Bodo Klump

Chemoradiation With and Without Surgery in Patients With Locally Advanced Squamous Cell Carcinoma of the Esophagus

PURPOSE Combined chemoradiotherapy with and without surgery are widely accepted alternatives for the curative treatment of patients with locally advanced esophageal cancer. The value of adding surgery to chemotherapy and radiotherapy is unknown. PATIENTS AND METHODS Patients with locally advanced squamous cell carcinoma (SCC) of the esophagus were randomly allocated to either induction chemotherapy followed by chemoradiotherapy (40 Gy) followed by surgery (arm A), or the same induction chemotherapy followed by chemoradiotherapy (at least 65 Gy) without surgery (arm B). Primary outcome was overall survival time. RESULTS The median observation time was 6 years. The analysis of 172 eligible, randomized patients (86 patients per arm) showed overall survival to be equivalent between the two treatment groups (log-rank test for equivalence, P < .05). Local progression-free survival was better in the surgery group (2-year progression-free survival, 64.3%; 95% CI, 52.1% to 76.5%) than in the chemoradiotherapy group (2-year progression-free survival, 40.7%; 95% CI, 28.9% to 52.5%; hazard ratio [HR] for arm B v arm A, 2.1; 95% CI, 1.3 to 3.5; P = .003). Treatment-related mortality was significantly increased in the surgery group than in the chemoradiotherapy group (12.8% v 3.5%, respectively; P = .03). Cox regression analysis revealed clinical tumor response to induction chemotherapy to be the single independent prognostic factor for overall survival (HR, 0.30; 95% CI, 0.19 to 0.47; P < .0001). CONCLUSION Adding surgery to chemoradiotherapy improves local tumor control but does not increase survival of patients with locally advanced esophageal SCC. Tumor response to induction chemotherapy identifies a favorable prognostic group within these high-risk patients, regardless of the treatment group.

Association of NOD2 (CARD 15) genotype with clinical course of Crohn's disease: a cohort study

BACKGROUND Crohns disease is a heterogeneous disorder for which NOD2 (CARD 15) has been identified as a susceptibility gene. We investigate the relation between NOD2 genotype and phenotypic characteristics of patients with Crohns disease. METHODS Hypotheses about the relation between NOD2 genotype and Crohns disease phenotype were generated retrospectively from a group of 446 German patients with this disorder. Positive findings (p<0.10) were verified in prospectively established cohorts of 106 German and 55 Norwegian patients with Crohns disease. All patients were genotyped for the main coding mutations in NOD2, denoted SNP8, SNP12, and SNP13, with Taqman technology. FINDINGS In the retrospective cohort, six clinical characteristics showed noteworthy haplotype association: fistulising, ileal, left colonic and right colonic disease, stenosis, and resection. In the German prospective cohort, these haplotype associations could be replicated for ileal (p=0.006) and right colonic disease (p < or =0.001). A similar trend was noted in the Norwegian patients. INTERPRETATION We recorded a distinct relation between NOD2 genotype and phenotype of Crohns disease. Test strategies with NOD2 variations to predict the clinical course of Crohns disease could lead to the development of new therapeutic paradigms.

Hypermethylation of the CDKN2/p16 Promoter During Neoplastic Progression in Barrett's Esophagus

BACKGROUND & AIMS Inactivation of the CDKN2/p16(INK4A) tumor-suppressor gene is one of the most frequent genetic alterations in human malignancies. In esophageal adenocarcinomas, mutations of the p16 gene or homozygous deletions of the gene locus 9p21 are rare. This study investigated whether p16 promoter hypermethylation is an alternative mechanism for p16 gene inactivation during neoplastic progression in Barretts esophagus. METHODS A methylation-specific polymerase chain reaction protocol was applied. A total of 95 specimens from 14 patients with Barretts esophagus were analyzed longitudinally. The p16 promoter status was compared with histomorphological findings. RESULTS p16 promoter hypermethylation was detected in 9 of the 10 patients who had displayed dysplasia at some time during surveillance, whereas none of the patients who had not displayed dysplasia during surveillance had p16 promoter hypermethylation. p16 promoter hypermethylation was detected in 3% (2 of 67) of the samples without dysplasia, 60% (3 of 5) of the samples with lesions indefinite for dysplasia, 55.6% (10 of 18) of the specimens with low-grade dysplasia, and 75% (3 of 4) of the specimens with high-grade dysplasia. CONCLUSIONS These data suggest that p16 promoter hypermethylation is a common mechanism of p16 gene inactivation during neoplastic progression in Barretts esophagus.

Determinants of life satisfaction in inflammatory bowel disease.

Background: In patients with Crohns disease (CD) and ulcerative colitis (UC), medical, sociodemographic, and psychologic “risk and protective” factors for general and health‐related life satisfaction (GLS and HRLS, respectively)‐defined as preference‐based judgments of general and health‐related quality of life‐have not been studied to date. Methods: A total of 429 of 868 (49%) outpatients (CD, n = 317; UC, n = 112) attending 3 tertiary care centers and members of the German Crohns Disease/Ulcerative Colitis Foundation completed the sociodemographic and medical questionnaires of the German “Competence Network Inflammatory Bowel Diseases,” the Hospital Anxiety and Depression Scale, and the “Questions on Life SatisfactionModules”. Disease activity was assessed by the German Inflammatory Bowel Disease Activity Index. “Questions on Life SatisfactionModules” data were compared with a representative sample of the German general population. Results: GLS and HRLS were reduced compared with the general German population (P < 0.005). Logistic regression showed that mental disorder was a risk factor of reduced GLS in CD [odds‐ratio (OR), 2.7; P < 0.01] and UC (OR, 6.3; P < 0.02). Membership in a self‐help organization offered no protection against reduced GLS in CD (OR, 0.5; P < 0.02). In CD, psychiatric (OR, 10.4; P < 0.01) and medical comorbidity (OR, 2.0; P < 0.02) and disease activity (OR, 4.0; P < 0.01) were risk factors of reduced HRLS, whereas in UC, only disease activity (OR, 6.6; P < 0.01) predicted reduced HRLS. Conclusions: To improve GLS and HRLS in inflammatory bowel disease, both the treatment of bowel disease and medical and psychiatric comorbidity are necessary. Strengthening of social support is an additional way to promote GLS.

Comparative analysis of histology, DNA content, p53 and Ki-ras mutations in colectomy specimens with long-standing ulcerative colitis

Neoplastic progression in patients with chronic ulcerative colitis is characterized by the development of epithelial dysplasia, which is accompanied by genetic alterations. This study determined the time of onset of p53 and Ki‐ras mutations as well as DNA aneuploidy during histological progression towards carcinoma. In all, 278 samples of 7 colectomy specimens were analyzed by flow cytometry, histology and single‐strand conformation polymorphism analysis. Of the samples, 22% (61/278) were dysplastic and 43% (122/278) aneuploid, while 25% (71/278) showed p53 and 4% (11/278) Ki‐ras mutations. The correlation between aneuploid status and p53 mutations varied among the patients. A strong correlation was noticed between histological progression from low‐grade dysplasia to carcinoma and p53 mutations as well as DNA aneuploidy. Ki‐ras mutations were found in 40% (2/5) of the carcinomatous samples. The correlation between p53 mutations and the histological status of the samples suggest the involvement of this genetic event in the development of colon cancer in patients with ulcerative colitis. In contrast to Ki‐ras mutations, the appearance of p53 mutations is an early event. Therefore p53 analysis might be helpful in the classification of indefinite dysplasia and in the identification of patients at risk for cancer development. Further studies are necessary to detect the additional genetic alterations preceding the development of DNA aneuploidy. Int. J. Cancer 76:1–6, 1998.© 1998 Wiley‐Liss, Inc.

Hypermethylation of tumor suppressor genes (p16INK4A, p14ARF and APC) in adenocarcinomas of the upper gastrointestinal tract

Aberrant promoter methylation is an important mechanism for gene silencing. In the present study, 50 Barretts esophagus‐associated esophageal adenocarcinomas (ADC), 50 cardiac ADC and 50 gastric ADC were investigated by means of methylation‐specific real‐time PCR for hypermethylation in the tumor suppressor genes APC, p16INk4A and p14ARF. Additionally, expression of p16INK4A protein in the carcinomas was assessed using immunohistochemistry. Marked differences in hypermethylation were found between esophageal, cardiac and gastric ADC in the APC gene (78% vs. 32% vs. 84%) and in the p16INK4A gene (54% vs. 36% vs. 10%). Hypermethylation of p14ARF was absent from esophageal ADC and present infrequently in cardiac (2%) and gastric ADC (10%). Complete loss of p16INK4A protein expression was detectable in 45% of all tumors and was significantly associated with hypermethylation of the p16INK4A gene (p<0.0001, χ2‐test). Our results suggest that hypermethylation of p16INK4A and APC are frequent findings in esophageal, cardiac and gastric ADC. Additionally, the data point to a tumor specific methylation pattern in upper gastrointestinal ADC.

Anxiety and depression in patients with inflammatory bowel disease: comparisons with chronic liver disease patients and the general population.

Background: Studies on anxiety and depression in inflammatory bowel disease (IBD) yielded inconsistent results. We compared anxiety and depression of patients with Crohns disease (CD) and ulcerative colitis (UC) controlled for sociodemographic and medical variables with age‐ and sex‐matched controls. Methods: In all, 422 IBD patients (50% females, 314 CD, 108 UC) of different settings were compared with 140 age‐ and sex‐matched patients with chronic liver diseases (CLD) of a tertiary care center and with 422 age‐ and sex‐matched persons of a representative sample of the general German population (GP). Anxiety and depression and probable mental disorder were assessed by the German version of the Hospital Anxiety and Depression Scale. Comparisons between CD and UC were adjusted for medical (disease activity, number of IBD‐associated diseases) and sociodemographic factors (age, gender, marital status). Results: CD and UC patients did not differ in the levels of anxiety and depression or in the frequency of a probable mental disorder. The levels of anxiety and depression of IBD patients with active disease were higher than that of the GP, but not of the IBD patients in remission. The depression score of the CLD sample was higher than that of the IBD sample (P < 0.001), but not the anxiety score. Mental disorders were more frequent in IBD patients with slight (27.7%) and moderate/severe disease activity (49.3%) compared to GP (10.4%) (P < 0.001), but not in IBD patients in remission (11.3%). Conclusions: Patients with active IBD should be screened for anxiety and depression. Inflamm Bowel Dis 2011

Serum soluble TNF receptor I and II levels correlate with disease activity in IBD patients

Background Tumor necrosis factor alpha (TNF&agr;) is a proinflammatory cytokine and an important mediator in the pathophysiology of inflammatory bowel disease (IBD). The effects of TNF&agr; are mediated by 2 specific receptors, a 55‐kDa protein (TNF‐RI) and a 75‐kDa receptor (TNF‐RII), which are usually bound to the cell surface. Soluble TNF receptors I and II (sTNF‐RI + II) are released by proteolytic cleavage of the extracellular domains of these receptors. Soluble TNF‐Rs act as TNF antagonists and can inhibit TNF&agr;‐mediated proinflammatory effects. Methods Levels of sTNF‐RI + II were measured using commercially available enzyme‐linked immunosorbent assays (ELISAs). Serum levels of sTNF‐RI + II of 76 healthy volunteers were compared to serum levels of 373 clinically well‐characterized patients with Crohns disease (CD) and 118 patients with ulcerative colitis (UC) with different disease activity from the German IBD competence network serum bank. CD patient subgroups were defined according to the Vienna Classification. Results The serum levels of sTNF‐RI were significantly increased in all groups (active, chronic active, and remission) of CD and UC patients compared to healthy controls. sTNF‐RII levels were significantly higher in active CD patients compared to UC patients with no overlap of the 95% confidence interval. Significantly higher values of sTNF‐RII compared to controls were also observed in CD patients and UC patients in remission. There was no statistically significant difference in sTNF‐RI or sTNF‐RII levels when patient subgroups were analyzed according to disease behavior or disease localization. Conclusion sTNF‐RI is upregulated in the serum of IBD patients compared to healthy controls and could be used as a marker for disease activity. sTNF‐RII levels are significantly more elevated in serum of active CD patients as compared to UC and could be used as an additional parameter to discriminate both diseases. (Inflamm Bowel Dis 2007)

Questions on life satisfaction (FLZM) in inflammatory bowel disease.

Background and aimsWhen assessing quality of care the outcome in terms of quality of life (QOL) is of major significance. This study examined QOL in IBD outpatients and the contribution of individual expectations and various other factors including disease activity.Patients and methodsThe study included 306 outpatients with Crohn’s disease and 109 with ulcerative colitis (UC). General and health-related QOL was quantified using the instrument Questions on Life SatisfactionModules. Disease activity was assessed by a questionnaire. Data were compared with a normal population sample.ResultsLife satisfaction scores on general items and on health-related items were significantly lower than in a control sample (60.5±37.3 and 74.4±41.5, respectively) among both CD patients (54.3±33.2, 59.1±38.8) and UC patients (45.4±34.0, 52.1±40.7). Scores were significantly related to severity of disease activity. IBD patients attributed particular importance to health-related issues.ConclusionBoth health-related and general life satisfaction is compromised in IBD outpatients, and health-related topics have major impact. Not surprisingly, inflammatory activity compromises QOL, which underlines the importance of anti-inflammatory strategies. The importance attributed to health-related features is higher in IBD patients than in the normal population.

Distribution of cell populations with DNA aneuploidy and p53 protein expression in ulcerative colitis

Objective: Patients with ulcerative colitis are at an increased risk for developing colorectal neoplasms. p53 mutations and the occurrence of DNA aneuploidies are common events in the development of sporadic colorectal neoplasias. This study tried to determine the frequency of these events during the development of colitisassociated colorectal neoplasms. Design/methods: Four colectomy specimens with a total of 124 biopsies were investigated. DNA content was measured by flow cytometry and p53 protein expression was detected by immunohistochemistry. These results were correlated with histological findings. Results: DNA aneuploidies were found in 58 (46.8%), and p53 protein expression in 30 samples (24.2%). The presence of DNA aneuploidy as well as of p53 protein expression correlated with the histological characteristics of neoplastic transformation. In areas without dysplasias or with indefinite dysplasias, 31.5% of the samples showed DNA aneuploidies and in about 9% of the samples p53 protein expression could be detected; 33.7% of samples without or with indefinite dysplasias showed p53 protein expression and/or DNA aneuploidies. Conclusion: These results show that the occurrence of DNA aneuploidies and nuclear p53 protein expression is a common event in the development of colitisassociated colorectal neoplasias. p53 protein expression seems to be an early event in this process. DNA aneuploidies occur even earlier and more frequently in the absence of p53 protein expression. Therefore, other genetic alterations besides p53 gene mutations might be involved in colitis‐associated tumour development.