Peripheral neuropathy induced by combination chemotherapy of docetaxel and cisplatin.

Docetaxel, a new semisynthetic taxoid that has demonstrated promising activity as an antineoplastic agent, was administered in combination with cisplatin to 63 patients in a dose-escalating study. As both drugs were known to be potentially neurotoxic, peripheral neurotoxicity was prospectively assessed in detail. Neuropathy was evaluated by clinical sum-score for signs and symptoms and by measurement of the vibration perception threshold (VPT). The severity of neuropathy was graded according to the National Cancer Institute's 'Common Toxicity Criteria'. The docetaxel-cisplatin combination chemotherapy induced a predominantly sensory neuropathy in 29 (53%) out of 55 evaluable patients. At cumulative doses of both cisplatin and docetaxel above 200 mg m(-2), 26 (74%) out of 35 patients developed a neuropathy which was mild in 15, moderate in ten and severe in one patient. Significant correlations were present between both the cumulative dose of docetaxel and cisplatin and the post-treatment sum-score of neuropathy (P < 0.01) as well as the post-treatment VPT (P < 0.01). The neurotoxic effects of this combination were more severe than either cisplatin or docetaxel as single agent at similar doses

A phase I and pharmacokinetic study of the combination of capecitabine and docetaxel in patients with advanced solid tumours

Capecitabine and docetaxel are both active against a variety of solid tumours, while their toxicity profiles only partly overlap. This phase I study was performed to determine the maximum tolerated dose (MTD) and side-effects of the combination, and to establish whether there is any pharmacokinetic interaction between the two compounds. Thirty-three patients were treated with capecitabine administered orally twice daily on days 1–14, and docetaxel given as a 1 h intravenous infusion on day 1. Treatment was repeated every 3 weeks. The dose of capecitabine ranged from 825 to 1250 mg m–2twice a day and of docetaxel from 75 to 100 mg m–2. The dose-limiting toxicity (DLT) was asthenia grade 2–3 at a dose of 1000 mg m–2bid of capecitabine combined with docetaxel 100 mg m–2. Neutropenia grade 3–4 was common (68% of courses), but complicated by fever in only 2.4% of courses. Other non-haematological toxicities were mild to moderate. There was no pharmacokinetic interaction between the two drugs. Tumour responses included two complete responses and three partial responses. Capecitabine 825 mg m–2twice a day plus docetaxel 100 mg m–2was tolerable, as was capecitabine 1250 mg m–2twice a day plus docetaxel 75 mg m–2. © 2000 Cancer Research Campaig

A phase Ib study of pertuzumab, a recombinant humanised antibody to HER2, and docetaxel in patients with advanced solid tumours

Pertuzumab represents the first in a new class of targeted therapeutics known as HER dimerisation inhibitors. We conducted a phase Ib study to determine the maximum-tolerated dose, the dose limiting toxicities (DLT), and pharmacokinetic (PK) interaction of docetaxel when administered in combination with pertuzumab. Initially, two dose levels of docetaxel (60 and 75 mg m−2) were explored in combination with a fixed dose of 1050 mg of pertuzumab; then two dose levels of docetaxel (75 and 100 mg m−2) were explored in combination following a fixed dose of 420 mg of pertuzumab with a loading dose of 840 mg. Both drugs were administered intravenously every 3 weeks. The latter dose of pertuzumab was allowed after an amendment to the original protocol when phase II data suggesting no difference in toxicity or activity between the 2 doses became available. Two patients out of two treated at docetaxel 75 mg m−2 in combination with pertuzumab 1050 mg suffered DLT (grade 3 diarrhoea and grade 4 febrile neutropaenia). Two out of five patients treated at docetaxel 100 mg m−2 in combination with pertuzumab 420 mg with a loading dose of 840 mg suffered DLT (grade 3 fatigue and grade 4 febrile neutropaenia). Stable disease was observed at four cycles in more than half of the patients treated and a confirmed radiological partial response with a >50% decline in PSA in a patient with hormone refractory prostate cancer were observed. There were no pharmacokinetic drug–drug interactions. The recommended phase II dose of this combination was docetaxel 75 mg m−2 and 420 mg pertuzumab following a loading dose of 840 mg

The Use of Telehealth Technology in Assessing the Accuracy of Self-Reported Weight and the Impact of a Daily Immediate-Feedback Intervention among Obese Employees

Objective. To determine the accuracy of self-reported body weight prior to and following a weight loss intervention including daily self-weighing among obese employees. Methods. As part of a 6-month randomized controlled trial including a no-treatment control group, an intervention group received a series of coaching calls, daily self-weighing, and interactive telemonitoring. The primary outcome variable was the absolute discrepancy between self-reported and measured body weight at baseline and at 6 months. We used general linear mixed model regression to estimate changes and differences between study groups over time. Results. At baseline, study participants underreported their weight by an average of 2.06 (se = 0.33) lbs. The intervention group self-reported a smaller absolute body weight discrepancy at followup than the control group. Conclusions. The discrepancy between self-reported and measured body weight appears to be relatively small, may be improved through daily self-monitoring using immediate-feedback telehealth technology, and negligibly impacts change in body weight

A new approach to physical activity maintenance: Rationale, design, and baseline data from the Keep Active Minnesota trial

<p>Abstract</p> <p>Background</p> <p>Since many individuals who initiate physical activity programs are highly likely to return to a sedentary lifestyle, innovative strategies to efforts to increase the number of physically active older adults who successfully <it>maintain </it>beneficial levels of PA for a substantial length of time are needed.</p> <p>Methods/Design</p> <p>The Keep Active Minnesota Trial is a randomized controlled trial of an interactive phone- and mail-based intervention to help 50–70 year old adults who have recently increased their physical activity level, maintain that activity level over a 24-month period in comparison to usual care. Baseline, 6, 12, and 24 month measurement occurred via phone surveys with kilocalories expended per week in total and moderate-to-vigorous physical activity (CHAMPS Questionnaire) as the primary outcome measures. Secondary outcomes include hypothesized mediators of physical activity change (e.g., physical activity enjoyment, self-efficacy, physical activity self-concept), body mass index, and depression. Seven day accelerometry data were collected on a sub-sample of participants at baseline and 24-month follow-up.</p> <p>Discussion</p> <p>The Keep Active Minnesota study offers an innovative approach to the perennial problem of physical activity relapse; by focusing explicitly on physical activity maintenance, the intervention holds considerable promise for modifying the typical relapse curve. Moreover, if shown to be efficacious, the use of phone- and mail-based intervention delivery offers potential for widespread dissemination.</p> <p>Trial registration</p> <p>ClinicalTrials.gov Identifier: NCT00283452.</p

Phosphoenolpyruvate Carboxykinase as the Sole Anaplerotic Enzyme in Saccharomyces cerevisiae

Pyruvate carboxylase is the sole anaplerotic enzyme in glucose-grown cultures of wild-type Saccharomyces cerevisiae. Pyruvate carboxylase-negative (Pyc–) S. cerevisiae strains cannot grow on glucose unless media are supplemented with C4 compounds, such as aspartic acid. In several succinate-producing prokaryotes, phosphoenolpyruvate carboxykinase (PEPCK) fulfills this anaplerotic role. However, the S. cerevisiae PEPCK encoded by PCK1 is repressed by glucose and is considered to have a purely decarboxylating and gluconeogenic function. This study investigates whether and under which conditions PEPCK can replace the anaplerotic function of pyruvate carboxylase in S. cerevisiae. Pyc– S. cerevisiae strains constitutively overexpressing the PEPCK either from S. cerevisiae or from Actinobacillus succinogenes did not grow on glucose as the sole carbon source. However, evolutionary engineering yielded mutants able to grow on glucose as the sole carbon source at a maximum specific growth rate of ca. 0.14 h–1, one-half that of the (pyruvate carboxylase-positive) reference strain grown under the same conditions. Growth was dependent on high carbon dioxide concentrations, indicating that the reaction catalyzed by PEPCK operates near thermodynamic equilibrium. Analysis and reverse engineering of two independently evolved strains showed that single point mutations in pyruvate kinase, which competes with PEPCK for phosphoenolpyruvate, were sufficient to enable the use of PEPCK as the sole anaplerotic enzyme. The PEPCK reaction produces one ATP per carboxylation event, whereas the original route through pyruvate kinase and pyruvate carboxylase is ATP neutral. This increased ATP yield may prove crucial for engineering of efficient and low-cost anaerobic production of C4 dicarboxylic acids in S. cerevisiae

Health Care Charges Associated With Physical Inactivity, Overweight, and Obesity

INTRODUCTION: Physical inactivity, overweight, and obesity are associated with increased morbidity and mortality. The objective of this study was to estimate the proportion of total health care charges associated with physical inactivity, overweight, and obesity among U.S. populations aged 40 years and older. METHODS: A predictive model of health care charges was developed using data from a cohort of 8000 health plan members aged 40 and older. Model cells were defined by physical activity status, body mass index, age, sex, smoking status, and selected chronic diseases. Total health care charges were estimated by multiplying the percentage of the population in each cell by the predicted charges per cell. Counterfactual estimates were computed by reclassifying all individuals as physically active and of normal weight while leaving other characteristics unchanged. Charges associated with physical inactivity, overweight, and obesity were computed as the difference between current risk profile total charges and counterfactual total charges. National population percentage estimates were derived from the National Health Interview Survey; those estimates were multiplied by the predicted charges per cell from the health plan analysis. RESULTS: Physical inactivity, overweight, and obesity were associated with 23% (95% confidence interval [CI], 10%–34%) of health plan health care charges and 27% (95% CI, 10%–37%) of national health care charges. Although charges associated with these risk factors were highest for the oldest group (aged 65 years and older) and for individuals with chronic conditions, nearly half of aggregate charges were generated from the group aged 40 to 64 years without chronic disease. CONCLUSION: Charges associated with physical inactivity, overweight, and obesity constitute a significant portion of total medical expenditures. The results underscore the importance of addressing these risk factors in all segments of the population

Phase I study on docetaxel and ifosfamide in patients with advanced solid tumours.

Docetaxel and ifosfamide have shown significant activity against a variety of solid tumours. This prompted a phase I trial on the combination of these drugs. This phase I study was performed to assess the feasibility of the combination, to determine the maximum tolerated dose (MTD) and the side effects, and to propose a safe schedule for further phase II studies. A total of 34 patients with a histologically confirmed solid tumour, who were not pretreated with taxanes or ifosfamide and who had received no more than one line of chemotherapy for advanced disease were entered into the study. Treatment consisted of docetaxel given as a 1-h infusion followed by ifosfamide as a 24-h infusion (schedule A), or ifosfamide followed by docetaxel (schedule B) every 3 weeks. Docetaxel doses ranged from 60 to 85 mg m(-2) and ifosfamide doses from 2.5 to 5.0 g m(-2). Granulocytopenia grade 3 and 4 were common (89%), short lasting and ifosfamide dose dependent. Febrile neutropenia and sepsis occurred in 17% and 2% of courses respectively. Non-haematological toxicities were mild to moderate and included alopecia, nausea, vomiting, mucositis, diarrhoea, sensory neuropathy, skin and nail toxicity and oedema. There did not appear to be any pharmacokinetic interaction between docetaxel and ifosfamide. One complete response (CR) (soft tissue sarcoma) and two partial responses (PRs) were documented. A dose of 75 mg m(-2) of docetaxel combined with 5.0 g m(-2) ifosfamide appeared to be manageable. Schedule A was advocated for further treatment

Associations between daily sitting time and the combinations of lifestyle risk factors in men

Background: Understanding the reciprocal role that multiple problematic behaviours play in men's health is important for intervention delivery and for reducing the healthcare burden. Data regarding the concurrence of problematic health behaviours is currently limited but offers insights into risk profiles, and should now include total time spent sitting/day. Methods: Self-reported data on lifestyle health behaviours was collected from 232 men aged ≥18 years who engaged in a men's health promotion programme delivered by 16 English Premier League Clubs. Results: Men at risk due to high sitting display multiple concurrent lifestyle risk factors, 88.6% displayed at least two ancillary risk factors and were three times more likely to report ≥2 lifestyle risk factors (OR. =3.13, 95% confidence interval (CI). =1.52-6.42) than those with low sitting risk. Significant differences in the mean number of risk factors reported between those participants in the higher risk (2.43. ±. 0.90) and lower risk (2.13. ±. 0.96) sitting categories were also found (P=0.015). Conclusions: Hard-to-reach men displayed multiple problematic concurrent behaviours, strongly linked to total sitting time. © 2012 WPMH GmbH