Weekly docetaxel versus CMF as adjuvant chemotherapy for elderly breast cancer patients: safety data from the multicentre phase 3 randomised ELDA trial

Within an ongoing multicentre phase 3 randomised trial (ELDA, cancertrials.gov ID: NCT00331097), early breast cancer patients, 65-79 years old, with average to high risk of recurrence, are randomly assigned to receive CMF (cyclophosphamide 600 mg/m2, methotrexate 40 mg/m2, fluorouracil 600 mg/m2, days 1-8) or docetaxel (35 mg/m2 days 1-8-15), every 4 weeks. Here we report an unplanned safety analysis prompted by an amendment introducing creatinine clearance as a tool to adjust methotrexate dose. Before such change, 101 patients with a median age of 70 were randomly assigned CMF (53 patients) or docetaxel (48 patients). At least one grades 3-4 toxic event of any type was reported in 40 (75.5%) and 19 (39.6%) patients with CMF and docetaxel, respectively (p=0.0002). Grades 3-4 hematological events were observed in 37 (69.8%) vs. 4 (8.3%) cases (p<0.0001) and grades 3-4 non-hematological toxicity in 12 (22.6%) vs. 15 (31.2%) patients (p=0.11), with CMF and docetaxel, respectively. A higher incidence of anemia, neutropenia, thrombocytopenia and febrile neutropenia was reported with CMF. Constipation, mucositis, nausea and vomiting were more common with CMF; diarrhoea, abdominal pain, dysgeusia, neuropathy and liver toxicity were more frequent with docetaxel. No significant interaction was found between the occurrence of severe toxicity and baseline variables, including creatinine clearance and geriatric activity scales. In conclusion, weekly docetaxel appears to be less toxic than CMF in terms of hematological toxicity.     

Effects of nitroglycerin treatment on baroreflex sensitivity and short-term heart rate variability in humans

OBJECTIVES: We set out to determine the effect of sustained treatment with nitroglycerin (GTN) on neural modulation of heart rate in humans. BACKGROUND: Acutely, exogenous and endogenous nitric oxide reduces sympathetic, while increasing vagal, outflow. An animal study showed loss of these effects during nitrate tolerance. METHODS: A total of 29 healthy men (age range, 18 to 32 years) received transdermal GTN (0.6 mg/h/24 h) or no therapy for six days in a parallel controlled trial. The reflex regulation of heart rate was assessed with the spontaneous baroreflex sensitivity (BRS) method. Heart rate variability was calculated both in time (standard deviation of mean RR interval [RRSD]) and frequency domains (Fast Fourier Transformation) over 10-min intervals. RESULTS: Systolic blood pressure was unchanged after continuous GTN, whereas mean RR interval decreased significantly (from 839 to 781 ms, p < 0.05). Nitroglycerin blunted BRS (p < 0.05). When compared with untreated subjects, RRSD was significantly lower after GTN, whereas the ratio of low to high frequencies was increased (all p < 0.05). CONCLUSIONS: Chronic GTN reduces tonic and reflex vagal heart rate modulation, resulting in greater relative sympathetic influence. Importantly, such changes in the regulation of chronotropic oscillations might have negative prognostic implications in both heart failure and coronary artery disease. Furthermore, because chronic GTN alters the blood pressure/heart rate relationship, our data suggest caution when using these variables as pharmacodynamic markers for the development of nitrate tolerance.     

The protection of rat liver autophagic proteolysis from the age-related decline co-varies with the duration of anti-ageing food restriction

Restricting caloric intake (CR) well below that of ad libitum (AL) fed animals retards and/or delays many characteristics of ageing and the occurrence and progression of age-associated diseases, efficacy depending on duration. The hypothesis that the anti-ageing effect of CR might involve stimulation of the cell-repair mechanism autophagy was tested. The effects of ageing and duration of anti-ageing CR on liver autophagic proteolysis (AP) were explored in male AL Sprague-Dawley rats aged 2-, 6-, 12- and 24-months; and 24-month-old rats on a CR diet initiated at 2-, 6- and 12-month of age or initiated at age 2-months and interrupted at age 18 months. The age-related changes in the regulation of AP were studied by monitoring the rate of valine release in the incubation medium from isolated liver cells by an HPLC procedure. Results show that the maximum attainable rate and the regulation of AP decline with increasing age; that changes are prevented by anti-ageing CR initiated at young age, that the protective effects of CR change with the duration of diet. It is concluded that the data are compatible with the hypothesis that AP and improved membrane maintenance might be involved in the antiageing mechanism of CR.     

Plasma PCSK9 levels and sepsis severity: an early assessment in the emergency department

Clinical and Experimental Medicine - The aim of the study is to evaluate the prognostic value of early PCSK9 levels in non-intubated septic patients admitted to the emergency department. This...     

Unilateral Plantar Flexors Static-Stretching Effects on Ipsilateral and Contralateral Jump Measures

The aim of this study was to evaluate the acute effects of unilateral ankle plantar flexors static-stretching (SS) on the passive range of movement (ROM) of the stretched limb, surface electromyography (sEMG) and single-leg bounce drop jump (SBDJ) performance measures of the ipsilateral stretched and contralateral non-stretched lower limbs. Seventeen young men (24 ± 5 years) performed SBDJ before and after (stretched limb: immediately post-stretch, 10 and 20 minutes and non-stretched limb: immediately post-stretch) unilateral ankle plantar flexor SS (6 sets of 45s/15s, 70-90% point of discomfort). SBDJ performance measures included jump height, impulse, time to reach peak force, contact time as well as the sEMG integral (IEMG) and pre-activation (IEMG_{pre-activation}) of the gastrocnemius lateralis. Ankle dorsiflexion passive ROM increased in the stretched limb after the SS (pre-test: 21 ± 4° and post-test: 26.5 ± 5°, p < 0.001). Post-stretching decreases were observed with peak force (p = 0.029), IEMG (P<0.001), and IEMG_{pre-activation} (p = 0.015) in the stretched limb; as well as impulse (p = 0.03), and jump height (p = 0.032) in the non-stretched limb. In conclusion, SS effectively increased passive ankle ROM of the stretched limb, and transiently (less than 10 minutes) decreased muscle peak force and pre-activation. The decrease of jump height and impulse for the non-stretched limb suggests a SS-induced central nervous system inhibitory effect.

Key points

• When considering whether or not to SS prior to athletic activities, one must consider the potential positive effects of increased ankle dorsiflexion motion with the potential deleterious effects of power and muscle activity during a simple jumping task or as part of the rehabilitation process.
• Since decreased jump performance measures can persist for 10 minutes in the stretched leg, the timing of SS prior to performance must be taken into consideration.
• Athletes, fitness enthusiasts and therapists should also keep in mind that SS one limb has generalized effects upon contralateral limbs as well.

Key words: Athletic training, exercise performance, exercise training, crossover, cross-education