Value through Innovation17 January 2013

Page content

jump to main navigation jump to meta navigation

Scientific Publications

Boehringer Ingelheim offers an overview of scientific publications on the following pages. This overview represents all publications of the last three years (YTD) where employees of Boehringer Ingelheim worldwide were involved.

51 publications regarding Oncology
  • Author:
    George S; Reichardt P; Lechner T; Li S; Cohen DP; Demetri GD
    Title:
    Hypertension as a potential biomarker of efficacy in patients with gastrointestinal stromal tumor treated with sunitinib.
    Source:
    Ann Oncol 23 (12) (art.no.mds179), 3180-3187 (2012)
  • Author:
    MacLeod SH; ElGadi MM; Bossi G; Sankar U; Pisio A; Agopsowicz K; Sharon D; Graham FL; Hitt MM
    Title:
    HER3 targeting of adenovirus by fiber modification increases infection of breast cancer cells in vitro, but not following intratumoral injection in mice.
    Source:
  • Author:
    Mross K; Dittrich C; Aulizky WE; Strumberg D; Schutte J; Schmid RM; Hollerbach S; Merger M; Munzert G; Fleischer F; Scheulen ME
    Title:
    A randomised phase II trial of the polo-like kinase inhibitor BI 2536 in chemo-nave patients with unresectable exocrine adenocarcinoma of the pancreas-a study within the Central European Society Anticancer Drug Research (CESAR) collaborative network.
    Source:
    Br J Cancer 107 (2), 280-286 (2012)
    Abstract:
    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
  • Author:
    Arrieta O; Campos-Parra AD; Zuloaga C; Aviles A; Sanchez-Reyes R; Manriquez MEV; Covian-Molina E; Martinez-Barrera L; Meneses A; Cardona A; Borbolla-Escoboza JR
    Title:
    Clinical and pathological characteristics, outcome and mutational profiles regarding non-small-cell lung cancer related to wood-smoke exposure.
    Source:
    J Thorac Oncol 7 (8), 1228-1234 (2012)
    Abstract:
    HYPOTHESIS:: Although smoking is the major risk factor for non-small-cell lung cancer (NSCLC), other factors are also associated with lung carcinogenesis, such as wood-smoke exposure (WSE). This article has been aimed at suggesting that lung cancer related to cigarette smoking and lung cancer related to WSE have different clinical and genetic characteristics. EXPERIMENTAL DESIGN:: A cohort of 914 lung cancer patients was prospectively studied; they had been treated at Mexico's National Cancer Institute between 2007 and 2010. The associations of WSE and cigarette smoking with clinical characteristics, mutation profile, response to chemotherapy, and epidermal growth factor receptor tyrosine kinase inhibitors were analyzed, and overall survival (OS) rate was calculated. The trial was registered with ClinicalTrials.gov: NCT01023828. RESULTS:: Of the lung cancer patients studied, 95.1% were classified as coming within the NSCLC histology subtype; 58% of the patients smoked cigarettes, 35% had a background of WSE (exposure to both cigarette smoke and wood smoke was documented in 12.1% of all patients), and 19.4% patients had no smoke-exposure background. WSE was associated with NSCLC and adenocarcinoma histology, and was also more frequently associated with epidermal growth factor receptor-mutations than cigarette-smoking patients were (50.0% cf. 19.4%), whereas KRAS mutations were less common in WSE patients (6.7%) than in smokers (21%). WSE patients had a higher epidermal growth factor receptor tyrosine kinase inhibitor response rate (39.7%) than smokers (18.8%). The NSCLC patient WSE group's OS was longer (22.7 months) than that for smokers (13.8 months). CONCLUSION:: NSCLC patients who smoked tobacco/cigarettes differed from those having a background of WSE regarding tumor histology, mutation profile, response rate, and OS, indicating that different carcinogenic mechanisms were induced by these two types of smoke exposure.
  • Author:
    Schuler M; Awada A; Harter P; Canon JL; Possinger K; Schmidt M; De Greve J; Neven P; Dirix L; Jonat W; Beckmann MW; Schuette J; Fasching PA; Gottschalk N; Besse-Hammer T; Fleischer F; Wind S; Uttenreuther-Fischer M; Piccart M; Harbeck N
    Title:
    A phase II trial to assess efficacy and safety to afatinib in extensively pretreated patients in HER2-negative metastatic breast cancer.
    Source:
    Breast Cancer Res Treat 134 (3), 1149-1159 (2012)
    Abstract:
    Afatinib (BIBW 2992) is an ErbB-family blocker that irreversibly inhibits signaling from all relevant ErbB-family dimers. Afatinib has demonstrated preclinical activity in human epidermal growth factor receptor HER2 (ErbB2)-positive and triple-negative xenograft models of breast cancer, and clinical activity in phase I studies. This was a multicenter phase II study enrolling patients with HER2-negative metastatic breast cancer progressing following no more than three lines of chemotherapy. No prior epidermal growth factor receptor-targeted therapy was allowed. Patients received 50-mg afatinib once daily until disease progression. Tumor assessment was performed at every other 28-day treatment course. The primary endpoint was clinical benefit (CB) for =4 treatment courses in triple-negative (Cohort A) metastatic breast cancer (TNBC) and objective responses measured by Response Evaluation Criteria in Solid Tumors in patients with HER2-negative, estrogen receptor-positive, and/or progesterone receptor-positive breast cancer (Cohort B). Fifty patients received treatment, including 29 patients in Cohort A and 21 patients in Cohort B. No objective responses were observed in either cohort. Median progression-free survival was 7.4 and 7.7 weeks in Cohorts A and B, respectively. Three patients with TNBC had stable disease for =4 treatment courses, one of them for 12 courses (median 26.3 weeks; range 18.9-47.9 weeks). The most frequently observed afatinib-associated adverse events (AEs) were gastrointestinal and skin-related side effects, which were manageable by symptomatic treatment and dose reductions. Afatinib pharmacokinetics were comparable to those observed in previously reported phase I trials. In conclusion, afatinib had limited activity in HER2-negative breast cancer. AEs were generally manageable and mainly affected the skin and the gastrointestinal tract. © 2012 The Author(s).
  • Author:
    Miller VA; Hirsh V; Cadranel J; Chen Y-M; Park K; Kim S-W; Zhou C; Su W-C; Wang M; Sun Y; Heo DS; Crino L; Tan E-H; Chao T-Y; Shahidi M; Cong XJ; Lorence RM; Yang JCH
    Title:
    Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): A phase 2b/3 randomised trial.
    Source:
    Lancet Oncol 13 (5), 528-538 (2012)
    Abstract:
    Background: Afatinib, an irreversible ErbB-family blocker, has shown preclinical activity when tested in EGFR mutant models with mutations that confer resistance to EGFR tyrosine-kinase inhibitors. We aimed to assess its efficacy in patients with advanced lung adenocarcinoma with previous treatment failure on EGFR tyrosine-kinase inhibitors. Methods: In this phase 2b/3 trial, we enrolled patients with stage IIIB or IV adenocarcinoma and an Eastern Cooperative Oncology Group performance (ECOG) performance score of 0-2 who had received one or two previous chemotherapy regimens and had disease progression after at least 12 weeks of treatment with erlotinib or gefitinib. We used a computer-generated sequence to randomly allocate patients (2:1) to either afatinib (50 mg per day) or placebo; all patients received best supportive care. Randomisation was done in blocks of three and was stratified by sex and baseline ECOG performance status (0-1 vs 2). Investigators, patients, and the trial sponsor were masked to treatment assignment. The primary endpoint was overall survival (from date of randomisation to death), analysed on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT00656136. Findings: Between May 26, 2008, and Sept 21, 2009, we identified 697 patients, 585 of whom were randomly allocated to treatment (390 to afatinib, 195 to placebo). Median overall survival was 10·8 months (95% CI 10·0-12·0) in the afatinib group and 12·0 months (10·2-14·3) in the placebo group (hazard ratio 1·08, 95% CI 0·86-1·35; p=0·74). Median progression-free survival was longer in the afatinib group (3·3 months, 95% CI 2·79-4·40) than it was in the placebo group (1·1 months, 0·95-1·68; hazard ratio 0·38, 95% CI 0·31-0·48; p<0·0001). No complete responses to treatment were noted; 29 (7%) patients had a partial response in the afatinib group, as did one patient in the placebo group. Subsequent cancer treatment was given to 257 (68%) patients in the afatinib group and 153 (79%) patients in the placebo group. The most common adverse events in the afatinib group were diarrhoea (339 [87%] of 390 patients; 66 [17%] were grade 3) and rash or acne (305 [78%] patients; 56 [14%] were grade 3). These events occurred less often in the placebo group (18 [9%] of 195 patients had diarrhoea; 31 [16%] had rash or acne), all being grade 1 or 2. Drug-related serious adverse events occurred in 39 (10%) patients in the afatinib group and one (<1%) patient in the placebo group. We recorded two possibly treatment-related deaths in the afatinib group. Interpretation: Although we recorded no benefit in terms of overall survival with afatinib (which might have been affected by cancer treatments given after progression in both groups), our findings for progression-free survival and response to treatment suggest that afatinib could be of some benefit to patients with advanced lung adenocarcinoma who have failed at least 12 weeks of previous EGFR tyrosine-kinase inhibitor treatment. Funding: Boehringer Ingelheim Inc. © 2012 Elsevier Ltd. |
  • Author:
    Yang JCH; Shih J-Y; Su W-C; Hsia T-C; Tsai C-M; Ou SHI; Yu C-J; Chang G-C; Hol C-L; Sequist LV; Dudek AZ; Shahidi M; Cong XJ; Lorence RM; Yang P-C; Miller VA
    Title:
    Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): A phase 2 trial.
    Source:
    Lancet Oncol 13 (5), 539-548 (2012)
    Abstract:
    Background: Afatinib is an irreversible ErbB-family blocker with preclinical activity in non-small-cell lung cancer (NSCLC) with EGFR mutations. We aimed to assess the efficacy of afatinib in patients with lung adenocarcinoma and EGFR mutations. Methods: In this phase 2 study, we enrolled patients from 30 centres in Taiwan and the USA with lung adenocarcinoma (stage IIIb with pleural effusion or stage IV) with EGFR mutations, who had no more than one previous chemotherapy regimen for advanced disease, an Eastern Cooperative Oncology Group performance status of 0-2, and no previous treatment with EGFR tyrosine-kinase inhibitors. We tested two afatinib starting doses: 50 mg daily and subsequently 40 mg daily, introduced to establish whether tolerability could be improved with retention of anti-tumour activity. The primary endpoint was the proportion of patients with a confirmed objective response (complete response or partial response), on the basis of Response Evaluation Criteria in Solid Tumors 1.0 (independent review). This study is registered with ClinicalTrials.gov, number NCT00525148. Findings: 129 patients were treated with afatinib, 99 with a starting dose of 50 mg and 30 with a starting dose of 40 mg. 79 (61%) of 129 patients had an objective response (two complete responses, 77 partial responses). 70 (66%) of the 106 patients with the two common activating EGFR mutations (deletion 19 or L858R) had an objective response, as did nine (39%) of 23 patients with less common mutations. Similar proportions of patients had an objective response when analysed by starting dose (18 [60%] of 30 patients at 40 mg vs 61 [62%] of 99 patients at 50 mg). Of the two most common adverse events (diarrhoea and rash or acne), grade 3 events were more common in patients receiving a 50 mg starting dose (22 [22%] of 99 patients for diarrhoea and 28 [28%] of 99 patients for rash or acne) than they were in those receiving a 40 mg starting dose (two [7%] of 30 patients for both diarrhoea and rash or acne); possibly treatment-related serious adverse events were also less common in patients receiving a 40 mg starting dose (two of 30 patients vs 14 of 99 patients). We recorded one possibly drug-related death (interstitial lung disease). Interpretation: Afatinib shows activity in the treatment of patients with advanced lung adenocarcinoma with EGFR mutations, especially in patients with deletion 19 or L858R mutations. The efficacy of afatinib 40 mg should be compared with chemotherapy or other EGFR tyrosine-kinase inhibitors in EGFR-mutation-positive NSCLC. Funding: Boehringer Ingelheim Inc. © 2012 Elsevier Ltd
  • Author:
    Thomssen C; Gnant M; Harbeck N; Dethling J; Langenfeld M; Mueser M; Muth M; Rieth A; Sperber T; Wilhelm O G; Zaun S
    Title:
    Current research of the pharmaceutical industry.
    Source:
    Breast Care 7 (2), 155-164 (2012)
  • Author:
    Pinn S
    Title:
    New drug therapies, dedicated specialists and desperately-ill patients - but who will fly the flag for service developments in lung cancer as NHS budgets come under pressure?
    Source:
    Source:
    Ecancermedicalscience 5 (1) art.no.209 (2012)
  • Author:
    Doebele R C; Conkling P; Traynor A M; Otterson G A; Zhao Y; Wind S; Stopfer P; Kaiser R; Camidge D R
    Title:
    A phase I, open-label dose-escalation study of continuous treatment with bibf 1120 in combination with paclitaxel and carboplatin as first-line treatment in patients with advanced non-small-cell lung cancer
    Source:
    Ann Oncol 23 (8), 2094-2102 (2012)
    Abstract:
    Abstract Background: BIBF 1120 is an oral potent inhibitor of vascular endothelial growth factor receptor, fibroblast growth factor receptor and platelet-derived growth factor receptor, the three key receptor families involved in angiogenesis. This phase I, open-label dose-escalation study investigated BIBF 1120 combined with paclitaxel (Taxol) and carboplatin in first-line patients with advanced (IIIB/IV) non-small-cell lung cancer. Patients and methods: Patients received BIBF 1120 (starting dose 50 mg b.i.d.) on days 2-21 and paclitaxel (200 mg/m 2) and carboplatin [area under curve (AUC) = 6 mg/ml/min] on day 1 of each 21-day cycle. Primary end points were safety and BIBF 1120 maximum tolerated dose (MTD) in this combination. Pharmacokinetics (PK) profiles were evaluated. Results: Twenty-six patients were treated (BIBF 1120 50-250 mg b.i.d.). BIBF 1120 MTD was 200 mg b.i.d. in combination with paclitaxel and carboplatin. Six dose-limiting toxicity events occurred during treatment cycle 1 (liver enzyme elevations, thrombocytopenia, abdominal pain, and rash). Best responses included 7 confirmed partial responses (26.9%); 10 patients had stable disease. BIBF 1120 200 mg b.i.d. had no clinically relevant influence on the PK of paclitaxel 200 mg/m 2and carboplatin AUC 6 mg/ml/min and vice versa. Conclusions: BIBF 1120 MTD was 200 mg b.i.d when given with paclitaxel and carboplatin; this combination demonstrated an acceptable safety profile. No relevant changes in PK parameters of the backbone chemotherapeutic agents or BIBF 1120 were observed. © the Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved
  • Author:
    Frost A; Mross K; Steinbild S; Hedborn S; Unger C; Kaiser R; Trommeshauser D; Munzert G
    Title:
    Phase I study of the PK1 inhibitor BI 2536 administered intravenously on three consecutive days in advanced solid tumours.
    Source:
    Curr Oncol 19 (1), 28-35 (2012)
  • Author:
    Bridges JFP; Mohamed AF; Finnern AW; Woehl A; Hauber A
    Title:
    Patients' preferences for treatment outcomes for advanced non-small cell lung cancer: A conjoint analysis.
    Source:
    Lung Cancer (Neth) Article in Press (2012)
  • Author:
    Eberl M; Klingler S; Mangelberger D; Loipetzberger A; Damhofer H; Zoidl K; Schnidar H; Hache H; Bauer H-C; Solca F; Hauser-Kronberger C; Ermilov AN; Verhaegen ME; Bichakjian CK; Dlugosz AA; Nietfeld W; Sibilia M; Lehrach H; Wierling C; Aberger F
    Title:
    Hedehog-EGFR cooperation response genes determine the oncogenic phenotype of basal cell carcinoma and tumour-initiating pancreatic cancer cells.
    Source:
    EMBO Mol Med 4 (3), 218-233 (2012)
  • Author:
    Lin NU; Winer EP; Wheatley D; Carey LA; Houston S; Mendelson D; Munster P; Frakes L; Kelly S; Garcia AA; Cleator S; Uttenreuther-Fischer M; Jones H; Wind S; Vinisko R; Hickish T
    Title:
    A phase II study of afatinib (BIBW 2992), an irreversible ErbB family blocker, in patients with HER2-positive metastatic breast cancer progressing after trastuzumab.
    Source:
    Breast Cancer Res Treat 133 (3), 1057-1065 (2012)
    Abstract:
    Afatinib is an oral, ErbB family blocker, which covalently binds and irreversibly blocks all kinase-compe-tent ErbB family members. This phase II, open-label, singlearm study explored afatinib activity in human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients progressing after trastuzumab treatment. Patients had stage IIIB/IV HER2-positive metastatic breast cancer, with progression following trastuzumab or trastuzumab intolerance and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Patients received 50 mg afatinib once-daily until disease progression. Primary endpoint was objective response rate (Response Evaluation Criteria in Solid Tumors 1.0), with tumor assessments every 8 weeks. Forty-one patients were treated. Patients had received a median of three prior chemotherapy lines (range, 0-15) and 68.3% had received trastuzumab for >1 year.Four patients (10% of 41 treated; 11% of evaluable patients) had partial response. Fifteen patients (37% of 41) had stable disease as best response and 19 (46% of 41) achieved clinical benefit. Median progression-free survival was 15.1 weeks (95% confidence interval [CI]: 8.1-16.7); median overall survival was 61.0 weeks (95% CI: 56.7-not evaluable). Most frequent common terminology criteria for adverse events grade 3 treatment-related adverse events were diarrhea (24.4%) and rash (9.8%). Afatinib monotherapy was associated with promising clinical activity in extensively pretreated HER2-positive breast cancer patients who had progressed following trastuzumab treatment.
  • Author:
    Shi J; Wang E; Zuber J; Rappaport A; Taylor M; Johns C; Lowe SW; Vakoc CR
    Title:
    The polycomp complex PRC2 supports aberrant self-renewal in a mouse model of MLL-AF9:Nras G12D acute myeloid leukemia.
    Source:
    Oncogene Article in Press (2012)
  • Author:
    Frost A; Mross K; Steinbild S; Hedborn S; Unger C; Kaiser R; Trommeshauser D; Munzert G
    Title:
    Phase I study of the Plk1 inhibitor BI 2536 administered intravenously on three consecutive days in advanced solid tumors.
    Source:
    Curr Oncol 19 (1), 28-35 (2012)
    Abstract:
    Background This open-label phase i study with an accelerated titration design was performed to determine the maximum tolerated dose of BI 2536, a potent, highly selective small-molecule polo-like kinase 1 (Plk1) inhibitor. Methods Patients with advanced solid tumours received a single 60-minute intravenous infusion of BI 2536 (50-70 mg) on days 1-3 of each 21-day treatment course. Recipients without disease progression or untenable toxicity could receive additional treatment courses. The maximum tolerated dose was determined based on dose-limiting toxicities. Other assessments included safety, pharmacokinetic profile, and antitumour activity according to the Response Evaluation Criteria in Solid Tumors. Results The study enrolled 21 patients. The maximum tolerated dose for BI 2536 was determined to be 60 mg for the study schedule. Dose-limiting toxicities included hematologic events, hypertension, elevated liver enzymes, and fatigue. The most frequently reported drug-related adverse events were mild-to-moderate fatigue, leukopenia, constipation, nausea, mucosal inflammation, anorexia, and alopecia. The pharmacokinetics of BI 2536 were linear within the dose range tested. Plasma concentration profiles exhibited multi compartmental pharmacokinetic behaviour, with a terminal elimination half-life of 20-30 hours. Conclusions In the present study, BI 2536 showed an acceptable safety profile warranting further investigation of Plk1 inhibitors in this patient population.
  • Author:
    Glaser SP; Lee EF; Trounson E; Bouillet P; Wei A; Fairlie WD; Izon DJ; Zuber J; Rappaport AR; Herold MJ; Alexander WS; Lowe SW; Robb L; Strasser A
    Title:
    Anti-apoptotic mcl-1 is essential for the development and sustained growth of acute myeloid leukemia.
    Source:
    Genes Dev 26 (2), 120-125 (2012)
    Abstract:
    Acute myeloid leukemia (AML) frequently relapses after initial treatment. Drug resistance in AML has been attributed to high levels of the anti-apoptotic Bcl-2 family members Bcl-x L and Mcl-1. Here we report that removal of Mcl-1, but not loss or pharmacological blockade of Bcl-x L, Bcl-2, or Bcl-w, caused the death of transformed AML and could cure disease in AML-afflicted mice. Enforced expression of selective inhibitors of prosurvival Bcl-2 family members revealed that Mcl-1 is critical for survival of human AML cells. Thus, targeting of Mcl-1 or regulators of its expression may be a useful strategy for the treatment of AML.
  • Author:
    Lavila-Alonso S; Bauer MMT; Abo-Ramadan U; Ristimaeki A; Halavaara J; Desmond RA; Wang D; Escutenaire S; Ahtiainen L; Saksela K; Tatlisumak T; Hemminki A; Pesonen S
    Title:
    Macrophage metalloelastase (MME) as adjuvant for intra-tumoral injection of oncolytic adenovirus and its influence on metastases development.
    Source:
    Cancer Gene Ther 19 (2), 126-134 (2012)
  • Author:
    Engstrom PF; Bloom MG; Demetri GD; Febbo PG; Goeckeler W; Ladanyi M; Robson M; Loy B; Murphy K; Nerenberg M; Papagni P; Sweetman RW; Tunis S
    Title:
    NCCN molecular testing white paper: Effectiveness, efficency and reimbursement.
    Source:
    J Natl Compr Cancer Netw 9 (Suppl.6), S1-S16 (2011)
  • Author:
    Adrian C; Zettl M; Christova Y; Freeman M; Taylor M
    Title:
    Tumor necrosis factor signaling requires iRhom2 to promote trafficking and activation of TACE.
    Source:
    Science 335 (6065), 225-228 (2012)
  • Author:
    Murakami H; Tamura T; Takahashi T; Nokihara H; Naito T; Nakamura Y; Nishio K; Seki Y; Sarashina A; Shahidi M; Yamamoto N
    Title:
    Phase I study of contiunous afatinib (BIBW 2992) in patients with advanced non-small cell lung cancer after prior chemotherapy/erlotinib/gefitnib (LUX-Lung 4).
    Source:
    Cancer Chemother Pharmacol 69 (4), 891-899 (2012)
    Abstract:
    Purpose: This Phase I study determined the maximum-tolerated dose (MTD) of afatinib (Afatinib is an investigational compound and its safety and efficacy have not yet been established) (BIBW 2992; trade name not yet approved by FDA), an irreversible inhibitor of epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor (HER)1 and 2, up to a dose of 50 mg/day in advanced non-small cell lung cancer (NSCLC), to establish the recommended dose for Phase II. Methods: Patients with advanced NSCLC who had received prior platinum-doublet chemotherapy and/or erlotinib/gefitinib therapy, or who were ineligible for, or not amenable to, treatment with established therapies, received oral afatinib once daily. The MTD was determined based on dose-limiting toxicities (DLTs); other assessments included safety, pharmacokinetic profile, antitumour activity according to response evaluation criteria in solid tumours and EGFR/HER1 mutation analysis where possible. Results: Twelve evaluable patients were treated at doses of 20-50 mg/day. One DLT was observed at 50 mg/day in Course 1 (Grade 3 mucositis). The most frequent drug-related adverse events were diarrhoea, dry skin, stomatitis, rash, paronychia and anorexia; most were Grade 1 or 2. Six out of 12 patients had tumour size reductions; durable stable disease was achieved in three patients including one with EGFR/HER1 exon 19 and T790 M mutations. Peak plasma concentrations of afatinib were reached 3-4 h after administration and declined with a half-life of 30-40 h. Afatinib 50 mg/day was well tolerated with an acceptable safety profile during Phase I. Conclusion: Recommended dose for Phase II was defined as 50 mg/day for Japanese patients; the same as for non-Japanese patients.
  • Author:
    Gurtner K; Hessel F; Eicheler W; Doerfler A; Zips D; Heider K-H; Krause M; Baumann M
    Title:
    Combined treatment of the immunoconjgate bivatuzumab mertansine and fractionated irradiation improves local tumour control in vivo.
    Source:
    Radiother Oncol 102 (3), 444-449 (2012)
    Abstract:
    Background and purpose: To test whether BIWI 1 (bivatuzumab mertansine), an immunoconjugate of the humanized anti-CD44v6 monoclonal antibody BIWA 4 and the maytansinoid DM1, given simultaneously to fractionated irradiation improves local tumour control in vivo compared with irradiation alone. Material and methods: For growth delay, FaDu tumours were treated with 5 intravenous injections (daily) of phosphate buffered saline (PBS, control), BIWA 4 (monoclonal antibody against CD44v6) or BIWI 1 (bivatuzumab mertansine) at two different dose levels (50 ?g/kg DM1 and 100 ?g/kg DM1). For local tumour control, FaDu tumours received fractionated irradiation (5f/5d) with simultaneous PBS, BIWA 4 or BIWI 1 (two dose levels). Results: BIWI 1 significantly improved local tumour control after irradiation with 5 fractions already in the lower concentration. The dose modifying factor of 1.9 is substantial compared to the majority of other modifiers of radiation response. Conclusion: Because of the magnitude of the curative effect, this approach is highly promising and should be further evaluated using similar combinations with improved tumour-specificity.
  • Author:
    Lavilla-Alonso S; Bauer MMT; Abo-Ramadan U; Ristimaeki A; Halavaara J; Desmond RA; Wang D; Escutenaire S; Ahtiainen L; Saksela K; Tatlisumak T; Hemminki A; Pesonen S
    Title:
    Macrophage metalloelastase (MME) as adjuvant for intra-tumoral injection of oncolytic adenovirus and its influence on metastases development.
    Source:
    Cancer Gene Ther 19 (2), 126-134 (2012)
    Abstract:
    Oncolytic adenoviruses are a promising treatment alternative for many advanced cancers, including colorectal cancer. However, clinical trials have demonstrated that single-agent therapy in advanced tumor masses is rarely curative. Poor spreading of the virus through tumor tissue is one of the major issues limiting efficacy. As oncolytic viruses kill preferentially cancer cells, high extracellular matrix (ECM) content constitutes potential barriers for viral penetration within tumors. In this study, the ECM-degrading proteases relaxin, hyaluronidase, elastase and macrophage metalloelastase (MME) were tested for their antitumor efficacy alone and in combination with oncolytic adenovirus. MME improved the overall antitumor efficacy of oncolytic adenovirus in subcutaneous HCT116 xenografts. In a liver metastatic colorectal cancer model, intra-tumoral treatment of primary tumors from HT29 cells with MME monotherapy or with oncolytic adenovirus inhibited tumor growth. Combination therapy showed no increased mortality in comparison with either monotherapy alone. Contradictory results of effects of MME on tumorigenesis and metastasis formation have been reported in the literature. This study demonstrates for the first time in a metastatic animal model that MME, as a monotherapy or in combination with oncolytic virus, does not increase tumor invasiveness. Co-administration of MME and oncolytic adenovirus may be a suitable approach for further optimization aiming at clinical applications for metastatic colorectal cancer.
  • Author:
    Arrieta O; Cardona AF; Federico Bramuglia G; Gallo A; Campos-Parra AD; Serrano S; Castro M; Aviles A; Amorin E; Kirchuk R; Cuello M; Borbolla J; Riemersma O; Becerra H; Rosell R
    Title:
    Genotyping non-small cell lung cancer (NSCLC) in latin America.
    Source:
    J Thorac Oncol 6 (11), 1955-1959 (2011)
    Abstract:
    Introduction: Frequency of mutations in EGFR and KRAS in non-small cell lung cancer (NSCLC) is different between ethnic groups; however, there is no information in Latin-American population. Methods: A total of 1150 biopsies of NSCLC patients from Latin America (Argentina, Colombia, Peru, and Mexico) were used extracting genomic DNA to perform direct sequencing of EGFR gene (exons 18 and 21) and KRAS gene in 650 samples. In Mexico, Scorpions ARMS was also used to obtain a genetic profile. Results: We report the frequency of mutations in EGFR and KRAS genes in four Latin-American countries (n = 1150). Frequency of EGFR mutations in NSCLC was 33.2% (95% confidence interval [CI] 30.5-35.9) (Argentina 19.3%, Colombia 24.8%, Mexico 31.2%, and Peru 67%). The frequency of KRAS mutations was 16.6% (95% CI 13.8-19.4). EGFR mutations were independently associated with adenocarcinoma histology, older age, nonsmokers, and absence of KRAS mutations. Overall response rate to tyrosine kinase inhibitors in EGFR-mutated patients (n = 56) was 62.5% (95% CI 50-75) with a median overall survival of 16.5 months (95% CI 12.4-20.6). Conclusions: Our findings suggest that the frequency of EGFR mutations in Latin America lies between that of Asian and Caucasian populations and therefore support the genetic heterogeneity of NSCLC around the world.
  • Author:
    Vermorken J; Rottey S; Ehrnrooth E; Pelling K; Lahogue A; Machiels J
    Title:
    A Phase Ib open-label study to assess contionuous oral treatment with afatinib (BIBW 2992) in combination with two chemotherapy regimens - cisplatin plus paclitaxel and cisplatin plus 5-fluorouracil in patients, with advanced solid tumours.
    Source:
    Eur J Cancer 47 (Supp.[1]), S145 (2011)
  • Author:
    Finocchiaro G; Santoro A; Grossi F; Bidoli P; Favaretto A; Clementi L; Massey D; Lorence R; Cappuzzo F
    Title:
    Phase II study of afatinib (BIBW 2992), an irreversible ErbB family blocker, in patients with EGFR FISH-positive advanced NSCLC.
    Source:
    Eur J Cancer 47 (Suppl.[1]), S593-S594 (2011)
  • Author:
    Pagnamenta A; Lise S; Deng A; Taylor JC; Harrison V; Kini U; Stewart H; Quaghebeur G; Keays DC
    Title:
    Exome sequencing in patients with rare cortical malformations.
    Source:
    J Med Genet 48 (Suppl.[1]), S75 (2011)
  • Author:
    Ledermann JA; Hackshaw A; Kaye S; Jayson G; Gabra H; McNeish I; Earl H; Perren T; Gore M; Persic M; Adams M; James L; Temple G; Merger M; Rustin G
    Title:
    Randomized phase II placebo-controlled trial of maintenance therapy using the oral triple angiokinase inhibitor BIBF 1120 after chemotherapy for relapsed ovarian cancer
    Source:
    J Clin Oncol 29 (28), 3798-3804 (2011)
    Abstract:
    Purpose: Inhibiting angiogenesis is one of the most promising avenues for new therapies for ovarian cancer. We investigated the efficacy and safety of a novel agent, BIBF 1120, a triple angiokinase inhibitor, after chemotherapy for relapsed disease. Patients and Methods: We conducted a randomized, double-blind, controlled phase II trial in 83 patients who had just completed chemotherapy for relapsed ovarian cancer, with evidence of response, but at high risk of further early recurrence. The patients were randomly assigned to receive maintenance therapy using BIBF 1120 250 mg or placebo, twice per day, continuously for 36 weeks. End points were progression-free survival (PFS), toxicity, and overall survival. Results: Thirty-six-week PFS rates were 16.3% and 5.0% in the BIBF 1120 and placebo groups, respectively (hazard ratio, 0.65; 95% CI, 0.42 to 1.02; P =.06). Four patients continued on BIBF 1120, including two patients for another year or more. The proportion of patients with any grade 3 or 4 adverse events was similar between the groups (34.9% for BIBF 1120 v 27.5% for placebo; P =.49; mostly grade 3). However, more patients on BIBF 1120 experienced diarrhea, nausea, or vomiting (mainly grade 1 or 2 and no grade 4). There was a higher rate of grade 3 or 4 hepatotoxicity in patients on BIBF 1120 (51.2%) compared with patients on placebo (7.5%; P < .001), but this was rarely of clinical significance, and patients continued with the trial treatment. A single-level dose reduction to 150 mg was made in 15 patients, all on active drug. Conclusion: BIBF 1120 is well tolerated and associated with a potential improvement in PFS. The observed treatment effect is sufficient to justify further study within a large phase III trial.
  • Author:
    Heider K-H; Kiefer K; Zenz T; Volden M; Stilgenbauer S; Ostermann E; Baum A; Lamche H; Kuepcue Z; Jacobi A; Mueller S; Hirt U; Adolf GR; Borges E
    Title:
    A novel Fc-engineered monoclonal antibody to CD37 with enhanced ADCC and high proapoptotic activity for treatment of B-cell malignancies.
    Source:
    Blood 118 (15), 4159-4168 (2011)
    Abstract:
    The tetraspanin CD37 is widely expressed in B-cell malignancies and represents an attractive target for immunotherapy with mAbs. We have chimerized a high-affinity mouse Ab to CD37 and engineered the CH2 domain for improved binding to human Fc?receptors. The resulting mAb 37.1 showed high intrinsic proapoptotic activity on malignant B cells accompanied by homotypic aggregation. Furthermore, the Ab-mediated high Ab-dependent cell-mediated cytotoxicity (ADCC) on lymphoma and primary CLL cells. mAb 37.1 strongly depleted normal B cells as well as spiked B-lymphoma cells in blood samples from healthy donors as well as malignant B cells in blood from CLL patients. In all assays, mAb 37.1 was superior to rituximab in terms of potency and maximal cell lysis. A single dose of mAb CD37.1 administered to human CD37- transgenic mice resulted in a reversible, dose-dependent reduction of peripheral B cells. In a Ramos mouse model of human B-cell lymphoma, administration of mAb 37.1 strongly suppressed tumor growth. Finally, a surrogate Fc-engineered Ab to macaque CD37, with in vitro proapoptotic and ADCC-activities very similar to those ofmAb 37.1, induced dose-dependent, reversible B-cell depletion in cynomolgus monkeys. In conclusion, the remarkable preclinical pharmacodynamic and antitumor effects of mAb 37.1 warrant clinical development for B-cell malignancies.
  • Author:
    Schoeffski P; Awada A; Dumez H; Gil T; Bartholomeus S; Wolter P; Toton M; Fritsch A; Glomb P; Munzert G
    Title:
    A phase 1 dose-escalation study of the novel Polo-like kinased inhibitor volasertib (BI 6727) in patients with advanced solid tumours.
    Source:
    Eur J Cancer 48 (2), 179-186 (2012)
    Abstract:
    Background: Volasertib (BI 6727) is a potent and selective cell-cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinase (Plk). This phase I dose-escalation study evaluated the maximum tolerated dose (MTD) of volasertib, safety and efficacy, and pharmacokinetic (PK) parameters. Methods: This trial followed an open-label, toxicity-guided dose-titration design. Patients with progressive advanced or metastatic solid tumours received a single 1-h infusion of volasertib every 3 weeks. A total of 65 patients were treated at doses of 12-450 mg. Results: Reversible haematological toxicity was the main side-effect; thrombocytopenia, neutropenia, and febrile neutropenia constituting the main dose-limiting events. Anaemia (all grades 22%; grade 3: 8%), neutropenia (15%; grade 3/4: 14%), fatigue (15%; grade 3: 2%), and thrombocytopenia (14%; grade 3/4: 14%) were the most frequent drug-related adverse events. The MTD was 400 mg; however, 300 mg was the recommended dose for further development based on overall tolerability. Three patients achieved confirmed partial response. Stable disease as best response was reported in 40% of patients. Two patients remained progression free for >1 year. PK analysis showed no indication of deviation from 'dose-linear PK' behaviour, a large volume of distribution (>4000 l), moderate clearance and a long half-life (?111 h). Conclusion: This first-in-man trial demonstrated a favourable PK profile of volasertib, with manageable toxicities. As expected, the most common events were haematological. Encouraging preliminary antitumour activity has been observed, supporting Plk inhibition as a therapeutic approach. Clinical development of volasertib in phase II monotherapy and combination trials is ongoing.
  • Author:
    Bogenrieder Th; Herlyn M
    Title:
    The molecular pathology of cutaneous melanoma.
    Source:
    Cancer Biomarkers 9 (1-6), 267-286 (2011)
    Abstract:
    Cutaneous melanoma is a highly aggressive cancer with still limited, but increasingly efficacious, standard treatment options. Recent preclinical and clinical findings support the notion that cutaneous melanoma is not one malignant disorder but rather a family of distinct molecular diseases. Incorporation of genetic signatures into the conventional histopathological classification of melanoma already has great implications for the management of cutaneous melanoma. Herein, we review our rapidly growing understanding of the molecular biology of cutaneous melanoma, including the pathogenic roles of the mitogen-associated protein kinase (MAPK) pathway, the phosphatidylinositol 3 kinase [PI3K]/phosphatase and tensin homologue deleted on chromosome 10 [PTEN]/Akt/mammalian target of rapamycin [mTOR])PTEN (phosphatase and tensin homolog) pathway, MET (hepatocyte growth factor), Notch signaling, and other key molecules regulating cell cycle progression and apoptosis. The mutation Val600Glu in the BRAF oncogene (designated BRAF(V600E)) has been associated with clinical benefit from agents that inhibit BRAF(V600E) or MEK (a kinase in the MAPK pathway). Cutaneous melanomas arising from mucosal, acral, chronically sun-damaged surfaces sometimes have oncogenic mutations in KIT, against which several inhibitors have shown clinical efficacy. These findings suggest that prospective genotyping of patients with melanoma, combined with the growing availability of targeted agents, which can be used to rationally exploit these findings, should be used increasingly as we work to develop new and more effective treatments for this devastating disease.
  • Author:
    Ioannou N; Dalgleish AG; Seddon AM; Mackintosh D; Guertler U; Solca F; Modjtahdi H
    Title:
    Anti-tumour activity of afatinib, an irreversible ErbB family blocker, in human pancreatic tumor cells.
    Source:
    Br J Cancer 105 (10), 1554-1562 (2011)
    Abstract:
    Background:The combination of the reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) erlotinib with gemcitabine obtained FDA approval for treating patients with pancreatic cancer. However, duration of response is often limited and there is currently no reliable predictive marker. Methods:We determined the sensitivity of a panel of human pancreatic tumour cell lines to treatment with afatinib, erlotinib, monoclonal antibody (mAb) ICR62, and gemcitabine, using the Sulforhodamine B colorimetric assay. The effect of these agents on cell signalling and cell-cycle distribution was determined by western blot and flow cytometry, respectively. Results:At 200 nM, ICR62 had no effect on growth of these tumour cells with the exception of BxPC-3 cells. BxPC-3 cells were also sensitive to treatment with afatinib and erlotinib with respective IC50 values of 11 and 1200 nM. Compared with erlotinib, afatinib was also more effective in inhibiting the growth of the other human pancreatic tumour cell lines and in blocking the EGF-induced phosphorylation of tyrosine, EGFR, MAPK, and AKT. When tested in BxPC-3 xenografts, afatinib induced significant delay in tumour growth. Conclusion:The superiority of afatinib in this study encourages further investigation on the therapeutic potential of afatinib as a single agent or in combination with gemcitabine in pancreatic cancer.
  • Author:
    Dolznig H; Puri Ch; Rupp Ch; Wieser E; Kerjaschki D; Garin-Chesa P; Haslinger Ch; Schweifer N
    Title:
    Modeling colon adenocarcinomas in vitro: A 3D co-culture system induces cancer-relevant pathways upon tumor cell and stromal fibroblast interaction.
    Source:
    Am J Pathol 179 (3), 487-501 (2011)
    Abstract:
    Activated tumor stroma participates in tumor cell growth, invasion, and metastasis. Normal fibroblasts and cancer-associated fibroblasts (CAFs) have been shown to display distinct gene expression signatures. This molecular heterogeneity may influence the way tumor cells migrate, proliferate, and survive during tumor progression. To test this hypothesis and to better understand the molecular mechanisms that control these interactions, we established a three-dimensional (3D) human cell culture system that recapitulates the tumor heterogeneity observed in vivo. Human colon tumor cells were grown as multicellular spheroids and subsequently co-cultured with normal fibroblasts or CAFs in collagen I gels. This in vitro model system closely mirrors the architecture of human epithelial cancers and allows the characterization of the tumor cellstroma interactions phenotypically and at the molecular level. Using GeneChip analysis, antibody arrays, and enzyme-linked immunosorbent assays, we demonstrate that the interaction of colon cancer cells with stromal fibroblasts induced different highly relevant cancer expression profiles. Genes involved in invasion, extracellular matrix remodeling, inflammation, and angiogenesis were differentially regulated in our 3D carcinoma model. The modular setup, reproducibility, and robustness of the model make it a powerful tool to identify target molecules involved in signaling pathways that mediate paracrine interactions in the tumor microenvironment and to validate the influence of these molecular targets during tumor growth and invasion in the supporting stroma.
  • Author:
    Zuber J; Shi J; Wang E; Rappaport AR; Herrmann H; Sison EA; Magoon D; Qi J; Blatt K; Wunderlich M; Taylor MJ; Johns C; Chicas A; Mulloy JC; Kogan SC; Brown P; Valent P; Bradner JE; Lowe SW; Vakoc CR
    Title:
    RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia.
    Source:
    Nature 478 (7370), 524-528 (2011)
    Abstract:
    Epigenetic pathways can regulate gene expression by controlling and interpreting chromatin modifications. Cancer cells are characterized by altered epigenetic landscapes, and commonly exploit the chromatin regulatory machinery to enforce oncogenic gene expression programs. Although chromatin alterations are, in principle, reversible and often amenable to drug intervention, the promise of targeting such pathways therapeutically has been limited by an incomplete understanding of cancer-specific dependencies on epigenetic regulators. Here we describe a non-biased approach to probe epigenetic vulnerabilities in acute myeloid leukaemia (AML), an aggressive haematopoietic malignancy that is often associated with aberrant chromatin states. By screening a custom library of small hairpin RNAs (shRNAs) targeting known chromatin regulators in a genetically defined AML mouse model, we identify the protein bromodomain-containing 4 (Brd4) as being critically required for disease maintenance. Suppression of Brd4 using shRNAs or the small-molecule inhibitor JQ1 led to robust antileukaemic effects in vitro and in vivo, accompanied by terminal myeloid differentiation and elimination of leukaemia stem cells. Similar sensitivities were observed in a variety of human AML cell lines and primary patient samples, revealing that JQ1 has broad activity in diverse AML subtypes. The effects of Brd4 suppression are, at least in part, due to its role in sustaining Myc expression to promote aberrant self-renewal, which implicates JQ1 as a pharmacological means to suppress MYC in cancer. Our results establish small-molecule inhibition of Brd4 as a promising therapeutic strategy in AML and, potentially, other cancers, and highlight the utility of RNA interference (RNAi) screening for revealing epigenetic vulnerabilities that can be exploited for direct pharmacological intervention.
  • Author:
    Nieves D; Isla D; Gonzalez-Rojas N; Brosa M; Finnern HW
    Title:
    Treatment patterns, use of resources, and costs of advanced non-small-cell lung cancer patients in Spain: results from a Delphi panel.
    Source:
    Clin Transl Oncol 13 (7), 460-471 (2011)
    Abstract:
    Approximately 80-85% of lung cancer patients are diagnosed with non-small-cell lung cancer (NSCLC), of which 50% of patients present with advanced or metastatic disease. The objective of this study was to describe treatment patterns, use of resources and costs associated with treating advanced or metastatic NSCLC patients in Spain. A two-round Delphi consensus panel of clinical experts was carried out to describe local clinical patterns based on treatment algorithms from SEOM and ASCO treatment guidelines. The panel consisted of 19 oncologists and 1 hospital pharmacist, who were asked during the first round to define therapeutic pathways for NSCLC by the patients' performance status, age and histology; to quantify the use of resources associated with the preparation and administration of anticancer pharmacotherapy; management of adverse events associated with anticancer pharmacotherapy; and best supportive care (BSC). The second round was used to try to reduce the variability of responses in some questions and to further describe differences between intravenous and oral therapy. 2009 unit costs were applied to the use of resources described by the clinical experts. The perspective of the study was from the Spanish National Healthcare System. Performance status guided therapy decision and led to differences in costs. Patients with a performance status of 0-2 were expected to receive anticancer pharmacotherapy while patients with a performance status of 3-4 received BSC including analgesics and corticosteroids. Anticancer pharmacotherapies containing cisplatin or carboplatin were used preferably in first-line treatment, while the usual second- and third-line treatments were docetaxel, erlotinib or pemetrexed monotherapy. The importance of the cost of anticancer pharmacotherapy as a proportion of total healthcare costs was higher for combination therapies containing bevacizumab or pemetrexed. The anticancer pharmacotherapies associated with adverse events like febrile neutropenia or infection increased the total treatment cost. Administration costs were more relevant in regimens containing cisplatin and were low for orally administered therapies. The total cost per patient with advanced or metastatic NSCLC from starting anticancer therapy until death was estimated to be between zs11,301 and zs32,754 depending on the number of treatment lines received. In the treatment of advanced or metastatic NSCLC, healthcare costs are impacted by line of treatment, patient performance status, type of administration of therapy and adverse event management.
  • Author:
    Zuber J; Rappaport AR; Luo WJ; Wang E; Chen C; Vaseva AV; Shi JW; Weissmueller S; Fellman C; Taylor MJ; Weissenboeck M; Graeber TG; Kogan SC; Vakoc CR; Lowe SW
    Title:
    An integrated apoproach to dissecting oncogene addiction implicates a MyB-coordinated self-renewal program as essential for leukemia maintenance.
    Source:
    Genes Dev 25 (15), 1628-1640 (2011)
    Abstract:
    Although human cancers have complex genotypes and are genomically unstable, they often remain dependent on the continued presence of single-driver mutations-a phenomenon dubbed "oncogene addiction." Such dependencies have been demonstrated in mouse models, where conditional expression systems have revealed that oncogenes able to initiate cancer are often required for tumor maintenance and progression, thus validating the pathways they control as therapeutic targets. Here, we implement an integrative approach that combines genetically defined mouse models, transcriptional profiling, and a novel inducible RNAi platform to characterize cellular programs that underlie addiction to MLL-AF9-a fusion oncoprotein involved in aggressive forms of acute myeloid leukemia (AML). We show that MLL-AF9 contributes to leukemia maintenance by enforcing a Myb-coordinated program of aberrant self-renewal involving genes linked to leukemia stem cell potential and poor prognosis in human AML. Accordingly, partial and transient Myb suppression precisely phenocopies MLL-AF9 withdrawal and eradicates aggressive AML in vivo without preventing normal myelopoiesis, indicating that strategies to inhibit Myb-dependent aberrant self-renewal programs hold promise as effective and cancer-specific therapeutics. Together, our results identify Myb as a critical mediator of oncogene addiction in AML, delineate relevant Myb target genes that are amenable to pharmacologic inhibition, and establish a general approach for dissecting oncogene addiction in vivo.
  • Author:
    Agrelo R
    Title:
    X inactivation and progenitor cancer cells.
    Source:
    Cancers 3 (2), 2169-2175 (2011)
    Abstract:
    In mammals, silencing of one of the two X chromosomes is necessary to achieve dosage compensation. The 17 kb non-coding RNA called Xist triggers X inactivation. Gene silencing by Xist can only be achieved in certain contexts such as in cells of the early embryo and in certain hematopoietic progenitors where silencing factors are present. Moreover, these epigenetic contexts are maintained in cancer progenitors in which SATB1 has been identified as a factor related to Xist-mediated chromosome silencing.
  • Author:
    Bouche O; Maindrault-Goebel F; de Gramont A; Ducreux M; Lledo G; Andre Th; Stopfer P; Merger M; Amellal N
    Title:
    Phase II trial of weekly alternating sequential BIBF 1120 and Afatinib for advanced colorectal cancer.
    Source:
    Anticancer Res 31 (6), 2271-2281 (2011)
    Abstract:
    Aim: The feasibility of an alternating regimen of BIBF 1120, a potent, oral, triple angiokinase inhibitor, and afatinib (BIBW 2992), a potent ErbB family blocker, was explored in patients with advanced pretreated colorectal cancer (CRC). Patients and Methods: Patients received repeated courses of alternating 7-day treatment periods, first with BIBF 1120 250 mg twice daily and then afatinib 50 mg once daily. The primary endpoint was the objective response rate; the incidence/severity of adverse events (AEs) and pharmacokinetics (PK) were determined. Results: Forty-six patients (>= 4 prior lines, most anti-VEGF and/or -EGFR pretreated) received BIBF 1120 and afatinib. No objective responses were observed; the best response was stable disease in 20 patients (43.5%). Seven patients (15.2%) remained progression-free for >= 16 weeks. Median progression-free survival was 1.9 months; median overall survival was 5.5 months. The most frequent drug-related AEs were diarrhoea (80.4%), asthenia (47.8%), nausea (43.5%) and rash (41.3%). PK assessments did not show obvious alterations for either drug. Conclusion: Weekly alternating administration of BIBF 1120 and afatinib is feasible; however, its efficacy was limited in this highly palliative patient population. - DERWENT Abstract - 2011-28396 DRUGU T P S <<LOGINID:SSSWISFTS:20110826>> AB This study explored the feasibility of an alternating regimen of BIBF-1120 and afatinib (BIBW-2992, AFA) in 46 patients with advanced pretreated colorectal cancer (CRC). No objective responses were observed; the best response was stable disease in 20 patients. The most frequent drug-related adverse events were diarrhea, asthenia, nausea and rash. PK assessments did not show obvious alterations for either drug. In conclusion, weekly alternating administration of BIBF-1120 and AFA is feasible; however, its efficacy was limited in this highly palliative patient population. Methods 46 Patients (28 male) with advanced pretreated CRC received repeated courses of alternating 7-day treatment periods, 1st with BIBF-1120 250 mg b.i.d. and then AFA 50 mg once daily. Results No objective responses were observed, and 8 patients experienced early clinical progression, discontinuing from the study without undergoing any follow-up radiological assessment. 7 Patients had remained progression-free 16 wk after initiating treatment with BIBF-1120 and AFA. The median PFS was 1.9 mth. Median overall survival was 5.5 mth. Adverse events regardless of relatedness to study drugs included diarrhea, asthenia, nausea, rash, abdominal pain, anorexia, vomiting, pyrexia, epistaxis, constipation, general physical health deterioration, mucosal inflammation, dyspnea, jaundice, increased ALT and AST, ascites, back pain, dehydration, dry skin, headache, and peripheral edema. Plasma values of AFA after drug administration, obtained on day 8, increased during the sampling period to 26.7 ng/ml at 3 hr after intake. Plasma levels of BIBF-1120, obtained on day 15, increased during the sampling period to 20.6 ng/ml at 3 hr after intake.
  • Author:
    Sistare FD; Christensen J; Storer RD; Reddy MV; Kraynak A; Liu M; Sherratt Ph; Soper K; Degeorge JJ; Morton D; Perry R; Roth A; Turmquist S; Alden C; Keller D; Jonghe SD; Bosmans V; Marien D; van Herden M; Trela B; Bienvenu J-G; Bjurstrom S; Evans J; Kinter L; Fransson-Steen R; Brewster D; Singer Th; Slim R; Colman K; Potenta D; Turner O; Dominick M; Woicke J; Hailey JR; Myer J; Mahrt Ch; Stoltz J; Bjurstrom D; Sistare FD
    Title:
    An analysis of pharmaceutical experience with decades of rat carcinogenicity testing: Support for a proposal to modify current regulatory guidelines.
    Source:
    Toxicol Pathol 39 (4), 716-744 (2011)
    Abstract:
    Data collected from 182 marketed and nonmarketed pharmaceuticals demonstrate that there is little value gained in conducting a rat two-year carcinogenicity study for compounds that lack: (1) histopathologic risk factors for rat neoplasia in chronic toxicology studies, (2) evidence of hormonal perturbation, and (3) positive genetic toxicology results. Using a single positive result among these three criteria as a test for outcome in the two-year study, fifty-two of sixty-six rat tumorigens were correctly identified, yielding 79% test sensitivity. When all three criteria were negative, sixty-two of seventy-six pharmaceuticals (82%) were correctly predicted to be rat noncarcinogens. The fourteen rat false negatives had two-year study findings of questionable human relevance. Applying these criteria to eighty-six additional chemicals identified by the International Agency for Research on Cancer as likely human carcinogens and to drugs withdrawn from the market for carcinogenicity concerns confirmed their sensitivity for predicting rat carcinogenicity outcome. These analyses support a proposal to refine regulatory criteria for conducting a two-year rat study to be based on assessment of histopathologic findings from a rat six-month study, evidence of hormonal perturbation, genetic toxicology results, and the findings of a six-month transgenic mouse carcinogenicity study. This proposed decision paradigm has the potential to eliminate over 40% of rat two-year testing on new pharmaceuticals without compromise to patient safety.
  • Author:
    Breitenbuecher F; Hoffarth S; Gauler ThC; Stergar SL; Kasper St; Koehler J; Schuler M; Worm K; Schmid KW; Maerten A
    Title:
    Highly sensitive detection of somatic epidermal growth factor receptor (EGFR) gene mutations in circulating tumor cells (CTC) from patients with non-small cell lung cancer (NSCLC) treated with cisplatin/pemetrexed or afatinib.
    Source:
    J Thorac Oncol 6 (6) (Supp.(S)), S956-S957 (2011)
  • Author:
    Agulnik J; Chin M; Chouaid Ch; Finnern H; Vansteenkiste J; Herder GJM; Amadori D; Ek L; Lester J; Ziske C; Eriksson J
    Title:
    Describing treatment, treatment outcomes, resource use and quality of life of advanced NSCLC patients - the lung cancer economics and outcomes research (LUCEOR) studies.
    Source:
    J Thorac Oncol 6 (6) (Supp. S]), S1404-S1405 (2011)
  • Author:
    Birk M; Buerkle A; Pekari K; Maier T; Schmidt M
    Title:
    Cell cycle-dependent cytotoxicity and mitotic spindle checkpoint dependency of investigational and approved antimitotic agents.
    Source:
    Int J Cancer 130 (4), 798-807 (2012)
    Abstract:
    The mitotic spindle checkpoint (SPC) is a highly regulated mechanism in eukaryotic cells that ensures the even distribution of the duplicated genome between daughter cells. Malfunction of the SPC or deregulated expression of SPC regulatory proteins is frequently associated with a poor response to chemotherapeutic agents. We investigated various approved and investigational mitosis-specific agents, including spindle poisons, an Eg5 kinesin inhibitor, inhibitors of polo-like kinase 1 (Plk1) or Aurora-B kinase, a benzamide class HDAC inhibitor and compounds identified in a chemical genetics screen for their cell cycle-dependent cytotoxicities and for their activities toward SPC deficient (HT29, Caco-2, T47D) and SPC proficient human cell lines (A2780, HCT116, SW480). Using the RKOp27 cell system that allows inducible cell cycle arrest by the tunable expression of the cdk inhibitor p27Kip1, we found an exquisite proliferation-dependent cytotoxicity for all compounds except the aurora kinase inhibitor VX-680. Cytotoxicity of the antimitotic compounds was in general higher on SPC proficient than on deficient cells. We found two exceptions, a benzamide HDAC inhibitor which was effective on SPC proficient and deficient cells and an investigational compound, BYK72767, with a yet unknown mode of action. The degree of increased mitotic index was no predictor of cytotoxicity of the compounds nor was the phosphorylation of BubR1. However, SPC deficient cell lines were able to tolerate mitotic arrest for far longer times than SPC proficient cells. We conclude that targeting of SPC deficient cancers with novel antimitotic principles remains a challenge but certain drug classes may be equally efficacious regardless of SPC status.
  • Author:
    Reck M; Kaiser R; Eschbach C; Stefanic M; Love J; Gatzemeier U; Stopfer P; von Pawel J
    Title:
    A phase II double-blind study to investigate efficacy and safety of two doses of the triple angiokinase inhibitor BIBF 1120 in patients with relapsed advanced non-small-cell lung cancer.
    Source:
    Ann Oncol 22 (6), 1374-1381 (2011)
    Abstract:
    Background: To assess the efficacy, safety, tolerability and pharmacokinetics of BIBF 1120 in patients with stage IIIB/IV non-small-cell lung cancer (NSCLC). Methods: Patients with locally advanced or metastatic relapsed NSCLC in whom first- or second-line platinumbased chemotherapy failed were randomly allocated to daily 250 mg BIBF 1120 b.i.d. or 150 mg BIBF 1120 b.i.d. Primary end points were progression-free survival (PFS) and objective tumour response (RECIST). Incidence and severity of adverse events (AEs) were reported. Results: Seventy-three patients received BIBF 1120. Median PFS was 6.9 weeks, with no significant difference between treatment arms. Median overall survival (OS) was 21.9 weeks. Eastern Cooperative Oncology Group (ECOG) 0-1 patients (n = 56) had a median PFS of 11.6 weeks and a median OS of 37.7 weeks. Tumour stabilisation was achieved in 46% of patients (ECOG 0-1 patients: 59%), with one confirmed partial response (250 mg b.i.d.). Most commonly reported drug-related AEs were nausea (57.5%), diarrhoea (47.9%), vomiting (42.5%), anorexia (28.8%), abdominal pain (13.7%) and reversible alanine transaminase (13.7%) and aspartate aminotransferase elevations (9.6%). BIBF 1120 displayed dose-linear pharmacokinetic characteristics. Conclusion: Continuous treatment with BIBF 1120 was well tolerated, with no difference in efficacy between treatment arms. PFS and objective response with single-agent treatment in advanced disease warrants further exploration. - DERWENT ABstract - This phase II double-blind, randomized study assessed the efficacy, safety, tolerability and pharmacokinetics of BIBF 1120 in 73 patients with locally advanced or metastatic relapsed NSCLC whom failed 1st- or 2nd-line platinum-based chemotherapy. Median PFS was 6.9 wk. Median overall survival (OS) was 21.9 wk. Eastern Cooperative Oncology Group (ECOG) 0-1 patients had a median PFS of 11.6 wk, and a median OS of 37.7 wk. Tumor stabilization was achieved in 46% of patients with 1 confirmed PR. Most commonly reported drug-related adverse events were nausea, diarrhea, vomiting, anorexia, abdominal pain, and reversible ALT and AST elevations. Continuous treatment with BIBF 1120 is well tolerated, with no difference in efficacy between treatment arms, PFS and objective response with single-agent treatment in advanced disease warrants further exploration. Methods 73 Patients with locally advanced or metastatic relapsed NSCLC whom failed 1st- or 2nd-line platinum-based chemotherapy were randomized to receive BIBF 1120 at 250 mg b.i.d. (n = 36, 26 male, mean age 62.7 yr) or 150 mg b.i.d. (n = 37, 18 male, mean age 62.4 yr). Results Median PFS for all patients was 6.9 wk. Median OS for all patients was 21.9 wk. PFS was longer in patients with baseline ECOG 0-1 than in those with ECOG 2. Patients with ECOG 0-1 had a median OS of 37.7 wk. Tumor stabilization was achieved in 46% of all patients and 59% in patients with ECOG 0-1. 1 Confirmed PR was observed in patients treated with BIBF 1120 at 250 mg. 4 Patients achieved a maximum decrease of at least 25% in tumor size. Among patients with ECOG 0-1, both doses (150 and 250 mg) of BIBF 1120 had comparable efficacy with 16 and 17 patients in BIBF 1120 at 150 mg and 200 mg experiencing clinical benefit. Adverse events were nausea, diarrhea, vomiting, anorexia, abdominal pain, ALT and AST elevations, dyspnea, hemoptysis, pulmonary bleeding, gamma glutamyl transferase elevation, elevated hepatic enzymes, increased bilirubin, hemorrhage, fatigue, weight decrease, constipation, dysgeusia, and peripheral sensory neuropathy. Within the BIBF 1120 at 150 mg b.i.d. dose group, BIBF 1120 plasma levels increased, with geometric mean BIBF 1120 values of 12.3, 13.2, and 18.2 ng/ml at 1, 2 and 3 hr after drug administration. Within the BIBF 1120 at 150 mg b.i.d. dose group, BIBF 1120 plasma levels increased within the 1st 3 hr after the 1st drug administration, with geometric mean BIBF 1120 values of 18.4, 28.1, 27.8 ng/ml at 1, 2 and 3 hr after drug administration.
  • Author:
    Soto E; Staab A; Doege C; Freiwald M; Munzert G; Troconiz IF
    Title:
    Comparison of different semi-mechanistic models for chemotherapy-related neutropenia: application to BI 2536 a Plk-1 inhibitor.
    Source:
    Cancer Chemother Pharmacol 68 (6), 1517-1527 (2011)
    Abstract:
    Purpose: The aim of this investigation was to compare the performance of a commonly used semi-mechanistic model for drug-related neutropenia with other semi-mechanistic models published in the literature. Methods: After their implementation in NONMEM VI, five semi-mechanistic models were assessed using the pharmacokinetic and absolute neutrophil count data obtained from 95 patients with non-small cell lung cancer receiving either 200 mg on day 1 or 50 or 60 mg on days 1, 2 and 3 of a 21-day treatment course with the new Plk-1 inhibitor BI 2536. The model performance was compared by means of predictive (visual and numerical) checks, precision in the parameter estimates and objective function-based measures. Details of model parameterization, model stability and run times are also provided. Results: The time course of the drug plasma concentrations was described by a three compartment model with a first-order elimination rate. With respect to neutropenia, all models were successfully implemented in NONMEM and provided reasonable fits for the median (although not all models described all percentiles of the data well), and in general precise parameter estimates. Conclusion: In the current evaluation performed in a single drug, none of the models showed superior performance compared to the most commonly used model first described by Friberg et al. (J Clin Oncol 20:4713-4721, 2002).
  • Author:
    Kuc C; Jenkins A; Van Dross RT
    Title:
    Arachidonoyl ethanolamide (AEA)-induced apoptosis is mediated by J-series prostaglandins and is enhanced by fatty acid amide hydrolase (FAAH) blockade.
    Source:
    Mol Carcinog 51 (2), 139-149 (2011)
    Abstract:
    The endocannabinoid arachidonoyl ethanolamide (AEA) is a potent inducer of tumor cell apoptosis however its mechanism of cytotoxicity is unclear. A previous report from our laboratory showed that AEA induced cell death in a cyclooxygenase-2 (COX-2)-dependent manner and in this report our data indicate that AEA-induced apoptosis is mediated by COX-2 metabolic products of the J-series. In experiments conducted with JWF2 keratinocytes which over-express COX-2, AEA caused a concentration-regulated increase in J-series prostaglandin production and apoptosis. Similarly, cell treatment with exogenously added J-series prostaglandins (15-deoxy, ?12,14 PGJ2 and PGJ2) induced apoptosis. AEA-induced apoptosis was inhibited by the antioxidant, N-acetyl cysteine, indicating that reactive oxygen species generation was required for apoptosis. Using antagonists of cannabinoid receptor 1, cannabinoid receptor 2, or transient receptor potential cation channel, subfamily V, member 1, it was observed that cannabinoid receptor inhibition did not block AEA-mediated cell death. In contrast, an inhibitor of fatty acid amide hydrolase (FAAH) potentiated AEA-induced J-series PG synthesis and apoptosis. These results suggest that the metabolism of AEA to J-series PGs regulates the induction of apoptosis in cells with elevated COX-2 levels. Our data further indicate that the proapoptotic activity of AEA can be enhanced by combining it with an inhibitor of FAAH. As such, AEA may be an effective agent to eliminate tumor cells that over-express COX-2.
  • Author:
    Song X; Varker H; Eichelbaum M; Stopfer P; Shahidi M; Wilson K; Kaiser R; Finnern HW
    Title:
    Treatment of lung cancer patients and concomitant use of drugs interacting with cytochrome p450 isoenzymes.
    Source:
    Lung Cancer (Neth) 74 (1), 103-111 (2011)
    Abstract:
    Objective: The majority of anticancer medicines used in the therapy of lung cancer patients are metabolized by cytochrome P450 (CYP450) enzymes, but little is known about the frequency of prescribed concomitant medicines interacting via the same enzyme system. This study analyzed the use of medications that could cause drug-drug interactions (inhibition or induction) in lung cancer patients before and during anticancer treatment. Research design and methods: In this retrospective cross sectional study, all lung cancer patients (ICD-9 codes 162.2-162.9, 231.2) aged ?18 years who received any anticancer medicines between 1/1/2004 and 6/30/2008 were identified in the US Thomson Reuters MarketScan® Claims Database. Patients had to have data for at least 12 months prior to (pre-period) and during their treatment, had no other cancer or use of other anticancer treatment in the pre-period. Patients with renal disease, renal failure, or liver failure were excluded. Drugs known to induce or inhibit P450 enzymes and used before and during lung cancer treatment were categorized with respect to their potency (strong, moderate, low). Results: Out of 144,959 lung cancer patients, 6647 (4.6%) patients met the study entry criteria. Mean age was 67 years, 53% were men, and mean Charlson combordity index was 3.5. 99% of patients received at least one drug known as a substrate, inhibitor or inducer of P450 (98% inhibitors, 93% inducers, 98% substrates) during the patient's anticancer treatment episode. Mean co-treatment duration with any CYP450 agent was 99 days (76% of the episode length); ?2 different CYP450 agents were prescribed during 98% of episodes, and ?10 different CYP450 agents were prescribed during 44% of episodes. Use of CYP450 agents was similar in the pre-treatment period: at least one CYP450 agent was prescribed during 99% of episodes (99% inhibitors, 79% inducers, 98% substrates). Conclusions: Drugs which may cause drug-drug interactions while affecting the CYP 450 enzymes are frequently prescribed both before and during anticancer treatment of lung cancer patients.
  • Author:
    Williams JG; Deschl U; Williams GM
    Title:
    DNA damage in fetal liver cells of turkey and chicken eggs dosed with aflatoxin B1.
    Source:
    Arch Toxicol 85 (9), 1167-1172 (2011)
    Abstract:
    The present study was undertaken to investigate the potential of the potent hepatocarcinogen aflatoxin B1 (AFB) to produce DNA damage in turkey and chicken fetal livers in ovo. Effects of a single injection of two different doses (0.062 and 6.2 ?g) of AFB were examined under both short-term (4 h) and longer-term (4 day) dosing of eggs from turkeys at 24 days and chickens at 18 days of development. Liver cells prepared from the fetuses were used to assess the extent of DNA damage by the alkaline single-cell gel electrophoresis (comet) assay. The results demonstrate that AFB produces dose-related DNA damage in the fetal livers of both turkeys and chicken at 4 h, which was reduced by 4 days. Turkey embryos appeared to be slightly more susceptible to AFB damage, although no difference in the survival between chicken and turkey fetuses was observed.
  • Author:
    Mori N; Wada A; Hirayama T; Parks ThP; Stratowa Ch; Yamamoto N
    Title:
    Activation of intercellular adhesion molecule 1 expression by helicobacter pylori is regulated by NF-kappa B in gastric epithelial cancer cells (Retraction of vol 68, pg 1806, 2000).
    Source:
    Infect Immun 79 (1), 542 (2011)
  • Author:
    Bakiri L; Reschke MO; Gefroh HA; Idarraga MH; Polzer K; Zenz R; Schett G; Wagner EF
    Title:
    Functions of Fos phosphorylation in bone homeostasis, cytokine response and tumourigenesis.
    Source:
    Oncogene 30 (13), 1506-1517 (2011)
    Abstract:
    Mice lacking c-fos develop osteopetrosis due to a block in osteoclast differentiation. Carboxy-terminal phosphorylation of Fos on serine 374 by ERK1/2 and serine 362 by RSK1/2 regulates Fos stability and transactivation potential in vitro. To assess the physiological relevance of Fos phosphorylation in vivo, serine 362 and/or serine 374 was replaced by alanine (Fos362A, Fos374A and FosAA) or by phospho-mimetic aspartic acid (FosDD). Homozygous mutants were healthy and skeletogenesis was largely unaffected. Fos C-terminal phosphorylation, predominantly on serine 374, was found important for osteoclast differentiation in vitro and affected lipopolysaccharide (LPS)-induced cytokine response in vitro and in vivo. Importantly, skin papilloma development was delayed in FosAA, Fos362A and Rsk2-deficient mice, accelerated in FosDD mice and unaffected in Fos374A mutants. Furthermore, the related Fos protein and putative RSK2 target Fra1 failed to substitute for Fos in papilloma development. This indicates that phosphorylation of serines 362 and 374 exerts context-dependent roles in modulating Fos activity in vivo. Inhibition of Fos C-terminal phosphorylation on serine 362 by targeting RSK2 might be of therapeutic relevance for skin tumours. Oncogene (2011) 30, 1506-1517; doi: 10.1038/onc.2010.542; published online 29 November 2010
  • Author:
    Ioannou I; Dalgleish AX; Seddon AM; Mackintosh D; Guertler U; Solca F; Modjtahedi H
    Title:
    Responses of human pancreatic tumour cells to treatment with anti-EGFR mAB ICR62 and the irreversible EGFR/HER1 and HER2 tyrosine kinase inhibitor BIBW2992.
    Source:
    ENA Berlin 2010, Berlin (Germany), Nov 16-19, 2010.Eur J Cancer 8 (7), 44-44 (2011)
    Abstract:
    This study investigated the growth response of human pancreatic tumor cell lines (Capan-1, Panc-1, FA-6, BxPc-3, PT-45, AsPc-1 and Miapaca-2) to treatment with anti-EGFR mAb ICR62 and BIBW-2992 and gemcitabine. Responses of pancreatic tumor cells to mAb ICR62 and BIBW-2992 was not so clear. Data indicated that no clear association between the expression levels of the EGFR family members and the response to treatment with BIBW-2992 and ICR62 was found. These results underlie the need for further investigation on the anti-tumour activity of the BIBW-2992 as a single agent and in combination with gemcitabine and/or other targeted therapies in pancreatic cancer. Methods Capan-1, Panc-1, FA-6, BxPc-3, PT-45, AsPc-1 and Miapaca-2 cells were incubated with mAb ICR62 200 nM and BIBW-2992. Results mAb ICR62 at maximum concentration of 200 nM showed no effect on growth of the tumour cell lines. Interestingly, of the 7 human pancreatic tumour cell lines examined, BXPC3 cells were highly sensitive to treatment with BIBW2992 with an IC50 value of <10 nM. The growth of other human pancreatic tumour cells was also inhibited by BIBW2992 with IC50 values ranging from 247 nM (ASPC1) to 821 nM (FA6). Mean fluorescence intensities (MFIs) for EGFR expression in these tumour cell lines was ranged from 32 (Miapaca-2) to 184 (PT45). In contrast, the levels of HER-2 expression in these cell lines were much lower and the MFI for HER-2 expression ranged from 11 (Panc-1) to 33 (Miapaca-2). Interestingly, all the human pancreatic cell lines tested were found to be negative for the expression of HER-3 and HER-4. We did not find any clear association between the expression levels of the EGFR family members and the response to treatment with BIBW-2992 and ICR62.
  • Author:
    Nolte T; Rittinghausen S; Kellner R; Krabe E; Kittel B; Rinke M; Deschl U
    Title:
    RITA -Registry of Industrial Toxicology Animal data: The application of historical control data for Leydig cell tumors in rats.
    Source:
    Exp Toxicol Pathol 63 (7-8), 645-656 (2011)
    Abstract:
    Historical data for Leydig cell tumors from untreated or vehicle treated rats from carcinogenicity studies collected in the RITA database are presented. Examples are given for analyses of these data for dependency on variables considered to be of possible influence on the spontaneous incidence of Leydig cell tumors. In the 7453 male rats available for analysis, only one case of a Leydig cell carcinoma was identified. The incidence of Leydig cell adenomas differed markedly between strains. High incidences of close to 100% have been found in F344 rats, while the mean incidence was 4.2% in Sprague-Dawley rats and 13.7% in Wistar rats. Incidences in Wistar rats were highly variable, primarily caused by different sources of animals. Mean incidences per breeder varied from 2.8 to 39.9%. Analyses for the dependency on further parameters have been performed in Wistar rats. In breeders G and I, the Leydig cell tumor incidence decreased over the observation period and with increasing mean terminal body weight. The incidence of Leydig cell tumors increased with mean age at necropsy and was higher in studies with dietary admixture compared to gavage studies. These parameters had no effect on Leydig cell tumor incidence in breeders A and B. Animals from almost all breeders had a considerably higher mean age at necropsy when bearing a Leydig cell adenoma than animals without a Leydig cell adenoma. Studies with longitudinal trimming of the testes had a higher incidence than studies with transverse trimming. The observed dependencies and breeder differences are discussed and explanations are given. Consequences for the use of historical control data are outlined. With the retrospective analyses presented here we were able to confirm the published features of Leydig cell adenomas and carcinomas. This indicates that the RITA database is a valuable tool for analyses of tumors for their biological features. Furthermore, it demonstrates that the RITA database is highly beneficial for the definition of reliable historical control data for carcinogenicity studies on a scientifically solid basis.
back to top