Subcutaneous Ustekinumab Provides Clinical Benefit for Two-Thirds of Patients With Crohn's Disease Refractory to Anti-Tumor Necrosis Factor Agents.

BACKGROUND & AIMS: Ustekinumab, a human monoclonal antibody against the p40 subunit of interleukins-12 and -23, is effective in inducing and maintaining remission in patients with luminal Crohn's disease (CD). We assessed the efficacy and safety of subcutaneous ustekinumab in patients with anti-tumor necrosis factor (anti-TNF) refractory CD. METHODS: We performed a retrospective observational study, collecting data from the Groupe d'Etude Thérapeutique des Affections Inflammatoires du tube Digestif on 122 consecutive patients with active CD refractory to anti-TNF therapy who received at least 1 subcutaneous injection of ustekinumab from March 2011 to December 2014, in 20 tertiary centers in Europe. Subjects were followed for at least 3 months. The primary outcome was clinical benefit, defined as reductions in symptoms and biochemical markers of CD and complete weaning from steroids, without surgery or immunosuppressant therapies. RESULTS: Seventy-nine patients (65%) had a clinical benefit within 3 months of receiving ustekinumab. Concomitant immunosuppressant therapy at study inclusion increased the odds for a clinical benefit from ustekinumab (odds ratio, 5.43; 95% confidence interval, 1.14-25.77; P = .03). Over a median follow-up period of 9.8 months (interquartile range, 5.3-14.5 months), the cumulative probabilities that patients maintained the clinical benefit for 6 and 12 months after introduction of ustekinumab were 93% and 68%, respectively. CONCLUSIONS: Almost two-thirds of patients with CD refractory to at least 1 anti-TNF agent receive clinical benefit from ustekinumab therapy, not requiring steroids for up to 12 months afterward. While awaiting results from ongoing trials, ustekinumab can be considered for use in these patients.

Risk of colorectal high-grade dysplasia and cancer in a prospective observational cohort of patients with inflammatory bowel disease.

BACKGROUND & AIMS: There is an unclear risk of colonic high-grade dysplasia (HGD) and colorectal cancer (CRC) among patients with inflammatory bowel disease (IBD) treated with immunosuppressants. We analyzed data on CRC development among patients with IBD enrolled in the observational cohort Cancers et Surrisque Associé aux Maladies Inflammatoires Intestinales En France (CESAME). METHODS: We followed and collected data from 19,486 patients with IBD (60.3% with Crohn's disease, 30.1% receiving thiopurine therapy) enrolled in CESAME from May 2004 and June 2005, and followed them until December 2007. When the study began, 2841 patients (14.6%) were characterized as having long-standing extensive colitis (ie, >10 years and involving ≥50% of the colon). Early lesions (HGD and CRC) were defined as those diagnosed within 10 years after diagnosis of IBD. RESULTS: Thirty-seven patients developed CRC during the follow-up period, and 20 developed colorectal HGD. The standardized incidence ratios of CRC were 2.2 for all IBD patients (95% confidence interval [CI]: 1.5-3.0; P < .0001), 7.0 for patients with long-standing extensive colitis (95% CI: 4.4-10.5; P < .001), and 1.1 for patients without long-standing extensive colitis (95% CI: 0.6-1.8; P = .84). Among patients with long-standing extensive colitis, the multivariate adjusted hazard ratio for colorectal HGD and cancer was 0.28 for those who received thiopurines compared with those who never received thiopurine therapy (95% CI: 0.1-0.9; P = .03). Twenty-two patients developed early lesions; 7 of these were related to IBD, based on histologic analysis. CONCLUSIONS: Patients with IBD and long-standing extensive colitis are at increased risk for CRC, although the risk is lower among patients receiving thiopurine therapy. Patients without long-standing extensive colitis have a risk for CRC similar to that of the general population, but they can develop IBD-related lesions within 10 years after diagnosis of IBD.

Survival and Predictive Factors of Chemotherapy With FOLFIRINOX as First-Line Therapy in Metastatic Pancreatic Cancer: A Retrospective Multicentric Analysis.

OBJECTIVES: The use of FOLFIRINOX (a combination of oxaliplatin, irinotecan, fluorouracil, and leucovorin) is one of the therapeutic standards in pancreatic adenocarcinoma. We analyzed progression-free survival (PFS) and overall survival (OS) and their predictive factors in patients treated with FOLFIRINOX as first-line therapy in metastatic pancreatic cancer. METHODS: This multicenter retrospective analysis included patients treated with FOLFIRINOX between 2011 and 2015. The Kaplan-Meier method was used to estimate OS and PFS. The statistical comparison for survival was performed by the log-rank test. Predictive factors were estimated in multivariate analysis with the use of a Cox model. RESULTS: One hundred and thirty-six patients were included (74 men, 62 women; median age, 62 years [range, 29-74 years]). The median PFS was 5.97 months (95% confidence interval, 4.4-6.63 months). The median OS was 8.93 months (95% confidence interval, 7.4-10.07 months). Prognostic factors in multivariate analysis were the use of granulocyte colony-stimulating factor, which appeared to be a good prognostic factor. Dose intensity of oxaliplatin (≥74.48%) and dose intensity of bolus of fluorouracil (>6.9%) appeared as pejorative factors. CONCLUSIONS: In patients with metastatic pancreatic adenocarcinoma treated with FOLFIRINOX in first line, dose modifications at the onset of adverse effects and early use of granulocyte-colony stimulating factor seem to be associated with a better survival.

Severe skin lesions cause patients with inflammatory bowel disease to discontinue anti-tumor necrosis factor therapy.

BACKGROUND & AIMS: Psoriasiform and eczematiform lesions are associated with anti-tumor necrosis factor (TNF)-α therapies. We assessed clinical characteristics, risk factors, and outcomes of skin disease in patients with inflammatory bowel diseases that presented with psoriasiform and eczematiform lesions induced by anti-TNF-α agents. METHODS: We studied 85 patients (69 with Crohn's disease, 15 with ulcerative colitis, and 1 with indeterminate colitis; 62 women) with inflammatory skin lesions (62 psoriasiform and 23 eczematiform lesions). RESULTS: Twenty-four patients had a history of inflammatory skin lesions and 15 had a familial history of inflammatory skin disease. Locations of eczematiform lesions varied whereas scalp and flexural varieties were mostly psoriasiform. Skin lesions emerged but inflammatory bowel disease was quiescent in 69 patients following treatment with any type of anti-TNF-α agent (60 with infliximab, 20 with adalimumab, and 5 with certolizumab). Topical therapy resulted in partial or total remission in 41 patients. Patients with psoriasiform lesions that were resistant to topical therapy and that changed anti-TNF-α therapies once or twice developed recurring lesions. Overall, uncontrolled skin lesions caused 29 patients to stop taking TNF-α inhibitors. CONCLUSIONS: Inflammatory skin lesions following therapy with TNF-α inhibitors occurred most frequently among women and patients with a personal or familial history of inflammatory skin disease; lesions did not correlate with intestinal disease activity. Recurring and intense skin lesions caused 34% of patients in this study to discontinue use of anti-TNF-α agents.

Azathioprine withdrawal in patients with Crohn's disease maintained on prolonged remission: a high risk of relapse.

BACKGROUND & AIMS: Azathioprine (AZA) withdrawal in Crohn's disease after long-term remission under treatment is controversial. In a Groupe d'Etude Thérapeutique des Affections Inflammatoires du tube Digestif randomized, double-blind, placebo-controlled trial, the hypothesis that AZA withdrawal was not inferior to AZA continuation in patients in prolonged clinical remission could not be shown. METHODS: A cohort of 66 patients in prolonged remission while being treated with AZA who stopped AZA, during or at the end of the randomized controlled trial, underwent long-term follow-up evaluation. The primary end point was clinical relapse. Prognostic factors of relapse were looked for through a proportional hazards model. RESULTS: Median durations of AZA therapy and of clinical remission were 68.4 months (interquartile range, 52.8-85.2 mo) and 63.6 months (interquartile range, 48.0-55.7 mo), respectively. The median follow-up time after AZA interruption was 54.5 months; 32 of 66 patients had a relapse. The cumulative probabilities +/- SE of relapse at 1, 3, and 5 years were 14.0% +/- 4.3%, 52.8% +/- 7.1%, and 62.7% +/- 7.2%, respectively. C-reactive protein concentration of 20 mg/L or greater (risk, 58.6; 95% confidence interval, 7.5-457; P = .002), hemoglobin level less than 12 g/dL (risk, 4.8; 95% confidence interval, 1.7-13.7; P = .04), and neutrophil count 4 x 10(9)/L or greater (risk, 3.2; 95% confidence interval, 1.6-6.3; P = .003) were associated independently with an increased risk of relapse. Among the 32 relapsing patients, 23 were retreated by AZA alone, all but 1 up to successful remission. CONCLUSIONS: Our results confirm that AZA withdrawal is associated with a high risk of relapse, whatever the duration of remission under this treatment. These data suggest that if AZA is well tolerated, it should not be interrupted.

L-arginine metabolism in dog kidney and isolated nephron segments.

The renal basic amino acid metabolism often differs in rodents, strict carnivores, and omnivore species. Given the pivotal role of L-arginine and L-ornithine in several metabolic pathways and the fact that the dog is closely related to humans, being also an omnivore, we tested whether L-arginine metabolism and L-ornithine catabolism take place in the dog kidney. We examined the metabolism of L-arginine in dog cortical tubules to integrate local L-arginine metabolism into a general physiological and metabolic framework. To achieve these goals, we first ascertained the protein expression of relevant enzymes by Western blot. L-Arginine catabolism was studied in suspensions of canine cortical proximal tubules, medullary thick ascending limbs, and papillary collecting ducts either incubated without exogenous L-arginine being added (small endogenous quantities) or incubated with L-arginine being added in supraphysiological amounts (2 mmol/L with or without the presence of alternative metabolic substrates, 2 mmol/L L-glutamine, or lactate). The results revealed that dog kidneys consumed L-citrulline and released L-arginine and L-ornithine. Argininosuccinate synthetase and lyase, arginase II, and ornithine aminotransferase were detected in the renal cortex. Arginase II activity was found in a suspension of proximal tubules by measuring the amounts of urea and L-ornithine produced. A fraction of this L-ornithine was further partially metabolized through the intramitochondrial ornithine aminotransferase pathway, leading to changes in L-glutamate, glucose, L-alanine, and ammonia metabolism without L-proline accumulation. Medullary thick ascending limbs expressed a very low arginase activity, whereas papillary collecting ducts did not. In conclusion, the dog kidney produces L-arginine. Part of this L-arginine is further catabolized by arginase II, suggesting that its physiological role was to produce L-ornithine for the body.

Frequent rearrangements and amplification of the CDX2 homeobox gene in human sporadic colorectal cancers with chromosomal instability.

The expression of the CDX2 gene, a crucial regulator of gut homeostasis, is altered in human colorectal cancers in parallel with de-differentiation. Here, we have investigated the chromosomal status of CDX2 in human sporadic colorectal cancers with the phenotype of chromosomal instability. Allelic imbalance determination showed frequent rearrangements at the CDX2 locus. The rearrangements correlated with CDX2 gene amplification, as assessed by quantitative PCR analysis. However, they were not predictive of the Cdx2 protein pattern. These data suggest that mechanisms other than structural alterations at the CDX2 locus account for the change of expression in colorectal cancers.

Interobserver Variation Study of the Rutgeerts Score to Assess Endoscopic Recurrence after Surgery for Crohn's Disease.

BACKGROUND: After resection surgery for Crohn's disease, recurrence of endoscopic lesions at the site of the anastomosis or in the neoterminal ileum is graded according to the Rutgeerts score (RS). The goal of this study was to test the interobserver variability for RS. METHODS: Thirteen trained endoscopists evaluated the RS on 39 videotapes of patients who had undergone resection for Crohn's disease with an ileocolonic anastomosis 6 months earlier. Videotapes were randomly assigned to endoscopists through a balanced incomplete block design. Each videotape was scored independently by four endoscopists, and each endoscopist evaluated 12 videotapes, making a total of 156 videotape assessments. Reproducibility levels of the RS were assessed through unweighted kappa estimates among multiple raters. The proportion of inappropriate therapeutic initiation was estimated by randomly selecting one endoscopist for each videorecording, assuming that the majority of endoscopists correctly classified endoscopic recurrence. RESULTS: The kappa estimates were 0.43 (95% confidence interval: 0.33-0.52) for the RS on a 5-grade scale, 0.47 (0.28-0.66) for RS < i2 vs. ≥ i2, and 0.64 (0.42-0.85) for RS ≤ i2 vs. > i2. The percentages of inappropriate therapeutic initiation were 12.8% (3.8-21.9) when initiation was triggered by a RS ≥ i2 and 8.3% (1.1-15.6) when initiation was triggered by a RS > i2 (p = 0.41). CONCLUSION: The reproducibility of the RS was moderate, especially when differentiating 10% of patients.

Costs of Crohn's Disease According to Severity States in France: A Prospective Observational Study and Statistical Modeling over 10 Years.

BACKGROUND: To describe the medico-economic characteristics of Crohn's disease (CD), we implemented a multicenter study in France. METHODS: From 2004 to 2006, disease severity states, direct (hospital and extra hospital) and indirect costs were prospectively collected over 1 year in patients with CD naive from anti-tumor necrosis factor alpha (infliximab) at inclusion. Economic valorization was performed from the French Social Insurance perspective, and a statistical modeling over 10 years was performed. RESULTS: In 341 patients, the mean total costs of management were &OV0556;6024 per year (&OV0556;4675 for direct costs). As compared to patients in remission, costs were 4 to 6 times higher in patients in an active period and 19 times higher for patients requiring surgery (SURG). The most important expense items were medical and surgical hospitalizations (56% of total costs), including cost of infliximab (36% of hospitalization costs, i.e., 20% of total costs), indirect costs (22%), and drugs (11%). The statistical modeling over 10 years showed that most of the clinical course was spent in drug-responsive state (54%) with 26% of costs or in remission (32%) with 11% of costs; time spent in a SURG state was small (3.2%) but generated 48% of total costs. CONCLUSIONS: Before the introduction of self-injectable anti-tumor necrosis factor alpha, the most important expenses were supported by hospitalizations, explaining why the most costly states were for patients requiring SURG or dependent on inhospital administrated drugs. Projected data show that most time is spent in a stabilized state with appropriate treatments or in remission, and that costs associated with SURG are high.

Cdx1 homeobox gene during human colon cancer progression.

The Cdx1 homeobox gene encodes an intestine-specific transcription factor with a pro-oncogenic function in vitro. Here we have analysed the pattern of Cdx1 in human colon cancer progression. Cdx1 expression remains at a high level in the majority of the polyps and it is even overexpressed in more than one-third of the specimens, consistent with the fact that the gene is an intestine-specific target of oncogenic pathways. However, Cdx1 decreases in one-fifth of the polyps, which is reminiscent of the loss of expression previously reported in the majority of carcinomas. Allelic imbalance analysis demonstrates that the Cdx1 locus located on chromosome 5q is a major site of genomic rearrangement in colorectal cancers, and that the frequency of the rearrangements increases during polyps to carcinoma progression. Allelic imbalance at the Cdx1 locus occurs in relation to, although not invariably in association with, the rearrangements at the APC locus on the same chromosomal arm. Xenografts of primary human colon carcinomas indicate that the level of Cdx1 mRNA correlates with the intensity of allelic imbalance. Together, these data show that Cdx1 exhibits a complex pattern during colorectal cancer progression. Given that Cdx1 has a pro-oncogenic function in vitro, the maintenance of a high level of expression in polyps, and even its overexpression in one-third of the specimens, suggest that this homeobox gene may be an important factor in the process toward malignant transformation during the first steps of tumorigenesis.

Factors contributing to infectious diarrhea-associated pancreatic enzyme alterations.

OBJECTIVES: Several pathogens have been involved as etiologic agents of acute pancreatitis. We studied 59 patients presenting acute infectious diarrhea in order to determine the incidence as well as to identify factors which may contribute to the occurrence of pancreatic enzyme alteration or true acute pancreatitis. METHODS: Patients were evaluated for serum lipase and amylase, and 24-hours urinary amylase. Clinical and biological parameters were noted. Abdominal sonography and rectosigmoidoscopy were performed. RESULTS: Pancreatic enzyme alteration was found in 24% of patients. Twelve had salmonellosis and 2 Campylobacter jejuni infection. They had more prolonged diarrhea, more frequent renal impairment and increased triglyceridemia. Triglyceridemia was correlated to blood amylase, inflammatory syndrome and renal impairment. Serum amylase was linked to serum urea and creatinine and to biological markers of inflammation. Three patients had true acute pancreatitis. CONCLUSION: Patients presenting dysentery-like infectious diarrhea and upper abdominal pain should be investigated for concomitant pancreatic reaction or acute pancreatitis which seems more frequent in patients with enterocolitis due to enteroinvasive microbes, mostly non-typhoidal Salmonella. Pancreatic disturbances are related to the severity of these infections. However, overt infectious diarrhea-associated pancreatitis is a rare event.

Immunogenicity and Safety of Influenza Vaccine in Inflammatory Bowel Disease Patients Treated or not with Immunomodulators and/or Biologics: A Two-year Prospective Study.

BACKGROUND AND AIMS: Data on the efficacy and safety of seasonal influenza vaccines in patients with inflammatory bowel disease (IBD) remain scarce. The aim of the study was to evaluate the impact of immunosuppressive (IS) therapeutics on serological response to 2-year influenza vaccination in IBD adults. METHODS: A multicentre prospective study performed in 255 IBD adults (18-64 years) receiving the trivalent influenza vaccine in the years 2009-2010 and 2010-2011. Haemagglutination inhibition (HI) titres were assessed before and 3 weeks and 6 months after vaccination. RESULTS: At inclusion, 31 patients were receiving no IS treatment (Group A), 77 were receiving IS treatment without anti-TNF (Group B) and 117 were receiving anti-tumour necrosis factor (TNF) treatment with or without IS treatment (Group C). Three weeks after the first vaccination, rates of seroprotection were 77, 75 and 66% for strain A/H1N12007 (p = 0.35), 77, 68 and 52% for strain A/H3N2 (p = 0.014) and 97, 96 and 95% for strain B (p = 0.99) in Groups A, B and C, respectively. Seroconversion rates for A/H1N12007 (67, 64 and 54%; p = 0.28), A/H3N2 (63, 50 and 41%; p = 0.074) and strain B (63, 76 and 60%; p = 0.078) were not significantly different among treatment groups. At 6 months after vaccination, seroprotection rates were lower in Group C compared with Groups A and B. Comparable results were observed for the second year of vaccination. No impact on Harvey-Bradshaw and Mayo scores was detected. CONCLUSIONS: Influenza vaccine yielded high seroprotection rates in IBD patients. Persistence of seroprotection was lower in patients with anti-TNF treatment. ClinicalTrials.gov, number NCT01022749.

In vitro modulation of inflammatory cytokine production by three lipid emulsions with different fatty acid compositions.

BACKGROUND AND AIMS: Studies have suggested that 100% long-chain triacylglycerols (LCTs) lipid emulsions exhibit immunosuppressive effects, sometimes suspected to favor infectious complications in patients receiving parenteral nutrition. Newer emulsions, in particular olive oil-based emulsions, seem to have lesser immunosuppressive effects. We studied the in vitro effect of 100% LCTs (Intralipide), 50% LCTs-50% medium chain triacylglycerols (Medialipide), and 80% olive oil-based lipid emulsions (ClinOleic) on inflammatory cytokines production by peripheral blood mononuclear cells (PBMCs). METHODS: PBMCs separated by gradient centrifugation, or whole blood, were incubated with 0.001%, 0.01%, 0.1% and 1% of the three tested lipid emulsions during 24h in the presence or absence of activation by lipopolysaccharide and phytohemagglutinin. Then, supernatants were collected and cytokines measured (ELISA). RESULTS: The three lipid emulsions reduced basal TNF-alpha and IL-1beta production in PBMCs and whole blood cultures. However, ClinOleic was significantly less powerful in TNF-alpha and IL-1beta inhibition by isolated PBMCs than Intralipide and Medialipide. Basal TNF-alpha production was equally inhibited by the three emulsions in whole blood, but IL-1beta production was not significantly modified by ClinOleic. Interleukin-6 and -8 were not affected. After cell activation, lipid emulsions exhibit no effect on cytokines production. CONCLUSION: ClinOleic induces a significantly lower in vitro inhibition of TNF-alpha and IL-1beta production by PBMCs than 100% LCTs or 50% LCTs-50% MCTs emulsions, and therefore might be more immune neutral. These effects vary from one subject to another, and disappeared after cell activation. Therefore, caution must be taken before extrapolation in vivo. Provided information should be taken into account for future design of clinical trials studying the immune modulating properties of lipid emulsions.

Potential usefulness of olive oil-based lipid emulsions in selected situations of home parenteral nutrition-associated liver disease.

Long-term (i.e. home) parenteral nutrition has been advocated to be responsible for several metabolic complications among which hepatic disorders have long been the most relevant in view of patients' prognosis. The increased knowledge of the pathophysiologic factors associated to parenteral nutrition-related liver disease as well as the regular improvement of the components and the techniques used for parenteral nutrition leaded progressively to a better prevention of these side effects. This case report focuses on the potential interest of olive oil-based lipid emulsions in home parenteral nutrition patients, in selected situations of home parenteral nutrition-associated metabolic liver disease.

18F-fluorodihydroxyphenylalanine PET/CT in patients with neuroendocrine tumors of unknown origin: relation to tumor origin and differentiation.

UNLABELLED: This work was performed to evaluate the performance of (18)F-fluorodihydroxyphenylalanine ((18)F-FDOPA) PET/CT in detecting primary neuroendocrine tumors (NETs) occult on morphologic and functional imaging, in relation to tumor origin and differentiation. METHODS: A retrospective study of NET patients who were investigated with (18)F-FDOPA PET/CT imaging in 2 academic endocrine tumor centers was conducted. Only patients with negative conventional and somatostatin receptor scintigraphy (SRS) results were studied. RESULTS: Twenty-seven patients were evaluated with (18)F-FDOPA PET/CT, 23 at their initial staging and 4 during their follow-up. The primary occult NET was localized by (18)F-FDOPA PET/CT in 12 patients (overall sensitivity, 44%; 52% in patients evaluated at initial diagnosis), leading to tumor resection in all cases. The primary tumors were distributed and graded as follows: 1 duodenum G2 lesion, 7 ileum G2 lesions, 2 terminal ileum G1 lesions, 1 pancreas G2 lesion, and 1 gallbladder G3 lesion. Patients with positive (18)F-FDOPA PET/CT results had higher values of serum chromogranin A (100% vs. 20%, P = 0.0003), serotonin, or urinary 5-hydroxyindolacetic acid (83% vs. 20%, P = 0.003). Two false-negative results were related to poorly differentiated duodenal and prostatic NETs (G3). (18)F-FDOPA PET/CT showed more metastatic anatomic regions than SRS in 17 patients. CONCLUSION: (18)F-FDOPA PET appears to be a sensitive functional imaging tool for the detection of primary NETs occult on SRS, especially tumors with a well-differentiated pattern and serotonin secretion.

The laminin response in inflammatory bowel disease: protection or malignancy?

Laminins (LM), basement membrane molecules and mediators of epithelial-stromal communication, are crucial in tissue homeostasis. Inflammatory Bowel Diseases (IBD) are multifactorial pathologies where the microenvironment and in particular LM play an important yet poorly understood role in tissue maintenance, and in cancer progression which represents an inherent risk of IBD. Here we showed first that in human IBD colonic samples and in murine colitis the LMα1 and LMα5 chains are specifically and ectopically overexpressed with a concomitant nuclear p53 accumulation. Linked to this observation, we provided a mechanism showing that p53 induces LMα1 expression at the promoter level by ChIP analysis and this was confirmed by knockdown in cell transfection experiments. To mimic the human disease, we induced colitis and colitis-associated cancer by chemical treatment (DSS) combined or not with a carcinogen (AOM) in transgenic mice overexpressing LMα1 or LMα5 specifically in the intestine. We demonstrated that high LMα1 or LMα5 expression decreased susceptibility towards experimentally DSS-induced colon inflammation as assessed by histological scoring and decrease of pro-inflammatory cytokines. Yet in a pro-oncogenic context, we showed that LM would favor tumorigenesis as revealed by enhanced tumor lesion formation in both LM transgenic mice. Altogether, our results showed that nuclear p53 and associated overexpression of LMα1 and LMα5 protect tissue from inflammation. But in a mutation setting, the same LM molecules favor progression of IBD into colitis-associated cancer. Our transgenic mice represent attractive new models to acquire knowledge about the paradoxical effect of LM that mediate either tissue reparation or cancer according to the microenvironment. In the early phases of IBD, reinforcing basement membrane stability/organization could be a promising therapeutic approach.

Immunohistochemical expression of CDX2, ß-catenin, and TP53 in inflammatory bowel disease-associated colorectal cancer.

BACKGROUND: Inflammatory bowel disease (IBD) exposes patients to an increased risk of colorectal cancer (i-CRC) and differences between i-CRC and sporadic colorectal cancer (s-CRC) pathogenesis were reported. In s-CRC, studies indicate abnormalities in the tumor-suppressor gene Cdx2. This study compared CDX2, ß-catenin, and TP53 expression in i-CRC, s-CRC, noncancer IBD, and normal control colonic mucosa. METHODS: Expression was investigated by immunohistochemistry in 10 normal, 20 s-CRC, 11 noncancer colonic IBD and 30 i-CRC samples, and in four samples of Crohn's disease (CD)-associated small bowel adenocarcinoma (i-SBA). RESULTS: In normal and noncancer IBD samples, CDX2 was confined to the colonocytes nuclei. CDX2 expression was normal in 90% of i-CRC, regardless of tumor differentiation or inflammation intensity. By contrast, CDX2 expression was altered in 45% s-CRC, particularly at the front of invasion in undifferentiated tumors. ß-Catenin was restricted to cell membrane in all controls, in 91% noncancer IBD, and in 84% i-CRC samples, whereas 35% s-CRC showed cytoplasmic redistribution and exclusive nuclear staining at the front of invasion. TP53 was strongly and homogeneously expressed in i-CRC nuclei compared to normal control or s-CRC, and increases with inflammation intensity. Nested or diffuse TP53 was found in 81.8% of noncancer IBD samples with a higher proportion of TP53-expressing cells in the most inflamed samples. CDX2, ß-catenin, and TP53 expression in CD-associated SBA appears similar to that of i-CRC. Neither Cdx2 nor ß-catenin alterations are prominent features of i-CRC. CONCLUSIONS: In i-CRC and CD-associated SBA, carcinogenesis is associated early with p53 mutations and to inflammation intensity.

Histologic characteristics of non-microsatellite-instable colon adenomas correlate with distinct molecular patterns.

Colon carcinogenesis encompasses the stepwise accumulation of genomic aberrations correlated with the transition of aberrant crypt-adenoma-carcinoma. Recent data have revealed that, in addition to the microsatellite-instable phenotype, the chromosome instability pathway, representing four fifth of the colon carcinoma, could be involved in heterogeneous molecular alterations. Our project was aimed at determining the existence of distinct molecular subtypes in 159 non-microsatellite-instable colon polyps and their correlation with histology and dysplasia, using allelotyping, MGMT promoter gene methylation status, and K-RAS mutation analyses. Allelic imbalance, MGMT methylation, and K-RAS mutations arise in 62%, 39%, and 32% of polyps, respectively. Only 14% of polyps had no alterations. A 2-way hierarchical clustering analysis of the allelic imbalances identified subgroups of polyps according to their allelic imbalance frequency and distribution. Not only tubulovillous adenoma but also high-grade adenomas were correlated with high global allelic imbalance frequency (P = .005 and P = .003), with allelic imbalance at microsatellites targeting chromosomes 1, 6, and 9. In conclusion, the data presented in this study show that a large heterogeneity exists in the molecular patterns of alterations in precancerous colon lesions, favoring different modes of tumor initiation. Therefore, molecular alterations correlated with tubulovillous-type and high-grade dysplasia could represent targets identifying predictive factors of progression.

Infliximab plus azathioprine for steroid-dependent Crohn's disease patients: a randomized placebo-controlled trial.

BACKGROUND & AIMS: The aim of this study was to evaluate the usefulness of short-term infliximab combined with azathioprine (AZA) or 6-mercaptopurine (6-MP) in steroid-dependent Crohn's disease patients. METHODS: Patients with active disease despite prednisone given for more than 6 months were eligible and were stratified as follows: the failure stratum consisted of patients receiving AZA/6-MP at a stable dose for more than 6 months, and the naive stratum consisted of patients not treated previously with AZA/6-MP. Patients were randomized to infliximab 5 mg/kg or placebo at weeks 0, 2, and 6. All patients were treated with AZA/6-MP maintained at a stable dose throughout the 52 weeks of the study. The primary end point was remission off steroids at week 24. RESULTS: Among the 113 enrolled patients (55 in the failure stratum), 57 were assigned to infliximab. At week 24, the success rate (intent-to-treat analysis) was higher in the infliximab group than in the placebo group (57% vs 29%; P = .003); at weeks 12 and 52, the corresponding rates were 75% vs 38% (P < .001) and 40% vs 22% (P = .04), respectively. In each stratum, the success rate was significantly higher in the infliximab group at weeks 12 and 24, and a trend was found at week 52. In the failure stratum, only 27% of the patients in the infliximab group were still in remission off steroids, compared with 52% in the naive stratum. Steroid resistance was less common and the cumulative dose of prednisone was lower in the infliximab group. CONCLUSIONS: Infliximab plus AZA/6-MP is more effective than AZA/6-MP alone in steroid-dependent Crohn's disease patients.

A randomized, double-blind, controlled withdrawal trial in Crohn's disease patients in long-term remission on azathioprine.

BACKGROUND & AIMS: An open study reported that patients with Crohn's disease in remission who have taken azathioprine for longer than 3.5 years are at low risk of relapse when azathioprine is discontinued. To confirm this observation, we performed a multicenter, double-blind, noninferiority withdrawal study. METHODS: Patients who were in clinical remission on azathioprine for > or = 42 months were randomized to continue azathioprine or to receive an equivalent placebo for 18 months. The primary end point was clinical relapse at 18 months. RESULTS: Forty patients were randomly assigned to receive azathioprine and 43 to receive placebo. Characteristics of patients at entry were similar in the 2 study groups. At 18 months, 3 patients had a relapse in the azathioprine group, and 9 had a relapse in the placebo group. Kaplan-Meier estimates of the relapse rate at 18 months were 8% +/- 4% and 21% +/- 6%, respectively. The hypothesis that placebo was inferior to azathioprine was not rejected (P = .195). Among the baseline variables, C-reactive protein level > 20 mg/L, time without steroids < 50 months, and hemoglobin level < 12 g/dL were found to be predictive of relapse in the multivariate analysis. CONCLUSIONS: This study shows that azathioprine withdrawal is not equivalent to continued therapy with azathioprine for maintenance of remission in patients with Crohn's disease who have been in remission on azathioprine for > or = 3.5 years. Thus, azathioprine maintenance therapy should be continued beyond 3.5 years.