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Biomedical subjects

S Hearn

Publications and source records attributed to S Hearn.

At least 19 recordsLinked to original sources
PubMed2001

Topotecan given as a 21-day infusion in the treatment of advanced ovarian cancer.

A phase II programme was carried out in both Europe and North America to evaluate the activity of topotecan administered as a 21-day continuous intravenous infusion to patients with recurrent ovarian cancer. The European results are reported here. Patients who had failed first line therapy with a platinum-based regimen received topotecan 0.4 mg/m(2)/day, as a 21-day infusion every 28 days. Patients were only permitted one prior regimen. 35 patients were enrolled and evaluable for response. 3 patients (8.6%) had a partial response to treatment (95% CI 1.8%, 23.1%) with a median time to response of 8.1 weeks and a median duration of response of 17.6 weeks. Response was also evaluated by CA125 and was also found to be 8%. For all 35 patients, median time to progression was 16.1 weeks and median survival was 43.6 weeks. The principal toxicity was myelosuppression although grade 4 neutropenia occurred in only 8.8% of patients (2.1% of courses) and infectious complications were relatively infrequent. Non-haematological toxicity was generally mild and mainly consisted of gastrointestinal events, alopecia and fatigue. A prolonged infusion of topotecan was well tolerated with a low incidence of severe neutropenia. Responses were seen in both North American and European patients. Response rates varied between the 2 studies possibly due to differences in patient demographics.

Abdominal Pain↗
PubMed2001

Preliminary results of combined therapy with topotecan and carboplatin in advanced non-small-cell lung cancer.

Topotecan is a topoisomerase I inhibitor and an analogue of camptothecin with demonstrated activity in small-cell lung cancer. However, less is known about the potential role of topotecan in advanced non-small-cell lung cancer (NSCLC). Platinum-based combination therapy is currently recommended in NSCLC patients presenting with good performance status. Because topotecan demonstrates a novel mechanism of action, its investigation in platinum combinations is warranted. In phase I/II trials of topotecan given as part of a cisplatin-based regimen, significant antitumor activity has been observed, providing the rationale for conducting further studies aimed at assessing survival benefit. However, this combination exhibits sequence dependence, with increasing hematologic toxicity observed when cisplatin is administered on day 1 of a 5-day topotecan course. Cisplatin has been associated with dose-limiting nonhematologic toxicities. Carboplatin exhibits a different toxicity profile compared with cisplatin, which makes it an attractive agent to study in combination. A hypothesis can be made that carboplatin in combination with newer agents such as topotecan might compare favorably with classic cisplatin-based regimens, particularly with respect to efficacy:toxicity ratio. Therefore, a phase II study was initiated to determine the efficacy, toxicity, and safety of carboplatin-topotecan combination in advanced NSCLC. Preliminary results reported here show that topotecan with carboplatin is generally well tolerated with manageable hematologic toxicity. Indirect comparison with cisplatin-topotecan combination suggests a lower incidence of dose-limiting nonhematologic toxicity. Whether or not the carboplatin-topotecan regimen is able to offer tumor response and survival benefit comparable to those observed with cisplatin-based combinations remains to be established.

Adult↗
PubMed2000

Phase I pharmacologic study of oral topotecan and intravenous cisplatin: sequence-dependent hematologic side effects.

PURPOSE: In in vitro studies, synergism and sequence-dependent effects were reported for the combination of topotecan and cisplatin. Recently, an oral formulation of topotecan became available. This phase I study was performed to assess the feasibility of the combination of oral topotecan and cisplatin, the pharmacokinetic interaction, and sequence-dependent effects. PATIENTS AND METHODS: Topotecan was administered orally (PO) daily for 5 days in escalating doses and cisplatin was given intravenously (IV) at a fixed dose of 75 mg/m(2) either before topotecan administration on day 1 (sequence CT) or after topotecan administration on day 5 (sequence TC) once every 3 weeks. Patients were treated in a randomized cross-over design. RESULTS: Forty-nine patients were entered onto the study; one patient was not eligible. Sequence CT induced significantly more severe myelosuppression than did sequence TC, and the maximum-tolerated dosage of topotecan in sequence CT was 1.25 mg/m(2)/d x 5. In sequence TC, the maximum-tolerated dosage of topotecan was 2.0 mg/m(2)/d x 5. Dose-limiting toxicity consisted of myelosuppression and diarrhea. Pharmacokinetics of topotecan and cisplatin were linear over the dose range studied; no sequence-dependent effects were observed. In addition, topotecan did not influence the protein binding of cisplatin or the platinum-DNA adduct formation in peripheral leukocytes in either sequence. CONCLUSION: The recommended dosages for phase II studies involving patients like the patients in our study are topotecan 1.25 mg/m(2)/d PO x 5 preceded by cisplatin 75 mg/m(2) IV day 1 once every 3 weeks, and topotecan 2.0 mg/m(2)/d PO followed by cisplatin 75 mg/m(2) IV day 5. No pharmacokinetic interaction could be discerned in our study. The antitumor efficacy of both schedules should be evaluated in a randomized phase II study.

Adult↗
PubMed2000

Phase II study of oral topotecan in advanced non-small cell lung cancer.

This study was designed to assess the activity of oral topotecan (TPT) in patients with advanced non-small cell lung cancer previously untreated with chemotherapy. Eligible patients had inoperable stage III or stage IV non-small cell lung cancer and were chemotherapy-naive. Other inclusion criteria were Eastern Cooperative Oncology Group performance status 0, 1, or 2, adequate bone marrow, and renal and hepatic function. Of 30 patients, 29 were assessable for response. Oral TPT was administered for 5 days every 21 days for up to six cycles unless disease progression or unacceptable toxicity occurred. Patients received a dose of 2.3 mg/m2/day for the first cycle. Dose modification for subsequent cycles was based on tolerability. Patients completed symptom questionnaires every 3 weeks. Pharmacokinetics were evaluated in all patients during cycle 1. Three patients had radiological responses with a reduction in tumor size of 30-40%. No patients achieved complete or partial responses to treatment. Thirteen patients had a stable disease (43.3%), and the median survival was 39.9 weeks with a 1-year survival of 33.3%. At the time of analysis, 27 patients had died. Median time to progression was 12.3 weeks. Treatment was well tolerated. A total of 125 cycles of treatment were completed. Twelve patients (40%) experienced grade III/IV neutropenia. Five patients (16.6%) had grade III/IV anemia. There were two episodes of grade III/IV thrombocytopenia. The main nonhematological toxicities consisted of grade III nausea (13%) and grade III vomiting (13%). The most frequently reported disease-related symptoms at baseline were dyspnea, cough, and fatigue. There was a subsequent improvement in patient scores of dyspnea in 17% of patients, 31% showed improvement in cough, and 32% showed improvement in fatigue. The mean area under the curve of TPT following 2.3 mg/m2 p.o. was 51.6 ng.h/ml (%SD, 25%). The area under the curve of TPT on day 1 of the first cycle was correlated with the percentage fall in leukocytes. Although oral TPT at the applied dose and schedule showed modest activity as a single agent, almost one-half of the patients had a stable disease, and median time to progression was 12.3 weeks. The overall median survival was a promising 39.9 weeks, and useful palliation of symptoms was seen.

Administration, Oral↗
PubMed1999

Phase I and pharmacologic study of the combination of paclitaxel, cisplatin, and topotecan administered intravenously every 21 days as first-line therapy in patients with advanced ovarian cancer.

PURPOSE: To evaluate the feasibility of administering topotecan in combination with paclitaxel and cisplatin without and with granulocyte colony-stimulating factor (G-CSF) support as first-line chemotherapy in women with incompletely resected stage III and stage IV ovarian carcinoma. PATIENTS AND METHODS: Starting doses were paclitaxel 110 mg/m2 administered over 24 hours (day 1), followed by cisplatin 50 mg/m2 over 3 hours (day 2) and topotecan 0.3 mg/m2/d over 30 minutes for 5 consecutive days (days 2 to 6). Treatment was repeated every 3 weeks. After encountering dose-limiting toxicities (DLTs) without G-CSF support, the maximum-tolerated dose was defined as 5 microg/kg of G-CSF subcutaneously starting on day 6. RESULTS: Twenty-one patients received a total of 116 courses at four different dose levels. The DLT was neutropenia. At the first dose level, all six patients experienced grade 4 myelosuppression. G-CSF support permitted further dose escalation of cisplatin and topotecan. Nonhematologic toxicities, primarily fatigue, nausea/vomiting, and neurosensory neuropathy, were observed but were generally mild. Of 15 patients assessable for response, nine had a complete response, four achieved a partial response, and two had stable disease. CONCLUSION: Neutropenia was the DLT of this combination of paclitaxel, cisplatin, and topotecan. The recommended phase II dose is paclitaxel 110 mg/m2 (day 1), followed by cisplatin 75 mg/m2 (day 2) and topotecan 0.3 mg/m2/d (days 2 to 6) with G-CSF support repeated every 3 weeks.

Adult↗
PubMed1997

The role of active inducible nitric oxide synthase expression in the pathogenesis of capillary leak syndrome resulting from interleukin-2 therapy in mice.

Previously, we showed that nitric oxide (NO) plays a major role in the pathogenesis of IL-2-induced capillary leak syndrome in healthy or mammary adenocarcinoma-bearing C3H/HeJ mice. NO synthase (NOS) inhibitors, such as NG-nitro-L-arginine methyl ester (L-NAME) reduced all the manifestations of IL-2-induced capillary leakage, without compromising the antitumor effects of IL-2. The present study was carried out on healthy C3H/HeJ mice subjected to one or two 4-day rounds of systemic IL-2 therapy with or without oral L-NAME therapy to: (a) identify the tissue source of NOS activity and NOS protein induced by IL-2 therapy; (b) identify histologically the nature of the structural damage to the lungs associated with IL-2 therapy-induced pulmonary edema; and (c) evaluate the effects of additional L-NAME therapy on the above-mentioned parameters. Results revealed that IL-2 therapy in healthy mice resulted in the expression of inducible NOS in numerous tissues including the endothelium and muscles of the anterior thoracic wall as well as splenic macrophages. One round of IL-2 therapy resulted in high levels of inducible NOS (iNOS) activity in the anterior thoracic wall accompanied by pleural effusion. After two rounds of IL-2 therapy, there was neither pleural effusion nor high iNOS activity in the thoracic wall. IL-2-induced pulmonary edema after one round of therapy correlated to both a significant rise in NO production measured in the serum and structural damage to the lungs and its capillaries. Addition of the NOS inhibitor L-NAME totally eradicated NOS activity but not necessarily iNOS expression. It also reduced IL-2-induced pulmonary edema and pleural effusion, restrained the rise in the levels of NO metabolites (nitrites and nitrates) in the serum and pleural effusion, and significantly restored the structural integrity of the lungs after one round of therapy. Thus, NOS inhibitors may be beneficial adjuncts to IL-2 therapy for cancer and infectious diseases.

Animals↗
PubMed1996

The potential effect of the UK 1990 height centile charts on community growth surveillance.

The UK 1990 height charts are derived from an up to date dataset and introduce a change in the centile lines, particularly the addition of the 0.4th centile. This study examined the likely impact of these changes. Height data from London school children (1990-1993) were examined using Tanner and Whitehouse (TW) and UK 1990 charts. Numbers of children with height below TW 3rd centile were compared with numbers below the UK 1990 3rd and 0.4th centiles. The TW charts identified only 1% of children below the TW 3rd centile, while the UK 1990 charts identified 3% below the 3rd and 0.4% below the 0.4th centiles. If the 3rd centile remains as the referral 'cut off' for short stature, the introduction of the UK 1990 charts would increase current workload two- to three-fold, while a change to the 0.4th centile would reduce it by 50%. A significant number of children with abnormalities may be excluded from further assessment as a result of this latter change. In this small scale community study it is not possible to assess the consequences of this change. The heights at diagnosis of children with growth hormone (GH) deficiency (peak GH < 20 mU/l during a standard provocation test) were therefore compared to the 0.4th centile (UK 1990 charts). Sixty eight children with heights < 2nd centile (UK 1990 charts) currently receiving GH replacement (17 female, 51 male, aged 9.7, SD 3.5, years) were assessed, and of these, 28 (41%) had heights at diagnosis between 0.4th and 2nd centile, with a mean height standard deviation score of -2.32 (SD 0.21). This suggests that if the 0.4th centile were to be used as the sole criterion for referral for slow growth, a significant proportion of children with abnormality would not be referred for further assessment. The UK 1990 2nd centile should replace the TW 3rd centile. Children below this should undergo an intermediary medical assessment to confirm height measurement, to exclude from referral children with mild familial short stature and to identify concerns regarding the child.

Body Height↗
PubMed1995

Characteristics of trophoblast cells migrating from first trimester chorionic villus explants and propagated in culture.

We developed a method of propagating pure first trimester human trophoblast cells growing out of primary explants of mechanically derived chorionic villus fragments (Yagel et al, 1989; Graham et al, 1992). We have now extensively characterized these cells during their initial outgrowth and in long-term culture, employing a variety of markers and techniques as outlined below. By double label immunofluorescence using epithelial (cytokeratin) and mesenchymal (vimentin) cell markers, we identified the chorionic villus migrant cell populations as pure trophoblast (39 per cent of outgrowths) or a mixture of trophoblast and fibroblast (61 per cent). Further phenotyping of the pure trophoblast outgrowths by double label immunostaining using anti-cytokeratin antibody and a panel of other primary antisera revealed that these cells exhibit a variety of markers characteristic of extravillous invasive trophoblast cells in situ: insulin-like growth factor (IGF)-II, NDOG-5, proliferating cell nuclear antigen (PCNA), human leucocyte antigen framework antigen (W6/32) and a distinct set of integrins including alpha 1, alpha 3, alpha 5, alpha v and beta 1 subunits and alpha v beta 3/beta 5 vitonectin receptor. They were negative for alpha 6 and beta 4 integrin subunits. Immunogold electron microscopy of explants grown on type IV collagen gel revealed the production of conventional and oncofetal types of fibronectin by mononucleate trophoblast cells and human placental lactogen by multinucleate cells. Immunolabelling, flow cytometry and immunoprecipitation revealed that this phenotypic profile was retained with complete fidelity in the long-term culture; thus, trophoblasts migrating out of first trimester chorionic villus explants and their propagated progeny belong to the invasive extravillous trophoblast of the placenta.

Cell Movement↗
PubMed1995

Construction of a community height surveillance programme: the Hackney growth initiative.

OBJECTIVES: To determine why, in the London Borough of Hackney before 1990, fewer children than expected were identified with remedial causes of short stature. To construct a practical model for height surveillance of 5 and 11 year old school entrants to improve the quality of child growth surveillance. SETTING: City and Hackney Borough, London, United Kingdom. METHODS: School nurses were trained by a clinical auxologist to measure children's height at school entry accurately and reproducibly. New procedures for measurement technique, plotting of data, referral, and audit were established. A reference manual was provided and a continuing training programme was started. RESULTS: During the first year the percentage of the target group measured was low. Changes in work practice led to improvements from 77% measured in the first year to 91% in the second year and 87% in the third year for 5 year olds. Improvements for 11 year olds were from 36% to 86% to 87% over the three years. Only 1.2% of 5 year olds and 2.6% of 11 year olds measured had height less than the third centile (compared with Tanner's height standards). CONCLUSIONS: School nurses measured height reliably. New audit procedures led to rapid changes in working practice and improvements in the percentage of children measured. The low numbers of short children previously identified with unrecognised abnormality may indicate an upward trend in height in this inner city population.

Body Height↗
PubMed1994

Taperloc femoral component. A 2-6-year study of the first 100 consecutive cases.

The first 100 consecutive patients who underwent insertion of the Taperloc (Biomet, Warsaw, IN) femoral stem were prospectively studied with a mean follow-up period of 3.8 years (range, 2-6 years). Two of the original 100 patients were lost, giving a 98% follow-up rate. The diagnoses included osteoarthritis (76 patients), avascular necrosis (19), rheumatoid arthritis (3), chrondrolysis (1), and post-traumatic arthritis (1). The mean age at surgery was 56 years (range, 25-79 years), mean weight was 78 kg (range, 45-127 kg), and the female to male ratio was 29:71. Charnley pain and function scores were 3.0 and 2.8 before surgery and 5.5 and 5.4 after surgery. Thigh pain was present in 2% of the patients at the final follow-up evaluation. There were no revisions. Radiographic signs of bone-ingrowth fixation (calcar atrophy, spot welds) were seen in 92 of 94 components (98%). No component had complete demarcation of the porous-coated zones. Fifty-two of 94 patients were able to be matched for age, sex, weight, diagnosis, and length of follow-up period with a series of patients who received a contemporary cemented total hip. In this matched subset, the Charnley pain and function scores were 5.6 and 5.5 for the cementless Taperloc stem and 5.7 and 5.5 for the cemented control group; this is not a significant difference. These data indicate a clinical performance equivalent to a matched group of contemporary cemented total hip arthroplasties.

Adult↗
PubMed1993

Ultrastructural analysis of gap junctions in C6 glioma cells transfected with connexin43 cDNA.

In the past, we transfected C6 glioma cells with connexin43 cDNA, resulting in a significant increase in connexin43 mRNA and protein, as well as reduced proliferation and tumorigenesis. To investigate the morphological aspects of increased connexin43 expression in these cells, we have used a combination of immunocytochemistry, cytochemistry, and electron microscopy. By confocal immunofluorescence microscopy, connexin43 protein was localized to the plasma membrane of transfected cells and extensive intracellular accumulations of connexin43 were also demonstrated. Freeze fracture preparations showed large aggregates of particles typical of mature gap junction plaques in the plasma membrane of these cells. Ultrastructural immunogold labeling with anti-connexin43 serum revealed that connexin43 protein was present in gap junctions in the plasma membrane, some of which were found in proximity to clathrin-coated pits. In addition, various intracellular membranous profiles were immunoreactive for connexin43, including annular profiles, some with fuzzy coats and some associated with lysosome-like structures. Enzyme cytochemistry revealed that these annular gap junction profiles were often associated with acid phosphatase-positive lysosomes. These studies on the intracellular localization of gap junction protein in connexin43-transfected cells are consistent with the functional expression of the transfected connexin43 cDNA and provide a useful model to study the pathways of gap junction assembly and degradation.

Acid Phosphatase↗