Search

Melatonin is effective for treating sleep–wake cycle disturbances and has been reported occasionally to decrease epileptic seizure frequency, with no long-term side effects. In this pilot study, the investigators examined the effect of melatonin on seizures, sleep quality, and behavior in 10 patients aged 9 to 32 years with intractable epilepsy. Patients were randomized to receive melatonin (10 mg daily at bedtime) followed by placebo or placebo followed by melatonin for 3 weeks each, with a 1-week washout period in between. Seizure frequency was monitored by daily diaries and actigraphy recordings; behavioral and sleep parameters were rated by caregivers. Diurnal seizures decreased significantly with melatonin compared with placebo ( P = .034, Wilcoxon test). Maximal number of seizures, seizure duration, sleep efficiency or latency, and behavioral parameters remained unchanged. No major side effects or seizure aggravation were documented. It is concluded that melatonin could be effective and safe for decreasing daytime seizure frequency in patients with intractable epilepsy.

Background Idiopathic intracranial hypertension may be associated with sleep apnea. This study evaluated the incidence of sleep breathing disorders in patients with idiopathic intracranial hypertension. Materials and Methods Overnight respiratory monitoring was performed in 22 untreated patients with idiopathic intracranial pressure diagnosed at a tertiary medical center over a two-year period and 12 sex- and age-matched control subjects. Breathing measures included heart rate, respiratory rate,oxygen saturation, and continuous end-tidal capnography. Sleep quality and daily fatigue were assessed by self-report questionnaires. Results Mean age of the study group was 32.6±12.2 years and of the control group, 37.0±12.9 years. Neither group had significant findings of hypoxia or hypercarbia during sleep, and there were no between-group differences in mean carbon dioxide level (patients, 35.8±4.41 mmHg; controls, 37.6±4.38 mmHg; p >0.02) or minimal oxygen saturation (96.35±1.99% and 5.69±1.71%, respectively; p >0.02). The study group had significantly more events of apnea (CO 2 ) per hour of sleep than the control group (1.21±1.38 and 0.92±0.56, respectively; p =0.02), although values were still within normal range ( Conclusion Idiopathic intracranial hypertension is not associated with a clinically significant nocturnal breathing abnormality, and hypercarbia is apparently not involved in the pathogenesis. However, it is possible that a subtle increase in paroxysmal sleep apnea (CO 2 ) events might be sufficient to cause vasodilatation of the cerebral blood vessels, thereby increasing intracranial pressure. Screening for sleep apnea may be appropriate in idiopathic intracranial hypertension patients, and further studies are needed to clarify this issue.

Mounting evidence indicates that growth of pathologically identical cancers in each individual patient is fueled by different sets of driving mutations. The need to identify these drivers stems from the recognized necessity for tailoring therapy and scheduling future surveillance. This personalized medical approach has been shown to result in better treatment outcomes. We present a novel Precision Cancer Analysis system (PCAS) capable of identifying activated signaling pathways by means of a transfected cell-based fluorescent reporter assay yielding a quantitative output of particular pathway activation levels. Being a functional platform PCAS reveals activated pathways regardless of the type of mutation behind it, i.e. whether it is already a known mutation or a variant of unknown significance (VUS) mutation. 20 cancer patients were sequenced for a panel of 37 genes and analyzed by the PCAS. This system quantifies oncogenic activity in the majority of the oncogenic signaling pathways altered by the patients' mutations through a functional assay and does not rely on prior knowledge of the mutations. The system produces a quantitative output enabling grading the different mutants of the same patient, providing prioritization for better drug selection.In 3 tested genes, 16 different mutations were identified- 4 in EGFR, 4 in PIK3CA and 8 in KRAS. Of these 10 were classified as known mutations for which functional annotation exists, and 6 were VUS. In addition to correctly annotating all known mutations, the PCAS further quantified oncogenic activity in all the VUS tested. Measuring the functional mechanism behind known mutations and VUS provides another layer of critical information to the physician. These results clearly demonstrate the value of a functional assay in accurately identifying the optimal course of treatment, particularly by its ability to add actionable information to VUS. The study produced a comprehensive delineation of the oncogenic activity of each patient's individual mutations demonstrating the ability of the PCAS to 1) accurately deliver comparable actionable information as found by NGS, 2) functionally characterize mutations annotated as VUS, and 3) monitor oncogenic activity of signaling pathways induced by different mutations and mutation-combinations enabling informed treatment decisions. Citation Format: Gabi Tarcic, Nir Peled, Zohar Barabash, Naama Barabash-Katzir, Shlomo Yaakobi, Eli Besser, Hani Nevo, Michael Vidne, Mariusz Adamek, Mordechai R. Kramer, Nikolai Goncharenko, Yakov Fellig, Karen Meir, Keith Mostov, Yoram Altschuler. Identification of the functional significance of mutations using the novel Precision Cancer Analysis System. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-B24.

PURPOSE: The role of local excision in patients with good histological response to neoadjuvant chemoradiation for locally advanced rectal cancer is unclear, mainly because of possible regional nodal involvement. This study aims to evaluate the correlation between pathological T and N stages following neoadjuvant chemoradiation for locally advanced rectal cancer and the outcome of patients with mural pathological complete response undergoing local excision. METHODS: This investigation was conducted as a retrospective analysis. Between January 1997 and December 2007, 320 patients with T3 to 4Nx, TxN+ or distal (≤6 cm from the anus) T2N0 rectal cancer underwent neoadjuvant concurrent chemoradiation followed by surgery. Radiotherapy was standard and chemotherapy consisted of common fluoropyrimidine-based regimens. RESULTS: After chemoradiation, 93% patients had radical surgery, 6% had local excision, and 3% did not have surgery. In the 291 patients undergoing radical surgery, the pathological T stage correlated with the N stage (P = .036). We compared the outcome of patients with mural complete pathological response (n = 37) who underwent radical surgery (group I) and those (n = 14) who had local excision only (group II). With a median follow-up of 48 months, 4 patients in group I had a recurrence and none in group II had a recurrence; one patient died in group I and none died in group II. Disease-free survival, pelvic recurrence-free survival, and overall survival rates were similar in both groups. CONCLUSION: In this retrospective study, nodal metastases were rare in patients with mural complete pathological response following neoadjuvant chemoradiation (3%), and local excision did not compromise their outcome. Therefore, local excision may be an acceptable option in these patients.

Accounting for 28% of all cancer deaths and causing 1.3 million deaths worldwide every year, lung cancer is the most lethal cancer. Diagnosing and treating cancer at its early stages, ideally during precancerous stages, could increase the 5-year survival rate by three- to four-fold with a potential for cure. Thus far, no screening method has been shown to decrease disease-specific mortality rate. The present review describes the rationale and issues related to early lung cancer screening, the management of screen-detected primary cancers and different approaches that have been tested for screening. These include imaging techniques, bronchoscopies, molecular screenings from different noninvasive or invasive sources, such as blood, sputum, bronchoscopic samples and exhaled breath.

Non-small-cell lung cancer (NSCLC) and melanoma are devastating diseases with high rates of recurrence. Current clinical recommendations include postoperative adjuvant chemotherapy in stages II and IIIA NSCLC, while there is a debate regarding its clinical benefit in stage IB. Recent Phase II trials have demonstrated a clinical benefit by postoperative vaccine with melanoma-specific antigen A3 (MAGE A3) in NSCLC and in stage IV melanoma. These trials have led to the current Phase III trials. MAGE A3 is a tumor-specific shared antigen that is frequently expressed in lung cancer and melanoma, as well as in few other tumors. Its level is associated with disease burden and with prognosis, while normal tissues do not express it, except the testis and the placenta. This review will summarize the recent developments and clinical experience with the MAGE A3 vaccine.

Rehabilitation is a central treatment modality for patients with chronic cardiopulmonary disease. Physical exertion for patients with pulmonary arterial hypertension (PAH) has typically been discouraged. Inpatient pulmonary rehabilitation has been shown to improve exercise capacity in patients with PAH. The present study aimed to evaluate outpatient pulmonary rehabilitation for patients with PAH.Twenty-two patients with PAH or chronic pulmonary thromboembolic disease were allocated to ambulatory rehabilitation (n = 11) or to the control group (n = 11). All patients were stable on PAH-specific medication. The rehabilitation group underwent 24 1-hour sessions of exercise training/rehabilitation over 12 weeks. Primary end points were change in 6-minute walking distance (6MWD) and peak oxygen uptake (VO(2)) on cardiopulmonary exercise testing. All of the patients assigned to rehabilitation and 9 control subjects completed the study. In the rehabilitation group, 6MWD increased by 32 m, and in the control group 6MWD decreased by 26 meters (P = .003). Peak VO(2) increased in the rehabilitation group by 1.1 mL kg(-1) min(-1) and decreased by 0.5 mL kg(-1) min(-1) in the control group (P .05). Peak work rate during cardiopulmonary exercise test also increased in the rehabilitation group, with borderline significance (P = .051). Echocardiography and blood N-terminal pro-brain natriuretic peptide levels were unchanged. No adverse events occurred due to the rehabilitation program.Ambulatory rehabilitation is a safe and efficacious treatment for patients with pulmonary hypertension already on medical therapy.clinicaltrials.gov ID: NCT00544726.

The management of lung abscess is usually conservative. However, in some cases drainage is necessary, commonly performed transcutaneously. Endobronchial catheter drainage is a potential alternative, though reported only sporadically. Transbronchial pigtail catheter drainage was used in 3 patients with refractory lung abscesses at our centre. The catheter was introduced endobronchially under bronchoscopic procedure. Laser was used to perforate the abscess wall through the airway into the abscess in order to provide a pathway for catheter insertion. An improvement in clinical and radiological parameters was noted immediately after catheter placement. The catheters were extracted after 4-6 days. All patients had a complete clinical recovery. Endobronchial catheters with the use of laser appear to be relatively safe and effective for the treatment of pulmonary abscess in selected patients in whom the abscess is adjacent to the central airway. When necessary, a bulge in an adjacent airway can be perforated with laser. To the best of our knowledge, there have been no previous reports of endobronchial drainage with the use of laser.

The epidermal growth factor receptor (EGFR), a member of the HER family of receptors, has become a well-established target for the treatment of patients with non-small cell lung cancer (NSCLC). Several EGFR-targeted agents produce objective responses in a minority of unselected patients, but a majority of those with EGFR-activating mutations; however, all responders eventually develop resistance. The modest activity of agents that target only EGFR may be due, in part, to the complexity and interdependency of HER family signaling. The interdependent signaling that occurs between EGFR and HER2 provides a rationale for the simultaneous inhibition of these receptors with reversible and irreversible inhibitors. Several agents with activity against both EGFR and HER2 are currently under development. Irreversible EGFR/HER2 tyrosine kinase inhibitors (TKIs) (e.g., BIBW 2992, HKI-272) and pan-HER TKIs (e.g., PF00299804) comprise a novel class of agents in clinical development that may prevent and overcome inherent and acquired resistance to first-generation reversible EGFR TKIs. Other agents in development include the monoclonal antibody pertuzumab, and XL-647, which inhibits EGFR and HER2, as well as multiple vascular endothelial growth factor receptor family members. Here we briefly review the currently available EGFR-targeted agents, discuss the rationale for extending inhibition to other HER family members, weigh the merits of irreversible HER family inhibition, and summarize preclinical and clinical data with EGFR/HER2 and pan-HER inhibitors under clinical development.

A highly sensitive and fast-response array of sensors based on gold nanoparticles, in combination with pattern recognition methods, can distinguish between the odor prints of non-small-cell lung cancer and negative controls with 100% accuracy, with no need for preconcentration techniques. Additionally, preliminary results indicate that the same array of sensors might serve as a better tool for understanding the biochemical source of volatile organic compounds that might occur in cancer cells and appear in the exhaled breath, as compared to traditional spectrometry techniques. The reported results provide a launching pad to initiate a bedside tool that might be able to screen for early stages of lung cancer and allow higher cure rates. In addition, such a tool might be used for the immediate diagnosis of fresh (frozen) tissues of lung cancer in operating rooms, where a dichotomic diagnosis is crucial to guide surgeons.

Objective: To assess the efficacy, the compliance, and the complications of the anterior mandibular positioning (AMP) device in obstructive sleep apnea syndrome (OSA) patients. Material & Methods: Polysomnographic sleep studies were performed on 38 patients before and two weeks (± 3 days) after continuous use of the AMP device. Twenty patients also underwent polysomnographic follow-up recordings after 1 year. Results: The mean apnea-hypopnea index (AHI) before treatment was 35.6 ± 17.7 and decreased significantly to 22.7 ± 15.8 after 2 weeks of treatment (p = 0.01). The mean AHI after 1 year of usage was 25.3 ± 12.9, differing significantly from the pretreatment AHI (p = 0.01). Seventy-one percent of patients used the device for 18.4 months (range 12–27). One-year clinical evaluation showed preserved dental status, preserved action of the masticatory muscles, and preserved function of the temporo-mandibular joint (TMJ). Eleven (29%) of the patients did not use the AMP device because of TMJ pain and/or unsatisfying results. Conclusions: The AMP device is well tolerated in 76% of patient. When tolerated, its compliance and efficiency are preserved across the year without long-term oral and jaw dysfunctions. Laryngoscope, 119:585–588, 200

Background Idiopathic pulmonary fibrosis (IPF) is a relentlessly progressive disease with a median survival of approximately 3 years. Measurements of lung volumes and diffusion capacity at rest are generally used to monitor the clinical course of IPF. Due to its high mortality, identification of patients at high risk is crucial for treatment strategies such as lung transplantation. This study was design to determine whether the simple 15-step climbing exercise oximetry test accurately characterizes disease severity and survival in patients with IPF. Methods The study population consisted of 51 patients with progressive IPF. Findings on the 15-step climbing test, pulmonary function tests, cardiopulmonary exercise test and 6-minute walk distance test were assessed at baseline. Participants were prospectively followed for ≥2 years to determine the relationship between the test parameters and survival. Results On univariate analysis, there were strong correlations between the 15-stair climbing test parameters and survival. On stepwise linear regression analysis, independent significant predictors of mortality were lowest saturation levels on the 15-step test and the 6-minute walk distance test. Conclusions The lowest saturation and desaturation areas on the 15-step oximetry test are significantly associated with long-term outcome in patients with IPF. We suggest that the 15-step test be used as a simple and reliable tool to predict severity and prognosis in IPF and to identify candidates for lung transplantation.

Bronchopulmonary fistula (BPF) is associated with high morbidity and mortality. It occurs as an uncommon but often severe complication of pneumonectomy. BPF may be treated by a range of surgical and medical techniques, including chest drain, Eloesser muscle flap, omental flap, transsternal bronchial closure, thoracoplasty, and prolonged therapy with antibiotic regimens. The use of bronchoscopy has been reported for the delivery of biological glue, coils, covered stents, and sealants. In this work, we describe a novel method of BPF closure using the Amplatzer device, which is commonly used for transcatheter closure of atrial septal defects.

SummaryWe prospectively assessed the diagnostic value of pleural fluid complement levels (total, C3, C4) in 135 patients with pleural effusion of five main etiologies, using novel markers. Complement levels correlated with pleural levels of protein, amylase, and transuded fluids. On univariate analysis, CHF-related pleural effusions were associated with significantly lower C4 levels than postsurgery or parapneumonic effusions. On multivariate analysis, pleural fluid C4 level was a significant predictor of CHF. Although the specificity, positive predictive value, and accuracy of the parameters were low in all diagnostic groups, their negative predictive value as well as the AUC ROC was high for CHF and post-LTX. We conclude that pleural fluid C4 levels can differentiate CHF-related pleural effusion from other etiologies and that normal level of C3 or C4 rule out CHF or LTX as causes of pleural effusion. Complement should be included in the assessment of pleural effusion when traditional diagnostic methods fail.

To identify the clinical and radiological features distinguishing Mycobacterium simiae respiratory infection from pulmonary tuberculosis, the demographics, underlying conditions, and clinical and radiological findings of 121 consecutive patients with pulmonary tuberculosis and 102 with M. simiae respiratory infection were compared retrospectively. In the M. simiae group, the patients were older (mean age 69 +/- 16 years vs. 47 +/- 21 years, p = 0.0001), with a female predominance (62% vs. 45%, p = 0.008). Only 4% were of Ethiopian origin compared to 25% of the tuberculosis group (p = 0.0001). M. simiae infection was associated with significantly higher rates of smoking history, underlying chronic obstructive pulmonary disease, zero human immunodeficiency virus (HIV) infection compared to 10% in the tuberculosis group (p = 0.001), blunted symptoms, and noncavitary infiltrates in the lower/middle lobes on chest X-ray. HIV-negative patients with M. simiae respiratory infection are distinguishable from patients with pulmonary tuberculosis by several demographic, clinical, and radiological features. These findings have important diagnostic and therapeutic implications.

Objective: Patients with end-stage lung disease very frequently die while awaiting lung transplantation. The aim of this study was to identify factors associated with mortality in patients referred for lung transplant assessment. Methods:The files of all consecutive patients listed for lung transplantation in Israel between 1997 and 2006 were reviewed and the data were compared statistically between those who survived to transplantation. Results: A total of 229 patients were listed for lung transplantation, of whom 42 (18.3%) died while awaiting transplantation. Comparison of the patients who survived to transplantation with those who did not using univariate analysis revealed that the died-waiting group was significantly older, used steroids to a greater extent, had more IPF patients and less emphysematous, and lower mean oxygen saturation at rest (p = 0.005). There were no between-group differences in comorbid diseases or pulmonary function measurements. The 6 min walk distance was strongly and inversely correlated with risk of death before transplantation (p = 0.005). On multivariate analysis, only oxygen saturation at rest was a significant independent risk factor for death while awaiting transplantation (OR 0.886; C.I. 0.805—0.974). Conclusions: There are several risk factors for death in the Israeli population listed for LTX, including age, steroid use, emphysematous patients and lower saturation at rest.

Objective: Post-transplant diabetes mellitus (PTDM) is a common and potentially serious complication after solid organ transplantation. There are only a few data, however, about the incidence of DM in patients undergoinglung transplantation. Patients and methods:The medical records of 119 consecutive patients who underwent lung transplantation from 1998 to September 2004 were reviewed. Patients were divided in three groups according to their diabetes status, including pre-transplant DM, the PTDM group and those without DM. Patient records and all laboratory data were reviewed and the clinical course of diabetes was monitored. All recipients were treated with tacrolimus based regimen. Results: Mean follow-up for all patients was 25 10. Twenty-three patients had DM in the pre-lung transplantation (LTX) DM group. PTDM developed in 34 of the remaining 96 patients (35.4%) with an incidence of 20%, 23% after 6 months and 12 months post-transplant. No significant difference was noted between 12 and 24 months post-LTX. The patients who developed DM were older (57 15 vs 53 13 years, p = 0.009), had increased BMI (26 5 vs 24 4, p = 0.0001), shorter time from diagnosis to LTX (21 13 vs 28 18 months, p = 0.007) more cytomegalovirus infection and more acute rejection and hyperglycemia in the first month after LTX. Four patients died in the PTDM group compared to nine patients in the no-DMgroup (12% vs 14%; p = 0.72). Conclusions: Post-transplant diabetes is a common complication in lung transplant patients receiving tacrolimus-based immunosuppression. The risk for developing PTDM is greatest among older recipients, those obese, and among recipients with more rejections episodes.

There are concerns about which lung to explant during single-lung transplantation (SLT). Traditionally, a quantitative lung perfusion scan (QLPS) is performed, and the better-perfused lung is retained. Occasionally, there is transplantation with graft "side-mismatching," where the less-well-perfused lung is retained. We performed a retrospective study of patients undergoing SLT at our institution to evaluate the effects of side-mismatching (according to the QLPS) on graft performance and outcome.We defined graft side-mismatching with a prospectively designed formula using baseline QLPS, and defined patients as either side-matched or side-mismatched. Data on mortality, requirement for cardiopulmonary bypass, relative graft perfusion, lung function and exercise capacity were obtained from institutional databases and patients' files.In a cohort of 114 patients, we defined 97 as having received a side-matched SLT and 17 as having received a side-mismatched graft. After lung transplantation, forced expiratory volume in 1 second (FEV(1)) and exercise capacity improved in both groups (p0.001). Patients with mismatched lungs had significantly higher relative graft perfusion post-operatively (p = 0.0012). There was no significant difference between the two groups (matched vs mismatched) in mortality, physiologic parameters and need for cardiopulmonary bypass.There is no apparent risk to the patient when a side-mismatched lung graft is transplanted. We conclude that side-mismatched lung transplantation appears to be feasible when required.

Summary Background Hypertension and tachycardia are common during fiber-optic bronchoscopy (FOB), and this may lead to cardiac ischemia. The prophylactic addition of a beta-adrenergic anatagonist might mask this response and prevent the deleterious cardiovascular effects of FOB. Methods We performed a randomized double-blind placebo-controlled trial of labetalol 10mg iv given with midazolam-alfentanil sedation. We monitored heart rate (HR) and systolic/diastolic blood pressure (SBP/DBP) throughout the bronchoscopy and calculated the rate-pressure product (RPP=(HR×SBP)/100). One-hundred twenty patients were enrolled. Results In the placebo group, there was no rise in HR, SBP, DBP or RPP, and there was no difference between the placebo and labetalol groups. Adverse events during bronchoscopy were similar in both groups. In a subgroup of patients undergoing interventional bronchoscopy, there was a trend towards lower SBP ( p =0.06). Conclusions Patients undergoing FOB under adequate midazolam-alfentanil sedation do not develop excessive sympathetic drive that may lead to cardiac stress. The addition of labetalol did not confer additional benefit or risk to the patients. (ClinicalTrials.gov number, NCT00394537).

SummaryIdiopathic pulmonary fibrosis (IPF) is often associated with exercise-induced hypoxemia. Although maximal oxygen consumption (VO2(max)) is considered the gold-standard index of functional capacity in IPF, its measurement requires sophisticated equipment and trained personnel. The aim of the present study was to investigate the value of the simple 15-steps climbing exercise oximetry test in patients with IPF.The 15-steps climbing test was administered to 51 patients with IPF. Pulmonary function tests (PFTs), cardiopulmonary exercise test (CPET), and the 6-min walk distance (6MWD) test were performed in the same session. Oxygen saturation in the 15-steps climbing test was measured by continuous oximetry, and quantified oxygen desaturation was determined by calculating the area under the curve of oxygen saturation from the beginning of exercise through the lowest desaturation point until recovery to baseline (“desaturation area”).There was a statistically significant correlation between all parameters of the 15-steps climbing test and both VO2(max) on the CPET (lowest saturation, p=0.002, r=0.43; saturation difference, p=0.02, r=−0.33; recovery time, p=0.02, r=−0.32; and desaturation area, p=0.005, r=−0.39), and carbon dioxide diffusion in the lungs (DLCO) on the PFTs (lowest saturation, p=0.0001, r=0.52; saturation difference, p=0.0002, r=−0.50; recovery time, p=0.0001, r=−0.53; and desaturation area, p=0.0001, r=−0.53). On stepwise linear regression analysis, independent significant predictors of VO2(max) were lowest saturation on the 15-steps test and the 6MWD.We concluded that the 15-steps oximetry test is a simple and accurate bedside tool for the evaluation of functional capacity in patients with IPF.

The aim of the present study was to evaluate whether soluble triggering receptor expressed on myeloid cells (sTREM-1) is present in the cerebrospinal fluid (CSF) of patients with acute meningitis and if its presence can predict bacterial infection. We found elevated levels of sTREM-1 in the CSF of seven of the nine (78%) patients with culture-positive specimens and in none of 12 (0%) patients with culture-negative specimens (sensitivity: 78%; specificity: 100%). The area under the receiver operating characteristic curve for sTREM-1 in the CSF as a predictor for bacterial meningitis was 0.889. This suggests that sTREM-1 is upregulated in the CSF of patients with bacterial meningitis with high specificity and that its presence can potentially assist clinicians in the diagnosis of bacterial meningitis.

Bronchiolitis obliterans syndrome (BOS) is one of the main causes of mortality after lung and bone marrow transplantation. Up to 75% of lung transplantation patients develop BOS within 5 years, whereas after bone marrow transplantation 14% of the patients develop the disease with 65% mortality within 3 years. Patients demonstrate gradual decrease in pulmonary functions with no significant anatomic/imagine findings. Therapeutic trials with high dose systemic corticosteroids, immune suppression and immunomodulation did not show any significant success. However, macrolides and especially azithromycin have recently been reported as highly efficient for BOS. This review summarizes information on the disease focusing on the clinical experience with azithromycin as a treatment for BOS.

e19120 Background: mNSCLC pts benefit from EGFR tyrosine kinase inhibitors (TKIs) but also from chemotherapy; the optimal sequencing of these treatments in not known. Methods: mNSCLC pts that recei...

e19031 Background: mNSCLC pts benefit from EGFR TKI treatment. However, resistance inevitably occurs and is difficult to treat. We wanted to evaluate the efficacy of an ErbB-family inhibitor, afati...

e22125 Background: Two major limitation for performing precision medicine based on next generation sequencing is the lack of ability to differentiate between passenger mutations and those with onco...

7570 Background: Pro-gastrin-releasing peptide (proGRP) is a precursor of the neuropeptide hormone produced by small cell lung cancer (SCLC) and considered as a potential serum marker for this disease. However, proGRP was shown to be more stable in plasma compared to serum. In this prospective study we evaluated the new proGRP assay in plasma format. Methods: Plasma proGRP was determined using the ARCHITECT i System (Abbott Diagnostics, Wiesbaden, Germany) in four cohorts: healthy individuals (n = 100) and patients with benign lung diseases (BLD, n = 102), non-small cell lung carcinoma (NSCLC, n = 241), and SCLC (n = 90). Results: The median (95 percentile) concentrations of plasma proGRP in healthy, BLD, NSCLC and SCLC were: 38 (64), 39 (64), 40 (121) and 680 (17695) pg/ml, respectively. There was no association with age, gender or smoking. The proGRP assay proved to be effective in distinguishing SCLC from NSCLC with area under the curve 0.941, 95%CI 0.906-0.975, 84.4% sensitivity, 95% specificity, at a...

e22123 Background: As no two tumors share the same molecular mechanism, each cancer patient presents a unique type of disease. Genomic profiling, especially NGS, has armed oncologists with new info...

e19005 Background: Rearranged during Transfection (RET) fusions have been reported in 1-2% of lung adenocarcinomas (LADC), KIF5B-RET fusion being the common variant, and less commonly CCDC6-RET, TR...

Summary Previous studies have shown conflicting results concerning mortality related to Clostridium difficile infection. The objective of this study was to determine the impact of C. difficile infection on short- and long-term mortality in hospitalised patients with antibiotic-associated diarrhoea. We therefore undertook a prospective caseecontrol study of 217 hospitalised patients who received antibiotics, developed diarrhoea and underwent stool enzyme immunoassay for C. difficile TOX A/B. The KaplaneMeier and the log-rank test were used to determine univariate survival analysis and a Cox regression model for multivariate analysis of 28 day and long-term mortality. Fifty-two (24%) of the 217 patients who met the study criteria were positive for C. difficile TOX A/B. The crude 28 day and long-term mortality rates of the entire cohort were 12.4% and 56%, respectively. On Cox regression analysis, hypoalbuminaemia, impaired functional capacity and elevated serum urea levels were found to be the only independent and statistically significant variables associated with long-term mortality. C. difficile toxin positivity per se was not associated with increased short- or long-term mortality rates. In conclusion, hypoalbuminaemia, renal failure, and impaired function capacity predict mortality due to antibiotic-associated diarrhoea, but C. difficile involvement by itself does not further increase the risk of death in these patients. a 2008 The Hospital Infection Society. Published by Elsevier Ltd. All rights reserved.

Stent insertion for bronchial stenosis has become common practice in lung transplantation and advanced lung malignancy, and for external compression of the airways for other reasons. Right main bronchus stenting may require blocking the right upper lobe by the stent, placing the patient at risk of recurrent pneumonia and atelectasis. In this study, three patients after insertion of a metal stent to the right main bronchus are described. In all cases, the right upper lobe was covered by the stent, and a laser (Nd:YAG) procedure was used to open a ‘window’ in the stent toward the right upper lobe with a follow-up of 1 year. We conclude that stent insertion to the right main bronchus may be followed by a laser therapy to open a ‘window’ toward the right upper lobe.

To evaluate the species distribution and antifungal susceptibility of Candida isolates in a tertiary institution in Israel, all consecutive isolates of Candida spp. recovered from blood during the last 2 years were studied. The isolates were identified by the germ tube test and the API ID 32C test (bioMérieux, Marcy l'Etoile, France). MICs of antifungal agents were determined by the E test. Candida albicans was the most commonly isolated species, accounting for 44% (63/142) of the isolates, followed by Candida tropicalis (25%; 35/142), Candida parapsilosis (20%; 29/142), Candida glabrata (10%; 14/142), and Candida krusei (0.7%; 1/142). All isolates were sensitive to amphotericin B and voriconazole. Resistance to fluconazole (using a high MIC of/=256 microg/ml) was found in 1.6% of C. albicans isolates, in 3.4% of C. parapsilosis isolates, and in 21.4% of C. glabrata isolates. Resistance to itraconazole was detected in 3.2% of C. albicans isolates, in 2.9% of C. tropicalis isolates, in 3.4% of C. parapsilosis isolates, and in 93% of C. glabrata isolates. Disparities in species distribution and antifungal susceptibility of Candida isolates from the institute studied versus Candida isolates from other centers and countries are described. The findings emphasize the need for continuous surveillance and further clinical investigational studies.

This study was devised to look at trends in the microbiological spectrum and susceptibility patterns of pathogens causing bacteraemia in paediatric febrile oncology patients. The retrospective study compared various microbiological aspects recorded for febrile oncology neutropenic patients treated with two different empirical antibiotic regimens (ceftazidime plus gentamicin during 1998-1999 and piperacillin/tazobactam plus amikacin during 2000-2002). Eighty-one bacteraemic episodes occurred in 41 patients. Overall, 132 (34 during 1998-1999 and 98 during 2000-2002) organisms were isolated: 84 (65%) Gram-negative bacteria, 39 (30%) Gram-positive bacteria and 7 (5%) fungi. Enterobacter spp. incidence decreased from 18 to 6% (P=0.07) while the recovery rates of Gram-positive organisms increased from 24 to 32% (P=0.4) during 2000-2002 compared with 1998-1999. MRSA were not isolated from any episode of bacteraemia. Five (18%) of the 28 Escherichia coli and Klebsiella spp. isolates were beta-lactamase producers (80% [4/5] isolated during 2000-2002). Twenty-seven of 28, 27/27, 23/28, 20/25 and 27/28 of these isolates were susceptible to imipenem, piperacillin/tazobactam, gentamicin, ceftazidime and ciprofloxacin, respectively. Thirty-two of 34 (94%) and 60/74 (81%) of the Gram-negative organisms isolated during 2000-2002 were susceptible to piperacillin/tazobactam and ceftazidime, respectively (P=0.076). No major differences in the microbial spectrum and antibiotic susceptibilities were recorded between the two consecutive study periods. An increase in the number of extended beta-lactamase producing E. coli and Klebsiella spp. occurred during 2000-2002. All beta-lactamase producing organisms were susceptible to piperacillin/tazobactam and initial empirical therapy with piperacillin/tazobactam was more appropriate than ceftazidime to cover most of the pathogens causing bacteraemia.

Acute pulmonary edema has been noted in swimmers and divers, and has been termed swimming-induced pulmonary edema (SIPE). The mechanisms and consequences of SIPE are unknown, and there are currently no series of carefully evaluated patients with this condition. Herein we report the clinical presentation, incidence of recurrence, findings on physical examination, chest radiography, and oxygen saturation in 70 trainees with a diagnosis of SIPE. We also report the results of forced spirometry in a subgroup of 37 swimmers.SIPE was diagnosed when severe shortness of breath and cough were reported during or after swimming, and were associated with evidence of pulmonary edema. During the years from 1998 to 2001, 70 cases of SIPE were documented in young healthy male subjects participating in a fitness-training program. Physical examination and pulse oximetry were performed immediately. Chest radiographs were obtained in all cases 12 to 18 h following onset of symptoms. In 37 swimmers, spirometry was performed at the time of chest radiography and again after 7 days.All subjects complained of severe shortness of breath. Sixty-seven of the 70 subjects (95.7%) had a prominent cough; in 63 subjects (90%), there was significant sputum production. Hemoptysis was observed in 39 subjects (55.7%). Mean arterial oxygen saturation after swimming was 88.4 +/- 6.6% breathing air, compared with 98 +/- 1.7% breathing air at rest before the start of the swimming trial (mean +/- SD) [p0.001]. Chest radiographs obtained 12 to 18 h after swimming were normal in all cases. Sixteen trainees (22.9%) had a recurrence of SIPE. Spirometry demonstrated restrictive lung function, which persisted for a week.In our trainee population, SIPE is a not uncommon, often recurrent phenomenon that significantly influences performance. It is not clear what predisposes to its occurrence or recurrence and what, if any, are its long-term effects.

This study investigated the clinical features of immunocompetent children with adenovirus infection requiring hospitalization. The files of 78 children (mean age 17 +/- 10 months) with community-acquired adenovirus infection admitted over a 2-year period were reviewed. The children were referred after 5.7 +/- 3.4 days of illness, all with fever (mean peak 39.8 +/- 0.8 degrees C). Temperature normalized after 3.5 +/- 2 days. Duration of hospitalization (mean, 7.0 +/- 3.9 days) correlated with lethargy, lung crackles, cracked lips, hypoxia, impaired liver tests, and high serum lactic dehydrogenase (LDH) concentration at admission. Serum LDH concentrations and hypoxemia predicted 70% of the variance in hospital stay. All patients recovered. Adenovirus infection may cause considerable morbidity, even in immunocompetent children. Disease severity, defined by duration of hospitalization, correlates with serum LDH concentrations and oxygen saturation at admission.

e19111 Background: Profiling lung cancer tumors for targetable GAs is the cornerstone for individualizing treatment for this disease. We hypothesized that NSCLC samples would be enriched in actiona...

7560 Background: The search for non-invasive diagnostic methods of lung cancer (LC) has led to new avenues of research, including the exploration of the exhaled breath. Previous studies have shown ...

e19023 Background: Exhale breath analysis can assist in early detection of lung cancer (LC). The cancerous cells induce biochemical changes that cause a release of various compounds to blood, some ...

8049 Background: Genomic rearrangements of ALK are the defining feature of a subset of lung non-small cell carcinomas (NSCLC), and predict response to ALK-targeted therapies. We reviewed our experi...

e18555 Background: SCLC stage is classified as limited (LD) or extensive (ED). ED is incurable while LD patients may survive. Gastrin-releasing peptide (GRP), an SCLC autocrine growth factor, assay...

*Sleep Laboratory, Technion–Israel Institute of Technology, Haifa; and †Department of Pediatric Neurology,Soroka Medical Center, Beer-Sheva, IsraelSummary: Purpose: Recently, melatonin has been associatedwith antiepileptic activity, most probably because of its anti-oxidant activity as a free radical scavenger. This study aimed toexpand the clinical experience with melatonin as an antiepilep-tic drug (AED) in humans.Methods: Six children (aged 2–15 years), with severe intrac-table seizures, were treated with 3 mg of oral melatonin 30 minbefore bedtime, in addition to their previous AED treatment for3 months. A diary of clinical seizure activity (time of day,duration, and type) was kept by parents for a month before andduring treatment. Five patients underwent a baseline polysom-nography, and three also were monitored during melatonintreatment.Results: With the exception of the parents of one child, allreported a significant clinical improvement in seizure activityduring treatment, particularly during the night. Sleep studiesshowed a decrease in epileptic activity in two of the threepatients who were monitored during treatment, and a change ofsleep efficiency from 84.2% to 89.7% (NS). Improvement indaytime behavior and in communication abilities was reportedby parents, although it was not objectively measured.Conclusions: This clinical observation adds to the growingdata showing the antiepileptic effect of melatonin. However,owing to the paucity of well-controlled studies, using melatoninas an AED should be limited to this specific group of patientswith intractable seizures.Key Words: Melatonin—Convulsions—Epilepsy—Treatment—Free radicals.

Five children with severe psychomotor retardation (mean age 8.2+/-3.6 years) and irregular sleep-wake patterns underwent 1 week of wrist actigraphic monitoring before and after treatment with 3 mg melatonin. Three underwent multiple measurements of urinary sulfatoxymelatonin levels. Urine sulfatoxymelatonin levels were abnormally low, without any significant day/night differences. Melatonin treatment increased nighttime sleep from 5.9+/-0.8 to 7.3+/-0.5 hours (paired t test, P

Hypertension is a common finding among obstructive sleep apnea (OSA) patients, and is thought to be caused by sympathetic hyperactivity. The present study compares the contributions of the respiratory disturbance index (RDI) as a reflection of sleep fragmentation, and the magnitude of oxygen desaturation, to sympathetic activation as indexed by urinary norepinephrine concentrations, as well as to morning and evening blood pressure in sleep apnea syndrome patients. Data (polysomnography, blood pressure [BP], and urine catecholamines) of 38 consecutive OSA patients (age, 46+/-14.5 years) were analyzed. Stepwise logistic regression analysis revealed that minimal oxygen saturation level (SaO2min) was a significant predictor of both morning and evening norepinephrine levels, and that 37% of morning systolic BP variance could be accounted for by a combination of age and norepinephrine, while 20% of the diastolic BP variance was accounted for by SaO2min alone. In contrast, RDI entered the prediction equation only when minimal oxygen saturation was rejected first. Our results indicate that the degree of nocturnal hypoxia is more closely associated with the level of sympathetic activation and with daytime level of blood pressure than with sleep fragmentation.

Radiation therapy is an established therapeutic option for lung cancer, but its use is limited due to side effects. Combining radiosensitizers with RT is a way to augment the efficacy of RT. Chromosome Region Maintenance Protein 1/Exportin 1 (CRM1/XPO1) is a key nuclear export protein, the cargoes of which are Tumor Suppressor Proteins (TSPs) such as p53, FOXO, PTEN, pRB and I-κB. Small molecule SINE block CRM1-dependent nuclear export and force the nuclear retention of TSPs, potentially sensitizing cells to RT. Suggested mechanisms include: 1) Induction of “genome fidelity review” by forced nuclear retention of TSPs; 2) Prevention of single stranded DNA break repair, and thereby reduction of resistance of cancer cells to RT. Methods: IC50 of KPT-SINE e.g. KPT-185 and clinical compound KPT-330, were determined in MTT assays using human NSCLC p53 wild type (wt) cancer cell lines H1299 and A549. Clonogenic assays in the SINE sensitive H1299 (IC50 100nM) and SINE-resistant A549 (IC50 1.7μM) lines were conducted in the presence or absence of escalating doses of radiation. An in vivo tumor xenograft model using the A-549 cell line in SCID mice was also conducted with KPT-330. Results: KPT-185 demonstrated inhibitory effects on the clonogenicity of two NSCLC cell lines in a dose dependent fashion. We showed that, while RT alone treatment caused coloines growing curve reduced to less than 75% tumor volume reduction when compared to vehicle, and a >65% reduction when compared to Cisplatin. In this model, KPT-330 was fairly well-tolerated, with minimal body weight loss by animals over the course of the study. Conclusions: These studies showed that KPT-SINE significantly inhibited the growth of two p53 wt NSCLC lines by MTT assay. Similar inhibition was observed in clonogenic assays with cells (A549) resistant to SINE. We described the additive effects of SINE and RT on NSCLC cell lines, suggesting that SINEs can act as radiosensitizers. We further demonstrated that SINEs are efficacious in vivo in the A549 xenograft model, and display superior efficacy when compared to Cisplatin. SINE compounds represent a promising novel therapy against NSCLC both as stand-alone agents and in combination with RT. These data support further development of SINE-based therapies for NSCLC. Further work on in vivo studies of KPT-SINE in combination with RT will be reported. Citation Format: Tami Rashal, Dilara McCauley, Maya Ilouze, Nir Raphael, Inessa Solomonik, Yaccov Lawrence, Ronen Shavit, Sharon Shacham, Michael Kauffman, Nir Peled. Combination tTerapy KPT-SINE (selective inhibitors of nuclear export) with radiotherapy have additive effects in non-small cell lung cancer (NSCLC) cells in vitro and in vivo. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2075. doi:10.1158/1538-7445.AM2013-2075

Introduction: Over the last decades many new chemo and targeted therapies were developed and approved to treat patients with non-small-cell lung cancer (NSCLC). Nevertheless, little progress has been achieved in improving the survival of these patients. Considering the heterogeneity of human cancer, it is well accepted that the ‘one-size-fits-all’ approach is suboptimal, and the need of personalized cancer therapy has been recognized. In light of these needs, PrediCare™ is medical software that provides personalized predictions of efficacy and drug induced toxicity for NSCLC patients. Accordingly, PrediCare™ is a supportive system for Oncologists in choosing the optimal tailored treatment for a patient considering the balance between efficacy, toxicity, and quality of life, given the approved treatment options. PrediCare™ is based on Optimata Virtual Patient® (OVP™) technology, a set of mechanistic and statistical bio-mathematical models that simulate the progression of solid tumor and effect of treatment. Integrating individual patient data (imaging, histopathology, blood analysis, urine analysis & genotype) into PrediCare™ will generate personal set of parameters that will be utilized to simulate tumor progression and effect of treatment. Methods: PrediCare™ is composed of the following main components: Drug Pharmacokinetics/Pharmacodynamics Module: models of drugs, as mono or combination therapies.Efficacy Module: simulates the predicted effect of different drugs on tumor size and subsequently on response and/or time to progression (TTP).Toxicity module: simulates the predicted likelihood for adverse events following administration of different drugs.Database: storage of PK/PD, Efficacy and Toxicity module background data as well as personal patient data.Engine: handles, executes, and integrate the different processes (models) and connect them with the database.Results Analyzer: Interpret the simulation results into clinical standards based on RECIST criteria and Common Toxicity Criteria. Personalizing the biomathematical models will be achieved in collaboration with Sheba Medical Center. Specifically, retrospective clinical data from 100 of NSCLC patients will be collected. The models will be fitted to the individual clinical outcomes and correlations between the fitted parameters and the individual data will be analyzed. Cross validation, predictions accuracy, bias and relative error will be performed to guarantee rigorous and quantitative personalized predictions. Summary: Developing PrediCare™ will address the major unmet need in personalized oncology, particularly: 1/Predicting optimal treatment for individual patients, 2/Developing individual screening programs based on best practices, technologies and research, and 3/Facilitating and accelerating oncology drug development through patient stratification and recommended treatment strategies. Conclusions: Implementing PrediCare™ in Medical Centers offers integration of a broad range of medical examinations and treatment options with unique predictive technology. This will assist health care providers in treating patients on an individual basis, insurance companies for efficient resources allocation and pharmaceutical companies for targeted clinical trials and informed Go/No-Go decision, ultimately leading to significant improvements of the treatment provided to the patients.