Analogies between reading of medical and religious texts.
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Attitude to Health↗
Biomedical subjects
Matthew Links
Publications and source records attributed to Matthew Links.
Phase I and pharmacokinetic study of weekly NV06 (Phenoxodiol), a novel isoflav-3-ene, in patients with advanced cancer.
BACKGROUND: We wished to define the maximum tolerated dose (MTD), toxicity, and pharmacokinetics of the novel isoflav-3-ene, NV06 (Phenoxodioltrade mark), a compound with a diphenolic structure related chemically and biologically to genistein and flavopiridol. PATIENTS AND METHODS: Twenty-one patients with advanced cancers were treated with weekly intravenous administration of NV06 at escalating dose levels with 1-4 patients at each dose cohort. Plasma sampling was undertaken to characterize the pharmacokinetic (PK) profile of the compound. RESULTS: Toxicity was minimal, with asymptomatic Grade 3 lymphocytopenia occurring in nine patients. Nine patients developed Grade 1 nausea, six patients developed Grade 1 increases in alkaline phosphatase, and six patients developed Grade 1 increases in transaminases. Two patients experienced hypersensitivity reactions. The MTD was not reached. Most patients had progressive disease on treatment but eight completed 12 weeks and two completed 24 weeks of treatment. The best response was stable disease of 6 months duration. The plasma half-life (T1/2), clearance (Cl), and volume of distribution (VD) were 304 (+/-91) min, 82 (+/-19) ml/min and 32,663 (+/-7,199) ml, respectively, for total NV06. CONCLUSIONS: NV06 is well tolerated and can be given safely as an intravenous infusion over 1-2 h at a dose of at least 30 mg/kg.
Adult↗
Review of patients with peritoneal malignancy treated with peritonectomy and heated intraperitoneal chemotherapy.
BACKGROUND: Peritoneal dissemination of malignancy is usually considered incurable. The purpose of the present study was to evaluate the efficacy of intraperitoneal chemohyperthermia and cytoreductive surgery. METHODS: The present article is a retrospective review of prospectively recorded data in 60 patients who underwent 71 peritonectomy procedures between January 1996 and May 2004. Hospital records, a database and department notes were studied. Conditions treated were pseudomyxoma peritoneii (PMP) and appendiceal cancer (23), mesothelioma (7), colorectal cancer (CRC, 15), ovarian cancer (6) and other forms of malignancy (9). Following cytoreductive surgery, early postoperative intraperitoneal chemotherapy (EPIC) was given in 47 procedures, five with added i.v. mitomycin C. In 34 procedures, heated intraperitoneal chemotherapy (HIPEC) was administered. A policy change was made from intravenous to intraperitoneal mitomycin C chemotherapy in December 2001. Peritoneal cancer index (PCI) was calculated for all procedures. RESULTS: Of the procedures, 23 had PCI < or = 10, 37 had PCI of 11-20, and 11 had PCI > 20. The median operation time was 9 h. Blood units transfused and length of hospital stay have declined. Mortality was 4/60 patients (6.7%), caused by pancytopenia and sepsis. Morbidity occurred in 28/71 procedures. The 3-year survival rate for the HIPEC group was 71% compared with 28% for the no HIPEC group. In the complete excision group, the 3-year survival rate was 52% compared with 13% for the incomplete excision group. The 3-year survival rate for PMP and appendiceal cancer was 74%. The 2-year survival rate for ovarian cancer was 67%, mesothelioma 57%, and CRC 50%, respectively. CONCLUSIONS: Morbidity is significantly associated with duration of surgery and units of blood transfused. Our findings are consistent with the international experience in patients treated with combined peritonectomy and HIPEC.
Adolescent↗
Peritoneal carcinomatosis from colorectal cancer and small bowel cancer treated with peritonectomy.
BACKGROUND: This study aims to assess the survival of patients who underwent peritonectomy, to assess the morbidity and mortality associated with the procedure and to review the published reports on the survival of patients with peritoneal spread of colorectal cancer (CRC). METHODS: Peritonectomy involves resection of all visible peritoneal tumour and is followed by heated intraperitoneal chemotherapy. Peritonectomy with heated intraperitoneal chemotherapy is associated with a 3-year survival of 30-50% in patients with low peritoneal cancer index (PCI) with peritoneal carcinomatosis from CRC. There are approximately 1000 patients in phase 2 studies and a large survival advantage was shown in a randomized control trial. We have carried out over 100 peritonectomy procedures. This study describes 22 patients with peritoneal spread of gastrointestinal cancer treated with peritonectomy between 1996 and March 2005. Twenty of these patients had primary colorectal cancer and two patients had primary small bowel cancer. RESULTS: Of the 22 patients who underwent peritonectomy, 8 patients are now deceased. The median follow up is now 16.1 months. At 12 months, the survival was 61.5% and at 24 months the survival was 46.1%, which are creditable results comparable with the world published reports. We found that those patients with all macroscopic residual tumour removed at the end of the procedure (completeness of cancer resection, CCR O) had improved 24-month survival compared with patients in whom there was incomplete tumour resection (53.3% survival vs 22.2%, respectively, P = 0.024). Patients with a PCI score less than 13 had better survival (P = 0.0003). CONCLUSIONS: Peritonectomy for peritoneal carcinomatosis from CRC offers patients improved survival. Our results are consistent with the published data with respect to improved survival in patients with low PCI and complete cytoreduction.
Adult↗
A phase 1 and pharmacokinetic study of gemcitabine and oxaliplatin in patients with solid tumors.
PURPOSE: This dose escalation study aimed to determine the recommended doses, toxicity and pharmacokinetics of oxaliplatin and gemcitabine given on days 1 and 8 every 21 days. This schedule may maximize dose intensity of both drugs with acceptable or reduced toxicity. PATIENT AND METHODS: Eligible patients had solid malignancies, no more than two prior courses of chemotherapy, ECOG performance status 0-2, neurotoxicity < or = NCI-CTC grade 1 and adequate organ function. Dose escalation commenced at oxaliplatin 40 mg/m(2) and gemcitabine 750 mg/m(2), both given on days 1 and 8 every 21 days, and reached oxaliplatin 80 mg/m(2) and gemcitabine 1,500 mg/m(2). The two highest dose levels were each expanded to six patients to gain additional toxicity data. RESULTS: There were no dose limiting toxicities related to treatment and an MTD was not reached. Five patients (24%) had grade 3 neutropenia, without associated infection, and seven patients (33%) had grade 3/4 thrombocytopenia. Neurotoxicity was mild and no worse than grade 1. Two patients with mesothelioma (10%) had partial responses and 11 patients (52%) had disease stabilization. No pharmacokinetic interaction between oxaliplatin and gemcitabine was detected. Dose intensity was maximal at level 4 (oxaliplatin 70 mg/m(2) and gemcitabine 1,250 mg/m(2)). CONCLUSIONS: This schedule allows oxaliplatin and gemcitabine to be delivered at the full dose intensity of each drug with excellent tolerability and predictable pharmacokinetics. The recommended doses for phase II studies are oxaliplatin 70 mg/m(2) and gemcitabine 1,250 mg/m(2) on days 1 and 8 every 21 days.
Adult↗
Off-trial evaluation of bisphosphonates in patients with metastatic breast cancer.
BACKGROUND: Bisphosphonate therapy has been readily accepted as standard of care for individuals with bone metastases from breast cancer. In this study we determined whether the proportion of patients experiencing a skeletal related event (SRE) in a clinical practice population was similar to that observed in phase III randomized controlled studies. METHODS: A retrospective chart review was conducted of 110 patients receiving intravenous bisphosphonates for advanced breast cancer. The proportion of patients experiencing at least one SRE after 12 months of therapy was determined. SRE included vertebral or non-vertebral fracture, cord compression, surgery and/or radiotherapy to bone. RESULTS: The proportion of patients who had an SRE was 30% (28 individuals) and the median time to first event was greater than 350 days. Non-vertebral events and radiotherapy were the most frequent type of SRE, while cord compression and hypercalcaemia were rare (1%). Most patients in the study had bone-only disease (58.2%) and most had multiple bone lesions. In the first 12 months the mean duration of exposure to intravenous bisphosphonates was 261 days and most patients remained on treatment until just before death (median 27 days). CONCLUSION: This study suggests that the rate of clinically relevant SREs is substantially lower than the event rate observed in phase III clinical trials. We attribute this lower rate to observational bias. In the clinical trial setting it is possible that over-detection of skeletal events occurs due to the utilisation of regular skeletal survey or radionucleotide bone scan, whereas these procedures are not routine in clinical practice. Phase IV observational studies need to be conducted to determine the true benefits of bisphosphonate therapy in order to implement rationale use of bisphosphonates.
Aged↗
Characterization of vaginal microflora of healthy, nonpregnant women by chaperonin-60 sequence-based methods.
OBJECTIVE: The purpose of this study was to use a novel method that was based on the application of chaperonin-60 sequencing to describe the vaginal microflora of 16 healthy women. STUDY DESIGN: Asymptomatic women consented for vaginal swabs to be collected at the time of a clinical pelvic examination. Total genomic DNA was isolated from the vaginal swabs. Degenerate, universal polymerase chain reaction primers were used to amplify an approximately 555 base pair region of the universal chaperonin-60 gene, which is found in all eubacteria and eukaryotes, from the total genomic DNA and libraries of cloned polymerase chain reaction products were constructed. Library clones were sequenced, and the resulting sequences were assigned to taxonomic groups on the basis of similarity to reference sequence data. Presence of Chlamydophila psittaci sequences in the samples was confirmed by species-specific polymerase chain reaction. RESULTS: Sixteen of the 23 women who were enrolled had normal flora by Nugent's score of <4 and had adequate polymerase chain reaction product for assessment. Vaginal flora libraries were dominated by a variety of sequences with similarity to Lactobacillus spp L. crispatus, L. iners, L. gasseri, L. jensenii, and L. buchneri. Other sequences that were identified included representatives of Gardnerella spp, sequences with similarity to Porphyromonas spp and Megasphaera spp and sequences identical to C psittaci. CONCLUSION: Culture-independent, chaperonin-60 sequence-based molecular methods can lead to the identification of greater diversity within defined taxa compared with those that are identified by standard culture-based methods and to the identification of novel organisms that were not previously associated with vaginal flora.
Adult↗
What survival benefits do premenopausal patients with early breast cancer need to make endocrine therapy worthwhile?
BACKGROUND: Adjuvant endocrine therapies such as tamoxifen, goserelin, and oophorectomy improve survival for premenopausal women diagnosed with early-stage breast cancer. However, these treatments often result in menopausal symptoms, sexual dysfunction, permanent infertility, or the need to delay pregnancy. We aimed to quantify the survival gains that premenopausal patients with early-stage breast cancer require to justify the side-effects and inconvenience of adjuvant endocrine treatments. METHODS: Participants consisted of 102 women who had been diagnosed with early-stage (stage I-II) breast cancer 6-60 months previously, who were aged 40 years or younger at diagnosis, and who had been treated for a minimum of 3 months with endocrine therapy (67 with tamoxifen alone, seven with goserelin alone, and 28 with tamoxifen and goserelin or oophorectomy). 76 patients also received chemotherapy, and 75 received radiotherapy. Participants attended a face-to-face patient-preference interview, in which they were presented with four hypothetical clinical scenarios that were used to quantify the gains in survival rate and life expectancy that women judged necessary to make their endocrine therapy worthwhile. They also completed a questionnaire on standard psychological measures. FINDINGS: About half of participants thought that adjuvant endocrine therapy was worthwhile for an absolute gain in survival of 2% from a baseline of either 65% or 85%, and for a gain in life expectancy of 3 months from a baseline of 5 years and of 6 months for a baseline of 15 years. Women who had had more severe endocrine side-effects required larger gains to make endocrine therapy worthwhile (univariate p=0.02, multivariate p=0.04). INTERPRETATION: Modest gains in survival are sufficient to make adjuvant endocrine treatment worthwhile for premenopausal women with early-stage breast cancer. Knowing and incorporating what women think should enhance shared decision-making.
Adolescent↗
The prevention and management of cardiovascular complications of chemotherapy in patients with cancer.
Cardiac toxicity of chemotherapeutic agents is a rapidly evolving area of increasing significance because of the increasing pool of long-term cancer survivors. The spectrum of cardiotoxicity with chemotherapeutic agents includes hypertension, QTc prolongation, acute cardiomyopathy, and bradyarrhythmias. The most common issue to arise has been cardiomyopathy with anthracyclines. Preventative strategies that have met with some success have included the use of less cardiotoxic analogs such as epirubicin and liposomal anthracycline preparations. The cardioprotectant agent dexrazoxane reduces cardiomyopathy but there are significant toxicity issues. Therefore, the main strategy for preventing cardiotoxicity remains careful monitoring with radionuclide angiography or echocardiography. The role of investigational markers of myocardial injury, such as troponin T or brain natriuretic peptide, remains of great interest. Management is according to conventional management of congestive heart failure. Trastuzumab is an antibody therapy directed against the human epidermal growth factor receptor-2 (HER2) receptor, which increases survival in patients with metastatic breast cancer and is under evaluation in the adjuvant setting. It also causes a decrease in left ventricular ejection fraction (LVEF) in a minority of patients. Incidence is increased if trastuzumab is given in conjunction with paclitaxel or anthracyclines. It differs from anthracycline cardiotoxicity in that it is not cumulative dose-dependent and often improves after withdrawal of treatment. Re-treatment with trastuzumab is often possible. Novel agents under development offer a different spectrum of toxicity to existing anticancer drugs and it appears likely that cardiovascular toxicity will be an important issue for many of these drugs, particularly those that target the tumor vasculature.
Antineoplastic Agents↗
BioMOBY: an open source biological web services proposal.
BioMOBY is an Open Source research project which aims to generate an architecture for the discovery and distribution of biological data through web services; data and services are decentralised, but the availability of these resources, and the instructions for interacting with them, are registered in a central location called MOBY Central. BioMOBY adds to the web services paradigm, as exemplified by Universal Data Discovery and Integration (UDDI), by having an object-driven registry query system with object and service ontologies. This allows users to traverse expansive and disparate data sets where each possible next step is presented based on the data object currently in-hand. Moreover, a path from the current data object to a desired final data object could be automatically discovered using the registry. Native BioMOBY objects are lightweight XML, and make up both the query and the response of a simple object access protocol (SOAP) transaction.
Computer Communication Networks↗