Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis.

Background Following the discovery that mutant KRAS is associated with resistance to anti-epidermal growth factor receptor (EGFR) antibodies, the tumours of patients with metastatic colorectal cancer are now profiled for seven KRAS mutations before receiving cetuximab or panitumumab. However, most patients with KRAS wild-type tumours still do not respond. We studied the effect of other downstream mutations on the efficacy of cetuximab in, to our knowledge, the largest cohort to date of patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab plus chemotherapy in the pre-KRAS selection era. Methods 1022 tumour DNA samples (73 from fresh-frozen and 949 from formalin-fixed, paraffin-embedded tissue) from patients treated with cetuximab between 2001 and 2008 were gathered from 11 centres in seven European countries. 773 primary tumour samples had sufficient quality DNA and were included in mutation frequency analyses; mass spectrometry genotyping of tumour samples for KRAS, BRAF, NRAS, and PIK3CA was done centrally. We analysed objective response, progression-free survival (PFS), and overall survival in molecularly defined subgroups of the 649 chemotherapy-refractory patients treated with cetuximab plus chemotherapy. Findings 40.0% (299/747) of the tumours harboured a KRAS mutation, 14.5% (108/743) harboured a PIK3CA mutation (of which 68.5% [74/108] were located in exon 9 and 20.4% [22/108] in exon 20), 4.7% (36/761) harboured a BRAF mutation, and 2.6% (17/644) harboured an NRAS mutation. KRAS mutants did not derive benefit compared with wild types, with a response rate of 6.7% (17/253) versus 35.8% (126/352; odds ratio [OR] 0.13, 95% CI 0.07-0.22; p<0.0001), a median PFS of 12. weeks versus 24 weeks (hazard ratio [HR] 1 98, 1.66-2.36; p<0.0001), and a median overall survival of 32 weeks versus 50 weeks (1.75, 1.47-2.09; p<0.0001). In KRAS wild types, carriers of BRAF and NRAS mutations had a significantly lower response rate than did BRAF and NRAS wild types, with a response rate of 8.3% (2/24) in carriers of BRAF mutations versus 38.0% in BRAF wild types (124/326; OR 0.15, 95% CI 0.02-0.51; p=0.0012); and 7.7% (1/13) in carriers of NRAS mutations versus 38.1% in NRAS wild types (110/289; OR 0.14, 0.007-0.70; p=0.013). PIK3CA exon 9 mutations had no effect, whereas exon 20 mutations were associated with a worse outcome compared with wild types, with a response rate of 0.0% (0/9) versus 36.8% (121/329; OR 0.00,0.00-0.89; p=0.029), a median PFS of 11.5 weeks versus 24 weeks (HR 2.52, 1.33-4.78; p=0.013), and a median overall survival of 34 weeks versus 51 weeks (3.29, 1.60-6.74; p=0.0057). Multivariate analysis and conditional inference trees confirmed that, if KRAS is not mutated, assessing BRAF, NRAS, and PIK3CA exon 20 mutations (in that order) gives additional information about outcome. Objective response rates in our series were 24.4% in the unselected population, 36.3% in the KRAS wild-type selected population, and 41.2% in the KRAS, BRAF, NRAS, and PIK3CA exon 20 wild-type population. Interpretation While confirming the negative effect of KRAS mutations on outcome after cetuximab, we show that BRAF, NRAS, and PIK3CA,exon 20 mutations are significantly associated with a low response rate. Objective response rates could be improved by additional genotyping of BRAF, NRAS, and PIK3CA exon 20 mutations in a KRAS wild-type population.

Fatores relacionados ao autocuidado de pessoas com diabetes mellitus atendidas em Serviço de Urgência no México

Estudo transversal com os objetivos de determinar a capacidade de autocuidado de pessoas com diabetes mellitus tipo 2 e relacionar tal capacidade com variáveis sociodemográficas e clínicas. Participaram 251 pessoas que ingressaram no Serviço de Urgência do Hospital Regional Mérida, em Yucatán, México, em 2006. Os dados foram obtidos mediante entrevista domiciliar dirigida, utilizando-se formulário, questionário e a Escala de Capacidade Autocuidado. Para a análise, utilizou-se a estatística descritiva e correlacional. Os resultados mostraram que 83 (33,5%) dos sujeitos apresentaram boa capacidade de autocuidado e 168 (66,5%), capacidade regular. Obteve-se correlação diretamente proporcional entre capacidade de autocuidado e anos de estudo (r=0,124; p<0,05), mas negativa para religião (rs=-0,435; p<0,05) e tempo de evolução da doença (r=-0,667; p<0,05). Para a promoção do autocuidado em pessoas com diabetes faz-se necessário considerar essas variáveis, bem como desenvolver novos estudos que enfoquem outras variáveis envolvidas no comportamento adotado em benefício da saúde.

Bloodstream infections related to totally implantable venous access port: What is the situation in our hospital?

Port-a-Cath© (PAC) are totally implantable devices that offer an easy and long term access to venous circulation. They have been extensively used for intravenous therapy administration and are particularly well suited for chemotherapy in oncologic patients. Previous comparative studies have shown that these devices have the lowest catheter-related bloodstream infection rates among all intravascular access systems. However, bloodstream infection (BSI) still remains a major issue of port use and epidemiology data for PAC-associated BSI (PABSI) rates differ strongly depending on studies. Also, current literature about PABSI risk factors is scarce and sometimes controversial. Such heterogeneity may depend on type of studied population and local factors. Therefore, the aim of this study was to describe local epidemiology and risk factors for PABSI in adult patients in our tertiary- care university hospital. We conducted a retrospective cohort study in order to describe local epidemiology. We also performed a nested case-control study to identify local risk factors of PABSI. We analyzed medical files of adult patients who had a PAC implanted between January 1st, 2008 and December 31st, 2009 and looked for PABSI occurrence before May 1st, 2011 to define cases. Thirty nine PABSI occurred in this population with an attack rate of 5.8%. We estimated an incidence rate of 0.08/1000 PAC-days using the case-control study. PABSI causative agents were mainly Gram positive cocci (62%). We identified three predictive factors of PABSI by multivariate statistical analysis: neutropenia on outcome date (Odds Ratio [OR]: 4.05; 95% confidence interval [CI]:1.05- 15.66; p=0.042), diabetes (OR: 11.53; 95% CI: 1.07-124.70; p=0.044) and having another infection than PABSI on outcome date (OR: 6.35; 95% CI: 1.50-26.86; p=0.012). Patients suffering from acute or renal failure (OR: 4.26; 95% CI: 0.94-19.21; p=0.059) or wearing another invasive device (OR: 2.99; 95%CI:0.96-9.31; p=0.059) did not have a statistically increased risk for developing a PABSI according to classical threshold (p<0.05) but nevertheless remained close to significance. Our study demonstrated that local epidemiology and microbiology of PABSI in our institution was similar to previous reports. A larger prospective study is required to confirm our results or to test preventive measures.

Incidence and outcomes of respiratory viral infections in lung transplant recipients: a prospective study.

BACKGROUND: The incidence and outcomes of respiratory viral infections in lung transplant recipients (LTR) are not well defined. The objective of this prospective study conducted from June 2008 to March 2011 was to characterise the incidence and outcomes of viral respiratory infections in LTR. METHODS: Patients were seen in three contexts: study-specific screenings covering all seasons; routine post-transplantation follow-up; and emergency visits. Nasopharyngeal specimens were collected systematically and bronchoalveolar lavage (BAL) was performed when clinically indicated. All specimens underwent testing with a wide panel of molecular assays targeting respiratory viruses. RESULTS: One hundred and twelve LTR had 903 encounters: 570 (63%) were screening visits, 124 (14%) were routine post-transplantation follow-up and 209 (23%) were emergency visits. Respiratory viruses were identified in 174 encounters, 34 of these via BAL. The incidence of infection was 0.83 per patient-year (95% CI 0.45 to 1.52). The viral infection rates upon screening, routine and emergency visits were 14%, 15% and 34%, respectively (p<0.001). Picornavirus was identified most frequently in nasopharyngeal (85/140; 60.7%) and BAL specimens (20/34; 59%). Asymptomatic viral carriage, mainly of picornaviruses, was found at 10% of screening visits. Infections were associated with transient lung function loss and high calcineurin inhibitor blood levels. The hospitalisation rate was 50% (95% CI 30% to 70.9%) for influenza and parainfluenza and 16.9% (95% CI 11.2% to 23.9%) for other viruses. Acute rejection was not associated with viral infection (OR 0.4, 95% CI 0.1 to 1.3). CONCLUSIONS: There is a high incidence of viral infection in LTR; asymptomatic carriage is rare. Viral infections contribute significantly to this population's respiratory symptomatology. No temporal association was observed between infection and acute rejection.

Estresse em profissionais de enfermagem: impacto do conflito no grupo e do poder do médico

Este estudo propôs-se a investigar o impacto das percepções de conflito intragrupal e de bases de poder do médico sobre o estresse de profissionais de enfermagem. Para tanto, foram aplicados em 124 técnicos e auxiliares de enfermagem de um hospital universitário as Escalas de Estresse no Trabalho, de Percepção de Bases de Poder do Supervisor e de Percepção de Conflitos Intragrupais e um formulário de dados sóciodemográficos. A maioria apresentou baixos níveis de estresse (58%), percebeu conflito intragrupal numa gradação média e o poder legítimo como o mais utilizado pelos médicos. Resultados de análises de regressão stepwise revelaram que conflito de tarefa e poder de coerção são preditores diretos de estresse, enquanto idade revelou-se preditor inverso. Destacam-se a importância do papel do médico responsável pela percepção de estresse na equipe de enfermagem e a necessidade de buscar soluções para os conflitos de tarefa e, consequentemente, reduzir o estresse nesses profissionais.

Importance clinique du caryotype en hématologie. [Clinical importance of karyotype in hematology.]

Cytogenic analysis of leukemic cells has proven to be a mandatory part of the diagnosis of malignant hemopathies. Recurring clonal cytogenetic abnormalities may be divided into those exclusively associated with myeloid disorders, those uniquely observed in lymphoid diseases, and those detected in both myeloid and lymphoid hemopathies. Several of the common defects are characteristic of specific FAB types or subtypes and are associated with specific clinico pathologic syndromes and clinical complications. Cytogenetic abnormalities have served to define relatively homogeneous subsets of malignant hemopathies which are not evident from morphological and other available markers. Cytogenetic findings have been demonstrated to be powerful indicators in predicting clinical course and outcome in patients and in guiding their management. Given the significant progress made in the treatment of malignant hemopathies, it is very important to identify parameters which may be used to predict whether patients will respond favorably to standard therapies or if they are unlikely to do so and require alternative strategies, such as bone marrow transplantation. Cytogenetic studies have also provided important insights into the understanding of malignant transformation processes. In a number of recurring chromosome translocations characteristic of leukemias and lymphomas the genes that are located at the breakpoints have been identified. Molecular analysis has revealed that alteration in expression of these genes or in the properties of the encoded proteins resulting from the rearrangements plays an integral part in malignant transformation. Studies of clonality have suggested that several chromosome abnormalities may arise in pluripotent hemopoietic stem cells, whereas others may originate in cells of more restricted lineage. The author focuses first on the implications of the karyotype in the diagnosis and the prognosis of myeloproliferative syndromes, acute leukemias and myelodysplastic syndromes, then on the interest of describing new clinical-cytogenetic associations. Finally, some of the recent results obtained in a cytogenetic study of myelodysplastic syndromes are discussed.

Théâtre de la guerre en Afrique, comprenant les régences d'Alger, de Tunis, Tripoli et de l'empire du Maroc : Avec plans détaillés de la baie et des fortifications de la ville d'Alger et de ses environs, d'après les meilleurs matériaux qu'on a pu se procurer sur ce pays / drefsé par Frémin géographe

Échelle(s) : [ca 1:5 085 000], 30 myriamètres [= 5,9 cm]

State Legislation Monitoring Report FY2004, February 2005

The Division of Criminal and Juvenile Justice Planning issued its first state legislation monitoring report in February 2002, covering the first six months’ impact of Senate File 543 (which enacted a number of sentencing changes) on the justice system; monitoring of the correctional impact of this bill was at the request of several members of the legislature. Since then, the Criminal and Juvenile Justice Planning Advisory Council has requested that CJJP monitor the correctional impact of enacted legislation of particular interest. This report covers monitoring results or future plans to monitor the following: 1. Changes in “crack” cocaine and “powder” cocaine penalties under Chapter 124.401 (effective FY2004; see p.3). 2. Commitments to prison involving manufacture, distribution, or possession of methamphetamine under Chapter 124.401 (see p.5). 3. Prosecution of offenders for child endangerment under Chapter 726.6(g) for permitting the presence of a child or minor at a location where a controlled substance manufacturing or a product possession violation occurs (see p.7). 4. Provision of an enhanced penalty for manufacturing of controlled substances under Chapter 124.401C when children are present and the offender is not charged under section 726.6(g) (see p. 7). 5. Creating a new offense when a retailer sells more than two packages of any product containing pseudoephedrine (chapter 126.23A) and providing for an enhanced penalty under Chapter 714.7C when a theft involves more than two packages of similar products (see p.8). 6. Establishment of parole eligibility at 70% of time served for persons sentenced under the “85% law” provisions of Iowa Code Section 902.12. (effective FY2005; see p. 9).

Vivência do sofrimento moral na enfermagem: percepção da enfermeira

Objetivando conhecer a percepção do sofrimento moral vivenciado, relacionando frequência e intensidade, realizou-se pesquisa Survey, utilizando escala Likert variando de 0 a 6 pontos, com 124 enfermeiras em hospitais do sul do Brasil, no ano de 2008. Mediante questionário autoaplicável e análise fatorial, foram identificados e validados quatro constructos. Os resultados finais foram obtidos através de três diferentes análises: 1) estatística descritiva; 2) análises de variância 3) regressão múltipla. O constructo que apresentou maior intensidade de percepção de vivência do sofrimento moral foi a falta de competência na equipe de trabalho (4,55), seguido pela negação do papel da enfermeira como advogada do paciente (4,30), obstinação terapêutica (3,60) e desrespeito à autonomia do paciente (3,57). Em relação à percepção da frequência do sofrimento moral, destacou-se, novamente, o constructo falta de competência na equipe de trabalho (2,42), seguido da obstinação terapêutica (2,26), negação do papel da enfermeira como advogada do paciente (1,71) e desrespeito à autonomia do paciente (1,42).

Soutien informatique dans la gestion de la douleur aiguë aux urgences: acceptation par les soignants et impact sur les connaissances des Recommandations de Pratiques Cliniques (RPC)

Dans une étude précédente, nous avons démontré qu'un soutieninformatique rappelant les Recommandations de Pratiques Cliniques(RPC) améliore la gestion de la douleur aiguë aux urgences à moyenterme (JEUR 2009;22:A88). Par contre, son acceptation par lessoignants et son impact sur leurs connaissances des RPC sontinconnus. But de l'étude: mesurer l'impact du logiciel en termesd'acceptation et connaissance des RPC par l'équipe soignante.Méthode: analyse de 2 questionnaires remplis par les médecins etinfirmiers: le 1er administré en pré-, post-déploiement et 6 mois plustard (phases P1, P2 et P3) qui a évalué: a) l'appréciation subjective desconnaissances des RPC par échelle de Lickert à 5 niveaux; b) lesconnaissances objectives des RPC à l'aide de 7 questions théoriques(score max. 7 points); le 2ème administré en P2 et P3, l'utilité perçue dulogiciel (échelle à 4 niveaux). Analyses statistiques par test de chi2outest exact de Fisher; p bilatéral <0.05 significatif. Résultats: la proportiondes soignants estimant avoir une bonne connaissance des RPC apassé de 48% (45/94) en P1, à 73% (83/114) puis 84% (104/124) en P2et P3, respectivement (p <0.0001). Score des connaissances: cftableau. Entre P2 et P3, l'appréciation globale de l'utilité du logiciel s'estaméliorée: la proportion des avis favorables a passé de 59% (47/79) à82% (96/117) (p = 0.001). Conclusion: ce logiciel a été bien accepté et apermis une amélioration significative des connaissances des RPC parles soignants.

Dependência funcional de idosos e a sobrecarga do cuidador

A finalidade deste estudo foi identificar a dependência funcional de idosos e a sobrecarga do cuidador. Trata-se de estudo epidemiológico e transversal realizado em 2009 com 574 idosos e 124 cuidadores em Ribeirão Preto-SP, por meio dos instrumentos MIF e Escala de Sobrecarga de Zarit. Entre os idosos, a maioria era do sexo feminino (67,8%), com média de 76,6 anos, baixa escolaridade (54,7%) e renda individual mensal de R$ 942,20. Apenas 15,7% foram identificados como dependentes. Dos cuidadores, 85,6% era do sexo feminino, com média de 56,5 anos e 90,3% eram familiares (filhas ou esposas). A média de sobrecarga dos cuidadores foi de 27,8 (±17,5). A dependência do idoso foi fator de risco para sobrecarga do cuidador (p<0,05). A abordagem preventiva e a intervenção precoce devem ser prioritárias para essa população. São necessárias a vigilância de uma equipe multidisciplinar de saúde, a aplicação de instrumentos de avaliação do comprometimento da funcionalidade e a intervenção para prevenção da sobrecarga dos cuidadores.