Artificial intelligence for detection of microsatellite instability in colorectal cancer-a multicentric analysis of a pre-screening tool for clinical application.

BACKGROUND: Microsatellite instability (MSI)/mismatch repair deficiency (dMMR) is a key genetic feature which should be tested in every patient with colorectal cancer (CRC) according to medical guidelines. Artificial intelligence (AI) methods can detect MSI/dMMR directly in routine pathology slides, but the test performance has not been systematically investigated with predefined test thresholds. METHOD: We trained and validated AI-based MSI/dMMR detectors and evaluated predefined performance metrics using nine patient cohorts of 8343 patients across different countries and ethnicities. RESULTS: Classifiers achieved clinical-grade performance, yielding an area under the receiver operating curve (AUROC) of up to 0.96 without using any manual annotations. Subsequently, we show that the AI system can be applied as a rule-out test: by using cohort-specific thresholds, on average 52.73% of tumors in each surgical cohort [total number of MSI/dMMR = 1020, microsatellite stable (MSS)/ proficient mismatch repair (pMMR) = 7323 patients] could be identified as MSS/pMMR with a fixed sensitivity at 95%. In an additional cohort of N = 1530 (MSI/dMMR = 211, MSS/pMMR = 1319) endoscopy biopsy samples, the system achieved an AUROC of 0.89, and the cohort-specific threshold ruled out 44.12% of tumors with a fixed sensitivity at 95%. As a more robust alternative to cohort-specific thresholds, we showed that with a fixed threshold of 0.25 for all the cohorts, we can rule-out 25.51% in surgical specimens and 6.10% in biopsies. INTERPRETATION: When applied in a clinical setting, this means that the AI system can rule out MSI/dMMR in a quarter (with global thresholds) or half of all CRC patients (with local fine-tuning), thereby reducing cost and turnaround time for molecular profiling.

Enhancing Low-Intensity Coaching in Parent Implemented Early Start Denver Model Intervention for Early Autism: A Randomized Comparison Treatment Trial.

Short-term low intensity parent implemented intervention studies for toddlers with autism spectrum disorder (ASD) have found it difficult to demonstrate significantly improved developmental scores or autism severity compared to community treatment. We conducted a randomized comparative intent-to-treat study of a parent implemented intervention to (1) test the effects of an enhanced version on parent and child learning, and (2) evaluate the sensitivity to change of proximal versus distal measures of child behavior. We randomized 45 children with ASD, 12-30 months of age, into one of two versions of parent-implemented Early Start Denver Model (P-ESDM), the basic model, in which we delivered 1.5 h of clinic-based parent coaching weekly, and an enhanced version that contained three additions: motivational interviewing, multimodal learning tools, and a weekly 1.5-h home visit. We delivered the intervention for 12 weeks and measured child and parent change frequently in multiple settings. We found a time-by-group interaction: parents in the enhanced group demonstrated significantly greater gains in interaction skills than did parents in the non-enhanced group. Both interventions were associated with significant developmental acceleration; however, child outcomes did not differ by group. We found a significant relationship between degree of change in parental interaction skill and rate of children's improvement on our proximal measure. Parents in both groups reported satisfaction with the intervention. These findings suggest that parent skills improved more in the enhanced group than the comparison group. Children in the two groups showed similar improvements. Rate of individual parent learning was associated with greater individual child progress on a measure quite proximal to the treatment, though not on standardized assessments.

Cat scratch colon.

BACKGROUND: Bright red linear marks in the right colon are occasionally seen but have never been described in the medical literature. We have termed this finding "cat scratch" colon. METHODS: This was a prospective examination of 8277 colonoscopies at a single endoscopy center in a private practice setting. All cases of cat scratch colon were biopsied, and the results read by two pathologists. RESULTS: A total of 21 cases of cat scratch colon were identified, all in the ascending colon and cecum, with a prevalence of 0.25%. The majority of cases were in women. Although the colon was histologically normal in most cases, there was a significantly higher proportion of collagenous colitis in patients with cat scratch colon compared with the total cohort (14% vs. 0.15%). CONCLUSIONS: The prevalence of bright red linear markings (cat scratch colon) in the cecum and ascending colon is 0.25%. These markings appear to be superficial breaks in the mucosa possibly secondary to barotrauma. Patients tend to be older women with higher proportion of collagenous colitis.

The pathology of malabsorption: current concepts.

Intestinal malabsorption results from a wide variety of causes, which can most easily be organized into three groups. Maldigestion arises from problems with mixing or with digestive mediators, and includes post-gastrectomy patients and those with deficiencies of pancreatic or intestinal enzymes, or of bile salts. Mucosal and mural causes of malabsorption are abundant, and include gluten-sensitive enteropathy, tropical sprue, autoimmune enteropathy, and HIV/AIDS-related enteropathy, as well as mural conditions such as systemic sclerosis. Finally, microbial causes of malabsorption include bacterial overgrowth, Whipple's disease, and numerous infections or infestations that are most frequently seen in immunocompromised patients. An overview of the most common and interesting entities in each of these categories follows, along with a discussion of current concepts. Mucosal conditions and microbial causes of malabsorption are given special attention.

The use of laparoscopic liver biopsies in pediatric patients with hepatic dysfunction following allogeneic hematopoietic stem cell transplantation.

Hepatic dysfunction following hematopoietic stem cell transplantation (HSCT) is common, but making the correct diagnosis can be challenging. Liver biopsies can serve as an important diagnostic tool when the etiology cannot be clearly determined by laboratory data, physical examination, and imaging studies. We reviewed 12 consecutive pediatric patients (seven males, five females, age 9-23 years) who received allogeneic HSCT and underwent a laparoscopic-guided liver biopsy for hepatic dysfunction of unknown etiology from 1998 to 2005. Biopsies were performed using a single-port technique with a 16 or 18 gauge, spring-loaded biopsy gun. The time from HSCT to biopsy ranged from 31 days to 821 days (median 92 days). No intra- or postoperative complications were observed. The initial clinical diagnosis was confirmed in seven patients, whereas the initial working diagnosis was inaccurate in the remaining five patients. Our results suggest that laparoscopic-guided liver biopsy is an informative and safe procedure in pediatric HSCT recipients; this approach helped delineate the true cause of hepatic dysfunction and changed our therapeutic approach in approximately 40% of the patients reviewed. While the safety record at our institution appears promising, a larger multi-institutional study would be necessary to more accurately describe the overall efficacy of this procedure in pediatric HSCT patients.

Expression of NOD2 in Paneth cells: a possible link to Crohn's ileitis.

BACKGROUND AND AIMS: Genetic variation in NOD2 has been associated with susceptibility to Crohn's disease (CD) and specifically with ileal involvement. The reason for the unique association of NOD2 mutations with ileal disease is unclear. To identify a possible link, we tested expression of NOD2 in intestinal tissue of CD patients and controls. PATIENTS AND METHODS: Fifty five specimens of ileum or colon from 21 CD patients, seven ulcerative colitis (UC) patients, and five controls with pathology other than CD or UC were stained for NOD2 using an immunoperoxidase method. RESULTS: Using a monoclonal antibody against NOD2 developed in our laboratory, we detected uniform expression of NOD2 in terminal ileum Paneth cells from controls and patients as well as in metaplastic Paneth cells in the colon. Mechanical purification showed enriched expression of NOD2 mRNA in ileal crypts. In Paneth cells, NOD2 was located in the cytosol in close proximity to the granules that contain antimicrobial peptides. We detected minimal NOD2 in the villous epithelium of the ileum or in the colonic epithelium from both CD patients and controls. CONCLUSIONS: These results suggest a role for NOD2 in the regulation of Paneth cell mediated responses against intestinal bacteria and a plausible mechanism to explain the selective association of NOD2 mutations with ileal disease. The impaired capacity of CD associated mutations to sense luminal bacteria may result in increased susceptibility to certain gut microbes.

Effect of cyclooxygenase-2 inhibition on human Helicobacter pylori gastritis: mechanisms underlying gastrointestinal safety and implications for cancer chemoprevention.

UNLABELLED: Cyclooxygenase (COX)-2 expression and prostaglandin production is increased by Helicobacter pylori infection. Non-selective COX inhibitors reduce prostaglandins and mucosal proliferation in infected mucosa and may reduce gastric cancer risk, but ulceration precludes their use. COX-2 inhibitors cause fewer ulcers and may be chemopreventive. Physiological studies of COX-2 inhibitors in humans with H. pylori infection have not been performed. AIM: To study the impact of COX-2 specific inhibition on gastric prostaglandin levels, H. pylori gastritis and proliferation. METHODS: Twenty infected (eight males, 12 females; age 38 +/- 1.8) and six uninfected (four males, two females; age 36 +/- 3.5) healthy volunteers received rofecoxib 25 mg daily for 14 days. Endoscopic biopsies were evaluated for prostaglandin E2 (PGE2) content, gastritis and proliferation. RESULTS: Before drug therapy, compared to uninfected, H. pylori-infected subjects had significantly higher: (a) gastric mucosal PGE2 (pg/mg tissue) in the gastric body and antrum, (b) H. pylori score in body and antrum and (c) mid-gland proliferation index in antrum and body. The COX-2 inhibitor did not significantly affect PGE2 levels, gastritis scores or proliferation indices in the body or antrum in the H. pylori-positive or -negative subjects. CONCLUSION: The predominant source of increased gastric PGE2 in H. pylori infection appears to be COX-1-derived. In non-ulcerated H. pylori gastritis, COX-2 inhibition does not affect cellular proliferation. Rofecoxib's lack of effect on gastric prostaglandin levels and proliferation in H. pylori-infected mucosa may explain the absence of an increased ulcer risk among COX-2 inhibitor users with H. pylori infection. The lack of significant effect on intermediate biomarkers raises uncertainty regarding the potential of specific COX-2 inhibitors for chemoprevention of gastric cancer.

Florid vascular proliferation of the colon related to intussusception and mucosal prolapse: potential diagnostic confusion with angiosarcoma.

With the exception of angiodysplasia, vascular abnormalities of the intestines are unusual. We describe a florid benign vascular proliferation of the colon in five adult patients, three of whom presented with idiopathic intussusception. In all cases, the proliferation was sufficiently exuberant to raise the possibility of angiosarcoma as a diagnostic consideration. The group included 2 males and 3 females with a median age of 43 years. Two patients were HIV positive. Four patients presented with a colonic mass; other symptoms at presentation included abdominal pain, diarrhea, bleeding, and bowel obstruction. In all cases, a florid lobular proliferation of small vascular channels lined by plump endothelial cells extended from the submucosa through the entire thickness of the bowel wall. The endothelial cells showed minimal nuclear atypia, and mitotic figures were infrequent. The overlying mucosa showed ulceration with ischemic-type changes, and had features of mucosal prolapse. A possible underlying arteriovenous malformation was identified in two cases. All patients were alive and well at last follow-up (interval, 6 months to 5 years). The presence of intussusception or mucosal prolapse in all of the cases suggests repeated mechanical forces applied to the bowel wall as a possible etiologic factor. The role of HIV infection in the pathogenesis of these lesions remains to be determined.

Organ-specific molecular classification of primary lung, colon, and ovarian adenocarcinomas using gene expression profiles.

Molecular classification of tumors based on their gene expression profiles promises to significantly refine diagnosis and management of cancer patients. The establishment of organ-specific gene expression patterns represents a crucial first step in the clinical application of the molecular approach. Here, we report on the gene expression profiles of 154 primary adenocarcinomas of the lung, colon, and ovary. Using high-density oligonucleotide arrays with 7129 gene probe sets, comprehensive gene expression profiles of 57 lung, 51 colon, and 46 ovary adenocarcinomas were generated and subjected to principle component analysis and to a cross-validated prediction analysis using nearest neighbor classification. These statistical analyses resulted in the classification of 152 of 154 of the adenocarcinomas in an organ-specific manner and identified genes expressed in a putative tissue-specific manner for each tumor type. Furthermore, two tumors were identified, one in the colon group and another in the ovarian group, that did not conform to their respective organ-specific cohorts. Investigation of these outlier tumors by immunohistochemical profiling revealed the ovarian tumor was consistent with a metastatic adenocarcinoma of colonic origin and the colonic tumor was a pleomorphic mesenchymal tumor, probably a leiomyosarcoma, rather than an epithelial tumor. Our results demonstrate the ability of gene expression profiles to classify tumors and suggest that determination of organ-specific gene expression profiles will play a significant role in a wide variety of clinical settings, including molecular diagnosis and classification.

Is it Crohn's disease? A severe systemic granulomatous reaction to sulfasalazine in patient with rheumatoid arthritis.

BACKGROUND: Sulfasalazine is a widely used anti-inflammatory agent in the treatment of inflammatory bowel disease and several rheumatological disorders. Although as many as 20% of treated patients may experience reversible, dose-dependent side effects, less frequent but potentially severe, systemic reactions have also been reported. CASE PRESENTATION: A severe systemic reaction to sulfasalazine developed in a 21-year old female with rheumatoid arthritis characterized by eosinophilia, granulomatous enteritis and myelotoxicity, cholestatic hepatitis, and seizures. The clinical course and management of this patient are presented as well as a review of the incidence and outcome of severe systemic reactions to sulfasalazine. CONCLUSIONS: Granulomatous myelotoxicity and enteritis developed in a 21 year old female within 3 weeks of initiating sulfasalazine for rheumatoid arthritis. Following a short course of corticosteroids, the patient had resolution of her cholestatic hepatitis, rash, eosinophilia, and gastrointestinal symptoms with no residual manifestations at 7 months follow-up. Although severe reactions to sulfasalazine are rare and unpredictable, practicing physicians should be aware of unusual clinical presentations of toxicity when prescribing sulfasalazine.

Reproducibility of the diagnosis of dysplasia in Barrett esophagus: a reaffirmation.

Morphologic assessment of dysplasia in Barrett esophagus, despite limitations, remains the basis of treatment. We rigorously tested modified 1988 criteria, assessing intraobserver and interobserver reproducibility. Participants submitted slides of Barrett mucosa negative (BE) and indefinite (IND) for dysplasia, with low-grade dysplasia (LGD) and high-grade dysplasia (HGD), and with carcinoma. Two hundred fifty slides were divided into 2 groups. The first 125 slides were reviewed, without knowledge of the prior diagnoses, on 2 occasions by 12 gastrointestinal pathologists without prior discussion of criteria. Results were analyzed by kappa statistics, which correct for agreement by chance. A consensus meeting was then held, establishing, by group review of the index 125 slides, the criteria outlined herein. The second 125-slide set was then reviewed twice by each of the same 12 pathologists, and follow-up kappa statistics were calculated. When statistical analysis was performed using 2 broad diagnostic categories (BE, IND, and LG v HG and carcinoma), intraobserver agreement was near perfect both before and after the consensus meeting (mean kappa = 0.82 and 0.80). Interobserver agreement was substantial (kappa = 0.66) and improved after the consensus meeting (kappa = 0.70; P =.02). When statistical analysis was performed using 4 clinically relevant separations (BE; IND and LGD; HGD; carcinoma), mean intraobserver kappa improved from 0.64 to 0.68 (both substantial) after the consensus meeting, and mean interobserver kappa improved from 0.43 to 0.46 (both moderate agreement). When statistical analysis was performed using 4 diagnostic categories that required distinction between LGD and IND (BE; IND; LGD; HGD and carcinoma), the pre-consensus meeting mean intraobserver kappa was 0.60 (substantial agreement), improving to 0.65 after the meeting (P <.05). Interobserver agreement was poorer, with premeeting and postmeeting mean values unchanged (kappa = 0.43 at both times). Interobserver agreement was substantial for HGD/carcinoma (kappa = 0.65), moderate to substantial for BE (kappa = 0.58), fair for LGD (kappa = 0.32), and slight for IND (kappa = 0.15). The intraobserver reproducibility for the diagnosis of dysplasia in BE was substantial. Interobserver reproducibility was substantial at the ends of the spectrum (BE and HG/carcinoma) but slight for IND. Both intraobserver and interobserver variation improved overall after the application of a modified grading system developed at a consensus conference but not in separation of BE, IND, and LGD. The criteria used by the group are presented. HUM PATHOL 32:368-978.

Dysplasia as a predictive marker for invasive carcinoma in Barrett esophagus: a follow-up study based on 138 cases from a diagnostic variability study.

The objective of endoscopic surveillance in Barrett esophagus (BE) is to assess the risk of subsequent development of invasive carcinoma. Criteria for morphologic evaluation of dysplasia, the presumed precursor lesion, have been established, although there are surprisingly few data in the literature correlating biopsy diagnosis of dysplasia with outcome. We collected follow-up information on 138 patients with BE whose initial endoscopic biopsy specimens had been selected for submission in an interobserver variability study performed by 12 pathologists with special interest in gastrointestinal pathology and reviewed blindly twice each by all the participants. Cases were scored as BE with no dysplasia, atypia indefinite for dysplasia (IND), low-grade dysplasia (LGD), high-grade dysplasia (HGD), intramucosal carcinoma, and frankly invasive carcinoma, thus generating 24 scores on each biopsy specimen. Clinical follow-up was obtained and correlated with both the submitting diagnoses and majority diagnoses. Kaplan-Meier statistics were used to compare both the submitting and majority diagnoses with outcome using detection or documentation of invasive carcinoma as the endpoint. Using the submitting diagnoses, no invasive carcinomas were detected in 44 cases diagnosed as BE (median follow-up, 38.5 months). Carcinomas were detected in 4 of 22 (18%) cases submitted as IND (median progression-free survival of 62 months), in 4 of 25 (15%) cases of LGD (median progression-free survival of 60 months), in 20 of 33 cases of HGD (median progression-free survival, 8 months), and all 13 (100%) cases submitted as adenocarcinoma. Grade on initial biopsy correlated significantly with progression to invasive carcinoma (log-rank P =.0001). Majority diagnosis was achieved in 99 of the cases. Using the majority diagnoses, no invasive carcinomas were found in 50 cases of BE (median follow-up, 48 months), and carcinomas were detected in 1 of 7 (14%) IND cases (80% progression-free survival at 2 months), 3 of 15 (20%) LGD (median progression-free survival, 60 months), 9 of 15 (60%) HGD (median progression-free survival, 7 months), and all 12 (100%) carcinoma. Initial grading again correlated significantly with progression to invasive carcinoma (log-rank P =.0001). However, there were 39 cases without a majority diagnosis. Among these, no carcinomas developed in 8 cases with an average score between BE and IND. Carcinomas were detected in 9 of 21 (43%) cases with an average score between IND and LGD, and 7 of 10 (70%) cases with an average score between LGD and HGD. There were ulcers in 8 of 39 cases (20%) of the "no-majority" group and in 13 of 99 (13%) of the majority cases. Of 21 total ulcerated cases, cancer was demonstrated in 15 (71%) of these on follow-up. These data support combining the IND and LGD categories for surveillance purposes. Cases without dysplasia may be followed up conservatively. The data obtained from submitted diagnoses as opposed to those from blind review suggest that knowledge of the clinical findings aids in diagnosis. The data also support the assertion that HGD is strongly associated with invasive carcinoma. Rebiopsy of ulcerated areas should be considered because they may harbor malignancy. Histologic grading of dysplasia using established criteria is a powerful prognosticator in BE. HUM PATHOL 32:379-388.

Familial risk of pancreatic cancer.

BACKGROUND: Pancreatic cancer is the fifth leading cause of cancer-related mortality in the United STATES: Although smoking and age are known risk factors for pancreatic cancer, several case reports and case-control studies have suggested that there is also a familial risk. We evaluated whether a family history of pancreatic cancer increases the risk of pancreatic cancer in first-degree relatives and whether smoking and younger age at cancer diagnosis further increase this risk. METHODS: We conducted in-person interviews with 247 patients ("case probands") with pancreatic cancer and 420 population-based control probands to collect risk factor data and pancreatic cancer family history for 1816 first-degree relatives of the case probands and 3157 first-degree relatives of the control probands. We analyzed the data by unconditional logistic regression models, with adjustment for correlated data by use of generalized estimating equations. All statistical tests were two-sided. RESULTS: A positive family history of pancreatic cancer (i.e., being related to a case proband) or ever-smoking cigarettes approximately doubled the risk of pancreatic cancer (relative risk [RR] = 2.49; 95% confidence interval [CI] = 1.32 to 4.69; RR = 2.04; 95% CI = 1.09 to 3.83, respectively). The RR increased to 8.23 (95% CI = 2.18 to 31.07) for relatives who ever smoked and were related to a case proband who was diagnosed before age 60 years. CONCLUSION: Routine questioning of patients about a family history of pancreatic cancer, the age of onset of this cancer in their relatives, and the patient's smoking status may identify individuals at high risk of pancreatic cancer. Future research exploring the genetic and environmental interactions associated with the risk of pancreatic cancer is critically important.

The role of Yersinia enterocolitica and Yersinia pseudotuberculosis in granulomatous appendicitis: a histologic and molecular study.

Granulomatous appendicitis is an enigmatic entity. Purported causes include Crohn's disease, foreign body reactions, sarcoidosis, and infectious agents; however, most cases remain idiopathic. Yersinia enterocolitica (YE) and Y. pseudotuberculosis (YP) have been implicated as causes of appendicitis, ileocolitis, and mesenteric adenitis. The authors examined the potential role of YE and YP in granulomatous appendicitis using histologic and molecular methods. Forty cases of granulomatous appendicitis were evaluated for histologic features including transmural inflammation, number and character of granulomas, and mucosal changes. Twort Gram, Grocott methenamine-silver (GMS), and Ziehl-Neelsen stains were evaluated, and polymerase chain reaction (PCR) analysis was performed to identify pathogenic YP and YE. Twenty-five percent (10 of 40) of the cases were positive for pathogenic Yersinia by PCR (four YE, four YP, and two with both species). Prominent histologic features included epithelioid granulomas with lymphoid cuffing, transmural inflammation with lymphoid aggregates, mucosal ulceration, and cryptitis. One Yersinia-positive case contained mural Gram-negative bacilli; fungal and acid-fast bacilli stains were all negative. Except for one culture-negative case, serologies and cultures were not done or results were unavailable. Two Yersinia-positive patients were diagnosed subsequently with Crohn's disease, suggesting a possible relationship between the two entities. No other patients developed significant sequelae. YE and YP are important causes of granulomatous appendicitis, and Yersinia infection may mimic Crohn's disease. No histologic features distinguish reliably between Yersinia species, or between Yersinia-positive and Yersinia-negative cases. Because special stains and cultures are often not diagnostic, PCR analysis is an excellent technique for the diagnosis of Yersinia.

Diffuse duodenitis associated with ulcerative colitis.

Backwash ileitis and postcolectomy pouchitis are well-recognized complications of ulcerative colitis (UC), whereas inflammation of the proximal small intestine is not. In contrast, small intestinal disease at any level is common in Crohn's disease (CD). Despite this well-established and accepted dogma, rare cases of histologically proven diffuse duodenitis (DD) associated with UC appear in the literature. In this study, we report our experience with similar cases exhibiting this unusual inflammatory phenomenon. Routine histologic sections from four cases of DD associated with well-documented UC were reviewed and the findings correlated with all available medical records. Multiple endoscopic biopsies showing histologic features of UC and colectomy specimens confirming severe ulcerative pancolitis were available for all cases. Varying degrees of active chronic inflammation and architectural mucosal distortion identical to UC were observed in pre- and postcolectomy duodenal biopsies of one of four and four of four cases, respectively. Similar inflammatory patterns were present postoperatively in the ileum in three of four cases and in the jejunum in one case. Endorectal pull-through (ERPT) procedures were performed in three of four patients and an end-to-end ileorectal anastomosis was done in one patient. Despite extensive upper gastrointestinal tract involvement, none of the patients developed postsurgical Crohn's-like complications during a follow-up period of 12 to 54 months. This suggests that patients with pancolitis and DD do not necessarily have CD, but rather may have UC and, most importantly, that successful ERPT procedures may be performed in these patients.

Decreased 13-S-hydroxyoctadecadienoic acid levels and 15-lipoxygenase-1 expression in human colon cancers.

13-S-Hydroxyoctadecadienoic acid (13-S-HODE), the product of 15-lipoxygenase (15-LOX) metabolism of linoleic acid, enhances cellular mitogenic responses to certain growth factors. Other observations have questioned whether 13-S-HODE has tumorigenic effects. Our study evaluated the hypothesis that 15-LOX-1 is overexpressed in colon cancers resulting in an increase in intracellular 13-S-HODE. 15-LOX-1 and 13-S-HODE were quantified using western blots, ELISA and immunohistochemistry in 18 human colon cancers with paired normal colonic mucosa. Additionally, 15-LOX-1 expression was measured by western blots in three transformed colonic cell lines and in a human umbilical vein endothelial cell line. Next, we evaluated 13-S-HODE effects on cellular proliferation, cell cycle distribution and apoptosis in a transformed colonic cell line (RKO). Cell cycle distributions were measured by flow cytometry and apoptosis was assessed by phase contrast microscopy, electron microscopy, flow cytometry and DNA fragmentation assay. 15-LOX-1 immunohistochemistry staining scores were reduced in tumor tissues (P

Stromal tumors of the abdominal colon: a clinicopathologic study of 20 cases.

Stromal tumors of the abdominal colon, the least common of all gastrointestinal stromal tumors, have not been well characterized. They have often been lumped with stromal tumors of the anorectum in order to achieve significant numbers for analysis, yet there are no data to prove that stromal tumors from these two sites are the same. In this study, we evaluated 20 colonic stromal tumors to identify clinical, morphologic, and immunophenotypic features that were useful in discriminating between those that had metastasized or caused death from those that had not metastasized or caused death. We found that colonic stromal tumors are morphologically heterogeneous, and the malignant ones are clinically aggressive. They often have metastases at presentation, and cause death in a short time. An infiltrative growth pattern in the muscularis propria, invasion of the mucosa, and high mitotic counts correlated significantly both with metastases and with death from tumor. We also found that dense cellularity correlated significantly with metastases, but not with death, and that coagulative necrosis correlated with death, but not with metastases.

Stromal tumors of the anorectum: a clinicopathologic study of 22 cases.

Stromal tumors of the anorectum are a rare group of mesenchymal tumors that often have a protracted clinical course. We sought to determine which clinical, morphologic, and immunophenotypic features correlated with an adverse outcome in 22 patients with anorectal stromal tumors. An adverse outcome, defined as either tumor recurrence or metastasis, occurred in nine patients. Seven patients had metastases, two of whom also had local recurrences. Four of these patients also died from their disease. One patient had one local recurrence, and one patient had two local recurrences; neither of these patients had metastases. Recurrences were found as long as 103 months and metastases as late as 117 months after initial presentation. However, for patients without an adverse outcome, maximum follow-up was only 84 months. Thus both recurrence and metastasis may not appear until several years after treatment, indicating that a long-term follow-up period, probably longer than available for many tumors without an adverse outcome in this study, is needed before a patient can be considered to be cured. Tumor size greater than five centimeters correlated with an adverse outcome. However, given the protracted course of these tumors and the relatively limited follow-up available, other features such as location within the muscularis propria, mitotic activity, necrosis, and pleomorphism that did not significantly correlate with an adverse outcome may become significant with longer follow-up periods. We also found that on the basis of morphologic appearance and whether tumors were confined to the submucosa or located within the muscularis propria, anorectal stromal tumors could be divided into three groups, and that the behavior of anorectal stromal tumors may also depend upon their phenotype. The largest group of 17 tumors was located within the muscularis propria, mitotically active, and composed of densely cellular spindle-shaped cells. A second group of two tumors was also located within the muscularis propria and was composed of spindle-shaped cells, but lacked dense cellularity and mitotic activity. The third group was composed of three submucosal, polypoid tumors.

Virtual microscopy and the Internet as telepathology consultation tools. A study of gastrointestinal biopsy specimens.

Telepathology (TP) is the practice of pathology at a distance using videomicroscopy and telecommunication tools. We explore the use of "virtual microscopy" techniques and the Internet as tools for TP gastrointestinal biopsy consultations. Thirty-five gastrointestinal biopsy specimens were photographed in Los Angeles by using a high-resolution digital camera, a light microscope, and a Pentium 166 microcomputer. Several (2-8) digital photomicrographs were collected at 40x or 100x optical magnification, using 2,700 x 3,400 pixel resolution. The photomicrographs illustrated all the tissue fragments present in 1 of the biopsy levels. They were saved in medium compression JPEG image format. These images can be magnified digitally up to 600% without visible degradation and scrolled at different magnifications on a video monitor, simulating examination under a light microscope. The images files (281 to 3,324 KB) were attached to e-mail messages containing patient information and sent through the Internet to Michigan for interpretation using a Power Macintosh 7100 system. The e-mail process was successful in 100% of instances; 2 files were corrupted owing to user error and had to be resent. Additional photos were requested in 1 case. In 33 of 35 cases, there was diagnostic concordance between the original and the TP diagnoses. The 2 discrepancies were due to diagnostic disagreement. This technology offers pathologists relatively inexpensive and effective tools for gastrointestinal TP consultations.

Cyclooxygenase-2 expression in gastric antral mucosa before and after eradication of Helicobacter pylori infection.

OBJECTIVE: Helicobacter pylori (H. pylori) causes chronic gastritis. The inducible prostaglandin synthetase cyclooxygenase 2 (COX-2) plays an important role in inflammatory conditions. We hypothesized that H. pylori-associated chronic gastritis would express COX-2 protein. Our aim was to evaluate the effect of eradication of H. pylori infection on COX-2 expression in the antral mucosa of patients before and after antibiotic therapy. METHODS: Tissues were obtained from patients with non-ulcer dyspepia undergoing H. pylori eradication. Ten patients with proven H. pylori infection and subsequent successful eradication were studied. Three biopsies of antral mucosa were evaluated before and after H. pylori eradication. The amount of acute and chronic inflammation was quantitated. Immunohistochemical staining for COX-2 was expressed as a percentage of the total number of cells and correlated with the degree of chronic inflammation. RESULTS: Specific immunostaining for COX-2 was observed in antral mucosa of patients infected with H. pylori. Patchy cytoplasmic staining was seen in surface epithelial cells and strong cytoplasmic staining for COX-2 was seen in parietal cells. Spotty cytoplasmic staining for COX-2 was also seen in lamina propria plasma cells, as well as there being macrophages present in the germinal centers of lymphoid aggregates. COX-2 expression could be detected both before and after eradication of H. pylori. The mean percentage of cells staining for COX-2 was significantly higher in H. pylori-infected mucosa, compared with mucosa after successful H. pylori eradication (33.4% +/- 5.4 vs 18.9% +/- 3.3, p = 0.038). COX-2 immunostaining correlated best with the chronic inflammation score (r2 = 0.78, p < 0.001). There was a strong correlation for those subjects who were H. pylori infected, as well as for those who had successful H. pylori eradication. CONCLUSIONS: H. pylori associated acute and chronic antral inflammation was associated with immunohistochemical detection of COX-2 protein in epithelial cells, in addition to associated mononuclear cells and parietal cells. Expression was reduced, but not eliminated, in the epithelium after successful eradication of H. pylori. Despite the reduction in COX-2 expression after H. pylori eradication, expression of COX-2 in epithelial cells remained and strongly correlated with the extent of the chronic inflammatory cell infiltrate. The clinical implications of H. pylori-associated induction of COX-2 expression for patients on selective COX-2 inhibitors, in addition to the role of COX-2 in gastric carcinogenesis, deserve further study.