Iridium-catalyzed asymmetric addition of imides to alkenes.

Enantioselective addition of an imide N-H bond to alkenes was realized by use of a cationic iridium catalyst. Bulky diphosphine ligands such as DTBM-segphos, DTBM-MeO-biphep, and DTBM-binap were indispensable for the reaction. A variety of styrene derivatives, allylsilanes, and norbornene were good substrates to give the corresponding chiral adducts with high enantioselectivity.

Comparison and Development of Immunohistochemical Diagnostic Criteria for Blastic Plasmacytoid Dendritic Cell Neoplasm.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy derived from the precursors of plasmacytoid dendritic cells. Diagnostic criteria for BPDCN have not been fully established. BPDCN is often diagnosed without other BPDCN markers than the 3 conventional markers (CD4, CD56, and CD123) in practice and case reports, although acute myeloid leukemia/myeloid sarcoma (AML/MS), which is always considered in the differential diagnosis of BPDCN, can express them. We reviewed published case reports on BPDCN and found that the diagnosis was made without any other BPDCN markers than the conventional markers in two-thirds of the cases. Next, 4 representative existing diagnostic criteria were applied to 284 cases of our cohort of BPDCN and mimics. The results differed in 20% (56/284) of the cases. The criterion based on the 3 conventional markers alone had a low concordance rate (80%-82%) with the other 3 criteria, which were almost concordant with each other. However, newly found minor limitations in these criteria prompted us to devise new diagnostic criterion for BPDCN composed of TCF4, CD123, TCL1, and lysozyme. We also revealed that CD123-positive AML/MS patients had a significantly poorer outcome than those with BPDCN and that 12% (24/205) of the cases were non-BPDCN even if all 3 conventional markers were positive, thus clarifying the risk of diagnosing BPDCN without more specific markers. In addition, histopathological features, such as the reticular pattern, which is not seen in BPDCN and suggests AML/MS, were also identified.

Ruthenium-catalysed N-alkylation of anilines with primary carbohydrate alcohols via borrowing hydrogen strategy.

Ruthenium-catalysed N-alkylation of anilines with sugar derivatives proceeded via the borrowing hydrogen strategy. Primary carbohydrate alcohols were successfully applied to N-alkylation of aniline derivatives to give the corresponding aminosugars in high yields.

Iridium-Catalyzed Enantioselective Intermolecular Hydroarylation of 1,1-Disubstituted Alkenes.

The catalytic enantioselective hydroarylation of 1,1-disubstituted alkenes proceeded by using a cationic iridium/(R)-binap complex to give the corresponding adducts in high yields with high enantioselectivity. The reaction of arenes substituted with heteroaromatic directing groups proceeded to give the addition products linear-selectively. Methallylamine derivatives were good acceptors to obtain high enantioselectivities. The adduct bearing maleimide moiety was readily transformed into the ß-chiral amine derivative without loss of the enantiomeric purity.

Asymmetric addition of an N-methyl C(sp3)-H bond to cyclic alkenes enabled by an iridium/phosphine-olefin catalyst.

Iridium-catalyzed asymmetric C-H addition of an N-methyl group on 3-trifluoromethyl-2-(N-methylamino)pyridine to cyclic alkenes was realized by using a phosphine-olefin ligand. Indene and its 7-substituted derivatives, acenaphthylene, and some bicyclic alkenes underwent the addition to give the corresponding products in good yields with high enantioselectivity.

Comparison of the impact of two post-remission therapy regimens on cardiac events in acute myeloid leukemia patients undergoing allogeneic hematopoietic stem cell transplantation.

High-dose cytarabine (HD-AraC) or anthracycline-containing chemotherapies are used as post-remission therapy for acute myeloid leukemia (AML) patients. However, it remains unclear which regimen would be better as post-remission therapy before allogeneic hematopoietic stem cell transplantation (allo-HSCT). Thus, we compared the incidence of cardiac events and event-free survival (EFS) after allo-HSCT at two Japanese hospitals between HD-AraC and anthracycline-containing post-remission therapy to clarify the safety of post-remission therapy. Of a total of 132 patients, 68 received HD-AraC (HD-AraC group) and 64 received anthracycline-containing chemotherapy (ANT group). HD-AraC was preferentially selected for core-binding factor AML patients (p = 0.008). The median cumulative anthracycline dose was 115.2 mg/m2 in the HD-AraC group and 318.7 mg/m2 in the ANT group (p < 0.0001). Cardiac events were observed in 18 (13.6%) patients during the follow-up period. The 3-year cumulative incidence of cardiac events was 9.1% in the HD-AraC group and 11.0% in the ANT group (p = 0.70). EFS at 3 years after allo-HSCT was 40.9% in the HD-AraC group and 39.6% in the ANT group (p = 0.51). In conclusion, incidence of cardiac events did not differ significantly between post-remission therapy regimens in AML patients who underwent allo-HSCT.

Accuracy of Urea Nitrogen and Creatinine Measurements in Postmortem Serum and Pericardial Fluid Compared With Antemortem Data.

ABSTRACT: Although several studies have measured urea nitrogen (UN) and creatinine (Cr) concentrations in postmortem serum and pericardial fluid, no recent antemortem biochemical data have been available for forensic autopsy, thereby making the evaluation of the accuracy of postmortem data difficult. This study compared antemortem (from emergency room results before the declaration of death) and postmortem serum UN and Cr concentrations, as well as postmortem serum and pericardial fluid values, in 51 forensic autopsy cases (postmortem interval within 87 hours). Postmortem UN concentrations were strongly correlated with antemortem data. Moreover, no significant difference between pericardial fluid UN concentrations and antemortem data was observed. Postmortem serum and pericardial fluid Cr values were also correlated with antemortem data, although postmortem values were significantly higher than antemortem ones. Given our observation of early postmortem elevation in Cr concentrations, such an elevation was attributed to rigor mortis. In conclusion, the current study demonstrated the utility of postmortem UN and Cr concentrations, in particular of those measured in the pericardial fluid.

Fatal intoxication due to transrectal methamphetamine overdose: A case report.

Methamphetamine (MA) abuse is common in Asian countries. The major ways of abuse include intravenous injection, absorption, and ingestion. Although two cases of survival after transrectal MA administration have been reported in the clinical field, to the best of our knowledge, there is no report of death due to intentional transrectal MA overdose. This is the first report of such a death. A single, 42-year-old male with a history of habitual MA use was found dead at his home. The police found numerous unused injectors in his closet. A rapid test of his urine was positive for MA. The cause of death was unclear, so a medicolegal autopsy was performed. RESULTS: Autopsy findings revealed a tubular plastic container without a lid in the rectum at the time of excision, with a small, open plastic bag inside. MA was detected in both the plastic container and the plastic bag. The MA concentration in the femoral vein blood was enough to cause death, and the cause of death was considered transrectal MA overdose. MA was absorbed through the lower part of the rectum, so the absorbed MA bypassed the liver and was transported directly to the systemic circulation. Since MA is largely metabolized in the liver, the absorbed MA was unaffected by the hepatic first-pass effect and may have caused more rapid and serious intoxication.

Enantioselective synthesis of 3-substituted dihydrobenzofurans through iridium-catalyzed intramolecular hydroarylation.

Intramolecular hydroarylation via C-H activation is one of the most powerful methods to synthesize carbo- and heterocyclic compounds, whereas we still have room for developing a highly enantioselective variant of the reaction. Here we describe Ir-catalyzed enantioselective intramolecular hydroarylation of m-allyloxyphenyl ketones. The enantioselective cyclization was efficiently catalyzed by a cationic iridium complex coordinated with a conventional chiral bisphosphine ligand to give benzofurans in high yields with high enantioselectivity. A carbonyl group of ketones functioned as an effective directing group for the C-H activation. In terms of synthetic utility, we also achieved one-pot synthesis of chiral 3-substituted dihydrobenzofurans from readily available allylic carbonates and m-hydroxyacetophenones via sequential Pd-catalyzed allylic substitution and Ir-catalyzed intramolecular hydroarylation.

Comparison of C-reactive protein levels between antemortem serum and postmortem serum and pericardial fluid.

Biochemical markers undergo postmortem changes that complicate diagnostic measurement. C-reactive protein (CRP) is one marker that is known to be useful in postmortem specimens, with high levels reported in forensic cases of sepsis, trauma, and ketoacidosis. In the present study, we included 30 cases (17 males and 13 females) that underwent forensic autopsy within 80 h of death and had a CRP result from two postmortem specimens (serum from cardiac blood and pericardial fluid) and an emergency room specimen. Antemortem results were taken at a time near to cardiopulmonary arrest and the declaration of death. CRP levels in postmortem serum and pericardial fluid correlated with those in antemortem serum. Although no significant difference was observed between the antemortem and postmortem serum levels, the pericardial level was significantly low and five false negatives were observed. We conclude that postmortem serum is suitable for use in CRP measurement, and in cases with high antemortem CRP levels, postmortem pericardial fluid may be an appropriate alternative.

Cytogenetics of Blastic Plasmacytoid Dendritic Cell Neoplasm: Chromosomal Rearrangements and DNA Copy-Number Alterations.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a skin-tropic hematopoietic malignancy. Approximately 60% of cases with analyzable karyotyping results show complex karyotypes. Losses are more frequently found than copy-number gains. Recurrently deleted regions include tumor suppressor genes. No specific chromosomal abnormalities have been demonstrated in BPDCN, but genomic rearrangements involving the MYB family genes and MYC were identified. One-third of cases of BPDCN harbor the 8q24 rearrangement, most frequently with 6p21 harboring RUNX2, which is associated with immunoblastoid cytomorphology and MYC expression. MYB rearrangement is detected in 20% of patients with BPDCN. We review copy-number alterations and chromosomal rearrangements.

Surgical resection for persistent localized pulmonary fungal infection prior to allogeneic hematopoietic stem cell transplantation: Analysis of six cases.

OBJECTIVE: Although invasive fungal disease (IFD) is an important complication in allogeneic hematopoietic stem cell transplantation (HSCT), the clinical significance of surgery, including the role of surgical resection for persistent pulmonary fungal disease prior to allogeneic HSCT in the current era with a variety of available antifungal agents, is controversial. We investigated the role of surgical resection. METHODS: We retrospectively investigated six patients who underwent surgical resection of suspected pulmonary fungal disease prior to allogeneic HSCT between April 2007 and June 2016 at our medical center. RESULTS: We present six patients who underwent surgical resection of suspected pulmonary fungal disease prior to allogeneic HSCT. In our case series, three of four patients who were given a presurgical diagnosis of possible IFD were given a proven diagnosis after surgery, including two cases of invasive aspergillosis (IA) and one case of mucormycosis. All surgeries were performed by video-assisted thoracic surgery (VATS) for lobectomy without major complications. Recurrence of IFD was not observed after allogeneic HSCT in any of the six patients. CONCLUSION: Our experience indicated that surgical resection of persistent localized pulmonary lesions of IFD before allogeneic HSCT was helpful for obtaining a definitive diagnosis and might be useful for reducing recurrence after HSCT.

Ruxolitinib shows activity against Hodgkin lymphoma but not primary mediastinal large B-cell lymphoma.

BACKGROUND: The upregulated expression of the JAK/STAT pathway promotes tumor growth in Hodgkin lymphoma (HL) and primary mediastinal large B-cell lymphoma (PMBCL). Based on the hypothesis that JAK2 is a therapeutic target, we performed a prospective pilot study using ruxolitinib. METHODS: Relapsed or refractory patients with HL or PMBCL were eligible for this study, and JAK2 amplification was assessed by fluorescence in situ hybridization. Ruxolitinib was administered orally at a dose of 20 mg twice daily for a 28-day cycle. Treatment was continued for up to 16 cycles or until progressive disease or intolerability. The primary objective was to assess the overall disease control rate comprising complete response (CR), partial response (PR), or stable disease (SD). RESULTS: We analyzed 13 HL patients and six PMBCL patients. All responders (one CR, five PR, and one SD) had HL whereas all cases of PMBCL progressed after first or second cycle. The disease control rate for HL was 54% (7/13) with median response duration of 5.6 months. JAK2 amplification was present in six of nine patients tested (four HL, two PMBCL), and three of these HL patients showed PR (n = 2) or SD (n = 1). None of the three HL patients shown to not have JAK2 amplification responded to ruxolitinib. Most treatment-related adverse events were grade 1 or 2 and manageable. CONCLUSIONS: Ruxolitinib has single-agent activity against HL but does not act against PMBCL with or without JAK2 amplification. TRIAL REGISTRATION: The study population was patients who had relapsed or refractory HL or PMBCL, and patients were registered for our pilot study after providing written informed consent between November 2013 and November 2015 (CilinicalTrials.gov: NCT01965119).

Rhodium-catalyzed asymmetric addition of arylboronic acids to 2H-chromenes leading to 3-arylchromane derivatives.

Asymmetric addition of arylboronic acids to 2H-chromenes proceeded in the presence of a hydroxorhodium/chiral diene catalyst to give 3-arylchromanes in high yields with high enantioselectivity. The reaction involves 1,4-Rh shift before protonation to release the addition product and to regenerate the hydroxorhodium species.

Successful outcome of second allogeneic bone marrow transplantation for blastic plasmacytoid dendritic cell neoplasm with MYC locus rearrangement.

A 62-year-old male was diagnosed with blastic plasmacytoid dendritic cell neoplasm (BPDCN) with a MYC rearrangement. Four months after the first unrelated bone marrow transplantation (BMT), he developed the relapsed BPDCN. After the achievement of partial remission following re-induction therapy, he underwent a second BMT from another unrelated donor, and experienced complete remission with grade II acute graft-versus-host disease and moderate chronic graft-versus-host disease. He remains alive in complete remission more than 71 months after the second BMT. These results suggested that donor change at the second transplantation may represent a considerable therapeutic option for patients with relapsed BPDCN.

Molecular heterogeneity in peripheral T-cell lymphoma, not otherwise specified revealed by comprehensive genetic profiling.

Peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) is a diagnosis of exclusion, being the most common entity in mature T-cell neoplasms, and its molecular pathogenesis remains significantly understudied. Here, combining whole-exome and targeted-capture sequencing, gene-expression profiling, and immunohistochemical analysis of tumor samples from 133 cases, we have delineated the entire landscape of somatic alterations, and discovered frequently affected driver pathways in PTCL, NOS, with and without a T-follicular helper (TFH) cell phenotype. In addition to previously reported mutational targets, we identified a number of novel recurrently altered genes, such as KMT2C, SETD1B, YTHDF2, and PDCD1. We integrated these genetic drivers using hierarchical clustering and identified a previously undescribed molecular subtype characterized by TP53 and/or CDKN2A mutations and deletions in non-TFH PTCL, NOS. This subtype exhibited different prognosis and unique genetic features associated with extensive chromosomal instability, which preferentially affected molecules involved in immune escape and transcriptional regulation, such as HLA-A/B and IKZF2. Taken together, our findings provide novel insights into the molecular pathogenesis of PTCL, NOS by highlighting their genetic heterogeneity. These results should help to devise a novel molecular classification of PTCLs and to exploit a new therapeutic strategy for this group of aggressive malignancies.

Enhanced oxygen reduction reaction performance of size-controlled Pt nanoparticles on polypyrrole-functionalized carbon nanotubes.

Size-controlled Pt nanoparticles were prepared on multi-wall carbon nanotubes (MWCNTs) decorated with polypyrrole matrix overlayers and exhibited superior oxygen reduction reaction (ORR) performance as electrocatalysts. The copolymerization of a new Pt4-pyrrole complex and pyrrole monomer in the presence of MWCNTs produced size-controlled Pt nanoparticles with diameters of 1.5 ± 0.5 nm. The present size-controlled Pt nanoparticles showed better durability than non-regulated Pt nanoparticles without polypyrrole and a commercial Pt/C catalyst during the ORR at the fuel cell cathode without substantial aggregation of the size-controlled Pt nanoparticles.

Negative impact of chronic graft-versus-host disease and glucocorticoid on the recovery of physical function after allogeneic hematopoietic stem cell transplantation.

Quality of life of patients who undergo allogeneic hematopoietic stem cell transplantation (HSCT) temporally deteriorates and recovers over several years. We retrospectively evaluate the impact of chronic graft-versus-host disease (GVHD) and glucocorticoid on physical recovery. We included 162 patients who underwent their first allogeneic HSCT between October 2010 and December 2015 in a single hospital. All patients are planned to undergo physical function tests before and 1, 3, 12 months after allogeneic HSCT. Scores of knee extension strength and distance covered in the 6-min walk test (6MWT) recovered at the 12-month assessment. Both chronic GVHD and high dose glucocorticoid were associated with delayed recovery of body mass index (BMI), hand grip strength, knee extension strength, and duration of standing on one foot. Lung GVHD and high dose glucocorticoid had negative impact on the distance covered in the 6MWT. A multivariate analysis revealed that chronic GVHD and glucocorticoid was an independent risk factor for decreased BMI and delayed recovery of muscle strength, respectively. Our results suggest that high-risk patients who have chronic GVHD or who receive glucocorticoid therapy may require reduced dose of glucocorticoid and long-term physical support to recover physical function after transplantation.