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Background: Cornea-derived transcript 6 (CDT6, also known as AngX) is an angiopoietin-related factor resulting in anti-tumour effect in vivo. However, a recent abstract reported that CDT6 can also induce angiogenesis and promotes tumour growth. In our previous work, CDT6 had failed to show pro- or anti-angiogenic effects. It is unknown if CDT6 expression occurs in human cancer., Materials and Methods: An array of human tumour cell lines and tumour tissues was tested for CDT6-gene expression using RT-PCR. To address the controversial role of CDT6 on angiogenesis in different tumour models, the expression levels of four factors of the angiogenic balance (VEGF, endostatin, TIMP-1 and PAI-1) were determined in CDT6-transfected and control cells of the human and murine melanoma cell lines BLM and B16-F10. Endostatin was significantly up-regulated by CDT6 expression in the human model and significantly down-regulated in the mouse model. None of 18 cell lines or 23 tumours expressed CDT6., Conclusion: This contradictory effect on endostatin expression in human and mouse models may be an explanation for the conflicting results for the effect of CDT6 expression on angiogenesis.

This paper focuses on the influence of chemoresistance on the herpes simplex virus (HSV-tk)/ganciclovir (GCV)-induced bystander effect (BE), as studied in a human small cell lung cancer (SCLC) cell line (GLC4) and its sublines with in vitro acquired resistance to adriamycin (GLC4/ADR), mitoxantrone (GLC4/MITO) and cisplatin (GLC4/CDDP). Chemoresistance for adriamycin, mitoxantrone and cisplatin significantly changed GCV sensitivity. A significant BE was found in all GLC4 cell lines. Compared to the parental GLC4 cell line, the BE was significantly higher only for the GLC4/ADR cell line. No expression of the nucleoside transporters MRP4 and MRP5 was detected. In all cell lines expression of connexin 43 was found, but modulation of gap junctional intercellular communication (GJIC) by 18-alpha-glycyrrhetinic acid did not significantly change the BE in any of the GLC4 cell lines. In conclusion, chemoresistance can influence the HSV-tk/GCV-induced BE, which seems not to be related to differences in MRP4/MRP5 expression or to differences in GJIC.

Background: The aim was to determine the maximum tolerable dose of oxaliplatin added to (oral) 5FU in irresectable rectal cancer., Patients and Methods: Nineteen patients were treated; 13 patients received 5FU/LV and 6 patients capecitabine. Oxaliplatin was administered on days 1 and 29 at dose levels 85 and 130 mg/m2. Four to seven weeks thereafter, surgery was performed., Results: In 6 patients treated with 85 mg/m2, one grade 3 elevation of liver transaminases occurred. Of 7 patients who received 130 mg/m2, 1 patient experienced a grade III thrombocytopenia and 1 patient died of neutropenic fever, probably due to an urosepsis. Six patients were treated with capecitabine, of whom 3 developed a grade III gastrointestinal toxicity. An R0 resection could be performed in 93%, a pT0-2N0 in 39%, with 2 pCR's., Conclusion: The addition of oxaliplatin at 85 mg/m2 on days 1 and 29 to radiotherapy and 5FU/LV or capecitabine in irresectable rectal cancer is feasible.

Background: The purpose of the study was to investigate whether cycle-related variations in circulating Vascular Endothelial Growth Factor (VEGF) levels would increase the metastatic potential at specific times during the menstrual cycle., Materials and Methods: VEGF levels in serum and whole blood were evaluated during the normal menstrual cycle in premenopausal women. Determination of the menstrual phase was based on hormonal measurements., Results: A total of 46 samples were taken of six menstrual cycles. Serum VEGF was inversely related with progesterone levels (r = -0.6, p = 0.012). Throughout the menstrual cycle the serum VEGF decreased indicating that the lowest VEGF level occurs during the secretory phase, which is compatible with the inverse relationship between serum progesterone and VEGF., Conclusion: These findings, however, do not suggest that individual VEGF levels can direct the optimal timing of surgical intervention in breast cancer.

Background: Intravenous administration of amifostine reduces chemotherapy-induced toxicity. Preclinical experiments showed a reduction in radiation-induced mucositis after local application of the active metabolite of amifostine (WR-1065). This study evaluated the effect of local application of WR-1065 on chemotherapy-induced oral mucositis., Patients and Methods: Non-small cell lung cancer patients treated with gemcitabine and epirubicin every 3 weeks for a maximum of five cycles were included. WR-1065 was administered during the second and third cycle as an oral rinse. Oral mucositis evaluation included WHO toxicity grading, a validated oral mucositis assessment scale (OMAS) and a questionnaire., Results: Twenty-four patients were evaluated for at least one control and one rinse cycle. Mucositis scores, pain and feeding difficulties increased from day 1 to day 15, and were not significantly different between the control and rinse cycles. Local application of WR-1065 leads to detectable quantities of WR-1065 in epithelial mucosa cells. A negative correlation between the WR-1065 concentration and OMAS score was found., Conclusion: No clinical detectable influence of WR-1065 on oral mucositis was found.

Patients with a germline mutation leading to a deficiency of the dihydropyrimidine dehydrogenase (DPD) enzyme are at risk from developing severe toxicity on the administration of 5FU-containing chemotherapy. We report on the implications of this inborn genetic error in two patients who received 5FU and oxaliplatin. A possible co-medication effect of oxaliplatin is considered, as are the consequences of screening for DPD deficiency.

Purpose: The aim of this study was to determine the relationship between survival and value of molecular markers in the primary tumour in a group of patients with irresectable rectal cancer, treated with preoperative chemo-radiotherapy., Materials and Methods: Immunohistochemistry for p53, p21, bcl-2 and Ki-67 was performed on pre-treatment biopsy specimens of 34 patients with irresectable rectal cancer. Preoperative treatment consisted of pelvic irradiation of 45-56 Gy, combined with 5FU and leucovorin (350/20 mg/m2 x 5 d; in weeks 1 and 5 during radiotherapy). The median follow-up was 38 months. Endpoints were pathological T-stage and survival after surgery., Results: Expression of p21 correlated significantly with survival (p=0.005). Survival and p21 expression also correlated significantly, when adjusted for tumour response (p=0.005, RR=4.8 (1.6-14.7))., Conclusion: Expression of p21 predicts a worse survival in irresectable rectal cancer treated with preoperative chemo-radiotherapy. No relationship was found between tumour response in chemo-radiotherapy and p53, bcl-2 or Ki-67.

Background: Cornea-derived transcript 6 (CDT6 = AngX) has been shown to have an anti-tumor effect., Materials and Methods: We transfected the murine melanoma cell line B16-F10 with the CDT6 gene and compared the sensitivity to cytostatic drugs of the resulting cell line, B16-CDT6, to that of the empty vector-transfected control cell line B16-CMV., Results: The B16-CDT6 line showed a significantly increased sensitivity to doxorubicin as well as a tendency towards a decreased sensitivity to cisplatin. To further resolve the mechanism of the increase in sensitivity to doxorubicin, we also tested the cytotoxic agents vincristine, etoposide and taxol. However no difference in sensitivity for these drugs was found between the B16-CDT6 and the control cell line., Conclusion: CDT6 increased the sensitivity to doxorubicin in a mechanism probably not related to interference with the efflux pumps MRP, Pgp or the DNA-associated target enzyme topoisomerase II. Altered gene expression induced by gene therapy might influence tumor sensitivity to chemotherapy.

Although there has been considerable experience with interferons in the treatment of malignancy and viral illnesses, acute renal failure as a side-effect of interferon treatment has rarely been reported. We present the case of a patient who developed acute on chronic renal failure 16 months after the initiation of interferon alpha 2b for a metastatic carcinoid tumor.

A 55-year-old man receiving alpha-interferon and interleukin-2 therapy for renal cell carcinoma presented with seizures and delirium. A CT-scan of the cerebrum did not reveal any disorder. Both alpha-interferon and interleukin-2 were stopped. Treatment with steroids led to complete regression of central nervous system symptomatology. We emphasize the importance of ruling out iatrogenesis in patients treated with alpha-interferon and/or interleukin-2 who display neuropsychiatric symptoms.

Occasionally long-term survival in disseminated melanoma can be obtained through chemotherapy. We treated 22 patients with disseminated melanoma with an outpatient regimen consisting of dacarbazine (DTIC) and carboplatin. Three patients had a complete response lasting 4+, 9 and 9 months (survival 4+, 10 and 16 months), respectively; 3 patients had a partial response lasting 4, 6 and 8 months (survival 6+, 11+ and 14 months), respectively. Overall response was 27% (95% confidence interval 11-50%). Toxicity was relatively mild and mainly due to nausea. In 3 patients the dose of carboplatin was reduced because of grade 4 haematological toxicity. This described easy outpatient regimen shows comparable results as other polychemotherapeutic regimens in disseminated melanoma, but with a relatively mild toxicity profile.

The reverse transcriptase polymerase chain reaction (RT-PCR) can be of clinical relevance in identifying malignant melanoma cells in blood or tissues of patients at risk for disseminated melanoma. The diagnostic value of this marker however, is still controversial. The objective of this study was to compare and quantify the difference in sensitivity of the nested RT-PCR for tyrosinase, with respect to the method utilized to produce the template c-DNA. We found a difference of a factor 10 in favor of a specific priming versus a random one. We concluded that this difference can be exploited in the analysis of blood samples. However, in the analysis of lymph node specimens, where the chance of positivity due to tyrosinase positive non-melanoma cells is much higher, the choice of a highly sensitive assay should be made with caution.

Background: The T cell receptor (TCR) is an heterodimeric protein on the cell membrane of cytotoxic T cells (CTLs). In CTLs TCRs mediate the recognition of target cells through interaction with specific, MHC class I presented peptides., Materials and Methods: As a model system to show proof of principle we chose the Jurkat/MA cell line and the HLA-A2.1 binding MAGE-3 derived peptide 271-279, as target specificity., Results: We show that this cell line can be successfully transduced with the dicistronic retroviral vector (LZRS) containing cDNAs encoding for the complete alpha and beta chains of the selected TCR. Following retroviral transduction, Jurkat/MA cells do express the anti-MAGE-3 TCR on their membrane. The transduced TCR is functional as travoductants are successfully triggered, upon stimulation with T2 cells or MAGE-3+ melanoma cells loaded with the MAGE-3 peptide., Conclusion: We conclude that TCR gene transfer is possible and it represents a powerful therapeutic tool for the genetical modification of T calls of patients sullering from cancer.

Twenty-nine patients with metastatic or T4 breast cancer who were in pathologically proven complete remission after induction chemotherapy, received intensification chemotherapy with autologous bone marrow support. Twelve patients had T4 breast cancer, 17 had metastatic disease. The median age was 42 years (27-52). Intensification consisted of cyclophosphamide 7 g/m2 i.v. and etoposide 1.5 g/m2 i.v. in 24 patients, or thiotepa 800 mg/m2 i.v. and mitoxantrone 50-75 mg/m2 i.v. in 5 patients. The median observation is 7 years. Median survival is 36 months. Ten year relapse-free survival is 20%. For patients with metastatic disease median survival is 34 months, time to relapse 18 months; two patients (12%) have survived disease-free for more than 6 years. The patients with T4 cancer have a median survival of 80 months and a median time to relapse of 53 months; four patients (33%) have survived more than 5 years disease-free.