O- vs. N-protonation of 1-dimethylaminonaphthalene-8-ketones: formation of a peri N–C bond or a hydrogen bond to the pi-electron density of a carbonyl group

X-ray crystallography and solid-state NMR measurements show that protonation of a series of 1-dimethylaminonaphthalene-8-ketones leads either to O protonation with formation of a long N–C bond (1.637–1.669 Å) between peri groups, or to N protonation and formation of a hydrogen bond to the π surface of the carbonyl group, the latter occurring for the larger ketone groups (C(O)R, R = t-butyl and phenyl). Solid state 15N MAS NMR studies clearly differentiate the two series, with the former yielding significantly more deshielded resonances. This is accurately corroborated by DFT calculation of the relevant chemical shift parameters. In the parent ketones X-ray crystallography shows that the nitrogen lone pair is directed towards the carbonyl group in all cases

Definitive and adjuvant radiotherapy for sinonasal squamous cell carcinomas: a single institutional experience

Background: The aim of this study was to evaluate the disease outcomes of patients treated with definitive and adjuvant radiotherapy for squamous cell carcinomas of the nasal cavity and paranasal sinuses in a single institution. Methods: Between 2007–2012 patients were retrospectively identified from electronic databases who had undergone surgery and adjuvant radiotherapy or definitive radiotherapy for sinonasal squamous cell carcinomas with curative intent. Results: Fourty three patients with sinonasal squamous cell carcinoma were identified (22 nasal cavity, 21 paranasal sinuses). 31/43 (72 %) had T3 or T4 disease; nodal stage was N0 in 38, N1 in 4, Na/b in 0 and N2c in 1 patient. Median age was 67 years (range 41–86). 18 (42 %) received definitive and 25 (58 %) adjuvant radiotherapy. Radiotherapy was delivered using either conventional radiotherapy (n = 39) or intensity modulated radiotherapy (n = 4). Elective neck radiotherapy was delivered to two patients. Chemotherapy was delivered to 6/43 (14 %) of patients. Two-year local control, regional control, distant metastases free survival, progression free survival, cause specific survival and overall survival were 81 %, 90 %, 95 %, 71 %, 84 % and 80 % respectively. There was no significant difference in outcome comparing patients who underwent surgery and adjuvant radiotherapy with patients receiving definitive radiotherapy (2 year locoregional disease free survival 75 % and 70 % respectively, p = 0.98). Pooly differentiated tumours were significantly associated with inferior disease outcomes. Local, regional, combined local and regional, and distant failure occurred in 7 (16 %), 3 (7 %), 1 (2 %) and 2 (5 %) of patients; all 3 regional recurrences were in patients with nasal cavity squamous cell carcinomas who had not undergone elective neck treatment. Conclusions: Definitive or adjuvant radiotherapy provides an effective treatment for sinonasal malignancies. The main pattern of failure remains local, suggesting the need for investigation of intensified local therapy. Whilst remaining uncommon, the cases of regional failure mean that the merits of elective lymph node treatment should be considered on an individual basis

Direct Functionalization of Nitrogen Heterocycles via Rh-Catalyzed C−H Bond Activation

Nitrogen heterocycles are present in many compounds of enormous practical importance, ranging from pharmaceutical agents and biological probes to electroactive materials. Direct functionalization of nitrogen heterocycles through C−H bond activation constitutes a powerful means of regioselectively introducing a variety of substituents with diverse functional groups onto the heterocycle scaffold. Working together, our two groups have developed a family of Rh-catalyzed heterocycle alkylation and arylation reactions that are notable for their high level of functional-group compatibility. This Account describes our work in this area, emphasizing the relevant mechanistic insights that enabled synthetic advances and distinguished the resulting transformations from other methods. We initially discovered an intramolecular Rh-catalyzed C-2 alkylation of azoles by alkenyl groups. That reaction provided access to a number of di-, tri-, and tetracyclic azole derivatives. We then developed conditions that exploited microwave heating to expedite these reactions. While investigating the mechanism of this transformation, we discovered that a novel substrate-derived Rh−N-heterocyclic carbene (NHC) complex was involved as an intermediate. We then synthesized analogous Rh−NHC complexes directly by treating precursors to the intermediate [RhCl(PCy3)2] with N-methylbenzimidazole, 3-methyl-3,4-dihydroquinazoline, and 1-methyl-1,4-benzodiazepine-2-one. Extensive kinetic analysis and DFT calculations supported a mechanism for carbene formation in which the catalytically active RhCl(PCy3)2 fragment coordinates to the heterocycle before intramolecular activation of the C−H bond occurs. The resulting Rh−H intermediate ultimately tautomerizes to the observed carbene complex. With this mechanistic information and the discovery that acid cocatalysts accelerate the alkylation, we developed conditions that efficiently and intermolecularly alkylate a variety of heterocycles, including azoles, azolines, dihydroquinazolines, pyridines, and quinolines, with a wide range of functionalized olefins. We demonstrated the utility of this methodology in the synthesis of natural products, drug candidates, and other biologically active molecules. In addition, we developed conditions to directly arylate these heterocycles with aryl halides. Our initial conditions that used PCy3 as a ligand were successful only for aryl iodides. However, efforts designed to avoid catalyst decomposition led to the development of ligands based on 9-phosphabicyclo[4.2.1]nonane (phoban) that also facilitated the coupling of aryl bromides. We then replicated the unique coordination environment, stability, and catalytic activity of this complex using the much simpler tetrahydrophosphepine ligands and developed conditions that coupled aryl bromides bearing diverse functional groups without the use of a glovebox or purified reagents. With further mechanistic inquiry, we anticipate that researchers will better understand the details of the aforementioned Rh-catalyzed C−H bond functionalization reactions, resulting in the design of more efficient and robust catalysts, expanded substrate scope, and new transformations

A single centre experience with sequential and concomitant chemoradiotherapy in locally advanced stage IV tonsillar cancer

<p>Abstract</p> <p>Background</p> <p>Chemo-radiotherapy offers an alternative to primary surgery and adjuvant therapy for the management of locally advanced stage IV squamous cell carcinomas of the tonsil.</p> <p>Methods</p> <p>A retrospective analysis was performed of the outcomes of 41 patients with locoregionally advanced squamous cell carcinoma of the tonsil treated non-surgically at the Yorkshire Cancer Centre between January 2004 and December 2005. Due to long radiotherapy waiting times, patients received induction chemotherapy with cisplatin and 5-fluorouracil followed by either cisplatin concurrent chemoradiotherapy or radiotherapy alone.</p> <p>Results</p> <p>Median age was 55 years (range 34-76 years) and 28 (68%) patients were male. 35/41 patients (85%) received 2 or more cycles of induction chemotherapy. Following induction chemotherapy, 32/41 patients (78%) had a clinical response. Concomitant chemotherapy was given to 30/41 (73%). All patients received the planned radiotherapy dose with no delays. There were no treatment related deaths. Six (15%) patients had gastrostomy tubes placed before treatment, and 22 (54%) required nasogastric tube placement during or after treatment for nutritional support. 17 patients required unplanned admissions during treatment for supportive care. At 4 months post treatment assessment 35 out of 41 (85%) patients achieved complete clinical and radiographic response. Median follow-up is 38 months (8-61 months). Local and regional control rate in complete responders at 3 years was 91%. Distant metastases have been found in 4 (9.8%) patients. Three year progression-free survival rate in all patients is 75%. The 3-year cause specific survival and overall survival are 75% and 66% respectively.</p> <p>Conclusion</p> <p>Cisplatin-based induction and concurrent chemoradiotherapy provides excellent tumour control with acceptable toxicity for patients with locally advanced tonsillar cancer.</p

The Impact of 18F-FDG PET CT Prior to Chemoradiotherapy for Stage III/IV Head and Neck Squamous Cell Carcinoma

Introduction. To determine the value of a FDG-PET-CT scan in patients with locally advanced head and neck squamous cell carcinoma (HNSCC) prior to chemoradiotherapy. Materials and Methods. Consecutive patients with stage III or IV HNSCC who had undergone a staging FDG-PET-CT scan prior to chemoradiotherapy between August 2008 and April 2011 were included. Clinical details and conventional imaging (CT and/or MRI) were, retrospectively, reviewed, a TNM stage was assigned, and levels of cervical lymph node involvement were documented. This process was repeated with the addition of FDG-PET-CT. Radiotherapy plans were reviewed for patients with an alteration identified on TNM staging and/or nodal level identification with FDG-PET-CT and potential alterations in radiotherapy planning were documented. Results. 55 patients were included in the analysis. FDG-PET-CT altered the TNM stage in 17/55 (31%) of patients, upstaging disease in 11 (20%) and downstaging in 6 (11%); distant metastases were identified by FDG-PET-CT in 1 (2%) patient. FDG-PET-CT altered the lymph node levels identified in 22 patients (40%), upclassifying disease in 16 (29%) and downclassifying in 6 (11%). Radiotherapy plans were judged retrospectively to have been altered by FDG-PET-CT in 10 patients (18%). Conclusions. The use of FDG-PET-CT potentially impacts upon both treatment decisions and radiotherapy planning

Remanufacturing as a means for achieving low-carbon SMEs in Indonesia

Remanufacturing can reduce the energy intensity and associated greenhouse gas (GHG) emissions significantly and increase the eco-efficiency of product systems by utilizing recovered end-of-life parts. This paper presents the GHG mitigation potential of technically feasible remanufactured alternators in Indonesian small- and medium-sized enterprizes. Life cycle assessment approach and Weibull ++8 software have been used to calculate environmental and quality parameters. Since existing remanufactured alternators have not been found to meet the technical criterion for customers’ satisfaction, a number of alternative remanufacturing strategies have been explored to identify an option that has not only reduced GHG emissions but also has satisfied reliability, durability and warranty period criterion. Three improvement scenarios involving three different remanufacturing strategies were investigated in this case study, and yielded useful insights in order to come up with a technically feasible remanufacturing strategy for reducing a significant amount of GHG emissions. The improvement scenario III, which maximizes the use of used components, was found to offer technically and environmentally feasible remanufacturing solutions. Overall, this research has found that about 7207 t of CO2 -eq GHG emissions and 111.7 TJ embodied energy consumption could potentially be avoided if 10 % of alternators in Indonesian automobile sector are remanufactured using technically feasible remanufacturing strategy

Xanthine oxidase inhibition and white matter hyperintensity progression following ischaemic stroke and transient ischaemic attack (XILO-FIST): a multicentre, double-blinded, randomised, placebo-controlled trial

BACKGROUND: People who experience an ischaemic stroke are at risk of recurrent vascular events, progression of cerebrovascular disease, and cognitive decline. We assessed whether allopurinol, a xanthine oxidase inhibitor, reduced white matter hyperintensity (WMH) progression and blood pressure (BP) following ischaemic stroke or transient ischaemic attack (TIA). METHODS: In this multicentre, prospective, randomised, double-blinded, placebo-controlled trial conducted in 22 stroke units in the United Kingdom, we randomly assigned participants within 30-days of ischaemic stroke or TIA to receive oral allopurinol 300 mg twice daily or placebo for 104 weeks. All participants had brain MRI performed at baseline and week 104 and ambulatory blood pressure monitoring at baseline, week 4 and week 104. The primary outcome was the WMH Rotterdam Progression Score (RPS) at week 104. Analyses were by intention to treat. Participants who received at least one dose of allopurinol or placebo were included in the safety analysis. This trial is registered with ClinicalTrials.gov, NCT02122718. FINDINGS: Between 25th May 2015 and the 29th November 2018, 464 participants were enrolled (232 per group). A total of 372 (189 with placebo and 183 with allopurinol) attended for week 104 MRI and were included in analysis of the primary outcome. The RPS at week 104 was 1.3 (SD 1.8) with allopurinol and 1.5 (SD 1.9) with placebo (between group difference −0.17, 95% CI −0.52 to 0.17, p = 0.33). Serious adverse events were reported in 73 (32%) participants with allopurinol and in 64 (28%) with placebo. There was one potentially treatment related death in the allopurinol group. INTERPRETATION: Allopurinol use did not reduce WMH progression in people with recent ischaemic stroke or TIA and is unlikely to reduce the risk of stroke in unselected people. FUNDING: The British Heart Foundation and the UK Stroke Association

Second-look PET-CT following an initial incomplete PET-CT response to (chemo)radiotherapy for head and neck squamous cell carcinoma

OBJECTIVES: The limited positive predictive value of an incomplete response on PET-CT following (chemo)radiotherapy for head and neck squamous cell carcinoma (HNSCC) means that the optimal management strategy remains uncertain. The aim of the study is to assess the utility of a 'second-look' interval PET-CT. METHODS: Patients with HNSCC who were treated with (chemo)radiotherapy between 2008 and 2017 and underwent (i) baseline and (ii) response assessment PET-CT and (iii) second-look PET-CT following incomplete (positive or equivocal scan) response were included. Endpoints were conversion rate to complete response (CR) and test characteristics of the second-look PET-CT. RESULTS: Five hundred sixty-two patients with HNSCC underwent response assessment PET-CT at a median of 17 weeks post-radiotherapy. Following an incomplete response on PET-CT, 40 patients underwent a second-look PET-CT at a median of 13 weeks (range 6-25) from the first response PET-CT. Thirty-four out of 40 (85%) patients had oropharyngeal carcinoma. Twenty-four out of 40 (60%) second-look PET-CT scans converted to a complete locoregional response. The primary tumour conversion rate was 15/27 (56%) and the lymph node conversion rate was 14/19 (74%). The sensitivity, specificity, positive predictive value and negative predictive value (NPV) of the second-look PET-CT were 75%, 75%, 25% and 96% for the primary tumour and 100%, 92%, 40% and 100% for lymph nodes. There were no cases of progression following conversion to CR in the primary site or lymph nodes. CONCLUSIONS: The majority of patients who undergo a second-look PET-CT convert to a CR. The NPV of a second-look PET-CT is high, suggesting the potential to avoid surgical intervention. KEY POINTS: • PET-CT is a useful tool for response assessment following (chemo)radiotherapy for head and neck squamous cell carcinoma. • An incomplete response on PET-CT has a limited positive predictive value and optimal management is uncertain. • These data show that with a 'second-look' interval PET-CT, the majority of patients convert to a complete metabolic response. When there is doubt about clinical and radiological response, a 'second-look' PET-CT can be used to spare patients unnecessary surgical intervention