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BackgroundPrevious analysis of COMBI-d (NCT01584648) demonstrated improved progression-free survival (PFS) and overall survival (OS) with combination dabrafenib and trametinib versus dabrafenib monotherapy in BRAF V600E/K-mutant metastatic melanoma. This study was continued to assess 3-year landmark efficacy and safety after ≥36-month follow-up for all living patients.Patients and methodsThis double-blind, phase 3 study enrolled previously untreated patients with BRAF V600E/K-mutant unresectable stage IIIC or stage IV melanoma. Patients were randomized to receive dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily) or dabrafenib plus placebo. The primary endpoint was PFS; secondary endpoints were OS, overall response, duration of response, safety, and pharmacokinetics.ResultsBetween 4 May and 30 November 2012, a total of 423 of 947 screened patients were randomly assigned to receive dabrafenib plus trametinib (n = 211) or dabrafenib monotherapy (n = 212). At data cut-off (15 February 2016), outcomes remained superior with the combination: 3-year PFS was 22% with dabrafenib plus trametinib versus 12% with monotherapy, and 3-year OS was 44% versus 32%, respectively. Twenty-five patients receiving monotherapy crossed over to combination therapy, with continued follow-up under the monotherapy arm (per intent-to-treat principle). Of combination-arm patients alive at 3 years, 58% remained on dabrafenib plus trametinib. Three-year OS with the combination reached 62% in the most favourable subgroup (normal lactate dehydrogenase and

Healthcare delivery systems frequently require interprofessional collaboration between members of several health and social care professions. In the United States, two of the largest are nursing and social work. How these two professions address incivility between faculty members is not well understood. This paper describes the results of an examination of Faculty-to-Faculty Incivility (FFI) by both social work and nursing educators. National surveys of U.S. social work faculty (n = 216) and nursing faculty (n = 588) indicate common concerns between the two groups. Nursing and social work educators experience similar rates of behaviors that may be considered FFI, but social workers are more likely to identify these behaviors as uncivil. Data suggest that there are differences between nursing and social work faculty in their beliefs about the causes of FFI, and also in their reported barriers to addressing FFI in the workplace. The discussion highlights concerns that are common between the groups, contextual aspects that differ between the two professions, and ways in which interprofessional collaboration between nurses and social workers in academia and healthcare can help to address this problem among both groups.

Although awareness of familial hypercholesterolemia (FH) is increasing, this common, potentially fatal, treatable condition remains underdiagnosed. Despite FH being a genetic disorder, genetic testing is rarely used. The Familial Hypercholesterolemia Foundation convened an international expert panel to assess the utility of FH genetic testing. The rationale includes the following: 1) facilitation of definitive diagnosis; 2) pathogenic variants indicate higher cardiovascular risk, which indicates the potential need for more aggressive lipid lowering; 3) increase in initiation of and adherence to therapy; and 4) cascade testing of at-risk relatives. The Expert Consensus Panel recommends that FH genetic testing become the standard of care for patients with definite or probable FH, as well as for their at-risk relatives. Testing should include the genes encoding the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin 9 (PCSK9); other genes may also need to be considered for analysis based on patient phenotype. Expected outcomes include greater diagnoses, more effective cascade testing, initiation of therapies at earlier ages, and more accurate risk stratification., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Secure clinical messaging and document exchange utilizing the Direct Protocol (Direct interoperability) has been widely implemented in health information technology (HIT) applications including electronic health records (EHRs) and by health care providers and organizations in the United States. While Direct interoperability has allowed clinicians and institutions to satisfy regulatory requirements and has facilitated communication and electronic data exchange as patients transition across care environments, feature and function enhancements to HIT implementations of the Direct Protocol are required to optimize the use of this technology., Objective: To describe and address this gap, we developed a prioritized list of recommended features and functions desired by clinicians to utilize Direct interoperability for improved quality, safety, and efficiency of patient care. This consensus statement is intended to inform policy makers and HIT vendors to encourage further development and implementation of system capabilities to improve clinical care., Methods: An ad hoc group of interested clinicians came together under the auspices of DirectTrust to address challenges of usability and create a consensus recommendation. This group drafted a list of desired features and functions that was published online. Comments were solicited from interested parties including clinicians, EHR and other HIT vendors, and trade organizations. Resultant comments were collected, reviewed by the authors, and incorporated into the final recommendations., Results: This consensus statement contains a list of 57 clinically desirable features and functions categorized and prioritized for support by policy makers, development by HIT vendors, and implementation and use by clinicians., Conclusion: Fully featured, standardized implementation of Direct interoperability will allow clinicians to utilize Direct messaging more effectively as a component of HIT and EHR interoperability to improve care transitions and coordination., Competing Interests: None., (Schattauer GmbH Stuttgart.)

Purpose of Review: In this review, we examine benefits and concerns associated with genetic testing in the clinical management of familial hypercholesterolemia (FH)., Recent Findings: Application of next-generation sequencing and other advances provide improved yield of causal mutations compared with older methods and help disclose underlying pathophysiology in many instances. Concerns regarding clinical application of genetic testing remain., Summary: More widespread application of genetic testing for FH in the USA may be forthcoming. When a genetic cause of FH can be identified or is known for the family, test results can provide more accurate individual diagnosis of FH, clarification of underlying pathophysiology, and greater clinical insight. However, several concerns persist, particularly cost to FH patients, potential discrimination, and inappropriate denial of clinically indicated therapies for patients without definitive genetic testing results.

Background: Dabrafenib plus trametinib treatment provides significant benefits over BRAF-inhibitor monotherapy in patients with BRAF V600E -mutant or BRAF V600K -mutant advanced melanoma; however, in many patients the disease progresses, leading to death. With many treatment options available, understanding clinical factors that predict long-term response and survival for treatments is important for optimisation of patient management. We aimed to identify clinical factors associated with long-term response and survival using pooled data from randomised trials of dabrafenib plus trametinib in patients with metastatic BRAF-mutant melanoma., Methods: We did a retrospective individual data analysis based on all published randomised trials that included treatment-naive patients with BRAF V600E -mutant or BRAF V600K -mutant metastatic melanoma who received the approved dose of dabrafenib 150 mg twice daily plus trametinib 2 mg once daily. Data were pooled from patients in the BRF113220 (part C; March 26, 2010, to Jan 15, 2015), COMBI-d (May 4, 2012, to Jan 12, 2015), and COMBI-v (June 4, 2012, to March 13, 2015) randomised trials. Patients with untreated brain metastases were not permitted to enrol in these trials. Baseline factors, identified a priori based on known melanoma clinical or prognostic characteristics, were analysed for association with progression-free survival and overall survival using univariate and multivariate analyses and assessed for hierarchical effect on outcomes using regression tree analyses. We also analysed factors identified after baseline, on treatment, and at progression, for associations with survival after progression. The trials included in this analysis are registered with ClinicalTrials.gov: BRF113220, number NCT01072175; COMBI-d, number NCT01584648; COMBI-v, number NCT01597908., Findings: 617 patients were included in this analysis with a median follow-up of 20·0 months (range 0-48·0, IQR 10·1-24·8); 396 patients had progression events (ie, disease progression or death) and 290 patients had died. Median progression-free survival (11·1 months [95% CI 9·7-12·9]), median overall survival (25·6 months [23·1-34·3]), 1-year progression-free survival (48% [44-52]) and overall survival (74% [71-78]), and 2-year progression-free survival (30% [26-34]) and overall survival (53% [49-57]) were consistent with those in the individual trials. Patients with normal lactate dehydrogenase (LDH) concentration and fewer than three organ sites containing metastases (n=237) had the longest 1-year progression-free survival (68% [95% CI 62-74]) and overall survival (90% [87-94]) and 2-year progression-free survival (46% [40-54]) and overall survival (75% [70-81]), whereas patients with LDH concentration at least two times the upper limit of normal (n=70) had the shortest 1-year progression-free survival (8% [3-19]) and overall survival (40% [29-55]) and 2-year progression-free survival (2% [0-13]) and overall survival (7% [3-19]). Of patients with disease progression (n=379), survival after progression was longest in those with progression in baseline or new non-CNS lesions (n=205; median 10·0 months [95% CI 7·9-12·0]) and shortest in those with new CNS lesions or concurrent progression in baseline and new lesions (n=171; median 4·0 months [3·5-4·9])., Interpretation: Several patient and clinical characteristics at and after baseline are associated with outcomes with dabrafenib plus trametinib, and durable benefit is possible with targeted treatment in defined patient subsets., Funding: Novartis., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Electronic data capture of case report forms, demographic, neuropsychiatric, or clinical assessments, can vary from scanning hand-written forms into databases to fully electronic systems. Web-based forms can be extremely useful for self-assessment; however, in the case of neuropsychiatric assessments, self-assessment is often not an option. The clinician often must be the person either summarizing or making their best judgment about the subject's response in order to complete an assessment, and having the clinician turn away to type into a web browser may be disruptive to the flow of the interview. The Mind Research Network has developed a prototype for a software tool for the real-time acquisition and validation of clinical assessments in remote environments. We have developed the clinical assessment and remote administration tablet on a Microsoft Windows PC tablet system, which has been adapted to interact with various data models already in use in several large-scale databases of neuroimaging studies in clinical populations. The tablet has been used successfully to collect and administer clinical assessments in several large-scale studies, so that the correct clinical measures are integrated with the correct imaging and other data. It has proven to be incredibly valuable in confirming that data collection across multiple research groups is performed similarly, quickly, and with accountability for incomplete datasets. We present the overall architecture and an evaluation of its use.

Approximately one-third of patients with advanced, HER2-positive breast cancer develop brain metastases. A significant proportion of women experience central nervous system (CNS) progression after standard radiation therapy. The optimal treatment in the refractory setting is undefined. This study evaluated the toxicity and efficacy of lapatinib in combination with chemotherapy among patients with HER2-positive, progressive brain metastases. Patients with HER2-positive breast cancer with progressive brain metastases after trastuzumab and cranial radiotherapy were included. The primary endpoint was CNS objective response, defined as a ≥ 50% volumetric reduction of CNS lesion(s) in the absence of new or progressive CNS or non-CNS lesions, or increasing steroid requirements. The study was closed early after 22 of a planned 110 patients were enrolled due to excess toxicity and lack of efficacy in the lapatinib plus topotecan arm. The objective response rate (ORR) in the lapatinib plus capecitabine arm was 38% (exact 95% confidence interval [CI] 13.9-68.4). No responses were observed in the lapatinib plus topotecan arm. Although the study was stopped prior to full enrollment, some promising indications of CNS activity were noted for lapatinib plus capecitabine. The combination of lapatinib plus topotecan was not active and was associated with excess toxicity.

Reactions of Re(V), tetradentate Schiff base complexes with tertiary phosphines have previously yielded both rearranged Re(V) and reduced Re(III) complexes. To further understand this chemistry, the rigid diiminediphenol (N(2)O(2)) Schiff base ligand sal(2)phen (N,N'-o-phenylenebis(salicylaldimine)) was reacted with (n-Bu(4)N)[ReOCl(4)] to yield trans-[ReOCl(sal(2)phen)] (1). On reaction with triphenylphosphine (PPh(3)), a rearranged Re(V) product cis-[ReO(PPh(3))(sal(2)phen*)]PF(6) (2), in which one of the imines was reduced to an amine during the reaction, and the reduced Re(III) products trans-[ReCl(PPh(3))(sal(2)phen)] (4) and trans-[Re(PPh(3))(2)(sal(2)phen)](+) (5) were isolated. Reaction of sal(2)phen with [ReCl(3)(PPh(3))(2)(CH(3)CN)] resulted in the isolation of [ReCl(2)(PPh(3))(2)(salphen)] (3). The compounds were characterized using standard spectroscopic methods, elemental analyses and single crystal X-ray crystallography.

Unlabelled: Gastrin-releasing peptide receptors (GRPr) are a member of the bombesin (BBN) receptor family. GRPr are expressed in high numbers on specific human cancers, including human prostate cancer. Therefore, copper-64 ((64)Cu) radiolabeled BBN(7-14)NH(2) conjugates could have potential for diagnosis of human prostate cancer via positron-emission tomography (PET). The aim of this study was to produce [(64)Cu-NO2A-(X)-BBN(7-14)NH(2)] conjugates for prostate cancer imaging, where X=pharmacokinetic modifier (beta-alanine, 5-aminovaleric acid, 6-aminohexanoic acid, 8-aminooctanoic acid, 9-aminonanoic acid or para-aminobenzoic acid) and NO2A=1,4,7-triazacyclononane-1,4-diacetic acid [a derivative of NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid)]., Methods: [(X)-BBN(7-14)NH(2)] Conjugates were synthesized by solid-phase peptide synthesis (SPPS), after which NOTA was added via manual conjugation. The new peptide conjugates were radiolabeled with (64)Cu radionuclide. The receptor-binding affinity was determined in human prostate PC-3 cells, and tumor-targeting efficacy was determined in PC-3 tumor-bearing severely combined immunodeficient (SCID) mice. Whole-body maximum intensity microPET/CT images of PC-3 tumor-bearing SCID mice were obtained 18 h postinjection (pi)., Results: Competitive binding assays in PC-3 cells indicated high receptor-binding affinity for the [NO2A-(X)-BBN(7-14)NH(2)] and [(nat)Cu-NO2A-(X)-BBN(7-14)NH(2)] conjugates. In vivo biodistribution studies of the [(64)Cu-NO2A-(X)-BBN(7-14)NH(2)] conjugates at 1, 4 and 24 h pi showed very high uptake of the tracer in GRPr-positive tissue with little accumulation and retention in nontarget tissues. High-quality, high-contrast microPET images were obtained, with xenografted tumors being clearly visible at 18 h pi., Conclusions: NO2A chelator sufficiently stabilizes copper(II) radiometal under in vivo conditions, producing conjugates with very high uptake and retention in targeted GRPr. Preclinical evaluation of these new peptide conjugates in tumor-bearing mice provides some impetus for clinical evaluation in human patients., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Background: In recent years, there has been an increased interest in using a multimodal approach with combined agents to treat postoperative nausea and vomiting. This study evaluated whether the addition of an oral dose of the neurokinin-1 receptor antagonist casopitant improved the antiemetic efficacy of an intravenous dose of ondansetron hydrochloride., Methods: The authors enrolled 702 premenopausal or perimenopausal, nonsmoking, female patients aged 18-55 yr with a history of postoperative nausea and vomiting and/or motion sickness undergoing a laparoscopic or laparotomic gynecologic surgical procedure or laparoscopic cholecystectomy with general anesthesia. Subjects were randomized to one of five treatment arms: standard ondansetron 4 mg with casopitant at 0, 50, 100, or 150 mg, or 0 mg ondansetron with casopitant at 150 mg (the latter arm was considered an exploratory study group and was included in the safety analysis but not in the efficacy analysis)., Results: A significantly greater proportion of patients in all of the active casopitant plus ondansetron groups achieved a complete response (i.e., no vomiting, retching, rescue medication, or premature withdrawal) during the first 24 h postoperatively versus those in the ondansetron-alone group (59-62% vs. 40%, respectively; P = 0.0006). All active doses seemed to be well tolerated; headache, dizziness, and constipation were the most frequently reported adverse events., Conclusions: Compared with ondansetron alone, the casopitant and ondansetron combination results in superior emesis prevention during the first 24 h postoperatively in female patients with known risk factors for postoperative nausea and vomiting.

Introduction: Human breast cancer, from which the T-47D cell line was derived, is known to overexpress the gastrin-releasing peptide receptor (GRPR) in some cases. Bombesin (BBN), an agonist for the GRPR, has been appended with a radionuclide capable of positron-emission tomography (PET) imaging and therapy. (64)Cu-NO2A-8-Aoc-BBN(7-14)NH(2) (NO2A=1,4,7-triazacyclononane-1,4-diacetate) has produced high-quality microPET images of GRPR-positive breast cancer xenografted tumors in mice., Methods: The imaging probe was synthesized by solid-phase peptide synthesis followed by manual conjugation of the 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) bifunctional chelator and radiolabeling in aqueous solution. The radiolabeled conjugate was subjected to in vitro and in vivo studies to determine its specificity for the GRPR and its pharmacokinetic profile. A T-47D tumor-bearing mouse was imaged with microPET/CT and microMRI imaging., Results: The (64)Cu-NO2A-8-Aoc-BBN(7-14)NH(2) targeting vector was determined to specifically localize in GRPR-positive tissue. Accumulation was observed in the tumor in sufficient quantities to allow for identification of tumors in microPET imaging procedures. For example, uptake and retention in T-47D xenografts at 1, 4 and 24 h were determined to be 2.27+/-0.08, 1.35+/-0.14 and 0.28+/-0.07 % ID/g, respectively., Conclusions: The (64)Cu-NO2A-8-Aoc-BBN(7-14)NH(2) produced high-quality microPET images. The pharmacokinetic profile justifies investigation of this bioconjugate as a potentially useful diagnostic/therapeutic agent. Additionally, the bioconjugate would serve as a good starting point for modification and optimization of similar agents to maximize tumor uptake and minimize nontarget accumulation.

Introduction: Targeted diagnosis of specific human cancer types continues to be of significant interest in nuclear medicine. 99mTc is ideally suited as a diagnostic radiometal for in vivo tumor targeting due to its ideal physical characteristics and diverse labeling chemistries in numerous oxidation states., Methods: In this study, we report a synthetic approach toward design of a new tridentate amine ligand for the organometallic aqua-ion [99mTc(H2O)3(CO)3]+. The new chelating ligand framework, 2-(N,N'-Bis(tert-butoxycarbonyl)diethylenetriamine) acetic acid (DTMA), was synthesized from a diethylenetriamine precursor and fully characterized by mass spectrometry and nuclear magnetic resonance spectroscopy (1H and 13C). DTMA was conjugated to H2N-(X)-BBN(7-14)NH2, where X=an amino acid or aliphatic pharmacokinetic modifier and BBN=bombesin peptide, by means of solid phase peptide synthesis. DTMA-(X)-BBN(7-14)NH2 conjugates were purified by reversed-phase high-performance chromatography and characterized by electrospray-ionization mass spectrometry., Results: The new conjugates were radiolabeled with [99mTc(H2O)3(CO)3]+ produced via Isolink radiolabeling kits to produce [99mTc(CO)3-DTMA-(X)-BBN(7-14)NH2]. Radiolabeled conjugates were purified by reversed-phase high-performance chromatography. Effective receptor binding behavior was evaluated in vitro and in vivo., Conclusions: [99mTc(CO)3-DTMA-(X)-BBN(7-14)NH2] conjugates displayed very high affinity for the gastrin releasing peptide receptor in vitro and in vivo. Therefore, these conjugates hold some propensity to be investigated as molecular imaging agents that specifically target human cancers uniquely expressing the gastrin releasing peptide receptor subtypes.

A number of human cancers are known to over-express the gastrin-releasing peptide receptor (GRPr) on cell surfaces. The high specificity and affinity of bombesin (BBN), an amphibian analogue of mammalian gastrin-releasing peptide, for the GRPr makes it an ideal candidate for delivery of diagnostic probes, such as 99mTc radiometal, to tumor sites. An optimized targeting agent possesses high tumor uptake with minimal uptake in normal tissues. In this study, 99mTc-targeting vectors of bombesin using various amino acid/aliphatic pharmacokinetic modifiers or linking groups were evaluated to determine the effect of the spacer on receptor binding affinity, internalization/externalization and biodistribution. Conjugates of the general type [DPR-X-BBN] (X = amino acid/aliphatic pharmacokinetic modifier) were synthesized by solid phase peptide synthesis (SPPS) and metallated with either low-valent, radioactive Tc-99m(I) or non-radioactive Re(I)-tricarbonyl precursors. All of the new non-metallated and metallated conjugates were characterized by electrospray ionization mass spectrometry (ESI-MS). Receptor binding affinity, internalization/externalization and biodistribution studies in normal (CF-1) and tumor (human prostate PC-3-bearing mice) are reported. The effectiveness of targeting xenografted PC-3 tumors in rodents for two of the new 99mTc-BBN conjugates is demonstrated herein using small animal single photon emission computed tomography (SPECT).

Background: Byssinosis, the cotton worker's lung disease persists today in many countries. Several agents have been investigated with respect to causality; among these are Gram-negative bacteria. These organisms are a source of lipopolysaccharide toxins, which are potentially hazardous to the respiratory tract. Despite byssinosis being most prevalent in countries where adequate preventive procedures are lacking, the majority of past studies have been conducted on cotton from the United States., Methods: The current investigation, involved the identification of Gram-negative bacteria from cotton lint samples originating in 12 world regions., Results: The current investigation, involved the identification of Gram-negative bacteria from cotton lint samples originating in 12 world regions., Conclusions: Building a bacterial profile of cotton samples with worldwide origins will be useful in isolating sources of these organisms, assessing the risk posed to industry, workers and ultimately assisting the prevention of byssinosis and related conditions., ((c) 2006 Wiley-Liss, Inc.)

There is mounting evidence that inhalation of fungal spores and their fragments and toxins may cause respiratory illness, particularly in indoor environments and industrial settings. However, analysis of these organisms on cotton has not been carried out in detail and, hence, further examination may prove important in identifying sources of these organisms and assessing the risks posed to cotton workers. This study identified fungi from cotton lint samples originating in 12 world regions and revealed six different fungal genera, with the following rank order of sample isolation incidence: Aspergillus > Cladosporium > Fusarium > Rhizopus > Penicillium > Alternaria. Aspergillus was the most common genus and Aspergillus niger in particular was the pecies most frequently identified. Improved understanding of the variety of organisms that contaminate cotton may help to reduce prevalence of organic dust-related lung diseases.

Four biological contaminants of cotton fibers (gram-negative bacterial cells, endotoxin, fungal cells, and (1-3)-beta-D-glucan) were measured in 13 cotton lint samples from international origins, using traditional microbiological spread plating and adaptation of the Limulus amoebocyte lysate (LAL) assay. Correlations were evaluated using Spearman's rank correlation analyses. Contamination levels ranged from 713 +/- 212 to 216,830 +/- 30,413 CFU/g gram-negative bacteria; 281 +/- 29 to 9,250 +/- 820 CFU/g fungal cells; 8.30 +/- 0.89 to 137.89 +/- 21.55 ng/g endotoxin; and 15.96 +/- 5.18 to 2,964.42 +/- 313.90 LAL-reactive units/g glucan. Positive correlations existed between all contaminants; however, they were significant only between fungal cells and glucan (p < 0.05) and between endotoxin and glucan (p < 0.01). The highly significant positive correlation between endotoxin and glucan has implications for the health risk posed by the cotton-production environment, as simultaneous inhalation of these agents may cause or exacerbate lung inflammation.

Background: The purpose of this study was to compare quality of life and overall toxicity in patients with advanced non-small-cell lung cancer (NSCLC) treated with vinorelbine-gemcitabine (VG) or carboplatin-paclitaxel (Taxol) (CP)., Patients and Methods: A total of 165 previously untreated patients were randomized to the two regimens. Quality of life was assessed by the Lung Cancer Symptom Scale (LCSS). Overall toxicity and secondary efficacy end points were evaluated by standard WHO criteria., Results: There was no significant difference in overall quality of life between the two treatments. Neutropenia, thrombocytopenia, peripheral neuropathy, and alopecia, were more common in the CP arm, whereas constipation was more frequent in the VG arm. Response rates were 14.6% in the VG arm and 16.9% in the CP arm. Median survival times were 7.8 and 8.6 months, and 1 year survival rates were 38.4% and 31.9%, respectively., Conclusions: Patients treated with VG experienced lower toxicity, but overall quality of life was similar in both arms. Efficacy seemed comparable between VG and CP. Our study shows that VG is a viable alternative to platinum-based chemotherapy in patients with advanced NSCLC.

Endotoxin is derived from Gram-negative bacterial membranes, and its inflammatory effects following inhalation are well characterized. The significance of this fact becomes apparent when the wide-ranging environments containing high levels of this microbial product are considered. Endotoxin is present in numerous industrial environments, especially where organic fibers are processed. Microbial contamination of these fibers mainly occurs at the agricultural stage. Materials such as flax and hemp are affected in this way, but the most important product in this context is cotton, from which chronic dust inhalation causes the disease byssinosis. Despite the fact that endotoxin constitutes a significant threat to public health, there are currently no occupational exposure limits for this toxicant. This communication describes the toxicology of endotoxin, and its role in inhalation-induced disease, focusing on measurement of airborne endotoxin in the occupational and domestic environments using the Limulus amebocyte lysate (LAL) enzyme assay. Following the success of the LAL assay for measuring endotoxin in dusts, our laboratory has examined its application to aqueous washes from cotton fibers. Reproducibility of the results was high, and data are presented displaying levels of endotoxin contamination in fibers from different cotton producing countries. Hence, worldwide comparison of industrial endotoxin concentrations can be readily made using this test. It would be highly desirable if the performance of the LAL assay facilitated introduction of industrial endotoxin safety limits, and in spite of minor surmountable shortcomings, the test is accurate, reliable, and well field-tested, so its continued widespread use may achieve this goal.

Background: We have continued to monitor the survival of patients randomised in a previously reported multicentre phase III study of topotecan versus paclitaxel in patients with advanced epithelial ovarian cancer who had failed one prior platinum-based regimen., Patients and Methods: Patients with bidimensionally measurable disease were randomised to topotecan (1.5 mg/m(2)/day for 5 days) or paclitaxel (175 mg/m(2)/day as a 3-h infusion) every 21 days. Patients were eligible for treatment with the alternate therapy at third line. The European Organisation for Research and Treatment of Cancer Quality of Life (EORTC QOL)-C30 questionnaire was also used to measure eight symptoms at baseline and during each course (pain, anorexia, diarrhoea, fatigue, nausea and vomiting, dyspnea, constipation and insomnia)., Results: A total of 226 patients were evaluable for response. Demographic characteristics were similar in both treatment groups, as were results of the EORTC QOL-30 questionnaire. For the topotecan group, median time to progression was 18.9 weeks (range <1 to 92.6+ weeks; 25% censored), and, for paclitaxel, 14.7 weeks (range <1 to 137.3+ weeks; 12.3% censored); P = 0.076. At 4 years post-randomisation, median survival in the topotecan group was 63.0 weeks (range <1 to 238.4+ weeks; 20.5% censored) and, for paclitaxel, 53.0 weeks (range <1 to 226.3+ weeks; 12.3% censored); P = 0.44., Conclusion: Topotecan continues to demonstrate comparable efficacy and survival to paclitaxel with manageable and non-cumulative haematological toxicity. Non-haematological toxicity was generally mild for both groups. The long-term survival rate indicates substantial therapeutic benefit for this group of patients receiving topotecan at relapse of ovarian cancer.

Topotecan is the only single-agent therapy approved by the U.S. Food and Drug Administration for the treatment of patients with recurrent small cell lung cancer (SCLC). Poor performance status (PS) at the time of relapse can hinder the ability of a patient to tolerate second-line chemotherapy. To investigate the feasibility of topotecan in the treatment of relapsed SCLC patients with PS 2 scores, we retrospectively analyzed data from five clinical trials that included 479 patients who were treated with single-agent topotecan at a dose of 1.5 mg/m2/day on days 1-5 of a 21-day course. Of these patients, 381 had a PS 0 or 1 and 98 had a PS 2. Topotecan was well tolerated by both patient groups. Hematologic toxicities were generally manageable, and neutropenia was noncumulative. With the exception of grade 3/4 anemia, the incidences of severe hematologic toxicities were not statistically different between the two groups. The nonhematologic toxicity profiles were also similar in the two patient groups. Treatment provided similar benefits, including antitumor response rates and symptom palliation, in PS 0/1 and PS 2 patients. As expected, the median overall survival time was shorter in patients with worse PS scores; the median overall survival times were 36.3 weeks, 25.4 weeks, and 16 weeks for PS 0, PS 1, and PS 2 patients, respectively. In conclusion, treatment with topotecan is feasible and well tolerated in patients with relapsed SCLC with suboptimal PS scores.

The Institute of Medicine stressed the need for continuous healing relationships, yet the delivery of health care has traditionally been confined to the physician office or hospital. We implemented an eHealth application tightly integrated with our electronic medical record system that provides patients with a convenient, continuously available communication channel to their physician's office. Patients can view summary data from their medical record, including the results of diagnostic tests, and request medical advice, prescription renewals, appointments, or updates to their demographic information. We have found that patients embrace this new communication channel and are using the service appropriately. Patients especially value electronic messaging with their physicians and timely access to their test results. While initially concerned about an increase in work, physicians have found that use of electronic messaging can be an efficient method for handling non-urgent communication with their patients. Online tools for patients, when integrated with an electronic medical record, can provide patients with better access to health information, improve patient satisfaction, and improve operational efficiency.

Purpose: To evaluate oral topotecan as single-agent, second-line therapy in patients with ovarian cancer previously treated with a platinum-based regimen., Patients and Methods: Patients (N = 116) received oral topotecan 2.3 mg/m2 daily for 5 days every 21 days. Eligibility criteria included histologic diagnosis of International Federation of Gynecology and Obstetrics stage III or IV epithelial ovarian cancer, bidimensionally measurable disease, prior platinum-containing chemotherapy, age > or = 18 years, performance status < or = 2, and life expectancy > or = 12 weeks., Results: Overall response rate was 21.6% (25 of 116 patients). Median duration of response was 25.0 weeks; median time to response was 8.4 weeks. Median time to progression was 14.1 weeks; median survival was 62.2 weeks. Grade 4 neutropenia was experienced by 50.4% of patients in 13.4% of courses administered. Grade 4 thrombocytopenia was experienced by 22.1% of patients in 5.1% of courses. Grade 3 or 4 anemia was experienced by 29.2% of patients in 8.5% of courses. Most frequent nonhematologic toxicities were predominantly (> 90%) grade 1 or 2 and included nausea, alopecia, diarrhea, and vomiting., Conclusion: Second-line oral topotecan administered at 2.3 mg/m2 for 5 days every 21 days demonstrated activity in patients with progressive or recurrent ovarian cancer after first-line platinum-based chemotherapy. This activity was comparable to that seen in previous studies with intravenous topotecan. Grade 4 neutropenia was less frequent with oral topotecan than previously reported for intravenous topotecan. Oral topotecan is an active, tolerable, and convenient formulation of an established agent for the second-line treatment of advanced epithelial ovarian cancer and may also facilitate exploring prolonged treatment schedules.

A phase II programme was carried out in both Europe and North America to evaluate the activity of topotecan administered as a 21-day continuous intravenous infusion to patients with recurrent ovarian cancer. The European results are reported here. Patients who had failed first line therapy with a platinum-based regimen received topotecan 0.4 mg/m(2)/day, as a 21-day infusion every 28 days. Patients were only permitted one prior regimen. 35 patients were enrolled and evaluable for response. 3 patients (8.6%) had a partial response to treatment (95% CI 1.8%, 23.1%) with a median time to response of 8.1 weeks and a median duration of response of 17.6 weeks. Response was also evaluated by CA125 and was also found to be 8%. For all 35 patients, median time to progression was 16.1 weeks and median survival was 43.6 weeks. The principal toxicity was myelosuppression although grade 4 neutropenia occurred in only 8.8% of patients (2.1% of courses) and infectious complications were relatively infrequent. Non-haematological toxicity was generally mild and mainly consisted of gastrointestinal events, alopecia and fatigue. A prolonged infusion of topotecan was well tolerated with a low incidence of severe neutropenia. Responses were seen in both North American and European patients. Response rates varied between the 2 studies possibly due to differences in patient demographics., (Copyright 2001 Cancer Research Campaign.)

In Phase II oncology studies, response rate has traditionally been used to assess activity. However stabilization of disease (SD) may also provide patient benefit. To assess the value of SD (stabilization of measurable disease for at least 8 weeks) as a predictor of survival following chemotherapy in patients with non-small cell lung cancer (NSCLC), we have analyzed data from 198 NSCLC patients receiving topotecan i.v. or orally as first-line therapy either as single agent or in combination. Proportional hazards (Cox) regression models showed that responders [complete response (CR) + partial response (PR), 1.5% and 11.6% respectively] had an estimated risk of death that was 9.8% (95% CI: 4.2% to 22.7%) of that for progressive disease (PD) (60.1% of the patient population). Similarly, patients with SD (26.8% of the patient population) showed a potential benefit with a risk of death that was 27.7% of the one of patients with PD (95% CI: 17.8% to 43.1%). In conclusion SD may be a useful indicator of patient benefit from chemotherapy for NSCLC.

To assess the value of disease stabilization (SD) as a predictor of survival following chemotherapy, data were analyzed from multicenter clinical trials in small cell lung cancer (SCLC) and ovarian cancer (OC) patients receiving various second-line chemotherapy regimens. In both patient populations, SD (lasting >8 weeks) and partial responses (PR) were associated with a survival benefit versus progressive disease (PD); interestingly, the survival benefit was similar between the two groups (PR and SD). These results suggest that, at least in these populations, SD may represent a potential benefit of chemotherapy and therefore the distinction between SD and PR may not be useful.

Purpose: Topotecan and cyclophosphamide, doxorubicin, and vincristine (CAV) were evaluated in a randomized, multicenter study of patients with small-cell lung cancer (SCLC) who had relapsed at least 60 days after completion of first-line therapy., Patients and Methods: Patients received either topotecan (1.5 mg/m2) as a 30-minute infusion daily for 5 days every 21 days (n = 107) or CAV (cyclophosphamide 1,000 mg/m2, doxorubicin 45 mg/m2, and vincristine 2 mg) infused on day 1 every 21 days (n = 104). Eligibility included the following: bidimensionally measurable disease, Eastern Cooperative Oncology Group performance status of less than or equal to 2, and adequate marrow, liver, and renal function. Response was confirmed by blinded independent radiologic review., Results: Response rate was 26 of 107 patients (24.3%) treated with topotecan and 19 of 104 patients (18.3%) treated with CAV (P = .285). Median times to progression were 13.3 weeks (topotecan) and 12.3 weeks (CAV) (P = .552). Median survival was 25.0 weeks for topotecan and 24.7 weeks for CAV (P = .795). The proportion of patients who experienced symptom improvement was greater in the topotecan group than in the CAV group for four of eight symptoms evaluated, including dyspnea, anorexia, hoarseness, and fatigue, as well as interference with daily activity (P< or =.043). Grade 4 neutropenia occurred in 37.8% of topotecan courses versus 51.4% of CAV courses (P<.001). Grade 4 thrombocytopenia and grade 3/4 anemia occurred more frequently with topotecan, occurring in 9.8% and 17.7% of topotecan courses versus 1.4% and 7.2% of CAV courses, respectively (P<.001 for both). Nonhematologic toxicities were generally grade 1 to 2 for both regimens., Conclusion: Topotecan was at least as effective as CAV in the treatment of patients with recurrent SCLC and resulted in improved control of several symptoms.

SNAP-25 (synaptosomal associated protein of 25 kDa) is a neural specific protein that has been implicated in the synaptic vesicle docking and fusion process. It is tightly associated with membranes, and it is one of the major palmitoylated proteins found in neurons. The functional role of palmitoylation for SNAP-25 is unclear. In this report, we show that the palmitate of SNAP-25 is rapidly turned over in PC12 cells, with a half-life of approximately 3 h, and the half-life for the protein is 8 h. Mutation of Cys to Ser at positions 85, 88, 90, and 92 reduced the palmitoylation to 9, 21, 42, and 35% of the wild-type protein, respectively. Additional mutations of either Cys(85,88) or Cys(90,92) nearly abolished palmitoylation of the protein. A similar effect on membrane binding for the mutant SNAP-25 was observed, which correlated with the degree of palmitoylation. These results suggest that all four Cys residues are involved in palmitoylation and that membrane association of SNAP-25 may be regulated through dynamic palmitoylation.

Evidence exists that the eosinophil plays an important role in mediating injury to bronchial epithelium in chronic asthma. Here, the role of the eosinophil in chronic inflammatory disease of the paranasal sinuses was studied with tissue from patients who underwent surgery for chronic sinusitis. Paranasal tissue from patients with chronic asthma and/or allergic rhinitis was extensively infiltrated with eosinophils. Immunofluorescent studies demonstrated a striking association between the presence of extracellular deposition of major basic protein and damage to sinus mucosa. The histopathology of paranasal respiratory epithelium appeared similar to that described in bronchial asthma. These findings suggest that the eosinophil acts as an effector cell in chronic inflammatory disease of paranasal respiratory epithelium. Thus, sinus disease in patients with asthma may be due to the same mechanisms that cause damage to bronchial epithelium.

A survey was conducted of acoustic noise levels in magnetic resonance (MR) imaging systems. Static magnetic flux and radio-frequency pulses did not affect the function of shielded sound-pressure detection equipment. Noise levels were measured at bore isocenter during a variety of imaging sequences in six MR imaging systems with magnetic fields of 0.35-1.5 T. Measured noise ranged from 82 to 93 dB on the A-weighted scale and from 84 to 103 dB on the linear scale. Noise levels increased during sequences employing thinner section thickness and shorter repetition and echo times and were independent of field strength. Gradient-coil noise in MR imaging is an annoyance but is well within safety guidelines.