Prognosis of stage II and III colon cancer treated with adjuvant 5-fluorouracil or FOLFIRI in relation to microsatellite status: results of the PETACC-3 trial?.

BACKGROUND: Although colon cancer (CC) with microsatellite instability (MSI) has a more favorable prognosis than microsatellite stable (MSS) CC, the impact varies according to clinicopathological parameters. We studied how MSI status affects prognosis in a trial-based cohort of stage II and III CC patients treated with 5-fluorouracil (5-FU)/leucovorin or FOLFIRI. MATERIALS AND METHODS: Tissue specimens of 1254 patients were tested for 10 different loci and were classified as MSI-high (MSI-H) when three or more loci were unstable and MSS otherwise. Study end points were overall survival (OS) and relapse-free survival (RFS). RESULTS: In stage II, RFS and OS were better for patients with MSI-H than with MSS CC [hazard ratio (HR) 0.26, 95% CI 0.10-0.65, P = 0.004 and 0.16, 95% CI 0.04-0.64, P = 0.01). In stage III, RFS was slightly better for patients with MSI-H CC (HR 0.67, 95% CI 0.46-0.99, P = 0.04), but the difference was not statistically significant for OS (HR 0.70, 95% CI 0.44-1.09, P = 0.11). Outcomes for patients with MSI-H CC were not different between the two treatment arms. RFS was better for patients with MSI-H than with MSS CC in the right and left colon, whereas for OS this was significant only in the right colon. For patients with KRAS- and BRAF-mutated CC, but not for double wild-type patients, RFS and OS were significantly better when the tumors were also MSI-H. An interaction test was statistically significant for KRAS and MSI status (P = 0.005), but not for BRAF status (P = 0.14). CONCLUSIONS: Our results confirm that for patients with stage II CC but less so for those with stage III MSI-H is strongly prognostic for RFS and OS. In the presence of 5-FU treatment, stage II patients with MSI-H tumors maintain their survival advantage in comparison with MSS patients and adding irinotecan has no added benefit. CLINICALTRIALSGOV IDENTIFIER: NCT00026273.

Relationship between dopamine D2 receptor occupancy, clinical response, and drug and monoamine metabolites levels in plasma and cerebrospinal fluid. A pilot study in patients suffering from first-episode schizophrenia treated with quetiapine.

Combining measurements of the monoamine metabolites in the cerebrospinal fluid (CSF) and neuroimaging can increase efficiency of drug discovery for treatment of brain disorders. To address this question, we examined five drug-naïve patients suffering from schizophrenic disorder. Patients were assessed clinically, using the Positive and Negative Syndrome Scale (PANSS): at baseline and then at weekly intervals. Plasma and CSF levels of quetiapine and norquetiapine as well CSF 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxyindole-acetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) were obtained at baseline and again after at least a 4 week medication trail with 600 mg/day quetiapine. CSF monoamine metabolites levels were compared with dopamine D(2) receptor occupancy (DA-D(2)) using [(18)F]fallypride and positron emission tomography (PET). Quetiapine produced preferential occupancy of parietal cortex vs. putamenal DA-D(2), 41.4% (p<0.05, corrected for multiple comparisons). DA-D(2) receptor occupancies in the occipital and parietal cortex were correlated with CSF quetiapine and norquetiapine levels (p<0.01 and p<0.05, respectively). CSF monoamine metabolites were significantly increased after treatment and correlated with regional receptor occupancies in the putamen [DOPAC: (p<0.01) and HVA: (p<0.05)], caudate nucleus [HVA: (p<0.01)], thalamus [MHPG: (p<0.05)] and in the temporal cortex [HVA: (p<0.05) and 5-HIAA: (p<0.05)]. This suggests that CSF monoamine metabolites levels reflect the effects of quetiapine treatment on neurotransmitters in vivo and indicates that monitoring plasma and CSF quetiapine and norquetiapine levels may be of clinical relevance.

Preserved capillary density of dorsal finger skin in treated hypertensive patients with or without type 2 diabetes

RESUME : La raréfaction des vaisseaux capillaires est une caractéristique de l'hypertension artérielle non traitée. Des données récentes indiquent que cette raréfaction peut être renversée par un traitement antihypertenseur chez les patients hypertendus non diabétiques. Malgré la fréquente association du diabète et de l'hypertension, on ne sait rien de la densité capillaire de patients diabétiques traités, souffrant d'hypertension artérielle. Nous avons dès lors recruté 21 patients normotendus (groupe contrôle), 25 patients souffrant uniquement d'hypertension artérielle , et 21 patients diabétiques (Diabète de type 2) souffrant également d'hypertension artérielle. Tous les patients hypertendus ont été traités avec un inhibiteur du système rénine-angiotensine, et une majorité présentait une tension artérielle moyenne en auto-contrôle à domicile de 135/85 mmHg ou moins. La densité capillaire a été évaluée par vidéomicroscopie sur la peau du dos des doigts et avec laser Doppler sur la peau de l'avant-bras (vasodilatation maximale induite par le chauffage local). Au final, il n'y avait pas de différence entre les groupes de l'étude, que ce soit lors des mesures de la densité capillaire sur le dos du doigt (groupe contrôle 101 ±11 capillaires, groupe des patients non- diabétiques hypertendus 99 ± 16, groupe des patients hypertendus et diabétiques 96 ± 18, p>0,5) ou lors des mesures de débit sanguin maximal sur la peau de l'avant-bras, un témoin indirect de la densité capillaire dans ce territoire (contrôles 666 ±114 unités de perfusion, non diabétique hypertendu 612 ± 126, hypertendus diabétiques 620 ±103, p> 0,5). En conclusion, notre étude est la première à démontrer que indépendamment de la présence ou non d'un diabète de type 2, la densité capillaire est normale chez les patients hypertendus présentant un contrôle raisonnable de la pression artérielle obtenue avec un bloqueur du système rénine-angiotensine.

Pharmacokinetic and pharmacodynamic responses in adult patients with Chagas disease treated with a new formulation of benznidazole

Pharmacological treatment of Chagas disease with benznidazole (BNZ) is effective in children in all stages, but it is controversial in chronically infected adults. We report the pharmacokinetics and pharmacodynamics in six adult patients with Chagas disease treated with the new BNZ formulation (ABARAX®) in doses between 2.5-5.5 mg/Kg/day. All but one patient had plasmatic BNZ concentrations within the expected range. All patients finalised treatment with nondetectable Trypanosoma cruziquantitative polymerase chain reaction, which remained nondetectable at the six month follow-up. Our data suggests parasitological responses with the new BNZ and supports the hypothesis that treatment protocols with lower BNZ doses may be effective.

Oral and general health-related quality of life in patients treated for oral cancer compared to control group.

BACKGROUND Health-related quality of life (HRQoL) is gaining importance as a valuable outcome measure in oral cancer area. The aim of this study was to assess the general and oral HRQoL of oral and oropharyngeal cancer patients 6 or more months after treatment and compare them with a population free from this disease. METHODS A cross-sectional study was carried out with patients treated for oral cancer at least 6 months post-treatment and a gender and age group matched control group. HRQoL was measured with the 12-Item Short Form Health Survey (SF-12); oral HRQoL (OHRQoL) was evaluated using the Oral Health Impact Profile (OHIP-14) and the Oral Impacts on Daily Performances (OIDP). Multivariable regression models assessed the association between the outcomes (SF-12, OHIP-14 and OIDP) and the exposure (patients versus controls), adjusting for sex, age, social class, functional tooth units and presence of illness. RESULTS For patients (n = 142) and controls (n = 142), 64.1% were males. The mean age was 65.2 (standard deviation (sd): 12.9) years in patients and 67.5 (sd: 13.7) years in controls. Patients had worse SF-12 Physical Component Summary scores than controls even in fully the adjusted model [β-coefficient = -0.11 (95% CI: -5.12-(-0.16)]. The differences in SF-12 Mental Component Summary were not statistically significant. Regarding OHRQoL patients had 11.63 (95% CI: 6.77-20.01) higher odds for the OHIP-14 and 21.26 (95% CI: 11.54-39.13) higher odds for OIDP of being in a worse category of OHRQoL compared to controls in the fully adjusted model. CONCLUSION At least 6 months after treatment, oral cancer patients had worse OHRQoL, worse physical HRQoL and similar psychological HRQoL than the general population.

Serological based monitoring of a cohort of patients with chronic Chagas disease treated with benznidazole in a highly endemic area of northern Argentina

This study aimed to evaluate well-documented diagnostic antigens, named B13, 1F8 and JL7 recombinant proteins, as potential markers of seroconversion in treated chagasic patients. Prospective study, involving 203 patients treated with benznidazole, was conducted from endemic areas of northern Argentina. Follow-up was possible in 107 out of them and blood samples were taken for serology and PCR assays before and 2, 3, 6, 12, 24 and 36 months after treatment initiation. Reactivity against Trypanosoma cruzi lysate and recombinant antigens was measured by ELISA. The rate of decrease of antibody titers showed nonlinear kinetics with an abrupt drop within the first three months after initiation of treatment for all studied antigens, followed by a plateau displaying a low decay until the end of follow-up. At this point, anti-B13, anti-1F8 and anti-JL7 titers were relatively close to the cut-off line, while anti-T. cruzi antibodies still remained positive. At baseline, 60.8% (45/74) of analysed patients tested positive for parasite DNA by PCR and during the follow-up period in 34 out of 45 positive samples (75.5%) could not be detected T. cruzi DNA. Our results suggest that these antigens might be useful as early markers for monitoring antiparasitic treatment in chronic Chagas disease.

Predicting response and survival in chemotherapy-treated triple-negative breast cancer.

BACKGROUND In this study, we evaluated the ability of gene expression profiles to predict chemotherapy response and survival in triple-negative breast cancer (TNBC). METHODS Gene expression and clinical-pathological data were evaluated in five independent cohorts, including three randomised clinical trials for a total of 1055 patients with TNBC, basal-like disease (BLBC) or both. Previously defined intrinsic molecular subtype and a proliferation signature were determined and tested. Each signature was tested using multivariable logistic regression models (for pCR (pathological complete response)) and Cox models (for survival). Within TNBC, interactions between each signature and the basal-like subtype (vs other subtypes) for predicting either pCR or survival were investigated. RESULTS Within TNBC, all intrinsic subtypes were identified but BLBC predominated (55-81%). Significant associations between genomic signatures and response and survival after chemotherapy were only identified within BLBC and not within TNBC as a whole. In particular, high expression of a previously identified proliferation signature, or low expression of the luminal A signature, was found independently associated with pCR and improved survival following chemotherapy across different cohorts. Significant interaction tests were only obtained between each signature and the BLBC subtype for prediction of chemotherapy response or survival. CONCLUSIONS The proliferation signature predicts response and improved survival after chemotherapy, but only within BLBC. This highlights the clinical implications of TNBC heterogeneity, and suggests that future clinical trials focused on this phenotypic subtype should consider stratifying patients as having BLBC or not.

Epiphyseal fracture of distal humerus in children, treated with bio-absorbable materials: one year follow-up

Introduction: The use of bioabsorbable materials for orthopaedic useand traumatic fracture fixation in children has been poorly investigatedin the litterature and the effects on growing bones seem contradictory.The aim of the study is to compare the clinical and radiological resultsand evolution between bioabsorbable and traditional K-Wires for thetreatment of elbow epiphyseal fractures in children.Method: From jan. 2008 to Dec. 2009 21 children with similar fracturesand age were separated in two groups according to the way of fracturefixation: bioabsorbable K-Wire group and traditional K-Wire group.Follow-up was done at 3, 6 and 12 month post-operatively. Range ofmotion and elbow stability were measured for all patients. Theradiological evolution of the two groups were compared in term ofconsolidation, ossous resorption and radiolucencies. The clinicalresults were compared according to the Mayo Elbow Peformancescore. Controlateral elbow is compared with injured elbow in the twogroups.Results: In the bioabsorbable K-wire group, there were 10 children,including 5 girles and 5 boys with an average age of 9.5 years, rangingfrom 5 to 14 years. They were 7 external condylar fractures and3 epitrochlear fractures. In the traditional K-Wire group there were11 children, 2 girls and 9 boys with an average age of 7.6 years,ranging from 4 to 14 years. There were 10 external condylar fracturesand 1 epitrochlear fracture. At first follow up. The Mayo ElbowPerformance score was 93.8 (85-100 )for the bioabsorbable K-Wiregroup and 95.5 (85-100) for the traditional K-Wire group. In twochildren from the bioabsorbable K-Wire group there were transitoryradiolucencies along the wire tract on the x-ray, without clinicalmanifestation of it.We didn't see any premature closure of growingcartilage.Discussion: There is no significant differencies in term of clinical andradiological outcome between the two groups. The use ofbioabsorbable pins seems to be a good alternative to removabletraditional materials, avoiding a second operation.

Can oxidative damage be treated nutritionally?

BACKGROUND & AIMS: Nutrition and dietary patterns have been shown to have direct impact on health of the population and of selected patient groups. The beneficial effects have been attributed to the reduction of oxidative damage caused by the normal or excessive free radical production. The papers aims at collecting evidence of successful supplementation strategies. METHODS: Review of the literature reporting on antioxidant supplementation trials in the general population and critically ill patients. RESULTS: Antioxidant vitamin and trace element intakes have been shown to be particularly important in the prevention of cancer, cardiovascular diseases, age related ocular diseases and in aging. In animal models, targeted interventions have been associated with reduction of tissue destruction is brain and myocardium ischemia-reperfusion models. In the critically ill antioxidant supplements have resulted in reduction of organ failure and of infectious complications. CONCLUSIONS: Antioxidant micronutrients have beneficial effects in defined models and pathologies, in the general population and in critical illness: ongoing research encourages this supportive therapeutic approach. Further research is required to determined the optimal micronutrient combinations and the doses required according to timing of intervention.

Immune responses to JC virus in patients with multiple sclerosis treated with natalizumab: a cross-sectional and longitudinal study.

BACKGROUND: Natalizumab is used to prevent relapses and progression of disability in patients with multiple sclerosis but has been associated with progressive multifocal leukoencephalopathy (PML). We aimed to better understand the associations between JC virus, which causes PML, and natalizumab treatment. METHODS: We prospectively assessed patients with multiple sclerosis who started treatment with natalizumab. Blood and urine samples were tested for the presence of JC virus DNA with quantitative real-time PCR before treatment and at regular intervals after treatment onset for up to 18 months. At the same timepoints, by use of proliferation and enzyme-linked immunospot assays, the cellular immune responses against JC virus, Epstein-Barr virus, cytomegalovirus, myelin oligodendrocyte glycoprotein, and myelin oligodendrocyte basic protein (MOBP) were assessed. Humoral immune response specific to JC virus was assessed with an enzyme immunoassay. The same experiments were done on blood samples from patients with multiple sclerosis before and 10 months after the start of interferon beta treatment. FINDINGS: We assessed 24 patients with multiple sclerosis who received natalizumab and 16 who received interferon beta. In patients treated with natalizumab, JC virus DNA was not detected in the blood at any timepoint. However, JC virus DNA was present in the urine of six patients and in most of these patients the concentrations of JC virus DNA were stable over time. Compared with pretreatment values, the cellular immune response was increased to cytomegalovirus at 6 months, to JC virus at 1, 9, and 12 months, and to Epstein-Barr virus and MOBP at 12 months. Humoral responses remained stable. There were no increases in cellular immune responses specific to the viruses or myelin proteins in the 16 patients treated with interferon beta. INTERPRETATION: Natalizumab increases cellular immune responses specific to viruses and myelin proteins in the peripheral blood after 1 year, without evidence of viral reactivation. FUNDING: Swiss National Foundation, Swiss Society for Multiple Sclerosis, and Biogen Dompé.

Lateral condyle fracture of the humerus in children treated with bioabsorbable materials.

The aim of this study was to compare clinical and radiological outcome of lateral condyle fracture of the elbow in children treated with bioabsorbable or metallic material. From January 2008 to December 2009, 16 children with similar fractures and ages were grouped according to the fixation material used. Children were seen at 3, 6, and 12 months and more than 4 years (mean 51.8 months) postoperatively. The clinical results were compared using the Mayo Elbow Performance Score (MEPS). Radiographic studies of the fractured and opposite elbow were assessed at last follow-up control. Twelve children had a sufficient followup and could be included in the study. Seven could be included in the traditional group and 5 in the bioabsorbable group. At 12 months, the MEPS was 100 for every child in both groups. Asymptomatic bony radiolucent visible tracks and heterotopic ossifications were noted in both groups. There were no significant differences in terms of clinical and radiological outcome between the two groups. The use of bioabsorbable pins or screws is a reasonable alternative to the traditional use of metallic materials for the treatment of lateral condyle fracture of the elbow in children.

Dose-dependent influence of didanosine on immune recovery in HIV-infected patients treated with tenofovir.

BACKGROUND: Antiretroviral therapy (ART) containing tenofovir disoproxil fumarate (TDF) and didanosine (ddI) has been associated with poor immune recovery despite virologic success. This effect might be related to ddI toxicity since ddI exposure is substantially increased by TDF. OBJECTIVE: To analyze whether immune recovery during ART with TDF and ddI is ddI-dose dependent. DESIGN AND METHODS: A retrospective longitudinal analysis of immune recovery measured by the CD4 T-cell slope in 614 patients treated with ART containing TDF with or without ddI. Patients were stratified according to the tertiles of their weight-adjusted ddI dose: low dose (< 3.3 mg/kg), intermediate dose (3.3-4.1 mg/kg) and high dose (> 4.1 mg/kg). Cofactors modifying the degree of immune recovery after starting TDF-containing ART were identified by univariable and multivariable linear regression analyses. RESULTS: CD4 T-cell slopes were comparable between patients treated with TDF and a weight-adjusted ddI-dose of < 4.1 mg/kg per day (n = 143) versus TDF-without-ddI (n = 393). In the multivariable model the slopes differed by -13 CD4 T cells/mul per year [95% confidence interval (CI), -42 to 17; P = 0.40]. In contrast, patients treated with TDF and a higher ddI dose (> 4.1 mg/kg per day, n = 78) experienced a significantly impaired immune recovery (-47 CD4 T cells/microl per year; 95% CI, -82 to -12; P = 0.009). The virologic response was comparable between the different treatment groups. CONCLUSIONS: Immune recovery is impaired, when high doses of ddI (> 4.1 mg/kg) are given in combination with TDF. If the dose of ddI is adjusted to less than 4.1 mg/kg per day, immune recovery is similar to other TDF-containing ART regimen.

Une insuffisance cardiaque traitée par glucocorticoïdes [A heart insufficiency treated by glucocorticoids]

Arrhythmogenic right ventricular dysplasia was diagnosed in 2000 in this 44-year-old male patient with a history of syncope. An internal defibrillator was implanted. Six years later the patient was readmitted with severe heart failure, and cardiac sarcoidosis was diagnosed by myocardial biopsy. Response to a course of glucorticoids was favourable. We herein review diagnostic strategies and therapeutic options in this rare disorder.