Patient-centered developments in colon- and rectal cancer with a multidisciplinary international team: From translational research to national guidelines.

Rarely, scientific developments centered around the patient as a whole are published. Our multidisciplinary group, headed by gastrointestinal surgeons, applied this research philosophy considering the most important aspects of the diseases "colon- and rectal cancer" in the long-term developments. Good expert cooperation/knowledge at the Comprehensive Cancer Center Ulm (CCCU) were applied in several phase III trials for multimodal treatments of primary tumors (MMT) and metastatic diseases (involving nearly 2000 patients and 64 centers), for treatment individualization of MMT and of metastatic disease, for psycho-oncology/quality of life involving the patients' wishes, and for disease prevention. Most of the targets initially were heavily rejected/discussed in the scientific communities, but now have become standards in treatments and national guidelines or are topics in modern translational research protocols involving molecular biology for e.g., "patient centered individualized treatment". In this context we also describe the paths we had to tread in order to realize our new goals, which at the end were highly beneficial for the patients from many points of view. This description is also important for students and young researchers who, with an actual view on our recent developments, might want to know how medical progress was achieved.

Bone marrow transplantation nephropathy after an intensified conditioning regimen with radioimmunotherapy and allogeneic stem cell transplantation.

UNLABELLED: Intensification of the conditioning regimen with a radioactively labeled anti-CD66 antibody is feasible before allogeneic stem cell transplantation. The use of radioimmunotherapy may deliver a significant dose of radiation to the kidneys. We therefore studied the incidence and clinical picture of bone marrow transplantation (BMT) nephropathy in our patients receiving radioimmunotherapy before allogeneic stem cell transplantation. METHODS: This study was a clinical trial of 114 consecutive patients who received conditioning with a radiolabeled anti-CD66 antibody-188Re (n = 93) or 90Y (n = 21)-between 1998 and 2003. RESULTS: Although BMT nephropathy has developed in none of the patients in the [90Y]anti-CD66 group, 6 of 93 patients receiving [188Re]anti-CD66 presented with signs of BMT nephropathy at a median of 11.5 mo after stem cell transplantation. The absorbed renal dose was significantly lower in the 90Y group (4 vs. 7 Gy, P < 0.0001). Of the patients receiving [188Re]anti-CD66 who are alive, BMT nephropathy developed in 19% (6/32). Five of 6 patients with BMT nephropathy received total-body irradiation. The patients presented with elevated serum creatinine, proteinuria, anemia, hypertension, and signs of microangiopathy. All 6 patients in whom BMT nephropathy has developed are alive at a median follow-up of 58 mo after stem cell transplantation, and 1 patient has entered a dialysis program. CONCLUSION: BMT nephropathy appears to be a significant problem after allogeneic stem cell transplantation with intensified conditioning using the 188Re-labeled anti-CD66 applied in this study, particularly when combined with total-body irradiation.

A radioprotective effect of imatinib (Gleevec) in human squamous carcinoma cells.

PURPOSE: To study the radiation response-modifying effect of imatinib (Gleevec) in a squamous cell carcinoma line, PECA. MATERIAL AND METHODS: Cytotoxicity was determined by colony forming and multiplying capacity. Drug stability was shown by HPLC. Multidrug resistance phenotype was studied by rhodamine-123 efflux. Cell-cycle responses were measured by flow cytometry. Homologous recombination repair was determined by Rad51 immunohistochemistry. RESULTS: Inactivating 50% of the PECA cells required approximately 7 microM imatinib. The drug did not decay nor was it degraded during test periods. Drug efflux occurred only to a minor extent. Multiplying capacity but not survival fractions revealed a radioprotective effect of imatinib. There were only minor cell-cycle alterations in the presence of imatinib but the rate of Rad51-positive repair foci was significantly increased. CONCLUSION: PECA cells apparently lack a highly specific target for imatinib. In cells surviving at high drug concentrations, imatinib may exert a radioprotective effect on multiplying capacity by inducing DNA repair. Under prolonged exposure, drug-resistant cells may show an accelerated recovery from acute or delayed radiation damage.

The influence of bromodeoxyuridine on the induction and repair of DNA double-strand breaks in glioblastoma cells.

AIMS: To examine the dose response of DNA damage and its modification by the radiosensitizer, 5-bromo-2'-deoxyuridine (BrdU). The sensitizing mechanism is analyzed with regard to its influence on the induction and repair of DNA double-strand breaks (DSBs). MATERIAL AND METHODS: Cells from three different human glioblastoma lines, A7, LH and U87MG, were X-irradiated with and without exposure to BrdU. DNA fragments were separated by field-inversion gel electrophoresis (FIGE) and quantified by fluorometry immediately and 24 h after irradiation. RESULTS: In all cell lines, the dose response followed a linear-quadratic rather than a purely linear function. BrdU-treated cells exhibited a significantly higher amount of mobile DNA. In repair experiments with and without BrdU, the amount of mobile DNA fell close to control values within 24 h. CONCLUSIONS: The linear-quadratic model appropriately describes the X-ray-induced fragmentation of DNA. BrdU sensitizing acts predominantly by increasing DNA fragility, and not by impairing damage repair. The amount of DSBs persistent after 24 h of repair is minimal, even after highly cytotoxic doses. However, it appears to depend on the extent of initial damage, causing sensitized cells to retain more DSBs than unsensitized cells.

Enhanced renal toxicity of total body irradiation combined with radioimmunotherapy.

PURPOSE: Total body irradiation (TBI) with and without additional radioimmunotherapy (RIT) was examined for renal toxicity after stem cell transplantation. PATIENTS AND METHODS: Serum creatinine levels of 35 patients (15 female, 20 male, median age 40.5 years, range 17-60 years) after TBI alone and of 23 patients (eight female, 15 male, median age 47, range 16-58 years) after TBI with additional RIT were determined between 10/1997 and 11/1999. TBI was performed by external-beam radiotherapy in six fractions over 3 days with renal doses of 12 Gy in the TBI-alone group and 6 Gy in the group with additional RIT. The mean kidney dose due to the (188)Re-radiolabeled antibody was estimated to be 8.3 Gy (2.3-11.6 Gy). RESULTS: Within 12 months after treatment, creatinine levels increased from 77 mmol/l (SD +/- 11) to 89 mmol/l (SD +/- 20) for TBI alone and from 78 mmol/l (SD +/- 13) to 144 mmol/l (SD +/- 52) for combined TBI and RIT. CONCLUSION: Despite a 50% reduction of the external-beam contribution to the kidney dose, the application of approximately 10 GBq (188)Re-labeled anti-CD66 monoclonal antibody with a calculated renal dose of 8.3 Gy (range 2.3-11.5 Gy) led to renal toxicity, as reported previously. In the absence of a positive dose-response relationship for the (188)Re-labeled antibody, the observation may be explained by an underestimation of the biologically effective dose and the inaccuracy of the dose determination at the glomerular level.