Celiac Disease and Other Causes of Duodenitis.

CONTEXT: - Patients who receive an upper gastrointestinal endoscopic examination frequently have biopsies taken from the duodenum. Accurate interpretation of duodenal biopsies is essential for patient care. Celiac disease is a common clinical concern, but pathologists need to be aware of other conditions of the duodenum that mimic celiac disease. OBJECTIVE: - To review the normal histologic features of duodenal mucosa and describe the clinical and histologic findings in celiac disease and its mimics, listing the differentiating features of biopsies with villous atrophy and epithelial lymphocytosis. DATA SOURCES: - The study comprises a literature review of pertinent publications as of November 30, 2016. CONCLUSIONS: - Celiac disease is a common cause of abnormal duodenal histology. However, many of the histologic features found in the duodenal biopsy of patients with celiac disease are also present in other conditions that affect the small bowel. Diagnostic precision may be enhanced by obtaining a careful patient history and by ancillary laboratory testing, particularly for the presence of antitissue transglutaminase antibodies.

Handling and Pathology Reporting of Gastrointestinal Endoscopic Mucosal Resection.

Endoscopic mucosal resection (EMR) is a non-invasive alternative to surgery that is now frequently used for resection of early lesions in both upper and lower parts of the gastrointestinal (GI) tract. One of the main advantages of these techniques is providing tissue for histopathological examination. Pathological examination of endoscopically resected specimens of GI tract is a crucial component of these procedures and is useful for prediction of both the risk of metastasis and lymph node involvement. As the first step, it is very important for the pathologist to handle the EMR gross specimen in the correct way: it should be oriented, and then the margins should be labeled and inked accurately before fixation. In the second step, the EMR pathological report should include all the detailed information about the diagnosis, grading, depth of invasion (mucosa only or submucosal involvement), status of the margins, and the presence or absence of lymphovascular invasion. The current literature (PubMed and Google Scholar) was searched for the words "endoscopic mucosal resection" to find all relevant publications about this technique with emphasis on the pathologist responsibilities.

Malignant Colorectal Polyps; Pathological Consideration (A review).

BACKGROUND: Routine screening colonoscopy is on the rise and pathologists have to deal with the ever larger numbers of excised colonic polyps. It is very important to optimize the patients' individual treatment and further surveillance. Pathologists play a critical role in management, as most of the clinical decisions concerning colonic polyp management are based on pathologic findings. One of the most important clinical issues in colonic adenomas is the diagnosis of malignancy and reporting its different aspects by the pathologist. The histologic type and the extent of carcinoma within a malignant polyp have considerable impact on the decisions of gastroenterologists and surgeons for further management. Therefore, the most recent literature regarding the diagnosis and reporting of the different features of malignant polyps was reviewed. DATA ACQUISITION: There is growing literature regarding the different pathologic features and reporting of malignant colonic polyps, and in this review, published articles that are listed on Google Scholar and Pub Med are discussed. CONCLUSION: Diagnosis of malignant colon polyp requires the presence of tumor cells that are penetrating beyond the muscular mucosa into submucosa (pT1). As well as establishing a diagnosis of malignant polyp, it is very important to report the size of the invasive component, the presence or absence of lymphovascular invasion, the degree of tumor differentiation and the distance of the carcinoma from the line of resection. Other important features that may be reported include: the presence or absence of tumor budding, the depth of tumor cell penetration into the submucosa, and results of immunohistochemistry for mismatch repair proteins and BRAF.

A Therapeutic Uricase with Reduced Immunogenicity Risk and Improved Development Properties.

Humans and higher primates are unique in that they lack uricase, the enzyme capable of oxidizing uric acid. As a consequence of this enzyme deficiency, humans have high serum uric acid levels. In some people, uric acid levels rise above the solubility limit resulting in crystallization in joints, acute inflammation in response to those crystals causes severe pain; a condition known as gout. Treatment for severe gout includes injection of non-human uricase to reduce serum uric acid levels. Krystexxa® is a hyper-PEGylated pig-baboon chimeric uricase indicated for chronic refractory gout that induces an immunogenic response in 91% of treated patients, including infusion reactions (26%) and anaphylaxis (6.5%). These properties limit its use and effectiveness. An innovative approach has been used to develop a therapeutic uricase with improved properties such as: soluble expression, neutral pH solubility, high E. coli expression level, thermal stability, and excellent activity. More than 200 diverse uricase sequences were aligned to guide protein engineering and reduce putative sequence liabilities. A single uricase lead candidate was identified, which showed low potential for immunogenicity in >200 human donor samples selected to represent diverse HLA haplotypes. Cysteines were engineered into the lead sequence for site specific PEGylation and studies demonstrated >95% PEGylation efficiency. PEGylated uricase retains enzymatic activity in vitro at neutral pH, in human serum and in vivo (rats and canines) and has an extended half-life. In canines, an 85% reduction in serum uric acid levels was observed with a single subcutaneous injection. This PEGylated, non-immunogenic uricase has the potential to provide meaningful benefits to patients with gout.

The differential effects of metronomic gemcitabine and antiangiogenic treatment in patient-derived xenografts of pancreatic cancer: treatment effects on metabolism, vascular function, cell proliferation, and tumor growth.

BACKGROUND: Metronomic chemotherapy has shown promising activity against solid tumors and is believed to act in an antiangiogenic manner. The current study describes and quantifies the therapeutic efficacy, and mode of activity, of metronomic gemcitabine and a dedicated antiangiogenic agent (DC101) in patient-derived xenografts of pancreatic cancer. METHODS: Two primary human pancreatic cancer xenograft lines were dosed metronomically with gemcitabine or DC101 weekly. Changes in tumor growth, vascular function, and metabolism over time were measured with magnetic resonance imaging, positron emission tomography, and immunofluorescence microscopy to determine the anti-tumor effects of the respective treatments. RESULTS: Tumors treated with metronomic gemcitabine were 10-fold smaller than those in the control and DC101 groups. Metronomic gemcitabine, but not DC101, reduced the tumors' avidity for glucose, proliferation, and apoptosis. Metronomic gemcitabine-treated tumors had higher perfusion rates and uniformly distributed blood flow within the tumor, whereas perfusion rates in DC101-treated tumors were lower and confined to the periphery. DC101 treatment reduced the tumor's vascular density, but did not change their function. In contrast, metronomic gemcitabine increased vessel density, improved tumor perfusion transiently, and decreased hypoxia. CONCLUSION: The aggregate data suggest that metronomic gemcitabine treatment affects both tumor vasculature and tumor cells continuously, and the overall effect is to significantly slow tumor growth. The observed increase in tumor perfusion induced by metronomic gemcitabine may be used as a therapeutic window for the administration of a second drug or radiation therapy. Non-invasive imaging could be used to detect early changes in tumor physiology before reductions in tumor volume were evident.

Immunophenotyping of ampullary carcinomata allows for stratification of treatment specific subgroups.

BACKGROUND: Ampullary carcinomata (AC) can be separated into intestinal (IT) or pancreatobiliary (PB) subtypes. Although morphological, immunohistochemical and molecular differentiation of IT and PB have been well documented; the prognostic significance of histological subtype and whether patients with either subtype benefit from differential chemotherapeutic regimens remains unclear. METHODS: As part of a larger cohort study, patients who underwent resection for AC or pancreatic ductal adenocarcinoma (PDAC) were retrospectively identified. Clinicopathological covariates and outcome were obtained and MUC1, MUC2, CDX2 and CK20 were assessed with immunohistochemistry. RESULTS: Of 99 ACs, the resultant immunophenotypes indicated 48% and 22% were IT and PB, respectively. Thirty (30%) cases were quadruple negative (QN). Within the PDAC cohort (N = 257), the most prevalent immunophenotype was QN (53%). Subsequently, all QN ACs were classified as PB immunohistochemically yielding 47.5% and 52.5% classified as IT and PB, respectively. Involved regional lymph nodes and elevated T-stage were significantly associated with PB compared with IT AC (p = 0.0032 and 0.0396, respectively). Progression-free survival revealed inferior survival for PB versus IT AC (p = 0.0156). CONCLUSIONS: AC can be classified into prognostic groups with unique clinicopathological characteristics using immunohistochemistry. Immunophenotypical similarity of PB and PDAC suggests that treatment regimens similar to those used in PDAC should be explored.

Tumor budding is an independent adverse prognostic factor in pancreatic ductal adenocarcinoma.

Tumor budding is a well-established adverse prognostic factor in colorectal cancer. However, the significance and diagnostic reproducibility of budding in pancreatic carcinoma requires further study. We aimed to assess the prognostic significance of tumor budding in pancreatic ductal adenocarcinoma, determine its relationship with other clinicopathologic features, and assess interobserver variability in its diagnosis. Tumor budding was assessed in 192 archival cases of pancreatic ductal adenocarcinoma using hematoxylin and eosin (H&E) sections; tumor buds were defined as single cells or nonglandular clusters composed of <5 cells. The presence of budding was determined through assessment of all tumor-containing slides, and associations with clinicopathologic features and outcomes were analyzed. Six gastrointestinal pathologists participated in an interobserver variability study of 120 images of consecutive tumor slides stained with H&E and cytokeratin. Budding was present in 168 of 192 cases and was associated with decreased overall survival (P=0.001). On multivariable analysis, tumor budding was prognostically significantly independent of stage, grade, tumor size, nodal status, lymphovascular invasion, and perineural invasion. There was substantial agreement among pathologists in assessing the presence of tumor budding using both H&E (K=0.63) and cytokeratin (K=0.63) stains. The presence of tumor budding is an independent adverse prognostic factor in pancreatic ductal carcinoma. The assessment of budding with H&E is reliable and could be used to better risk stratify patients with pancreatic ductal adenocarcinoma.

Primary peritoneal ependymoma.

Extra-axial ependymomas are exceedingly rare neuroectodermal tumors that arise outside the central nervous system. The majority behave in a benign clinical fashion. In this case, an elderly woman developed an intraperitoneal ependymoma that after surgical excision recurred twice over a period of twenty four years. At each presentation, the tumor demonstrated identical histologic appearances with prominent rosettes as well as perivascular pseudorosettes. Immunohistochemistry showed strong positivity for glial fibrilary acidic protein, estrogen receptors, CAM 5.2 and CD99 with weak staining for pankeratin. Staining was negative for epithelial membrane antigen (EMA) and S-100. Ultrastructurally, the neoplasm showed neuroectodermal features, including filamentous cytoplasm and abundant intercellular bridges. The patient had no lesions in the central nervous system or the para-spinal region, suggesting that this tumor arose spontaneously within the abdominal cavity.

Analysis of microsatellite instability in gastric mucosa-associated lymphoid tissue lymphoma.

In Helicobacter pylori gastritis, constant antigenic stimulation triggers a sustained B-cell proliferation. Errors made during this continuous DNA replication are supposed to be corrected by the DNA mismatch repair mechanism. Failure of this mismatch repair mechanism has been described in hereditary non-polyposis colorectal cancer (HNPCC) and results in a replication error phenotype. Inherent to their instability during replication, microsatellites are the best markers of this replication error phenotype. We aimed to evaluate the role of defects in the DNA mismatch repair (MMR) mechanism and microsatellite instability (MSI) in relation to the most frequent genetic anomaly, translocation t(11;18)(q21;q21), in gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Therefore, we examined 10 microsatellite loci (BAT25, BAT26, D5S346, D17S250, D2S123, TGFB, BAT40, D18S58, D17S787 and D18S69) for instability in 28 patients with MALT lymphomas. In addition, these tumors were also immunostained for MLH1, MSH2, MSH6 and PMS2, as well as screened for the presence of t(11;18)(q21;q21) by real-time polymerase chain reaction (RT-PCR). We found MSI in 5/28 (18%) lymphomas, with MSI occurring in both t(11;18)(q21;q21)-positive and -negative tumors. One tumor displayed high levels of instability, and, remarkably, this was the only case displaying features of a diffuse large B-cell lymphoma. All microsatellite unstable lymphomas showed a loss of MSH6 expression. In conclusion, our data suggest that a MMR-defect may be involved in the development of gastric MALT lymphomas, and that a defect of MSH6 might be associated with those MSI-driven gastric lymphomas.

Does neoadjuvant therapy alter KRAS and/or MSI results in rectal adenocarcinoma testing?

To our knowledge, the genotoxic effects of neoadjuvant chemoradiation therapy on molecular diagnostic testing results are unknown. However, if neoadjuvant treatments were to alter molecular test results, clinical decision-making could be misled. This raises questions about the appropriateness of using posttreatment tumor for testing. To address this, rectal adenocarcinomas both before and after neoadjuvant treatment were evaluated for alterations in KRAS and microsatellite instability (MSI) testing. Neoadjuvant chemoradiation therapy is common in this tumor type, and alterations in these 2 tests would significantly impact management. A total of 17 rectal adenocarcinoma patients with available pretreatment and posttreatment tumor were studied. MSI testing used the revised National Cancer Institute panel of 5 mononucleotide microsatellite repeats, comparing cancers with matched normal control tissues. KRAS codon 12-point and 13-point mutations were examined by polymerase chain reaction amplification and bidirectional sequencing. MSI and KRAS results were unchanged comparing rectal cancer tissue before and after chemoradiotherapy in all 17 patients (P=1.000; 95% CI: 0.3969-2.520). All 17 tumors (100%) were microsatellite stable. KRAS testing identified 12 (72%) wild-type tumors and 5 (28%) codon 12 or 13 mutant tumors with identical KRAS point mutations before and after treatment. The identified MSI and KRAS mutational prevalences parallel those reported in the rectal cancer literature. Neoadjuvant therapy did not alter KRAS codon 12 or 13 or MSI results in rectal adenocarcinoma, providing evidence that either pretreatment biopsy or posttreatment resection tissues are appropriate for testing.

Inhibition of VEGF induces cellular senescence in colorectal cancer cells.

Vascular endothelial growth factor (VEGF) inhibitors, such as bevacizumab, have improved outcomes in metastatic colorectal cancer (CRC). Recent studies have suggested that VEGF can delay the onset of cellular senescence in human endothelial cells. As VEGF receptors are known to be upregulated in CRC, we hypothesized that VEGF inhibition may directly influence cellular senescence in this disease. In our study, we observed that treatment with bevacizumab caused a significant increase (p < 0.05) in cellular senescence in vitro in several CRC cells, such as MIP101, RKO, SW620 and SW480 cells, compared to untreated or human IgG-treated control cells. Similar results were also obtained from cells treated with a VEGFR2 kinase inhibitor Ki8751. In vivo, cellular senescence was detected in MIP101 tumor xenografts from 75% of mice treated with bevacizumab, while cellular senescence was undetectable in xenografts from mice treated with saline or human IgG (p < 0.05). Interestingly, we also observed that the proportion of senescent cells in colon cancer tissues obtained from patients treated with bevacizumab was 4.4-fold higher (p < 0.01) than those of untreated patients. To understand how VEGF inhibitors may regulate cellular senescence, we noted that among the two important regulators of senescent growth arrest of tumor cells, bevacizumab-associated increase in cellular senescence coincided with an upregulation of p16 but appeared to be independent of p53. siRNA silencing of p16 gene in MIP101 cells suppressed bevacizumab-induced cellular senescence, while silencing of p53 had no effect. These findings demonstrate a novel antitumor activity of VEGF inhibitors in CRC, involving p16.

Absence of MMP2 expression correlates with poor clinical outcomes in rectal cancer, and is distinct from MMP1-related outcomes in colon cancer.

PURPOSE: Treatments for colorectal cancer (CRC) are primarily disease stage based. However, heterogeneity in outcome within even a single stage highlights its limitations in predicting disease behavior. Recently, the role of gene expression as predictive and prognostic markers has been explored. Our objectives were to identify consistently differentially expressed genes through meta-analysis of high-throughput gene-expression studies, and evaluate their predictive and prognostic significance in colon (CC) and rectal (RC) cancers. EXPERIMENTAL DESIGN: Publications applying high-throughput gene- expression technologies to specific CRC stages were identified. A vote counting strategy was used to identify the most significant differentially expressed genes. Their predictive and prognostic values were independently assessed in a tissue microarray of 191 cases of stage II-IV CC/RC from two tertiary care centers. Their biological effects were also examined in vitro. RESULTS: MMP1 and MMP2 were identified as consistently underexpressed in liver metastasis compared with primary CRC. Shorter time to distant metastasis and overall survival occurred in stage III CC lacking MMP1 expression, and in stage III RC lacking MMP2. MMP1 levels in stage II and III CC were associated with increased likelihood of distant metastasis, whereas the risk of local recurrence in stage III RC could be stratified by MMP2. Promotion of cell invasion of CRC cell lines exposed to MMP1/2 inhibitors were confirmed in vitro. CONCLUSIONS: MMP1 and MMP2 may be useful biomarkers that can help stratify patients at higher risk of developing recurrence in colorectal cancer, and guide individualized treatment decisions to achieve better outcomes.

Familial adenomatous polyposis-rendering a diagnosis based on recognition of an unusual primary thyroid neoplasm.

It has been well established in the literature that the cribriform-morular variant of papillary thyroid carcinoma (CMVPTC) has been observed with higher frequency in familial adenomatous polyposis (FAP) patients. In the usual setting, patients with FAP are identified based on their germline mutations and the diagnosis of thyroid neoplasm is made after the FAP diagnosis. We herein report a case in which the recognition of a CMVPTC led to the initial diagnosis of FAP. The histological and clinical features of CMVPTC are reviewed with emphasis on its relationship to FAP.

Periodic acid-schiff is superior to hematoxylin and eosin for screening prophylactic gastrectomies from CDH1 mutation carriers.

Hereditary diffuse gastric cancer (HDGC), an autosomal dominant cancer susceptibility syndrome, is largely attributable to germline mutations and deletions in the gene encoding E-cadherin, CDH1. Asymptomatic, mutation-positive individuals often choose prophylactic gastrectomy for cancer risk reduction. Examination of the entire mucosa of prophylactic gastrectomy specimens is essential and shows occult gastric cancers in most cases. We hypothesized that primary screening entire cases stained with periodic acid-Schiff (PAS) instead of hematoxylin and eosin (H&E) could improve diagnostic accuracy and speed of detecting invasive signet-ring adenocarcinoma. Serial sections from 6 prophylactic gastrectomy specimens with molecularly confirmed CDH1 mutations were stained with PAS and H&E, respectively (108 to 164 blocks per case). PAS-stained and H&E-stained slides were randomized for each case and examined microscopically for the presence of invasive signet-ring cells. The time to examine each slide was recorded. Our results showed that significantly fewer lesions were missed (ie, the lesion was initially identified on only 1 section, but present on both sections) on PAS-stained slides (6 missed lesions) than on H&E-stained slides (23 missed lesions); (P<0.05). Furthermore, it took significantly less time to screen a PAS-stained case (3 h 05+/-41 min) than an H&E-stained case (4 h 59+/-1 h 2 min) (P<0.05). Selected lesions were confirmed as epithelial by pan-keratin-positive immunohistochemistry. Thus, doing PAS staining instead of H&E on CDH1 mutation-positive prophylactic gastrectomy specimens may increase the detection rate of adenocarcinoma while reducing screening time.

Insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) overexpression in pancreatic ductal adenocarcinoma correlates with poor survival.

BACKGROUND: Pancreatic ductal adenocarcinoma is a lethal disease with a 5-year survival rate of 4% and typically presents in an advanced stage. In this setting, prognostic markers identifying the more aggressive tumors could aid in management decisions. Insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3, also known as IMP3 or KOC) is an oncofetal RNA-binding protein that regulates targets such as insulin-like growth factor-2 (IGF-2) and ACTB (beta-actin). METHODS: We evaluated the expression of IGF2BP3 by immunohistochemistry using a tissue microarray of 127 pancreatic ductal adenocarcinomas with tumor grade 1, 2 and 3 according to WHO criteria, and the prognostic value of IGF2BP3 expression. RESULTS: IGF2BP3 was found to be selectively overexpressed in pancreatic ductal adenocarcinoma tissues but not in benign pancreatic tissues. Nine (38%) patient samples of tumor grade 1 (n = 24) and 27 (44%) of tumor grade 2 (n = 61) showed expression of IGF2BP3. The highest rate of expression was seen in poorly differentiated specimen (grade 3, n = 42) with 26 (62%) positive samples. Overall survival was found to be significantly shorter in patients with IGF2BP3 expressing tumors (P = 0.024; RR 2.3, 95% CI 1.2-4.8). CONCLUSIONS: Our data suggest that IGF2BP3 overexpression identifies a subset of pancreatic ductal adenocarcinomas with an extremely poor outcome and supports the rationale for developing therapies to target the IGF pathway in this cancer.

Tumor expression of integrin-linked kinase (ILK) correlates with the expression of the E-cadherin repressor snail: an immunohistochemical study in ductal pancreatic adenocarcinoma.

Integrin-linked kinase (ILK) is a key molecule involved in mediating several biological functions including cell-matrix interactions, angiogenesis, and invasion, as well as playing a role in epithelial to mesenchymal transition (EMT) in cancer cells. In ductal pancreatic adenocarcinoma, increased expression of ILK has been linked to tumor prognosis and correlated with increased chemoresistance to drugs, such as gemcitabine. However, the precise relationship between ILK, Snail, E-cadherin, and N-cadherin expression on the stepwise development of pancreatic cancer is unknown. Hence, the purpose of this work was to investigate levels of expression of ILK, Snail, and the cadherins in pancreatic intraepithelial neoplasia (PanIN), and cancer. Resection specimens of 25 randomly selected patients, who underwent a pyloric preserving pancreatoduodenectomy for ductal pancreatic adenocarcinoma, were utilized for this study. Formalin-fixed paraffin embedded pancreatic tissue was immunostained for ILK, E-cadherin, N-cadherin, and Snail by standard techniques. The extent of staining positivity was scored and the results correlated with clinicopathological parameters. In 23 of 25 cases, ILK expression showed extensive positivity (>50%), while two cases did not demonstrate any ILK staining. PanIN grades 1 (n = 16), 2 (n = 11), and 3 (n = 19) lesions demonstrated only focal positivity (<10%) for ILK. E-cadherin showed a reciprocal staining pattern to ILK in 21 of 25 cases, with only focal expression of the marker in pancreatic adenocarcinoma. Interestingly, 15 of 19 PanIN-3 lesions expressed extensive E-cadherin staining. N-cadherin, however, was moderately expressed in the majority of cases (n = 18). Snail expression (n = 22) correlated with ILK expression in ductal pancreatic adenocarcinoma (rho = 0.8168, p = 0.02), but only minimal Snail staining activity was detected in PanIN lesions. The increase in expression of the E-cadherin repressor Snail, as well as the related increase in the ILK expression, may point towards an ILK-mediated induction, opening possible avenues for targeted drug therapy.

A rare case of isolated duodenal metastases from hepatocellular carcinoma associated with p53 and ki-67 expression: a case report.

Hepatocellular carcinoma (HCC) is the most common primary tumor of the liver worldwide. The incidence of HCC is increasing in North America secondary to rises in chronic liver disease from alcohol abuse and viral hepatitis. HCC most commonly metastasizes hematogenously or through lymphatics to the lungs and regional lymph nodes. Involvement of small bowel is rare and typically results from direct invasion and extension. We examined the molecular features related to this extremely rare case of isolated duodenal metastasis of HCC and noted p53 and Ki-67 positive staining. Here, we review the possible molecular and immunohistochemical studies that may aid definitive diagnosis and the evidence for the management of metastatic hepatocellular carcinoma.

Synthesis and structure-activity relationship of aminopyrimidine IKK2 inhibitors.

The synthesis and structure-activity relationship of a novel series of aminopyrimidines are exemplified. Results of key compounds from within this series in the E-selectin reporter cell assay are also reported.

Chronic advanced gastric cancer: clinicopathologic analysis of survival data.

Patients with advanced gastric cancer who survived 5 years or more were studied. They were divided into 2 groups: 31 who later died of their disease (chronic patients) and 33 who were apparently cured (cured patients). Each survivor was matched with a patient who died within 5 years (control patients). The clinical and pathologic features of each group were compared. The 5-year survivors were easily distinguished from the controls by histologic stage, size of neoplasm, intratumoral eosinophil counts, extent of fibrosis; and by most histologic classifications. Chronic patients resembled cured patients in mean age (56 years), stage, size, site, percentage with lymphatic and neural invasion, eosinophil counts, extent of fibrosis, and characteristics in most histologic classifications. Chronic cancers differed from cured cancers by having less venous invasion, fewer solid tumors, more mucinous carcinomas, a lesser proportion of intestinal to diffuse cancers (World Health Organization), and more intracellular mucin production (Goseki). Chronic cancers were lower stage and smaller with less lymphatic, venous, and neural invasion than controls. Their superior overall survival time was largely because of longer progression-free survival. We conclude that chronic advanced gastric cancer patients differ both from cured patients and control patients. The use of pathologic features in addition to the standard Lauren classification better separated the chronic cancers from the cured cancers and showed differences in behavior between histologic types.

Granulomatous hepatitis associated with etanercept therapy.

Etanercept has recently been implicated in the induction of granulomatous reactions. We describe a patient with rheumatoid arthritis who developed granulomatous hepatitis after taking etanercept. Infectious and metabolic causes of liver disease had been excluded and the liver biopsy was not typical of sarcoidosis. Liver enzyme abnormalities improved after etanercept was discontinued. We suggest that etanercept was responsible for the development of granulomatous hepatitis. This has not been previously described and adds to the increasing reports of rare granulomatous reactions induced by etanercept therapy.