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Biomedical subjects

P Harper

Publications and source records attributed to P Harper.

At least 19 recordsLinked to original sources
PubMed1998

[Porphyria cutanea tarda is the most common type of porphyria. Medical control is a team work].

Porphyria cutanea tarda (PCT) is probably the most common of the porphyrias. The development of skin fragility and blisters are the symptoms that generally bring the patient to the notice of the dermatologist. During the past decade the disease has been recognised as being of heterogeneous aetiology, and a pathogenetic classification has been proposed. The significance of subtyping for the choice of management strategy is currently appreciated, as is the need of close monitoring owing to the risk of the common PCT-associated liver conditions. Preferably the PCT patient should be managed by a dermatologist and a hepatologist working in concert and supported by a specialised porphyria laboratory. The use of a structured management protocol should be considered.

Diagnosis, Differential↗
PubMed1998

[Prevention of acute intermittent porphyria is the best solution. Most important are early diagnosis and counseling].

Recent mapping of acute intermittent porphyria (AIP) in Sweden has confirmed its very high prevalence in northern districts, though about fifty per cent of the gene carriers are to be found in the central and southern parts of the country. More than eighteen different AIP mutations are currently recognised in the Swedish kindreds. One mutations, evidently originating in northern Sweden, is predominant. As AIP is a pharmacogenetic disease, more than 200 substances being currently known to precipitate the neuropsychiatric symptoms, the greatest care is required in prescribing drugs to carriers of genetic predisposition to the disease. Guidelines are provided in the booklet. Drugs contraindicated in acute porphyria (Läkemedel farliga vid akut porfyri), jointly issued by the Swedish Porphyria Association and the Corporation of Swedish Pharmacists (Apoteksbolaget). Where doubt exists, specialists should be consulted since there are a number of factors that may contribute to an adverse reaction. Early diagnosis, preferably before puberty, and counselling are the cornerstones of management, and genetic analysis the diagnostic tool of choice, applicable in most families. In the symptomatic phase, glucose or haem arginate is effective in reversing the metabolic processes responsible for the exacerbation. Recently, the hepatic and late renal manifestations of the disease have been recognised, and early detection of the associated conditions is recommended. This includes monitoring for paraneoplastic prodromes of hepatocellular cancer.

Genetic Counseling↗
PubMed1998

[Risk of liver failure in erythropoietic protoporphyria. Be alert for sings of cholestatic development!].

Erythropoietic protoporphyria (EPP) presents clinically as a painful skin reaction to sun-light exposure. The profoundly disabling psychosocial consequences of the disease often go unnoticed by the physician, and the need to monitor the patient for hepatic complications is not generally recognised. The article describes the clinical and biochemical course in a 51-year-old man with EPP, who within a few days developed signs of acute hepatic failure. The case emphasises the importance of a well designed monitoring programme that allows close evaluation of the patient's current porphyrin metabolism, and indicates what measures should be considered.

Cholestasis, Intrahepatic↗
PubMed1998

[Porphyria--a metabolic mine field].

The porphyrias, uncommon conditions often eluding diagnosis, extremely susceptible to inappropriate treatment and associated with severe late manifestations, are representative of the small groups of scarce and complex diseases that are difficult to manage without specialised resources. A network of offices with diagnostic and consultative support from a national specialist centre is probably the most cost effective way of meeting the patients' demands in terms of highly specialised medical experience coupled with close contact and continuity This approach, adopted by the Swedish Porphyria Centre, is based on well structured and regularly updated programmes for the management of porphyria patients.

Counseling↗
PubMed1998

Randomized trial of dose-intensity with single-agent carboplatin in patients with epithelial ovarian cancer. London Gynaecological Oncology Group.

PURPOSE: We have examined the role of an increase in cisplatin dose-intensity in patients with advanced epithelial ovarian cancer by means of single-agent carboplatin therapy. PATIENTS AND METHODS: Two hundred twenty-seven patients were randomized to treatment and eligible for analysis. The dose of carboplatin was calculated according to the Calvert formula. One hundred seventeen patients received carboplatin at an area under the concentration time curve (AUC) of 6 for six courses, administered every 28 days, and 110 patients received carboplatin at an AUC of 12 for four courses, administered every 28 days. Patients were eligible provided they had not received prior chemotherapy or radiotherapy and had International Federation of Gynecology and Obstetrics stages II to IV or relapsed stage I epithelial ovarian cancer. RESULTS: The planned total-dose increase was 33% for the patients treated with carboplatin AUC 12, but the received percentage total-dose increase was 20%. There were no differences in progression-free or overall survival between the two treatment arms; the overall survival rate at 5 years was 31% and 34% of patients treated at AUCs 6 and 12, respectively. There was significantly more toxicity associated with carboplatin AUC 12, which resulted in more treatment delays and/or dose reductions (52% v 18%; P < .001). CONCLUSION: We have shown that carboplatin can be delivered at an AUC of 12 for four courses without granulocyte colony-stimulating factor support, although significant hematologic toxicity occurs. Nonhematologic toxicities were not clinically significant. Carboplatin offers an opportunity to intensify cisplatin therapy, but a greater than two-fold increase in dose-intensity probably needs to be achieved before significant effects on survival will be produced and hematologic support will be required.

Adult↗
PubMed1997

Large phlebotomy in variegate porphyria.

There are no reports on effects of large blood losses in acute hepatic porphyria. In the present study we report the experiences of repeated large therapeutic phlebotomies in a patients with porphyria cutanea tarda coexisting with variegate porphyria. Neither a series of 12 phlebotomies, 300 mL each, resulting in a 17% decrease in blood haemoglobin, nor a single 400 mL phlebotomy activated the acute porphyric condition. It is concluded that the increased bone marrow metabolic throughput resulting from blood loss, in acute types of porphyria does not overload the normoblast or leukocyte precursor haem synthetic pathways in a way which will increase porphyrin precursor excretion or trigger acute porphyric symptoms.

Female↗
PubMed1997

Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer.

PURPOSE: We report the results of a prospectively randomized study that compared the combination of epirubicin, cisplatin, and protracted venous infusion fluorouracil (5-FU) (ECF regimen) with the standard combination of 5-FU, doxorubicin, and methotrexate (FAMTX) in previously untreated patients with advanced esophagogastric cancer. PATIENTS AND METHODS: Two hundred seventy-four patients with adenocarcinoma or undifferentiated carcinoma were randomized and analyzed for survival, tumor response, toxicity, and quality of life (QL). RESULTS: The overall response rate was 45% (95% confidence interval [CI], 36% to 54%) with ECF and 21% (95% CI, 13% to 29%) with FAMTX (P = .0002). Toxicity was tolerable and there were only three toxic deaths. The FAMTX regimen caused more hematologic toxicity and serious infections, but ECF caused more emesis and alopecia. The median survival duration was 8.9 months with ECF and 5.7 months with FAMTX (P = .0009); at 1 year, 36% (95% CI, 27% to 45%) of ECF and 21% (95% CI, 14% to 29%) of FAMTX patients were alive. The median failure-free survival duration was 7.4 months with ECF and 3.4 months with FAMTX (P = .00006). The global QL scores were better for ECF at 24 weeks, but the remaining QL data showed no differences between either arm of the study. Hospital-based cost analysis on a subset of patients was similar for each arm and translated into an increment cost of $975 per life-year gained. CONCLUSION: The ECF regimen results in a survival and response advantage, tolerable toxicity, better QL and cost-effectiveness compared with FAMTX chemotherapy. This regimen should now be considered the standard treatment for advanced esophagogastric cancer.

Adenocarcinoma↗
PubMed1997

Effects of administration of antioxidants in acute intermittent porphyria.

In order to elucidate the question of free radical involvement in acute porphyric crisis, antioxidants were administered to two acute intermittent porphyria patients with long-standing recurrent attacks. Clinical condition and urinary excretion of porphyrins and porphyrin precursors were monitored before, during and after an eight week therapy with daily doses of vitamin E, beta-carotene, ascorbic acid, selenium, vitamin Q, acetylcysteine, mannitol and carnitine. Blood cell trace element profiles were followed. The administration of the compound antioxidant formula was found not to further impair the clinical or biochemical conditions of the patients but the incidence of the recurrent crises or the severity of the symptoms were not positively affected. Aberrant blood cell trace element profiles with increased granulocyte manganese were normalized during treatment, on cessation of the therapy again resuming the abnormal pretreatment patterns, which may suggest an origin in oxidative stress. No correlation was observed between the concentration of granulocyte manganese and the excretion of 5-aminolaevulinic acid. Indications for participation of this porphyrin precursor in a radical generating process leading to generalized mitochondrial superoxide dismutase induction, as conceivably signalled by increased intracellular manganese, were thus not obtained. The failure to note a clinical response to antioxidant therapy may be due to factors dependent upon dosage of, or interaction between, the antioxidant compounds given, or on restricted bioavailability of the antioxidants at critical anatomical sites, and does not per se invalidate the model of acute porphyria as a hyperoxidative condition.

Adult↗
PubMed1997

Sequence variation at the phenylalanine hydroxylase gene in the British Isles.

Using mutation and haplotype analysis, we have examined the phenylalanine hydroxylase gene in the phenylketonuria populations of four geographical areas of the British Isles: the west of Scotland, southern Wales, and southwestern and southeastern England. The enormous genetic diversity of this locus within the British Isles is demonstrated in the large number of different mutations characterized and in the variety of genetic backgrounds on which individual mutations are found. Allele frequencies of the more common mutations exhibited significant nonrandom distribution in a north/south differentiation. Differences between the west of Scotland and southwestern England may be related to different events in the recent and past histories of their respective populations. Similarities between southern Wales and southeastern England are likely to reflect the heterogeneity that is seen in and around two large capital cities. Finally, comparison with more recently colonized areas of the world corroborates the genealogical origin by range expansion of several mutations.

Alleles↗
PubMed1997

Hereditary spastic paraplegia: LOD-score considerations for confirmation of linkage in a heterogeneous trait.

Hereditary spastic paraplegia (HSP) is a degenerative disorder of the motor system, defined by progressive weakness and spasticity of the lower limbs. HSP may be inherited as an autosomal dominant (AD), autosomal recessive, or an X-linked trait. AD HSP is genetically heterogeneous, and three loci have been identified so far: SPG3 maps to chromosome 14q, SPG4 to 2p, and SPG4a to 15q. We have undertaken linkage analysis with 21 uncomplicated AD families to the three AD HSP loci. We report significant linkage for three of our families to the SPG4 locus and exclude several families by multipoint linkage. We used linkage information from several different research teams to evaluate the statistical probability of linkage to the SPG4 locus for uncomplicated AD HSP families and established the critical LOD-score value necessary for confirmation of linkage to the SPG4 locus from Bayesian statistics. In addition, we calculated the empirical P-values for the LOD scores obtained with all families with computer simulation methods. Power to detect significant linkage, as well as type I error probabilities, were evaluated. This combined analytical approach permitted conclusive linkage analyses on small to medium-size families, under the restrictions of genetic heterogeneity.

Chromosomes, Human, Pair 14↗
PubMed1997

Pathogenic mechanisms of the acute porphyric attack: speculative roles of manganese associated enzymes.

The significantly increased concentrations of granulocyte manganese in subjects with AIP may be an indication of overexpression of manganese-associated enzymes. In this study we present further observations related to this phenomenon and speculate that this may provide a rational basis for hypotheses attempting to explain the pathogenesis of the acute attack of porphyria. Such hypotheses are advanced with regard to pyruvate carboxylase, mitochondrial superoxide dismutase and glutamine synthetase, three manganese-dependent enzymes associated with either ALA-generating or ALA-dependent processes. The metabolic impacts in acute porphyria of these enzymes would be functions of the current energy charge of the organism, and would thus explain the protecting and ameliorating effects of glucose in these conditions. Although granulocytes from AIP subjects have elevated manganese concentrations, this did not appear to be associated with increased activities of two enzymes assayed, pyruvate carboxylase or mitochondrial superoxide dismutase. However, enzyme activities in white blood cells do not necessarily represent the levels of catalytic activity in cell types involved in the phenotypic expression of porphyria. Thus it proposed that hypotheses along these new lines of thinking are not flawed by the apparently missing correlations, and should not be therefore discarded. The possible roles of manganese-associated enzymes in the mechanisms behind the acute porphyric attack are discussed in some detail in the paper.

Adult↗
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↗