Challenges in molecular testing in non-small-cell lung cancer patients with advanced disease

Lung cancer diagnostics have progressed greatly in the previous decade. Development of molecular testing to identify an increasing number of potentially clinically actionable genetic variants, using smaller samples obtained via minimally invasive techniques, is a huge challenge. Tumour heterogeneity and cancer evolution in response to therapy means that repeat biopsies or circulating biomarkers are likely to be increasingly useful to adapt treatment as resistance develops. We highlight some of the current challenges faced in clinical practice for molecular testing of EGFR, ALK, and new biomarkers such as PDL1. Implementation of next generation sequencing platforms for molecular diagnostics in non-small-cell lung cancer is increasingly common, allowing testing of multiple genetic variants from a single sample. The use of next generation sequencing to recruit for molecularly stratified clinical trials is discussed in the context of the UK Stratified Medicine Programme and The UK National Lung Matrix Trial.

Ovarian suppression using luteinizing hormonereleasing hormone agonists during chemotherapy to preserve ovarian function and fertility of breast cancer patients: A meta-analysis of randomized studies

Background: The role of temporary ovarian suppression with luteinizing hormone-releasing hormone agonists (LHRHa) in the prevention of chemotherapy-induced premature ovarian failure (POF) is still controversial. Our meta-analysis of randomized, controlled trials (RCTs) investigates whether the use of LHRHa during chemotherapy in premenopausal breast cancer patients reduces treatment-related POF rate, increases pregnancy rate, and impacts disease-free survival (DFS). Methods: A literature search using PubMed, Embase, and the Cochrane Library, and the proceedings of major conferences, was conducted up to 30 April 2015. Odds ratios (ORs) and 95% confidence intervals (CIs) for POF (i.e. POF by study definition, and POF defined as amenorrhea 1 year after chemotherapy completion) and for patients with pregnancy, as well hazard ratios (HRs) and 95% CI for DFS, were calculated for each trial. Pooled analysis was carried out using the fixed- and random-effects models. Results: A total of 12 RCTs were eligible including 1231 breast cancer patients. The use of LHRHa was associated with a significant reduced risk of POF (OR 0.36, 95% CI 0.23-0.57; P < 0.001), yet with significant heterogeneity (I2 = 47.1%, Pheterogeneity = 0.026). In eight studies reporting amenorrhea rates 1 year after chemotherapy completion, the addition of LHRHa reduced the risk of POF (OR 0.55, 95% CI 0.41-0.73, P < 0.001) without heterogeneity (I2 = 0.0%, Pheterogeneity = 0.936). In five studies reporting pregnancies, more patients treated with LHRHa achieved pregnancy (33 versus 19 women; OR 1.83, 95% CI 1.02-3.28, P = 0.041; I2 = 0.0%, Pheterogeneity = 0.629). In three studies reporting DFS, no difference was observed (HR 1.00, 95% CI 0.49-2.04, P = 0.939; I2 = 68.0%, Pheterogeneity = 0.044). Conclusion: Temporary ovarian suppression with LHRHa in young breast cancer patients is associated with a reduced risk of chemotherapy-induced POF and seems to increase the pregnancy rate, without an apparent negative consequence on prognosis.

Novel pharmacogenomic markers of irinotecan-induced severe toxicity in metastatic colorectal cancer patients

L’irinotécan est un agent de chimiothérapie largement utilisé pour le traitement de tumeurs solides, particulièrement pour le cancer colorectal métastatique (mCRC). Fréquemment, le traitement par l’irinotécan conduit à la neutropénie et la diarrhée, des effets secondaires sévères qui peuvent limiter la poursuite du traitement et la qualité de vie des patients. Plusieurs études pharmacogénomiques ont évalué les risques associés à la chimiothérapie à base d’irinotécan, en particulier en lien avec le gène UGT1A, alors que peu d’études ont examiné l’impact des gènes codant pour des transporteurs. Par exemple, le marqueur UGT1A1*28 a été associé à une augmentation de 2 fois du risque de neutropénie, mais ce marqueur ne permet pas de prédire la toxicité gastrointestinale ou l’issue clinique. L’objectif de cette étude était de découvrir de nouveaux marqueurs génétiques associés au risque de toxicité induite par l’irinotécan, en utilisant une stratégie d’haplotype/SNP-étiquette permettant de maximiser la couverture des loci génétiques ciblés. Nous avons analysé les associations génétiques des loci UGT1 et sept gènes codants pour des transporteurs ABC impliqués dans la pharmacocinétique de l’irinotécan, soient ABCB1, ABCC1, ABCC2, ABCC5, ABCG1, ABCG2 ainsi que SLCO1B1. Les profils de 167 patients canadiens atteints de mCRC sous traitement FOLFIRI (à base d’irinotécan) ont été examinés et les marqueurs significatifs ont par la suite été validés dans une cohorte indépendante de 250 patients italiens. Nous avons découvert dans la région intergénique en aval du gène UGT1, un nouveau marqueur (rs11563250G) associé à un moindre risque de neutropénie sévère (rapport des cotes (RC)=0.21; p=0.043 chez les canadiens, RC=0.27; p=0.036 chez les italiens, et RC=0.31 p=0.001 pour les deux cohortes combinées). De plus, le RC est demeuré significatif après correction pour multiples comparaisons (p=0.041). Par ailleurs, pour l’haplotype défini par les marqueurs rs11563250G et UGT1A1*1 (rs8175347 TA6), le RC était de 0.17 (p=0.0004). Un test génétique évaluant ces marqueurs permettrait d’identifier les patients susceptibles de bénéficier d’une augmentation de dose d’irinotécan. En revanche, une autre combinaison de marqueurs, ABCC5 rs3749438 et rs10937158 (T–C), a prédit un risque plus faible de diarrhée sévère dans les deux cohortes (RC = 0.43; p=0.001). La coexistence des marqueurs ABCG1 rs225440T et ABCC5 rs2292997A a prédit un risque accru de neutropénie (RC=5.93; p=0.0002), alors qu’une prédiction encore plus significative a été obtenue lorsque ces marqueurs sont combinés au marqueur de risque bien établi UGT1A1*28 rs8175347 (RC=7.68; p<0.0001). Enfin, les porteurs de l’allèle de protection UGT1 rs11563250G en absence d’allèles de risque, ont montré une incidence réduite de neutropénie sévère (8.2% vs. 34.0%; p<0.0001). Nous concluons que ces nouveaux marqueurs génétiques prédictifs pourraient permettre d’améliorer l’évaluation du risque de toxicité et personnaliser le traitement à base d’irinotécan pour les patients atteints du cancer colorectal métastatique.

Predictors of maternal mortality among critically ill obstetric patients

Aim Evaluation of the predictors of maternal mortality among critically ill obstetric patients managed at the intensive care unit (ICU). Methods A case control study to evaluate the predictors of maternal mortality among critically ill obstetric patients managed at the intensive care unit (ICU) of the University of Ilorin Teaching Hospital, Ilorin, Nigeria from 1st January 2010 to 30th June 2013. Participants were critically ill obstetric patients who were admitted and managed at the ICU during the study period. Subjects were those who died while controls were age and parity matched survivors. Statistical analysis was with SPSS-20 to determine chi square, Cox-regression and odds ratio; p value < 0.05 was significant. Results The mean age of subjects and controls were 28.92 ± 5.09 versus 29.44 ± 5.74 (p = 0.736), the level of education was higher among controls (p = 0.048) while more subjects were of low social class (p = 0.321), did not have antenatal care (p = 0.131) and had partners with lower level of education (p = 0.156) compared to controls. The two leading indications for admission among subjects and controls were massive postpartum haemorrhage and severe preeclampsia or eclampsia. The mean duration of admission was higher among controls (3.32 ± 2.46 versus 3.00 ± 2.58; p = 0.656) while the mean cost of ICU care was higher among the subjects (p = 0.472). The statistical significant predictors of maternal deaths were the patient’s level of education, Glasgow Coma Scale (GCS) score, oxygen saturation, multiple organ failure at ICU admission and the need for mechanical ventilation or inotrophic drugs after admission. Conclusion The clinical state at ICU admission of the critically ill obstetric patients is the major outcome determinant. Therefore, early recognition of the need for ICU care, adequate pre-ICU admission supportive care and prompt transfer will improve the outcome.

The posttraumatic growth inventory: Factor structure and invariance in a sample ofbreast cancer patients and in a non-clinical sample

The Posttraumatic Growth Inventory (PTGI) is frequently used to assess positive changes following a traumatic event. The aim of the study is to examine the factor structure and the latent mean invariance of PTGI. A sample of 205 (M age = 54.3, SD = 10.1) women diagnosed with breast cancer and 456 (M age = 34.9, SD = 12.5) adults who had experienced a range of adverse life events were recruited to complete the PTGI and a socio-demographic questionnaire. We use Confirmatory Factor Analysis (CFA) to test the factor-structure and multi-sample CFA to examine the invariance of the PTGI between the two groups. The goodness of fit for the five-factor model is satisfactory for breast cancer sample (χ2(175) = 396.265; CFI = .884; NIF = .813; RMSEA [90% CI] = .079 [.068, .089]), and good for non-clinical sample (χ2(172) = 574.329; CFI = .931; NIF = .905; RMSEA [90% CI] = .072 [.065, .078]). The results of multi-sample CFA show that the model fit indices of the unconstrained model are equal but the model that uses constrained factor loadings is not invariant across groups. The findings provide support for the original five-factor structure and for the multidimensional nature of posttraumatic growth (PTG). Regarding invariance between both samples, the factor structure of PTGI and other parameters (i.e., factor loadings, variances, and co-variances) are not invariant across the sample of breast cancer patients and the non-clinical sample.

Update in the management of critically ill burned patients

The management of critically ill burn patients is challenging. These patients have to be managed in specialized centers, where the expertise of physicians and nursing personnel guarantees the best treatment. Mortality of burn patients has improved over the past decades due to a better understanding of burn shock pathophysiology, optimal surgical management, infection control and nutritional support. Indeed, a more aggressive resuscitation, early excision and grafting, the judicious use of topical antibiotics, and the provision of an adequate calorie and protein intake are key to attain best survival results. General advances in critical care have also to be implemented, including protective ventilation, glycemic control, selective decontamination of the digestive tract, and implementation of sedation protocols.

Caracterización de los pacientes críticos ventilados en la Fundación Santa Fe de Bogotá 2009 a 2013

Objetivo: Caracterizar a los pacientes que recibieron ventilación mecánica en las unidades de cuidado intensivo (UCI) de la Fundación Santa Fe de Bogotá entre los años 2009 y 2013. Metodología: Se analizó una cohorte retrospectiva de los pacientes en UCI que requirieron soporte ventilatorio mecánico al ingreso a la unidad independientemente de la causa. Resultados: La media de edad de los pacientes fue 63,83 años; el diagnóstico más frecuente de ingreso fue revascularización miocárdica, seguido por neumonía y recambio valvular aórtico; en el 43% de los casos la causa de la falla fue el estado postoperatorio. Los modos ventilatorios más frecuentemente utilizados fueron SIMV (27,5%) y ventilación asistida controlada (26,12%). El 50% de los pacientes fueron ventilados con PEEP < 6 cmH2O. La mortalidad bruta fue del 15%. 22% de los pacientes tuvieron estancia prolongada en UCI. Se aplicó protocolo de retiro de ventilación mecánica en el 77% de los pacientes. La duración de la ventilación mecánica es mayor a medida que aumenta la edad del paciente entre los 60 y los 80 años. La mortalidad es cercana al 50% alrededor de los 50 años y mayor a 80% después de los 80 años. El soporte ventilatorio por cinco o más días aumentó la mortalidad a 80% o más. Discusión y Conclusiones: Estos resultados son comparables a los encontrados en estudios previos. Este estudio puede ser considerado como el primer paso para generar un registro adecuado de la ventilación de la mecánica de las unidades de cuidado intensivo del país.

Evaluación del desempeño pronóstico de dos puntajes de predicción de mortalidad a siete días en pacientes adultos oncológicos críticamente enfermos admitidos a una unidad de cuidados intensivos en Bogotá

Introducción Los sistemas de puntuación para predicción se han desarrollado para medir la severidad de la enfermedad y el pronóstico de los pacientes en la unidad de cuidados intensivos. Estas medidas son útiles para la toma de decisiones clínicas, la estandarización de la investigación, y la comparación de la calidad de la atención al paciente crítico. Materiales y métodos Estudio de tipo observacional analítico de cohorte en el que reviso las historias clínicas de 283 pacientes oncológicos admitidos a la unidad de cuidados intensivos (UCI) durante enero de 2014 a enero de 2016 y a quienes se les estimo la probabilidad de mortalidad con los puntajes pronósticos APACHE IV y MPM II, se realizó regresión logística con las variables predictoras con las que se derivaron cada uno de los modelos es sus estudios originales y se determinó la calibración, la discriminación y se calcularon los criterios de información Akaike AIC y Bayesiano BIC. Resultados En la evaluación de desempeño de los puntajes pronósticos APACHE IV mostro mayor capacidad de predicción (AUC = 0,95) en comparación con MPM II (AUC = 0,78), los dos modelos mostraron calibración adecuada con estadístico de Hosmer y Lemeshow para APACHE IV (p = 0,39) y para MPM II (p = 0,99). El ∆ BIC es de 2,9 que muestra evidencia positiva en contra de APACHE IV. Se reporta el estadístico AIC siendo menor para APACHE IV lo que indica que es el modelo con mejor ajuste a los datos. Conclusiones APACHE IV tiene un buen desempeño en la predicción de mortalidad de pacientes críticamente enfermos, incluyendo pacientes oncológicos. Por lo tanto se trata de una herramienta útil para el clínico en su labor diaria, al permitirle distinguir los pacientes con alta probabilidad de mortalidad.

Can metaphors and analogies improve communication with seriously ill patients?

OBJECTIVE: It is not known how often physicians use metaphors and analogies, or whether they improve patients' perceptions of their physicians' ability to communicate effectively. Therefore, the objective of this study was to determine whether the use of metaphors and analogies in difficult conversations is associated with better patient ratings of their physicians' communication skills. DESIGN: Cross-sectional observational study of audio-recorded conversations between patients and physicians. SETTING: Three outpatient oncology practices. PATIENTS: Ninety-four patients with advanced cancer and 52 physicians. INTERVENTION: None. MAIN OUTCOME MEASURES: Conversations were reviewed and coded for the presence of metaphors and analogies. Patients also completed a 6-item rating of their physician's ability to communicate. RESULTS: In a sample of 101 conversations, coders identified 193 metaphors and 75 analogies. Metaphors appeared in approximately twice as many conversations as analogies did (65/101, 64% versus 31/101, 31%; sign test p < 0.001). Conversations also contained more metaphors than analogies (mean 1.6, range 0-11 versus mean 0.6, range 0-5; sign rank test p < 0.001). Physicians who used more metaphors elicited better patient ratings of communication (rho = 0.27; p = 0.006), as did physicians who used more analogies (Spearman rho = 0.34; p < 0.001). CONCLUSIONS: The use of metaphors and analogies may enhance physicians' ability to communicate.

Positive fluid balance is associated with reduced survival in critically ill patients with cancer

Background There are no studies that describe the impact of the cumulative fluid balance on the outcomes of cancer patients admitted to intensive care units ICUs. The aim of our study was to evaluate the relationship between fluid balance and clinical outcomes in these patients. Method One hundred twenty-two cancer patients were prospectively evaluated for survival during a 30-day period. Univariate (Chi-square, t-test, MannWhitney) and multiple logistic regression analyses were used to identify the admission parameters associated with mortality. Results The mean cumulative fluid balance was significantly higher in non-survivors than in survivors [1675?ml/24?h (4712921) vs. 887?ml/24?h (104557), P?=?0.017]. We used the area under the curve and the intersection of the sensibility and specificity curves to define a cumulative fluid balance value of 1100?ml/24?h. This value was used in the univariate model. In the multivariate model, the following variables were significantly associated with mortality in cancer patients: the Acute Physiology and Chronic Health Evaluation II score at admission [Odds ratio (OR) 1.15; 95% confidence interval (CI) (1.051.26), P?=?0.003], the Lung Injury Score at admission [OR 2.23; 95% CI (1.293.87), P?=?0.004] and a positive fluid balance higher than 1100?ml/24?h at ICU [OR 5.14; 95% CI (1.4518.24), P?=?0.011]. Conclusion A cumulative positive fluid balance higher than 1100?ml/24?h was independently associated with mortality in patients with cancer. These findings highlight the importance of improving the evaluation of these patients' volemic state and indicate that defined goals should be used to guide fluid therapy.

Pretreatment malnutrition and quality of life - association with prolonged length of hospital stay among patients with gynecological cancer: A cohort study

Background Length of hospital stay (LOS) is a surrogate marker for patients' well-being during hospital treatment and is associated with health care costs. Identifying pretreatment factors associated with LOS in surgical patients may enable early intervention in order to reduce postoperative LOS. Methods This cohort study enrolled 157 patients with suspected or proven gynecological cancer at a tertiary cancer centre (2004-2006). Before commencing treatment, the scored Patient Generated - Subjective Global Assessment (PG-SGA) measuring nutritional status and the Functional Assessment of Cancer Therapy-General (FACT-G) scale measuring quality of life (QOL) were completed. Clinical and demographic patient characteristics were prospectively obtained. Patients were grouped into those with prolonged LOS if their hospital stay was greater than the median LOS and those with average or below average LOS. Results Patients' mean age was 58 years (SD 14 years). Preoperatively, 81 (52%) patients presented with suspected benign disease/pelvic mass, 23 (15%) with suspected advanced ovarian cancer, 36 (23%) patients with suspected endometrial and 17 (11%) with cervical cancer, respectively. In univariate models prolonged LOS was associated with low serum albumin or hemoglobin, malnutrition (PG-SGA score and PG-SGA group B or C), low pretreatment FACT-G score, and suspected diagnosis of cancer. In multivariable models, PG-SGA group B or C, FACT-G score and suspected diagnosis of advanced ovarian cancer independently predicted LOS. Conclusions Malnutrition, low quality of life scores and being diagnosed with advanced ovarian cancer are the major determinants of prolonged LOS amongst gynecological cancer patients. Interventions addressing malnutrition and poor QOL may decrease LOS in gynecological cancer patients.

Probiotics and diarrhoea management in enterally tube fed critically ill patients : what is the evidence?

Objective: The aim of this literature review is to identify the role of probiotics in the management of enteral tube feeding (ETF) diarrhoea in critically ill patients.---------- Background: Diarrhoea is a common gastrointestinal problem seen in ETF patients. The incidence of diarrhoea in tube fed patients varies from 2% to 68% across all patients. Despite extensive investigation, the pathogenesis surrounding ETF diarrhoea remains unclear. Evidence to support probiotics to manage ETF diarrhoea in critically ill patients remains sparse.---------- Method: Literature on ETF diarrhoea and probiotics in critically ill, adult patients was reviewed from 1980 to 2010. The Cochrane Library, Pubmed, Science Direct, Medline and the Cumulative Index of Nursing and Allied Health Literature (CINAHL) electronic databases were searched using specific inclusion/exclusion criteria. Key search terms used were: enteral nutrition, diarrhoea, critical illness, probiotics, probiotic species and randomised clinical control trial (RCT).---------- Results: Four RCT papers were identified with two reporting full studies, one reporting a pilot RCT and one conference abstract reporting an RCT pilot study. A trend towards a reduction in diarrhoea incidence was observed in the probiotic groups. However, mortality associated with probiotic use in some severely and critically ill patients must caution the clinician against its use.---------- Conclusion: Evidence to support probiotic use in the management of ETF diarrhoea in critically ill patients remains unclear. This paper argues that probiotics should not be administered to critically ill patients until further research has been conducted to examine the causal relationship between probiotics and mortality, irrespective of the patient's disease state or projected prophylactic benefit of probiotic administration.

Information interventions for orienting patients and their carers to cancer care facilities

Background: Cancer patients experience distress and anxiety related to their diagnosis, treatment and the unfamiliar cancer centre. Strategies with the aim of orienting patients to a cancer care facility may improve patient outcomes. Although meeting patients' information needs at different stages is important, there is little agreement about the type of information and the timing for information to be given. Orientation interventions aim to address information needs at the start of a person's experience with a cancer care facility. The extent of any benefit of these interventions is unknown. Objectives: To assess the effects of information interventions which orient patients and their carers/family to a cancer care facility, and to the services available in the facility. Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 2); MEDLINE (OvidSP) (1966 to Jun 2011), EMBASE (Ovid SP) (1966 to Jun 2011), CINAHL (EBSCO) (1982 to Jun 2011), PsycINFO (OvidSP) (1966 to Jun 2011), review articles and reference lists of relevant articles. We contacted principal investigators and experts in the field. Selection Criteria: Randomised controlled trials (RCTs), cluster RCTs and quasi-RCTs evaluating the effects of information interventions that orient patients and their carers/family to a cancer care facility. Data collection and analysis: Results of searches were reviewed against the pre-determined criteria for inclusion by two review authors. The primary outcomes were knowledge and understanding; health status and wellbeing, evaluation of care, and harms. Secondary outcomes were communication, skills acquisition, behavioural outcomes, service delivery, and health professional outcomes. We pooled results of RCTs using mean differences (MD) and 95% confidence intervals (CI). Main results: We included four RCTs involving 610 participants. All four trials aimed to investigate the effects of orientation programs for cancer patients to a cancer facility. There was high risk of bias across studies. Findings from two of the RCTs demonstrated significant benefits of the orientation intervention in relation to levels of distress (mean difference (MD) -8.96 (95% confidence interval (CI) -11.79 to -6.13), but non-significant benefits in relation to state anxiety levels (MD -9.77 (95% CI -24.96 to 5.41). Other outcomes for participants were generally positive (e.g. more knowledgeable about the cancer centre and cancer therapy, better coping abilities). No harms or adverse effects were measured or reported by any of the included studies. There were insufficient data on the other outcomes of interest. Authors conclusion: This review has demonstrated the feasibility and some potential benefits of orientation interventions. There was a low level of evidence suggesting that orientation interventions can reduce distress in patients. However, most of the other outcomes remain inconclusive (patient knowledge recall/ satisfaction). The majority of studies were subject to high risk of bias, and were likely to be insufficiently powered. Further well conducted and powered RCTs are required to provide evidence for determining the most appropriate intensity, nature, mode and resources for such interventions. Patient and carer-focused outcomes should be included.

A systematic review on quality of life among patients at 1 year after treatment for head and neck cancer

Introduction: Although advances in treatment modalities have improved the survival of head and neck (H&N) cancer patients over recent years, survivors’ quality of life (QoL) could be impaired for a number of reasons. The investigation of QoL determinants can inform the design of supportive interventions for this population. Objectives: To examine the QoL of H&N cancer survivors at 1 year after treatment and to identify potential determinants affecting their QoL. Methods: A systematic search of literature was done in December 2011 in five databases: Pubmed, Medline, Scopus, Sciencedirect and CINAHL, using combined search terms ‘head and neck cancer’, ‘quality of life’, ‘health-related quality of life’ and ‘systematic review’. The methodological qualities of selected studies were assessed by two reviewers using predefined criteria. The study characteristics and results were abstracted and summarized. Results: Thirty-seven studies met all inclusion criteria with methodological quality from moderate to high. The global QoL of H&N cancer survivors returned to baseline at 1 year after treatment. Significant improvement showed in emotional functioning while physical functioning, xerostomia, sticky/insufficient saliva, and fatigue were consistently worse at 12 months compared with baseline. Age, cancer sites and stages, social support, smoking, presence of feeding tube are significant QoL determinants at 12 months. Conclusions: Although the global QoL of H&N cancer survivors recover by 12 months after treatment, problems with physical functioning, fatigue, xerostomia and sticky saliva persist. Regular assessment should be carried out to monitor these problems. Further research is required to develop appropriate and effective interventions for this population.