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Biomedical subjects

H J Keizer

Publications and source records attributed to H J Keizer.

At least 55 records · Page 3Linked to original sources
PubMed1996

Resection of residual retroperitoneal masses in testicular cancer: evaluation and improvement of selection criteria. The ReHiT study group. Re-analysis of histology in testicular cancer.

Residual retroperitoneal masses may remain after chemotherapy for metastatic non-seminomatous testicular cancer, which harbour residual tumour or totally benign tissue (necrosis/fibrosis). These residual masses may be effectively removed by a surgical resection. We evaluated current selection criteria and tried to develop alternative criteria in a data set of 544 patients, who had retroperitoneal lymph node dissection of residual masses. Six resection policies were identified from the literature. Two alternative policies were developed with logistic regression analysis. Evaluation of the policies focused on the true-positive rate (resection in case of tumour), and the false-positive rate (resection in case of necrosis). It appeared that most current policies use the size of the residual mass (> or = 10 mm or > or = 20 mm) as the predominant selection criterion. This resulted in high true-positive rates (most > 90%), but false-positive rates between 37% and 87%. The alternative policies included five well-known predictors of necrosis in addition to residual mass size (primary tumour histology, prechemotherapy levels of the three tumour markers alphafetoprotein (AFP), human chorionic gonadotropin (HCG) and lactate dehydrogenase (LDH) and mass shrinkage during chemotherapy). This strategy resulted in improved true- and false-positive rates, even when categories of the predictors were simplified for practical application. We conclude that a simple statistical model, based on a limited number of patient characteristics, provides better guidelines for patient selection than those currently used in clinical practice.

Adult↗
PubMed1996

Isolated liver perfusion with mitomycin C in the treatment of colorectal cancer metastases confined to the liver.

We evaluated the technical feasibility of isolated liver perfusion (ILP) in the treatment of patients with colorectal cancer metastases confined to the liver, and investigated whether ILP allows exposure of the tumor to high concentrations of mitomycin C (MMC). Furthermore, survival time and tumor response were studied. Nine patients were treated with 30 mg/m2 MMC recirculated for one hour in the isolated circuit. The MMC concentration in the perfusate and plasma was measured using a high-performance liquid chromatography assay. All complications directly related to the surgical procedure were treated effectively (no mortality). The peak concentration of MMC in the perfusate was 5 to 11 times higher than that measured in the plasma of patients treated with 20 to 60 mg/m2 MMC i.v., and the concentration remained significantly higher during the whole perfusion period. In contrast, the peak concentration of MMC in plasma was approximately two thirds of the lowest peak plasma level measured after i.v. administration of 10 mg/m2 MMC. No systemic toxicity was observed in any of our patients. However, four patients developed veno-occlusive disease of the liver which was mild in three but lethal in one. One of the eight evaluable patients had an objective complete response (25 months), one an objective partial response and five others a clear reduction in tumor size (25-50%). The median survival time was 17 months. This study demonstrates that ILP is technically feasible in patients, and in comparison with systemic therapy allows exposure of hepatic metastases to much higher concentrations of MMC, while systemic toxicity is absent. Remarkably, this single exposure to a high concentration of MMC resulted in a complete response and a median survival time comparable to that in recently published hepatic artery infusion studies with floxuridine and leucovorin. However, due to the hepatotoxicity we are continuing our studies with melphalan to further exploit the possible therapeutic benefit of ILP.

Adult↗
PubMed1996

Randomized placebo-controlled trial of granulocyte-macrophage colony-stimulating factor in patients with chemotherapy-related febrile neutropenia.

PURPOSE: To determine whether granulocyte-macrophage colony-stimulating factor (GM-CSF) used in addition to standard inpatient antibiotic therapy shortens the period of hospitalization due to chemotherapy-induced neutropenic fever. PATIENTS AND METHODS: One hundred thirty-four patients with a hematologic (n = 47) or solid tumor (n = 87) who had severe neutropenia (< 0.5 x 10(9)/L) and fever (> 38.5 degrees C once or > 38 degrees C twice over a 12-hour observation period) were randomly assigned to receive GM-CSF 5 micrograms/kg/d (n = 65) or placebo (n = 69) in conjunction with broad-spectrum antibiotics for a minimum of 4 days and a maximum of 14 days. GM-CSF/placebo and antibiotics were stopped if the neutrophil count was greater than 1.0 x 10(9)/L and temperature less than 37.5 degrees C during 2 consecutive days, or for a leukocyte count > or = 10 x 10(9)/L, both followed by a 24-hour observation period (hospitalization period). RESULTS: Compared with placebo, GM-CSF enhanced neutrophil recovery. Median neutrophil counts at day 4 were 2.5 x 10(9)/L (range, 0 to 25) in the GM-CSF arm and 1.3 x 10(9)/L (range, 0 to 9) in the placebo arm (P < .001). No significant difference was observed with regard to median number of days with less than 1.0 x 10(9)/L neutrophils (4 v 4) or days of fever (3 v 3). The median number of days patients were hospitalized while on study was comparable in the GM-CSF and placebo groups at 6 (range, 3 to 14) versus 7 (range, 4 to 14), respectively, according to an intention-to-treat analysis (P = .27). Quality-of-life scores in 90 patients demonstrated significant differences in favor of the placebo group. Hospital costs were significantly higher for GM-CSF-treated patients if GM-CSF was included in the price (median costs, $4,140 [US] for GM-CSF v $590 for placebo; P < .05). CONCLUSION: These results indicate that GM-CSF does not affect the number of days for resolution of fever or the hospitalization period for this patient group, although a significant effect of GM-CSF was observed on neutrophil recovery.

Adolescent↗
PubMed1995

Ifosfamide treatment as a 10-day continuous intravenous infusion.

Experimental and clinical studies on ifosfamide indicate that fractionated treatment regimens have a higher efficacy compared to a single short-term infusion. In addition, protracted continuous infusion, in general, is often less toxic without loss of antitumour activity. To study the toxicity of a 10-day continuous infusion at increasing dosages of ifosfamide and mesna, 24 patients with a variety of advanced cancers (colon 10, pancreas 5, adenocarcinoma with unknown primary 5, and 4 others) received a total of 60 cycles (range 1-6 cycles, median 2) at 3 to 4 week intervals. The ifosfamide and mesna doses ranged from 654 mg m-2 day-1 to 1562 mg m-2 day-1 for a total of ten doses. Twenty-two patients were chemotherapy-naive. Pharmacia-Deltec CADD-1 pumps and Port-a-Cath implantable venous access devices were used. The dose-limiting toxicity was leucopenia without thrombocytopenia. At a dose of 1300 mg m-2 day-1 in 30% of the cycles in 7 patients leucopenia of WHO grades 3 and 4 was observed, while at higher dosages this percentage increased to 73%. Haemoglobin values usually decreased during the infusion with a mean of 1 mmol/l (range 0.3-2.5 mmol/l), frequently with partial or full recovery by the next cycle. The next most disturbing side-effect was fatigue (50% of patients WHO grades 2 and 3), and nausea and vomiting requiring drug treatment in 75% of patients. Renal failure and haematuria did not occur. There were two catheter-related complications: thrombosis (1 patient) and mechanical obstruction (1 patient). One patient developed severe encephalopathy at day 6 (total dose 18 g ifosfamide) with complete recovery after cessation of the infusion. In summary, a tolerable ifosfamide dose using this regimen in this previously largely untreated patient group appears to be 1200-1300 mg m-2 day-1 for 10 days. Fatigue is a frequent complaint and might be explained as a kind of neurotoxicity. The treatment can be administered to outpatients.

Adult↗
PubMed1995

Prediction of residual retroperitoneal mass histology after chemotherapy for metastatic nonseminomatous germ cell tumor: multivariate analysis of individual patient data from six study groups.

PURPOSE: To develop a statistical model that predicts the histology (necrosis, mature teratoma, or cancer) after chemotherapy for metastatic nonseminomatous germ cell tumor (NSGCT). PATIENTS AND METHODS: An international data set was collected comprising individual patient data from six study groups. Logistic regression analysis was used to estimate the probability of necrosis and the ratio of cancer and mature teratoma. RESULTS: Of 556 patients, 250 (45%) had necrosis at resection, 236 (42%) had mature teratoma, and 70 (13%) had cancer. Predictors of necrosis were the absence of teratoma elements in the primary tumor, prechemotherapy normal alfa-fetoprotein (AFP), normal human chorionic gonadotropin (HCG), and elevated lactate dehydrogenase (LDH) levels, a small prechemotherapy or postchemotherapy mass, and a large shrinkage of the mass during chemotherapy. Multivariate combination of predictors yielded reliable models (goodness-of-fit tests, P > .20), which discriminated necrosis well from other histologies (area under the receiver operating characteristic (ROC) curve, .84), but which discriminated cancer only reasonably from mature teratoma (area, .66). Internal and external validation confirmed these findings. CONCLUSION: The validated models estimate with high accuracy the histology at resection, especially necrosis, based on well-known and readily available predictors. The predicted probabilities may help to choose between immediate resection of a residual mass or follow-up, taking into account the expected benefits and risks of resection, feasibility of frequent follow-up, the financial costs, and the patient's individual preferences.

Analysis of Variance↗
PubMed1994

Inhibition of fluorouracil catabolism in cancer patients by the antiviral agent (E)-5-(2-bromovinyl)-2'-deoxyuridine.

The thymidine analogue (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVdUrd), which is an antiviral agent effective against herpes simplex virus type 1 and varicella zoster virus, has also proved to be a potent inhibitor of dihydrouracil dehydrogenase, the major degrading enzyme of the anticancer drug fluorouracil (FUra). To evaluate the effect of BVdUrd on the pharmacokinetics of FUra in cancer patients, BVdUrd was administered orally at a daily dose of 250 mg (five patients) or 3 x 250 mg (five patients). FUra was infused at doses of 110-400 mg over 10 min. Blood and urine samples were collected regularly during a period of up to 50 h. BVdUrd was rapidly absorbed, peak plasma levels of 0.6-7.1 micrograms/ml being achieved after 1-2 h. Following a rapid decline, plasma BVdUrd levels remained higher than 10 ng/ml for up to 2 days after BVdUrd administration. The total body clearance of FUra was approximately 61/h and t1/2 markedly increased to 4-7 h. The mean urinary excretion of FUra was 50%. No differences in FUra kinetics were observed between patients receiving one or three oral doses of BVdUrd. We conclude that the concomitant use and subsequent interaction of FUra and the antiviral agent BVdUrd resulted in an impressive inhibition of FUra breakdown and marked increase of renal clearance. The findings indicate that the simultaneous use of FUra and drugs resembling this antiviral agent in patients may result in unexpected toxicity. Further experience with BVdUrd and new analogues might enable the development of new FUra treatment schedules and treatment designs e.g. combinations with leucovorin.

Adult↗
PubMed1994

Predictors of residual mass histology following chemotherapy for metastatic non-seminomatous testicular cancer: a quantitative overview of 996 resections.

Following chemotherapy for metastatic non-seminomatous testicular cancer, surgical resection may demonstrate that residual masses contain purely benign tissue (necrosis), or potentially malignant tissues (histologically viable cancer cells or mature teratoma). The morbidity, mortality and costs of resection demand that resection is based on empirical data rather than on subjective judgements. We reviewed 996 resections from 19 studies to quantify predictors of the histology at resection. Predictors were analysed for each study and combined in a pooled odds ratio (OR). Predictors of necrosis were: (1) a teratoma-negative primary tumour (OR = 5.1); (2) normal tumour markers before chemotherapy [alpha-fetoprotein (AFP): OR = 2.8; human chorionic gonadotrophin (HCG): OR = 1.9; both AFP and HCG: OR = 5.7]; (3) a smaller postchemotherapy abdominal mass (e.g. < or = 20 mm: OR = 3.7); (4) a large shrinkage (> or = 90%: OR = 3.1); (5) lung resections versus abdominal resections (OR = 1.7). Cancer was found in only 4% of residual retroperitoneal masses < or = 20 mm. Further research may combine the primary tumour histology, marker level and mass size to improve clinical guidelines, which define subgroups of patients for whom the benefits of resection do not outweigh the risks.

Biomarkers, Tumor↗
PubMed1993

Determination of chloroacetaldehyde, a metabolite of oxazaphosphorine cytostatic drugs, in plasma.

A derivatization high-performance liquid chromatographic method with ultraviolet detection to monitor the plasma concentration of chloroacetaldehyde, a neurotoxic metabolite of oxazaphosphorine drugs, is presented. To prevent the rapid degradation of chloroacetaldehyde, the plasma samples are stabilized with formaldehyde. The method is linear in the concentration range 1-250 nmol/ml. Blood samples from a patient who was treated with a ten-day continuous infusion of ifosfamide were assayed. The chloroacetaldehyde concentrations did not exceed 10 nmol/ml.

Acetaldehyde↗
PubMed1993

Prognosis after resection of residual masses following chemotherapy for metastatic nonseminomatous testicular cancer: a multivariate analysis.

Following chemotherapy for metastatic nonseminomatous testicular cancer, 86 patients with normal serum markers AFP and HCG underwent resection of residual tumour masses (63 laparotomy, 11 thoracotomy, 12 both). Prognostic factors for relapse and survival were analysed with Kaplan-Meier curves and Cox regression analysis. Putative prognostic factors included age, the primary histology, prechemotherapy level of the tumour markers AFP and HCG, the extent of disease (lymph nodes, lung and hepatic metastases) before and after chemotherapy, the histology of the resected material and the completeness of the surgical procedure. Eleven patients relapsed during follow-up (median 47 months), accounting for a 5 year relapse free percentage of 87.4%. Adverse prognostic factors were (1) prechemotherapy level of HCG (> or = 10,000 IU l-1; (2) incomplete resection; and (3) the extent of disease, especially of lung metastases (prechemotherapy number < or = 3,4-19, > or = 20; or size after chemotherapy > 1 cm; or presence of any residual lung metastasis after chemotherapy without residual abdominal metastases). The histology found at resection was not associated with the risk of relapse, which might be explained by the effectiveness of postresection chemotherapy, which in the majority of these patients was a salvage regimen rather than two further cycles of the initial cytostatics. A good and a poor risk group were formed, based on HCG level and completeness of resection. The effect of salvage chemotherapy after resection of viable cancer cells needs further investigation.

Adult↗
PubMed1992

Gas chromatographic determination of 2- and 3-dechloroethylifosfamide in plasma and urine.

The metabolic oxidation of one of the chloroethyl groups of the antitumour drug ifosfamide leads to the formation of the inactive metabolites 2- and 3-dechloroethylifosfamide together with the neurotoxic metabolite chloroacetaldehyde. A very sensitive capillary gas chromatographic method, requiring only 50 microliters of plasma or urine, has been developed to measure the amounts of the drug and the two inactive metabolites in a single run. Calibration curves were linear (r > 0.999) in the concentration ranges from 50 ng/ml to 100 micrograms/ml in plasma and from 100 ng/ml to 1 mg/ml in urine.

Chromatography, Gas↗
PubMed1992

Determination of N7-methylguanine in DNA of white blood cells from cancer patients treated with dacarbazine.

An ELISA method was used to determine N7-methylguanine (N7-MeGua) adducts in DNA of white blood cells from cancer patients treated with the methylating antitumor drug dacarbazine by i.v. administration. From four patients who received dacarbazine only, at dosages of 250, 400 or 800 mg/m2, the blood samples were collected before and several days after administration, and from one patient also during the first few hours. N7-MeGua levels increased rapidly during the first hour after treatment, hardly changed during the following 7 h and decreased during the next days (half-life of approximately 72 h). The adduct levels appeared to be dose-dependent. Blood cells were also analyzed from three patients who received dacarbazine (225 mg/m2) in combination with other chemotherapeutic drugs during three successive days. One of these patients showed a larger initial level of N7-MeGua and a cumulative increase with the dacarbazine dose compared to the other two patients. For several patients adduct levels were monitored during two chemotherapy cycles, for which quite similar data were obtained.

Adult↗
PubMed1992

A randomized trial of two doses of granisetron in the treatment of chemotherapy-induced emesis. Dutch results within a multinational study.

Granisetron is a new serotonin-receptor antagonist with considerable activity in preclinical models and early clinical studies against drug-induced nausea and vomiting. In a randomized, double-blind trial, two dose levels of granisetron were compared with regard to their efficacy and safety if given to patients receiving emetogenic chemotherapy with or without cisplatin. The present paper reports the Dutch experience with 125 patients included in this international trial. The two dose levels (40 and 160 micrograms/kg given once i.v. prior to chemotherapy) were equally effective in preventing acute emesis and nausea (within the first 24 h); in the group receiving cisplatin doses of 50 mg/m2 or more, 39% of patients had a complete response (no vomiting and mild nausea at most), with a complete response rate of 82% in the patients receiving moderately emetogenic chemotherapy. Sixty-three percent of patients receiving highly emetogenic chemotherapy with a complete response within 24 h lost this response during the next 6 days, as did 20% of the other patients. Headache was the most frequently reported adverse event (18%), followed by constipation (6%) and dizziness (4%). All adverse events were mild and occurred equally frequently at both dose levels. Granisetron at 40 micrograms/kg i.v. given once is effective in the prevention of acute chemotherapy-induced emesis and nausea, in particular in patients receiving moderately emetogenic therapy.

Adult↗
PubMed1991

Right ventricle wall motion abnormalities in patients treated with chemotherapy.

Doxorubicin is a cytotoxic agent used in the treatment of patients with various malignancies. Its clinical value is limited by a dose-related cardiotoxicity. Wall motion was analyzed in 52 patients during different stages of treatment. Eleven patients were studied once, and in 41 patients serial radionuclide ventriculography was performed from 2 to 5 times. Abnormal wall motion was found in 96 out of 1,062 segments (9.0%), of which 33 out of 735 (4.5%) were in the left ventricle (LV) and 65 out of 327 (19.9%) were in the right ventricle (RV). The number of abnormalities in the RV was significantly higher than in the LV (P less than 0.001). Regional analysis of LV and RV in 109 40 degrees LAO studies and in 102 75 degrees LAO studies showed abnormal wall motion in the following segments: LV--posterobasal 6 (5.9%), inferior 2 (2.0%), anterior 5 (4.9%), anteroseptal 11 (10.1%), apical 5 (4.6%), posterolateral 4 (3.7%); RV--septal 44 (40.4%), apex 15 (13.8%), and the free wall 6 (5.5%). The left ventricular ejection fraction decreased from 74% median (M) in baseline studies to 54% (M) in the highest dose group (greater than 650 mg/m2). The present data show an increased number of wall motion abnormalities in the RV compared with the LV, particularly in the RV septum (P less than 0.001).

Antineoplastic Combined Chemotherapy Protocols↗