Biomedical subjects

N H Mulder

Publications and source records attributed to N H Mulder.

At least 361 records · Page 20Linked to original sources

PubMedDate not supplied

Effect of specific or random c-DNA priming on sensitivity of tyrosinase nested RT-PCR: potential clinical relevance.

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.

Biomarkers, Tumor↗

PubMedDate not supplied

Dacarbazine DTIC and carboplatin as an outpatient treatment for disseminated malignant melanoma.

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.

Adolescent↗

PubMedDate not supplied

Delirium after interleukin-2 and alpha-interferon therapy for renal cell carcinoma.

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.

Antineoplastic Combined Chemotherapy Protocols↗

PubMedDate not supplied

Screening for infectious foci in breast cancer patients prior to high-dose chemotherapy and stem cell transplantation.

UNLABELLED: Cancer patients treated with high-dose chemotherapy (HDC) followed by peripheral stem cell transplantation are at risk for infections during neutropenia. Our standard policy was to screen for potential infectious foci prior to HDC. Screening for infectious foci consisted of chest and sinus roentgenograms and a visit to the ear-nose-throat surgeon (ENT surgeon) and the dentist. The purpose of this study was to evaluate this approach. Between 1993 and 2000, 73 breast cancer patients received HDC. RESULTS: All chest roentgenograms were normal. ENT screening yielded in three (symptomatic) patients a potential infectious focus. In 32 patients (44%) a potential dental infectious focus was diagnosed and treated. During neutropenia after HDC clinical infections occurred in 15 patients (21%). In only 5 patients (7%) the infection focus was probably the upper respiratory tract. CONCLUSION: Potential ENT infectious foci were infrequent and all were symptomatic. Potential dental infectious foci were seen quite often; whether they would have had clinical impact if left untreated remains speculative.

Adult↗

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5FU and oxaliplatin-containing chemotherapy in two dihydropyrimidine dehydrogenase-deficient patients.

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.

Aged↗

PubMedDate not supplied

Dose escalation of dacarbazine combined with interferon alpha-2a, G-CSF and ondansetron in patients with metastatic melanoma.

To define the activity of an individually escalated dacarbazine (DTIC) dose combined with interferon-alpha-2a (IFN), granulocyte-colony stimulating-factor (G-CSF) and ondansetron, 20 patients (pts) with metastatic melanoma were treated with DTIC, ondansetron 8 mg iv, G-CSF 300 micrograms sc and IFN 9 MU sc. Treatment was performed every 21 days to a maximum of 6 courses. DTIC dose was escalated with 250 mg/m2 in case of acceptable toxicity to 1250, 1500 and 1750 mg/m2 in (projected/realized), 14/19, 8/11 and 0/5 pts, respectively. Dose escalation prohibiting toxicities were thrombocytopenia (10 pts), leukopenia (9 pts), and nausea/vomiting (2 pts). Four partial remissions were observed, for a response rate of 20% (95% confidence interval, 6 to 44%). Duration of responses was 1, 2, 3 and 3 months. Median overall survival was 8 months.

Adult↗

PubMedDate not supplied

High-dose methotrexate, vincristine and cisplatin as salvage treatment for relapsed non-seminomatous germ-cell cancer.

Eight patients with non-seminomatous testicular cancer relapsing after primary chemotherapy were treated with salvage chemotherapy consisting of high-dose methotrexate (12 g/m2), vincristine (1.2 mg/m2) weekly for four weeks, followed after an interval of four weeks by 3 times 100 mg/m2 cisplatin (50 mg/m2 on day 1 and 2) every 10 days. This regimen resulted in 2 partial (PR) and 2 complete responses (CR). The two patients achieving CR remain disease-free for 43+ and 53+ months. Toxicity was mainly methotrexate-related and could be ameliorated to a large extent by leucovorin rescue. This small study shows that methotrexate, vincristine, followed by cisplatin is effective in the treatment of relapsed non-seminomatous testicular cancer at the cost of manageable toxicity.

Adult↗

PubMedDate not supplied

Long-term results of induction- and intensification chemotherapy supported with autologous bone marrow reinfusion in patients with disseminated or T4 breast 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.

Adult↗

PubMedDate not supplied

Thymidylate synthase levels in tumor biopsies from patients with colorectal cancer.

Catalytic activity and FdUMP binding characteristics of thymidylate synthase (TS) were determined in 22 tumor biopsies of patients to be treated (15) or just treated (7) for colorectal cancer with 5-fluorouracil and leucovorin. In 19 samples both parameters could be determined and were found to represent a wide range (15-20 fold). High values of activity correlated with no response, but low values of binding or activity were found in responders as well as in non-responders. It is concluded that the determination of parameters related to TS function is feasible in tumor biopsies and its relevance for clinical management deserves further study.

Adult↗

PubMedDate not supplied

Effective conditioning regimen for premenopausal patients with advanced breast cancer.

UNLABELLED: The aim of the study was to define an effective regimen as induction treatment in chemotherapy naive patients with advanced breast cancer as preparation for ablative chemotherapy. PATIENTS AND METHODS: Patients with locally advanced or metastatic breast cancer (AJCC stage IIIB or IV) received 5-fluorouracil, methotrexate with leucovorin rescue and prednisone, alternating with doxorubicin and vincristine for six cycles. Results One hundred and eleven patients were eligible. All patients were evaluable for toxicity and seventy were evaluable for response. Thirty patients achieved a complete remission (43%) and 24 a partial remission (34%). Hematological toxicity was acceptable, as in 7% of 602 treatment cycles patients were admitted for neutropenic fever. Patients with liver metastases had a higher incidence of leucopenic fever, 32% compared to 15% for all patients, and a 25% incidence of cerebellar neuropathy compared to 9% for all patients. Mucositis more severe than WHO grade I occurred in 8% of cycles. Nausea and vomiting were not severe and cardiac or renal toxicity did not occur. Thromboembolic events occurred in 7% of the patients. CONCLUSIONS: This induction regimen carries a 43% complete and 77% overall remission rate, which is high compared to other conventional and even escalated regimens. The toxicity profile is acceptable except for the higher incidence of leucopenic fever and the reversible 5-FU cerebellar syndrome in patients with liver metastases.

Adolescent↗

PubMedDate not supplied

Combined modulation by leucovorin and alpha-2a interferon of fluoropyrimidine mediated growth inhibition.

UNLABELLED: One way to improve fluoropyrimidine activity is the use of leucovorin (LV). Another way is the use of alpha-2a interferon (alpha-IF). The mechanism of the alpha-IF effect on fluoropyrimidines has not yet been elucidated. Besides, only limited data area available on double modulation (LV and alpha-IF) of fluoropyrimidines. Therefore, the modulating capacity of both drugs was tested in a fluoropyrimidine resistant (COLO 320) and a sensitive (SW 948) cell line. Also, the binding capacity of thymidylate synthase (TS) to 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP) and TS catalytic activity were studied in both cell lines as well as the effects of 5-fluorouracil (5-FU) and alpha IF on enzyme activity. COLO 320 had, compared to SW 948, a 7.5 fold higher FdUMP binding capacity to TS. TS activity was 4.4 and 11.3 fold higher at 10 and 1 mM substrate, respectively. In COLO 320 enhancement of 5-FU, either by LV or by alpha-IF, was not possible. Since LV did enhance 5-fluoro-2' deoxyuridine (FUdR) activity, it is conceivable that 5-FU mediated growth inhibition in COLO 320 is not TS mediated. SW 948 was sensitive to both modulating agents with a 2.4 fold lower IC50 for 5-FU/LV, 6.8 fold lower IC50 for 5-FU/alpha-IF and a 11.2 fold lower IC50 for 5-FU/LV/alpha-IF. Effects of LV and alpha-IF on FUdR were comparable but less pronounced, with a 3.4 fold lower IC50 for FUdR/LV/alpha-IF compared with FUdR alone. Thymidine, which circumvents TS inhibition, neutralized the synergistic effects of alpha-IF, indicating that alpha-IF enhancement is mediated via inhibition of DNA synthesis. However, no direct effects of alpha-IF on FdUMP binding or catalytic activity could be demonstrated. IN CONCLUSION: alpha-IF can increase 5-FU/LV mediated growth inhibition in fluoropyrimidine sensitive colorectal cancer cells. FdUMP binding capacity and catalytic activity of TS may predict sensitivity to (modulation of) fluoropyrimidines.

Adenocarcinoma↗

PubMedDate not supplied

The myc family of oncogenes and their presence and importance in small-cell lung carcinoma and other tumour types.

The myc family of cellular oncogenes, c-myc, N-myc, encodes three highly related, cell cycle specific, nuclear phospho-proteins. All are able to transform primary rat embryo fibroblasts when cotransfected with the c-ras oncogene. Myc family genes are differentially expressed with respect to tissue type and developmental stage and dramatic changes in their expression coincide with critical developmental transitions in many cell lineages. Their conservation as distinct genes over a large phylogenetic distance and their unique pattern of expression in developing embryos support the view that each member of the myc family may have an important and discrete biological activity. The nuclear localization and the presence of contiguous regions containing the basic region/helix-loop-helix/leucine zipper motifs suggest that myc-encoded proteins are involved in gene expression during growth and differentiation. The role of myc-oncogene amplification and/or overexpression in tumourigenesis is still not clear, but application of new biotechnological tools as transfection vectors and the antisense strategy may lead to a better understanding of the importance of the myc family of oncogenes. Transfection of cells with oncogenes in expression vectors conferring high levels of oncoprotein are used to analyze the influence of overexpression of the oncogene, while incubation with an appropriate antisense oligonucleotide leading to an inhibition of oncogene expression may give some clues to the necessity, function and importance of the oncogene. These two techniques have proven to be useful tools in the illumination of the function of these ubiquitous (proto-) oncogenes and probably will help to clarify at least a part of their role in, for instance, apoptosis, tumourigenesis and the development of resistance to antitumour drugs.

Apoptosis↗

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Review of current clinical experience with prolonged (oral) etoposide in cancer treatment.

Prolonged oral etoposide monotherapy is an effective treatment in patients with small cell lung cancer (SCLC) and refractory malignant lymphoma. It shows remarkable activity in relapsed or refractory breast and ovarian cancer (response rates up to 35% and 26%), and was also active in refractory germ cell tumours. Results in small numbers of patients with haematological malignancies merit further investigation. There is considerable pharmacokinetic variability after oral etoposide administration and further investigations are needed to establish optimal dose. Side effects (in particular leucopenia and universal alopecia) should not be underestimated, especially in elderly bad risk patients.

Administration, Oral↗

PubMedDate not supplied

Neo-adjuvant chemotherapy with carboplatin, 4-epiadriamycin and teniposide (CET) in locally advanced cancer of the cardia and the lower oesophagus: a phase II study.

Disappointing results after surgery alone for locally advanced adenocarcinoma of the cardia and the distal oesophagus (stage IIIB/IV) prompted us to combine surgery with neo-adjuvant chemotherapy. With a remission rate of about 70% the combination of etoposide, adriamycin and cisplatin (EAP) has been considered to be the superior treatment, but it has inherent severe toxicity. The authors conducted a phase II study of combined treatment with Carboplatin, 4-Epiadriamycin and Teniposide (CET) to ameliorate this toxicity and to evaluate the effectivity of this regimen in patients with these unresectable tumours. A regimen of 4 cycles of Carboplatin 300mg/m2, 4-Epiadriamycin 80mg/m2 and Teniposide 100mg/m2 was administered intravenously. Treatment cycles were repeated every 3 weeks in patients with initially unresectable adenocarcinoma of the gastro-oesophageal junction proven at laparotomy and/or CT scanning. Nineteen patients were studied and 17 underwent a second laparotomy in an attempt to resect the tumour radically. Eleven patients (65%) of the re-explored group achieved tumour reduction, enabling resection with curative intent. Recurrences, however occurred in 9 patients after a median of 9.5 (4-42) months. One patient died postoperatively as a result of pulmonary embolism. Only one patient remained free of disease after 42+ months. Leucopenia and thrombocytopenia of WHO grade 23 occurred in 58% and 37% of the patients, respectively. This regimen appears to be effective in patients with locally advanced adenocarcinoma of the cardia and the distal oesophagus. Although it can be used in an outpatient setting, the overall toxicity is relatively high and the results are comparable with other less toxic regimens.

Adult↗

PubMedDate not supplied

Clinical value of TPS, CEA and CA 15-3 in breast cancer patients.

Serum TPS, CA 15-3 and CEA levels were measured in 121 women with breast cancer. The combination of TPS (which measures tumour activity) and CA 15-3 (which measures tumour mass) had a sensitivity of 72% to detecting metastatic disease (n = 71). All 3 markers could significantly discriminate local versus distant metastatic relapsed breast cancer and TPS was more often elevated in the case of bone metastases. In a total of 46 relapsed patients and 49 situations which required therapeutic changes because of progressive disease, the response to treatment (hormonal or chemotherapy) was recorded together with tumour marker changes (25% +/-). After 3 months of therapy TPS (68%) responded earlier and faster than CEA (38%) or CA 15-3 (49%) with no progression (SD+PR+CR). The correlation with clinical deterioration after 6 months of therapy was 44% for TPS 33% for CEA and 28% for CA 15-3. In patients with bone metastases, TPS in addition to CA 15-3 could be used to monitor therapy.

Adult↗

PubMedDate not supplied

The additive effect of peripheral blood stem cells, harvested with low-dose cyclophosphamide, to autologous bone marrow reinfusion on hematopoietic reconstitution after ablative chemotherapy in breast cancer patients with localized disease.

The additive effect of peripheral blood stem cells (PBSCs) to autologous bone marrow transplantation (ABMT) on haematopoietic reconstitution, after ablative chemotherapy in patients with locally advanced breast cancer, was evaluated. Patients were treated with induction chemotherapy, followed by ablative chemotherapy consisting of mitoxantrone and thiotepa. Group I (n = 14) received ABMT and granulocyte macrophage-colony stimulating factor (GM-CSF), group II (n = 11) received ABMT, PBSCs and granulocyte-colony stimulating factor (G- CSF). PBSCs were harvested after a low-dose cyclophosphamide (750 mg/m2), followed by G-CSF. Stem cell harvest was routinely started 12 days after cyclophosphamide. Compared to group I, group II showed a significant reduction in the median number of days for leukocytes < 0.5 x 10(9)/L 4.5 days, leukocytes < 1.0 x 10(9) / l 5.5 days, platelets < 20 x 10(9)/ l 9 days and platelets < 40 x 10(9) / l 12.5 days. The median number of transfusions of platelets fell from 11.5 to 7 and of red blood cells from 8.5 to 6. The median hospitalisation duration declined from 40.5 to 30 days, fever above 38 degrees C with 7.5 days, fever above 38.5 degrees C with 4 days and antibiotic treatment with 8.5 days in group I versus group II. Improvement of haematological recovery, duration of fever and hospitalisation was observed by the addition of PBSCs, obtained after a relatively low-dose cyclophosphamide and G-CSF and stem cell pheresis on fixed days, to autologous bone marrow and growth factor in the period after ablative chemotherapy.

Adult↗

PubMedDate not supplied

Red blood cell glutathione levels in lung cancer patients treated by radiation and continuously infused carboplatin.

Intrinsic resistance in non-small cell lung cancer (NSCLC) curtails the efficacy of chemotherapy and radiotherapy. Glutathione (GSH) may be one of the factors responsible for this phenomenon as it counteracts the cytotoxic effects of platinum containing drugs and radiation. GSH levels were studied in red blood cells of seven smoking patients with NSCLC treated with continuously infused carboplatin and concomitant radiotherapy for 6 weeks. The levels of red blood cell GSH remained unchanged during prolonged combined treatment and were similar to those in non-smoking volunteers. In vitro, in a cell-free system, it was demonstrated that GSH-platinum complex formation occurred with both cisplatin and carboplatin in a time-dependent manner and that this formation decreased total GSH as measured with Tietze's method. This implies that increased consumption of GSH by platinum and free radicals produced by carboplatin and radiation, respectively, seems to induce GSH in red blood cells resulting in an unchanged total GSH level. Although GSH in red blood cells may be relevant as a detoxification pool for platinum, it had no impact on response rates in these patients with NSCLC.

Antineoplastic Agents↗

PubMedDate not supplied

Human DNA topoisomerase II: biochemistry and role in chemotherapy resistance (review).

Recently, it has been discovered that DNA topoisomerases are the target of many anti-cancer drugs which were already widely used in the clinic. Using the latest molecular biological techniques much has been learned about the function of DNA topoisomerases in normal cells and in cancer cells, and about how anticancer drugs inhibit these enzymes. In this review we present an overview of the function of human type II DNA topoisomerases, how they are inhibited by certain drugs and on how cancer cells may become resistant to these drugs.

Animals↗