Biweekly Cetuximab Plus FOLFOX6 as First-Line Therapy in Patients With RAS Wild-Type Metastatic Colorectal Cancer: The CEBIFOX Trial.

BACKGROUND: The multicenter, single-arm, phase II study CEBIFOX evaluated the efficacy of a biweekly cetuximab administration in combination with FOLFOX6 as first-line therapy in KRAS (exon 2) wild-type (wt) metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Patients received FOLFOX6 with cetuximab (500 mg/m2) every second week. Primary endpoint was objective response rate (ORR), among others secondary endpoints were safety, progression-free survival (PFS), overall survival (OS), and patient-reported outcome (PRO). The impact on the treatment efficacy was evaluated in explorative subgroup analyses, including extended molecular profiling and primary tumor location. RESULTS: In total, 57 were included in the intention-to-treat (ITT) analyses. New RAS mutations were detected in 14.0% by post hoc next-generation sequencing analysis in 43 patients. The ORR in the all RASwt population was 70.3% with a median PFS and OS of 10.9 (95% confidence interval [CI], 9.0-12.9) and 33.8 (95% CI, 21.1-45.5) months. Grade 3-5 adverse events occurred in 66.7% of the ITT, without significant impact on the PRO. Patients with right-sided primary tumors had a reduced ORR (54.5%), and median PFS and OS (10.1 and 23.8 months). BRAF mutations were detected in 11.3%. These patients had a significantly lower ORR, and median PFS and OS. Patients with RASwt/BRAFwt tumors had a notably high median PFS and OS of 14.3 and 38.9 months. CONCLUSIONS: This study supports the efficacy and safety of biweekly cetuximab given in combination with FOLFOX6 in patients with RASwt/BRAFwt mCRC with left-sided primary tumor. CEBIFOX is the first trial reporting the complete dataset, including extended molecular profiling and tumor location of a biweekly administered cetuximab/FOLFOX6 in mCRC. Clinical trial number: NCT01051167.

Six versus eight doses of rituximab in patients with aggressive B cell lymphoma receiving six cycles of CHOP: results from the "Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas" (PETAL) trial.

Standard first-line treatment of aggressive B cell lymphoma comprises six or eight cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus eight doses of rituximab (R). Whether adding two doses of rituximab to six cycles of R-CHOP is of therapeutic benefit has not been systematically investigated. The Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas (PETAL) trial investigated the ability of [18F]-fluorodesoxyglucose PET scanning to guide treatment in aggressive non-Hodgkin lymphomas. Patients with B cell lymphomas and a negative interim scan received six cycles of R-CHOP with or without two extra doses of rituximab. For reasons related to trial design, only about a third underwent randomization between the two options. Combining randomized and non-randomized patients enabled subgroup analyses for diffuse large B cell lymphoma (DLBCL; n = 544), primary mediastinal B cell lymphoma (PMBCL; n = 37), and follicular lymphoma (FL) grade 3 (n = 35). With a median follow-up of 52 months, increasing the number of rituximab administrations failed to improve outcome. A non-significant trend for improved event-free survival was seen in DLBCL high-risk patients, as defined by the International Prognostic Index, while inferior survival was observed in female patients below the age of 60 years. Long-term outcome in PMBCL was excellent. Differences between FL grade 3a and FL grade 3b were not apparent. The results were confirmed in a Cox proportional hazard regression model and a propensity score matching analysis. In conclusion, adding two doses of rituximab to six cycles of R-CHOP did not improve outcome in patients with aggressive B cell lymphomas and a fast metabolic treatment response.

Altered treatment of chronic lymphocytic leukemia in Germany during the last decade.

Chronic lymphocytic leukemia (CLL) is the most common subtype of adult leukemia in the western world. We here report a nationwide survey monitoring the treatment decisions concerning CLL patients in Germany in 2011 and compare treatment trends to sequential surveys performed previously during the last decade. The rate of patients diagnosed in early stages (Binet A/B) notably increased (2006: 66 %, 2009: 71 %, 2011: 77 %) over the years. From 2006 to 2009, the most frequent applied regime switched from chlorambucil to fludarabine containing regimes (2006 chlorambucil: 32 %, 2009: 14 %, fludarabine 2006: 23 %, 2009: 37 %). In 2011, the combination of rituximab with bendamustine (31 %) was most frequent used followed by the rituximab-fludarabine-cyclophosphamide (22 %) regime. Further, immune-chemotherapies were administered significantly more often over the observation period (2006: 15 %, 2011: 73 %). Taken together, this data reflects the change of treatment strategies over the last decade in clinical reality.

Changes in the diagnosis and treatment of patients with low grade lymphoma in Germany: years 2006-2009.

Today's treatment options for indolent lymphoma and chronic lymphocytic leukemia (CLL) range from watch & wait, immunochemotherapy up to allogeneic transplantation. We describe changes in the diagnosis and treatment of indolent lymphoma and CLL in Germany between 2006 and 2009. Two nation-wide surveys in the fourth quarter of 2006 and 2009 included patients with indolent lymphoma and CLL. Data from 576 patients from 46 centers in Q4/2006 were compared with data from 521 patients from 57 centers in Q4/2009. The subpopulation of patients ≥ 70 years of age and the number of patients with comorbidities increased from 39% to 55% and 47% to 55%, respectively. Both in indolent lymphoma and CLL, Rituximab and R-based immunochemotherapy (50.6% vs. 64.4%) as well as bendamustine (4.8 % vs. 24%) were much more frequently applied. In contrast, high dose chemotherapy consolidation was almost abandoned in first line treatment. Supportive care is given more frequently, with exception of erythropoietin and immunoglobulins. Our national survey confirmed that scientific results were rapidly transferred into clinical care of indolent lymphoma.

Analysis of bevacizumab-based preoperative radiochemotherapy in patients with locally advanced rectal cancer on surgery-associated spectrum of complications.

BACKGROUND: Preoperative radiochemotherapy (RCT) is a standard of care for patients with locally advanced rectal cancer (LARC; stages II and III). Results of our phase II study (BevXelOx-RT) have shown that this regimen is feasible but without a significant improvement of pathological complete response. Whether preoperatively administered bevacizumab, due to its specific toxicity profile, leads to increased rates of surgical complications is currently a subject for debate. This analysis focusses on the surgery-associated spectrum of complications. METHODS: Data from 62 patients with rectal cancer (uT3-4; N0/1, M0) of the phase II trial were analyzed. Patients received radiotherapy (50.4/1.8 Gy fractions), simultaneous bevacizumab 5 mg/kg (d1, d15, d29), and capecitabine 825 mg/m(2) twice daily (d1-14, d22-35), oxaliplatin 50 mg/m(2) (d1, d8, d22, d29). Four to six weeks after RCT, surgical resection was performed. RESULTS: Overall, 69/69 patients underwent surgery, and 66 (95.7 %) patients had R0 resection. Surgery was mainly conducted (in 66 %) by highly experienced surgeons (>20 resections of rectal cancer/year) with differences between the institutions due to the operative procedures but without effects on the rate of R0 resection or complications. The average duration of surgery was 239 min (±10). Frequency of multivisceral resections (11 %), intraoperative (8 %) and postoperative (43 %) complications were all in the expected range. In particular, we did not observe an increased rate of postoperative bleedings (3 %). The postoperative mortality rate was 0 %. CONCLUSIONS: Quantity and the kind of surgery-associated spectrum of complications followed by a preoperative bevacizumab-containing RCT regimen in patients with LARC were in line with comparable trials of bevacizumab-based approaches.

Phase II trial of preoperative radiochemotherapy with concurrent bevacizumab, capecitabine and oxaliplatin in patients with locally advanced rectal cancer.

BACKGROUND: Preoperative radiochemotherapy (RCT) with 5-FU or capecitabine is the standard of care for patients with locally advanced rectal cancer (LARC). Preoperative RCT achieves pathological complete response rates (pCR) of 10-15%. We conducted a single arm phase II study to investigate the feasibility and efficacy of addition of bevacizumab and oxaliplatin to preoperative standard RCT with capecitabine. METHODS: Eligible patients had LARC (cT3-4; N0/1/2, M0/1) and were treated with preoperative RCT prior to planned surgery. Patients received conventionally fractionated radiotherapy (50.4 Gy in 1.8 Gy fractions) and simultaneous chemotherapy with capecitabine 825 mg/m2 bid (d1-14, d22-35) and oxaliplatin 50 mg/m2 (d1, d8, d22, d29). Bevacizumab 5 mg/kg was added on days 1, 15, and 29. The primary study objective was the pCR rate. RESULTS: 70 patients with LARC (cT3-4; N0/1, M0/1), ECOG < 2, were enrolled at 6 sites from 07/2008 through 02/2010 (median age 61 years [range 39-89], 68% male). At initial diagnosis, 84% of patients had clinical stage T3, 62% of patients had nodal involvement and 83% of patients were M0. Mean tumor distance from anal verge was 5.92 cm (± 3.68). 58 patients received the complete RCT (full dose RT and full dose of all chemotherapy). During preoperative treatment, grade 3 or 4 toxicities were experienced by 6 and 2 patients, respectively: grade 4 diarrhea and nausea in one patient (1.4%), respectively, grade 3 diarrhea in 2 patients (3%), grade 3 obstipation, anal abscess, anaphylactic reaction, leucopenia and neutropenia in one patient (1.4%), respectively. In total, 30 patients (46%) developed postoperative complications of any grade including one gastrointestinal perforation in one patient (2%), wound-healing problems in 7 patients (11%) and bleedings in 2 patients (3%). pCR was observed in 12/69 (17.4%) patients. Pathological downstaging (ypT < cT and ypN ≤ cN) was achieved in 31 of 69 patients (44.9%). All of the 66 operated patients had a R0 resection. 47 patients (68.1%) underwent sphincter preserving surgery. CONCLUSIONS: The addition of bevacizumab and oxaliplatin to RCT with capecitabine was well tolerated and did not increase perioperative morbidity or mortality. However, the pCR rate was not improved in comparison to other trials that used capecitabine or capecitabine/oxaliplatin in preoperative radiochemotherapy.

Gemcitabine plus erlotinib followed by capecitabine versus capecitabine plus erlotinib followed by gemcitabine in advanced pancreatic cancer: final results of a randomised phase 3 trial of the 'Arbeitsgemeinschaft Internistische Onkologie' (AIO-PK0104).

OBJECTIVE: AIO-PK0104 investigated two treatment strategies in advanced pancreatic cancer (PC): a reference sequence of gemcitabine/erlotinib followed by 2nd-line capecitabine was compared with a reverse experimental sequence of capecitabine/erlotinib followed by gemcitabine. METHODS: 281 patients with PC were randomly assigned to 1st-line treatment with either gemcitabine plus erlotinib or capecitabine plus erlotinib. In case of treatment failure (eg, disease progression or toxicity), patients were allocated to 2nd-line treatment with the comparator cytostatic drug without erlotinib. The primary study endpoint was time to treatment failure (TTF) after 1st- and 2nd-line therapy (TTF2; non-inferiority design). KRAS exon 2 mutations were analysed in archival tumour tissue from 173 of the randomised patients. RESULTS: Of the 274 eligible patients, 43 had locally advanced and 231 had metastatic disease; 140 (51%) received 2nd-line chemotherapy. Median TTF2 was estimated with 4.2 months in both arms; median overall survival was 6.2 months with gemcitabine/erlotinib followed by capecitabine and 6.9 months with capecitabine/erlotinib followed by gemcitabine, respectively (HR 1.02, p=0.90). TTF for 1st-line therapy (TTF1) was significantly prolonged with gemcitabine/erlotinib compared to capecitabine/erlotinib (3.2 vs 2.2 months; HR 0.69, p=0.0034). Skin rash was associated with both TTF2 (rash grade 0/1/2-4:2.9/4.3/6.7 months, p<0.0001) and survival (3.4/7.0/9.6 months, p<0.0001). Each arm showed a safe and manageable toxicity profile during 1st- and 2nd-line therapy. A KRAS wild-type status (52/173 patients, 30%) was associated with an improved overall survival (HR 1.68, p=0.005). CONCLUSION: Both treatment strategies are feasible and demonstrated comparable efficacy; KRAS may serve as biomarker in patients with advanced PC treated with erlotinib.

[HER2 testing and targeted therapy in advanced gastric cancer]. / HER2-Diagnostik und zielgerichtete Therapie beim fortgeschrittenen Magenkarzinom.

A large phase III study on the use of the HER2 antibody trastuzumab in locally advanced or metastatic gastric cancer has now been completed. Patients whose tumors were either scored on immunohistochemistry (IHC) as 3+ (independently of the result of fluorescence in situ hybridization (FISH)) or as IHC2+ and FISH+ were found, in a planned subgroup analysis, to have a median overall survival time of 16.0 months--versus 11.8 months when trastuzumab was not given. In light of these data, trastuzumab was therefore approved by the European Medicines Agency (EMEA) for metastasizing patients with this HER2 test result. It should be noted that the IHC scoring system for gastric cancer was modified compared to that for breast cancer. If the same criteria as are used for breast cancer were used for gastric cancer, this would lead to a large number of false negatives; around half of the patients who would benefit from trastuzumab would not be identified. Workshops for pathologists and round robin tests are being carried out to introduce the new scoring system.

[Neoadjuvant and surgical treatment for rectal cancer]. / Neoadjuvante und operative Therapie des Rektumkarzinoms.

According to the 2008 guidelines on colorectal cancer, whether preoperative therapy is indicated for rectal cancer should be judged based on the T and N categories. A few centres limit the indication for preoperative radio(chemo)therapy to patients with tumours that, according to magnetic resonance tomography (MRT), extend to the fascia mesorectalis or are 1 mm or less away from it - so-called circumferential resection margin-positive or CRM-positive tumours. Omitting preoperative therapy for MRT CRM-negative tumours is, however, a matter that still requires further study in clinical trials. The high rate of distant metastases continues to be a problem. Assuming that pathohistological complete remission (pCR) is a predictive marker of long-term disease-free survival after neoadjuvant radiochemotherapy, attempts are now being undertaken to intensify the neoadjuvant therapy. Phase II trials show improved pCR rates by combining the preoperative radiation with the double combinations oxaliplatin or irinotecan plus infusional or oral 5-FU (capecitabine). In the case of limited T1 rectal cancer without further risk factors, transanal local excision can be used.

EGF and HGF levels are increased during active HBV infection and enhance survival signaling through extracellular matrix interactions in primary human hepatocytes.

The hepatitis B virus (HBV) is a major causative agent of chronic liver disease and subsequent liver cirrhosis worldwide. The reduced sensitivity of virus-infected liver cells to apoptosis may play a role in the failure to remove virus-infected cells and eventually promote viral chronicity. The purpose of our study was to investigate whether survival factors induced during compensatory liver regeneration may protect hepatocytes against apoptosis. We evaluated the serum levels of hepatocyte growth factor (HGF) and epidermal growth factor (EGF) in HBV-infected patients and found significant increases in HGF and EGF in patients with active virus infection. In primary human hepatocytes we show that HGF and EGF have a protective effect against CD95-mediated apoptosis and cytotoxic T-cell killing. Simultaneous treatment with both regeneration factors enhanced the cytoprotective effect. The PI 3-K/Akt kinase inhibitor, wortmannin, and the STAT3 pathway inhibitor, Tyrphostin AG490, both effectively attenuated the cytoprotective effect of HGF and EGF. Furthermore, we show an EGF/HGF-dependent upregulation of beta(1)-integrin chains, increased adhesion to extracellular matrix and an increase in focal adhesions, suggesting outside-in signaling from the extracellular matrix as an additional cytoprotective mechanism. Our study demonstrates that HGF and EGF can interfere with CD95-mediated apoptosis and the action of cytotoxic T-cells through multiple mechanisms in human hepatocytes. Together our results argue that a survival mileau generated by activation of liver regeneration factors may be a risk factor for establishing viral persistence.

[Treatment of advanced pancreatic carcinoma]. / Therapie des fortgeschrittenen Pankreaskarzinoms.

Gemcitabine monotherapy extends survival times in locally advanced or metastatic pancreatic carcinoma compared with supportive treatment alone. Among patients who develop skin lesions of grade 2 or more, giving erlotinib in addition doubles survival times - from 5.9 to 10.5 months. Attempting therapy with gemcitabine plus erlotinib is therefore sensible. In patients with a good performance status, survival times can be extended using the combinations gemcitabine plus capecitabine or gemcitabine plus platinum. Radiochemotherapy is not sensible. For second-line treatment, oxaliplatin, 5-FU, and folic acid can be used.

[Multimodality treatment for colorectal cancer]. / Multimodale Therapie des Rektumkarzinoms.

Preoperative radiochemotherapy has clear advantages compared to postoperative therapy in rectal carcinoma of UICC stages II and III, and is indicated according to current guidelines. However, it does not reduce the rate of distant metastases. There is therefore a clear need to improve pre- and postoperative systemic treatment, in order to improve survival times. New combination chemotherapy regimens (5-FU/FS + oxaliplatin as well as XELOX) are being tested both pre and postoperatively, in some cases in combination with antibodies (bevacizumab or cetuximab). Instead of conventional neoadjuvant radiotherapy (50.4 Gy over 5-6 weeks), which is combined with neoadjuvant chemotherapy, preoperative short-term radiotherapy (5 x 5 Gy in 5 days) can be used. The advantages and disadvantages must be weighed up on an individual basis until results of the Berlin trial are available.

Gefitinib in combination with oxaliplatin and 5-fluorouracil in irinotecan-refractory patients with colorectal cancer: a phase I study of the Arbeits gemeinschaft Internistische Onkologie (AIO).

BACKGROUND: The aim of the study was to establish the recommended dose and to evaluate the safety of gefitinib plus FUFOX regimen in irinotecan-refractory colorectal carcinoma (CRC). PATIENTS AND METHODS: Patients with advanced CRC progressing on fluoropyrimidine/irinotecan-based chemotherapy and with an ECOG performance level 0-2 were enrolled. Four dose levels with sequential dose escalation of oral gefitinib and FUFOX were tested. Each cycle consisted of 5 weeks with gefitinib given daily to weekly FUFOX x4 to be repeated at day 36. RESULTS: Eighteen patients were enrolled. No dose-limiting toxicity (DLT) was observed at the dose levels L1-L3. At L4 diarrhea was the major DLT requiring treatment interruption in 3 patients. Other grade 3/4 toxicities were observed with skin rash, paresthesia, anemia, and nausea/vomiting (n = 1 each). Grade 1/2 toxicities consisted of diarrhea (n = 9), mucositis (8), skin rash (10), paresthesia (10), nausea (7) as well as leukopenia (2) and fever (1). Clinical benefit was seen in 11 of 16 evaluable patients (69%): 4 patients showed partial response (25%), 7 stable disease (44%). Median time to progression was 219 days (range 50-387 days). CONCLUSION: Gefitinib at a dose of 250 mg daily in combination with weekly 5-fluorouracil at 2,000 mg/m(2) or gefitinib at a dose of 500 mg daily with 5-fluorouracil at 1,600 mg/m(2) plus oxaliplatin has an acceptable safety profile.

All-trans retinoic acid for treatment of chronic hepatitis C.

BACKGROUND/AIMS: In vitro studies in the subgenomic hepatitis C virus (HCV) replicon system have identified all-trans retinoic acid (ATRA) as a potential therapeutic against hepatitis C. Thus, the antiviral potential of this drug should be assessed in vivo. METHODS: Twenty highly treatment experienced serotype 1 patients with non-response to conventional or pegylated interferon-alpha (Peg-/IFN-alpha) and ribavirin were randomly assigned to 12 weeks of monotherapy with ATRA (group A) or a combination of ATRA and PegIFN-alpha2a (group B). HCV RNA was assessed by bDNA assay and if negative by highly sensitive polymerase chain reaction. RESULTS: During treatment, five of 10 patients in group A had a drop of viraemia >1log, while in group B after 8 weeks five of 10 dropped >2log, and three of 10 cleared HCV RNA from serum. Viraemia relapsed after treatment cessation. ATRA was rather well tolerated, with transient headache, dry skin and mucosa representing the most common side effects. CONCLUSIONS: The viral load reduction under ATRA monotherapy, although limited and transient, supports the antiviral activity of ATRA. However, the rapid loss of HCV RNA in three of 10 previous non-responders under ATRA and PegIFN-alpha2a treatment demonstrates a strong additive or synergistic ATRA effect and calls for a controlled trial to assess the therapeutic potential of this drug.

Incidence of HAV and HBV infections and vaccination rates in patients with autoimmune liver diseases.

OBJECTIVES: Hepatitis A virus (HAV) or hepatitis B virus (HBV) superinfection is associated with an increased mortality in patients with chronic liver diseases (CLD). Despite official recommendations, it was reported that the vaccination rate against HAV is low in patients with chronic hepatitis C infection. To evaluate the situation in patients with autoimmune liver diseases, we conducted a retrospective cohort study. METHODS: Susceptibility to HAV and HBV infections, course of HAV and HBV infections, vaccination rates against HAV and HBV, and efficacy of hepatitis A/B vaccines were evaluated by antibody testing in 225 patients with autoimmune liver diseases during 1,677 person-years. RESULTS: Susceptibility to HAV/HBV infection was 51/86%. Incidence of HAV/HBV infection was 1.3/1.4 per 1,000 person-years. One HAV infection occurred, but the patient recovered spontaneously. Two patients were HBV-infected after receiving an anti-HBc-positive (antibody to hepatitis B core antigen) donor graft during orthotopic liver transplantation, and one of them developed chronic HBV infection. Vaccination rates were 11% (HBV) and 13% (HAV), respectively. Seventy-six percent of the vaccinated patients (HBV vaccine) developed anti-HBs (antibody to hepatitis surface antigen) >or=10 UI/L. Ten out of 13 vaccinated patients, showing a low or nonresponse to hepatitis B vaccine, had concomitant immunosuppressive therapy. Anti-HAV was detectable in all patients after administration of HAV vaccine. CONCLUSIONS: Patients with autoimmune liver diseases have a high susceptibility to HAV and HBV infections. Vaccination rates are low in this patient cohort and efficacy of hepatitis B vaccine is reduced due to immunosuppressive therapy. Improving adherence to vaccine recommendations is essential to prevent HAV and HBV infections in patients with autoimmune liver diseases.

Antibody persistence and immune memory elicited by combined hepatitis A and B vaccination in older adults.

Response to hepatitis A and B vaccines has been reported to decline with age. This open, prospective, single-site study examined the long-term response to the combined hepatitis A/B vaccine Twinrix in 98 primary responders aged 45-67 years. Levels of antibody against hepatitis A virus (HAV) and hepatitis B surface antigen (HBs) were tested 30 months after initial vaccination. At this stage, all participants remained seropositive for anti-HAV and 70% for anti-HBs. A booster vaccination was offered to those who had responded to the first vaccination but then lost protective levels of anti-HBs. An anamnestic response was observed in all cases.

Overexpression of STAT-1 by adenoviral gene transfer does not inhibit hepatitis B virus replication.

OBJECTIVES: Interferons are known to inhibit the replication of hepatitis B viruses (HBV) in several animal models in vitro and in vivo as well in humans. The STAT-1 protein plays a central role in the biological activity of both type I and type II interferons. The lack of functional STAT-1 renders cells and organisms susceptible to bacterial and viral infectious agents. We analysed whether the overexpression of STAT-1 protein enhances the biological interferon response and whether it elicits antiviral activity against HBV in vitro. METHODS: To achieve an efficient STAT-1 overexpression in primary liver cells and hepatoma cells, we generated a recombinant, replication-deficient adenovirus expressing human STAT-1 (Adv-STAT-1). We analysed whether the overexpression of STAT-1 inhibits the replication of duck HBV and human HBV in vitro using Western blot analysis, the immunofluorescence of viral proteins and quantification of HBV-DNA copies, respectively. RESULTS: In the duck model of HBV infection the overexpression of STAT-1 neither inhibited an established infection nor prevented the establishment of duck HBV replication when administered simultaneously with Adv-STAT-1. These observations were confirmed in an in-vitro model of human HBV infection using the human hepatoma cell line HepG2.2.15, which continuously replicates HBV. CONCLUSION: These data demonstrate that the over-expression of STAT-1 alone is not sufficient to strengthen the biological response of interferon as an antiviral agent.

A genetic basis for IFN-gamma production and T-bet expression in humans.

Th1 and Th2 cytokines secreted by polarized effector T cells play a pivotal role in the development of autoimmune and allergic diseases. However, the genetic basis of cytokine production by T lymphocytes in humans is poorly understood. In this study, we investigated the genetic contribution to cytokine production and regulation of T cell-specific transcription factors in a prospective twin study. We found a substantial genetic contribution to the production of Th1 cytokines such as IFN-gamma and TNF-alpha with heritabilities of 0.85 (95% confidence intervals, 0.74-0.95) and 0.72 (0.50-0.93), respectively, whereas no genetic influence on production of the Th2 signature cytokine IL-4 was observed. Furthermore, the intrapair variability in IFN-gamma production by isolated T cells was lower in monozygotic than in dizygotic twins. In contrast to GATA-3, NFAT, and NF-kappaB, intrapair variability of T-bet, the master transcription factor of Th1 cells, was very low among monozygotic and high among dizygotic twins, indicative of a strong genetic influence on T-bet (heritability 0.93, 95% confidence interval, 0.84-1.0). Our data provide novel insights into the genetic regulation of human Th cell polarization. These data suggest that signature cytokines and cytokine signaling events of Th1 rather than Th2 cells are genetically determined and implicate that Th2-associated diseases in humans might be due to genetic variations in Th1 cytokine regulation via T-bet. This concept is highlighted by the recent finding that inactivation of the T-bet gene in mice results in development of clinical hallmark features of asthma.

A functional polymorphism in the IL-10 promoter influences the response after vaccination with HBsAg and hepatitis A.

The immune response to hepatitis B surface antigen (HBsAg) is mostly genetically determined. Interleukin 10 (IL-10) is a central immunoregulatory cytokine with important effects on B-cells. We have studied the influence of IL-10 promoter polymorphisms on the immune response to HBsAg and hepatitis A vaccination. We vaccinated 202 twin pairs in an open prospective study with a combined recombinant HBsAg/inactivated hepatitis A vaccine. IL-10 promoter polymorphisms were investigated in all individuals and their influence on anti-HBs, and anti-HAV responsiveness was studied. In the multiple regression analysis accounting for smoking, gender, body mass index and age, the ACC haplotype (-1082, -819 and -592) had a strong influence on anti-HBs production. Individuals carrying the ACC haplotype had anti-HBs titres almost twice as high as individuals without this haplotype. In contrast, anti-HAV production was suppressed by the presence of the -1082A allele in comparison with individuals homozygous for the -1082G allele. The contribution of the shared IL-10 promoter haplotype accounted for 27% of the genetic influence on anti-HBs antibody response. In conclusion, genetic variability in the IL-10 promoter is an important modulator of the immune response against hepatitis viral antigens.