplasms diagnosed between 1979-1996 in mestizo patients seen at two different institutions. One of them (INC) is an oncological hospital, whereas the other one (INN) is a general hospital which treats patients with benign as well as malignant gastrointestinal diseases. RESULTS: A hundred and sixty three (8.8%) gastric lymphomas were identified from 1,854 gastric malignant tumors. The incidence of PGL showed a two to three-fold increase in the last years of the study in both institutions. The increased frequency was highly significant when compared to the initial rate. This increase does not appear to be due to patient selection criteria nor to the number of malignant gastric tumors in our institutions. CONCLUSIONS: Our results indicate an increased frequency of PGL the patient population of two National Institutes of Health in Mexico during the last years. Additional studies are necessary in order to define in the increase in PGL is limited to certain geographical areas or ethnic groups.

[Multiorgan resection in T4 colonic adenocarcinoma. Report of a case]. / Resección multiorgánica en adenocarcinoma de colon T4. Informe de un caso.

BACKGROUND: Colorectal cancer is the second among gastrointestinal malignancies in Mexico Locally advanced disease or metastatic lesions are frequently found. To resect or not such a tumor is a difficult decision. OBJECTIVE: To report a case of colon cancer with multivisceral invasion resected and to review the published information. CLINICAL MATERIAL: A 43 year-old Mexican male with rectal bleeding and weight loss with a tumor located in transverse colon with direct invasion to stomach. CT scan demonstrated invasion to spleen and pancreas. En-bloc radical-extended right colectomy, total gastrectomy, distal pancreatectomy, splenectomy and left adrenalectomy was performed. Adjuvant chemotherapy was used. At 12-month follow-up he is asymptomatic, without neoplasic activity and with good quality of life. CONCLUSION: An aggressive multiorganic resection in T4 colorectal tumors is justified in selected cases. The high morbidity and mortality of these procedures must be evaluated individually, and if permissive must be performed.

Pathologic features of the gastric mucosa adjacent to primary MALT-lymphomas.

The frequency of reported cases of primary gastric mucosa-associated lymphoid tissue (MALT)-lymphoma is increasing worldwide. Helicobacter pylori plays a preponderant role in its pathogenesis. Gastric MALT-lymphoma arises from nonrecirculating centrocytelike cells located at the periphery of reactive lymphoid follicles, which are common in patients infected with this microorganism. Histopathologic features other than lymphoid follicles have not been well described. In this study the authors describe the morphologic changes in the gastric mucosa adjacent to MALT-lymphomas. From the files of the departments of pathology at the Instituto Nacional de Cancerologia and the Instituto Nacional de la Nutricion in Mexico City, primary gastric MALT-lymphomas were retrieved. Patients with hematoxylin-eosin-stained histologic sections, including the overt neoplasia and the neighboring gastric mucosa, were selected. Lymphoid follicles as well as intestinal metaplasia, atrophy, and eosinophils were evaluated as present or absent and graded as proposed by the Updated Sydney System for gastritis. Fifty-one patients were eligible for analysis. There were 35 low-grade and 16 high-grade primary MALT-lymphomas. Forty-seven patients (92.6%) showed reactive lymphoid follicles in the neighboring mucosa, 32 patients (69.5%) had intestinal metaplasia, and 26 patients (54.1%) demonstrated atrophy. In 41 patients (73.8%) there was an increased number of eosinophils. Our findings suggest that lymphoid follicles, intestinal metaplasia, atrophy, and eosinophils in an endoscopic biopsy are markers of both gastric lymphoma and carcinoma.

Epstein-Barr virus-associated gastric carcinoma in Mexico: analysis of 135 consecutive gastrectomies in two hospitals.

Epstein-Barr virus (EBV) has been implicated in the genesis of gastric carcinoma. The presence of clonal episomal viral forms in the nuclei of neoplastic gastric epithelial cells suggests that viral infection occurs before the development of gastric carcinoma. Mexico is a country at high risk for gastric cancer-it is the second cause of death among patients who die of cancer in that country. A series of 135 consecutive non-selected gastrectomies from two hospitals in Mexico City were analyzed to search for EBV in gastric carcinomas. EBV-encoded small non-polyadenylated RNA (EBER) in situ hybridization was performed on 5-microm paraffin-embedded tissue sections. Age, gender, anatomical site, histological type, and invasiveness of gastric carcinomas were obtained from the records in the corresponding Departments of Pathology. Eleven (8.15%) of the 135 cases were EBER-1-positive gastric carcinomas. Six occurred in males and five in females. In three women, the neoplasia was localized in the antrum. Five of the 11 cases were lymphoepithelioma-like carcinomas and, in two of them, an unusual foreign body-type inflammation was observed. Environmental factors could influence the distinctive pathologic features of EBV-associated gastric carcinoma in the Mexican population.

Single-step PCR amplification and enzyme restriction analysis of the entire Helicobacter pylori cytotoxin vacA gene for genetic variability studies.

To monitor changes along the entire Helicobacter pylori vac A gene we carried out full-length single-step PCR amplification in 21 gastritis and gastric cancer isolates. HindIII restriction analysis led us to detect a > 400-bp internal insertion in vacA subsequently shown to be a direct 451-bp gene duplication. We found HindIII profiles for 16 genes that allowed their grouping into two restriction patterns that were related to theoretical profiles for previously sequenced Western genes. Comparisons with theoretical HindIII patterns for Japanese isolates appear suggestive of geographical H. pylori clonality. Full-length single-step PCR amplification seems suitable for quick restriction pattern assignment and detection of gene size changes.

Intestinal type: diffuse type ratio of gastric carcinoma in a Mexican population.

This study was performed in order to define the histological patterns of gastric carcinoma according to Lauren's classification and the IT:DT ratio in a Mexican population. We analyzed the relative frequency of intestinal-type and diffuse-type carcinomas in a group of patients, diagnosed at the Instituto Nacional de Cancerologia in Mexico City between 1982 and 1992. Of the 460 cases of gastric cancer, 242 (52.7%) were of the intestinal-type, 206 (44.7%) of the diffuse type, and 12 (2.6%) others. A predominance of the diffuse type among the younger age groups (< 50 years) was observed-the transitional age for men and women occurred in the sixth decade. The global intestinal: diffuse ratio was 1.2 and increased with age. This ratio remained similar during the 11 years of the analysis. Men had a higher proportion of intestinal type carcinoma than women. These findings indicate that Mexico is not a low risk area for gastric cancer with a consistently low intestinal: diffuse type ratio. Despite differences in geographic and demographic patterns, the intestinal and diffuse types of gastric carcinoma have common etiological factors.

Helicobacter pylori and lymphoid follicles in primary gastric MALT-lymphoma in Mexico.

We reviewed our cases of gastric MALT-lymphomas over a 12-year period at a national oncological referral center, the Instituto Nacional de Cancerología in Mexico City, looking for morphological evidence of Helicobacter pylori infection near the primary neoplasia. H pylori as well as lymphoid follicles and chronic active gastritis were carefully searched for in the adjacent mucosa. There were 23 (85%) low-grade and four (15%) high-grade MALT-lymphomas. H pylori microorganisms were found adjacent to the neoplasia in 23 cases (85%; CI 95% = 72-99%) but the lymphoid follicles were seen in 15 of 23 (65%; CI = 56-74%). Chronic active gastritis was present in 25 cases (93%; Cl = 90-95%). There was a close association between H pylori and gastric MALT-lymphoma. Lymphoid follicles were a reliable indicator of infection and the claimed pathophysiological substrate for MALT-lymphoma. We conclude that patients in whom gastric lymphoid follicles are detected, must remain under clinical follow-up since H pylori is a plausible promoter of neoplastic transformation.

[Cystadenoma of the biliary tract]. / Cistadenoma de vías biliares.

The case of a 12-year-old boy with the diagnosis of intrahepatic biliary duct cystadenoma is presented. A critical review of the literature revealed less than 100 cases described at present. Differential diagnosis with other intrahepatic cystic lesions of varied etiology is discussed too.

Cystic dilatation of the cystic duct: a new type of biliary cyst.

A case of a patient with a congenital cyst that was localized solely to the cystic duct is presented. We propose including this anomaly in the biliary cyst classifications, which currently include choledochal and intrahepatic and extrahepatic biliary cysts. The diagnosis and management of this new type of cyst in addition to other types of biliary cysts are discussed.