Fibo ten Kate

Hapten‐induced colitis associated with maintained Th1 and inflammatory responses in IFN‐γ receptor‐deficient mice

IFN‐γ is a potent pro‐inflammatory cytokine thought to be involved in the pathogenesis of Crohns disease. To further define the role of IFN‐γ in intestinal inflammation, we studied the effects of intra‐colonic 2,4,6‐trinitrobenzene sulfonic acid (TNBS) instillation in mice with a functionally inactivated IFN‐γ receptor 1 (IFN‐γR1– / –). Our results indicate that IFN‐γ is not necessary for the induction of hapten‐induced colitis: after TNBS administration both wild‐type and IFN‐γR1– / – mice lost body weight, and the histological features of TNBS‐induced colitis were comparable. Colons of IFN‐γR1– / – mice contained a greater number of cells, represented by macrophages and CD4+ T cells; caudal lymph node cells produced more IFN‐γ and TNF‐α upon stimulation in vitro. Moreover, IL‐18 and IL‐12 p40 RNA levels were comparably up‐regulated after TNBS treatment in IFN‐γR1– / – wild‐type mice. These findings demonstrate that IFN‐γ is dispensable for the development of TNBS‐induced colitis. Importantly, the production of Th1 cytokines (e. g. IFN‐γ and TNF‐α) by caudal lymph node T lymphocytes was enhanced rather than decreased in IFNγR1– / – mice with no evidence for default Th2 development.

Gastroesophageal reflux: prevalence in adults older than 28 years after correction of esophageal atresia.

Objective: To study the incidence of gastroesophageal reflux (GER)related complications after correction of esophageal atresia (EA). Summary Background Data: The association of EA and GER in children is well known. However, little is known about the prevalence of GER and its potential complications in adults who have undergone correction of EA as a child. Methods: Prospective analysis of the prevalence of GER and its complications over 28 years after correction of EA by means of a questionnaire, esophagogastroscopy, and histologic evaluation of esophageal biopsies. Results: The questionnaire was returned by 38 (95%) of 40 patients. A quarter of the patients had no complaints. Swallowing solid food was a problem for 13 patients (34%), and mashed foods for 2 (5%). Heartburn was experienced by 7 patients (18%), retrosternal pain by 8 (21%). However, none of the patients were using antireflux medication. Twenty-three patients (61%) agreed to undergo esophagogastroscopy, which showed macroscopic Barrett esophagus in 1 patient, which was confirmed by histology. One patient developed complaints of dysphagia at the end of the study. A squamous cell esophageal carcinoma was diagnosed and treated by transthoracic subtotal esophagectomy. Conclusions: This study shows a high incidence of GER-related complications after correction of EA, but it is still very disputable if all EA patients should be screened at an adult age.

Adjuvant Chemotherapy of Superficial Transitional Cell Bladder Carcinoma:Preliminary Results of a European Organization for Research onTreatment of Cancer Randomized Trial Comparing Doxorubicin Hydrochloride, Ethoglucid and Transurethral Resection Alone

Patients with superficial transitional cell carcinoma of the bladder were entered in a randomized clinical trial to compare the efficacies of transurethral resection alone or followed by bladder instillation of doxorubicin hydrochloride or ethoglucid (Epodyl) for 1 year. Results showed that adjuvant chemotherapy with the selected drugs prolonged the mean interval between recurrences. Mild systemic toxicity and chemical cystitis were observed in 3 and 3 per cent, respectively, of the patients given ethoglucid, and in 5 and 4 per cent, respectively, of those taking doxorubicin.

Contrasting roles of IL-12p40 and IL-12p35 in the development of hapten-induced colitis

IL‐12(p70), a heterodimer composed of two subunits (p35 and p40), is a key cytokine for Th1 mediated inflammatory responses. We dissected the role of IL‐12 in the development of 2,4,6‐trinitrobenzene sulfonic acid (TNBS)‐induced colitis by studying mice deficient in IL‐12p40, IL‐12p35, or IL‐12Rβ1. TNBS‐treated IL‐12Rβ1–/– and IL‐12p35–/– mice developed only a mild disease associated with low level IL‐18 expression in IL‐12p35–/– mice. In contrast, IL‐12p40–/– mice developed more severe colitis than wild‐type mice associated with high level colonic IL‐18 expression. Administration of IL‐12p40 neutralizing mononuclear antibody dramatically increased pathology in IL‐12p35–/– mice similar to disease scored in IL‐12p40–/– mice. Numbers of IFN‐γ‐producing cells infiltrating the lamina propria were comparably augmented in the different groups of IL‐12‐mutant and wild‐type mice. These results demonstrate that IL‐12p40, in contrast to IL‐12p70, inhibits TNBS‐induced colitis and IL‐18 expression independent of IFN‐γ.

Adjuvant Chemotherapy for Superficial Transitional Cell Bladder Carcinoma: Long-term Results of a European Organization for Research and Treatment of Cancer Randomized Trial Comparing Doxorubicin, Ethoglucid and Transurethral Resection Alone

PURPOSE We compared the efficacy of transurethral resection alone or transurethral resection followed by bladder instillations of doxorubicin or ethoglucid for 1 year in patients with superficial bladder carcinoma, and followed them long term for the incidence of progression to muscle invasion. MATERIALS AND METHODS A total of 443 patients with superficial transitional cell carcinoma of the bladder was randomized. After randomization of 206 patients the control arm was closed to patient entry based on the results of an interim analysis showing a significant difference in favor of those receiving adjuvant chemotherapy. RESULTS Final analysis of treatment results for recurrence included 432 patients at a median followup of 3.4 years for time to first recurrence, 5 years for analysis of time to invasion (Category T2 disease or worse) and 10.7 years for duration of survival. Time to first recurrence was significantly prolonged by both drugs compared to transurethral resection alone (doxorubicin versus transurethral resection alone p < 0.001 and ethoglucid versus control p < 0.001). Recurrence rate per year was 0.30 for both adjuvant treatment arms and 0.68 for the resection only group. Progression to muscle invasion was rare (15.1% of cases) and not apparently different in the 3 treatment arms. Of the 423 patients death from any cause in 199 and from malignant disease in 59 was not correlated with treatment. However, there was a strong correlation between death from malignant disease, and T category and tumor grade. CONCLUSIONS In regard to time to first recurrence and recurrence rate per year this study indicates that adjuvant chemotherapy with doxorubicin and ethoglucid using the indicated schedule is superior to transurethral resection alone. However, progression in stage or survival was not influenced by the treatment regimen.

Gains and Amplifications of c-myc, EGFR, and 20.q13 Loci in the No Dysplasia–Dysplasia–Adenocarcinoma Sequence of Barrett's Esophagus

The progression of Barretts esophagus to esophageal adenocarcinoma is often characterized by the accumulation of genetic abnormalities. The goal was to evaluate the copy number alterations of several oncogene loci, including 7p12 [epidermal growth factor receptor (EGFR)], 8q24 (c-myc), and 20q13 in the sequence of no dysplasia–dysplasia–adenocarcinoma of Barretts esophagus. Fluorescence in situ hybridization with DNA probes for the centromeric region of chromosome 7 and the locus-specific regions of 7p12 (EGFR), 8q24 (c-myc), and 20q13 was applied on 99 brush cytology specimens of patients with Barretts esophagus with different stages of dysplasia or esophageal adenocarcinoma. Gains (3-4 copies) of chromosome 17, 8q24 (c-myc), and 20q.13 loci were found in the low frequencies in nondysplastic Barretts esophagus. Their frequencies increased with the stage of dysplasia and reached a high incidence in esophageal adenocarcinoma. Amplification (>4 copies) of at least 1 of the loci was observed in 14% of high-grade dysplasia and increased to 50% in esophageal adenocarcinoma (P = 0.015). The most frequently amplified locus was c-myc (18%), followed by 20q13 (13%) and EGFR (11%) in the high-grade dysplasia/esophageal adenocarcinoma cases. High amplification levels (>10 copies) of the loci were more frequent in esophageal adenocarcinoma (72%) compared with high-grade dysplasia (20%; P = 0.049). Amplifications of the c-myc, EGFR, and 20q12 loci may serve as diagnostic markers to identify patients with Barretts esophagus with high-grade dysplasia or esophageal adenocarcinoma. Gains of the loci might be of value as prognostic markers because they are already present in nondysplasia cases and may precede the later event of the amplification as observed in high-grade dysplasia and esophageal adenocarcinoma. (Cancer Epidemiol Biomarkers Prev 2008;17(6):1380–5)

Specific Inhibition of c-Raf Activity by Semapimod Induces Clinical Remission in Severe Crohn’s Disease

There is a substantial need for novel treatment strategies in Crohn’s disease (CD), a chronic relapsing inflammatory disease of the gut. In an earlier study, we reported clinical efficacy of a 2-wk treatment with semapimod (CNI-1493) in 12 patients with therapy resistant CD. The aim of this study was to identify the cellular target underlying semapimod action. In vitro experiments with murine macrophages showed impaired MAPK signaling and decreased cytokine production due to semapimod treatment. In vitro kinase assays revealed c-Raf as a direct molecular target of semapimod, and semapimod did not affect b-Raf enzymatic activity. Immunohistochemistry performed on paired colon biopsies obtained from CD patients (n = 6) demonstrated increased expression of phospho-MEK, the substrate of Raf. Strikingly, phospho-MEK levels were significantly decreased in patients with a good clinical response to semapimod, but no decrease in phospho-MEK expression was observed in a clinically nonresponsive patient. In conclusion, this study identifies c-Raf as a molecular target of semapimod action and suggests that decreased c-Raf activity correlates with clinical benefit in CD. Our observations indicate that c-Raf inhibitors are prime candidates for the treatment of CD.

Phase 1/2 study of intravesical epirubicin in patients with carcinoma in situ of the bladder

A total of 34 patients with grade 3 carcinoma in situ of the bladder entered a phase 1/2 study with epirubicin to examine the rate of antitumor activity, the type and frequency of local side effects, and the absorption and recovery rates. The selected doses were 30, 50 and 80 mg. Of the patients 22 were evaluable for report of treatment results. A total of 16 patients had a complete remission proved by biopsy and conversion of urine cytology findings. Mean duration of complete remission was 22.4 months (range 7+ to 50+ months). After a mean followup of 35.3 months (range 14 to 59 months) 8 of 16 patients were still in complete remission, 3 died of a myocardial infarction, 3 had recurrent grade 3 carcinoma in situ, 2 had increase to a higher T category (stages T2 and T4a), and 2 had recurrent papillary stage Ta, grade 2 (1) and stage T1, grade 2 (1) transitional cell carcinoma of the bladder. Six of the 22 patients had no response to 1 or 2 treatment courses with a higher dose. Plasma concentrations of epirubicin after instillation were close to the detection limit of the assay (0.5 to 2.0 ng/ml. plasma).

Veno-Occlusive Disease as a Complication of Preoperative Chemotherapy for Wilms Tumor: A Clinico-Pathological Analysis

Vincristine (VCR) and actinomycin D (ACD) form the backbone of chemotherapeutic regimens of Wilms tumor treatment. Veno‐occlusive disease (VOD) is a potentially life‐threatening complication of ACD.

Effect of bevacizumab added preoperatively to oxaliplatin on liver injury and complications after resection of colorectal liver metastases.

Chemotherapy (CTx) before resection of colorectal liver metastases (CRLM) may cause hepatic injury and postoperative complications. To ascertain whether adding bevacizumab, a monoclonal antibody against VEGF, to oxaliplatin‐based CTx has an influence on liver injury and postoperative complications.