Are random biopsies still useful for the detection of neoplasia in patients with IBD undergoing surveillance colonoscopy with chromoendoscopy?

BACKGROUND: Colonoscopy with pan-chromoendoscopy (CE) is superior to standard colonoscopy in detecting neoplasia in patients with IBD. Performing random biopsies in unsuspicious mucosa after CE remains controversial. METHODS: Consecutive patients with IBD who underwent surveillance colonoscopy using CE were prospectively included. The standardised procedure used CE, performed targeted biopsies or endoscopic resection on suspicious lesions and then quadrant random biopsies every 10 cm. A panel of five expert pathologists reviewed histological slides with dysplasia. Logistic regression model was used to evidence the factors associated with neoplasia in any or in random biopsies. RESULTS: 1000 colonoscopes were performed in 1000 patients (495 UC, 505 Crohn's colitis). In 82 patients, neoplasia was detected from targeted biopsies or removed lesions, and among them dysplasia was detected also by random biopsies in 7 patients. Importantly, in 12 additional patients dysplasia was only detected by random biopsies. Overall, 140 neoplastic sites were found in 94 patients, 112 (80%) from targeted biopsies or removed lesions and 28 (20%) by random biopsies. The yield of neoplasia by random biopsies only was 0.2% per-biopsy (68/31 865), 1.2% per-colonoscopy (12/1000) but 12.8% per-patient with neoplasia (12/94). Dysplasia detected by random biopsies was associated with a personal history of neoplasia, a tubular appearing colon and the presence of primary sclerosing cholangitis (PSC). CONCLUSIONS: Despite their low yield, random biopsies should be performed in association with CE in patients with IBD with a personal history of neoplasia, concomitant PSC or a tubular colon during colonoscopy. TRIAL REGISTRATION NUMBER: IRB 001508, Paris 7 University.

Colorectal cancer in inflammatory bowel diseases: CT features with pathological correlation.

PURPOSE: To describe CT features of inflammatory bowel disease (IBD)-related colorectal cancer and correlate the imaging findings with histopathological findings. MATERIALS AND METHODS: CT imaging findings in 17 patients with IBD-related colorectal cancer were retrospectively evaluated. Imaging findings were correlated with surgical and histopathological findings. Univariate and multivariate analyses explored the relationships between CT and histopathological variables. RESULTS: Two different CT patterns were individualized including clearly visible soft tissue mass (8/17; 47%) (Type 1 tumor) or stenosis with marked circumferential thickening resembling inflammation (9/17; 53%) (Type 2 tumor). At univariate analysis, thickness of tumor-free colorectal wall at CT was greater in Crohn disease (median, 13 mm) than in ulcerative colitis (median, 7 mm) (P = 0.011). Significant association was found between presence of signet ring cells and Type 2 tumor at CT (6/9, 67% P = 0.009) and colonic dilatation proximal to tumor (5/6, 83%; P = 0.035). At multivariate analysis, free-fluid effusion was the single independent CT variable predictive for the presence of signet ring cells (odds ratio = 50; 95% CI 2.56-977.02; P = 0.01). CONCLUSION: Colorectal cancer in IBD displays two main features on CT. Type 2 tumors and free-fluid effusion correlate with presence of signet ring cells. Knowledge of these findings is critical to help suggest the diagnosis.

Presentation and long-term follow-up of refractory celiac disease: comparison of type I with type II.

BACKGROUND & AIMS: Refractory celiac disease (RCD) was recently subdivided into 2 subtypes (RCD I and II) based on a normal or abnormal phenotype of intraepithelial lymphocytes (IELs), respectively. It is not clear, however, if these 2 entities differ in their presentation at diagnosis or long-term outcome. We compared the clinical and biological characteristics of RCD I and RCD II at diagnosis, the risk of developing an overt lymphoma, and the predictive factors of survival. METHODS: Medical files of 14 patients with RCD I and 43 with RCD II were analyzed retrospectively. Predictive factors of overt lymphoma and survival were studied in univariate and multivariate analyses. RESULTS: At diagnosis, malnutrition, ulcerative jejunitis, and lymphocytic gastritis were more common in patients with RCD II than RCD I (P< .05). Overt lymphomas occurred in 2 patients with RCD I and 16 with RCD II. In the univariate analysis, abnormal IEL phenotype and increased age at diagnosis of RCD were predictive factors for overt lymphoma. Abnormal IEL phenotype (P< .01), clonality (P= .01), and overt lymphoma (P= .001) predicted short survival time. Only abnormal IEL phenotype (P= .03) and overt lymphoma (P= .04) were predictive in the multivariate analysis. The 5-year survival rate was 93% in patients with RCD I and 44% with RCD II. CONCLUSIONS: RCD II has a much more severe presentation and prognosis than patients with RCD I; <44% of patients with RCD II survive 5 years after diagnosis. Abnormal IEL phenotype is a predictive factor but not a necessary condition for the development of overt lymphoma.

Morphological adaptation with preserved proliferation/transporter content in the colon of patients with short bowel syndrome.

In short bowel syndrome (SBS), although a remaining colon improves patient outcome, there is no direct evidence of a mucosal colonic adaptation in humans. This prospective study evaluates morphology, proliferation status, and transporter expression level in the epithelium of the remaining colon of adult patients compared with controls. The targeted transporters were Na+/H+ exchangers (NHE2 and 3) and oligopeptide transporter (PepT1). Twelve adult patients with a jejuno-colonic anastomosis were studied at least 2 yr after the last surgery and compared with 11 healthy controls. The depth of crypts and number of epithelial cells per crypt were quantified. The proliferating and apoptotic cell contents were evaluated by revealing Ki67, PCNA, and caspase-3. NHE2, NHE3, PepT1 mRNAs, and PepT1 protein were quantified by quantitative RT-PCR and Western blot, respectively. In patients with SBS compared with controls, 1) hyperphagia and severe malabsorption were documented, 2) crypt depth and number of cells per crypt were 35% and 22% higher, respectively (P < 0.005), whereas the proliferation and apoptotic levels per crypt were unchanged, and 3) NHE2 mRNA was unmodified; NHE3 mRNA was downregulated near the anastomosis and unmodified distally, and PepT1 mRNA and protein were unmodified. We concluded that, in hyperphagic patients with SBS with severe malabsorption, adaptive colonic changes include an increased absorptive surface with an unchanged proliferative/apoptotic ratio and well-preserved absorptive NHE2, NHE3, and PepT1 transporters. This is the first study showing a controlled nonpharmacological hyperplasia in the colon of patients with SBS.

Celiac disease in adults: evaluation with MDCT enteroclysis.

OBJECTIVE: The purpose of this article is to present the MDCT enteroclysis features of the multiple complications of celiac disease and illustrate why this technique is helpful to adult patients with celiac disease. CONCLUSION: MDCT enteroclysis findings can suggest the diagnosis in adult patients with unknown celiac disease, and many complications of celiac disease can be recognized because of their characteristic appearance. Familiarity with these signs can help in appropriate planning of further diagnostic procedures.

KIT overexpression and amplification in gastrointestinal stromal tumors (GISTs).

The tyrosine kinase receptor KIT plays a major role in gastrointestinal stromal tumors (GISTs) oncogenesis. Indeed, 95% of GISTs express KIT protein, and about 70% exhibit activating mutations of the KIT gene. However, little is known about KIT overexpression mechanisms in these tumors, and the correlation with KIT mutations. GISTs with mutations within exon 11 (n=12) or 9 (n=1) of KIT were compared with GISTs without KIT mutations in exons 9, 11, 13, and 17 (n=10), two of them had PDGFRA mutations. KIT amplification was studied by real-time PCR of KIT and beta-ACTIN genes, and by fluorescence in situ hybridization (FISH) using KIT and chromosome 4 centromere specific probes. KIT transcripts and protein expression were quantified by reverse transcription real-time PCR and Western blot respectively. Genomic analysis revealed a single mutated GIST with KIT amplification. KIT protein and RNA levels were highly variable in GISTs but closely correlated (r=0.82, P<1.10(-5)), and were higher in GISTs with KIT mutations (P=0.07 and P=0.03 respectively). In conclusion, contrasting with the regulation of other tyrosine kinase receptors, KIT overexpression in GISTs is rarely related to a gene amplification, which suggests a deregulation of KIT gene transcription.

Herpes simplex virus type 1 colitis in a patient with common variable immunodeficiency syndrome.

We report on a case of herpes simplex virus (HSV) type 1 colitis in a 69-year-old patient with common variable immunodeficiency syndrome. A treatment with polyvalent immunoglobulins was discontinued in April 2001. In March 2004 she developed chronic diarrhoea related to rectosigmoidal and caecal ulcerations. In November 2004, HSV was recovered in tissue culture from colonic biopsies. Valaciclovir was then started, leading the patient to clinical remission at day 4, and continued for a 6-week course (without any secondary antiviral prophylaxis). Colonic biopsies were negative for HSV by tissue culture and PCR within 3 weeks of antiviral treatment. Intravenous polyvalent immunoglobulin infusions were readministered within the third week of antiviral treatment. She has declared no clinical event since this period. Three months after the antiviral treatment was achieved, a rectosigmoidoscopy showed an ad-integrum macroscopic and histological mucosal healing whereas PCR was negative for HSV in the colonic tissue. As a large proportion of patients with common variable immunodeficiency syndrome present not only as a humoral immunodeficiency but also as a defect in the cellular immunity compartment (with T-cell deficits), HSV, as well as cytomegalovirus, should be investigated in patients with common variable immunodeficiency syndrome presenting colitis.

Multidrug resistance proteins in gastrointestinal stromal tumors: site-dependent expression and initial response to imatinib.

Gastrointestinal stromal tumors (GIST) are the most frequent mesenchymal tumors of the digestive tract and respond poorly to chemotherapy. A tyrosine kinase inhibitor treatment, imatinib mesylate, was recently shown to have antitumor effects in metastatic patients. However, this drug is a substrate for multidrug resistance (MDR) proteins. Therefore, we investigated the expression of ABCB1 (P-glycoprotein), ABCC1 (MRP1), and ABCG2 (BCRP) by Western blotting in 21 GISTs and 3 leiomyosarcomas. All the GISTs were positive for either ABCB1 (86% of cases) or ABCC1 expression (62%), but negative for ABCG2. ABCB1 was expressed in all gastric GISTs, but in only 67% of nongastric GISTs. By contrast, ABCC1 expression was more common in nongastric tumors (78% versus 42%). The levels of these MDR proteins in gastric GISTs were higher for ABCB1 (P = 0.007) and lower for ABCC1 (P = 0.004) compared with nongastric GISTs. We found no correlation between MDR protein expression and the risk assessment. None of the six patients treated with imatinib was resistant, although all were positive for at least one MDR protein. These results confirm that gastric and nongastric GISTs have different biological characteristics and suggest that MDR proteins do not impair the initial response of the tumor to imatinib.

[Chronic intestinal pseudo-obstruction]. / Pseudo-obstruction intestinale chronique.

Chronic intestinal pseudo-obstruction (CIPO) is a disease characterized by episodes resembling mechanical obstruction in the absence of organic, systemic, or metabolic disorders. Pseudo-obstruction is an uncommon condition and can result from primary (40%) or secondary (60%) causes. The most common symptoms are nausea, vomiting, abdominal distension, abdominal pain and constipation or diarrhea. These symptoms are usually present many years before CIPO diagnosis. They can lead to severe electrolyte disorders and malnutrition. Principles for management of patients with CIPO are: to establish a correct clinical diagnosis in excluding mechanical obstruction; to perform a symptomatic and physiologic assessment of the gastrointestinal tract involved; to look for extra-intestinal manifestations, especially for myopathy and neuropathy; to discuss in some cases a surgery for full-thickness intestinal biopsies, and/or a neuromuscular biopsy in case of mitochondrial cytopathy suspicion. The management is primarily focused on symptom control and nutritional support to prevent weight loss and malnutrition. Treatment of CIPO includes prokinetic agents which may help to reduce gastrointestinal symptoms Courses of antibiotics may be needed in patients with symptoms suggestive of bacterial overgrowth. When necessary, enteral nutrition is preferred. In carefully selected patients, feeding jejunostomy with or without decompression gastrostomy may be tried. Long term parenteral nutrition should be reserved for patients who can not tolerate enteral nutrition. Intestinal transplantation can be discussed in selected patients.

High expression of both mutant and wild-type alleles of c-kit in gastrointestinal stromal tumors.

Most gastrointestinal stromal tumors (GISTs) contain activating mutations of the proto-oncogene c-kit. The GNNK- isoform of c-kit has a greater oncogenic potential than the GNNK+ isoform. We studied tumors from 29 patients with GIST, 19 of whom had c-kit mutations, and compared them to normal cells and HMC-1 mast cell line. c-kit transcripts were quantified by real-time PCR. The ratios of GNNK-/+ isoforms and of wild-type/mutant alleles were determined by RT-PCR and fluorometric quantification. On average, GISTs contained 1.9 times more c-kit transcripts than the HMC-1 cell line and GISTs with c-kit mutations contained 2.8 times more c-kit transcripts than those without (P=0.003). The median GNNK-/+ isoform ratios in GISTs with and without c-kit mutations were 4.4 and 4.1, respectively, and there was no difference in the GNNK-/+ ratios between the GISTs and the control samples. Both mutant and wild-type alleles of c-kit were expressed in similar amounts in 13/15 mutant GISTs. The oncogenic effects of KIT in GISTs are not related to the higher expression level of the GNNK- isoform. The high expression level of both mutated and wild-type allele transcripts of c-kit suggests that interactions between spontaneously activated and normal c-kit receptors are important in GIST tumorigenesis.

Brain damage after heat stroke.

Cerebellar syndromes and radiologic cerebellar atrophy after hyperpyrexia have occasionally been reported, mostly in neuroleptic malignant syndromes, but neuropathologic studies are extremely rare. We studied 3 patients (a 74-year-old woman, a 63-year-old man, and an 80-year-old man) who had heat stroke during heat waves in France. One patient had generalized seizures and died 28 hours after admission. The other patients survived one month and 2 months after admission; both had palatal myoclonus, and in one case, magnetic resonance imaging showed high signal intensity in the cerebral peduncles. The main neuropathology in the 3 cases was severe diffuse loss of Purkinje cells associated with heat shock protein 70 expression by Bergmann glia. In situ end labeling was negative in surviving Purkinje cells, suggesting that the mechanism of neuronal death was not apoptosis. Degeneration of Purkinje cells axons resulted in myelin pallor of the white matter of the folia and of the hilum of the dentate nuclei. DNA internucleosomal breakages were identified by in situ end labeling in the dentate nuclei and centromedian nuclei of the thalamus and were associated with degeneration of the cerebellar efferent pathways: superior cerebellar peduncles, decussation of the superior cerebellar peduncles (Wernekinck commissure), and dentatothalamic tract. These findings suggest that the mechanisms of neuronal death in the dentate nuclei and centromedian nuclei of the thalamus was different from that in Purkinje cells and more likely resulted from deafferentation. Ammon's horn and other areas susceptible to hypoxia were spared. These observations confirm the selective vulnerability of Purkinje cells to heat-induced injury and involvement of the cerebellar efferent pathways in palatal myoclonus.

Clinical, histological and molecular follow-up of 60 patients with gastric marginal zone lymphoma of mucosa-associated lymphoid tissue.

The persistence of gastric lymphoma after Helicobacter pylori eradication may be difficult to evidence on endoscopic and histological examination. The aims of the study were to evaluate the detection of monoclonal immunoglobulin H (IgH) gene rearrangement in endoscopically infiltrated and normal mucosa at diagnosis and during follow-up in order to determine its clinical and prognostic impact. We studied 60 gastric marginal zone lymphomas of mucosa-associated lymphoid tissue (MALT), and IgH monoclonality was detected at diagnosis in 52 patients (87%). The endoscopically normal mucosa contained clonal lymphomatous cells in 69% of cases before remission. A complete histological remission (HR) was observed in 28 patients (47%). Among them, 23 were followed for molecular remission (MR). The median delay was 10 months to achieve HR and 18 months to achieve MR. Interestingly, patients with HR but not MR had a longer delay to achieve HR (21 months) (P=0.0006) and a more frequent clonal normal mucosa at diagnosis (88%) than patients with both HR and MR (10 months and 39%, respectively). The presence of monoclonal B cells at both infiltrated and normal sites may therefore identify patients with a longer delay to achieve complete response, suggesting that molecular dissemination may require therapeutic intensification.

Could immunosuppressive drugs reduce recurrence rate after second resection for Crohn disease?

BACKGROUND: The aim of this study was to assess the possible benefit of postoperative immunosuppressive drugs administration (ie, azathioprine, 6-mercaptopurine, or methotrexate) on long-term surgical recurrence rate after second anastomotic ileocolonic resection. METHODS: From 1984 to 2000, 26 patients with CD underwent second resection for ileocolonic anastomotic recurrence. There were 14 women and 12 men (mean age +/- SD: 34 +/- 9 years). Two groups of patients were compared according to the postoperative treatment: immunosuppressive (IS) drugs group was composed of 14 patients, and control group was composed of 12 patients receiving either salicylates (n = 5) or no treatment (n = 7). RESULTS: Clinical recurrence rate at 3 years was significantly lower in the IS group than in the control group (3/12, 25% vs 6/10, 60%; P < 0.05). Although not significant, after a mean follow-up of 80 +/- 46 months (extr. 17-178 months) after the second resection, clinical recurrence rate at follow-up was also lower in IS group (6/14, 43%) than in control group (9/12, 75%). The mean delay of recurrence was similar in both groups (27 +/- 13 months vs 28 +/- 21; NS). A third intestinal resection was performed less frequently in the IS group than in control group (2/14, 17% vs 7/12, 58%; P < 0.02). CONCLUSIONS: In patients treated with IS drugs, the rate of postoperative recurrence after second ileocolonic CD resection is lower than in untreated patients. Our results suggest that IS drugs should be evaluated prospectively for prevention of second postoperative CD recurrence.

Subtotal colectomy for severe acute colitis: a 20-year experience of a tertiary care center with an aggressive and early surgical policy.

BACKGROUND: Management of severe acute colitis (SAC) complicating inflammatory bowel disease remains a challenge despite significant advances in medical therapy. The aim of this study was to report a 20-year experience with subtotal colectomy (STC) performed for SAC. STUDY DESIGN: A total of 164 consecutive patients with a mean age of 37 +/- 15 years (range 16 to 86 years) underwent STC for SAC defined according to the criteria of Truelove and Witts. The decision for surgical treatment was based on clinical, biologic, radiologic, and endoscopic severity criteria both at entry and during hospitalization after failure to improve under medical treatment. A Brooke ileostomy was made to the right iliac fossa and a sigmoidostomy was made to the midline incision. All complications before discharge were recorded as in-hospital morbidity or mortality. RESULTS: Colonoscopy was performed in 153 patients and endoscopic diagnosis of SAC was confirmed by pathologic examination in 84% of the cases. STC was performed on an emergency basis in 40 patients with complications and only after failure of medical treatment in the remaining 124 patients. The mortality rate was 0.6%. The overall morbidity rate was 33%; 24 patients required reoperation, including 8% undergoing reoperation during followup for small bowel obstruction. Definitive pathologic diagnosis changed in one half of the patients; the final diagnosis was Crohn's disease in 110 cases, ulcerative colitis in 35, and indeterminate colitis in 19. CONCLUSIONS: Our results demonstrated the safety of STC performed in a tertiary care center for patients with SAC who presented with complications or failed to respond to intensive medical therapy.

Pitfalls and mimickers at 64-section helical CT that cause negative appendectomy: an analysis from 1057 appendectomies.

PURPOSE: To determine the rate of negative appendectomy and clarify the causes of negative appendectomy in patients with clinically suspected acute appendicitis who had surgery after 64-section helical computed tomography (CT). MATERIAL AND METHODS: A retrospective analysis of 1057 patients who had appendectomy after 64-section helical CT was performed to determine the rate of negative appendectomy. The 64-section helical CT examinations obtained with submillimeter and isotropic voxels in the patients with negative appendectomy were analyzed by two readers and compared to clinical, operative and histopathological reports, discharge summaries and original radiology reports. RESULTS: The negative appendectomy rate was 1.7% (18/1057). Appendix enlargement (>6 mm) and fat stranding were present in 17 (17/18; 94%) and 6 patients (6/18; 33%), respectively. In 13 patients (13/18; 72%) 64-section helical CT findings were consistent with acute appendicitis. Interpretive errors in original imaging reports were identified in five patients (5/18; 28%). CONCLUSION: The preoperative use of 64-section helical CT results in a very low rate of negative appendectomy. Patients with negative appendectomy have 64-section helical CT findings consistent with a diagnosis of acute appendicitis in the majority of cases. Interpretive errors are less frequent.