Oxaliplatin and 5-FU/folinic acid (modified FOLFOX6) with or without aflibercept in first-line treatment of patients with metastatic colorectal cancer: the AFFIRM study.

BACKGROUND: The combination of aflibercept with FOLFIRI has been shown to significantly prolong overall survival in patients with metastatic colorectal cancer (mCRC) after progression on oxaliplatin-based therapy. This trial evaluated the addition of aflibercept to oxaliplatin-based first-line treatment of patients with mCRC. PATIENTS AND METHODS: Patients with mCRC were randomized to receive first-line therapy with mFOLFOX6 plus aflibercept (4 mg/kg) or mFOLFOX6 alone. The primary end point of this phase II study was the progression-free survival (PFS) rate at 12 months in each arm. The analysis of efficacy between the arms was a pre-planned secondary analysis. RESULTS: Of 236 randomized patients, 227 and 235 patients were evaluable for the primary efficacy analysis and safety, respectively. The probabilities of being progression-free at 12 months were 25.8% [95% confidence interval (CI) 17.2-34.4] for the aflibercept/mFOLFOX6 arm and 21.2% (95% CI 12.2-30.3) for the mFOLFOX6 arm. The median PFS was 8.48 months (95% CI 7.89-9.92) for the aflibercept/mFOLFOX6 arm and 8.77 months (95% CI 7.62-9.27) for the mFOLFOX6 arm; the hazard ratio of aflibercept/mFOLFOX6 versus mFOLFOX6 was 1.00 (95% CI 0.74-1.36). The response rates were 49.1% (95% CI 39.7-58.6) and 45.9% (95% CI 36.4-55.7) for patients treated with and without aflibercept, respectively. The most frequent treatment-emergent grade 3/4 adverse events (AEs) excluding laboratory abnormalities reported for aflibercept/mFOLFOX6 versus mFOLFOX6 were neuropathy (16.8% versus 17.2%) and diarrhea (13.4% versus 5.2%). Neutropenia grade 3/4 occurred in 36.1% versus 29.3%. The most common vascular endothelial growth factor inhibition class-effect grade 3/4 AEs for aflibercept/mFOLFOX6 versus mFOLFOX6 were hypertension (35.3% versus 1.7%), proteinuria (9.2% versus 0%), deep vein thrombosis (5.9% versus 0.9%) and pulmonary embolism (5.9% versus 5.2%). CONCLUSION: No difference in PFS rate was observed between treatment groups. Adding aflibercept to first-line mFOLFOX6 did not increase efficacy but was associated with higher toxicity. CLINICAL TRIAL NUMBER: NCT00851084, www.clinicaltrials.gov, EudraCT 2008-004178-41.

Abituzumab combined with cetuximab plus irinotecan versus cetuximab plus irinotecan alone for patients with KRAS wild-type metastatic colorectal cancer: the randomised phase I/II POSEIDON trial.

BACKGROUND: Integrins are involved in tumour progression and metastasis, and differentially expressed on colorectal cancer (CRC) cells. Abituzumab (EMD 525797), a humanised monoclonal antibody targeting integrin αν heterodimers, has demonstrated preclinical activity. This trial was designed to assess the tolerability of different doses of abituzumab in combination with cetuximab and irinotecan (phase I) and explore the efficacy and tolerability of the combination versus that of cetuximab and irinotecan in patients with metastatic CRC (mCRC) (phase II part). METHODS: Eligible patients had KRAS (exon 2) wild-type mCRC and had received prior oxaliplatin-containing therapy. The trial comprised an initial safety run-in using abituzumab doses up to 1000 mg combined with a standard of care (SoC: cetuximab plus irinotecan) and a phase II part in which patients were randomised 1 : 1 : 1 to receive abituzumab 500 mg (arm A) or 1000 mg (arm B) every 2 weeks combined with SoC, or SoC alone (arm C). The primary end point was investigator-assessed progression-free survival (PFS). Secondary end points included overall survival (OS), response rate (RR) and tolerability. Associations between tumour integrin expression and outcomes were also assessed. RESULTS: Phase I showed that abituzumab doses up to 1000 mg were well tolerated in combination with SoC. Seventy-three (arm A), 71 (arm B) and 72 (arm C) patients were randomised to the phase II part. Baseline characteristics were balanced. PFS was similar in the three arms: arm A versus SoC, hazard ratio (HR) 1.13 [95% confidence interval (CI) 0.78-1.64]; arm B versus SoC, HR 1.11 (95% CI 0.77-1.61). RRs were also similar. A trend toward improved OS was observed: arm A versus SoC, HR 0.83 (95% CI 0.54-1.28); arm B versus SoC, HR 0.80 (95% CI 0.52-1.25). Grade ≥3 treatment-emergent adverse events were observed in 72%, 78% and 67% of patients. High tumour integrin αvß6 expression was associated with longer OS in arms A [HR 0.55 (0.30-1.00)] and B [HR 0.41 (0.21-0.81)] than in arm C. CONCLUSION: The primary PFS end point was not met, although predefined exploratory biomarker analyses identified subgroups of patients in whom abituzumab may have benefit. The tolerability of abituzumab combined with cetuximab and irinotecan was acceptable. Further study is warranted. CLINICALTRIALS.GOV IDENTIFIER: NCT01008475.

[Plexiform angiomyxoid myofibroblastic tumour of the stomach]. / Plexiformer angiomyxoider myofibroblastischer Tumor des Magens.

Recently the so-called plexiform angiomyxoid myofibroblastic tumors (PAMT) have emerged as a new entity of gastric soft tissue tumors and the light microscopic and immunohistological characteristics have now been well described. Until now PAMTs have not yet been reported in the German speaking literature. Worthy of note is that PAMTs can be diagnosed safely in sufficient biopsy material which enables adequate therapeutic steps to be initiated without delay, because PMATs although considered to be benign, can cause serious complications.

Cetuximab in combination with weekly 5-fluorouracil/folinic acid and oxaliplatin (FUFOX) in untreated patients with advanced colorectal cancer: a phase Ib/II study of the AIO GI Group.

BACKGROUND: This two-part phase Ib/II study investigated the feasibility of administering cetuximab in combination with oxaliplatin and infusional 5-fluorouracil (5-FU)/folinic acid (FA) in a weekly schedule (AIO FUFOX protocol) as first-line treatment in patients with epidermal growth factor receptor-detectable advanced colorectal cancer. PATIENTS AND METHODS: Cetuximab was administered weekly: 400 mg/m(2) initial dose, then 250 mg/m(2) and FUFOX: oxaliplatin 50 mg/m(2), FA 500 mg/m(2) and 5-FU as a 24-h infusion at either 1500 or 2000 mg/m(2) administered for 4 weeks followed by a 1-week rest (one cycle). RESULTS: Dose-limiting toxicity (grade 3 diarrhea) occurred in 3 of 14 assessable patients receiving 5-FU at standard 2000 mg/m(2). This dose was administered to a further 25 patients. Cetuximab combined with FUFOX was generally well tolerated with the most common grade 3/4 adverse events being diarrhea (27%) and paresthesia (16%). The confirmed response rate for patients receiving 5-FU at standard 2000 mg/m(2) (N = 41) was 56%, with a median duration of 9.3 months. Median progression-free and overall survival times including all 49 patients were 8.1 (95% confidence interval 6.0-9.7) and 28.2 months, respectively. Cetuximab pharmacokinetics seemed not to be different for combination with FUFOX compared with cetuximab/irinotecan combinations. CONCLUSION: This protocol is well tolerated and shows promising efficacy supporting further investigation.

[TACE: therapy of the HCC before liver transplantation--experiences]. / TACE: Therapie des HCC vor Lebertransplantation -- Erfahrungen.

PURPOSE: Analysis of the course of disease in patients with histologically proven HCC before and after orthotopic liver transplantation (LTx) who received transarterial chemoembolization (TACE). MATERIAL AND METHODS: Thirty-five of a total collective of 363 patients with histologically proven HCC underwent LTx. Before LTx, all patients were treated with sequential TACE. According to treatment pattern, TACE should be performed every 6 weeks, using a suspension consisting of max. 10 mg Mitomycin C as well as 10 - 30 ml iodized oil (Lipiodol). Patients were classified according to the Milano criteria. Criteria were called exceeded if the tumor size was > 5 cm and/or > 3 tumors larger than 3 cm were found. Therapy success and liver function were examined by means of spiral CT and laboratory controls. Investigation parameters included the number of tumor knots as well as the maximum tumor size. Additionally, the Lipiodol accumulation, the patency of the portal vein and the occurrence of complications were checked. RESULTS: Altogether, 184 TACE procedures were accomplished (5.3 +/- 3.3, range 1 - 14). The waiting period up to the transplantation amounted to 366 +/- 255 days (range 44 - 1137). The average number of tumor knots for each patient was 3.1 +/- 2.2 before and 2.9 +/- 2.2 after TACE (p = 0.887). The average tumor size was 4.2 +/- 2.5 before and 2.8 +/- 1.4 after TACE. The Milano criteria to LTx crossed 17/35 patients. Patients with exceeded Milan criteria showed a highly significant size reduction of the tumor after TACE (p = 0.001); in 9/17 cases the transplantation criteria were secondarily fulfilled through downstaging. A successful LTx was accomplished in 35/35 cases. Follow up after LTx was 769 +/- 509 days. The tumor recurrence in patients with exceeded vs. fulfilled transplantation criteria was 11.1 % vs. 11.8 % (p = 0.99). The recurrence free survival was 93.3 %, 82.5 % and 82.5 % at 1, 3 and 5 years, respectively. There were no relevant differences between patients with exceeded vs. fulfilled transplantation criteria (p = 0.99). CONCLUSION: The sequential TACE is an effective method for the therapy of the HCC before LTx in selected patients. A relevant downsizing could be achieved by TACE in patients with advanced HCC. Patients with larger tumors showed a significantly stronger size reduction after TACE. The recurrence rate and the survival rate for patients with advanced or small tumors do not differ.

A TNF-alpha promoter polymorphism is associated with juvenile onset psoriasis and psoriatic arthritis.

Tumor necrosis factor-alpha is considered to be one of the important mediators in the pathogenesis of psoriasis. A strong association of juvenile onset psoriasis with the major histocompatibility complex encoded HLA-Cw6 antigen has been reported but it is unclear whether Cw6 itself or a closely linked gene is involved in the pathogenesis. This study has focused on the association of promoter polymorphisms of the major histocompatibility complex encoded tumor necrosis factor-alpha gene with psoriasis and psoriatic arthritis. Tumor necrosis factor-alpha promoter polymorphisms were sought by sequence-specific oligonucleotide hybridization and by direct sequencing in Caucasian patients with juvenile onset psoriasis and with psoriatic arthritis and in healthy controls. A mutation at position -238 of the tumor necrosis factor-alpha promoter was present in 23 of 60 patients (38%; p < 0.0001; p[corr] < 0.008) with juvenile onset psoriasis and in 20 of 62 patients (32%; p < 0.0003; p[corr] < 0.03) with psoriatic arthritis, compared with seven of 99 (7%) Caucasian controls. There was a marked increase of homozygotes for this mutation in the psoriasis group. Another mutation at position -308 was found in similar proportions of patients and controls. Our study shows a strong association of the tumor necrosis factor-alpha promoter polymorphism at position -238 with psoriasis and psoriatic arthritis. Our findings suggest that this promoter polymorphism itself or a gene in linkage disequilibrium with tumor necrosis factor-alpha predispose to the development of psoriasis.

TAP-polymorphisms in juvenile onset psoriasis and psoriatic arthritis.

Juvenile onset psoriasis is strongly associated with the HLA-class I genes Cw6 and B57 whereas patients with psoriatic arthritis show an increased frequency of HLA-B27. It is unclear whether additional major histocompatibility genes also increase disease susceptibility. The TAP genes (transporter associated with antigen processing) encode two membrane-spanning proteins that translocate antigenic peptides from the cytoplasm into the endoplasmic reticulum. Comparison of 60 patients with juvenile onset psoriasis, 63 psoriatic arthritis patients, and 101 caucasoid controls revealed an increase of the TAP1*0101 allele in the psoriasis group, that could not be explained by linkage to other investigated HLA genes. There were no differences for TAP2 alleles.

The influence of major histocompatibility complex class II genes and T-cell Vbeta repertoire on response to immunization with HBsAg.

Nonresponsiveness to HBsAg vaccination is observed in 5-10% of vaccine recipients and is possibly caused by a defect in the T helper cell compartment. The immune response to HBsAg is influenced by genes of the major histocompatibility complex. We have investigated MHC class I and class II antigens in 53 adult responders and 73 nonresponders. Results obtained in this first study were tested in a second study with 56 responders and 62 nonresponders from an infant vaccination trial. In addition, the peripheral Vbeta-chain T-cell receptor repertoire was investigated using monoclonal antibodies and flow-cytometry in 26 adult responders and 38 nonresponders. As previously reported, nonresponsiveness to HBsAg vaccination was associated with DRB1*3 and DRB1*7. In addition, DRB1*13 was significantly increased among vaccine responders (35.2% vs 5.4%;p < 0.0001) suggesting an immune response promoting effect for this allele whereas the closely related allele DRB1*14 was associated with nonresponse in the infant study. There was no evidence for a hole in the T cell receptor Vbeta repertoire. In conclusion, in agreement with results obtained in mice there appears to be a hierarchy of DRB1* genes in the HBsAg immune response. The possible differential association of DRB1*13 and DRB1*14 may allow the identification of differences between responsiveness and nonresponsiveness to a few amino acid differences in the beta1-domain of the class II heterodimer.

Pathogenesis of human leukocyte antigen B27-positive arthritis. Information from clinical materials.

In the spondyloarthropathies human leukocyte antigen (HLA) B27 confers a strong genetic predisposition to the development and to the chronicity of disease after extra-articular infection with certain gram-negative bacteria. The close relationships between infection, HLA-B27, other genetic factors, and the host immune system, however, still are unexplained. HLA-B27-positive arthritis continues to be an area of intensive investigation in basic and clinical research. New animal models with HLA-B27 transgenic mice and rats, as well as recent developments in understanding the processes involved in signal transduction, cytokine production, and human T-lymphocyte activation, contribute to the development of new pathogenic models of the spondyloarthropathies. This article summarizes the current concepts of the cause and pathogenesis of the spondyloarthropathies resulting from studies of clinical materials. The host-microbial interplay in human disease, namely in bacteria-induced reactive arthritis, may eludicate principle disease mechanisms in acute disease and in the development of chronic autoimmune arthritis or ankylosing spondylitis.

LMP polymorphisms do not influence disease expression in psoriatic arthritis.

OBJECTIVES: To investigate the potential role of the HLA-linked LMP2 (low molecular weight protein) and LMP7 gene polymorphisms in conjunction with HLA class I and class II genes on the disease pattern in individuals with psoriatic arthritis (PsA). METHODS: Sixty-three patients with PsA and 99 unrelated controls were typed for HLA-class I and II antigens. LMP2 and LMP7 polymorphisms were determined by PCR and subsequent single stranded conformation polymorphism (SSCP) analysis or restriction enzyme digestion. RESULTS: PsA was associated with B27 (p < 0.0004), B57 (p < 0.002) and Cw2 (p < 0.008). Spondylarthritis was strongly associated with HLA-B27 (p < 0.000001), Cw2 (p < 0.0003) and DR4 (p < 0.008). For the polyarthritic pattern the only association was with B57 (p < 0.007). There was no association between the LMP2 or LMP7 genotypes and any particular disease pattern. CONCLUSIONS: These findings do not support an involvement of the HLA linked LMP2 and LMP7 gene polymorphisms in disease expression in psoriatic arthritis in addition to the known HLA class I and II associations.

Hepatocellular carcinoma in a patient with hereditary hemochromatosis and noncirrhotic liver. A case report.

A case of a 62-year-old patient with hereditary hemochromatosis is reported, who developed hepatocellular carcinoma (HCC) in the absence of cirrhosis and other potential risk factors for HCC. Occurrence of HCC in patients with genetic hemochromatosis and noncirrhotic liver is a rare event which has previously been described only six times and appears to be limited to male patients.

[Enteropathic spondylarthritis in chronic inflammatory bowel diseases: prevalence, manifestation pattern and HLA association]. / Enteropathische Spondarthritiden bei chronisch entzündlichen Darmerkrankungen: Prävalenz, Befallsmuster und HLA-Assoziation.

BACKGROUND: Enteropathic spondylarthropathies (SpA) are the most frequent extraintestinal manifestation of the chronic inflammatory bowel disease (IBD), Crohn's disease (CD) and Ulcerative Colitis (UC). It was the aim of the present study, to analyze a large number of IBD patients for the prevalence and pattern of joint manifestation and the association of SpA with the extend of bowel involvement and HLA-haplotype. PATIENTS AND METHODS: 521 patients (409 CD and 112 UC) were prospectively analyzed over a period of one year. SpA was diagnosed on the basis of an appropriate patient history as well as clinical, radiological and immunoserological parameters. RESULTS: SpA was diagnosed in 10.7% of all CD and 14.4% of all UC patients. In 26.8% of all patients symptoms of SpA occurred prior to and in 14.4% simultaneously with IBD. 28.1% of all patients presented with isolated peripheral arthritis, 26.8% of all patients showed an isolated involvement of the spine or sacroiliic joints and 45.1% of all patients presented with combined involvement. 2/12 UC patients with SpA suffered from rectosigmoiditis, 5/12 from partial colitis and 5/12 had pancolitis. In CD patients with SpA, 8/59 had isolated colitis, 8/59 ileocolitis and 31/59 isolated small bowel involvement. There was a positive correlation between SpA and HLA-B27 (p < 0.01). CONCLUSION: Enteropathic spondylarthropathies are an important extraintestinal manifestation of IBD. Spondylarthropathies occur irrespective of the extend of IBD and frequently become symptomatic prior to IBD. These and recent data describing inflammatory bowel disease in patients with SpA of unknown etiology suggest that both diseases have a common pathogenetic background.

Genetic and environmental contributions to plasma C-reactive protein and interleukin-6 levels--a study in twins.

Elevated baseline levels of acute-phase proteins such as C-reactive protein (CRP) or cytokines like interleukin-6 (IL-6) are known risk factors for atherosclerosis and cardiovascular disease (CVD) events. However, until today, there is only controversial information about the contribution of genetic and environmental factors. Therefore, we performed an open prospective study in 108 monozygotic (MZ) and 60 same-sex dizygotic (DZ) twin pairs to analyse the genetic and environmental contributions to plasma CRP and IL-6 levels. Heritability of IL-6 was 0.61, indicating that plasma IL-6 levels are to a major part influenced by genetic determinants; however, for CRP, heritability was only 0.22, pointing to a moderate genetic influence. Plasma CRP levels were strongly influenced by female gender, older age and especially the body mass index. Our data underline the central role of IL-6 in low-grade inflammation contributing to atherosclerosis and CVD.

[ASCO-Update 2005--Highlights of the 41st Meeting of the American Society of Clinical Oncology/ASCO 2005]. / ASCO-Update 2005 - Neuigkeiten vom 41. Meeting der American Society of Clinical Oncology/ASCO 2005.

Currently, the treatment of gastrointestinal cancers is rapidly changing due to the implementation of novel chemotherapeutic agents as well as the introduction of targeted therapies into treatment protocols. The following review provides an overview of the most important clinical trials in esophageal, gastric, colorectal, pancreatic and hepatobiliary cancer that were presented at the annual meeting of the American Society of Clinical Oncology.

Randomised phase II evaluation of irinotecan plus high-dose 5-fluorouracil and leucovorin (ILF) vs 5-fluorouracil, leucovorin, and etoposide (ELF) in untreated metastatic gastric cancer.

An open-label randomised comparison of efficacy and tolerability of irinotecan plus high-dose 5-fluorouracil (5-FU) and leucovorin (LV) (ILF) with etoposide plus 5-FU/LV (ELF) in patients with untreated metastatic or locally advanced gastric cancer. One cycle of ILF comprised six once-weekly infusions of irinotecan 80 mg m(-2), LV 500 mg m(-2), 24-h 5-FU 2000 mg m(-2), and ELF comprised three once-daily doses of etoposide 120 mg m(-2), LV 300 mg m(-2), 5-FU 500 mg m(-2). In all, 56 patients received ILF and 58 ELF. Median age was 62 years, Karnofsky performance 90%, and disease status was comparable for both arms. The objective clinical response rates after 14 weeks treatment (primary end point) were 30% for ILF and 17% for ELF (risk ratio (RR) 0.57, 95% confidence interval (CI) 0.29-1.13, P = 0.0766). Overall response rates over the entire treatment period for ILF and ELF were 43 and 24%, respectively (RR 0.56, 95% CI 0.33-0.97; P = 0.0467). For ILF and ELF, respectively, median progression-free survival was 4.5 vs 2.3 months, time to treatment failure was 3.6 vs 2.2 months (P = 0.4542), and overall survival was 10.8 vs 8.3 months (P = 0.2818). Both regimens were well tolerated, the main grade 3/4 toxicities being diarrhoea (18%, ILF) and neutropenia (57%, ELF). The data from this randomised phase II study indicate that ILF provides a better response rate than ELF, and that ILF should be investigated further for the treatment of metastatic gastric cancer.

[New chemotherapeutic options in advanced gastric cancer]. / Neue Chemotherapeutika in der Therapie des fortgeschrittenen Magenkarzinoms.

Over the last years the therapeutic possibilities for advanced gastric cancer have significantly increased. Here we discuss the new chemotherapeutic options and the existing results in palliative therapy.

[Genetic hemochromatosis and the HFE gene: from molecular genetics to clinical diagnosis]. / Genetische Hämochromatose und das HFE-Gen: von der Molekulargenetik zur klinischen Diagnostik.

More than 90% of patients with genetic hemochromatosis carry a characteristic mutation in the HFE-gene (C282Y). HFE modulates the iron uptake by the transferrin receptor. Duodenal crypt cells of HFE-knockout mice show low intracellular iron concentrations which lead to an upregulation of the divalent metal transporter and enhanced iron uptake by duodenal enterocytes. Heterozygosity for the C282Y mutation appears to alter the course of other liver diseases like porphyria cutanea tarda and nonalcoholic steatohepatitis.

Cytokine gene polymorphisms relevant for the spondyloarthropathies.

Results of sibling and twin studies suggest that a substantial proportion of susceptibility to spondyloarthropathies arises from genes outside the human leukocyte antigen (HLA) region. There is increasing evidence that the pattern of cytokine secretion influences the course of spondyloarthropathies. A Th2 cytokine pattern (low tumor necrosis factor [TNF]-TNF-alpha low interferon [IFN]-gamma, and high interleukin [IL]-10) dominates in the joints of reactive arthritis patients. For IL-10 and TNF-alpha a substantial proportion of cytokine production is under genetic control and influenced by genetic polymorphisms. Here we review the evidences for association of TNF-alpha and IL-10 polymorphisms with spondyloarthropathies and their functional implications.

Psoriatic arthritis: clinical aspects, genetics, and the role of T cells.

In the last 2 years there has been considerable progress in investigating the genetic and immunologic background of psoriasis and psoriatic arthritis. This review focuses on genetics and the role of T-cells in the immunopathogenesis of the disease, with particular reference to psoriatic arthritis.