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Biomedical subjects

E F Smit

Publications and source records attributed to E F Smit.

At least 73 records · Page 4Linked to original sources
PubMed1997

A quantitative reverse transcriptase polymerase chain reaction-based assay to detect carcinoma cells in peripheral blood.

The presence of tumour cells in the circulation may predict disease recurrence and metastasis. To improve on existing methods of cytological or immunocytological detection, we have developed a sensitive and quantitative technique for the detection of carcinoma cells in blood, using the reverse transcriptase polymerase chain reaction (RT-PCR) identifying transcripts of the pancarcinoma-associated tumour marker EGP-2 (KSA or 17-1A antigen). The amount of EGP2 mRNA was quantified using an internal recombinant competitor RNA standard with known concentration and which is both reversely transcribed and co-amplified in the same reaction, allowing for a reliable assessment of the initial amount of EGP2 mRNA in the sample. Calibration studies, seeding blood with MCF-7 breast carcinoma cells, showed that the assay can detect ten tumour cells among 1.0 x 10(6) leucocytes. The PCR assay revealed that normal bone marrow expresses low levels of EGP2 mRNA, although immunocytochemistry with the anti-EGP2 MAb MOC31 could not identify any positively stained cell. Analyses using this RT-PCR assay may prove to have applications to the assessment of circulating tumour cells in clinical samples.

Antigens, Neoplasm↗
PubMed1995

Oral therapy for small cell lung cancer.

After a remarkable improvement of the very poor prognosis of small cell lung cancer with very simple therapy such as iv and oral cyclophosphamide the role of oral therapy has become minimal. However, since more than a decade results of combination chemotherapy are at a plateau and it is necessary to reconsider the role of simple therapy in patients without the prospect of cure. Oral therapy might be worthwhile because it is probably less effecting the quality of life of the patient and makes it unnecessary to visit the hospital frequently. All drugs available for oral use with known activity against small cell lung cancer are reviewed. The best example of the success of oral therapy is etoposide, other candidates that need to be tested in a modern way are oral cyclophosphamide and hexamethylmelamine. New concepts of prolonged chemotherapy and dose-intensity are easier evaluated by using oral drugs. The discovery of the activity of prolonged oral etoposide is an excellent example how to test a new concept in a very simple way.

Administration, Oral↗
PubMed1995

Phase I study of high-dose epirubicin and vinorelbine in previously untreated non-small-cell lung cancer stage IIIB-IV.

The aim of the study was to determine the maximum tolerated dose (MTD) for the combination of high-dose epirubicin and vinorelbine in chemotherapy-naive patients with inoperable non-small-cell lung cancer (NSCLC). Twenty-one patients with stage IIIB and IV NSCLC were treated in a single-centre study with escalating doses of epirubicin and vinorelbine given on an outpatient basis. The first dose level comprised epirubicin 100 mg m-2 on day 1 and vinorelbine 20 mg m-2 (days 1 and 8) given intravenously every 3 weeks. Escalating doses for epirubicin and vinorelbine were respectively 120 (day 1) and 20 (days 1 and 8), 120 (day 1) and 25 (days 1 and 8) and 135 (day 1) and 25 (days 1 and 8) mg m-2. Inclusion criteria were age < or = 75 years, ECOG performance score < or = 2 and normal renal, hepatic and bone marrow functions. Dose-limiting toxicities were thrombocytopenia grade II and neutropenia grade III on day 8, febrile neutropenia, and neutropenia lasting > 7 days. No dose-limiting toxicity (DLT) was observed at the first dose level; at the 135/25 mg m-2 dose level three out of six patients had a DLT which was considered as unacceptable. The only non-haematological toxicity reaching grade III was nausea/vomiting. One patient showed cardiac toxicity. No neurotoxicity and no treatment-related deaths were seen. The maximum tolerated dose of epirubicin and vinorelbine is 135 mg m-2 (day 1) and 25 mg m-2 (days 1 and 8) respectively, causing mainly haematological toxicity. The recommended dose of epirubicin and vinorelbine for phase II studies is found to be 120 mg m-2 and 20 mg m-2 respectively.

Adult↗
PubMed1995

Teniposide for brain metastases of small-cell lung cancer: a phase II study. European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group.

PURPOSE: Here we report the results of a phase II study of teniposide, one of the most active drugs against small-cell lung cancer (SCLC), in patients with brain metastases. PATIENTS AND METHODS: Patients with SCLC who presented with brain metastases at diagnosis (n = 11) or during follow-up evaluation after treatment (n = 69) were treated with teniposide at a dose of 150 mg/m2 intravenously on days 1, 3, and 5 at 3-week intervals in an outpatient setting. Response in the brain was evaluated by brain computed tomography (CT) after two, six, and 12 courses. RESULTS: In 26 of 80 assessable patients, an intracranial response was seen, with a response rate of 33% (95% confidence interval, 22% to 44%). The median response duration was 5.4 months for patients with a complete response (CR) and 4.2 months for patients with a partial response (PR). Patients who required corticosteroids for peritumoral edema had a significantly lower response rate than patients who did not receive corticosteroids. Neurologic function at the start of treatment had a significant influence (neurologic function 1 better than 2, respectively, better than 3 and 4; P < .001), as did the number of cycles of previous chemotherapy (0 better than 1 to 5 cycles, respectively, better than > 5 cycles; P = .043). Grade 3/4 leukocytopenia and thrombocytopenia were seen in 3% and 39%, respectively, of 80 patients. Toxicity-related death was seen in eight patients, seven of whom were previously treated with chemotherapy. CONCLUSION: Teniposide is active against brain metastases of SCLC. It is a suitable drug for palliation, especially of patients without extensive pretreatment and with a good neurologic function and performance status. Patients previously treated with cranial radiotherapy are also candidates for this therapy. If systemic chemotherapy is considered for tumor progression outside the brain, radiotherapy of brain metastases might be omitted or delayed pending the effect of chemotherapy. The use of corticosteroids in patients with brain metastases treated with chemotherapy might influence the efficacy of the chemotherapy.

Adult↗
PubMed1995

Pharmacokinetics and scintigraphy of indium-111-DTPA-MOC-31 in small-cell lung carcinoma.

UNLABELLED: Radiolabeled MOC-31 retains its immunoreactivity and shows good in vivo immunolocalization to human SCLC xenografted in nude rats. METHODS: We evaluated the immunotargeting properties and safety of 111In-labeled monoclonal antibody (MAb) MOC-31 (125 MBq, 5 mg) in six patients with histologically proven small-cell lung cancer (SCLC). Scintigraphy and pharmacokinetics were performed up to 3 days after injection. RESULTS: No adverse reactions were found after injection of MAb MOC-31. Pharmacokinetics obtained from plasma radioactivity showed plasma disappearance described most properly by a monoexponential model with a mean half-life value of 17.0 +/- 1.4 hr. HPLC analysis documented the monomeric MOC-31 without evidence of immune complexes or radioactive lower molecular weight fractions. Mean 24-hr urinary excretion of radioactivity was 4.3% of the injected dose. Scintigraphy detected primary tumor or metastases in five of six patients. Localization of radioactivity in normal tissue was restricted, but additional experiments need to be performed to elucidate possible cross-reactivity of MOC-31 with normal tissue in vivo. CONCLUSION: Preliminary results justify further studies to reveal the possible usefullness of radiolabeled MOC-31 in the therapeutic and diagnostic management of SCLC.

Antibodies, Monoclonal↗
PubMed1994

[Bacteremia caused by Streptococcus salivarius and S. Milleri, and colonic carcinoma].

There is a well-known association between colon carcinoma and bacteraemia with Streptococcus bovis biotype I. There are also associations, less well known, with other streptococci of the viridans group. In three patients, a man of 44, a woman of 53 and one of 52 years old, colorectal carcinomas were diagnosed in association with bacteraemia with S. salivarius, S. milleri, and S. salivarius respectively.

Adenocarcinoma↗
PubMed1994

Surgical resection for small cell carcinoma of the lung: a retrospective study.

BACKGROUND: A retrospective review was undertaken of the survival of 21 patients with histologically proven small cell carcinoma of the lung resected between 1977 and 1991. METHODS: Twenty one patients (20 men) of median age 60 (range 44-73) years underwent surgical resection. Patients were subjected to standard clinical staging procedures. Preoperative diagnosis was small cell carcinoma of the lung in 13, non-small cell lung cancer in one, and uncertain in seven patients. Clinical staging was stage I disease in 11 and stage II in 10 patients. RESULTS: Resection included pneumonectomy in 12 cases, lobectomy in eight, and one wedge resection. Resection was complete in 16 patients. Postoperative histopathological examination confirmed small cell carcinoma of the lung in 19 specimens and mixed small cell and non-small cell carcinoma of the lung in two. Pathological staging was stage I in 11, stage II in three, and stage III in seven patients. The final pathological diagnosis of the resected specimens (n = 18) was atypical carcinoid in one, pure small cell carcinoma of the lung in 15, and mixed small cell and non-small cell carcinoma of the lung in two patients. Fourteen patients also received chemotherapy and 10 received prophylactic cranial irradiation postoperatively. Excluding the patient with a final diagnosis of atypical carcinoid, the median survival (n = 20) was 29 months (range two to 133+). Median survival for patients with pathological stage I and II disease (n = 13) was 40 months (range nine to 133+) and for patients with pathological stage III disease (n = 7) 20 months (range two to 116+). The median disease free survival was 23 months. Eleven patients relapsed between two and 101 months. There was no advantage for those patients who received postoperative chemotherapy. CONCLUSION: Curative resection offers the best chance for long term survival in patients with small cell carcinoma of the lung with very limited stage disease.

Adult↗
PubMed1994

Quantitation of DNA topoisomerase II alpha messenger ribonucleic acid levels in a small cell lung cancer cell line and two drug resistant sublines using a polymerase chain reaction-aided transcript titration assay.

BACKGROUND: We have modified a polymerase chain reaction (PCR)-aided transcript titration assay (1) in order to allow quantitation of low amounts of DNA topoisomerase II alpha mRNA in small RNA samples. EXPERIMENTAL DESIGN: The titration assay was used to quantitate the amount of DNA topoisomerase II alpha mRNA in a human small cell lung carcinoma cell line, GLC4 and its drug-resistant sublines, GLC4/ADR and GLC4/CDDP. These cell lines show differences in DNA topoisomerase II alpha protein level and DNA topoisomerase II enzyme activity. To validate the titration assay, the results were compared with the results of a DNA topoisomerase II enzyme activity assay and DNA topoisomerase II alpha northern and western blotting assays. RESULTS: Using the titration assay, we were able to quantitate DNA topoisomerase II alpha mRNA on a picogram level starting with less than 1 micrograms of total RNA/cell line. GLC4/ADR showed a markedly decreased DNA topoisomerase II alpha mRNA level that seemed to be unchanged in GLC4/CDDP when compared with the parental cell line. The results obtained with this assay are confirmed by the western blot data and are not in contradiction with the northern blot results obtained for the three cell lines. CONCLUSIONS: The DNA topoisomerase II alpha titration assay is a highly sensitive new technique to study the role of DNA topoisomerase II alpha in drug resistance and may help to identify cancer types and patients most likely to respond to DNA topoisomerase II targeted drugs. The decrease in DNA topoisomerase II alpha protein level and DNA topoisomerase II activity in GLC4/ADR may result from transcriptional down regulation of DNA topoisomerase II alpha.

Antigens, Neoplasm↗
PubMed1993

Carboplatin as second line treatment for recurrent or progressive brain metastases from small cell lung cancer.

Patients with brain metastases from small cell lung cancer (SCLC) have a poor prognosis. Although most patients die from metastatic disease outside the central nervous system, this disabling metastatic site often needs treatment to mitigate the signs and symptoms of intracranial disease. The effect of carboplatin (400 mg/m2 every 4 weeks) as second line treatment for recurrent or progressive brain metastases was studied in 20 SCLC patients. 19 patients could be evaluated: 16 by contrast enhanced brain computer tomography (CT) scan (2 patients had complete response, 6 partial response, 4 stable disease and 4 progressive disease) and 3 patients clinically, who had progressive disease. The objective response rate in the brain was 40% (95% CI:22-61%). The median response duration was 8 weeks (range 2-29). The median survival was 15 weeks (range 1-44). Previous cranial irradiation appeared to be beneficial for survival. There was only mild haematological and gastrointestinal toxicity. Carboplatin has activity against brain metastases and gives palliation in responding patients.

Adult↗
PubMed1993

Testing the possible non-cross resistance of two equipotent combination chemotherapy regimens against small-cell lung cancer: a phase II study of the EORTC Lung Cancer Cooperative Group.

The Goldie-Coldman hypothesis of alternating non-cross resistant combination chemotherapy regimens for small-cell lung cancer has never been adequately evaluated. In previously reported studies non-cross resistance and/or equipotency of the combinations used had not been tested before the phase III study was started. We describe two combination chemotherapy regimens with comparable efficacy against small-cell lung cancer and present a phase II test of their possible non-cross resistance. Patients clinically resistant to cyclophosphamide, doxorubicin and etoposide (CDE), were treated with the second-line regimen consisting of vincristine, ifosfamide, mesna and carboplatin (VIMP) (n = 25). This resulted in 1 complete and 14 partial responses, response rate 60% [95% confidence interval (CI): 38.7-78.9%]. Patients clinically resistant to vincristine, carboplatin (n = 22) or ifosfamide, mesna, carboplatin (n = 21) were treated with CDE, resulting in 6 complete responses and 16 partial responses, response rate 51% (95% CI: 35.5-66.7%). The clinical value of such a degree of non-cross resistance has to be evaluated in a phase III study.

Adult↗
PubMed1992

In vitro response of human small-cell lung-cancer cell lines to chemotherapeutic drugs; no correlation with clinical data.

Three cell lines derived from small-cell lung carcinoma (SCLC) tumors of patients who had no clinical response after treatment with a multi-drug regimen were compared to 3 cell lines derived from tumors of patients who, upon treatment, showed a complete clinical response. These 2 groups of cell lines were considered to represent the in vitro counterparts of the 2 extremes of the clinical spectrum of sensitivity for chemotherapeutic drugs in small-cell lung cancer. To assess whether the in vivo (in)sensitivity of a tumor to a certain drug regimen is retained in vitro, the cell lines were tested for drug sensitivity using the microtiter-well tetrazolium assay and the results were compared with the in vivo data. No correlation was found. Since in vitro models using cell lines are based on the assumption that a cell line reflects the properties of the tumor from which it is derived, several additional parameters such as MAb staining against different SCLC-associated antigens and DNA content were analyzed in the biopsies and the cell lines. The results showed that selection of discrete tumor-cell populations in vitro occurs. Results of in vitro chemosensitivity testing for individual SCLC patients should be interpreted with caution.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

Phase II study of high-dose epirubicin and etoposide in advanced non-small cell lung cancer.

25 consecutive patients with advanced non-small cell lung cancer (NSCLC) were treated with high-dose epirubicin (HDE) 135 mg/m2 and etoposide 60 mg/m2 (days 1-3) every 3 weeks. 121 courses, (median 6, range 1-7), were administered and evaluable for toxicity: WHO grades III/IV leukocytopenia in 60/36 (80%) courses, thrombocytopenia in 18/6 (20%) and grades II/III anaemia in 31/6 (31%). Median (range) left ventricular ejection fraction (LVEF) fell from 63% (53-73, n = 25) to 60% (48-73 n = 16) after 5 courses (P < 0.02). 2 patients had a drop of more than 15% in LVEF with an epirubicin dose of 675 mg/m2. Apart from 1 patient who had tachycardia 6 months after the last course, no patient had congestive heart failure. There were 2 complete and 7 partial responses [total 9/25 (36%, 95% confidence interval: 18-57.5%)]. Median survival is 31.8 (4.3-75) weeks. Combination HDE and etoposide in NSCLC offers no advantage over HDE alone and is more toxic.

Aged↗
PubMed1992

A phase II study of high dose epirubicin in unresectable non small cell lung cancer.

Epirubicin (EPI), a doxorubicin analogue, is reported to have equal antitumour activity with lower cardiac and systemic toxicity. Recently, the maximum tolerated dose of this drug has been revised upwards with reported increased response rates in several malignancies. We initiated a phase II study of high-dose EPI as initial treatment for patients with advanced non-small cell lung cancer (NSCLC) (stage III and IV). Between May 1988 and November 1989, 25 patients were entered. The starting dose of EPI was 135 mg m-2, with dose attenuations and escalations of 15 mg m-2 based on mid-cycle evaluation of toxicity. Treatment was repeated every 3 weeks. Nine partial responses (36%, 95% CI: 18-57.5%) and 11 patients with disease stabilisation (44%) were observed. Median (range) time to progression was 19 (3-70) weeks. Median (range) survival is 32 (9-116+) weeks. There were no treatment related deaths. Major side effects were leukocytopenia WHO grade III/IV (23% of courses) and mucositis WHO grade II/III (15% of courses). In two patients left ventricular ejection fraction decreased greater than 15% compared to baseline values after a cumulative Epirubicin dose of 435 mg m-2, and therefore went off study. In none of the patients clinical signs of congestive heart failure were observed. We conclude from our data that high-dose EPI, contrary to previous negative studies using lower doses of EPI, ranks amongst the most active regimens against advanced NSCLC. Toxicity of high-dose EPI is moderate. Further evaluation of this compound in combination regimens is recommended.

Adult↗
PubMed1992

Second-line carboplatin-based chemotherapy for small cell lung cancer: the Groningen experience.

In this report, the results of two phase II studies and one pilot study of second-line carboplatin-based chemotherapy for small cell lung cancer are described. Carboplatin plus vincristine given with or without ifosfamide resulted in response rates of 36% and 53%, respectively, in so-called chemotherapy-resistant patients. Toxicity of the carboplatin/vincristine regimen was mild (hematologic toxicity grade 4 was seen with 13% of the courses), whereas the combination including ifosfamide resulted in grade 4 thrombocytopenia in 57% of the courses and grade 4 leukocytopenia in 49%. A partial response was seen in one of nine patients with progression of brain metastases after chemotherapy, and in three patients the neurologic function score improved, with minor tumor reduction evident on computed tomography scan of the brain. We conclude that carboplatin is a useful agent for second-line chemotherapy in patients with an early relapse after induction chemotherapy.

Adult↗
PubMed1992

Phase I study of oral teniposide (VM-26).

A phase I study of teniposide administered orally for 5 consecutive days was performed. The first dose was 60 mg/m2/d, with increments of 25 mg/m2/d. Nineteen patients entered the study and received a total of 77 courses with a median of two (range, 1 to 12). Dose-limiting toxicity occurred at 160 mg/m2/d and consisted of myelosuppression, mainly leukocytopenia, and gastrointestinal toxicity. Sufficient recovery of blood counts was seen by day 21 to allow for a repeat course. Two patients, treated with teniposide doses of 110 and 160 mg/m2/d, respectively, were considered toxic deaths. Partial alopecia was frequent at doses above 85 mg/m2/d. Retching and vomiting during administration of the drug were encountered in virtually all patients. Oral teniposide 135 mg/m2/d for 5 consecutive days on a 3-week schedule is recommended for evaluation of antitumor efficacy in phase II studies.

Administration, Oral↗
PubMed1992

Treatment of brain metastases of small cell lung cancer with teniposide.

Over 50% of patients with small cell lung cancer (SCLC) will develop symptomatic brain metastases during the course of their disease. Results of whole brain radiotherapy, the standard treatment, are rather poor and relapses are frequent. Thus, new modes of therapy are urgently needed for these patients. In this study, the efficacy of teniposide was evaluated at a dose of 150 mg/m2 intravenously on days 1, 3, and 5 at 3-week intervals. In 11 of 26 evaluable patients an intracranial response was observed. Median response duration was 23 weeks (range, 9 to 50). Toxicity was acceptable, with grades 3/4 leukocytopenia and thrombocytopenia reported in 37% and 16%, respectively, of 123 courses. Therefore, teniposide is an effective agent against brain metastases of SCLC and is suitable for palliation of these patients.

Aged↗
PubMed1992

A phase I study of daily oral teniposide for 20 days.

In this phase I study, teniposide was administered orally for 20 consecutive days to patients with refractory cancers. All patients but one were pretreated. When given for 20 consecutive days, the maximum tolerated dose of teniposide was 100 mg/d. Myelosuppression was the dose-limiting toxicity, and occurred between days 17 and 31. In all patients blood counts had sufficiently recovered by day 35 to begin another 20-day course. Gastrointestinal toxicity persisted in 6 of 15 patients despite antiemetics. Total alopecia was observed in 10 of 13 patients at risk. We recommend teniposide 100 mg/d for 20 consecutive days for evaluation of antitumor efficacy in phase II studies.

Administration, Oral↗