Molecular determinants of drug-specific sensitivity for epidermal growth factor receptor (EGFR) exon 19 and 20 mutants in non-small cell lung cancer

We hypothesized that aberrations activating epidermal growth factor receptor (EGFR) via dimerization would be more sensitive to anti-dimerization agents (e.g., cetuximab). EGFR exon 19 abnormalities (L747_A750del; deletes amino acids LREA) respond to reversible EGFR kinase inhibitors (TKIs). Exon 20 in-frame insertions and/or duplications (codons 767 to 774) and T790M mutations are clinically resistant to reversible/some irreversible TKIs. Their impact on protein function/therapeutic actionability are not fully elucidated.In our study, the index patient with non-small cell lung cancer (NSCLC) harbored EGFR D770_P772del_insKG (exon 20). A twenty patient trial (NSCLC cohort) (cetuximab-based regimen) included two participants with EGFR TKI-resistant mutations ((i) exon 20 D770>GY; and (ii) exon 19 LREA plus exon 20 T790M mutations). Structural modeling predicted that EGFR exon 20 anomalies (D770_P772del_insKG and D770>GY), but not T790M mutations, stabilize the active dimer configuration by increasing the interaction between the kinase domains, hence sensitizing to an agent preventing dimerization. Consistent with predictions, the two patients harboring D770_P772del_insKG and D770>GY, respectively, responded to an EGFR antibody (cetuximab)-based regimen; the T790M-bearing patient showed no response to cetuximab combined with erlotinib. In silico modeling merits investigation of its ability to optimize therapeutic selection based on structural/functional implications of different aberrations within the same gene.     

Health care assistants' role,function and development: results of a national survey

Intensive care has developed as a speciality since the 1950s; during this time there have been major technological advances in health care provision leading to a rapid expansion of all areas of critical care. The ongoing problem of recruiting appropriately qualified nurses has affected staffing levels in many units and continues to be a national problem. For many, the answer lies in employing health care assistants to support the work of registered nurses. A key aim of the British Association of Critical Care Nurses is to promote the art and science of critical care nursing by providing representation for its members, by responding to political and professional change and by producing and publishing position statements. A primary component of the work surrounding the development of this second position statement was the gathering of contemporary information in relation to the role of health care assistants within critical care units throughout the UK, through a survey of 645 critical care units within the UK. At present the impact upon the role of the critical care nurse is not fully understood, with research in this area suggesting that although there is a role for the health care assistant in the critical care environment, this should only be undertaken with a full analysis of this impact upon the work of the registered nurse.     

Ondansetron versus a chlorpromazine and dexamethasone combination for the prevention of nausea and vomiting: a prospective, randomised study to assess efficacy, cost effectiveness and quality of life following single-fraction radiotherapy

 Lower hemibody radiotherapy is an effective palliative treatment for patients with widespread bone metastases, but is frequently associated with the unpleasant side effects of nausea and vomiting. Patients often require admission to hospital for at least an overnight stay, with its inevitable costs. This study has investigated the clinical efficacy and safety profile of ondansetron, a 5HT₃ receptor antagonist, and compared it to a standard antiemetic combination, chlorpromazine and dexamethasone. Sixty-six patients were randomised to receive antiemetic prophylaxis with either oral ondansetron or a combination of chlorpromazine and dexamethasone (33 patients in each arm): 60 were treated with lower abdominal radiotherapy (8 Gy mid-plane dose) and 6 with radiotherapy to the upper lumbar spine (12.5 Gy incident dose). Patients were assessed for severity of nausea and vomiting and for whether they would use the same antiemetic again. Quality of life was assessed using the Functional Living Index Cancer (FLIC) and Functional Living Index Emesis (FLIE) quality-of-life questionnaires. A detailed cost–benefit analysis was also performed. Ondansetron scored highly as an antiemetic, being significantly better at controlling emesis on all four study days (P<0.001) and significantly better at controlling nausea on day 1 (P<0.001) than the standard combination of chlorpromazine and dexamethasone. Quality of life was better in the ondansetron-treated group, and ondansetron was found to be safe with no significant adverse effects. As a result, 98% of patients and investigators would use ondansetron again. Cost–benefit analysis revealed that, when complete control of emesis is the aim, ondansetron is not unduly expensive compared to the standard antiemetic regimen. As ondansetron was clearly effective in patients receiving hemibody irradiation it seems it would be prudent to adopt it for use in such patients routinely. The use of ondansetron would allow them to be treated as outpatients, with the attendant financial and psychosocial benefits of such an approach.     

Hemodynamic monitoring in shock and implications for management

Objective

Shock is a severe syndrome resulting in multiple organ dysfunction and a high mortality rate. The goal of this consensus statement is to provide recommendations regarding the monitoring and management of the critically ill patient with shock.

Methods

An international consensus conference was held in April 2006 to develop recommendations for hemodynamic monitoring and implications for management of patients with shock. Evidence-based recommendations were developed, after conferring with experts and reviewing the pertinent literature, by a jury of 11 persons representing five critical care societies.

Data synthesis

A total of 17 recommendations were developed to provide guidance to intensive care physicians monitoring and caring for the patient with shock. Topics addressed were as follows: (1) What are the epidemiologic and pathophysiologic features of shock in the ICU? (2) Should we monitor preload and fluid responsiveness in shock? (3) How and when should we monitor stroke volume or cardiac output in shock? (4) What markers of the regional and micro-circulation can be monitored, and how can cellular function be assessed in shock? (5) What is the evidence for using hemodynamic monitoring to direct therapy in shock? One of the most important recommendations was that hypotension is not required to define shock, and as a result, importance is assigned to the presence of inadequate tissue perfusion on physical examination. Given the current evidence, the only bio-marker recommended for diagnosis or staging of shock is blood lactate. The jury also recommended against the routine use of (1) the pulmonary artery catheter in shock and (2) static preload measurements used alone to predict fluid responsiveness.

Conclusions

This consensus statement provides 17 different recommendations pertaining to the monitoring and caring of patients with shock. There were some important questions that could not be fully addressed using an evidence-based approach, and areas needing further research were identified.     

Enlarged parietal foramina: a review of genetics, prognosis, radiology, and treatment

Introduction

Enlarged parietal foramina are variable ossification defects in the parietal bones that present as symmetric radiolucencies on skull radiographs. In contrast to the normal small parietal foramina, enlarged parietal foramina are a hereditary condition and genes associated with it have been identified.

Methods

A literature review was performed to discuss the many known findings related to enlarged parietal foramina.

Conclusions

Even though they remain asymptomatic in the majority of cases, they may be associated with other pathologies and occasionally become symptomatic. This article provides a comprehensive review of the current knowledge of enlarged parietal foramina.     

The role of transbronchial needle aspiration in the diagnosis of bronchogenic carcinoma

BACKGROUND: For many years in the United States transbronchial needle aspiration (TBNA) has been used with flexible bronchoscopy to diagnosis bronchogenic carcinoma, but very few data are available from the United Kingdom. METHODS: All bronchoscopies performed for suspected bronchial carcinoma at Papworth Hospital, Cambridge, United Kingdom, over the last 3 years were reviewed retrospectively. Patients with peribronchial disease, as evidenced by submucosal infiltration or extrinsic compression on bronchoscopy, were selected for TBNA. Patients with computed tomography evidence of subcarinal lymphadenopathy were also included. In total we identified 78 patients: 67 with peribronchial disease and 21 with subcarinal lymphadenopathy. All 78 patients underwent TBNA, and in 8 of these TBNA was performed in 2 sites. RESULTS: Malignancy was confirmed in 66 of the 78 patients. TBNA was positive in 31/66 (47%) of the patients who had proven bronchogenic carcinoma. Additional staging information was obtained in 9/21 patients (42.8%) who underwent subcarinal lymph node aspiration. We also found that TBNA was diagnostic in 1 patient with tuberculosis and 1 with sarcoidosis. There was only 1 important TBNA complication, which was a small pneumothorax. CONCLUSION: In our preliminary experience with selected patients suspected to have bronchogenic carcinoma (based on peribronchial disease or subcarinal lymphadenopathy), we found TBNA a safe and useful tool.     

Effect of extended pre-incubation with chlamydia pneumoniae and extended incubation with antimicrobial on the minimum inhibitory concentrations (MICs) of five antimicrobials

There is no single standard methodology for in vitro susceptibility testing for Chlamydia pneumoniae, but many investigators pre-incubate this organism with the cell monolayer for 1 h prior to adding antimicrobial and incubating for 72 h. The aim of this study was to determine the effect of extended C. pneumoniae pre-incubation, and extended incubation in the presence of antimicrobial, on the MICs of 5 antimicrobials. MICs were determined for 5 ATCC strains of C. pneumoniae by employing similar methods as those previously described in the literature. MICs were then determined following 1, 4, 6, 20 and 24 h C. pneumoniae pre-incubation. Finally, MICs were determined following 1 and 24 h C. pneumoniae pre-incubation, and 48 and 72 h incubation with antimicrobial and organism. Extending the incubation time in the presence of antimicrobial from 48 to 72 h had little or no effect on MICs. Similarly, pre-incubation periods of less than 20 h had little effect on MICs, but MICs increased significantly with 20 and 24 h pre-incubation.