Palliative treatment of colorectal cancer with secondary metastasis resection in Germany - impact of the multidisciplinary treatment approach on prognosis and cost: the Northern Bavaria IVOPAK I Project.

PURPOSE: The aim of this study was to evaluate the quality of care and interdisciplinary cooperation in the palliative treatment of colorectal cancer (CRC), including the associated costs. PATIENTS AND METHODS: 103 patients were enrolled from 13 institutions to reflect the existing clinical treatment reality and costs of palliative CRC treatment. We present the clinical outcome of the patients and compare the results obtained in the 3 centers with double-figure recruitment numbers (centers A, B, and C). RESULTS: First-line treatment with 5-fluorouracil monotherapy was applied in exceptional cases. The regular treatment method comprised either an irinotecan- (30%) or an oxaliplatin-based regimen (32%). Biological agents were added to the treatment of 33 patients (32%). The median overall survival (OS) of the total patient collective was 25 months. The OS differed significantly in 2 out of the 3 centers, ranging between 27 and 11 months. Secondary metastasis resections were performed in 26% of the total patient collective. The center with the most favorable outcome results also had the lowest costs for palliative treatment and care, including the lowest drug costs. CONCLUSION: A combined chemotherapy treatment was the rule. Concerning biological agents, a significant lack of their application in first-line treatment and the quality of interdisciplinary cooperation have to be addressed.

Comparison of Hemospray® and Endoclot™ for the treatment of gastrointestinal bleeding.

BACKGROUND: Gastrointestinal (GI) bleeding is a common indication for endoscopy. For refractory cases, hemostatic powders (HP) represent "touch-free" agents. AIM: To analyze short term (ST-within 72 h-) and long-term (LT-within 30 d-) success for achieving hemostasis with HP and to directly compare the two agents Hemospray (HS) and Endoclot (EC). METHODS: HP was applied in 154 consecutive patients (mean age 67 years) with GI bleeding. Patients were followed up for 1 mo (mean follow-up: 3.2 mo). RESULTS: Majority of applications were in upper GI tract (89%) with following bleeding sources: peptic ulcer disease (35%), esophageal varices (7%), tumor bleeding (11.7%), reflux esophagitis (8.7%), diffuse bleeding and erosions (15.3%). Overall ST success was achieved in 125 patients (81%) and LT success in 81 patients (67%). Re-bleeding occurred in 27% of all patients. In 72 patients (47%), HP was applied as a salvage hemostatic therapy, here ST and LT success were 81% and 64%, with re-bleeding in 32%. As a primary hemostatic therapy, ST and LT success were 82% and 69%, with re-bleeding occurring in 22%. HS was more frequently applied for upper GI bleeding (P = 0.04). CONCLUSION: Both HP allow for effective hemostasis with no differences in ST, LT success and re-bleeding.

Endoscopic full-thickness resection with an over-the-scope clip device (FTRD) in the colorectum: results from a university tertiary referral center.

BACKGROUND AND STUDY AIMS: The full-thickness resection device (FTRD) represents a novel endoscopic treatment method for lesions unresectable with conventional endoscopic techniques. The overall aim of this study was to evaluate technical success and in toto resection rates, recurrence rates, as well as immediate or late complications in patients who underwent polyp removal with the FTRD. PATIENTS AND METHODS: Data from a prospectively collected database of 12 patients who underwent 13 over-the-scope clip-based full-thickness resections between June 2015 and June 2017 were analyzed. Follow-up endoscopy was performed in 11 out of 12 patients. RESULTS: 13 full-thickness resections were performed in 7 males and 5 females (mean age 64.3 ± 6.3 years). Mean size of the lesions removed with FTRD was 17 ± 4 mm. Location was rectum (n = 6), cecum (n = 2), ascending colon (n = 2), left flexure (n = 1) and right flexure (n = 2). Mean procedure time was 68 ± 35 minutes and mean hospital stay was 2.5 ± 1.2 days. 2 patients developed post-polypectomy syndrome, which resolved after conservative treatment. No perforations and no immediate surgical revision were needed. Histology of the 13 lesions removed with FTRD showed 5 adenomas with low grade intraepithelial neoplasia (IEN), 4 high grade IEN, 1 fibrosis, 1 fibrosis without dysplasia and 2 adenocarcinomas. Technical success was achieved in all procedures (13/13, 100 %). R0 resection was achieved in 10/12 patients (83.3 %). 2 patients underwent surgery because of recurrence or not evaluable margins. In 1 patient no residual malignancy was proven in histological examination, in the other patient residual low grade IEN adenoma. CONCLUSION: FTRD is a minimally invasive approach with good success rate of complete resection and minimal side effects.

Weekly High-dose 5-Fluorouracil as 24-hour Infusion Combined with Sodium Folinic Acid (AIO regimen) Plus Irinotecan in Second-line and Sequential Therapy of Metastatic Colorectal Cancer (CRC).

BACKGROUND/AIM: The aim of this work was to evaluate the efficacy and safety of second-line treatment with weekly high-dose 5-fluorouracil (5-FU) as a 24-hour infusion (24-h inf.) combined with sodium folinic acid (FA) (AIO-regimen) plus irinotecan (Iri.) after pretreatment with AIO-regimen plus oxaliplatin (L-OHP). PATIENTS AND METHODS: Patients with non-resectable distant CRC metastases were enrolled in a prospective phase II study for palliative second-line treatment after previous progression of first-line treatment in accordance with the AIO-regimen plus oxaliplatin. On an outpatient basis, the patients received a treatment regimen comprising of weekly 80 mg/m2 irinotecan in the form of a 1-hour i.v. infusion and 2,000 mg/m2 5-FU combined with 500 mg/m2 sodium folinic acid administered as a 24-h infusion i.v. once weekly. RESULTS: During second-line treatment, a total of 59 patients received 520 chemotherapy applications. As the main higher-grade symptom of toxicity, diarrhea (NCI-CTC-toxicity grade 3) presented in 8 patients (13.6%, 95%CI=5.1-23.7), followed by leukocytopenia (CTC grade 3) in 3 patients (5.1%, 95%CI=0-11.9), followed by thrombocytopenia (CTC grade 3) in 1 patient (1.7%, 95%CI=0-5.1). Fifty-nine patients were evaluable for treatment response. The remission data can be summarized as follows: complete remission (CR); n=0; partial remission (PR); n=6 (10%; 95%CI=3.4-18.6); stable disease (SD); n=31 (53%; 95%CI=39.0-64.4); progressive disease (PD); n=19 (33%; 95%CI=20.3-44.1). The median progression-free survival (PFS) rate (n=59) was 4.2 months (range=3.8-5.8 months). The median survival time counted from the start of second-line treatment (n=59) 14.2 months (range 8.2-17.3 months) and the median survival time counted from the start of first-line therapy (n=59) 25 months (range 19-27 months). CONCLUSION: Palliative second-line treatment according to the AIO regimen plus irinotecan offers both a favourable toxicity profile and promising efficacy in second-line and palliative sequential therapy.

Treatment of nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause for elevated liver enzymes in the developed nations. Beyond prevention programs which are of particular interest because of the increasing number of overweight children, treatment should be focussed on the most important risk factors, obesity and insulin resistance. As a consequence of elucidating the pathomechanisms of NAFLD, the number of potential therapeutic options increased. However, many studies investigating the therapeutic effect show shortcomings in at least one of the following points: lack of a serial liver biopsy, short term of treatment and limited number of included patients. The second generation insulin sensitizer pioglitazone and rosiglitazone show the most promising improvements in NAFLD, but weight gain and potential hepatotoxicity calls for attention. In conclusion, a general recommendation for the application of specific drugs cannot be given. Besides controlled clinical trials, weight reduction and physical activity to improve insulin sensitivity in obese patients should be the priority objective.

Advances in hepatitis C therapy: What is the current state - what come's next?

Chronic hepatitis C virus (HCV) infection affects 80-160 million people worldwide and is one of the leading causes of chronic liver disease. It is only a few years ago that standard treatment regimes were based on pegylated interferon alpha and ribavirin. However, treatment of HCV has undergone a revolutionary change in recent years. The admission of the nucleotide polymerase inhibitor Sofosbuvir enabled an interferon-free regimen with direct antiviral agents (DAA). Meanwhile seven DAAs are available and can be applied in several combinations for 8 to 24 wk depending on HCV genotype and patient characteristics such as cirrhosis and chronic renal failure. High rates of sustained virological response (SVR) rates can be achieved with these novel drugs. Even in difficult to treat populations such as patients with liver cirrhosis, HCV-human immunodeficiency virus co-infections, after liver transplantion, or with chronic kidney disease comparable high rates of SVR can be achieved. The anticipated 2(nd) generation DAAs are strikingly effective in patients so far classified as difficult to treat including decompensated liver cirrhosis or post-transplant patients. These 2(nd) generations DAAs will have higher resistance barriers, higher antiviral effects and a pan-genotypic spectrum. This review highlights the current state of the art of antiviral treatment in hepatitis C and gives an outlook for upcoming therapies.

Capecitabine and irinotecan with and without bevacizumab for advanced colorectal cancer patients.

AIM: To investigate the efficacy and safety of cape-citabine plus irinotecan +/- bevacizumab in advanced or metastatic colorectal cancer patients. METHODS: Forty six patients with previously untreated, locally-advanced or metastatic colorectal cancer (mCRC) were recruited between 2001-2006 in a prospective open-label phase II trial, in German community-based outpatient clinics. Patients received a standard capecitabine plus irinotecan (CAPIRI) or CAPIRI plus bevacizumab (CAPIRI-BEV) regimen every 3 wk. Dose reductions were mandatory from the first cycle in cases of > grade 2 toxicity. The treatment choice of bevacizumab was at the discretion of the physician. The primary endpoints were response and toxicity and secondary endpoints included progression-free survival and overall survival. RESULTS: In the CAPIRI group vs the CAPRI-Bev group there were more female than male patients (47% vs 24%), and more patients had colon as the primary tumor site (58.8% vs 48.2%) with fewer patients having sigmoid colon as primary tumor site (5.9% vs 20.7%). Grade 3/4 toxicity was higher with CAPIRI than CAPIRI-Bev: 82% vs 58.6%. Partial response rates were 29.4% and 34.5%, and tumor control rates were 70.6% and 75.9%, respectively. No complete responses were observed. The median progression-free survival was 11.4 mo and 12.8 mo for CAPIRI and CAPIRI-Bev, respectively. The median overall survival for CAPIRI was 15 mo (458 d) and for CAPIRI-Bev 24 mo (733 d). These differences were not statistically different. In the CAPIRI-Bev, group, two patients underwent a full secondary tumor resection after treatment, whereas in the CAPIRI group no cases underwent this procedure. CONCLUSION: Both regimens were well tolerated and offered effective tumor growth control in this outpatient setting. Severe gastrointestinal toxicities and thromboembolic events were rare and if observed were never fatal.

Cutting edge: a key pathogenic role of IL-27 in T cell- mediated hepatitis.

The signals driving T cell activation in T cell-mediated fulminant hepatitis are not fully understood. In this study, we identify the cytokine IL-27p28/EBI3 as a major pathogenic factor in the ConA model of T cell-mediated hepatitis. We found an up-regulation of hepatic EBI3 and p28 expression and augmented levels of IL-27 in wild-type mice after ConA administration, suggesting a potential pathogenic role of this cytokine in ConA hepatitis. Consistently, IL-27 EBI3-deficient mice were almost completely protected from ConA-induced liver damage. Such protection was associated with reduced levels of IFN-gamma and its signaling proteins pSTAT-1 and T-bet. Finally, in vivo blockade of IL-27 function using a soluble IL-27 receptor fusion protein led to reduced pSTAT1 levels and suppression of liver injury. Taken together, these data demonstrate a key pathogenic role of IL-27 in T cell-mediated liver injury. Furthermore, in vivo blockade of IL-27 emerges as a novel potential therapy for T cell-mediated hepatitis.

Enhanced sensitivity to CD95-induced apoptosis in ob/ob mice.

Hepatocyte apoptosis was recently described for NASH patients. The pathomechanisms are incompletely understood, but upregulation of the death receptor Fas was detectable on hepatocytes of NASH patients. We analyzed the sensitivity of fatty liver against CD95/Fas-mediated apoptotic cell death by injection of agonistic anti-Fas antibody (Jo2) in obese ob/ob mice and lean control animals. Ob/ob mice died within 12 hrs, whereas control animals survived. Liver enzymes were significantly increased compared to those in control mice (P < 0.001). Histological analysis and also TUNEL assay of liver sections from ob/ob mice exhibited massive liver injury. Activity of caspase 3 was significantly more enhanced in livers of ob/ob mice after Jo2 challenge. The increased sensitivity was confirmed in vitro by using ob/ob-derived primary hepatocytes. CD95 expression was similar in ob/ob and control mice. However, hepatocytes from ob/ob mice revealed a decreased mitochondrial membrane potential, suggesting that mitochondria play a potential role in this increased susceptibility.

IL-28A is a key regulator of T-cell-mediated liver injury via the T-box transcription factor T-bet.

BACKGROUND & AIMS: T-cell-mediated fulminant hepatitis is a potentially life-threatening event for which the underlying pathogenic mechanisms are not fully understood. Here, we demonstrate a key regulatory role of IL-28A in T-cell-mediated hepatitis. METHODS: We cloned the murine IL-28A gene by reverse-transcription polymerase chain reaction, assessed the effects of recombinant IL-28A, and generated IL-28A-transgenic mice. RESULTS: IL-28A induced TH1 cytokine production by CD4+ T lymphocytes in a T-bet-dependent manner and was up-regulated in a murine model of T-cell-mediated hepatitis upon Con A administration. In vivo, CD4+ T cells from newly created IL-28A-transgenic animals revealed an increased proliferation and proinflammatory TH1 cytokine production, as compared with wild-type mice. In addition, IL-28A-transgenic mice showed markedly augmented Con A-induced hepatitis with up-regulated interferon-gamma cytokine production, as compared with wild-type mice. Transgenic mice exhibited an up-regulation of the interferon-gamma-T-bet signaling pathway in Con A hepatitis, and augmented hepatitis in these mice was suppressed by crossing them with T-bet-deficient mice. In addition, in vivo blockade of interferon-gamma but not IL-4 suppressed augmented liver inflammation in transgenic mice, suggesting that IL-28A induces the T-bet signaling pathway in T-cell-induced hepatitis. Finally, IL-28A-specific antisense phosphorothioate oligonucleotides suppressed liver pathology in Con A-treated wild-type mice, as compared with the case of control oligonucleotides. CONCLUSIONS: IL-28A emerges as a key regulatory cytokine with pathogenic function in T-cell-mediated liver injury. Thus, targeting of IL-28A represents a potential novel approach for therapy of Th1-mediated inflammatory diseases such as T-cell-mediated hepatitis.

Weekly treatment with irinotecan, folinic acid and infusional 5-fluorouracil (ILF) in patients with advanced gastric cancer.

Although 5-fluorouracil remains the mainstay of treatment for advanced gastric cancer (AGC), no standard chemotherapy regimen exists. Combinations of irinotecan with folinic acid and infusional 5-fluorouracil (5-FU) (ILF) have shown good efficacy with acceptable toxicity in patients with metastatic colorectal cancer. At present, only sparse data on ILF are available for AGC. Therefore we conducted a prospective study of this combination in 25 consecutive patients with metastatic gastric cancer. Median age was 63 years, 10 had received prior chemotherapy and 13 presented initially with peritoneal carcinosis. Treatment consisted of irinotecan 80 mg/m2, folinic acid 500 mg/m2 and infusional 5-FU 2.0 g/m2 over 24 h, given weekly for 6 weeks followed by a 1-week rest. Grade 3/4 hematologic toxicity occurred in six patients (anemia = 4, neutropenia = 1 and leukopenia = 1). Non-hematologic toxicity consisted mainly of nausea/vomiting (grade 3/4 in six patients) and diarrhea (grade 3/4 in 10 patients). The overall response rate was 20% for first- and second-line treatment, with two complete and three partial responses. Another nine patients (36%) had stable disease, for a tumor control rate of 56%. Median time to progression was 4 months, median overall survival and survival for patients with tumor control was 7 and 13 months, respectively. We conclude that ILF is a feasible outpatient regimen with manageable toxicity that provides tumor control in a high proportion of patients with advanced gastric cancer, even among those with unfavorable prognostic features.