Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial.

BACKGROUND: Platinum-based doublet chemotherapy is recommended to treat advanced non-small-cell lung cancer (NSCLC) in fit, non-elderly adults, but monotherapy is recommended for patients older than 70 years. We compared a carboplatin and paclitaxel doublet chemotherapy regimen with monotherapy in elderly patients with advanced NSCLC. METHODS: In this multicentre, open-label, phase 3, randomised trial we recruited patients aged 70-89 years with locally advanced or metastatic NSCLC and WHO performance status scores of 0-2. Patients received either four cycles (3 weeks on treatment, 1 week off treatment) of carboplatin (on day 1) plus paclitaxel (on days 1, 8, and 15) or five cycles (2 weeks on treatment, 1 week off treatment) of vinorelbine or gemcitabine monotherapy. Randomisation was done centrally with the minimisation method. The primary endpoint was overall survival, and analysis was done by intention to treat. This trial is registered, number NCT00298415. FINDINGS: 451 patients were enrolled. 226 were randomly assigned monotherapy and 225 doublet chemotherapy. Median age was 77 years and median follow-up was 30.3 months (range 8.6-45.2). Median overall survival was 10.3 months for doublet chemotherapy and 6.2 months for monotherapy (hazard ratio 0.64, 95% CI 0.52-0.78; p<0.0001); 1-year survival was 44.5% (95% CI 37.9-50.9) and 25.4% (19.9-31.3), respectively. Toxic effects were more frequent in the doublet chemotherapy group than in the monotherapy group (most frequent, decreased neutrophil count (108 [48.4%] vs 28 [12.4%]; asthenia 23 [10.3%] vs 13 [5.8%]). INTERPRETATION: Despite increased toxic effects, platinum-based doublet chemotherapy was associated with survival benefits compared with vinorelbine or gemcitabine monotherapy in elderly patients with NSCLC. We feel that the current treatment paradigm for these patients should be reconsidered. FUNDING: Intergroupe Francophone de Cancérologie Thoracique, Institut National du Cancer.

Adaptive tuning of perceptual timing to whole body motion.

In a previous work we have shown that sinusoidal whole-body rotations producing continuous vestibular stimulation, affected the timing of motor responses as assessed with a paced finger tapping (PFT) task (Binetti et al. (2010). Neuropsychologia, 48(6), 1842-1852). Here, in two new psychophysical experiments, one purely perceptual and one with both sensory and motor components, we explored the relationship between body motion/vestibular stimulation and perceived timing of acoustic events. In experiment 1, participants were required to discriminate sequences of acoustic tones endowed with different degrees of acceleration or deceleration. In this experiment we found that a tone sequence presented during acceleratory whole-body rotations required a progressive increase in rate in order to be considered temporally regular, consistent with the idea of an increase in "clock" frequency and of an overestimation of time. In experiment 2 participants produced self-paced taps, which entailed an acoustic feedback. We found that tapping frequency in this task was affected by periodic motion by means of anticipatory and congruent (in-phase) fluctuations irrespective of the self-generated sensory feedback. On the other hand, synchronizing taps to an external rhythm determined a completely opposite modulation (delayed/counter-phase). Overall this study shows that body displacements "remap" our metric of time, affecting not only motor output but also sensory input.

HIV-1 elite controllers: beware of super-infections.

Super- and co-infection with HIV-1 are generally associated with accelerated disease progression. We report on the outcome of super-infection in two HIV-1 infected individuals previously known as elite controllers. Both presented an acute retroviral syndrome following super-infection and showed an immuno-virological progression thereafter. Host genotyping failed to reveal any of the currently recognized protective factors associated with slow disease progression. This report indicates that elite controllers should be informed of the risk of super-infection, and illustrates the complexity of mounting broad anti-HIV immunity.

Biomarkers of angiogenesis for the development of antiangiogenic therapies in oncology: tools or decorations?

Since 2004, four antiangiogenic drugs have been approved for clinical use in patients with advanced solid cancers, on the basis of their capacity to improve survival in phase III clinical studies. These achievements validated the concept introduced by Judah Folkman that the inhibition of tumor angiogenesis could control tumor growth. It has been suggested that biomarkers of angiogenesis would greatly facilitate the clinical development of antiangiogenic therapies. For these four drugs, the pharmacodynamic effects observed in early clinical studies were important to corroborate activities, but were not essential for the continuation of clinical development and approval. Furthermore, no validated biomarkers of angiogenesis or antiangiogenesis are available for routine clinical use. Thus, the quest for biomarkers of angiogenesis and their successful use in the development of antiangiogenic therapies are challenges in clinical oncology and translational cancer research. We review critical points resulting from the successful clinical trials, review current biomarkers, and discuss their potential impact on improving the clinical use of available antiangiogenic drugs and the development of new ones.

Association of biomarkers of lipid modification with functional and morphological indices of coronary stenosis severity in stable coronary artery disease.

Biomarkers of blood lipid modification and oxidative stress have been associated with increased cardiovascular morbidity. We sought to determine whether these biomarkers were related to functional indices of stenosis severity among patients with stable coronary artery disease. We studied 197 consecutive patients with stable coronary artery disease due to single vessel disease. Fractional flow reserve (FFR) ≤ 0.80 was assessed as index of a functionally significant lesion. Serum levels of secretory phospholipase A2 (sPLA2) activity, secretory phospholipase A2 type IIA (sPLA2-IIA), myeloperoxydase (MPO), lipoprotein-associated phospholipase A2 (Lp-PLA2), and oxidized low-density lipoprotein (OxLDL) were assessed using commercially available assays. Patients with FFR > 0.8 had higher sPLA2 activity, sPLA2 IIA, and OxLDL levels than patients with FFR ≤ 0.8 (21.25 [16.03-27.28] vs 25.85 [20.58-34.63] U/mL, p < 0.001, 2.0 [1.5-3.4] vs 2.6 [2.0-3.4] ng/mL, p < 0.01; and 53.0 [36.0-71.0] vs 64.5 [50-89.25], p < 0.001 respectively). Patients with FFR > 0.80 had similar Lp-PLA2 and MPO levels versus those with FFR ≤ 0.8. sPLA2 activity, sPLA2 IIA significantly increased area under the curve over baseline characteristics to predict FFR ≤ 0.8 (0.67 to 0.77 (95 % confidence interval [CI]: 0.69-0.85) p < 0.01 and 0.67 to 0.77 (95 % CI: 0.69-0.84) p < 0.01, respectively). Serum sPLA2 activity as well as sPLA2-IIA level is related to functional characteristics of coronary stenoses in patients with stable coronary artery disease.

Nutritional influences on lipogenesis and thermogenesis after a carbohydrate meal.

In vivo lipogenesis and thermogenesis were studied for 24 h after ingestion of 500 g of carbohydrate (CHO) in subjects who had consumed either a high-fat, a mixed, or a high-CHO diet during the 3-6 days preceding the test. CHO oxidation and conversion to fat was significantly less in the high-fat diet group (222 +/- 5 g) than in the mixed (300 +/- 13 g) or high-CHO diet (331 +/- 7 g) groups, resulting in a greater glycogen storage in the high-fat (278 +/- 6 g) than in the other two groups (197 +/- 11 and 170 +/- 2 g). Net lipogenesis occurred sooner and lasted longer in the high-CHO group, amounting to 0.8 +/- 0.5, 3.4 +/- 0.6, and 9 +/- 1 g of lipid synthesized in the high-fat, mixed, and high-CHO groups, respectively. The thermic effect of the CHO load was 5.2 +/- 0.5% on the high-fat, 6.5 +/- 0.4% on the mixed diet, and 8.6 +/- 0.4% on the high-CHO diet. Significant relationships were demonstrated between the postabsorptive nonprotein respiratory quotient and net lipogenesis after the CHO load (r = 0.82) and between net lipogenesis and the increase in energy expenditure (r = 0.71). It is concluded that the antecedent diet influences the amount of net lipogenesis and the magnitude of thermogenesis after a large CHO test meal. However, lipogenesis remains too limited even after such large CHO intakes to cause an increase in the body's fat content.

Deaths rates in public hospitals of eastern cape province of South Africa.

BACKGROUND: South Africa (SA) is experiencing a rapid epidemiologic transition as a consequence of political, economic and social changes. In this study we described, based on hospital data, the mortality patterns of Non communicable Diseases (NCD), Communicable Diseases (CD), the NCD/CD ratios, and the trends of deaths. METHODS: We conducted a cross-sectional survey of all deaths occurring in several public hospitals in the Eastern Cape Province of SA between 2002 and 2006. Causes of deaths were coded according to the ICD 10 Edition. RESULTS: A total of 107380 admissions responded to the inclusion criteria between 2002 and 2006. The crude death rate was 4.3% (n=4566) with a mean age of 46±21 years and a sex ratio of 3.1 men (n=3453): 1 woman (n=1113). Out of all deaths, there were 62.9% NCD (n=2872) vs. 37.1% CD (n=1694) with NCD/CD ratio of 1.7. The ratio NCD/CD deaths in men was 1.3 (n=1951/1502) vs. NCD/CD deaths in women of 1.9 (n=735/378). The peak of deaths was observed in winter season. The majority of NCD deaths were at age of 30-64 years, whereas the highest rate of CD deaths was at age< 30 years. The trend of deaths including the majority of NCD, increased from 2002 to 2006. There was a tendency of increase in tuberculosis deaths, but a tendency of decrease in HIV/AIDS deaths was from 2002 to 2006. CONCLUSION: Non-communicable diseases are the leading causes of deaths in rural Eastern Cape province of SA facing Post-epidemiologic transition stages. We recommend overarching priority actions for the response to the Non-communicable Diseases: policy change, prevention, treatment, international cooperation, research, monitoring, accountability, and re-orientation of health systems.

Prise en charge du cholestérol pour prévenir le risque cardiovasculaire:recommandations américaines 2013.Prise de position du Groupe de travail Suisse Lipides et Athérosclérose (GSLA).

Les dernières recommandations américaines de l'American College of Cardiology et de l'American Heart Association proposent d'abaisser le seuil de prescription de statines pour la prévention cardiovasculaire primaire, et d'abandonner les cibles de LDL-cholestérol pour utiliser le plus souvent des statines de haute intensité. Le Groupe de travail Suisse Lipides et Athérosclérose (GSLA) pense que ces recommandations ne devraient pas être appliquées en Suisse, car elles augmenteraient très fortement le nombre de personnes à bas risque sous statines, chez qui le rapport bénéfice/risque au long cours est incertain, et pourraient diminuer l'importance du style de vie, première priorité dans la prévention cardiovasculaire primaire. En outre, l'abandon des cibles de LDL-cholestérol limite l'individualisation de la prise en charge quant au choix du type et du dosage de la statine, et pourrait diminuer l'adhérence thérapeutique. Pour ces raisons, le GSLA recommande de poursuivre avec les stratégies de prévention bien établies en Suisse et résumées dans les recommandations du GSLA 2012.

Comparison of microsatellite instability and chromosomal instability in predicting survival of patients with T3N0 colorectal cancer.

BACKGROUND: At least 2 apparently independent mechanisms, microsatellite instability (MSI) and chromosomal instability, are implicated in colorectal tumorigenesis. Their respective roles in predicting clinical outcomes of patients with T3N0 colorectal cancer remain unknown. METHODS: Eighty-eight patients with a sporadic T3N0 colon or rectal adenocarcinoma were followed up for a median of 67 months. For chromosomal instability analysis, Ki-ras mutations were determined by single-strand polymerase chain reaction, and p53 protein staining was studied by immunohistochemistry. For MSI analysis, DNA was amplified by polymerase chain reaction at 7 microsatellite targets (BAT25, BAT26, D17S250, D2S123, D5S346, transforming growth factor receptor II, and BAX). RESULTS: Overall 5-year survival rate was 72%. p53 protein nuclear staining was detected in 39 patients (44%), and MSI was detected in 21 patients (24%). MSI correlated with proximal location (P <.001) and mucinous content (P <.001). In a multivariate analysis, p53 protein expression carried a significant risk of death (relative risk = 4.0, 95% CI = 1.6 to 10.1, P =.004). By comparison, MSI was not a statistically significant prognostic factor for survival in this group (relative risk = 2.2, 95% CI = 0.6 to 7.3, P =.21). CONCLUSIONS: p53 protein overexpression provides better prognostic discrimination than MSI in predicting survival of patients with T3N0 colorectal cancer. Although MSI is associated with specific clinicopathologic parameters, it did not predict overall survival in this group. Assessment of p53 protein expression by immunocytochemistry provides a simple means to identify a subset of T3N0 patients with a 4-times increased risk for death.

Pirosi: avete la scelta per la presa a carico a breve termine!: revisione Cochrane per il medico di famiglia.

Cet article présente les résultats de la revue systématique: van Pinxteren B, Sigterman KE, Bonis P, Lau J, Numans ME. Short-term treatment with proton pump inhibitors, H2-receptor antagonists and prokinetics for gastro-oesophageal reflux disease-like symptoms and endoscopy negative reflux disease. Cochrane Database of Systematic Reviews 2010, Issue 11, Art. No.: CD002095. DOI: 10.1002/14651858.CD002095.pub4. PMID: 21069670.

Aberrant crypt foci in patients with neoplastic and nonneoplastic colonic disease.

Aberrant crypt foci (ACF) are putative preneoplastic lesions that might represent the earliest morphological lesion visible in colonic carcinogenesis. However, findings concerning the growth and morphological features of these lesions in human studies suggest that ACF are highly heterogeneous in nature. In this study, we evaluated the morphological features of a large number of ACF in colon mucosa of 26 patients with colorectal carcinoma (CRC), four patients with adenoma as well as seven patients with nonneoplastic colonic diseases. By dissecting microscope, 508 ACF were identified, and of these, 378 were sampled for histological examination. The median ACF density (number of ACF/cm2) was significantly higher in the left colon than in the right colon (0.047 v 0.014 ACF/cm2). Unexpectedly, in our series, the overall ACF density was higher in the nonneoplastic colonic diseases than in CRC (0.13 v 0.032 ACF/cm2, P=.0087), cases of nonneoplastic diseases, however, being limited to 7 patients. ACF were significantly larger in colons with CRC or adenoma than in colons with nonneoplastic disease (P < .03). On histological examination, we observed 133 ACF with normal epithelium, 189 ACF with hyperplasia, 27 ACF with atypical hyperplasia, and 29 ACF with dysplasia. We noted a progressive increase of median ACF size from normal mucosa to hyperplasia, atypical hyperplasia, and dysplasia. Dysplastic ACF were more frequently observed in patients with CRC or adenoma and showed predominantly elongated crypt orifices (P < .0001). We conclude that ACF are histologically heterogeneous, encompass a spectrum of lesions of which only a subset are associated with dysplasia and then represent an early step in colorectal carcinogenesis. ACF with dysplasia are characterized by larger size, elongated crypt orifices, and an association with CRC.