Person:

Lauwers, Gregory Y.

Background: Metastatic pancreatic adenocarcinoma has a short median overall survival (OS) of 5–6 months. However, a subgroup of patients survives more than 1 year. We analyzed the survival outcomes of this subgroup and evaluated clinical and pathological factors that might affect survival durations. Methods: We identified 20 patients with metastatic or recurrent pancreatic adenocarcinoma who received single-agent gemcitabine and had an OS longer than 1 year. Baseline data available after the diagnosis of metastatic or recurrent disease was categorized as: 1) clinical/demographic data (age, gender, ECOG PS, number and location of metastatic sites); 2) Laboratory data (Hematocrit, hemoglobin, glucose, LDH, renal and liver function and CA19-9); 3) Pathologic data (margins, nodal status and grade); 4) Outcomes data (OS, Time to Treatment Failure (TTF), and 2 year-OS). The lowest CA19-9 levels during treatment with gemcitabine were also recorded. We performed a univariate analysis with OS as the outcome variable. Results: Baseline logarithm of CA19-9 and total bilirubin had a significant impact on OS (HR = 1.32 and 1.31, respectively). Median OS and TTF on gemcitabine were 26.9 (95% CI = 18 to 32) and 11.5 (95% CI = 9.0 to 14.3) months, respectively. Two-year OS was 56.4%, with 7 patients alive at the time of analysis. Conclusion: A subgroup of patients with metastatic pancreatic cancer has prolonged survival after treatment with gemcitabine. Only bilirubin and CA 19-9 levels were predictive of longer survival in this population. Further analysis of potential prognostic and predictive markers of response to treatment and survival are needed.

Background: Lymph node metastases are prognostically significant in pancreatic ductal adenocarcinoma. Little is known about the significance of direct lymph node invasion. Aim: The aim of this study is to find out whether direct lymph node invasion has the same prognostic significance as regional nodal metastases. Methods: Retrospective review of patients resected between 1/1/1993 and 7/31/2008. “Direct” was defined as tumor extension into adjacent nodes, and “regional” was defined as metastases to peripancreatic nodes. Results: Overall, 517 patients underwent pancreatic resection for adenocarcinoma, of whom 89 had one positive node (direct 26, regional 63), and 79 had two positive nodes (direct 6, regional 68, both 5). Overall, survival of node-negative patients was improved compared to patients with positive nodes (N0 30.8 months vs. N1 16.4 months; p < 0.001). There was no survival difference for patients with direct vs. regional lymph node invasion (p = 0.67). Patients with one positive node had a better overall survival compared to patients with ≥2 positive nodes (22.3 and 15 months, respectively; p < 0.001). The lymph node ratio (+LN/total LN) was prognostically significant after Cox regression (p < 0.001). Conclusions: Isolated direct invasion occurs in 20% of patients with one to two positive nodes. Node involvement by metastasis or by direct invasion are equally significant predictors of reduced survival. Both the number of positive nodes and the lymph node ratio are significant prognostic factors.

Autoimmune pancreatitis (AIP) shows a unique spectrum of histologic features and commonly presents with an abundant IgG4-positive (IgG4+) plasma cell infiltration. However, differentiating AIP from other mass lesions, particularly pancreatic cancer [invasive ductal carcinoma (IDC)] can be clinically challenging. In this study, we evaluated the validity of IgG4 and IgG immunohistochemistry of ampullary and periampullary tissue for the diagnosis of AIP. Our study group consisted of 14 resected AIP cases with appropriate ampullary sections. Superficial ampullary tissue and "shouldering" duodenal mucosa were evaluated for several histologic variables. Immunohistochemistry for IgG4 and IgG was performed. The number of IgG4 and IgG-positive plasma cells was counted and an IgG4+ to IgG+ plasma cells ratio (IgG4/IgG ratio) was evaluated. A control cohort was composed of IDC (n=30) and chronic pancreatitis (CP) (n=29). Although an overlap was present between the groups, the overall inflammation and number of plasma cells in and around the ampulla was significantly increased in AIP compared with CP and IDC. Furthermore, although there was some overlap in the crude number of IgG4+ plasma cells of the ampullary and duodenal tissue between AIP, IDC, and CP, an IgG4/IgG ratio, especially of the ampulla, seems diagnostically useful in differentiating AIP from other "mass forming" lesions. When a cut-off of 0.10 was applied, the diagnostic sensitivity and specificity of the ampullary IgG4/IgG ratio was 86% and 95%, respectively. In conclusion, evaluation of ampullary histology and IgG4/IgG ratio might be proven beneficial in discriminating AIP from other mass forming pancreatic lesions.

Gastric adenocarcinoma is the second leading cause of cancer death worldwide. Epstein–Barr virus (EBV) is present in the malignant cells of approximately 10% of cases. It is unclear whether EBV is being missed in some gastric adenocarcinomas due to insensitive test methods or partial EBV genome loss. In this study, we screened 113 gastric adenocarcinomas from low- and high-incidence regions (United States and Central America) for the presence of EBV using a battery quantitative real-time PCR (Q-PCR) assays targeting disparate segments of the EBV genome (BamH1W, EBNA1, LMP1, LMP2, BZLF1, EBER1) and histochemical stains targeting EBV-encoded RNA (EBER), the latent proteins LMP1 and LMP2, and the lytic proteins BMRF1 and BZLF1. EBV DNA was detected by Q-PCR in 48/75 United States cancers (64%) and in 38/38 Central American cancers (100%), which was a significant differrence. EBER was localized to malignant epithelial cells in 8/48 (17%) United States and 3/38 (8%) Central American cancers. Viral loads were considerably higher for EBER-positive vs EBER-negative cancers (mean 162 986 vs 62 EBV DNA copies per 100 000 cells). A viral load of 2000 copies per 100 000 cells is recommended as the threshold distinguishing EBER-positive from EBER-negative tumors. One infected cancer selectively failed to amplify the LMP2 gene because of a point mutation, whereas another cancer had an atypical pattern of Q-PCR positivity suggesting deletion of large segments of the EBV genome. Three different viral latency profiles were observed in the cancers based on constant expression of EBER and focal or variable expression of LMP1 or LMP2, without lytic protein expression. We conclude that EBV DNA levels generally reflect EBER status, and a panel of at least two Q-PCR assays is recommended for sensitive identification of infected cancers.

Clinical studies converge on the observation that circulating cytokines are elevated in most cancer patients by anti-vascular endothelial growth factor (VEGF) therapy. However, the source of these molecules and their relevance in tumor escape remain unknown. We examined the gene expression profiles of cancer cells and tumor-associated macrophages in tumor biopsies before and 12 days after monotherapy with the anti-VEGF antibody bevacizumab in patients with rectal carcinoma. Bevacizumab up-regulated stromal cell-derived factor 1alpha (SDF1alpha), its receptor CXCR4, and CXCL6, and down-regulated PlGF, Ang1, and Ang2 in cancer cells. In addition, bevacizumab decreased Ang1 and induced neuropilin 1 (NRP1) expression in tumor-associated macrophages. Higher SDF1alpha plasma levels during bevacizumab treatment significantly associated with distant metastasis at three years. These data show that VEGF blockade up-regulates inflammatory pathways and NRP1, which should be evaluated as potential targets for improving anti-VEGF therapy.

OBJECTIVES: Photodynamic therapy (PDT) is increasingly used for the treatment of patients with Barrett's esophagus (BE) with dysplasia or early carcinoma. Post-PDT, some patients show residual BE either exposed to the luminal surface (nonburied) or buried underneath reepithelialized squamous mucosa (buried BE). Buried BE may be a serious clinical problem since it can go unnoticed during surveillance endoscopies. The neoplastic potential of buried BE is poorly understood. The aim of this study was to evaluate the biological characteristics of nonburied and buried BE in patients treated with PDT. METHODS: Twelve patients selected from a cohort of 52 BE patients who received PDT for high-grade dysplasia or intramucosal adenocarcinoma were used for this study because they all had both pre- and post-PDT (nonburied), and post-PDT buried, BE biopsies, without dysplasia, available for analysis. The biopsies were immunostained for Ki-67, p53, cyclin D1, bcl-2, TGF-alpha, EGFR, and AMACR. High fidelity DNA histograms were obtained by image cytometry analysis of Feulgen stained slides, and used to determine peak DNA index (DI), DNA heterogeneity, and 5N exceeding rate (5NER). Comparisons were made between pre-PDT nonburied BE and post-PDT nonburied and buried BE. RESULTS: Pre-PDT BE showed an elevated Ki-67 crypt proliferation rate (43.3%) and p53, bcl-2, TGF-alpha, and EGFR positivity in 8%, 25%, 75%, and 25% of cases, respectively. Cyclin D1 and AMACR were negative in all cases. High fidelity DNA histograms showed mild aneuploidy in 73% of cases. Post-PDT buried BE showed a significantly lower Ki-67 crypt proliferation rate (29.9%) in comparison to nonburied BE, in both pre- PDT (43.3%) and post-PDT (44.4%) biopsies (P < 0.05), but similar rates of positivity for the other peptide markers. In contrast to pre-PDT nonburied BE biopsies, high fidelity DNA histograms revealed that none of the buried BE (0%), and only 2/9 (11%) nonburied BE post-PDT, showed aneuploidy. CONCLUSIONS: Pre-PDT nonburied BE, without dysplasia, shows elevated crypt proliferation and mild, but frequent, DNA content abnormalities. Post-PDT, nonburied BE shows persistently elevated crypt proliferation, but significantly less frequent DNA content abnormalities, whereas buried BE shows decreased crypt proliferation and normal DNA content profile. These results suggest that post-PDT buried BE may have a lower neoplastic potential than pre-PDT BE.

Microsatellite instability (MSI) has been reported in various tumors, with colon cancer as the prototype. However, little is known about MSI in Barrett esophagus (BE)-associated adenocarcinoma. Thus, the aim of this study was to compare the clinicopathologic and molecular features of BE-associated adenocarcinomas with and without MSI. The study cohort consisted of 76 patients with BE-associated adenocarcinomas (66 male, 10 female), with a mean age of 65.1 years. Immunohistochemistry (IHC) for MLH1, MSH2, MSH6, PMS2, and CD3 and in situ hybridization for Epstein-Barr virus-encoded RNA were performed. MLH1 and PMS2 expression was lost by IHC in 5 cases (6.6%); of these, 5 showed high-level MSI (MSI-H) by polymerase chain reaction assay, and 4 showed hMLH1 promoter methylation. Histologically, tumors with MSI-H were heterogenous and included conventional adenocarcinomas with tumor-infiltrating lymphocytes (n=1), medullary carcinoma (n=2), signet ring cells (n=1), and signet ring cell and mucinous components (n=1). Compared with tumors negative for MSI by IHC, BE-associated adenocarcinomas with MSI-H were associated with older patient age (P=0.0060), lymphovascular invasion (P=0.027), and significantly larger numbers of tumor-infiltrating lymphocytes (P<0.0001). However, there was no statistical difference in overall survival between the 2 groups (P=0.285). In conclusion, MSI-H is uncommon in BE-associated adenocarcinomas, but is associated with clinicopathologic features fairly similar to sporadic microsatellite unstable colorectal cancers. Given the growing evidence that indicates lack of benefits from adjuvant therapy with fluorouracil in the colonic counterpart, it may be important to identify MSI-H in BE-associated adenocarcinomas.

Introduction: A histologic diagnosis of chronic colitis raises a relatively limited differential diagnosis that includes inflammatory bowel disease, long-standing infections, and chronic ischemia. In routine clinical practice, inflammatory bowel disease accounts for the majority of cases of chronic colitis. Although a variety of drug-induced injury patterns in the colon have been recognized, there are few well-documented examples of drug-induced chronic colitis. In this study, we report the clinical, histologic, and follow-up data on 17 cases of histologically documented cases of chronic colitis in which a definitive etiologic factor could not be identified. Methods: Using our electronic databases we recorded all cases of chronic colitis in adults over an 8-year period. Patients with a history (prior or subsequent) of inflammatory bowel disease were excluded. Cases showing histologic features of ischemic, pseudomembranous, or granulomatous colitis were excluded. The biopsies were evaluated and semiquantitatively scored for established histologic features of activity and chronicity. The clinical, endoscopic, and follow-up data, including drug usage, was recorded. Results: There were 10 males and 7 females and the mean age was 59 years. The majority of cases involved the cecum or ascending colon (16 of 17 cases). A majority of patients were asymptomatic (n=11), and in others, indications for colonoscopy were occult blood (n=3), hematochezia (n=2), and melena (n=1). The most common mucosal abnormality was erythema (n=10), ulcers (n=3), congestion (n=3), and edematous mucosa (n=1). All cases showed histologic features of chronicity and showed either basal plasmacytosis (94%) or crypt architectural distortion (94%). Eight (47%) patients reported nonsteroidal anti-inflammatory drugs (NSAID) use. Withdrawal of NSAIDs in 2 cases resulted in normalization of the colonic mucosa. On follow-up, all 17 patients were asymptomatic (median follow-up 42.8 mo) and did not progress to inflammatory bowel disease. Conclusions: We report a series of 17 histologically documented cases of incidental chronic colitis without a conventional etiology. However, both the frequent usage of NSAIDs, and normalization of mucosal changes after withdrawal of this drug suggest that NSAIDs may account for this cecal-based chronic colitis. The awareness of this histologically dramatic but clinically innocuous form of chronic colitis may avoid errors in mucosal biopsy diagnosis.

Spectrally encoded confocal microscopy and optical frequency domain imaging are two non-contact optical imaging technologies that provide images of tissue cellular and architectural morphology, which are both used for histopathological diagnosis. Although spectrally encoded confocal microscopy has better transverse resolution than optical frequency domain imaging, optical frequency domain imaging can penetrate deeper into tissues, which potentially enables the visualization of different morphologic features. We have developed a co-registered spectrally encoded confocal microscopy and optical frequency domain imaging system and have obtained preliminary images from human oesophageal biopsy samples to compare the capabilities of these imaging techniques for diagnosing oesophageal pathology.

Micropapillary carcinoma (MPC) of the stomach is a rare, newly recognized entity, and only 2 patients with this histology have been reported. We investigated clinicopathologic features, expression of mucin (MUC2, MUC5AC, MUC6, CD10) and cytokeratin profiles (CK7 and CK20), epidermal growth factor receptors (EGFR and HER2), prognostic markers (p53 and Ki-67), and outcomes in 11 MPCs of the stomach. The proportion of MPC component ranged from 5% to 70%. Micropapillary features were often found at the deep advancing edge of the tumor. Endolymphatic tumor emboli were found in 10 cases (91%) and lymph node metastases were found in 4 cases (36%). In MPCs, positive expression was observed for Ki-67 (82%), CK7 (73%), EGFR (64%), p53 (64%), MUC5AC (45%), MUC6 (36%), and CK20 (27%). However, MUC2, CD10, and HER2 expression was negative in all cases. In 9 conventional adenocarcinomas and 11 papillary adenocarcinomas with multiple endolymphatic tumor emboli, used as control, positive expression was observed for Ki-67 (100%), CK7 (90%), EGFR (80%), CK20 (70%), p53 (70%), MUC5AC (70%), MUC6 (60%), MUC2 (40%), CD10 (25%), and HER2 (15%). Expression of MUC2, CK20, and the Ki-67 labeling index was significantly higher in control adenocarcinomas as compared with MPCs (P<0.05). However, there was no significant difference in other clinicopathologic features and overall patient survival. Subclassification of MPCs into 2 subgroups according to the proportion of micropapillary component (cut-off value was 20%) failed to find any significant clinicopathologic differences (P>0.05). Although MPCs in other organs show a poor prognosis, this does not seem to be true for gastric MPCs. Further larger studies are necessary to confirm our initial findings.