Improving the turnaround time of molecular profiling for advanced non-small cell lung cancer: Outcome of a new algorithm integrating multiple approaches.

BACKGROUND: Molecular tumor profiling to identify oncogenic drivers and actionable mutations has a profound impact on how lung cancer is treated. Especially in the subgroup of non-small cell lung cancer (NSCLC), molecular testing for certain mutations is crucial in daily clinical practice and is recommended by international guidelines. To date, a standardized approach to identify druggable genetic alterations are lacking. We have developed and implemented a new diagnostic algorithm to harmonize the molecular testing of NSCLC. PATIENTS AND METHODS: In this retrospective analysis, we reviewed 119 patients diagnosed with NSCLC at the University Hospital Zurich. Tumor samples were analyzed using our standardized diagnostic algorithm: After the histological diagnosis was made, tissue samples were further analyzed by immunohistochemical stainings as well as the real-time PCR test Idylla™. Extracted DNA was further utilized for comprehensive genomic profiling (FoundationOne®CDx, F1CDx). RESULTS: Out of the 119 patients were included in this study, 100 patients were diagnosed with non-squamous NSCLC (nsqNSCLC) and 19 with squamous NSCLC (sqNSCLC). The samples from the nsqNSCLC patients underwent testing by Idylla™ and were evaluated by immunohistochemistry (IHC). F1CDx analysis was run on 67 samples and 46 potentially actionable genomic alterations were detected. Ten patients received the indicated targeted treatment. The median time to test results was 4 days for the Idylla test, 5 days for IHC and 13 days for the F1CDx. CONCLUSION: In patients with NSCLC, the implementation of a standardized molecular testing algorithm provided information on predictive markers for NSCLC within a few working days. The implementation of broader genomic profiling led to the identification of actionable targets, which would otherwise not have been discovered.

Near-fatal asthma as clinical manifestation in onset diabetic patient: Case report / Asma casi fatal como manifestación clínica en paciente diabética debut: Reporte de caso

Near-fatal asthma (NFA) is defined as the most severe form of asthma characterized by a refractory asthma attack with an arterial carbon dioxide tension (PaCO2) greater than 45 mmHg and altered consciousness, requiring mechanical ventilation. We reported the case of 40-year-old female patient, obese and asthmatic with irregular treatment who presented dyspnea accompanied by severe oppressive chest pain and loss of consciousness, with generalized cyanosis and severe shortness of breath, for which she underwent emergency endotracheal intubation and mechanical ventilation. Laboratory tests show decompensated respiratory acidosis, glycemia of 258 mg / dl and HbA1C of 7.94%; her diagnosing diabetes mellitus. Asthmatic patients with type 2 diabetes mellitus who have irregular treatment for both diseases are at increased risk of manifesting near-fatal asthma.

El asma casi fatal (ACF) se define como la forma más severa de asma que se caracteriza por una crisis asmática refractaria con una presión parcial de dióxido de carbono (PaCO2) mayor a 45 mmHg y alteración de la conciencia que requiere ventilación mecánica. Presentamos a una paciente femenina de 40 años, obesa y asmática con tratamiento irregular que acude por disnea acompañada de dolor torácico tipo opresivo de intensidad severa y pérdida de la conciencia, con cianosis generalizada y dificultad intensa para respirar por lo que se le realiza intubación endotraqueal de emergencia y ventilación mecánica. En los exámenes de laboratorio se encuentra acidosis respiratoria descompensada, glicemia de 258 mg/dl y HbA1C de 7.94%; diagnosticándole diabetes mellitus. Los pacientes asmáticos con diabetes mellitus tipo 2 que tienen un tratamiento irregular para ambas enfermedades presentan mayor riesgo de manifestar un asma casi fatal.

Access to essential anticancer medicines for children and adolescents in Europe.

BACKGROUND: Essential anticancer medicines are an indispensable component of multidisciplinary treatment of paediatric malignancies. A European Society for Medical Oncology (ESMO) study reported inequalities in the availability of anticancer medicines for adult solid tumours and provided a model for the present survey. The aim of this survey was to assess the accessibility of essential medicines used in paediatric cancer patients aged 0 to 18 years across Europe from 2016 to 2018. METHODS: A list of medicines was drawn with input from the European Society for Paediatric Oncology (SIOP Europe) Clinical Research Council referring to the World Health Organization Model List of Essential Medicines for Children (WHO EMLc) 2017. A survey was sent to nominated national clinician and pharmacist rapporteurs and parent associations in up to 37 countries; answers were obtained from 34 countries. RESULTS: The full survey list contained 68 medicines, including 24 on the WHO EMLc 2017. Health professionals reported that 35% of all medicines were prescribed off-label in at least one country and that 44% were always available in >90% of countries. Only 63% of the EMLc 2017 medicines were reported as always available. The main determinant of unavailability was shortages, reported for 72% of medicines in at least one country. Out-of-pocket costs were reported in eight countries. Twenty-seven percent of orally administered medicines were never available in child-friendly formulations. Parents detailed individual efforts and challenges of facilitating ingestion of oral medicines as prescribed. Inequalities in access to pain control during procedures were reported by parents across Europe. CONCLUSIONS: Children and adolescents with cancer in Europe experience lack of access to essential medicines. Urgent actions are needed to address shortages, financial accessibility, availability of safe age-appropriate oral formulations, and pain management across Europe.

Pretransplantation Donor-Recipient Pair Seroreactivity Against BK Polyomavirus Predicts Viremia and Nephropathy After Kidney Transplantation.

Kidney transplant donors are not currently implicated in predicting BK polyomavirus (BKPyV) infection in kidney transplant recipients. It has been postulated, however, that BKPyV infection originates from the kidney allograft. Because BKPyV seroreactivity correlates with BKPyV replication and thus might mirror the infectious load, we investigated whether BKPyV seroreactivity of the donor predicts viremia and BKPyV-associated nephropathy (BKPyVAN) in the recipient. In a retrospective cohort of 407 living kidney donor-recipient pairs, pretransplantation donor and recipient sera were tested for BKPyV IgG levels and correlated with the occurrence of recipient BKPyV viremia and BKPyVAN within 1 year after transplantation. Donor BKPyV IgG level was strongly associated with BKPyV viremia and BKPyVAN (p < 0.001), whereas recipient BKPyV seroreactivity showed a nonsignificant inverse trend. Pairing of high-BKPyV-seroreactive donors with low-seroreactive recipients resulted in a 10-fold increased risk of BKPyV viremia (hazard ratio 10.1, 95% CI 3.5-29.0, p < 0.001). In multivariate analysis, donor BKPyV seroreactivity was the strongest pretransplantation factor associated with viremia (p < 0.001) and BKPyVAN (p = 0.007). The proportional relationship between donor BKPyV seroreactivity and recipient infection suggests that donor BKPyV seroreactivity reflects the infectious load of the kidney allograft and calls for the use of pretransplantation BKPyV serological testing of (potential) donors and recipients.

Bacteremic pneumococcal pneumonia: clinical outcomes and preliminary results of inflammatory response.

PURPOSE: Further examination of clinical outcomes and inflammatory response of bacteremic pneumococcal community-acquired pneumonia (CAP) is of great interest to enhance the care of patients with pneumococcal CAP. METHODS: This is a secondary analysis of the Community Acquired Pneumonia Organization (CAPO) to compare the time to clinical stability (TCS), length of hospital stay (LOS), and in-hospital mortality of hospitalized pneumococcal CAP patients with and without bacteremia. To measure the effect of bacteremia in pneumococcal CAP patients on outcomes, we modeled all-cause in-hospital mortality using a Poisson regression model, and TCS and LOS using Cox proportional hazards models. Adjusted multivariate regression models were also used to predict the probability of occurrence of each of the study outcomes. To investigate the inflammatory response, we measured the plasma levels of pro- and anti-inflammatory cytokines [tumor necrosis factor (TNF)-α, interleukin (IL)-1rα, IL-6, IL-8, IL-10], inflammatory biomarkers [C-reactive protein (CRP), pro-calcitonin (PCT), and B-type natriuretic peptide (BNP)], and peripheral blood neutrophil responses in 10 patients, 4 bacteremic and 6 non-bacteremic pneumococcal CAP, upon admission and every other day during the first 6 days of hospitalization. Functional data were presented as median and standard error of the median (SEM); due to small number of samples no statistical comparisons were performed between groups. RESULTS: From 833 pneumococcal CAP patients, 394 patients (47 %) were bacteremic. Bacteremic pneumococcal CAP were less likely to reach TCS with an adjusted hazard ratio (AHR) of 0.82 (95 % CI 0.69-0.97; p = 0.02) and had higher in-hospital mortality with an AHR of 1.63 (95 % CI 1.06-2.50, p = 0.026). Bacteremic pneumococcal CAP patients had a longer LOS than non-bacteremic pneumococcal CAP (p < 0.003). Higher plasma levels of CRP, PCT, and BNP were found in bacteremic than in non-bacteremic patients. The bacteremic group had consistently higher plasma levels of both pro- and anti-inflammatory cytokines. The blood neutrophil functional responses were similar in both groups of patients. CONCLUSIONS: Bacteremic pneumococcal CAP patients were significantly associated with higher in-hospital mortality, lower TCS, and longer LOS. HIV-infected patients showed a greater mortality which was not statistically significant. Bacteremic pneumococcal CAP patients had higher levels of biomarkers and systemic cytokines.

Impact of medications on mIBG uptake, with specific attention to the heart: Comprehensive review of the literature.

BACKGROUND: A critical review of the literature on drug interactions with mIBG uptake was performed to allow formulation of contemporary guidance regarding withholding medications prior to clinical imaging studies. METHODS: Published information was extracted on the experimental system used, the quantitative characteristics of the measurements, and whether any data directly examining cardiac tissues were included. Level of evidence for each medication category was assessed on a qualitative scale of very low, low, medium, or high. Strength of medication effect for inhibition of mIBG uptake was judged as none, weak, moderate, or strong. RESULTS: The only medications for which level of evidence was judged high were labetalol and reserpine. Level of evidence was judged medium for tricyclic antidepressants, calcium channel blockers, and antiarrhythmics (specifically amiodarone). Evidence was judged sufficient to recommend withholding labetalol and the tricyclic antidepressants prior to mIBG cardiac imaging. Mechanistic evidence was sufficient to suggest consideration of withdrawal of sympathomimetic amines and serotonin-norepinephrine reuptake inhibitors (SNRIs). CONCLUSIONS: As there is strong evidence for inhibition of mIBG uptake in only a small number of compounds, clinical decisions regarding withdrawal of concomitant medications should be individualized by considering the potential consequences of a false-positive (artificially low cardiac uptake) imaging result.

Vitamin D deficiency is associated with greater tumor size and poorer outcome in Merkel cell carcinoma patients.

BACKGROUND: Merkel cell polyomavirus has been recognized to be associated with Merkel cell carcinoma (MCC), but the evolution of this cancer probably depends on various factors. Vitamin D deficiency, defined by serum 25-hydroxyvitamin D levels <50 nmol/L, seems to influence cancer behavior and progression, but has never been assessed in MCC patients. OBJECTIVES: First, to evaluate whether vitamin D deficiency was associated with tumor characteristics and prognosis in a cohort of MCC patients. Second, to assess expression of the vitamin D receptor (VDR) in MCC tumors. METHODS: Clinical findings, Merkel cell polyomavirus markers and vitamin D status were assessed in a cohort of French MCC patients. The study was limited to the 89 patients for whom the serum sample had been collected within 3 years after the diagnosis of MCC. Correlation between vitamin D deficiency and MCC characteristics and outcome were determined in regression analyses. VDR expression in MCC tumours was assessed by immunohistochemistry. RESULTS: Vitamin D deficiency was noted in 65.1% of the patients and was independently associated with greater tumor size at diagnosis (P = 0.006) and with metastasis recurrence (HR, 2.89; 95% CI, 1.03 to 8.13; P = 0.043), but not with death from MCC, although there was a trend (HR, 5.28; 95% CI, 0.75 to 36.96; P = 0.093). VDR was found to be strongly expressed in all 28 MCC tumor specimens investigated. CONCLUSION: The association between vitamin D deficiency and MCC characteristics and outcome, together with detection of the VDR in MCC cells, suggest that vitamin D could influence the biology of MCC.

Malignant spinal cord compression: NICE guidance, improvements and challenges.

BACKGROUND AND AIM: Malignant spinal cord compression (mSCC) is one of the most serious complications of cancer. Recent NICE guidance has aimed to improve patient pathways and outcomes for patients with mSCC. We have examined the current presentations, management and outcomes for patients with mSCC in West London following the implementation of the NICE guidance. MATERIALS AND METHODS: The electronic records and clinical notes were reviewed for all patients assessed for confirmed or potential mSCC at Charing Cross Hospital in 2012. Details on the number of referrals, the proportion with confirmed mSCC, the cancer diagnosis, treatment and outcome were analysed. RESULTS: 191 patients were reviewed with 127 (66%) cases of confirmed mSCC. The commonest tumour types were prostate cancer (26 cases), lung cancer (26), breast cancer (21) and kidney cancer (15). 21% of the patients had no previous cancer diagnosis; mSCC was their presenting diagnostic event. Radiotherapy was the predominant management, 24% of the patients had first line surgical treatment. At presentation 62% of patients were either chair or bed bound. Treatment brought important mobility benefits to all patients groups with 20% of the initially chair or bed bound patients leaving the hospital with independent mobility. CONCLUSION: Enhanced patients pathways with ease of access, rapid assessment and prompt treatment can improve outcomes. Despite these pathways many patients still present with gross motor impairment and over 20% have no previous diagnosis of cancer. Ongoing work to maintain awareness for patients and primary care of the diagnosis and emergency pathways is essential to optimize outcomes.

Efficacy of a general practitioner training campaign for early detection of melanoma in France.

BACKGROUND: To date, no strategy for improving early diagnosis of melanoma has been evaluated on a population basis in France. OBJECTIVE: To evaluate the efficacy of a general practitioner (GP) awareness and training campaign in a pilot French geographical region (Champagne-Ardenne), including 1.34 million inhabitants, 1241 GPs, 56 dermatologists and a population-based melanoma registry. METHODS: All GPs received repeated awareness postal mailings in 2008 and 398 (32.1%) attended training sessions organized by 27 dermatologists. The pre- (2005-7) and post-campaign (2009-11) periods were compared for the following: primary endpoint - the world-standardized incidence of very thick melanomas (VTM) (Breslow thickness ≥ 3 mm); secondary endpoints--the mean Breslow thickness; the proportions of VTM and of thin (< 1 mm) melanomas among invasive cases; and the ratio of in situ/all melanoma cases. Similar measures were performed in the control area of Doubs/Belfort territory (655,000 ha), where no similar campaign was carried out. RESULTS: The incidence of VTM decreased from 1.07 to 0.71 per 100 000 habitants per year (P = 0.01), the mean Breslow thickness from 1.95 to 1.68 mm (P = 0.06) and the proportion of VTM from 19.2% to 12.8% (P = 0.01). The proportion of thin and in situ melanomas increased from 50.9% to 57.4% (P = 0.05) and from 20.1% to 28.2% (P = 0.001), respectively. No significant variation was observed in Doubs/Belfort territory. CONCLUSION: These results strongly support the efficacy of such a campaign targeting GPs and provide a rationale for a larger public health campaign in France, including training of GPs by dermatologists and encouraging patients to ask their GP for a systematic skin examination.

First online measurements of sulfuric acid gas in modern heavy-duty diesel engine exhaust: implications for nanoparticle formation.

To mitigate the diesel particle pollution problem, diesel vehicles are fitted with modern exhaust after-treatment systems (ATS), which efficiently remove engine-generated primary particles (soot and ash) and gaseous hydrocarbons. Unfortunately, ATS can promote formation of low-vapor-pressure gases, which may undergo nucleation and condensation leading to formation of nucleation particles (NUP). The chemical nature and formation mechanism of these particles are only poorly explored. Using a novel mass spectrometric method, online measurements of low-vapor-pressure gases were performed for exhaust of a modern heavy-duty diesel engine operated with modern ATS and combusting low and ultralow sulfur fuels and also biofuel. It was observed that the gaseous sulfuric acid (GSA) concentration varied strongly, although engine operation was stable. However, the exhaust GSA was observed to be affected by fuel sulfur level, exhaust after-treatment, and driving conditions. Significant GSA concentrations were measured also when biofuel was used, indicating that GSA can be originated also from lubricant oil sulfur. Furthermore, accompanying NUP measurements and NUP model simulations were performed. We found that the exhaust GSA promotes NUP formation, but also organic (acidic) precursor gases can have a role. The model results indicate that that the measured GSA concentration alone is not high enough to grow the particles to the detected sizes.

The role of general practitioners in diagnosis of cutaneous melanoma: a population-based study in France.

BACKGROUND: Little data are available concerning the role of general practitioners (GPs) in the diagnosis of melanoma. OBJECTIVES: To evaluate the actual role of GPs in a population-based study covering five regions of France and 8·2 million inhabitants. MATERIALS AND METHODS: A survey of cancer registries and pathology laboratories, and questionnaires to practitioners were used to identify incident melanomas in 2008, and evaluate characteristics of patients (age, sex, area of residence, social isolation), tumours (Breslow, ulceration, location, histological type), and GPs (training, conditions of practice), and their influence on patterns of diagnosis and Breslow thickness. RESULTS: Among 898 melanomas, 376 (42%) were first diagnosed in a general practice setting (GP group). Breslow thickness was much higher in the GP group than in other melanomas (median: 0·95 vs. 0·61 mm, P < 0·0001). Multivariate analysis identified an older age, lower limb location, nodular subtype and Breslow thickness as factors associated with the GP group. Within this group, 52·5% of melanomas were detected by patients (median Breslow thickness: 1·30 mm) and 47·5% by GPs (median Breslow thickness: 0·80 mm, P = 0·0009), including 8% during a systematic full-body skin examination. Previous GP training on melanoma was associated with active detection by GPs. Male sex and social isolation of patients were associated with thicker melanomas, whereas active detection by GPs was associated with thinner CMs. CONCLUSIONS: GPs play a key role in melanoma diagnosis in France, but still frequently detect thick tumours. Increasing awareness and training of GPs and focusing attention on male and/or socially isolated patients should help to improve early detection of melanoma.

123I-meta-iodobenzylguanidine scintigraphy for the detection of neuroblastoma and pheochromocytoma: results of a meta-analysis.

CONTEXT: (123)I-mIBG scintigraphy has been in clinical use for more than 20 yr for diagnostic assessment of patients with neural crest and neuroendocrine tumors. Prospective validation of the performance characteristics of this method has recently been published. OBJECTIVE: A meta-analysis was performed to obtain best estimates of performance characteristics of (123)I-mIBG imaging for the two most common applications, evaluation of patients with neuroblastoma and pheochromocytoma. DATA SOURCES: Articles published between 1980 and 2007 were identified from searches of multiple computer databases, including MEDLINE, BIOSIS, EMBASE, and SciSearch. STUDY SELECTION: Primary inclusion criteria were: acceptable reference standard(s) for confirming subjects with disease (histopathology and/or a combination of imaging and catecholamine results); reference standards applied to all subjects who received (123)I-mIBG; and data on a minimum of 16 patients confirmed to have or not have the disease(s) under consideration. Two physician reviewers independently evaluated all articles against the inclusion/exclusion criteria. Twenty-two of 100 articles reviewed were included in the final analysis. DATA EXTRACTION: The two reviewers extracted the data from eligible articles using a standardized form, capturing both study quality and efficacy information. Disagreements were resolved by consensus. DATA SYNTHESIS: Sensitivity of (123)I-mIBG scans for detection of neuroblastoma was 97% [95% confidence interval (CI), 95 to 99%]; data were insufficient to estimate specificity. For pheochromocytoma, with application of the random-effects model, sensitivity and specificity were 94% (95% CI, 91-97%) and 92% (95% CI, 87-98%), respectively. CONCLUSION: Based upon the literature, (123)I-mIBG scintigraphy has sensitivity and specificity greater than 90% for detection of neuroblastoma and pheochromocytoma.

Exploring differences in drug doses between Japan and Western countries.

Japan is unique among Asian countries in that it requires inclusion of substantial domestic clinical trial data in new drug application data packages. Some question the need for this and call for globalization of approved doses. The current study examines international differences in maximum daily dose of drugs approved in Japan between 2001 and 2007, and for all cardiovascular system (CVS) and central nervous system (CNS) drugs marketed in Japan. For 32% of the drugs approved in Japan between 2001 and 2007, the maximum recommended dose in the United States was > or =2 times higher than the maximum dose approved in Japan. Dose differences were rare for antitumor and antiviral drugs and also for priority-review and orphan drugs. Of all the price-listed CVS drugs currently available in Japan, 65% had maximum doses that were > or =2 times higher in the Netherlands than in Japan; similarly, 57% of the drugs had maximum doses that were > or =2 times higher in the United States than in Japan. For CNS drugs, these figures were 32% (the Netherlands) and 29% (United States). These results underscore the necessity to carry out quantitative analyses to determine the causes of these differences.

Prevalence and risk factors of focal sparing in hepatic steatosis.

PURPOSE: The prevalence, localization and potential risk factors for focal sparing were prospectively assessed in subjects with sonographically detectable hepatic steatosis as part of a population-based cross-sectional study. MATERIALS AND METHODS: A total of 1,624 persons (n = 906 women; n = 718 men) were evaluated using ultrasonography, laboratory testing and a standardized questionnaire. The following were excluded from the analysis: subjects with reported alcohol consumption > 40 g/day (males) or > 20 g/day (females), those with known chronic hepatitis B or C infection, elevated serum transaminases (AST: m > 44 U/l, f > 33 U/l; ALT: m > 45 U/l, f > 35 U/l) and prior right nephrectomy. RESULTS: The prevalence of focal sparing in patients with hepatic steatosis (grade I) was 25.6 % for men and 13.0 % for women. In patients with grade II/III disease, the prevalence was 70.9 % for men and 77.6 % for women. The most common site of focal sparing was in segment IV. The average diameter was 22.3 mm (range 7 - 84 mm). No correlation was found for postulated risk "age" (p = 0.09) or "status post cholecystectomy" (p = 0.09). Male sex (p = 0.02) and metabolic syndrome (odds ratio, 2.1; 95 % confidence interval, 1.1 - 4.1; p = 0.02) were confirmed as risk factors. CONCLUSION: Sonographic evidence of focal sparing in subjects with hepatic steatosis is associated with an increased risk for metabolic syndrome and may be an easily obtained diagnostic criterion in routine clinical settings.

Usefulness of 123I-MIBG scintigraphy in the evaluation of patients with known or suspected primary or metastatic pheochromocytoma or paraganglioma: results from a prospective multicenter trial.

UNLABELLED: Although (123)I-MIBG has been in clinical use for the imaging of pheochromocytoma for many years, a large multicenter evaluation of this agent has never been performed. The present study was designed to provide a prospective confirmation of the performance of (123)I-MIBG scintigraphy for the evaluation of patients with known or suspected primary or metastatic pheochromocytoma or paraganglioma. METHODS: A total of 81 patients with a prior history of primary or metastatic pheochromocytoma or paraganglioma and 69 with suspected pheochromocytoma or paraganglioma based on symptoms of catecholamine excess, CT or MRI findings, or elevated catecholamine or metanephrine levels underwent whole-body planar and selected SPECT 24 h after the administration of (123)I-MIBG. Images were independently interpreted by 3 masked readers, with consensus requiring agreement of at least 2 readers. Final diagnoses were based on histopathology, correlative imaging, catecholamine or metanephrine measurements, and clinical follow-up. RESULTS: Among 140 patients with definitive diagnoses (91, disease present; 49, disease absent), (123)I-MIBG planar scintigraphy had a sensitivity and specificity of 82%. For patients evaluated for suspected disease, sensitivity and specificity were 88% and 84%, respectively. For the subpopulations of adrenal (pheochromocytoma) and extraadrenal (paraganglioma) tumors, sensitivities were 88% and 67%, respectively. The addition of SPECT increased reader confidence but minimally affected sensitivity and specificity. CONCLUSION: This prospective study demonstrated a sensitivity of 82%-88% and specificity of 82%-84% for (123)I-MIBG imaging used in the diagnostic assessment of primary or metastatic pheochromocytoma or paraganglioma.

(123)I-mIBG scintigraphy in patients with known or suspected neuroblastoma: Results from a prospective multicenter trial.

BACKGROUND: A prospective trial was conducted to confirm the diagnostic performance of (123)I-mIBG scintigraphy in patients with known or suspected neuroblastoma. PROCEDURE: One hundred patients (mean age 4.7 years) were enrolled, 86 with a previous diagnosis of neuroblastoma, 13 with suspected disease based upon symptoms, imaging findings, and elevated catecholamines, and one adult with an abdominal tumor thought to be of neuroendocrine origin. All patients underwent whole-body planar imaging 24 hr following IV administration of 1-10 mCi (37-370 MBq) (123)I-mIBG. SPECT imaging of the thorax/abdomen/pelvis was performed in 51 patients. Images were interpreted by three blinded readers, with consensus requiring agreement of at least two readers. Disease status was confirmed by histopathology, imaging results, catecholamine measurements, and follow-up. RESULTS: Sixty-four patients had active disease, 30 were without disease, and 6 were judged indeterminate because of insufficient confirmatory data. (123)I-mIBG scintigraphy had a sensitivity of 88% (56/64) and specificity of 83% (25/30). Sensitivity was 91% (30/33) among the subset of subjects who had both planar and SPECT imaging. Among 53 patients with recent histopathology, sensitivity and specificity were 93% and 92%, respectively. Most false-negative interpretations were in patients with minimal residual disease (n = 4), while false-positive interpretations generally involved atypical adrenal or other physiological uptake (n = 4). CONCLUSIONS: This prospective multicenter trial of (123)I-mIBG scintigraphy documents high sensitivity and specificity of this imaging technique in patients with both newly diagnosed and previously treated neuroblastoma.

Epidemiology of obesity and hypertension and related risk factors in Uzbekistan.

OBJECTIVE: This study examined the prevalence of obesity and hypertension and associated behavioral risk factors in adult men and women in Uzbekistan. The study also examined the association between obesity and hypertension. METHOD: The analysis used data from the 2002 Uzbekistan Health Examination Survey, which included a nationally representative sample of 2333 men aged 15-59 years and 5463 women aged 15-49 years. The survey measured height, weight and blood pressure and included questions on physical activity, dietary habits, tobacco smoking, alcohol use and other characteristics. The analysis was conducted using binary and multinomial logistic regression methods, separately for men and women. RESULTS: Eating animal source protein and tobacco smoking in the past were positively associated with obesity, but there were no consistent associations with other dietary indicators, physical activity level or alcohol use. Obese men and women were about three times as likely to suffer from hypertension as those with a normal BMI (odds ratio (OR)=3.01; 95% confidence interval (CI): 1.67-5.44; P<0.001 for men and OR=2.82; 95% CI: 2.05-3.86; P<0.001 for women), independent of physical activity level, dietary habits, tobacco smoking and other factors. For men, the risk of hypertension was strongly positively associated with BMI only at BMI levels above 25 kg/m(2), but for women a positive relationship was observed at all BMI levels. CONCLUSION: The study found a strong positive association between obesity and hypertension in adult men and women in Uzbekistan. The shape of the relationship between BMI and hypertension is different for women than for men, requiring further research to explore this relationship.

Myelotoxicity of trichothecenes and apoptosis: an in vitro study on human cord blood CD34+ hematopoietic progenitor.

Previous studies have revealed that hematological disorders associated with trichothecenes intoxication in humans could result from hematopoiesis inhibition. The most frequent and potent trichothecene mycotoxins are T-2 toxin and deoxynivalenol (DON), respectively. Apoptosis induction by these two toxins was investigated in vitro on human hematopoietic progenitors (CD34+ cells). Hoechst coloration, DNA fragmentation and annexin-V/PI labeling in flow cytometry showed that T-2 toxin, in contrast to DON, induced apoptosis in CD34+ cells. T-2 toxin effect was dose- and time-dependent with a significant increase of apoptotic cells as early as 3h after incubation at 10(-7) M and a maximum reached at 12 h. This observation evidenced the high sensitivity of hematopoietic progenitors to T-2 toxin. The inhibition of T-2 toxin-induced apoptosis by a pan-caspase inhibitor (Z-VAD-fmk) suggested the involvement of caspases. The proportional increase of caspase-3 specific activity (DEVDase) with T-2 toxin concentration confirmed its role in the process. After incubation of CD34+ cells with T-2 toxin, in conditions that induced apoptosis, clonal expansion of granulo-monocytes, erythrocytes and megakaryocytes precursors was dose-dependently inhibited. The hematological effects observed in T-2 toxin mycotoxicosis could then be assigned to hematopoiesis inhibition by apoptosis. Different mechanisms that need to be further elucidated are involved in DON myelotoxicity.