Observation of Electron Bernstein Wave Heating in a Reversed Field Pinch.

The first observation of rf heating in a reversed field pinch (RFP) using the electron Bernstein wave (EBW) is demonstrated on the Madison Symmetric Torus. Propagation across and heating in a stochastic magnetic field is observed. Novel techniques are required to measure the suprathermal electron tail generated by EBW heating in the presence of intense Ohmic heating. rf-heated electrons directly probe the edge transport properties in the RFP; measured loss rates imply a large noncollisional radial diffusivity.

Thyroid abnormalities following the use of cytotoxic T-lymphocyte antigen-4 and programmed death receptor protein-1 inhibitors in the treatment of melanoma.

CONTEXT: Checkpoint inhibitors are emerging as important cancer therapies but are associated with a high rate of immune side effects, including endocrinopathy. OBJECTIVE: To determine the burden of thyroid dysfunction in patients with melanoma treated with immune checkpoint inhibitors and describe the clinical course. DESIGN AND PATIENTS: Consecutive patients with melanoma treated with either ipilimumab, nivolumab, pembrolizumab or the combination of ipilimumab and nivolumab were identified. Baseline thyroid function tests were used to exclude those with pre-existing thyroid abnormalities, and thyroid function tests during treatment used to identify those with thyroid dysfunction. RESULTS: Rates of overt thyroid dysfunction were in keeping with the published phase 3 trials. Hypothyroidism occurred in 13·0% treated with a programmed death receptor-1 (PD-1) inhibitor and 22·2% with a combination of PD-1 inhibitor and ipilimumab. Transient subclinical hyperthyroidism was observed in 13·0% treated with a PD-1 inhibitor, 15·9% following a PD-1 inhibitor, and 22·2% following combination treatment with investigations suggesting a thyroiditic mechanism rather than Graves' disease, and a high frequency of subsequent hypothyroidism. Any thyroid abnormality occurred in 23·0% following ipilimumab, 39·1% following a PD-1 inhibitor and 50% following combination treatment. Abnormal thyroid function was more common in female patients. CONCLUSION: Thyroid dysfunction occurs commonly in patients with melanoma treated with immune checkpoint inhibitors, with rates, including subclinical dysfunction, occurring in up to 50%.

Efficacy and toxicity of treatment with the anti-CTLA-4 antibody ipilimumab in patients with metastatic melanoma after prior anti-PD-1 therapy.

BACKGROUND: Recent phase III clinical trials have established the superiority of the anti-PD-1 antibodies pembrolizumab and nivolumab over the anti-CTLA-4 antibody ipilimumab in the first-line treatment of patients with advanced melanoma. Ipilimumab will be considered for second-line treatment after the failure of anti-PD-1 therapy. METHODS: We retrospectively identified a cohort of 40 patients with metastatic melanoma who received single-agent anti-PD-1 therapy with pembrolizumab or nivolumab and were treated on progression with ipilimumab at a dose of 3 mg kg(-1) for a maximum of four doses. RESULTS: Ten percent of patients achieved an objective response to ipilimumab, and an additional 8% experienced prolonged (>6 months) stable disease. Thirty-five percent of patients developed grade 3-5 immune-related toxicity associated with ipilimumab therapy. The most common high-grade immune-related toxicity was diarrhoea. Three patients (7%) developed grade 3-5 pneumonitis leading to death in one patient. CONCLUSIONS: Ipilimumab therapy can induce responses in patients who fail the anti-PD-1 therapy with response rates comparable to previous reports. There appears to be an increased frequency of high-grade immune-related adverse events including pneumonitis that warrants close surveillance.

Serum lactate dehydrogenase as an early marker for outcome in patients treated with anti-PD-1 therapy in metastatic melanoma.

BACKGROUND: Treatment with programmed death receptor-1 (PD-1) antibodies is associated with high response rates in patients with advanced melanoma. Reliable markers for early response and outcome are still sparse. METHODS: We evaluated 66 consecutive patients with advanced/metastatic melanoma treated with nivolumab or pembrolizumab between 2013 and 2014. The main objectives of this study were to investigate whether, first, serum lactate dehydrogenase (LDH) at baseline (normal vs above the upper limit of normal) correlates with overall survival (OS), and, second, whether the change of LDH during treatment predicts response before the first scan and OS in patients with an elevated baseline LDH. RESULTS: After a median follow-up of 9 months, patients with an elevated baseline LDH (N=34) had a significantly shorter OS compared with patients with normal LDH (N=32; 6-month OS: 60.8% vs 81.6% and 12-month OS: 44.2% vs 71.5% (log-rank P=0.0292). In those 34 patients with elevated baseline LDH, the relative change during treatment was significantly associated with an objective response on the first scan: the 11 (32%) patients with partial remission had a mean reduction of -27.3% from elevated baseline LDH. In contrast, patients with progressive disease (N=15) had a mean increase of +39%. Patients with a relative increase over 10% from elevated baseline LDH had a significantly shorter OS compared with patients with ⩽ 10% change (4.3 vs 15.7 months, log-rank P<0.00623). CONCLUSIONS: LDH could be a useful marker at baseline and during treatment to predict early response or progression in patients with advanced melanoma who receive anti-PD-1 therapy.

Diffuse large B-cell lymphoma in elderly patients: a retrospective analysis.

BACKGROUND: Few data on patterns of care and outcomes are available for elderly patients with diffuse large B-cell lymphoma (DLBCL) outside of clinical trials. METHODS: We identified patients with DLBCL older than 60 years from a regional cancer registry between 2000 and 2010. Based on registry data and chart review, 128 patients from the oncology network of Eastern Switzerland were analysed for patient characteristics, treatment and outcomes of DLBCL. Three age groups were compared: 60-69, 70-79 and over 80 years old. RESULTS: Median age was 73 years (range: 60 to 95 years). 52/121 treated patients received 6 cycles of R-CHOP/CHOP, of those 30 (58%), 18 (35%) and 4 (7%) patients were 60-69 years, 70-79 years or older than 80 years respectively, with a significant difference by age group, p=0.001. Median OS of patients 60-69, 70-79, and 80 years and older receiving 6 cycles of R-CHOP/CHOP were: 54 months, 31 months and 24 months respectively. In comparison, patients receiving other than 6 cycles of R-CHOP/CHOP treatment regimens had a median OS of 22 months, 17 months and 6 months, respectively. In the multivariable analysis other than 6 cycles of R-CHOP/CHOP were significantly associated with poor survival. The risk of dying increased by a mean of 6% for each year of age from age 60 years onwards. CONCLUSION: In conclusion, treatment regimens other than 6 cycles of R-CHOP/CHOP were significant predictors for survival in our oncology network. The possibility of using R-CHOP treatment regimen should be seriously considered in elderly patients with DLBCL.

Off-label use of anticancer drugs in eastern Switzerland: a population-based prospective cohort study.

PURPOSE: Prevalence data on the off-label use (OLU) of anticancer drugs are limited despite OLU being controversial for medical, pharmaco-economic, and ethical reasons. We therefore quantified and characterized the OLU of anticancer drugs and compared OLU based on the national drug label with international treatment recommendations. METHODS: We prospectively collected data on patients receiving systemic anticancer therapy between October and December 2012 at hospitals affiliated with the Eastern Switzerland Oncology Network. Individual data on patient characteristics, tumor disease, and systemic treatment were collected, and each individual treatment was compared with the national drug label and international treatment guidelines. RESULTS: A total of 985 consecutive patients receiving 1,737 anticancer drug treatments were included in the study. Overall, 32.4 % of all patients received at least one off-label drug, corresponding to 27.2 % of all anticancer drugs administered. Major reasons for OLU were the lack of approval for the specific disease entity (15.7 %) and modified application of the anticancer drug (10 %). OLU that was unsupported by the current European Society for Medical Oncology (ESMO) treatment recommendations was rare (6.6 %) but higher for bevacizumab (29.6 %) due to its use in treating advanced ovarian cancer beyond the second-line setting and advanced breast cancer beyond the first-line setting and for lenalidomide (22.6 %) due to its use in treating Non-Hodgkin lymphoma. CONCLUSIONS: Based on data collected on our patient cohort, OLU of anticancer drugs in a European clinical setting applies to one-third of all cancer patients. ESMO-unsupported use of chemotherapies or molecularly-targeted drugs is rare, opposing concerns that the off-label use of newer anticancer drugs is a substantial clinical problem.

Depressive symptoms and rates of bone loss at the hip in older men.

UNLABELLED: In this prospective cohort study, depressive symptoms were associated with higher rates of bone loss in older men. Poorer performance on physical function tests partly explained the association between depressive symptoms and bone loss, suggesting that efforts to increase exercise and improve physical performance in depressed men may be beneficial. INTRODUCTION: The aim of this study was to ascertain whether depressive symptoms are associated with increased rates of bone loss at the hip in older men. METHODS: A population-based prospective cohort study of 2,464 community-dwelling men, aged 68 and older, enrolled in the Osteoporosis in Men Sleep Ancillary Study had depressive symptoms assessed by the Geriatric Depression Scale (GDS). Subjects were categorized as depressed if GDS ≥6 at the initial examination. Bone mineral density (BMD) at the hip was measured using dual-energy X-ray absorptiometry at the initial and follow-up examination (average 3.4 years between exams). Use of antidepressant medications was assessed by interview and verified from medication containers at the two examinations. A computerized dictionary was used to categorize type of medication. RESULTS: In a base model adjusted for age, race/ethnicity, and clinic site, the mean total hip BMD decreased 0.70 %/year in 136 men with a GDS score of ≥6 compared to 0.39 %/year in 2,328 men with a GDS score of <6 (p = 0.001). Walking speed and timed chair stand partly explained the association between depressive symptoms and rates of bone loss. CONCLUSION: Depression, as defined by a score of 6 or greater on the Geriatric Depression Scale, is associated with an increased rate of bone loss at the hip in this cohort of older men. Adjustment for walking speed and timed chair stand attenuated the strength of the association, suggesting that differences in physical functioning do partially explain the observed association.

Optimization studies of the ITER low field side reflectometer.

Microwave reflectometry will be used on ITER to measure the electron density profile, density fluctuations due to MHD/turbulence, edge localized mode (ELM) density transients, and as an L-H transition monitor. The ITER low field side reflectometer system will measure both core and edge quantities using multiple antenna arrays spanning frequency ranges of 15-155 GHz for the O-mode system and 55-220 GHz for the X-mode system. Optimization studies using the GENRAY ray-tracing code have been done for edge and core measurements. The reflectometer launchers will utilize the HE11 mode launched from circular corrugated waveguide. The launched beams are assumed to be Gaussian with a beam waist diameter of 0.643 times the waveguide diameter. Optimum launcher size and placement are investigated by computing the antenna coupling between launchers, assuming the launched and received beams have a Gaussian beam pattern.

Analysis of the ITER low field side reflectometer transmission line system.

A critical issue in the design of the ITER low field side reflectometer is the transmission line (TL) system. A TL connects each launcher to a diagnostic instrument. Each TL will typically consist of ∼42 m of corrugated waveguide and up to ten miter bends. Important issues for the performance of the TL system are mode conversion and reflections. Minimizing these issues are critical to minimizing standing waves and phase errors. The performance of TL system is analyzed and recommendations are given.

Collisional damping of electron bernstein waves and its mitigation by evaporated lithium conditioning in spherical-tokamak plasmas.

The first experimental verification of electron Bernstein wave (EBW) collisional damping, and its mitigation by evaporated Li conditioning, in an overdense spherical-tokamak plasma has been observed in the National Spherical Torus Experiment (NSTX). Initial measurements of EBW emission, coupled from NSTX plasmas via double-mode conversion to O-mode waves, exhibited <10% transmission efficiencies. Simulations show 80% of the EBW energy is dissipated by collisions in the edge plasma. Li conditioning reduced the edge collision frequency by a factor of 3 and increased the fundamental EBW transmission to 60%.

Electron Bernstein wave emission based diagnostic on National Spherical Torus Experiment (invited).

National Spherical Torus Experiment (NSTX) is a spherical tokamak (ST) that operates with n(e) up to 10(20) m(-3) and B(T) less than 0.6 T, cutting off low harmonic electron cyclotron (EC) emission widely used for T(e) measurements on conventional aspect ratio tokamaks. The electron Bernstein wave (EBW) can propagate in ST plasmas and is emitted at EC harmonics. These properties suggest thermal EBW emission (EBE) may be used for local T(e) measurements in the ST. Practically, a robust T(e)(R,t) EBE diagnostic requires EBW transmission efficiencies of >90% for a wide range of plasma conditions. EBW emission and coupling physics were studied on NSTX with an obliquely viewing EBW to O-mode (B-X-O) diagnostic with two remotely steered antennas, coupled to absolutely calibrated radiometers. While T(e)(R,t) measurements with EBW emission on NSTX were possible, they were challenged by several issues. Rapid fluctuations in edge n(e) scale length resulted in >20% changes in the low harmonic B-X-O transmission efficiency. Also, B-X-O transmission efficiency during H modes was observed to decay by a factor of 5-10 to less than a few percent. The B-X-O transmission behavior during H modes was reproduced by EBE simulations that predict that EBW collisional damping can significantly reduce emission when T(e)<30 eV inside the B-X-O mode conversion (MC) layer. Initial edge lithium conditioning experiments during H modes have shown that evaporated lithium can increase T(e) inside the B-X-O MC layer, significantly increasing B-X-O transmission.

Degradation of tetrahydro-beta-carbolines in the presence of nitrite: HPLC-MS analysis of the reaction products.

Motivated by the identification of numerous novel tetrahydro-beta-carboline-carboxylic acids in food samples, we studied the reactions of tetrahydro-beta-carbolines in the presence of nitrosating agents. The anticipated formation of nitroso derivatives from unsubstituted tetrahydro-beta-carbolines, and from tetrahydro-beta-carboline-3-carboxylic acids was indicated by HPLC-MS/MS analysis and validated by the characteristic product ion spectra of the respective nitroso compounds. In addition, oxidative decarboxylation resulted in formation of the corresponding dihydro-beta-carbolines, and in the generation of the beta-carbolines harman or norharman. Subsequently, we studied the reactivity of tetrahydro-beta-carboline-1-carboxylic acids derived from the Pictet-Spengler condensation of indole amines with alpha-oxo acids. Again, in the presence of nitrosating agents the rapid disappearance of the starting material was obvious, but no nitroso derivatives could be observed. Instead, further HPLC-MS/MS studies demonstrated that dihydro-beta-carbolines were the major products of tetrahydro-beta-carboline-1-carboxylic acids. Finally, we demonstrated that freshly isolated nitroso-precursors spontaneously decomposed to yield harman alkaloids. In conclusion, we revealed that nitroso-tetrahydro-beta-carbolines can represent intermediates involved in the generation of beta-carbolines, and we established a novel pathway for the formation of harman alkaloids from nutritional tetrahydro-beta-carbolines.

Reaction of tryptophan with carbohydrates: mechanistic studies on the formation of carbohydrate-derived beta-carbolines.

Numerous carbohydrate-derived beta-carbolines have been identified for the first time in model reactions of tryptophan with glucose and ribose, as well as in food samples. Extending these structural studies, we performed detailed investigations to elucidate the corresponding intermediates and formation pathway of these alkaloids. Degradation experiments with purified tryptophan glycoconjugates established that only glyco-tetrahydro-beta-carboline-3-carboxylic acids, and not the N-glycosides nor the C-glycoconjugates represented the direct precursors of carbohydrate-derived beta-carbolines. In addition, the significance of the oxidative decarboxylation reaction as the initial step for formation of 1-substituted beta-carbolines was proven. Finally, the stereochemistry of the carbohydrate-derived side chain was studied by means of CD spectroscopy and HPLC-CD experiments. These detailed stereochemical analyses yielded experimental evidence for the racemization steps required for formation of the carbohydrate-derived harman alkaloids and confirmed the proposed reaction pathway.

A photometric screening method for dimeric naphthylisoquinoline alkaloids and complete on-line structural elucidation of a dimer in crude plant extracts, by the LC-MS/LC-NMR/LC-CD triad.

An efficient evaluation procedure for the chemical screening and on-line structural elucidation of dimeric naphthylisoquinoline alkaloids has been developed. The method is based on the lead tetraacetate oxidation of the central binaphthalene core of the alkaloids. UV spectra of the extracts after addition of the oxidant show, in the presence of naphthylisoquinoline dimers, the appearance of a characteristic long-wavelength absorption indicative of dinaphthoquinones. The efficiency and relevance of the method has been demonstrated in the discovery of a constitutionally and configurationally new dimeric naphthylisoquinoline alkaloid, named ancistrogriffithine A (4), from the previously uninvestigated Asian liana Ancistrocladus griffithii. After verification of this screening result by LC-ESI-MS/MS, the constitution and the relative configuration of the compound were elucidated on line, by LC-NMR and LC-CD on the extract. Using an LC-NMR-WET-ROESY experiment, itwas possible for the first time to determine the relative axial configuration of a natural biaryl compound on line, by observing long-range ROE interactions. Finally, an oxidative degradation right on the extract delivered the absolute configuration of 4, without isolation of the alkaloid. Ancistrogriffithine A is the as yet only dimeric naphthylisoquinoline from an Asian Ancistrocladaceae plant.

Reaction of tryptophan with carbohydrates: identification and quantitative determination of novel beta-carboline alkaloids in food.

The formation of various carbohydrate-derived beta-carbolines was observed when model reactions of tryptophan with glucose were studied by means of HPLC with diode array detection, as well as by means of HPLC-MS. Isolation of these compounds and subsequent characterization by tandem mass spectrometry and NMR spectroscopy led to the identification of diastereomeric 1-(1,3,4,5-tetrahydroxypent-1-yl)-9H-pyrido[3,4-b]indoles (1a/b), 1-(1,4,5-trihydroxypent-1-yl)-9H-pyrido[3,4-b]indoles (2a/b), and E/Z isomers of 1-(1,5-dihydroxypent-3-en-1-yl)-9H-pyrido[3,4-b]indole (3a/b). HPLC-MS was used to prove the presence of these novel beta-carboline alkaloids in various food samples. In addition, quantitative determination of beta-carbolines 1a, 1b, and 2a/b in numerous products was achieved by means of HPLC with fluorometric detection. Concentrations ranged from 12 to 1922 microg/L for 1a and 1b and from 3 to 644 microg/L for 2a/b. The highest concentrations of all carbohydrate-derived beta-carbolines under study were found in ketchup, soy sauce, and fish sauce.

Duodenogastric reflux and foregut carcinogenesis: analysis of duodenal juice in a rodent model of cancer.

The incidence of esophageal adenocarcinoma is increasing rapidly. In rats, surgically induced duodenoesophageal reflux is carcinogenic. One proposed mechanism of carcinogenesis is based on the reaction of physiological bile acids with nitrite to produce carcinogenic N:-nitroso amides. To test this hypothesis, duodenal juice was analyzed for endogenously formed N:-nitroso bile acids and its genotoxicity was determined. Esophagojejunostomy was performed on 15 Sprague-Dawley rats to produce duodeno-esophageal reflux. At the time of surgery and 2 and 6 weeks later, duodenal contents were aspirated and analyzed immediately. High performance liquid chromatography coupled to tandem mass spectrometry was used to detect bile acids and their nitroso derivates. Genotoxicity was assessed using a micronucleus test. The characteristic pattern of bile acid derivatives, with taurocholic acid (TCA) and glycocholic acid (GCA) as the predominant conjugates, was detected in all samples. However, even selective reaction monitoring experiments failed to demonstrate the presence of any N:-nitroso-TCA or N:-nitroso-GCA. In addition, other nitroso derivatives could not be detected in any of the samples by neutral loss experiments monitoring the loss of nitric oxide (detection limit 0.1% of the concentration of TCA). All samples were cytotoxic, but neither the preoperative nor the postoperative samples were genotoxic. Duodenal juice was cytotoxic but not genotoxic. Tumorigenesis of esophageal adenocarcinoma in the rodent model could not be linked to a specific carcinogen, especially not to nitroso bile acids. Chronic inflammation is likely to be the mechanism of carcinogenesis by duodenogastric reflux.

Tryptophan-N-glucoside in fruits and fruit juices.

In extracts prepared from various fruits as well as in fruit juices a single tryptophan glycoconjugate was detected by HPLC-MS analysis. Product ion spectra demonstrated the N-glycosidic linkage of a hexose moiety to the indole nitrogen. For structure elucidation, the novel tryptophan glycoside was isolated from pear juice and identified as N(1)-(beta-D-glucopyranosyl-(4)C(1))-L-tryptophan by (1)H, HH-COSY and (13)C NMR spectroscopy. Finally, we disclosed the biosynthetic origin of the novel tryptophan metabolite by demonstrating the enzymatic glycosylation of deuterium-labeled tryptophan, which was applied to pear fruit.

Race, presenting signs and symptoms, use of carotid artery imaging, and appropriateness of carotid endarterectomy.

BACKGROUND AND PURPOSE: We sought to determine whether there are racial differences in use of carotid artery imaging after controlling for clinical factors and to ascertain racial differences in presenting signs and symptoms and overall appropriateness for carotid endarterectomy (CE). METHODS: We performed a retrospective cohort study of 803 patients older than 45 years, hospitalized between 1991 and 1994 at any of 4 Veterans Affairs Medical Centers, with a discharge diagnosis of transient ischemic attack or ischemic stroke. Clinical data were abstracted from the medical record, including presenting symptoms, diagnostic test results, and use of surgical procedures. Appropriateness for CE was determined according to RAND criteria. RESULTS: Black patients were more likely than white patients to present with stroke (78% versus 55%) but less likely to present with transient ischemic attack (22% versus 45%; P=0.001). There was no racial difference in medical comorbidity or preoperative risk. Black patients were less likely to have an imaging study of their carotid arteries (67% versus 79%; P=0.001). Race remained an independent predictor of imaging after adjustment for clinical factors (odds ratio=1.50; 95% CI, 1.06 to 2.13). Because of higher prevalence of significant carotid artery stenosis, whites were significantly more likely than blacks to be assessed as appropriate candidates for surgery with the use of RAND criteria (18% versus 4%; P=0.001). CONCLUSIONS: Use of carotid artery imaging, a critical step in determining eligibility for CE, is influenced by the patient's race after controlling for clinical presentation. Adjustment for appropriateness of CE reduces but does not eliminate the importance of race.

Electrospray ionization-tandem mass spectrometry for the analysis of tryptophan derivatives in food.

Our knowledge about bioactive tryptophan derivatives in the diet is rather limited. Consequently, our attention was focused on the efficient profiling, i.e. the structure specific detection, of novel tetrahydro-beta-carbolines and tryptophan glycoconjugates in food samples. Applying HPLC-MS/MS for screening and structural characterization, numerous products derived from the reaction of tryptophan with alpha-oxo acids and carbohydrates could be identified by means of neutral loss scanning. Subsequently, product ion experiments followed by the synthesis of the respective reference compounds accomplished structure elucidation of tryptophan derivatives.