Jochen Schütte

One vs Three Years of Adjuvant Imatinib for Operable Gastrointestinal Stromal Tumor A Randomized Trial

CONTEXT Adjuvant imatinib administered for 12 months after surgery has improved recurrence-free survival (RFS) of patients with operable gastrointestinal stromal tumor (GIST) compared with placebo. OBJECTIVE To investigate the role of imatinib administration duration as adjuvant treatment of patients who have a high estimated risk for GIST recurrence after surgery. DESIGN, SETTING, AND PATIENTS Patients with KIT-positive GIST removed at surgery were entered between February 2004 and September 2008 to this randomized, open-label phase 3 study conducted in 24 hospitals in Finland, Germany, Norway, and Sweden. The risk of GIST recurrence was estimated using the modified National Institutes of Health Consensus Criteria. INTERVENTION Imatinib, 400 mg per day, orally for either 12 months or 36 months, started within 12 weeks of surgery. MAIN OUTCOME MEASURES The primary end point was RFS; the secondary end points included overall survival and treatment safety. RESULTS Two hundred patients were allocated to each group. The median follow-up time after randomization was 54 months in December 2010. Diagnosis of GIST was confirmed in 382 of 397 patients (96%) in the intention-to-treat population at a central pathology review. KIT or PDGFRA mutation was detected in 333 of 366 tumors (91%) available for testing. Patients assigned for 36 months of imatinib had longer RFS compared with those assigned for 12 months (hazard ratio [HR], 0.46; 95% CI, 0.32-0.65; P < .001; 5-year RFS, 65.6% vs 47.9%, respectively) and longer overall survival (HR, 0.45; 95% CI, 0.22-0.89; P = .02; 5-year survival, 92.0% vs 81.7%). Imatinib was generally well tolerated, but 12.6% and 25.8% of patients assigned to the 12- and 36-month groups, respectively, discontinued imatinib for a reason other than GIST recurrence. CONCLUSION Compared with 12 months of adjuvant imatinib, 36 months of imatinib improved RFS and overall survival of GIST patients with a high risk of GIST recurrence. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00116935.

jun-B inhibits and c-fos stimulates the transforming and trans-activating activities of c-jun

We have cloned the human jun-B gene and determined its sequence and transforming and trans-activating activities. jun-B is less potent that c-jun in transforming and immortalizing primary rat embryo cells in cooperation with activated ras (effects enhanced by c-fos and TPA); unlike c-jun, jun-B does not transform Rat-1A cells alone. However, cotransfection of c-jun and jun-B into primary rat embryo cells with c-Ha-ras results in a significant decrease in transformation compared with c-jun alone, an event reversed by TPA. Cotransfection of c-jun and jun-B with or without c-fos into F9 teratocarcinoma cells results in decreased trans-activation of AP-1 compared with either gene alone. Introduction of jun-B into primary rat c-jun/ras transformants or c-jun into jun-B/ras transformants also results in a decrease in trans-activation. These findings demonstrate that, whereas jun-B and c-jun each participate in AP-1 trans-activation and malignant transformation, interactions between them involve negative regulation.

Resection of residual disease in patients with metastatic gastrointestinal stromal tumors responding to treatment with imatinib

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. Long‐term survival of patients with metastatic disease has only been observed in patients with completely resected disease. Recently, the tyrosine kinase inhibitor imatinib has been found to yield responses in the majority of patients with metastatic GIST suggesting improved resectability in responding patients. Combined treatment approaches including resective surgery after imatinib treatment in patients with advanced metastatic disease have rarely been explored. We report a series of 90 patients with metastatic GIST in whom treatment with imatinib enabled 12 patients with mostly recurrent and extensive disease to be considered for resection of residual disease. In 11 of these patients, complete resection could be achieved. Viable tumor cells were found in all but one resected specimens suggesting that despite favorable radiological or clinical responses, imatinib is unlikely to induce pathological complete responses. Until more mature data from prospective trials are available, these data suggest that an early aggressive surgical approach should be considered for all patients with metastatic GIST. Further trials investigating a combined surgical and pre/postoperative treatment with imatinib in patients with advanced metastatic GIST are warranted.

Structural and functional analysis of the cytidine deaminase gene in patients with acute myeloid leukaemia

Gene transfer of the cytidine deaminase (CDD) cDNA has recently been shown to induce cellular resistance to cytarabine (AraC) in vitro. To investigate the role for CDD in acute myeloid leukaemia (AML) we analysed the CDD activity and CDD gene structure in blast material from well‐defined patients with untreated and AraC refractory (RF) AML. Median CDD activity in previously untreated AML was significantly lower than in RF‐AML blasts (P = 0.015) and was significantly lower in patients with complete remission than with blast persistence following induction chemotherapy (P = 0.043). Structural investigation of the CDD gene by Southern analyses and RT‐PCR showed no detectable aberrations. Sequence analysis of the CDD cDNA from nine RF‐AML patients showed inconsistent aberrations in three patients. Semiquantitative assessment of CDD mRNA expression revealed a significant correlation with CDD activity. In conclusion, concordant with another recent study our data suggest a correlation of pretherapeutic CDD activity with induction treatment response. Besides the previously described prognostic impact of mdr1 expression, this result could be useful for the development of risk‐adapted AML treatment strategies and warrants further studies of CDD activity in well‐defined cohorts of AML patients and of the mechanisms involved in the regulation of CDD activity.

Efficacy of ifosfamide in refractory malignant diseases and uroprotection by mesna: results of a clinical phase II-study with 151 patients

In a clinical phase II study 151 patients with refractory malignant diseases were treated with ifosfamide (60 mg/kg/day i.v. days 1-5, q 21-28 days). Altogether, 490 courses of treatment were given, 92 with conventional prophylactic measures (continuous infusion of 3-4 litre physiological saline plus alkalinization of the urine) and 398 with mesna prophylaxis (12 mg/kg i.v., 0, 4 and 8 h after administration of ifosfamide). The overall response rate (min. 25% tumor reduction) was 67/151 (44%) including four complete remissions in a fairly unfavourable patient group with testicular teratoma (39/87), soft tissue sarcoma (10/16), malignant melanoma (2/7), osteogenic sarcoma (3/6), Ewings sarcoma (2/6), lymphoma and acute leukemia (5/7) or other histologies (6/22). The response rate in patients pretreated by cyclophosphamide containing regimen was 7/19 (36%) including one complete remission and one partial remission. Mesna was highly effective in reducing the frequency of hemorrhagic cystitis from 25/92 (27%) to 16/398 (4%) ifosfamide courses. The antitumor activity of ifosfamide in testicular cancer was not reduced by mesna. In conclusion, ifosfamide with the potent uroprotector mesna appears to compare favourably with the most active agents in the treatment of malignant diseases.

Transfer of the cytidine deaminase cDNA into hematopoietic cells

In order to investigate whether transfer of the cytidine deaminase (CDD) cDNA would increase chemotherapy resistance to cytosine arabinoside (ara-C) we used a retroviral vector expressing both, neomycin phosphotransferase and the CDD cDNA, to transduce hematopoietic cells from cell lines and from murine bone marrow (BM). After coculture on producer clones with a viral titer of 1 x 10(5) CFU/ml and up to 3-fold increased CDD enzymatic activity, WEHI-3 cell line and primary hematopoietic cells were exposed to ara-C in clonogenic assays. A transduction efficiency of 34.8 +/- 6.2% could be determined for BM clonogenic progenitor cells by G418 resistance. We could observe significantly more colonies (77 +/- 3.1%) surviving from transduced primary BM cells than from mock cells (51.7 +/- 9.3%) at 10(-8) mol/l ara-C. At 10(-7) mol/l ara-C 8.7% of BM cells became absolutely resistant after retroviral transduction. Our data confirm that CDD represents another candidate gene for increasing resistance to cytotoxic drugs in hematopoietic cells.

Analysis of the p53 gene in patients with isochromosome 17q and Ph1-positive or -negative myeloid leukemia

Increased incidence of p53 gene aberrations or chromosome 17p monosomy resulting from an isochromosome 17q [i(17q)] has been observed with transition of chronic myelogenous leukemia (CML) to myeloid blast crisis (BC), and in some patients with poor risk acute myeloid leukemia (AML) progressing from myelodysplastic syndrome (MDS). These data suggested that disease progression may be linked to bi-allelic inactivation of p53. Here, we report on p53 gene analyses of nine patients with CML-BC and AML who showed an i(17q) as characteristic cytogenetic anomaly. Using Southern blots, agarose gel electrophoresis and single-strand conformation polymorphism analyses of PCR products from genomic DNA and cDNA, spanning exons 4 through 9, we did not detect any structural abnormalities of the remaining p53 allele. These findings question the hypothesis that p53 gene alterations are the principal molecular event responsible for progression of CML chronic phase or MDS to i(17q)-positive CML-BC or AML, respectively.

Minimal deletion of 3p13-->14.2 associated with immortalization of human uroepithelial cells.

Immortalization and tumorigenic transformation of many human cell types, including human uroepithelial cells (HUCs), are frequently associated with loss of genetic material from the short arm of chromosome 3 (3p). In addition, losses of 3p have been observed in many human cancers including renal cell carcinoma, lung cancer, breast cancer, and bladder cancer. Genetic studies suggest that there are at least two regions on 3p in which tumor suppressor genes might be located, but the precise location of these genes is not known. We studied chromosome 3 losses that were specifically associated with immortalization of five independent human papilloma virus 16 (HPV16) E6‐ or E7‐transformed HUCs. Cytogenetic analysis showed that the smallest common region of deletion was 3p14.1→14.2. Fluorescence in situ hybridization using a 3p13→14‐specific yeast artificial chromosome (YAC) contig showed the precise localization of the breakpoints to be in 3p13 and 3p14.2, thus defining the smallest common overlap of 3p deletions in HPV16 E6‐ or E7‐immortalized HUCs. These results suggest the presence in this region of genes involved in the control of senescence in vitro and possibly tumorigenesis in vivo. Genes Chromosomes Cancer 21:39–48, 1998.

Risk factors for gastrointestinal stromal tumor recurrence in patients treated with adjuvant imatinib.

Little is known about the factors that predict for gastrointestinal stromal tumor (GIST) recurrence in patients treated with adjuvant imatinib.

Ifosfamide in combination chemotherapy for sarcomas and testicular carcinomas.

The efficacy of ifosfamide combination chemotherapy was studied in 164 patients, 94 with advanced testicular carcinoma and 70 with metastatic sarcoma. Ifosfamide was given at 40-60 mg/kg/day i.v. on five consecutive days every 3-4 weeks together with mesna prophylaxis with 8 mg/kg i.v. being used at 0, 4 and 8 h after ifosfamide administration. Of 70 sarcoma patients 57 were evaluable for response, of whom 49 had received prior chemotherapy. The overall response rate was 46% (26/57) including 3 complete (CR) and 14 partial remissions (PR). Ninety-four patients with germ cell tumours of the testis were treated. Of 16 seminoma patients 15 achieved CR or PR. Seventy-eight patients with nonseminomatous testicular cancer who had received previous chemotherapy were either treated with ifosfamide/etoposide (n = 63, remission rate: 30%) or ifosfamide/cisplatin (n = 15, CR + PR: 33%). These results indicate that ifosfamide alone or in combination is active in sarcomas, seminomas and teratomas and that further studies are warranted employing the drug in first-line regimens.