Efficacy of PI3K pathway inhibitors as single agents in metastatic breast cancer

L’objectiu del cribatge molecular és seleccionar pacients que es beneficiïn especialment de teràpies dirigides. S’analitza l’activitat en monoteràpia de fàrmacs inhibidors de la via de PI3K/AKT/mTOR (PI3Ki) en pacients amb càncer de mama metastàtic (CMM) i s’exploren potencials predictors de benefici clínic. La mitjana de temps a la progressió és de 2.6 mesos en 38 pacients incloses. No existeix correlació entre alteracions de la via i l’eficàcia, excepte en pacients amb mutació de PIK3CA que van millor al tractar-se amb un PI3Ki alfa-especific. Aquests resultats emfatitzen la necessitat d’un adequat cribatge molecular previ al tractament amb teràpies dirigides en CMM

Evaluation de l'efficacite antihypertensive de l'isradipine SRO par enregistrement tensionnel en ambulatoire. [Evaluation of the antihypertensive efficacy of isradipine SRO as assessed by ambulatory blood pressure determination]

The calcium channel blocker isradipine has become recently available in a form with delayed release (isradipine SRO). The anti-hypertensive efficacy and tolerance of this preparation at a single daily dose of 5 mg was studied in 40 patients with uncomplicated essential hypertension over a period of 6 weeks. Blood pressure during office visits decreased under Isradipine SRO from 164/105 +/- 16/7 to 144/93 +/- 12/7 mmHg (mean +/- 1 standard deviation p < 0.001). Using ambulatory blood pressure recording we could show that antihypertensive efficacy of the new galenic form persisted over 24 hours. During the day the blood pressure dropped from 150/95 +/- 13/7 to 141/91 +/- 13/7 mmHg (p < 0.001), during the night from 131/85 +/- 13/3 to 121/81 +/- 15/9 mmHg (p < 0.001). Heart-rate was not changed by treatment and the drug was well tolerated. Isradipine SRO at a single dose is thus well suited for antihypertensive treatment.

Efficacy of clinical guideline implementation to improve the appropriateness of chest physiotherapy prescription among inpatients with community-acquired pneumonia

BACKGROUND: Although there is no strong evidence of benefit, chest physiotherapy (CP) seems to be commonly used in simple pneumonia. CP requires equipment and frequently involves the assistance of a respiratory therapist, engendering a significant medical workload and cost. AIM: To measure and compare the efficacy of two modalities of chest physiotherapy (CP) guideline implementation on the appropriateness of CP prescription among patients hospitalised for community-acquired pneumonia (CAP). PATIENTS AND METHODS: We measured the CP prescription rate and duration in all consecutive CAP inpatients admitted in a division of general internal medicine at an urban teaching community hospital during three consecutive one-year time periods: (1) before any guideline implementation; (2) after a passive implementation by medical grand rounds and guideline diffusion through mailing; (3) after adding a one-page reminder in the CAP patient's medical chart highlighting our recommendations. Death and recurrent hospitalisation rates within one year after hospitalisation were recorded to assess whether CP prescription reduction, if any, impaired patient outcomes. RESULTS: During the three successive phases, 127, 157, and 147 patients with similar characteristics were included. Among all CAP inpatients, the CP prescription rate decreased from 68% (86/127) to 51% (80/157), and to 48% (71/147), respectively (P for trend <0.01 for trend). A significant reduction in CP duration was observed after the active guideline implementation (12.0, 11.0, 7.0days, respectively) and persisted after adjustment for length of stay. Reductions in CP prescription rate and duration were also observed among CAP patients with COPD CP prescription rate: 97% (30/31), 67% (24/36), 75% (35/47), respectively (P<0.01 for trend). The mean cost of CP per patient was reduced by 56%, from $709 to $481, and to $309, respectively. Neither the in-hospital deaths, the one-year overall recurrent hospitalisation nor the one-year CAP-specific recurrent hospitalisation significantly differed between the three phases. CONCLUSION: Both passive and active implementation of guidelines appear to improve the appropriateness of CP prescription among inpatients with CAP without impairing their outcomes. Restricting CP use to patients who benefit from this treatment might be an opportunity to decrease CAP medical cost and workload.

Analgesic efficacy of intravenous perfusion of lidocaine, ketamine or a combination after laparotomy in a placebo-controlled, randomized, double-blind prospective study

In acute postoperative pain management intravenous lidocaine and/or ketamine have been advocated because of their morphine-sparing effect. The goal of this prospective, randomised, double-blind study was to assess morphine consumption with different regimens of intravenous infusion of lidocaine, ketamine or both during 48 hours following laparotomy. Patients were randomised into four groups. Group L, K, and KL received intravenous lidocaine, ketamine or a combination, respectively, before incision and during 48 hours postoperatively. The control group (C) received a similar volume of saline bolus and infusion. Postoperative analgesia included morphine delivered by a patient-controlled analgesia device. Primary outcome was the cumulative morphine consumption and pain, sedation scores, pressure algometry and side effects were our secondary outcomes. Cognition and psychomotor performance were also tested. Out of 57 eligible patients, 44 completed the study. Lidocaine reduced the cumulative morphine consumption compared with the control group (mean 0.456 mg.kg-1 +/- 0.244 (SD) versus 0.705 +/- 0.442, respectively, Ρ < 0.001). Pain scores during movement were statistically lower in all three treatment groups. Psychometric tests showed that the lidocaine group expressed more depressed feelings and sadness compared to the control group. Lidocaine administration had a morphine-sparing effect with a 36% reduction of morphine consumption while ketamine alone or combined with lidocaine did not. As a whole, our results suggest that intravenous lidocaine may offer advantages for postoperative analgesia. We propose lidocaine as a new alternative for pain control that needs to be studied further in future multicentric studies.

Efficacy of brief motivational intervention at army conscription to address alcohol use and related problems: a randomized controlled trial

Objectives: The aim of this study was to evaluate the efficacy of brief motivational intervention (BMI) in reducing alcohol use and related problems among binge drinkers randomly selected from a census of 20 year-old French speaking Swiss men and to test the hypothesis that BMI contributes to maintain low-risk drinking among non-bingers. Methods: Randomized controlled trial comparing the impact of BMI on weekly alcohol use, frequency of binge drinking and occurrence of alcohol-related problems. Setting: Army recruitment center. Participants: A random sample of 622 men were asked to participate, 178 either refused, or missed appointment, or had to follow military assessment procedures instead, resulting in 418 men randomized into BMI or control conditions, 88.7% completing the 6-month follow-up assessment. Intervention: A single face-to-face BMI session exploring alcohol use and related problems in order to stimulate behaviour change perspective in a non-judgmental, empathic manner based on the principles of motivational interviewing (MI). Main outcome measures: Weekly alcohol use, binge drinking frequency and the occurrence of 12 alcohol-related consequences. Results: Among binge drinkers, we observed a 20% change in drinking induced by BMI, with a reduction in weekly drinking of 1.5 drink in the BMI group, compared to an increase of 0.8 drink per week in the control group (incidence rate ratio 0.8, 95% confidence interval 0,66 to 0,98, p = 0.03). BMI did not influence the frequency of binge drinking and the occurrence of 12 possible alcohol-related consequences. However, BMI induced a reduction in the alcohol use of participants who, after drinking over the past 12 months, experienced alcohol-related consequences, i.e., hangover (-20%), missed a class (-53%), got behind at school (-54%), argued with friends (-38%), engaged in unplanned sex (-45%) or did not use protection when having sex (-64%). BMI did not reduce weekly drinking in those who experienced the six other problems screened. Among non-bingers, BMI did not contribute to maintain low-risk drinking. Conclusions: At army conscription, BMI reduced alcohol use in binge drinkers, particularly in those who recently experienced alcohol-related adverse consequences. No preventive effect of BMI was observed among non-bingers. BMI is an interesting preventive option in young binge drinkers, particularly in countries with mandatory army recruitment.

Salt subtraction in patients on maintenance hemodialysis. Efficacy and limitations.

In 6 hypertensive patients with terminal renal failure maintained on hemodialysis, the effects of 'salt subtraction' and of sequential ultrafiltrating were evaluated. Following each of 3 weekly hemodialysis sessions, salt subtraction was carried out by ultrafiltrating 1 liter and simultaneously infusing an equal volume of 5% dextrose. This resulted in a net sodium loss without hypovolemia. After a 2-week period of this procedure, the blood pressure prior to dialysis was lower (156/76 +/- 12/5 mm Hg) than after a comparable number of sequential ultrafiltration sessions (181/88 +/- 10/6 mm Hg; mean +/- SEM). This difference was not statistically significant. At the same time, body weight was comparable at 64.4 +/- 3 and 64.7 +/- 4 kg, respectively. Neither plasma renin activity nor plasma catecholamines responded with a clear increase to either procedure. The limited effect on blood pressure and the renin system of a marked sodium removal during salt subtraction suggests that sodium must still be present in excess in these patients. The procedure of salt subtraction appears safe and subjectively well tolerated, but it can probably not be used as the sole means of decreasing total body sodium without associating dietary measures to reduce sodium intake.

Profile of male adolescents with conduct disorder on intellectual efficacy, cognitive flexibility, cognitive coping, impulsivity and alexithymia: a comparison with high-risk controls

Background and Objectives: To specify which of the documented cognitive and emotional deficits characterize adolescents with conduct disorder (CD) compared with high-risk controls. Methods: High-risk adolescent males with and without CD were compared on intellectual efficiency, cognitive flexibility, impulsivity, alexithymia, and cognitive coping strategies. Substance use was controlled for in analyses. Results: Both groups showed normal intellectual efficiency and cognitive flexibility, as weil as heightened alexithymia and bebavioral impulsivity. Youths with CD evidenced more self-defeating and black-and-white tbinking under stress, and more acting-out under negative affect, than those without CD. Conclusions: Deficits specifie to CD resided in facets of emotional functioning and cognitive coping that might be targeted by a coping skills intervention.

Causes développementales dans la variabilité de l'efficacité et de la toxicité des antalgiques en pédiatrie [Developmental causes in variability of efficacy and toxicity of analgesics in pediatrics]

The intensity of pain perception and its sensibility to analgesic drugs is highly variable and unpredictable between individuals. Drug disposition varies during development due to the physiological maturation of enzymatic systems and physiological processes responsible for the absorption, distribution, elimination and effect at the site of action. Many of those developmental variables are not yet clearly defined, but their consideration is important for avoiding potential risks of ineffective or toxic treatment. Implications of those developmental changes for day-to-day clinical practice depend on the age of the child, on the type of drug, on the underlying disease and on the potential co-administration of other chemicals.

Comprehensive annual financial report of the University of Northern Iowa, Cedar Falls, Iowa for the years ended June 30, 2008 and 2007

Comprehensive annual financial report of the University of Northern Iowa, Cedar Falls, Iowa for the years ended June 30, 2008 and 2007

Efficacy of garenoxacin in treatment of experimental endocarditis due to Staphylococcus aureus or viridans group streptococci.

The activity of garenoxacin was investigated in rats with experimental endocarditis due to staphylococci and viridans group streptococci (VGS). The staphylococci tested comprised one ciprofloxacin-susceptible and methicillin-susceptible Staphylococcus aureus (MSSA) isolate (isolate 1112), one ciprofloxacin-susceptible but methicillin-resistant S. aureus (MRSA) isolate (isolate P8), and one ciprofloxacin-resistant mutant (grlA) of P8 (isolate P8-4). The VGS tested comprised one penicillin-susceptible isolate and one penicillin-resistant isolate (Streptococcus oralis 226 and Streptococcus mitis 531, respectively). To simulate the kinetics of drugs in humans, rats were infused intravenously with garenoxacin every 24 h (peak and trough levels in serum, 6.1 and 1.0 mg/liter, respectively; area under the concentration-time curve [AUC], 63.4 mg. h/liter) or levofloxacin every 12 h (peak and trough levels in serum, 7.3 and 1.5 mg/liter, respectively; AUC, 55.6 mg. h/liter) for 3 or 5 days. Flucloxacillin, vancomycin, and ceftriaxone were used as control drugs. Garenoxacin, levofloxacin, flucloxacillin, and vancomycin sterilized >/=70% of the vegetations infected with both ciprofloxacin-susceptible staphylococcal isolates (P < 0.05 versus the results for the controls). Garenoxacin and vancomycin also sterilized 70% of the vegetations infected with ciprofloxacin-resistant MRSA isolate P8-4, whereas treatment with levofloxacin failed against this organism (cure rate, 0%; P < 0.05 versus the results obtained with the comparator drugs). Garenoxacin did not select for resistant derivatives in vivo. In contrast, levofloxacin selected for resistant variants in four of six rats infected with MRSA isolate P8-4. Garenoxacin sterilized 90% of the vegetations infected with both penicillin-susceptible and penicillin-resistant isolates of VGS. Levofloxacin sterilized only 22 and 40% of the vegetations infected with penicillin-susceptible S. oralis 226 and penicillin-resistant S. mitis 531, respectively. Ceftriaxone sterilized only 40% of those infected with penicillin-resistant S. mitis 531 (P < 0.05 versus the results obtained with garenoxacin). No quinolone-resistant VGS were detected. In all the experiments successful quinolone treatment was predicted by specific pharmacodynamic criteria (D. R. Andes and W. A. Craig, Clin. Infect. Dis. 27:47-50, 1998). The fact that the activity of garenoxacin was equal or superior to those of the standard comparators against staphylococci and VGS indicates that it is a potential alternative for the treatment of infections caused by such bacteria.

Efficacy of daptomycin in implant-associated infection due to methicillin-resistant Staphylococcus aureus: importance of combination with rifampin.

Limited treatment options are available for implant-associated infections caused by methicillin (meticillin)-resistant Staphylococcus aureus (MRSA). We compared the activity of daptomycin (alone and with rifampin [rifampicin]) with the activities of other antimicrobial regimens against MRSA ATCC 43300 in the guinea pig foreign-body infection model. The daptomycin MIC and the minimum bactericidal concentration in logarithmic phase and stationary growth phase of MRSA were 0.625, 0.625, and 20 microg/ml, respectively. In time-kill studies, daptomycin showed rapid and concentration-dependent killing of MRSA in stationary growth phase. At concentrations above 20 microg/ml, daptomycin reduced the counts by >3 log(10) CFU/ml in 2 to 4 h. In sterile cage fluid, daptomycin peak concentrations of 23.1, 46.3, and 53.7 microg/ml were reached 4 to 6 h after the administration of single intraperitoneal doses of 20, 30, and 40 mg/kg of body weight, respectively. In treatment studies, daptomycin alone reduced the planktonic MRSA counts by 0.3 log(10) CFU/ml, whereas in combination with rifampin, a reduction in the counts of >6 log(10) CFU/ml was observed. Vancomycin and daptomycin (at both doses) were unable to cure any cage-associated infection when they were given as monotherapy, whereas rifampin alone cured the infections in 33% of the cages. In combination with rifampin, daptomycin showed cure rates of 25% (at 20 mg/kg) and 67% (at 30 mg/kg), vancomycin showed a cure rate of 8%, linezolid showed a cure rate of 0%, and levofloxacin showed a cure rate of 58%. In addition, daptomycin at a high dose (30 mg/kg) completely prevented the emergence of rifampin resistance in planktonic and adherent MRSA cells. Daptomycin at a high dose, corresponding to 6 mg/kg in humans, in combination with rifampin showed the highest activity against planktonic and adherent MRSA. Daptomycin plus rifampin is a promising treatment option for implant-associated MRSA infections.

Evaluation par des médecins installés de l'efficacité antihypertensive de la débrisoquine, de la méthyldopa et du propranolol [Evaluation by practicing physicians of the antihypertensive efficacy of debrisoquin, methyldopa and propranolol]

The antihypertensive effect of debrisoquine (20 mg/day), methyldopa (100 mg/day) and propranolol (160 mg/day) was compared to that obtained with a placebo in a controlled trial carried out by a group of 14 internists. Forty-eight patients with uncomplicated essential hypertension were included. Mefruside (25 mg/day) was first given alone for 6 weeks ("open phase" of the trial) and to this diuretic was then added in double-blind fashion and randomized sequence a placebo or an active drug. Each of the 4 blind phases lasted 4 weeks. At the end of the "open phase", blood pressure in seated position averaged 168/111 +/- 19.6/13.5 mm Hg (mean +/- SD). A significant blood pressure decrease was observed after 4 weeks of treatment with the placebo as well as with the investigated compounds. With the placebo blood pressure was reduced to 158/102 +/- 19.6/13.5 mm Hg (p less than 0.001). The magnitude of the additional blood pressure decrease induced by the active drugs was relatively small and varied from 4 (debrisoquine) to 10 mm Hg (methyldopa, p less than 0.01) for the systolic and from 3 (debrisoquine, p less than 0.05) to 5 mm Hg (propranolol, p less than 0.05) for the diastolic. The percentage of patients with systolic pressure of less than or equal to 140 mm Hg and with diastolic pressure of less than 90 mm Hg during administration of either drug was not greater than 40 to 20% respectively. Propranolol appeared to be better tolerated than the other antihypertensive agents. These rather disappointing blood pressure results suggest that the efficacy of antihypertensive agents in private practice cannot be extrapolated from studies carried out in specialized hypertension clinics.

Isolated limb perfusion with tumor necrosis factor and melphalan for non-resectable soft tissue sarcomas : long-term results on efficacy and limb salvage in a selected group of patients

Rapport de synthèse : Introduction : La perfusion isolée de membre (isolated limb perfusion, ou ILP) par TNF-alpha et melphalan, utilisés en association, est une stratégie de prise en charge chirurgicale des sarcomes non opérables des extrémités. Elle a été en partie développée au CHUV dans les années 1990, sous l'impulsion du Professeur F. Lejeune, ancien Chef du Service d'oncologie médicale (CePO). Les résultats des 31 premiers patients ont été publiés en 2000 dans l'European Journal of Surgical Oncology. Les données dans la littérature manquant sur les résultats à long terme, nous avons revu tous les patients traités au CHUV depuis 1992 pour tenter des de déterminer ces résultats à long terme, en se focalisant sur l'efficacité du traitement, symbolisée par le taux de sauvetage de membres, autrement condamnés à l'amputation ou à une chirurgie mutilante. Matériel et méthode : Etude rétrospective. De 1992 à mars 2006, 51 patients ont été traités par ILP dans notre institution, certains à deux reprises (58 ILP au total). Quatre-vingt-huit pour cent présentaient un sarcome de haut grade de malignité, et 84% une tumeur localement avancée (T2b NO Mo ou plus). Résultats : Le follow-up moyen est de 38.9 mois (4-159, médiane 22 mois), on note 21 % de complications immédiates et 23% de complications tardives ou chroniques. Une réponse complète (nécrose totale ou disparition de la tumeur) a été observée dans 25% des cas, une réponse partielle (>50% de nécrose ou de diminution de taille tumorale) dans 42%, une stabilité de la maladie dans 14% et une progression tumorale dans 14%. Un traitement adjuvant a été entrepris dans 31 % des cas, une résection des résidus tumoraux a pu être effectuée chez 65% des patients. On note un taux de récidive locale de 35% (après 20,3 mois en moyenne) et un taux de récidive à distance de 45% (après 13,4 mois en moyenne). Le disease-free survival est de 14,9 mois et la survie à 5 ans de 43,5%. Le taux d'amputation s'élève à 24%. Conclusion : La perfusion isolée de membre est un traitement grevé d'un taux élevé de complications, mais il peut étre entrepris dans les sarcomes les plus sévères avec un succès significatif. Ainsi, dans notre série, une chirurgie mutilante (en général l'amputation) a pu être épargnée à 76% des patients.

Efficacy of a hip flexion assist orthosis in adults with hemiparesis after stroke.

Background During gait, the hip flexors generate 40% of the total power. Nevertheless, no device has been tested extensively for clinical purposes to cope with weakness in the hip flexors in patients with stroke. Objective The purpose of this study was to assess the efficacy and safety of a newly developed hip flexion assist orthosis in adult patients with hemiparesis after stroke. Design The study used a prospective, randomized, before-after trial design. The inclusion criteria were hemiparesis resulting from stroke (onset ≥8 weeks); ability to walk, even if with assistance; and hip flexion weakness (Medical Research Council Scale score ≤4).¦METHODS: /b> The main outcome measures were the 10-Meter Walk Test and the Six-Minute Walk Test. Patients also were evaluated with the Trunk Control Test, the Functional Ambulation Categories, the Motricity Index, and hip flexor strength on the Medical Research Council Scale. Sixty-two survivors of stroke were tested in random order with and without the orthosis. Any adverse event associated with its use was recorded.¦RESULTS: /b> Both the Six-Minute Walk Test and the 10-Meter Walk Test scores improved with the use of the orthosis. A significant negative correlation was found for improvement between scores on the 2 main outcome measures with the orthosis and the Functional Ambulation Categories scores. The improvement in Six-Minute Walk Test scores with the orthosis was related inversely to hip flexor strength.¦CONCLUSIONS: /b> The data showed that the use of a hip flexion assist orthosis can improve gait in patients with poststroke hemiparesis, particularly those with more severe walking impairment.