Forensic analysis of the deuterium/hydrogen isotopic ratios of the nerve agent sarin, its reaction by-product diisopropyl methylphosphonate and their precursors by 2H SNIF-NMR.

The Deuterium/Hydrogen (D/H) isotope ratios of sarin (5), diisopropyl methylphosphonate (3) and their precursors Isopropanol (1), methylphosphonic acid dichloride (2) and methylphosphonic acid difluoride (4) were measured by the 2H SNIF-NMR technique. The D/H isotope ratios of 1 show a large variation. It is shown, that the formation of 3 by reaction of 1 with 2, the fluorination of 2 to form 4 and the reaction of 4 with 1 to form 5, the D/H isotope ratios of the methyl and isopropyl moieties in 3, 4 and 5 are not significantly changed compared to 1 and 2.

Experimental Study of Fatigue and Fracture Behavior of Carbon Fiber-Reinforced Polymer (CFRP) Straps.

The hanger is one of the important components for through and half-through arch bridges. Conventional steel hangers are vulnerable to corrosion due to corrosive environments. Therefore, a new type of bridge hangers consisting of Carbon Fiber-Reinforced Polymer (CFRP) straps was developed recently. The CFRP straps are self-anchored, which is formed by layers-winding, and they have great advantages in corrosive environments such as high resistance to corrosion. In this study, the fatigue and fracture behavior of CFRP straps has been experimentally investigated. Firstly, the tensile testing of four CFRP strap specimens was conducted to investigate the static fracture behavior of CFRP straps, and three stages were observed, including delamination, cracking, and brittle rupture. Then, a fatigue test of thirty-nine specimens (four groups) was carried out to study the fatigue behavior of CFRP straps, where two types of pins, titanium alloy pin and CFRP pin, and two loading frequencies, 10 Hz and 15 Hz, were used. The number of cycles to failure, displacement, fatigue failure strain, outside surface temperature at the vertex of specimen, and scanning electron microscope (SEM) photographs were recorded and analyzed to investigate the fatigue behavior of CFRP straps. The experiment results show that the temperature development at the vertex of the CFRP strap varies obviously if different pins are used due to the different friction coefficients. In addition, the fatigue life of CFRP straps decreases significantly with the increase in loading rate for the titanium pin, while it only reduces slightly with the increase in loading rate for the CFRP pin.

Successful Treatment of a Resistant Subclone in ALK-Rearranged NSCLC.

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) are established effective therapies in patients with ALK-rearranged advanced non-small-cell lung cancer (NSCLC). Upon progressive disease, patients normally receive a subsequent ALK TKI. However, when disease progression occurs in a limited number of sites, an oligoprogressive approach is a treatment option. In our case, FDG-PET/CT scan detected a progressive site in a patient with ceritinib therapy. Biopsy of the lesion was not possible because of its location. Progression was therefore confirmed by liquid biopsy with identification of the resistant subclone ALK G1202R. Definitive radiotherapy of the progressive site led to the disappearance of the ALK-resistant mutation. Meanwhile, ceritinib therapy was continued. The absence of disease both on repeated imaging and liquid biopsy indicates that eradication of a resistant subclone with an oligoprogressive treatment approach might be possible.

Severe reaction to radiotherapy provoked by hypomorphic germline mutations in ATM (ataxia-telangiectasia mutated gene).

BACKGROUND: A minority of breast cancer (BC) patients suffer from severe reaction to adjuvant radiotherapy (RT). Although deficient DNA double-strand break repair is considered the main basis for the reactions, pretreatment identification of high-risk patients has been challenging. METHODS: To retrospectively determine the etiology of severe local reaction to RT in a 39-year-old woman with BC, we performed next-generation sequencing followed by further clinical and functional studies. RESULTS: We found a -4 intronic variant (c.2251-4A>G) in trans with a synonymous (c.3576G>A) variant affecting the ATM DNA-repair gene (NG_009830.1, NM_000051.3) which is linked to autosomal recessive ataxia-telangiectasia (A-T). We verified abnormal transcripts resulting from both variants, next to a minor wild-type transcript leading to a residual ATM kinase activity and genomic instability. Follow-up examination of the patient revealed no classic sign of A-T but previously unnoticed head dystonia and mild dysarthria, a family history of BC and late-onset ataxia segregating with the variants. Additionally, her serum level of alpha-fetoprotein (AFP) was elevated similar to A-T patients. CONCLUSION: Considering the variable presentations of A-T and devastating impact of severe reactions to RT, we suggest a routine measurement of AFP in RT-candidate BC patients followed by next-generation sequencing with special attention to non-canonical splice site and synonymous variants in ATM.

Impact of Early Prophylactic Cranial Irradiation With Hippocampal Avoidance on Neurocognitive Function in Patients With Limited Disease Small Cell Lung Cancer. A Multicenter Phase 2 Trial (SAKK 15/12).

PURPOSE: Our purpose was to evaluate neurocognitive function (NCF) and clinical outcomes after early hippocampal avoidance (HA) prophylactic cranial irradiation (PCI) in limited disease (LD) small cell lung cancer (SCLC). METHODS AND MATERIALS: In a phase 2 trial, patients with LD SCLC received HA-PCI concomitant with the second cycle of chemotherapy and thoracic radiation therapy. All patients underwent objective NCF testing at baseline, 6 weeks, and 6 and 12 months after HA-PCI. NCF tests included Hopkins Verbal Learning Test Revised, Controlled Oral Word Association, and Trail Making Tests A and B. The primary endpoint was NCF decline at 6 months after HA-PCI. We assumed ≤30% of patients with no NCF decline to be unpromising. Secondary endpoints included brain metastases-free survival (BMFS), overall survival (OS), and safety of the concomitant treatment. RESULTS: Among the 44 patients enrolled in the trial, 38 had evaluable NCF assessment at 6 months after HA-PCI. The proportion of evaluable patients showing no NCF decline at 6 and 12 months was 34.2% (90% confidence interval [CI], 21.6-48.8) and 48.5% (95% CI, 30.8-66.5), respectively. Median follow-up was 13.2 months (95% CI, 12.6-14.1). At 12 months, BMFS was 84.2% and OS was 87.7% (95% CI, 73.0-94.7). Four patients died of SCLC, 1 of respiratory failure, 1 of hemorrhage, and 1 for unknown reason. The most frequently reported grade ≥3 acute adverse events were anemia (21.4%), febrile neutropenia (19.1%), and fatigue (14.3%). CONCLUSIONS: The proportion of patients showing no NCF decline 6 and 12 months after early HA-PCI does not appear to be better than, but rather similar to, that observed in patients receiving sequential PCI without HA. Early HA-PCI in LD SCLC is feasible, with observation of promising BMFS and OS in this selected population.

Skeletal muscle mass correlates with increased toxicity during neoadjuvant radiochemotherapy in locally advanced esophageal cancer: A SAKK 75/08 substudy.

BACKGROUND: Sarcopenia, the critical depletion of skeletal muscle mass, is an independent prognostic factor in several tumor entities for treatment-related toxicity and survival. In esophageal cancer, there have been conflicting results regarding the value of sarcopenia as prognostic factor, which may be attributed to the heterogeneous patient populations and the retrospective nature of previous studies. The aim of our study was therefore to determine the impact of sarcopenia on prospectively collected specific outcomes in a subgroup of patients treated within the phase III study SAKK 75/08 with trimodality therapy (induction chemotherapy, radiochemotherapy and surgery) for locally advanced esophageal cancer. METHODS: Sarcopenia was assessed by skeletal muscle index at the 3rd lumbar vertebra (L3) in cross-sectional computed tomography scans before induction chemotherapy, before radiochemotherapy and after neoadjuvant therapy in a subgroup of 61 patients from four centers in Switzerland. Sarcopenia was determined by previously established cut-off values (Martin et al., PMID: 23530101) and correlated with prospectively collected outcomes including treatment-related toxicity, postoperative morbidity, treatment feasibility and survival. RESULTS: Using the published cut-off values, the prevalence of sarcopenia increased from 29.5% before treatment to 63.9% during neoadjuvant therapy (p < 0.001). Feasibility of neoadjuvant therapy and surgery was not different in initially sarcopenic and non-sarcopenic patients. We observed in sarcopenic patients significantly increased grade ≥ 3 toxicities during chemoradiation (83.3% vs 52.4%, p = 0.04) and a non-significant trend towards increased postoperative complications (66.7% vs 42.9%, p = 0.16). No difference in survival according to sarcopenia could be observed in this small study population. CONCLUSIONS: Trimodality therapy in locally advanced esophageal cancer is feasible in selected patients with sarcopenia. Neoadjuvant chemoradiation increased the percentage of sarcopenia. Sarcopenic patients are at higher risk for increased toxicity during neoadjuvant radiochemotherapy and showed a non-significant trend to more postoperative morbidity.

3-weekly or weekly cisplatin concurrently with radiotherapy for patients with squamous cell carcinoma of the head and neck - a multicentre, retrospective analysis.

BACKGROUND: Concurrent chemoradiotherapy with cisplatin is standard for patients (pts) with loco-regionally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) and for patients with resected SCCHN with high-risk features. The standard regimen includes 3-weekly cisplatin, but weekly regimens are often used to lower toxicity. Reaching a cumulative dose of ≥200 mg/m2 cisplatin was shown being associated with improved outcome. We herein investigated cumulative dose reached and toxicities between the 3-weekly and weekly cisplatin regimens with concurrent radiotherapy. METHODS: Multicentre, retrospective analysis of all patients undergoing combined RCT with cisplatin treated at 3 centres in Switzerland between 06/2008 and 12/2015. RESULTS: Three hundred fourteen pts. were included (3-weekly, N = 127; weekly, N = 187). Median cumulative cisplatin dose was 200 mg/m2 (IQR 150-300) for pts. treated with a 3-weekly schedule and 160 mg/m2 (120-240) for the weekly schedule, consequently more pts. treated with a 3-weekly schedule reached a cumulative dose ≥200 mg/m2 (75.6% vs. 47.1%, p < 0.001). This association was also observed in multivariable analysis adjusted for age and sex (OR 3.46, 95% confidence interval [CI], 2.1-5.7). The 3-weekly regimen led to a higher rate of acute renal toxicity (33.1% vs. 20.9%, p = 0.022). In the landmark analysis, we could not confirm that a cisplatin dose ≥200 mg/m2 is associated with better survival (HR 1.3, 95% CI 0.8-1.9). CONCLUSIONS: Significantly more patients receive a cumulative cisplatin dose of ≥200 mg/m2, when treated with a 3-weekly schedule compared to weekly dosing. The previously reported association between a cumulative cisplatin dose ≥200 mg/m2 and improved outcome could not be shown in our study.

EBR Strengthening Technique for Concrete, Long-Term Behaviour and Historical Survey.

Epoxy bonded steel plates (externally bonded reinforcemen: EBR) for the strengthening of concrete structures were introduced to the construction industry in the late 1960s, and the use of fibre reinforced polymers (FRPs) was introduced in the 1990s, which means that these techniques have already been used in construction for 50 and 25 years, respectively. In the first part of the paper, a historical survey of the development and introduction of these strengthening techniques into the construction industry are presented. The monitoring of such applications in construction is very important and gives more confidence to this strengthening technique. Therefore, in the second part of the paper, two long-term monitoring campaigns over an extraordinarily long duration will be presented. Firstly, a 47-year monitoring campaign on a concrete beam with an epoxy bonded steel plate and, secondly, a 20-year monitoring campaign on a road bridge with epoxy bonded CFRP (carbon fibre reinforced polymers) strips are described. The paper is an expanded version of the paper presented at the SMAR2017 Conference.

Fatigue and Durability of Laminated Carbon Fibre Reinforced Polymer Straps for Bridge Suspenders.

Steel cables and suspenders in bridges are at high risk of corrosion-fatigue and in some cases of fretting-fatigue in their anchorages. These factors greatly limit the service stresses of a specific cable system and involve expensive protection measures. In order to investigate the above limitations, the fretting fatigue behaviour of pin-loaded carbon fibre reinforced polymer (CFRP) straps was studied as models for corrosion-resistant bridge suspenders. Two types of straps were tested: small model straps with a sacrificial CFRP ply and large full-scale straps. In a first phase, five fully laminated and carbon pin-loaded CFRP model straps were subjected to an ultimate tensile strength test. Thereafter, and in order to assess their durability, 20 model straps were subjected to a fretting fatigue test, which was successfully passed by 4 straps. An S-N curve was generated for a load ratio of 0.1 and a frequency of 10 Hz. In a second phase, one full-scale strap was tested for its ultimate tensile strength and two full-scale straps were fatigue-tested. The influence of fretting fatigue loading on the residual mechanical properties of the straps was also assessed, and although fretting fatigue represented an important limitation for laminated CFRP straps, it could be shown that the investigated CFRP tension members can compete with the well-established steel suspenders.

Neoadjuvant radiotherapy combined with capecitabine and sorafenib in patients with advanced KRAS-mutated rectal cancer: A phase I/II trial (SAKK 41/08).

BACKGROUND: KRAS mutation occurs in ∼40% of locally advanced rectal cancers (LARCs). The multitarget tyrosine kinase inhibitor sorafenib has radiosensitising effects and might improve outcomes for standard preoperative chemoradiotherapy in patients with KRAS-mutated LARC. METHODS: Adult patients with KRAS-mutated T3/4 and/or N1/2M0 LARC were included in this phase I/II study. The phase I dose-escalation study of capecitabine plus sorafenib and radiotherapy was followed by a phase II study assessing efficacy and safety. Primary end-points were to: establish the maximum tolerated dose of the regimen in phase I; determine the pathologic complete response (pCR) rate in phase II defined as Dworak regression grade 3 and 4. RESULTS: Fifty-four patients were treated at 18 centres in Switzerland and Hungary; 40 patients were included in the single-arm phase II study. Recommended doses from phase I comprised radiotherapy (45 Gy in 25 fractions over 5 weeks) with capecitabine 825 mg/m2 twice daily × 33 plus sorafenib 400 mg/d. Median daily dose intensity in phase II was radiotherapy 100%, capecitabine 98.6%, and sorafenib 100%. The pCR rate (Dworak 3/4) was 60% (95% CI, 43.3-75.1%) by central independent pathologic review. Sphincter preservation was achieved in 89.5%, R0 resection in 94.7%, and downstaging in 81.6%. The most common grade 3 toxicities during phase II included diarrhoea (15.0%), skin toxicity outside radiotherapy field (12.5%), pain (7.5%), skin toxicity in radiotherapy field, proctitis, fatigue and cardiac ischaemia (each 5%). CONCLUSIONS: Combining sorafenib and standard chemoradiotherapy with capecitabine is highly active in patients with KRAS-mutated LARC with acceptable toxicity and deserves further investigation. www.clinicaltrials.gov: NCT00869570.

Induction chemoradiation in stage IIIA/N2 non-small-cell lung cancer: a phase 3 randomised trial.

BACKGROUND: One of the standard options in the treatment of stage IIIA/N2 non-small-cell lung cancer is neoadjuvant chemotherapy and surgery. We did a randomised trial to investigate whether the addition of neoadjuvant radiotherapy improves outcomes. METHODS: We enrolled patients in 23 centres in Switzerland, Germany and Serbia. Eligible patients had pathologically proven, stage IIIA/N2 non-small-cell lung cancer and were randomly assigned to treatment groups in a 1:1 ratio. Those in the chemoradiotherapy group received three cycles of neoadjuvant chemotherapy (100 mg/m(2) cisplatin and 85 mg/m(2) docetaxel) followed by radiotherapy with 44 Gy in 22 fractions over 3 weeks, and those in the control group received neoadjuvant chemotherapy alone. All patients were scheduled to undergo surgery. Randomisation was stratified by centre, mediastinal bulk (less than 5 cm vs 5 cm or more), and weight loss (5% or more vs less than 5% in the previous 6 months). The primary endpoint was event-free survival. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00030771. FINDINGS: From 2001 to 2012, 232 patients were enrolled, of whom 117 were allocated to the chemoradiotherapy group and 115 to the chemotherapy group. Median event-free survival was similar in the two groups at 12·8 months (95% CI 9·7-22·9) in the chemoradiotherapy group and 11·6 months (8·4-15·2) in the chemotherapy group (p=0·67). Median overall survival was 37·1 months (95% CI 22·6-50·0) with radiotherapy, compared with 26·2 months (19·9-52·1) in the control group. Chemotherapy-related toxic effects were reported in most patients, but 91% of patients completed three cycles of chemotherapy. Radiotherapy-induced grade 3 dysphagia was seen in seven (7%) patients. Three patients died in the control group within 30 days after surgery. INTERPRETATION: Radiotherapy did not add any benefit to induction chemotherapy followed by surgery. We suggest that one definitive local treatment modality combined with neoadjuvant chemotherapy is adequate to treat resectable stage IIIA/N2 non-small-cell lung cancer. FUNDING: Swiss State Secretariat for Education, Research and Innovation (SERI), Swiss Cancer League, and Sanofi.

Detection and identification of hydrolysis products of sulfur mustards at trace levels in environmental samples using liquid chromatography solid phase extraction combined with off-line nuclear magnetic resonance analysis.

An LC-UV-SPE NMR method for the analysis of polar hydrolysis products of the chemical warfare agents known as sulfur mustards at low ppm levels in environmental samples is developed. The hydrolysis products thiodiglycol (I), bis(2-hydroxyethylthio)methane (II), 1,2-bis(2-hydroxyethylthio)ethane (III), 1,3-bis(2-hydroxyethylthio)propane (IV), 1,4-bis(2-hydroxyethylthio)butane (V), 1,5-bis(2-hydroxyethylthio)pentane (VI), bis(2-hydroxymethylthioethyl)ether (VII) and bis(2-hydroxyethylthioethyl)ether (VIII) are baseline separated within 11 min by the LC gradient program and trapped post-column on SPE cartridges. After elution in 2mm o.d. NMR tubes (1)H NMR spectra were recorded. Recoveries vary from 43±5 for I to 102±5% for VI and are limited by volume breakthrough. The detection limits of the LC-SPE NMR method vary between 200 ng for V and 450 ng for I. Increasing the injection volume is shown to be more effective than multiple trapping for the analytes I-VIII to increase the amount of material trapped on the SPE cartridges. The applicability of the developed method to the analysis of environmental samples was tested by the analysis of sample 293 provided by the 29th Official OPCW (Organization for the Prohibition of Chemical Weapons) Proficiency Test. The chromatographic and (1)H NMR data obtained by the method are highly reproducible and provide acceptable data for the identification of chemicals related to CWC (Chemical Weapons Convention) in case an off-site analysis for the verification of the CWC or OPCW Proficiency Tests according to the OPCW criteria for the acceptance of chromatographic and (1)H NMR spectral data.

Transient severe non-proliferative retinopathy in an adolescent with type 1 diabetes and chronic myeloid leukemia.

The onset of diabetic retinopathy correlates with the long-term quality of glycemic control. A 17-yr-old adolescent with type 1 diabetes presented unexpectedly with acute non-proliferative retinopathy despite good glycemic control. Two months later chronic myeloid leukemia (CML) was diagnosed. Chemotherapy was initiated and within a few weeks the patient was in full remission concerning leukemia. Retinopathy completely resolved within 8 months. The patient was in good metabolic control throughout the course. To our knowledge, this is the first report of CML-triggered retinopathy in a well-controlled diabetic adolescent. In case of unexpected retinopathy in patients with type 1 diabetes, other potential causes of retinopathy should be considered.

Avoiding glucocorticoid administration in a neurooncological case.

Restricting glucocorticoid (GC) use in the treatment of patients with a solid tumor may help improving outcome. Here, we report administration of celecoxib rather than dexamethasone to prevent brain edema in a patient with a cerebellar glioblastoma multiforme WHO grade IV (GBM) upon the patient's request, as well as determining cerebrospinal fluid (CSF) and serum concentrations. CSF concentration (0.04 microM) was 54 times below serum concentration (2.18 microM), or 2500 times below levels inhibiting GBM cells in vitro (100 microM), revealing a blood CSF barrier for celecoxib. The patient did not require dexamethasone for the entire treatment. GC administration hence was avoided successfully in this case. The role of COX-2 inhibitors in treatment of GBM is detailed, leading to the conclusion of a pressing need for a clinical evaluation of non-steroidal COX-2 inhibitors with the ability to penetrate into brain tumors.

Concomitant cisplatin significantly improves locoregional control in advanced head and neck cancers treated with hyperfractionated radiotherapy.

PURPOSE: To determine whether the application of two courses of cisplatin simultaneously with hyperfractionated radiotherapy improves the outcome in locally advanced and/or node-positive nonmetastatic carcinomas of the head and neck, compared with hyperfractionated radiotherapy alone. PATIENTS AND METHODS: From July 1994 to July 2000, 224 patients with squamous cell carcinomas of the head and neck (excluding nasopharynx and paranasal sinus) were randomly assigned to hyperfractionated radiotherapy (median dose, 74.4 Gy; 1.2 Gy twice daily) or the same radiotherapy combined with two cycles of concomitant cisplatin (20 mg/m2 on 5 days of weeks 1 and 5). The primary end point was time to any treatment failure; secondary end points were locoregional failure, metastatic relapse, overall survival, and late toxicity. RESULTS: There was no difference in radiotherapy between both treatment arms (74.4 Gy in 44 days). The full cisplatin dose was applied in 93% and 71% of patients during the first and second treatment cycles, respectively. Acute toxicity was similar in both arms. Median time to any treatment failure was not significantly different between treatment arms (19 months for combined treatment and 16 months for radiotherapy only, respectively) and the failure-free rate at 2.5 years was 45% and 33%, respectively. Locoregional control and distant disease-free survival were significantly improved with cisplatin (log-rank test, P = .039 and .011, respectively). The difference in overall survival did not reach significance (log-rank test, P = .147). Late toxicity was comparable in both treatment groups. CONCLUSION: The therapeutic index of hyperfractionated radiotherapy is improved by concomitant cisplatin.

Application of nonselective 1D (1)H-(31)P inverse NMR spectroscopy to the screening of solutions for the presence of organophosphorus compounds related to the chemical weapons convention.

1D nonselective (1)H-(31)P HSQMBC, HSQC, and (31)P decoupled HSQC NMR experiments were applied to the screening of original OPCW proficiency test samples for the presence of organophosphorus (OP) compounds related to the Chemical Weapons Convention. The HSQC and HSQMBC spectra are compared to 1D (1)H NMR spectra with WET solvent suppression and (31)P[(1)H] spectra of the same samples. The 1D nonselective HSQC and HSQMBC experiments are shown to be the most sensitive NMR experiments to selectively screen samples for the presence of organophosphorus(OP) compounds. These experiments are at least three times more sensitive than the (31)P[(1)H] NMR experiment and allow the determination of the number of OP compounds present in the sample and their alkyl group bound to the phosphorus atom. Samples spiked at the 5-10 ppm level can be screened within an hour for the presence of OP compounds, whereas for the (31)P[(1)H] experiments, an overnight acquisition is necessary. The sensitivity of the experiments decreases in the order (31)P decoupled HSQC, HSQMBC, and HSQC. For the different alkyl groups, the sensitivity of these experiments decreases in the order methyl approximately isopropyl > ethyl > propyl.