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Biomedical subjects

S B Kaye

Publications and source records attributed to S B Kaye.

At least 127 records · Page 7Linked to original sources
PubMed1996

A pilot study of combination therapy with interferon-alpha-2a and 5-fluorouracil in metastatic carcinoid and malignant endocrine pancreatic tumours.

BACKGROUND: In view of the encouraging single agent response rates to interferon and 5-fluorouracil (5-FU) in malignant carcinoid and endocrine pancreatic tumours and the theoretical benefits of combination therapy with 5-FU and interferon in other tumours a study was designed to look at the feasibility of this combination, given for 12 months, in these tumours. PATIENTS AND METHODS: Patients were treated with 5-FU 750 mg/m2 by intravenous bolus every week and 3 Mega Units of recombinant interferon-alpha-2a subcutaneously 3 times per week increasing, as tolerated, to 6 then 9 MU. Fifteen patients were entered into the study. RESULTS: One patient died suddenly of an unrelated illness and is not assessed. None of the remaining 14 patients had radiological evidence of response to treatment, although 6 had stable disease lasting for 7 to 64 weeks (median 40 weeks). Two patients did have biochemical evidence of a response, i.e., a 50% reduction in baseline urinary 5HIAA for 26 and 52 weeks. Treatment toxicity was significant. Six patients stopped treatment prematurely because of either nausea and/or diarrhoea. Overall treatment duration ranged from 4 to 64 weeks (median 7.5 weeks). CONCLUSION: Overall we found the treatment to be disappointing in terms of tolerance and response rate and do not recommend its use in malignant carcinoid or endocrine pancreatic tumours.

Adult↗
PubMed1996

Downgaze paresis following severe head trauma in a child.

A 4 1/2-year-old girl developed a downgaze paresis following severe head trauma. Magnetic resonance imaging showed evidence of peri-aqueductal lesions in the rostral midbrain in the region of the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF). Twenty five weeks following the injury, the downgaze paresis remained unchanged but she developed convergence retraction nystagmus on attempted upgaze. Repeat imaging did not show any change in the lesions in the rostral midbrain. This report provides further evidence for the riMLF in the control of downgaze, and a synkinesis is postulated for the development of the convergence retraction nystagmus.

Child, Preschool↗
PubMed1996

Short-course adjuvant chemotherapy in high-risk stage I nonseminomatous germ cell tumors of the testis: a Medical Research Council report.

PURPOSE: This United Kingdom Medical Research Council (UK-MRC) study prospectively evaluated efficacy and long-term toxicity of adjuvant chemotherapy in high-risk stage I nonseminomatous germ cell tumors of the testis (NSGCTT). PATIENTS AND METHODS: Eligible patients were those identified by the local histopathologist as having features confirmed in MRC surveillance studies to indicate an approximate 50% risk of relapse. Central histopathology review was undertaken. Chemotherapy consisted of two courses of cisplatin 100 mg/m2, bleomycin 30 mg weekly x 3, and etoposide 120 mg/m2 x 3, every 21 days (BEP). RESULTS: One hundred fourteen eligible cases were enrolled. Median time of follow-up was 4 years, with 93 patients followed-up for at least 2 years. There have been two relapses, including one patient who did not have a germ cell tumor (GCT), according to the reference histopathologist. This patient is alive with active disease, the other has died. There was one death after a cerebrovascular accident during treatment. Assessment of fertility, lung function, and audiometry pretreatment and more than 9 months posttreatment indicated no clinically significant changes. A mean decrease in transfer factor coefficient (KCO) of 15% of the predicted value was noted, but no patient had symptomatic respiratory dysfunction. CONCLUSION: There have been only two relapses among 114 cases of high-risk stage I NSGCTT treated with two courses of adjuvant BEP chemotherapy. The 95% confidence interval (CI) excludes a true relapse rate of more than 5%. Of 104 patients confirmed on histopathology review to have GCT, there has been only one relapse. Adjuvant chemotherapy is free from significant long-term toxicity, offering an effective alternative to surveillance or retroperitoneal lymph node dissection (RPLND) followed by surveillance, and may be preferred by some patients.

Adult↗
PubMed1996

Mature results of a randomized trial of two doses of cisplatin for the treatment of ovarian cancer. Scottish Gynecology Cancer Trials Group.

PURPOSE: In 1992, we reported the first results of a randomized study in ovarian cancer, comprising two doses of cisplatin and indicated a significant difference (P = .0008) in median survival. Four years later, we now describe the results of this trial. PATIENTS AND METHODS: After a median follow-up of 4 years and 9 months, 115 of 159 cases of advanced ovarian cancer, originally randomized to receive six cycles of cyclophosphamide 750 mg/m2 and either a high dose (HD) of 100 mg/m2 cisplatin or a low dose (LD) of 50 mg/m2 (LD) cisplatin, have now died. RESULTS: The overall survival for HD and LD patients is 32.4% and 26.6%, respectively, and the overall relative death rate is 0.68 (P = .043). This represents a reduction in overall benefit with longer follow-up compared with the first 2 years (relative death rate of 0.52). Toxicity, particularly neurotoxicity, is still evident in the fourth year (10/31 on HD compared with 1/24 on LD). CONCLUSION: Our recommended dose of cisplatin in combination schedule is therefore 75 mg/m2, representing the optimal balance between efficacy and toxicity.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

Clinical drug resistance: the role of factors other than P-glycoprotein.

Clinical drug resistance is a major obstacle to successful chemotherapy for cancer. When it occurs, resistance to a wide range of agents is noted. This clinical observation should not be confused with so-called "multidrug resistance," which is a laboratory-based phenomenon, whereby cross-resistance in experimental models to structurally unrelated compounds is seen and is due to increased expression of P-glycoprotein (PGP). In the majority of cases of clinical drug resistance in solid tumors it is likely that other factors will play a major role. These other factors can be defined as pharmacologic or cellular. Pharmacologic factors are those that prevent an adequate degree of tumor cell exposure and include considerations of dose and schedule of drug, and also of drug metabolism, which may relate to concomitant medication and to genetic variations. Clinical maneuvers to circumvent drug resistance by increasing dose are so far of unproven value. Cellular factors are those that apply at the tumor cell itself, and it is probable that multiple mechanisms exist. These include considerations of drug uptake, activation/inactivation, and changes in target enzymes and in DNA repair processes. After DNA damage has occurred, a key determinant of the sensitivity of the tumor cell is its ability to undergo apoptosis. It is conceivable that failure to engage this process is a key factor in resistance to a number of drug classes, although there is little clinical evidence to support this at present. However, the genetic controls for the process of apoptosis are now being unraveled, and if this notion proves correct, the possibility will exist for the design of more rational means of circumventing drug resistance to a wide range of agents. In the meantime, strategies that should be pursued further in order to overcome this key clinical problem include further exploration of alternating or sequential drug schedules and using new non-cross-resistant agents, such as taxoids.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Characterization of extensive genetic alterations in ductal carcinoma in situ by fluorescence in situ hybridization and molecular analysis.

BACKGROUND: The molecular genetic analysis of invasive breast cancer has identified breast cancer as a genetically complex disease. Ductal carcinoma in situ (DCIS) is thought to represent a preinvasive step in breast cancer progression, yet we know little about its biologic behavior or the genetic alterations present. Because of the increasing diagnosis of DCIS by mammography screening and the debate over how DCIS should be managed, there is a clear need to define the molecular events underlying the development of DCIS. PURPOSE: Our purpose was to identify patterns of genetic alterations in DCIS. METHODS: A group of 30 formalin-fixed, paraffin-embedded blocks of tissue collected from 1987 through 1989 from 21 patients with DCIS was studied. Chromosomal imbalances were determined by interphase cytogenetic analysis using the fluorescence in situ hybridization (FISH) technique. DNA probes were used that recognize chromosome-specific repetitive sequence loci at the centromeres of chromosomes 1, 3, 4, 6, 7, 8, 9, 10, 11, 16, 17, and 18. FISH was also used to detect ERBB2 gene amplification in DCIS. To complement the FISH studies, microsatellite analysis of markers near the BRCA1 region of chromosome 17 was done on tissue microdissected from multiple areas of DCIS. Chromosomal imbalances were determined by comparisons of chromosomal indices (total number of hybridization spots per total number of nuclei counted) of normal and DCIS tissue, using the two-sided Mann-Whitney test. RESULTS: Using FISH, we have identified patterns of DNA loss and gain of certain chromosome-specific centromeric markers in DCIS. We observed frequent gains of markers on chromosomes 3, 10, and 17 as well as loss of chromosome 18-specific centromeric sequences. ERBB2 gene amplification was detected in tumors from four of 15 patients studied and was clearly limited to the tumor cells within the ducts. Because of the availability of topologically distinct regions of tumors from individuals, we were able to show that paired tumor specimens from individuals share genetic alterations and also have unique ones, suggesting clonal diversity within tumors. The combination of FISH and microsatellite analyses suggested that alterations in chromosome 17 may be quite complex; three of five patients whose samples were analyzed had allelic imbalance at markers on the long arm of chromosome 17. CONCLUSIONS: FISH and microsatellite analyses are useful in detecting extensive genetic alterations in DCIS. Examinations of DCIS tissue using these techniques have identified chromosomes 1, 3, 10, 16, 17, and 18 as candidate sites worthy of immediate study. IMPLICATIONS: This approach may give direction to future research aimed at precisely mapping loci altered in DCIS and help in understanding the biologic events associated with tumor progression or recurrence.

Breast Neoplasms↗
PubMed1995

Phase I clinical and pharmacokinetic study of 3'-deamino-3'-(2-methoxy-4-morpholinyl)doxorubicin (FCE 23762).

Methoxymorpholinyldoxorubicin (FCE 23762) is a novel, highly lipophilic doxorubicin analogue. It possesses potent in vitro and in vivo antitumor activity including efficacy in multidrug-resistant tumor cell lines. It is also metabolically activated in vivo resulting in an 80-fold increase in potency over the parent drug. In this phase I study the drug was administered by i.v. bolus injection at 3-week intervals. Fifty-three patients with refractory solid tumors were treated; 133 courses of FCE 23762 were administered at doses ranging from 30 to 2250 micrograms/m2. The dose limiting toxicity was reversible myelo-suppression (granulocytopenia and thrombocytopenia), demonstrating a delayed nadir and recovery in comparison to doxorubicin. Other toxicities included transient elevation of hepatic transaminases, delayed and prolonged nausea and vomiting, mucositis, anorexia, fatigue, and diarrhea. Heavily pretreated patients demonstrated more myelosuppression than previously untreated patients at 1250 micrograms/m2. No cardiotoxicity was observed. Four objective tumor responses were seen: one complete response in a patient with pelvic recurrence of cervical cancer; one partial response in a patient with cutaneous and lymph gland metastases from head and neck cancer; and two minor responses in patients with liver metastases from colorectal cancer. Plasma concentrations of FCE 23762 and its 13-dihydro metabolite, FCE 26176, were measured in 20 patients at doses > or = 675 micrograms/m2, using HPLC with fluorescence detection. The area under the plasma concentration-time curve ranged from 30 to 80 ng/h/ml; plasma data suggested linear kinetics in the range of tested doses (although there was considerable interpatient variability). The maximum tolerated dose defined in this study using this schedule is 1500 micrograms/m2. A safe phase II dose for previously untreated patients using this schedule is 1250 micrograms/m2; however, this may actually be below the optimal dose for this patient population.

Adult↗
PubMed1995

Interphase cytogenetic analysis of erbB2 and topoII alpha co-amplification in invasive breast cancer and polysomy of chromosome 17 in ductal carcinoma in situ.

Breast cancer is a genetically complex disease. Fluorescence in situ hybridisation can be used to analyse the genetics of breast-cancer progression in interphase cytogenetics. We have analysed the histological distribution of erbB2 and topoll alpha co-amplification in paraffin sections of invasive breast cancer and show that the co-amplified loci share the same histological distribution in the tumour and have a similar nuclear distribution within individual nuclei. Regions of the tumours without amplification are easily recognized and tumours with erbB2 and topoll alpha co-amplification can be distinguished from those with erbB2 amplification alone. In addition, FISH was used to show polysomy of chromosome 17 in non-invasive ductal carcinoma in situ of the breast and erbB2 amplification in both the invasive and non-invasive components of a breast cancer biopsy. This report of an interphase cytogenetic analysis of non-invasive breast carcinoma in situ demonstrates the usefulness of FISH for the genetic study of breast cancer progression.

Aneuploidy↗
PubMed1995

Taxoids.

Explore the source record for details and available documents.

Antineoplastic Agents, Phytogenic↗
PubMed1995

Changes in the incidence and mortality of testicular cancer in Scotland with particular reference to the outcome of older patients treated for non-seminomatous germ cell tumours.

This paper describes the temporal pattern of germ cell testicular cancer in Scotland between 1960 and 1990. The effect of age on the prognosis of patients with non-seminomatous germ cell tumours (NSGCT) has been assessed by studying all patients presenting in the West of Scotland between 1975 and 1989. Between 1960 and 1990, the number of testicular germ cell tumours registered has increased more than 2-fold; mortality rates have declined equally dramatically. Univariate and multivariate analysis of the data obtained on 440 patients with NSGCT showed age was not a prognostic factor influencing survival. 52 were patients over 40 years at presentation; their 5 years survival was 71% compared with 79% in the younger patients (n = 388). This small survival difference is probably explained by the higher proportion of older patients treated before 1980. Treatment for this older group should be approached with the same curative intent as for younger patients and the same expectation of success.

Adolescent↗
PubMed1995

Docetaxel in advanced ovarian cancer: preliminary results from three phase II trials. EORTC Early Clinical Trials Group and Clinical Screening Group, and the MD Anderson Cancer Center.

Docetaxel has been evaluated in 293 patients with advanced ovarian cancer in three phase II trials. All patients had previously received cisplatin and/or carboplatin as first-line treatment. In all three studies, treatment comprised docetaxel 100 mg/m2 as a 1 h intravenous infusion every 3 weeks, without premedication for hypersensitivity reactions or emesis. To date, 200 patients are evaluable for response. Of these, 63 patients achieved complete or partial response, giving an overall response rate of 31.5% (95% confidence interval 24-39%) for all evaluable patients, or 21.5% for all patients entered in the studies. Of the 57 patients whose disease had progressed either during previous therapy or within 4 months of discontinuing previous therapy, 13 (23%) responded to docetaxel (EORTC data). Major adverse effects of docetaxel observed in approximately half the patients (particularly those who received more than four courses) included skin reactions and fluid retention. Grade III or IV neutropenia was common but short-lived. Severe acute hypersensitivity reactions occurred in approximately 5% of patients. Docetaxel now warrants evaluation as part of first-line therapy. Studies aimed at reducing the incidence of fluid retention and skin reactions with docetaxel are ongoing.

Adult↗
PubMed1995

Colonic adenocarcinoma associated ectopic ACTH secretion: a case history.

A 57-year-old woman developed features of Cushing's syndrome after resection of a Duke's C adenocarcinoma of the sigmoid colon. Biochemical and endocrine investigation indicated ectopic production of adrenocorticotrophic hormone (ACTH) as the cause for her condition. Hepatic metastases were detected by computed tomography (CT) scan. Histology of the original tumour displayed neuroendocrine characteristics but no definite evidence of ACTH synthesis. Treatment was instituted to control her hypercortisolism, and chemotherapy initiated to reduce the production of ectopic hormone. A clinical, biochemical and radiological response was obtained with complete resolution of her Cushing's syndrome. The tumour relapsed after several months with distant metastases, but no further endocrine abnormality was noted. A review of ectopic ACTH producing adenocarcinoma is given along with a discussion of the major pathological and therapeutic features of the case.

ACTH Syndrome, Ectopic↗
PubMed1995

Cisplatin, vincristine and ifosphamide combination chemotherapy of metastatic seminoma: results of EORTC trial 30874. EORTC GU Group.

The aims of the trial were to establish the response rate and determine the toxicity of combination chemotherapy with ifosphamide, vincristine and cisplatin (HOP regimen) in advanced metastatic seminoma and to study the role of post-chemotherapy consolidation treatment. Patients with bulky metastatic non-alpha-fetoprotein-producing seminomas were eligible for this phase II study [serum human chorionic gonadotropin < 200 U l-1 (< 40 ng l-1)] if they presented with abdominal masses > or = 10 cm or had extra-gonadal seminoma or had relapsed after previous radiotherapy. The HOP regimen consisted of four 3-weekly cycles of the following drug combination: ifosphamide (days 1-5, 1.2 mg m-2 day-1), vincristine (day 1, 2 mg) and cisplatin (days 1-5, 20 mg m-2 day-1). Residual masses persisting 6 months after chemotherapy could be considered for consolidation surgery or radiotherapy. Maximal response to the HOP chemotherapy (evaluated at any time) was based on the WHO criteria. The median observation time was 2.5 years (range 1.8-5.5 years). Thirteen institutions treated 42 eligible patients within the study (testicular cancer stage > or = IID, 25; extragonadal, 5; relapse after previous radiotherapy, 12). Two patients were not evaluable for response owing to premature treatment discontinuation. Maximal response was as follows: complete remission (CR), 26 (65%); partial remission (PR) 11 (28%); no change (NC), 2 (5%); progressive disease (PD), 1 (3%). Four patients have died, three from their malignancy (two without previous irradiation and one with prior radiotherapy). The fourth patient died of treatment-related toxicity. The 3 year survival for all 42 eligible patients was 90%. Dose reduction and treatment postponement were necessary in 25 and 14 patients respectively. Ten patients experienced granulocytic fever. Previously irradiated patients tolerated chemotherapy as well as non-irradiated patients. Immediately after HOP chemotherapy a mass persisted in 16 of 17 patients with retroperitoneal masses of > or = 100 mm at presentation. Three of these residual lesions were resected within the following 6 months showing complete necrosis. Four lesions dissolved spontaneously during the first year of follow-up. Nine lesions persisted for > or = 1 year (one after consolidation radiotherapy) without leading to relapse. Four of seven patients with mediastinal lesions achieved CR and three a PR after HOP chemotherapy. The HOP chemotherapy regimen is highly effective in patients with advanced metastatic seminoma or those relapsing after previous radiotherapy, but is associated with a high risk of toxicity, in particular myelotoxicity.

Aged↗
PubMed1995

Phase I study of accelerated FEC with granulocyte colony-stimulating factor (Lenograstim) support.

With the aim of increasing the dose intensity of chemotherapy in breast cancer, 14 patients with stage II-IV breast cancer were treated with FEC chemotherapy at 2 week intervals together with granulocyte colony-stimulating factor (G-CSF) 5 micrograms kg-1 s.c. on days 2-14. Five of six patients completed six courses of 5-fluorouracil 600 mg m-2, epirubicin 60 mg m-2 and cylcophosphamide 600 mg m-2 within 11 weeks. Eight patients were treated with 5-fluorouracil 700 mg m-2, epirubicin 70 mg m-2 and cyclophosphamide 700 mg m-2 and four had dose-limiting toxicity with sepsis, thrombocytopenia or mucositis. All patients who received G-CSF had satisfactory neutrophil counts by day 15 of each course. Cumulative anaemia and thrombocytopenia were observed, but treatment at the first dose was tolerable. Seven of eight patients with measurable disease had partial responses. This regimen permits a 50% increase in dose intensity compared with conventional treatment at 3 week intervals and warrants further evaluation.

Adolescent↗
PubMed1995

Four cycles of BEP versus an alternating regime of PVB and BEP in patients with poor-prognosis metastatic testicular non-seminoma; a randomised study of the EORTC Genitourinary Tract Cancer Cooperative Group.

We have investigated whether an alternating induction chemotherapy regimen of PVB/BEP is superior to BEP in patients with poor-prognosis testicular non-seminoma. A total of 234 eligible patients were randomised to receive an alternating schedule of PVB/BEP for a total of four cycles or four cycles of BEP. Poor prognosis was defined as any of the following: lymph node metastases larger than 5 cm, lung metastases more than four in number or larger than 2 cm, haematogenic spread outside the lungs, such as in liver and bone, human chorionic gonadotrophin > 10,000 IU l-1 or alphafetoprotein > 1000 IU l-1. The complete response (CR) rates to PVB/BEP and BEP were similar, 76% and 72% respectively (P = 0.58). In addition, there was no significant difference in relapse rate, disease-free and overall survival at an average follow-up of 6 years. The 5-year progression-free and survival rates in both treatment groups were approximately 80%. The PVB/BEP regime was more toxic with regard to bone marrow function; the frequencies of leucocytes below 1000 microliters-1, leucocytopenic fever and platelets below 25,000 microliters-1, throughout four cycles were 28% vs 5% (P < 0.001), 16% vs 5% (P = 0.006), and 10% vs 1% (P = 0.001) respectively. Neuropathy also occurred more often in the PVB/BEP arm: 47% vs 25% (P = 0.001). This study shows that an alternating regimen of PVB/BEP is not superior to BEP and that it is more myelo- and neurotoxic.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

Phase II trials of rhizoxin in advanced ovarian, colorectal and renal cancer.

Rhizoxin is a tubulin-binding anti-neoplastic agent which is active in a range of murine tumour models. The recommended schedule, of intravenous (i.v.) bolus administration at a dose of 2 mg m-2 every 3 weeks, has been assessed in three phase II trials of ovarian, renal and colorectal cancer. In general terms the drug was fairly well tolerated, but the response rate was disappointing: 0/18, colorectal cancer; 0/18, renal cancer; 1 partial response (PR)/17, ovarian cancer.

Adult↗