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Biomedical subjects

P Harper

Publications and source records attributed to P Harper.

At least 91 records · Page 5Linked to original sources
PubMed1997

The role of docetaxel (Taxotere) as a single agent or in combination before local treatment of non-small cell lung cancer.

Neoadjuvant therapy in the treatment of stage IIIa/b non-small cell lung cancer (NSCLC) has the potential to reduce tumor size in patients whose tumors were previously inoperable. This report describes the design and status of an ongoing randomized, phase III study of docetaxel (Taxotere; Rhône-Poulenc Rorer, Antony, France) as neoadjuvant treatment in patients with stage IIIa/b NSCLC, as well as of two phase II studies of combination neoadjuvant therapies. A phase III, multicenter, international, randomized trial is in progress which compares docetaxel with no neoadjuvant chemotherapy in patients with histologically confirmed, previously untreated NSCLC with stage IIIa N2(T0-3) or T3 (N0-1) disease or stage IIIb disease that can be treated radically. Patients are assigned to receive three cycles of docetaxel or no neoadjuvant therapy. Definitive therapy is administered immediately or within 6 weeks of the third cycle of docetaxel. The primary objective of the study is median survival. Secondary end points include response rate, tumor resectability, survival after surgery and after curative-intent radiation, time to disease progression, and quality of life. To date, 110 of the planned 292 patients have been randomized. It is anticipated that the study will be completed in 1998. A phase I/II dose escalation study of the combination of docetaxel and cisplatin as neoadjuvant treatment of patients with stage IIIa T1-T3 NSCLC with N2 disease on mediastinoscopy is ongoing. The objectives of the study are to determine the clinical response to chemotherapy, the pathologic response after surgery, and survival. A phase II, multicenter, nonrandomized trial of the combination of docetaxel and carboplatin as neoadjuvant therapy in patients with stage IIIa N2 NSCLC is in progress. The primary objective of the study is to determine the response rate after chemotherapy. The results of both studies should be available by late 1997. The ultimate hope is that there is potential for neoadjuvant chemotherapy to provide a significant benefit for patients with advanced NSCLC.

Antineoplastic Agents, Phytogenic↗
PubMed1997

ICON 2 and ICON 3 data in previously untreated ovarian cancer: results to date.

The second International Collaborative Ovarian Neoplasm study (ICON 2), was a large, international randomized study of cyclophosphamide/doxorubicin/cisplatin (CAP) versus single-agent carboplatin in patients with previously untreated ovarian cancer. Patients in the CAP arm received 500 mg/m2 cyclophosphamide, 50 mg/m2 doxorubicin, and 50 mg/m2 cisplatin. Carboplatin was dosed to an area under the concentration-time curve of 5. Chemotherapy was given every 3 weeks for a total of 6 months for each regimen. Results of a 1995 interim analysis in 1,377 patients showed that overall, the total dose received in the CAP group was greater than 75% of the planned dose, with 75% of patients receiving greater than 87%, greater than 80%, and greater than 83% of the planned doses of cisplatin, doxorubicin, and cyclophosphamide, respectively. Of carboplatin patients, 75% received greater than 1,450 mg/m2 (of a median planned dose of 1,800 mg/m2). There were significant differences in grades 3/4 toxicity between the two arms: leukopenia occurred in 34% of CAP patients versus 10% of carboplatin patients, alopecia in 70% versus 3%, nausea and vomiting in 21% versus 9%, and mucositis in 21% versus 0%, respectively. However, thrombocytopenia was more frequent in the carboplatin group (16% v 7%). At the 1996 analysis, 1,526 patients had been entered, 1,498 had been randomized, and 740 had progressed or died. The interim conclusions were that although the more toxic CAP regimen may improve progression-free survival by a small amount, there was no evidence of any survival benefits or difference within the subgroups. Given that a sufficient number of patients had been accrued to ICON 2 and that starting accrual for ICON 3 markedly slowed accrual to ICON 2, the trial was closed. The full analysis of ICON 2 should be available in the summer of 1997. ICON 3 was designed to consider the role of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in previously untreated ovarian cancer. Patients received paclitaxel at a dose of 175 mg/m2 (3-hour infusion) in combination with carboplatin dosed to an area under the concentration-time curve of 5 (based on chromium ethylenediamine tetraacetic acid) or 6 (based on calculated creatinine clearance). The control arm was either CAP or carboplatin. Patients were randomized 2:1 in favor of the control arm. In all, 1,070 patients have been entered to date. At the first planned interim analysis, in April 1996 in 434 patients, it was too early to provide efficacy data. The plan was to continue accruing to the trial to a maximum of 2,000 patients, with review in mid-1997, when the events for analysis will be virtually doubled and the data can be interpreted in light of the results of the Intergroup study (European Organization for Research and Treatment of Cancer, the National Cancer Institute of Canada, and the Scottish study) and Gynecologic Oncology Group trial 132.

Alopecia↗
PubMed1996

Characterization of six mutations in exon 37 of neurofibromatosis type 1 gene.

Neurofibromatosis type 1 (NF1) is one of the most common inherited disorders, with an incidence of 1 in 3,000. We screened a total of 320 unrelated NF1 patients for mutations in exon 37 of the NF1 gene. Six independent mutations were identified, of which three are novel, and these include a recurrent nonsense mutation identified in 2 unrelated patients at codon 2281 (G2281X), a 1-bp insertion (6791 ins A) resulting in a change of TAG (tyrosine) to a TAA (stop codon), and a 3-bp deletion (6839 del TAC) which generated a frameshift. Another recurrent nonsense mutation, Y2264X, which was detected in 2 unrelated patients in this study, was also previously reported in 2 NF1 individuals. All the mutations were identified within a contiguous 49-bp sequence. Further studies are warranted to support the notion that this region of the gene contains highly mutable sequences.

Adult↗
PubMed1995

'Tomudex' (ZD1694): results of a randomised trial in advanced colorectal cancer demonstrate efficacy and reduced mucositis and leucopenia. The 'Tomudex' Colorectal Cancer Study Group.

'Tomudex' (ZD1694), a direct and specific thymidylate synthase (TS) inhibitor entered phase III studies in November 1993. We present here the first analysis of a randomised multicentre, international phase III study. 439 patients with previously untreated advanced colorectal cancer were randomised to Tomudex 3.0 mg/m2 given once every 3 weeks or 5-fluorouracil (5-FU) 425 mg/m2 and leucovorin (LV) 20 mg/m2 for 5 days (the Mayo regimen), given every 4-5 weeks. Patients were evaluated weekly for toxicity and every 12 weeks for objective response. The two groups were well matched in terms of demographic characteristics. The mean age of the patients was 61 years and most had either liver (78%) or lung (25-29%) metastases. Ninety seven per cent of patients allocated to Tomudex and 94% of those allocated to 5-FU plus LV had measurable disease. Response was assessed using WHO/UICC criteria; all response data were source validated; 19.8% of patients who received Tomudex and 12.7% of patients who received 5-FU plus LV had complete or partial responses (P = 0.059, odds ratio 1.7, 95% confidence limits 0.98-2.81). There were no statistically significant differences in time to progression or survival between the two groups. Patients who received Tomudex spent a substantially shorter time in hospital for dosing and had significantly lower rates of grade 3 and 4 toxicities such as leucopenia and mucositis. Patients who received Tomudex had a significantly higher incidence of reversible grade 3 or 4 increase in transaminases, which appear to be of limited clinical significance. Improvement in quality of life, weight gain and performance status was seen in both groups. Tomudex has benefits in terms of higher response rates, reduced toxicity and more frequent palliative benefits when compared with 5-FU plus LV in the management of advanced colorectal cancer, and has a more convenient administration schedule.

Adult↗
PubMed1995

Volunteers or victims: patients' views of randomised cancer clinical trials.

Randomised clinical trials are essential for the objective evaluation of different treatment strategies in cancer. However, in the field of oncology, very few of the eligible patients are entered into trials, and most treatments have only been tested on a small percentage of patients. For doctors, a major deterrent to participating in trials is the lack of resources--particularly time, but often also the local facilities. This report suggests that patients themselves are willing to take part in clinical research, and are attracted by being treated by a doctor with a specialist interest in the disease and encouraged by the possibility that their progress will be monitored closely. With the recent NHS changes, it is timely for the Department of Health and other national health departments to consider carefully what can be done to ensure that no new treatments are adopted without effective evaluation. This will require departments of health to identify and implement ways to facilitate accrual of appropriate numbers of patients onto research protocols (whether non-randomised phase I or phase II studies or large, multicentre phase III trials) over short time periods.

Adolescent↗
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↗
PubMed1995

Increased liver carnitine content in obese women.

In experimental animals the enhancement of hepatic fatty acid oxidation and ketogenic capacity is accompanied by a rise in the concentration of liver carnitine. Massive obesity is characterized by enhanced fatty acid turnover, insulin resistance, and often a fatty liver. Carnitine concentrations were determined in liver, abdominal muscle tissue, and blood in morbidly obese women. The liver and muscle carnitine concentrations were significantly higher in the obese subjects than in the lean control subjects. These findings suggest an increase of the whole-body carnitine pool. In the obese subjects there was also a significant positive correlation between liver and muscle carnitine concentrations. In the majority of the obese subjects fatty changes could be demonstrated in the liver. The plasma insulin concentration tended to be positively correlated with the degree of fat infiltration and negatively correlated with the liver carnitine content. It is concluded that the liver carnitine content is significantly increased in obese women, which agrees with the finding in experimental animals.

Adult↗
PubMed1995

Markers for vulnerability in acute porphyria. A hypothesis paper.

Previously symptomatic and permanently asymptomatic carriers of a gene mutation for acute intermittent porphyria as well as matched controls were screened with regard to a series of variables of possible relevance to the development of porphyric symptoms. The basis for the study was a concept of acute porphyria as a condition of a permanent system overload of oxidative stress, with long term effects on hepatic and renal tissue, and with instances of periodic overload of free radicals giving rise to acute neurologic involvement. Leukocyte concentrations of manganese, calcium, iron and zinc, as well as erythrocyte calcium differed between the groups, acute intermittent porphyria gene carriers, irrespective of previous porphyric illness, showing significantly higher levels than the controls. Manganese was found to be the most discriminative component of all the 78 variables investigated, accounting for about 98 per cent of the variance between the groups. An increment, by a factor of four, in cellular manganese is suggestive of an increase, in acute intermittent porphyria, of a manganese associated enzyme, e.g. glutamine synthetase, pyruvate carboxylase or mitochondrial superoxide dismutase. The best fit into the model considered is provided by a theory focused on superoxide dismutase, induced in response to superoxide anion radical produced from aminolaevulinic acid. In porphyria gene carriers seemingly resistant to porphyric manifestations, an increase in potentially prooxidant cellular iron is matched by a proportional increment in manganese, i.e. presumably by a corresponding mitochondrial superoxide dismutase induction. This mechanism is not operative in porphyric individuals prone to development of neuropsychiatric symptoms. In acute intermittent porphyria with a history of porphyric illness there is a positive correlation between erythrocyte manganese and serum folate and a negative correlation between leukocyte ferrochelatase activity and serum cobalamin concentration. This may mirror a role of the cobalamin-folate system in the acute porphyric process.

Adult↗
PubMed1994

Adolescent measles vaccination. Response rates to mailings addressed to patients vs parents.

OBJECTIVE: To determine the measles vaccination rate in adolescents that could be achieved with a mailed notification of the recommendation, and to determine if the response rate differed if the mailing was addressed to the parents or to the adolescents. DESIGN: Randomized trial. SETTING: A family medicine residency training clinic serving a low-socioeconomic population. PATIENTS OR OTHER PARTICIPANTS: Four hundred forty-nine adolescents aged 12 through 18 years who were seen in the clinic within the previous 21 months without receiving a documented second dose of measles vaccine were randomized into two groups. INTERVENTION: A letter recommending measles revaccination was sent to the parents in one group (parent group) and to the adolescents themselves in the second group (adolescent group). The content of both letters was basically the same, but they differed in style and reading level. MAIN OUTCOME MEASURE: Measles vaccinations administered to adolescents during the 2-month period following mailing of the letters. RESULTS: Twenty-eight patients were excluded after randomization. Fifty-six letters were undeliverable after two mailing attempts. Eleven (6.3%) of 176 adolescents in the parent group and five (2.6%) of 189 adolescents in the adolescent group received the measles vaccination (P > .05). CONCLUSIONS: Although the adolescents whose parents received the letter were twice as likely to be vaccinated, the response rate was poor in both groups. The letter campaign was not an effective method to reach adolescents for measles revaccination.

Adolescent↗
PubMed1994

A Cancer Research Campaign (CRC) phase II trial of CB10-277 given by 24 hour infusion for malignant melanoma.

The decarbazine analogue CB10-277 has been investigated for anti-tumour activity in a phase II study on malignant melanoma. Treatment was administered as a slow infusion of 12,000 mg m-2 over 24 h and repeated every 3 weeks. A total of 28 patients were entered into the study, of whom 23 were eligible for review. A total of 64 courses was given. There was one objective partial response in 22 patients assessable for response. The major toxicities were leucopenia and thrombocytopenia. CB10-277 in this schedule therefore does not appear to have major activity in melanoma.

Adult↗