Early tumor regrowth is a contributor to impaired survival in patients with completely resected advanced ovarian cancer. An exploratory analysis of the Intergroup trial AGO-OVAR 12.

OBJECTIVE: Surgical assessment of residual tumor provides the strongest prognostic information in advanced ovarian cancer (AOC), with the best outcome observed after complete resection. Postoperative radiological assessment before initiation of chemotherapy can supplement the information obtained by surgical assessment; however, it may also reveal conflicting findings. METHODS: Patients with AOC enrolled in the AGO-OVAR 12 trial underwent baseline imaging before the first chemotherapy cycle. The findings from surgical and radiologic assessment for disease extend were compared. Additionally, an integrated approach was assessed. RESULTS: Complete data from all 3 assessment methods were available for 1345 patients. Of 689 patients with complete resection, tumor was observed in 28% and 22% of patients undergoing radiologic and integrated assessment, respectively. Patients with surgical- radiological and surgical-integrated concordant findings showed a 5-year overall survival (5Y-OS) of 72% and 71%, whereas patients with surgical-radiological and surgical-integrated discordant results showed inferior 5Y-OS of 47% and 49%, respectively. Patients with surgically assessed residual disease had a 5-YOS of 37%. The interval between surgery and baseline assessment was independently associated with discordance between assessment methods, which might reflect early tumor regrowth. CONCLUSIONS: Baseline tumor assessment before chemotherapy provides information that stratifies patients with complete resection into different prognostic groups. Integrating the data from different assessment methods might lead to improved definitions of prognostic groups. Further investigation to determine if earlier initiation of chemotherapy after debulking surgery could increase survival of patients with early tumor regrowth is warranted.

A randomised phase II trial of the Polo-like kinase inhibitor BI 2536 in chemo-naïve patients with unresectable exocrine adenocarcinoma of the pancreas - a study within the Central European Society Anticancer Drug Research (CESAR) collaborative network.

BACKGROUND: BI 2536, a novel Polo-like kinase 1 inhibitor, was assessed in patients with unresectable advanced exocrine adenocarcinoma of the pancreas. METHODS: The study employed a two-stage design. Randomised first-line patients received BI 2536 200 mg on day 1 (n=43) or 60 mg on days 1-3 (n=43) every 21 days. Recruitment of second-line patients was planned for a second stage dependent on an interim analysis demonstrating ≥ 2 responses in the first 18 evaluable patients following 12 weeks of treatment and/or tumour control ≥ 12 weeks in 5 patients per schedule. Primary end point was objective response rate (ORR). RESULTS: By independent review, ORR was 2.3% (all partial) and 24.4% had stable disease as confirmed best response. The second stage was not initiated. Median overall and progression-free survivals were 149 (95% confidence interval (CI), 91-307) and 46 days (95% CI, 44-56). Most common drug-related adverse events were neutropenia (37.2%), leukopenia (29.1%), fatigue (29.1%) and nausea (22.1%); most common grade 3/4-related events were neutropenia (36.0%), leukopenia (27.9%) and thrombocytopenia (8.1%). CONCLUSION: Given the low ORR and poor survival, further development of BI 2536 monotherapy is not warranted in this population.

Retroperitoneal gas gangrene after colonoscopic polypectomy without bowel perforation in an otherwise healthy individual: report of a case.

BACKGROUND: Abdominal gas gangrene caused by clostridia species is rare and usually associated with organ perforation, immune suppression, or advanced malignoma. CASE REPORT: A 61-year-old man was admitted with severe back pain 1 day after uncomplicated colonoscopic polypectomy. With the exception of preexisting minor depression, the patient had been previously in excellent health. The computed tomography scan showed retroperitoneal emphysema in the left psoas muscle. During exploratory laparotomy, a spreading retroperitoneal phlegmon with pneumoretroperitoneum and a secondary peritonitis were found. A macroscopic perforation of the gut, particularly at the polypectomy sites was excluded. After the operation, the patient evolved in a septic shock condition and had pulmonary failure. Before hyperbaric oxygen therapy could be employed, the patient died. The autopsy showed a massive gas gangrene of the retroperitoneum caused by Clostridium perfringens, but no macroscopic bowel perforation was detected. RESULTS: This is the first report of a case of gas gangrene after uncomplicated polypectomy without macroscopic perforation in an otherwise healthy individual. A microperforation due to mucosal defect after polypectomy was most likely the entry point for the bacteria. CONCLUSION: We conclude that clostridial myonecrosis should be considered in unclear abdominal infections, even if the patient's history is not typical as in the present case.

Defining the roles of perforin, Fas/FasL, and tumour necrosis factor alpha in T cell induced mucosal damage in the mouse intestine.

BACKGROUND AND AIMS: Mucosal flattening and epithelial cell apoptosis are typical features of T cell induced inflammatory diseases of the bowel, such as coeliac disease and graft versus host disease. Mice injected with a T cell activating anti-CD3 antibody develop a severe diarrhoeal illness. We describe the histological features of this enteropathy and define the effector mechanisms involved in T cell induced mucosal injury in this in vivo model. METHODS: Wild-type and genetically modified mice were injected with the anti-CD3 antibody 3C11 (50 microg). Changes in the murine intestine were characterised by light microscopy analysis and terminal uridine nick-end labelling (TUNEL) assay. The role of perforin, Fas/Fas ligand (FasL), tumour necrosis factor alpha (TNF-alpha), and interferon gamma (IFN-gamma) in T cell induced mucosal damage was assessed using selected immunodeficient mouse strains. RESULTS: T cell activation caused severe damage, including small intestinal mucosal flattening and apoptosis of crypt epithelial cells. Mucosal damage was unaltered in anti-CD3 treated mice lacking IFN-gamma, Fas, or TNF-alpha receptors. In mice lacking TNF-alpha receptors and Fas (TNF-R1xR2 lpr/lpr strain), enterocyte apoptosis was diminished but there was no significant reduction in tissue damage. Apoptosis and mucosal injury were significantly reduced in perforin knockout mice. Abrogation of both FasL and perforin (perforin KOxgld mice) further significantly reduced tissue damage and apoptotic bodies. CONCLUSIONS: T cell induced mucosal injury is mediated by the combined effect of multiple pathways but predominantly by perforin. The redundancy of the mechanisms of tissue damage will have significant impact on therapeutic strategies aimed at specific and targeted inhibition of inflammatory processes.

Intestinal macrophages lack CD14 and CD89 and consequently are down-regulated for LPS- and IgA-mediated activities.

The intestinal mucosa normally displays minimal inflammation despite the close proximity between mucosal macrophages and lumenal bacteria. Macrophages interact with bacteria and their products through CD14, a surface receptor involved in the response to LPS, and CD89, the receptor for IgA (FcalphaR). Here we show that resident macrophages isolated from normal human intestine lack CD14 and CD89. The absence of CD14 and CD89 was not due to the isolation procedure or mucosal cell products, but was evident at the transcriptional level, as the macrophages expressed neither CD14- nor CD89-specific mRNAs, but did express Toll-like receptor 2 and 4 transcripts. Consistent with their CD14(-) phenotype, lamina propria macrophages displayed markedly reduced LPS-induced cytokine production and LPS-enhanced phagocytosis. In addition, IgA-enhanced phagocytosis was sharply reduced in lamina propria macrophages. Thus, the absence of CD14 and CD89 on resident intestinal macrophages, due to down-regulated gene transcription, causes down-modulated LPS- and IgA-mediated functions and probably contributes to the low level of inflammation in normal human intestinal mucosa.

Characterization of enteric functional changes evoked by in vivo anti-CD3 T cell activation.

Specific in vivo T cell activation initiated by treatment with anti-CD3 antibodies leads to diarrhea and structural damage of the intestinal mucosa. In this study, the effect of T cell-induced mucosal damage on jejunal epithelial ion transport, muscle contractility, and neuronal ACh release was assessed in Ussing chambers, organ baths, and a specialized perfusion apparatus, respectively. Time-matched control mice received hamster serum containing irrelevant antibodies. Jejunal segments from anti-CD3-treated mice displayed a significantly elevated epithelial baseline short-circuit current (which indicates increased ion transport) and a concomitant reduction in responsiveness to prosecretory stimuli (nerve stimulation, carbachol, and forskolin). Longitudinal smooth muscle displayed altered spontaneous contractile activity, length-tension relationships, and carbachol-stimulated contraction in tissues excised from mice 20 and 40 h posttreatment. Anti-CD3 treatment did not affect stimulated ACh release from myenteric plexus neurons. We conclude that specific T cell activation via anti-CD3 antibody results in dramatic alterations in jejunal epithelial and smooth muscle function. Such T cell-induced changes in intestinal function may contribute to the symptomatology of T cell-mediated enteropathies, including graft-versus-host disease, celiac disease, and idiopathic inflammatory bowel disease.

[Unusual case of disseminated sarcoidosis with prominent gastrointestinal symptoms]. / Ungewöhnlicher Fall einer disseminierten Sarkoidose mit führender gastrointestinaler Symptomatik.

HISTORY AND ADMISSION FINDINGS: A 63-year-old man had for 10 months suffered from marked weight loss, night sweats, diffuse abdominal pain and increased stool frequency. He was admitted to evaluate an ultrasonically abnormal focus in the liver parenchyma and elevated liver function parameters. His sclerae were obviously icteric and he looked under-weight. INVESTIGATIONS: He had a hypochromic microcytic anemia and abnormal liver and pancreatic function tests: total bilirubin 3.11 mg/dl, direct bilirubin 2.21 mg/dl, GOT21U/l, gamma-GT 422 U/l, alkaline phosphatase 1449 U/l, alpha-amylase 481 U/l, lipase 2827 U/l. The serum creatinine level was elevated to 1.47 mg/dl. Computed tomography revealed enlarged liver and spleen as well as an enlargement of intraabdominal lymph nodes, chest radiogram and endoscopic cholangio-pancreatography were unremarkable. Biopsies from the lower duodenum, large intestine, bone marrow and liver showed inflammatory changes with Langhans-type mononuclear granulomas. Together with these findings an increased activity of the angiotensin-converting-enzyme (ACE) indicated sarcoidosis, other causes having been excluded. TREATMENT AND COURSE: All signs and symptoms rapidly improved under prednisolone, and 4 weeks after begin of treatment the biochemical abnormalities had clearly regressed. The raised serum levels of soluble IL-2 receptors and of neopterin, measures of sarcoidosis activity, had decreased. Activity of ACE had fallen. CONCLUSION: Sarcoidosis can present with diverse clinical signs and symptoms. In a case of multi-system disease that cannot be readily classified, sarcoidosis should be included in the differential diagnosis.

Isolation and purification of CD14-negative mucosal macrophages from normal human small intestine.

Mucosal macrophages play a fundamental role in the regulation of immunological events and inflammation in the small intestine. Because no information is available on normal small intestinal macrophages, we developed a technique for the isolation and purification of jejunal lamina propria macrophages in order to study their phenotype and activity. From sections of normal human jejunum, lamina propria mononuclear cells were isolated by neutral protease digestion and then subjected to counterflow centrifugal elutriation to purify the macrophages. The cells isolated by this procedure contained < 1% CD3+ lymphocytes and displayed the size distribution, morphological features, ultrastructure and phagocytic activity of mononuclear phagocytes. In contrast to blood monocytes, however, mucosal macrophages from the jejunum did not exhibit adherence properties or express CD14, a receptor for the lipopolysaccharide-binding protein. The purification of large numbers of lamina propria macrophages by this procedure offers the opportunity to define the role of this cell in the physiological inflammation characteristic of normal intestinal mucosa and the pathological inflammation associated with small intestinal diseases.