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Biomedical subjects

Peter Harper

Publications and source records attributed to Peter Harper.

17 recordsLinked to original sources
PubMed2003

Surgical margins in cutaneous melanoma (2 cm versus 5 cm for lesions measuring less than 2.1-mm thick).

BACKGROUND: This study addressed the question of whether limited surgery for primary malignant melanoma with a 2-cm margin is as good as a 5-cm margin. An update of a 16-year follow-up is provided. METHODS: Nine European Centers, over a period of 5 years, prospectively randomized 337 patients with melanoma measuring less than 2.1 mm in thickness to undergo a local excision with either a 2-cm or a 5-cm margin. Three hundred twenty-six patients were eligible for statistical analysis. Excluded from the trial were patients older than 70 years; those with melanomas from the toe, nail, or finger; and those with acral-lentiginous melanoma. A separate randomization was performed to independently test an adjuvant treatment with a nonspecific immunostimulant, isoprinosine, compared with observation. The median follow-up time was 192 months (16 years) for the estimation of survival and disease recurrences. RESULTS: There were 22 tumor recurrences in the 2-cm arm and 33 in the 5-cm arm. The median time to disease recurrence was 43 months and 37.6 months, respectively. The 10-year disease-free survival rates were 85% for the group with a 2-cm margin and 83% for the group with a 5-cm margin. There was no difference in the 10-year overall survival rates (87% vs. 86%). Isoprinosine did not demonstrate any activity in this setting. CONCLUSIONS: The authors concluded that for melanoma less than 2.1-mm thick, a margin of excision of 2 cm is sufficient. A larger margin of 5 cm does not appear to have any impact on either the rate or the time to disease recurrence or on survival.

Adult↗
PubMed2003

Update on gemcitabine/carboplatin in patients with advanced non-small cell lung cancer.

Platinum-based chemotherapy regimens comprise a standard treatment approach for patients with advanced and metastatic non-small cell lung cancer (NSCLC). Based on results from randomized studies and meta-analyses, it has been established that such therapy significantly improves survival and maintains or improves quality of life relative to best supportive care. Combinations of cisplatin or carboplatin with gemcitabine, a newer-generation nucleoside antimetabolite with single-agent activity of 20% to 26% in advanced NSCLC, have shown antitumor activity and are well tolerated. In many studies in the advanced-disease setting, carboplatin has replaced cisplatin because of its improved nonhematologic toxicity profile and greater ease of administration. Encouraging results in the phase II setting have led to the design and implementation of several phase III studies of gemcitabine/carboplatin in the treatment of patients with advanced NSCLC. Results of three phase III trials involving more than 900 patients not previously treated with chemotherapy are discussed herein. These studies compared gemcitabine/carboplatin versus gemcitabine alone, gemcitabine/carboplatin versus gemcitabine/cisplatin, and gemcitabine/carboplatin versus mitomycin/ifosfamide/cisplatin (MIP), a regimen commonly used in Europe. Results show that gemcitabine/carboplatin efficacy was equivalent or superior to that achieved with single-agent gemcitabine or other platinum-based treatments. The regimen was well tolerated overall, and available data from one study show a significant improvement in quality of life. Thus, gemcitabine/carboplatin appears to be a viable option in the first-line treatment of advanced NSCLC. The results of one study reviewed suggest that gemcitabine/carboplatin can be considered for the treatment of patients over 70 years old.

Aged↗
PubMed2002

Multicenter phase III study of uracil/tegafur and oral leucovorin versus fluorouracil and leucovorin in patients with previously untreated metastatic colorectal cancer.

PURPOSE: This phase III study was designed to demonstrate equivalence in survival of oral uracil/tegafur (UFT) and oral leucovorin (LV) to conventional intravenous (IV) fluorouracil (5-FU) and LV in previously untreated metastatic colorectal carcinoma. Safety was also compared. PATIENTS AND METHODS: Eight hundred sixteen patients were randomized to receive either UFT (300 mg/m(2)/d) and LV (75 or 90 mg/d) for 28 days every 35 days or IV bolus 5-FU (425 mg/m(2)/d) and LV (20 mg/m(2)/d) for 5 days every 28 days. RESULTS: UFT/LV produced survival comparable to the IV 5-FU/LV regimen. Median survival was 12.4 months (95% confidence interval [CI], 11.2 to 13.6 months) with UFT/LV and 13.4 months (95% CI, 11.6 to 15.4 months) with 5-FU/LV (P =.630). The hazard ratio for survival was 0.964 (95.6% CI, 0.826 to 1.125), supporting equivalent survival. The overall response rate did not differ between treatment arms (UFT/LV, 11.7%; 5-FU/LV, 14.5%; P =.232). Median time to progression favored 5-FU/LV (UFT/LV, 3.5 months; 5-FU/LV, 3.8 months; P =.011), but tumor assessment schedules differed between arms. UFT/LV significantly improved safety compared with 5-FU/LV. Diarrhea, nausea and vomiting, and stomatitis and mucositis were significantly less frequent with UFT/LV, as was myelosuppression. Patients treated with UFT/LV had fewer episodes of febrile neutropenia (P <.001) and documented infections (P <.05). Increased bilirubin, without other liver function abnormalities, was observed more often with UFT/LV (P <.001). Concomitant medications were more frequent with 5-FU/LV, including use of antibiotics, growth factors, and antiemetics. CONCLUSION: UFT/LV provided a safer, more convenient oral alternative to a standard bolus IV 5-FU/LV regimen for metastatic colorectal cancer while producing equivalent survival.

Administration, Oral↗
PubMed2002

Mutations in TITF-1 are associated with benign hereditary chorea.

Benign hereditary chorea (BHC) (MIM 118700) is an autosomal dominant movement disorder. The early onset of symptoms (usually before the age of 5 years) and the observation that in some BHC families the symptoms tend to decrease in adulthood suggests that the disorder results from a developmental disturbance of the brain. In contrast to Huntington disease (MIM 143100), BHC is non-progressive and patients have normal or slightly below normal intelligence. There is considerable inter- and intrafamilial variability, including dysarthria, axial dystonia and gait disturbances. Previously, we identified a locus for BHC on chromosome 14 and subsequently identified additional independent families linked to the same locus. Recombination analysis of all chromosome 14-linked families resulted initially in a reduction of the critical interval for the BHC gene to 8.4 cM between markers D14S49 and D14S278. More detailed analysis of the critical region in a small BHC family revealed a de novo deletion of 1.2 Mb harboring the TITF-1 gene, a homeodomain-containing transcription factor essential for the organogenesis of the lung, thyroid and the basal ganglia. Here we report evidence that mutations in TITF-1 are associated with BHC.

Amino Acid Sequence↗
PubMed2002

Influenza vaccination and chemotherapy: a shot in the dark?

Influenza infection is a potential cause of excess morbidity in patients who are immunosuppressed because of haemato-oncological malignancy or its treatment. Therefore vaccination against influenza is recommended in these patient groups. This systematic review of the literature and vaccine manafacturers' data assesses the current levels of knowledge concerning influenza vaccination in this patient group. There is a paucity of data, and the patient groups in the studies are heterogeneous. Serological responses are generally lower than expected in healthy controls and may be critically dependent on the timing of vaccination relative to chemotherapy. Antibody levels considered protective in healthy individuals may not prevent clinical infection in those with malignant disease. There are no data on protection from clinical infection. The vaccine appears to be well tolerated in this patient group. It is reasonable to offer vaccination to patients receiving treatment for haemato-oncological disorders. However, the degree of clinical protection afforded may be inferior to that experienced by healthy individuals. Further trials are warranted to assess the magnitude of benefit and optimal schedules of vaccination.

Antibodies, Viral↗
PubMed2002

Effect of renal impairment on the pharmacokinetics and tolerability of capecitabine (Xeloda) in cancer patients.

PURPOSE: The primary objective of this study was to investigate the influence of renal impairment on the pharmacokinetics of capecitabine and its metabolites in cancer patients. Capecitabine (Xeloda) is an orally administered precursor of 5'-deoxy-5-fluorouridine (5'-DFUR), which is preferentially activated to 5-fluorouracil (5-FU) in tumors. METHODS: A total of 27 patients were enrolled, of whom 24 were evaluable for pharmacokinetics (6 with normal renal function, 8 with mild, 6 with moderate, and 4 with severe renal impairment at baseline). Patients received capecitabine orally at the standard dosing regimen (1250 mg/m(2) capecitabine twice daily for 2 weeks followed by a 1-week rest period). On study days 1 and 14, blood samples were collected to evaluate the pharmacokinetics of capecitabine and its metabolites. The relationship between the area under the plasma concentration-time curve (AUC) and creatinine clearance (CL(CR)) was assessed by log-linear regression analysis. RESULTS: The primary pharmacokinetic parameter with respect to the effect of renal dysfunction was systemic exposure to 5'-DFUR, 5-FU and FBAL determined on study day 14. Renal impairment led to an increase in the systemic exposure to 5'-DFUR and FBAL (23% and 109% increase in AUC, respectively) for a 50% reduction in CL(CR). By contrast, renal impairment may lead to decreased exposure to 5'-DFCR. There was no evidence for an effect of renal impairment on systemic exposure to 5-FU or capecitabine. Renal impairment did not have a major effect on peak concentration (C(max)) or elimination half-life (t(1/2)) of capecitabine, 5'-DFCR, 5'-DFUR, and 5-FU. However, in the case of FBAL, moderate or severe renal impairment caused up to a twofold increase in C(max) and prolongation of t(1/2). All patients with severe renal impairment (four patients) had drug-related grade 3 or 4 adverse-events (AEs) and serious AEs. Patients with moderate renal impairment experienced a similar number of grade 3 or 4 AEs (six of nine patients) but had a higher incidence of serious AEs (three of nine patients) when compared with those with normal renal function (four of six patients and one of six patients, respectively). A similar effect was seen in patients with mild renal dysfunction (grade 3 or 4 AEs in four of eight patients; serious AEs in three of eight patients). The relationship between systemic exposure to capecitabine or its metabolites and safety was investigated using logistic regression. This exploratory analysis showed a strong positive relationship between AUC of 5'-DFUR and treatment-related grade 3 or 4 AEs, whereas there was no relationship with exposure to capecitabine, 5'-DFCR, 5-FU or FBAL. CONCLUSIONS: Renal impairment has no effect on the pharmacokinetics of capecitabine or 5-FU, but leads to an increase in the systemic exposure to 5'-DFUR and FBAL. However, only the AUC of 5'-DFUR is correlated with safety. Based on the safety results in patients with severe renal impairment, a dose modification cannot be recommended for these patients and they should not be treated with capecitabine. Additional data from the clinical safety database and pharmacokinetic results from the present study support the recommendation that patients with moderate renal impairment should be treated with 75% of the recommended standard starting dose to achieve systemic exposure comparable to that in patients with normal renal function.

Antimetabolites, Antineoplastic↗
PubMed2002

Non-platinum gemcitabine combinations in non-small cell lung cancer.

Lung cancer remains the most common cause of cancer related death. Although the primary goal of therapy is improvement in survival, improvement of symptoms, and quality of life are also important. Platinum-based chemotherapy has been shown to confer a modest but statistically significant survival benefit. Platinum-based therapy, however, has been associated with significant toxicity. Newer agents, such as gemcitabine, vinorelbine, paclitaxel, docetaxel, and irinotecan have been introduced into clinical practice. These agents have different mechanisms of activity and improved toxicity profiles. Combinations of these novel agents have been developed in an attempt to improve the toxicity profile and efficacy of the treatment of non-small cell lung cancer. This paper evaluates gemcitabine-based non-platinum combinations in the treatment of non-small cell lung cancer. Ongoing research evaluating the optimal dose, schedule, and combination is important in achieving improved outcomes in terms of survival and quality of life.

Aged↗
PubMed2002

Predictive DNA-testing for Huntington's disease and reproductive decision making: a European collaborative study.

This European collaborative study addresses the question whether a predictive test result for Huntington's disease (HD) has an effect on subsequent reproduction by comparing carriers and non-carriers of the Huntington mutation. A unique characteristic of this study is that this evaluation is done in persons at reproductive age who had a predictive test after the identification of the Huntington gene and who were counselled in one of the participating centres. Data were collected for 180 carriers and 271 non-carriers who received a predictive test result in the period 1993-1998 in Aberdeen, Athens, Cardiff, Leiden, Leuven, Paris or Rome. The mean age of the total study group was 31.5 years and for about half of the group the follow-up interval was 3 years or more, with a maximum of 7 years. The collaborative study clearly revealed an overall impact of the predictive test result on subsequent reproduction: 14% of the carriers had one or more subsequent pregnancies vs 28% of the non-carriers. In the total carrier group a prenatal test was carried out in about two thirds of the pregnancies and one child was born after preimplantation genetic diagnosis; artificial insemination by donor, egg cell donation or adoption were not reported. A more refined analysis was performed in the subgroup with a follow-up interval of at least 3 years and who reported 'family planning' as a motive to apply for predictive testing in the pretest period. The complexity of this motive is discussed. In this subgroup with a desire for children in the pretest period the effect of the predictive test result was more pronounced: 69% of the non-carriers had subsequent pregnancies while only 39% of the carriers who mentioned 'family planning' as one of the major reasons to apply for predictive testing had a subsequent pregnancy. Of the carriers with one or more subsequent pregnancies the percentage using prenatal diagnosis was slightly higher than the percentage not using it, although there were clear differences from one centre to another. The latter group's decisions may seem more intriguing but may be partially understood based on stage theories of health behaviour. Last, but not least, whatever option is chosen by a couple at increased risk of transmitting the Huntington mutation, it is of the utmost importance that professionals fully respect this decision and support the couple.

Adult↗
PubMed2002

Prenatal testing for Huntington's disease: a European collaborative study.

This European study involving seven genetic centres from six countries - Aberdeen, Cardiff (UK), Leiden (Netherlands), Leuven (Belgium), Paris (France), Rome (Italy), Athens (Greece) has gathered information on prenatal testing by direct mutation analysis and exclusion testing for Huntington's disease (HD) from the six European countries during the period 1993-1998. Data describing the parent belonging to the HD family was collected; this included their sex and age as well as their risk of developing HD. Information about previous pregnancies, the rank of the pregnancy being tested and its outcome was also gathered. In addition the number of previous prenatal tests for HD was recorded. Three hundred and five results were recorded by the participating countries between 1993 and 1998. The largest groups came from the UK (157) and the Netherlands (90). The mean age for the parent from the HD family was 30.8 years. In half of the tests the prospective parent was an asymptomatic gene carrier, 42% remained at risk, and 6% of the prospective parents were already showing clinical features of HD. 65% of tests performed used mutation analysis.

Adolescent↗
PubMed2002

Current clinical practices for ovarian cancers.

Ovarian cancer is one of the most aggressive gynecologic cancers. It shows its symptoms late and is consequently often diagnosed at an advanced stage. The search for a more effective chemotherapy regimen, therefore, is of great importance. Since 1996, the combination of cisplatin and paclitaxel has been proven to prolong survival in comparison with older regimens containing cisplatin and cyclophosphamide. In addition, the introduction of carboplatin in combination with paclitaxel showed similar efficacy but preferable toxicity profiles when compared with cisplatin in combination with paclitaxel. Representative studies evaluating paclitaxel combination therapies as well as new trends in the treatment of ovarian cancer are summarized in this article.

Anemia↗
PubMedDate not supplied

Panel discussion.

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Adolescent↗