Catalytic intramolecular hydroamination of aminoallenes using titanium and tantalum complexes of sterically encumbered chiral sulfonamides

Catalysis using earth abundant metals is an important goal due to the relative scarcity and expense of precious metal catalysts. It would be even more beneficial to use earth abundant catalysts for the synthesis of common pharmaceutical structural motifs such as pyrrolidine and pyridine. Thus, developing titanium catalysts for asymmetric ring closing hydroamination is a valuable goal. In this work, four sterically encumbered chiral sulfonamides derived from naturally occurring amino acids were prepared. These compounds undergo protonolysis reactions with Ti(NMe₂)₄ or Ta(NMe₂)₅ to give monomeric complexes as determined by both DOSY NMR and X-ray crystallography. The resulting complexes are active for the ring closing hydroamination hepta-4,5-dienylamine to give a mixture of tetrahydropyridine and pyrrolidine products. However, the titanium complexes convert 6-methylhepta-4,5-dienylamine exclusively to 2-(2-methylpropenyl)pyrrolidine in higher enantioselectivity than those previously reported, with enantiomeric excesses ranging from 18–24%. The corresponding tantalum complexes were more selective with enantiomeric excesses ranging from 33–39%

Lancet

BACKGROUND: In 2015, the second cycle of the CONCORD programme established global surveillance of cancer survival as a metric of the effectiveness of health systems and to inform global policy on cancer control. CONCORD-3 updates the worldwide surveillance of cancer survival to 2014. METHODS: CONCORD-3 includes individual records for 37.5 million patients diagnosed with cancer during the 15-year period 2000-14. Data were provided by 322 population-based cancer registries in 71 countries and territories, 47 of which provided data with 100% population coverage. The study includes 18 cancers or groups of cancers: oesophagus, stomach, colon, rectum, liver, pancreas, lung, breast (women), cervix, ovary, prostate, and melanoma of the skin in adults, and brain tumours, leukaemias, and lymphomas in both adults and children. Standardised quality control procedures were applied; errors were rectified by the registry concerned. We estimated 5-year net survival. Estimates were age-standardised with the International Cancer Survival Standard weights. FINDINGS: For most cancers, 5-year net survival remains among the highest in the world in the USA and Canada, in Australia and New Zealand, and in Finland, Iceland, Norway, and Sweden. For many cancers, Denmark is closing the survival gap with the other Nordic countries. Survival trends are generally increasing, even for some of the more lethal cancers: in some countries, survival has increased by up to 5% for cancers of the liver, pancreas, and lung. For women diagnosed during 2010-14, 5-year survival for breast cancer is now 89.5% in Australia and 90.2% in the USA, but international differences remain very wide, with levels as low as 66.1% in India. For gastrointestinal cancers, the highest levels of 5-year survival are seen in southeast Asia: in South Korea for cancers of the stomach (68.9%), colon (71.8%), and rectum (71.1%); in Japan for oesophageal cancer (36.0%); and in Taiwan for liver cancer (27.9%). By contrast, in the same world region, survival is generally lower than elsewhere for melanoma of the skin (59.9% in South Korea, 52.1% in Taiwan, and 49.6% in China), and for both lymphoid malignancies (52.5%, 50.5%, and 38.3%) and myeloid malignancies (45.9%, 33.4%, and 24.8%). For children diagnosed during 2010-14, 5-year survival for acute lymphoblastic leukaemia ranged from 49.8% in Ecuador to 95.2% in Finland. 5-year survival from brain tumours in children is higher than for adults but the global range is very wide (from 28.9% in Brazil to nearly 80% in Sweden and Denmark). INTERPRETATION: The CONCORD programme enables timely comparisons of the overall effectiveness of health systems in providing care for 18 cancers that collectively represent 75% of all cancers diagnosed worldwide every year. It contributes to the evidence base for global policy on cancer control. Since 2017, the Organisation for Economic Co-operation and Development has used findings from the CONCORD programme as the official benchmark of cancer survival, among their indicators of the quality of health care in 48 countries worldwide. Governments must recognise population-based cancer registries as key policy tools that can be used to evaluate both the impact of cancer prevention strategies and the effectiveness of health systems for all patients diagnosed with cancer. FUNDING: American Cancer Society; Centers for Disease Control and Prevention; Swiss Re; Swiss Cancer Research foundation; Swiss Cancer League; Institut National du Cancer; La Ligue Contre le Cancer; Rossy Family Foundation; US National Cancer Institute; and the Susan G Komen Foundation

Worldwide trends in population-based survival for children, adolescents, and young adults diagnosed with leukaemia, by subtype, during 2000–14 (CONCORD-3) : analysis of individual data from 258 cancer registries in 61 countries

Background Leukaemias comprise a heterogenous group of haematological malignancies. In CONCORD-3, we analysed data for children (aged 0–14 years) and adults (aged 15–99 years) diagnosed with a haematological malignancy during 2000–14 in 61 countries. Here, we aimed to examine worldwide trends in survival from leukaemia, by age and morphology, in young patients (aged 0–24 years). Methods We analysed data from 258 population-based cancer registries in 61 countries participating in CONCORD-3 that submitted data on patients diagnosed with leukaemia. We grouped patients by age as children (0–14 years), adolescents (15–19 years), and young adults (20–24 years). We categorised leukaemia subtypes according to the International Classification of Childhood Cancer (ICCC-3), updated with International Classification of Diseases for Oncology, third edition (ICD-O-3) codes. We estimated 5-year net survival by age and morphology, with 95% CIs, using the non-parametric Pohar-Perme estimator. To control for background mortality, we used life tables by country or region, single year of age, single calendar year and sex, and, where possible, by race or ethnicity. All-age survival estimates were standardised to the marginal distribution of young people with leukaemia included in the analysis. Findings 164563 young people were included in this analysis: 121328 (73·7%) children, 22963 (14·0%) adolescents, and 20272 (12·3%) young adults. In 2010–14, the most common subtypes were lymphoid leukaemia (28205 [68·2%] patients) and acute myeloid leukaemia (7863 [19·0%] patients). Age-standardised 5-year net survival in children, adolescents, and young adults for all leukaemias combined during 2010–14 varied widely, ranging from 46% in Mexico to more than 85% in Canada, Cyprus, Belgium, Denmark, Finland, and Australia. Individuals with lymphoid leukaemia had better age-standardised survival (from 43% in Ecuador to ≥80% in parts of Europe, North America, Oceania, and Asia) than those with acute myeloid leukaemia (from 32% in Peru to ≥70% in most high-income countries in Europe, North America, and Oceania). Throughout 2000–14, survival from all leukaemias combined remained consistently higher for children than adolescents and young adults, and minimal improvement was seen for adolescents and young adults in most countries. Interpretation This study offers the first worldwide picture of population-based survival from leukaemia in children, adolescents, and young adults. Adolescents and young adults diagnosed with leukaemia continue to have lower survival than children. Trends in survival from leukaemia for adolescents and young adults are important indicators of the quality of cancer management in this age group.peer-reviewe

Global survival trends for brain tumors, by histology: analysis of individual records for 556,237 adults diagnosed in 59 countries during 2000–2014 (CONCORD-3)

Background: Survival is a key metric of the effectiveness of a health system in managing cancer. We set out to provide a comprehensive examination of worldwide variation and trends in survival from brain tumors in adults, by histology. Methods: We analyzed individual data for adults (15–99 years) diagnosed with a brain tumor (ICD-O-3 topography code C71) during 2000–2014, regardless of tumor behavior. Data underwent a 3-phase quality control as part of CONCORD-3. We estimated net survival for 11 histology groups, using the unbiased nonparametric Pohar Perme estimator. Results: The study included 556,237 adults. In 2010–2014, the global range in age-standardized 5-year net survival for the most common sub-types was broad: in the range 20%–38% for diffuse and anaplastic astrocytoma, from 4% to 17% for glioblastoma, and between 32% and 69% for oligodendroglioma. For patients with glioblastoma, the largest gains in survival occurred between 2000–2004 and 2005–2009. These improvements were more noticeable among adults diagnosed aged 40–70 years than among younger adults. Conclusions: To the best of our knowledge, this study provides the largest account to date of global trends in population-based survival for brain tumors by histology in adults. We have highlighted remarkable gains in 5-year survival from glioblastoma since 2005, providing large-scale empirical evidence on the uptake of chemoradiation at population level. Worldwide, survival improvements have been extensive, but some countries still lag behind. Our findings may help clinicians involved in national and international tumor pathway boards to promote initiatives aimed at more extensive implementation of clinical guidelines

Total sleep time obtained from actigraphy versus sleep logs in an academic sleep center and impact on further sleep testing

R Robert Auger,1,2 Ranji Varghese,1 Michael H Silber,1,3 Nancy L Slocumb1 1Center for Sleep Medicine, 2Department of Psychiatry and Psychology, 3Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN, USA Background: While actigraphy has been deemed ideal for the longitudinal assessment of total sleep time (TST) by select groups, endorsement has not been universal and reimbursement is lacking, preventing its widespread use in clinical practice. This study compares longitudinal TST data obtained by actigraphy and logs preceding a clinical evaluation, and secondarily ascertains whether longitudinal TST impacts clinicians' decisions to proceed with further sleep testing. Methods: This was a retrospective, consecutive chart review spanning about 4 months in an academic sleep center. Eighty-four patients wore actigraphs in anticipation of clinical evaluations. Concomitant completion of sleep logs is routinely requested in this setting. Longitudinal TST data available in complete form was reviewed in a blinded fashion among a subset of these patients. A review of text from clinical notes of an expanded cohort with complete actigraphy data (regardless of the degree of completion of logs) enabled determination of the frequency and rationale for cancellation of prescheduled sleep testing. Results: Of 84 actigraphy recordings, 90% produced complete data, and 30% produced fully completed logs. Among the subset with both available in complete form, significant mean TST differences were observed on weekends (7.06 ± 2.18 hours versus 8.30 ± 1.93 hours, P = 0.009), but not on weekdays (7.38 ± 1.97 hours versus 7.72 ± 1.62 hours, P = 0.450) for actigraphy and logs, respectively. Further analyses revealed poor agreement between the two measures, with predominantly increased TST estimation with logs. Among those with complete actigraphy data (±logs), testing was cancelled in 11 (15%), eight of whom (73%) presented with hypersomnia and three of whom (27%) presented with insomnia. Determination of insufficient sleep time was cited as the primary reason for cancellation (64%). Conclusion: Actigraphy and sleep logs provided discrepant mean TST data on weekends only, and the latter predominantly estimated increased TST. Actigraphy was completed more reliably than logs. Longitudinal TST information influenced clinicians' decisions to proceed with further testing, particularly among patients presenting with hypersomnia. Keywords: sleep diaries, polysomnography, multiple sleep latency testin

Influence of bidentate ligand donor types on the formation and stability in 2 + 1 fac-[M I (CO) 3 ] + (M = Re, 99m Tc) complexes

In the last two decades, a number of chelate strategies have been proposed for the fac-[M (CO) ] (M = Re, Tc) core in radiopharmaceutical applications. However, the development of new ligands/complexes with improved function and in vivo performance has been limited in recent years. Expanding on our previous studies using the 2 + 1 labeling strategy, a series of bidentate ligands (neutral vs. anionic) containing an aromatic amine in combination with monodentate pyridine analogs or imidazole were explored to determine the influence of the bidentate and monodentate ligands on the formation and stability of the respective complexes. The 2 + 1 complexes with Re and Tc were synthesized in two steps and characterized by standard radio/chemical methods. X-ray characterization and density functional theory analysis of the Re 2 + 1 complexes with the complete bidentate series with 4-dimethylaminopyridine were conducted, indicating enhanced ligand binding energies of the neutral over anionic ligands. In the Tc studies, anionic bidentate ligands had significantly higher formation yields of the 2 + 1 product, but neutral ligands appear to have increased stability in an amino acid challenge assay. Both bidentate series exhibited improved stability by increasing the basicity of the pyridine ligands

Catalytic intramolecular hydroamination of aminoallenes using titanium and tantalum complexes of sterically encumbered chiral sulfonamides

Catalysis using earth abundant metals is an important goal due to the relative scarcity and expense of precious metal catalysts. It would be even more beneficial to use earth abundant catalysts for the synthesis of common pharmaceutical structural motifs such as pyrrolidine and pyridine. Thus, developing titanium catalysts for asymmetric ring closing hydroamination is a valuable goal. In this work, four sterically encumbered chiral sulfonamides derived from naturally occurring amino acids were prepared. These compounds undergo protonolysis reactions with Ti(NMe₂)₄ or Ta(NMe₂)₅ to give monomeric complexes as determined by both DOSY NMR and X-ray crystallography. The resulting complexes are active for the ring closing hydroamination hepta-4,5-dienylamine to give a mixture of tetrahydropyridine and pyrrolidine products. However, the titanium complexes convert 6-methylhepta-4,5-dienylamine exclusively to 2-(2-methylpropenyl)pyrrolidine in higher enantioselectivity than those previously reported, with enantiomeric excesses ranging from 18–24%. The corresponding tantalum complexes were more selective with enantiomeric excesses ranging from 33–39%