Neutral Chromium Complex with a Cr≡Si Triple Bond: Synthesis and Photoinduced H-H and Benzene C-H Bond Activation.

A neutral silylyne complex with a Cr≡Si triple bond was prepared by dehydrogenation of a chromium silylene complex with Cr-H and Si-H bonds, and was isolated as monomeric crystals, unlike dimeric forms of its tungsten and molybdenum congeners. The strong Cr(δ-)-Si(δ+) bond polarity was revealed by the reaction with MeOH and DFT calculations. The chromium silylyne complex reacted with H2 under LED (365 nm) irradiation to reproduce the precursor silylene complex with a (H)Cr=Si(H) moiety, as a result of 1,2-H-H addition across the Cr≡Si triple bond. Similarly, the chromium silylyne complex reacted with benzene under irradiation to afford an 1,2-addition product with a (H)Cr=Si(Ph) moiety, via benzene C-H bond activation accompanied by Si-C bond forming.

Laryngeal widening and adequate ventilation by expiratory pressure load training improve aerobic capacity in COPD: a randomised controlled trial.

RATIONALE: Despite strategies acting on peripheral airway obstruction in chronic obstructive pulmonary disease (COPD), exercise intolerance remains inadequately improved. We hypothesised that laryngeal narrowing is a potential treatment target of expiratory pressure load training (EPT) to improve exercise intolerance in COPD. METHODS: The effect of 3-month EPT was assessed in 47 patients with COPD divided into Global Initiative for Chronic Obstructive Lung Disease (GOLD) mild-to-moderate (I-II) and severe-to-very severe (III-IV), randomly allocating 1:1 to EPT or control groups. The primary outcome was endurance time in the constant work rate exercise test in GOLD III-IV patients. RESULTS: Compared with controls, EPT increased: (1) endurance time, with estimated treatment effect: +703 (95% CI: 379 to 1031) s, p=0.0008 (GOLD I-II); +390 (95% CI: 205 to 574) s, p=0.0006 (GOLD III-IV); (2) peak oxygen uptake (p=0.0086 in GOLD I-II; p=0.0004 in GOLD III-IV); (3) glottic dilatation ratio at maximum collapse on laryngoscopy in the submaximal exercise (p=0.0062 in GOLD I-II; p=0.0001 in GOLD III-IV); and (4) the inflection point of expiratory tidal volume relative to minute ventilation during the incremental exercise (p=0.0015 in GOLD I-II; p=0.0075 in GOLD III-IV). Across GOLD grades, the responses of glottic dilatation ratio at maximum collapse and the expiratory tidal volume at the inflection point were selected as more influential variables correlating with the improvement in peak oxygen uptake and endurance time, respectively. CONCLUSION: These results show that EPT improved aerobic capacity and endurance time with larger laryngeal widening and adequate ventilation despite advanced COPD. TRIAL REGISTRATION NUMBER: UMIN000041250.

Neutral Silylyne Complex of Molybdenum: Synthesis, Properties, and Access to Silaiminoacyl Complexes via [2+3] Cycloaddition.

A neutral silylyne complex of molybdenum was synthesized by the stepwise dehydrogenation method and its properties were compared with those of the tungsten analog. The complex takes a dimeric form as crystals but afford a monomer-dimer equilibrium in solution. The replacement of the central metal from W to Mo led to a monomer dominant (~98 %) solution at room temperature. The monomer-dimer dynamics was investigated based on thermodynamic parameters. The molybdenum silylyne complex underwent [2+2] cycloaddition with alkynes much faster than the tungsten analog. The reactions with organic azides led to the formation of the first example of silaiminoacyl complexes through [2+3] cycloaddition. The structures and bonding aspects of the products were clarified by multiple measurements and DFT calculations.

Clinical Implications of t(11;14) in Patients with Multiple Myeloma Undergoing Autologous Stem Cell Transplantation.

Conventional cytogenetic analyses and fluorescent in situ hybridization (FISH) are helpful for stratifying patients with multiple myeloma (MM) into high-risk [t(4;14), t(14;16), and/or del 17p] and standard-risk [t(11;14)] categories. However, the prognosis of patients with MM treated with autologous stem cell transplantation (ASCT) stratified according to these categories remains unclear. This retrospective observational study analyzed 97 patients with MM who received a single, planned ASCT after treatment with 200 mg/m2 melphalan between 2001 and 2011. The patients were grouped according to chromosomal abnormality, including t(11;14) (n = 45), t(4;14) (n = 31), del 17p (n = 10), t(11;14) with del 17p (n = 7), and t(4;14) with del 17p (n = 4). Median overall survival (OS) of the t(11;14) group (64.1 months) was not significantly different from that of the t(4;14) group (not reached), but it was significantly longer than that of the del 17p group (23.0 months; P = .002). G-banding revealed that the median OS of the t(11;14) group with additional chromosomal abnormalities (ACAs) (46.2 months) was significantly shorter than that of the t(11;14) group without ACAs (not reached; P = .005) and the t(4;14) group (not reached; P = .010). These findings highlight the importance of G-banding in patients with t(11;14) MM.

Reactions of a Silylyne Complex with Aldehydes: Formation of W-Si-O-C Four-Membered Metallacycles and Their Metathesis-Like Fragmentation.

A tungsten silylyne complex having a W≡Si triple bond reacted with two molecules of aldehydes at room temperature to give W-Si-O-C four-membered metallacycles by [2+2] cycloaddition and subsequent formyl hydrogen transfer from one aldehyde molecule to another. Upon heating to 70 °C, the four-membered metallacycles underwent metathesis-like fragmentation cleanly to afford carbyne complexes and "silanoic esters," in a manner similar to that of metallacyclobutadiene, an intermediate of alkyne metathesis reactions, and dimerization of the latter products gave 1,3-cyclodisiloxanes. The "silanoic ester" was also trapped by pivalaldehyde to give a [2+2] cycloaddition product in high yield.

Impact of HIV Infection on Transplant Outcomes after Autologous Peripheral Blood Stem Cell Transplantation: A Retrospective Study of Japanese Registry Data.

Autologous stem cell transplantation (ASCT) is a treatment option for HIV-positive patients with non-Hodgkin lymphoma (NHL) and multiple myeloma (MM). However, the prognosis after ASCT in HIV-positive Japanese patients remains unclear. The aim of this study was to evaluate the impact of HIV infection on transplant outcomes after ASCT in Japan. Using the national database of the Japan Society for Hematopoietic Cell Transplantation, we retrospectively evaluated patients with NHL (n = 3862) and MM (n = 2670) who underwent their first ASCT between 2001 and 2014. The presence of HIV antibody was used to diagnose HIV infection. Fifty-six patients with NHL (1.4%) and 23 with MM (.8%) were positive for HIV antibody. Among patients with NHL overall survival (OS) was lower in HIV-positive patients than in HIV-negative patients (5-year OS: HIV-positive patients, 44% versus HIV-negative patients, 65%; P < .001). In a multivariate analysis HIV infection was significantly associated with an increased risk of overall mortality (hazard ratio, 2.30; P < .001). The incidence of relapse was higher in HIV-positive patients (P = .036), whereas there was a similar incidence of nonrelapse mortality (P = .879). OS in patients with MM was similar between those with/without HIV infection (5-year OS: HIV-positive patients, 61% versus HIV-negative patients, 63%; P = .988). HIV infection was associated with a higher risk of overall mortality and relapse after ASCT for NHL in a Japanese population.

Enlarged spleen is associated with low neutrophil and platelet engraftment rates and poor survival after allogeneic stem cell transplantation in patients with acute myeloid leukemia and myelodysplastic syndrome.

Primary graft failure can be a cause of early morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT), as it leads to a high risk of severe infections and bleeding. Splenomegaly is associated with primary graft failure in patients of myelofibrosis, but the association between splenomegaly and outcomes after HSCT in patients with myeloid malignancies has not been previously evaluated. The aim of this study was to investigate the effect of spleen volume on engraftment kinetics in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). We enrolled 85 patients. The median spleen volume was 146 cm3 (quartile 88-201 cm3). The adjusted hazard ratios for neutrophil and platelet engraftments were 0.17 (0.07-0.40, p < 0.001) and 0.19 (0.05-0.69, p = 0.011), respectively, for the high-risk group, at a cutoff splenic volume of 320 cm3. Overall survival at 3 years after HSCT was significantly poor in the high-risk group with an adjusted hazard ratio of 13.8 (2.61-72.4, p = 0.002). Enlarged spleen was associated with low neutrophil and platelet engraftment rates and poor survival after allogeneic HSCT in patients of AML and MDS.

Impact of hematopoietic stem cell transplantation in patients with relapsed or refractory mantle cell lymphoma.

Rituximab has been shown to improve outcomes in patients with B-cell lymphoma. However, patients with relapsed or refractory (R/R) mantle cell lymphoma (MCL) still have a poor prognosis, and the choice between high-dose therapy with autologous hematopoietic cell transplantation (HCT) and allogeneic HCT remains controversial in these patients. We retrospectively analyzed the risk factors for outcomes in 162 R/R MCL patients who received autologous (n = 111) or allogeneic (n = 51) HCT between 2004 and 2014. The median overall survival (OS) rates were 48 and 65 months in the autologous and allogeneic HCT groups, respectively (P = 0.20). Significant risk factors for overall survival in R/R MCL patients after autologous HCT were > 60 years of age at HCT (P = 0.017), higher score of HCT-specific comorbidity index at HCT (P = 0.033), and receiving MCEC (ranimustine + carboplatin + etoposide + cyclophosphamide) regimen (P = 0.017), while higher performance status at HCT (P = 0.011) and longer interval from diagnosis to HCT (P = 0.0054) were risk factors after allogeneic HCT. Strategies that carefully select R/R MCL patients for autologous HCT may allow the identification of individuals suitable for allogeneic HCT.

Correction to: Impact of hematopoietic stem cell transplantation in patients with relapsed or refractory mantle cell lymphoma.

The original version of this article contained a mistake in fig. 1a. "Autologous HCT(n=111)" should be changed to "Allogeneic HCT (n=51)". Correct figure is presented below.

[Mitoxantrone, etoposide, and cytarabine combination therapy for acute myeloid leukemia patients failing to achieve a complete remission after induction chemotherapy: a single-center experience].

Optimal salvage chemotherapy has not been established for patients with acute myeloid leukemia (AML) who fail to attain complete remission (CR) after one course of induction chemotherapy. This retrospective study aimed to assess the efficacy and safety of an MEC (mitoxantrone, 6 mg/m2, 1-3 days; etoposide, 80 mg/m2, 1-6 days; cytarabine, 1 g/m2, 1-6 days) regimen in patients with AML who failed to attain CR after one course of induction chemotherapy. Twenty-four patients were included in this study (median age, 58 years; range, 28-79 years). After one course of MEC, 11 patients (45.8%) attained CR. Febrile neutropenia was observed in all patients, and acute infection was observed in 7 patients (29.2%). However, no therapy-related death occurred. All patients eligible for transplantation and who attained CR after MEC salvage chemotherapy underwent allogeneic hematopoietic stem cell transplantation. The MEC regimen exhibited a good response rate with tolerable adverse events. Therefore, the MEC regimen can be safely used as a salvage treatment for patients with AML who failed to attain CR after one course of induction chemotherapy.

Utility of a simple prognostic stratification based on platelet counts and serum albumin levels in elderly patients with diffuse large B cell lymphoma.

Few studies have examined the prognostic impact of blood markers [other than the five factors in the enhanced International Prognostic Index (NCCN-IPI)] in elderly patients with diffuse large B cell lymphoma (DLBCL). We retrospectively analyzed 391 DLBCL patients receiving rituximab plus anthracycline-containing chemotherapy to examine the prognostic impact of simple blood markers. The NCCN-IPI was more accurate for discriminating prognoses than the original IPI. Multivariate analysis identified platelet count (<100,000/µl) and albumin (<3.5 g/dl) levels as significantly associated with lower overall survival (OS), independently of the NCCN-IPI. These parameters stratified patients into three risk groups: platelet-albumin (PA) score low (platelet count ≥100,000/µl, albumin ≥3.5 g/dl, n = 243); intermediate (platelet count <100,000/µl, albumin ≥3.5 g/dl or platelet count ≥100,000/µl, albumin <3.5 g/dl, n = 125); and high (platelet count <100,000/µl, albumin <3.5 g/dl, n = 23). The 5-year OS rates were 81.5, 48.6, and 20.2 %, respectively (p < 0.001). Notably, most patients with a low platelet count (n = 30) were stratified into the high-risk subgroup, suggesting that platelet count was prognostic for high-risk patients with a dismal outcome. In elderly patients (n = 291), the prognostic value of the NCCN-IPI might be diminished because the low-risk category was excluded; however, the PA score was predictive of survival: the 5-year OS rates for PA score low (n = 171), intermediate (n = 101), and high (n = 19) groups were 77.6, 47.9, and 19.0 %, respectively (p < 0.001). Platelet count and albumin levels are useful prognostic factors, and their combined use can predict survival, even in elderly patients.

Clinical impact of pretransplant use of multiple tyrosine kinase inhibitors on the outcome of allogeneic hematopoietic stem cell transplantation for chronic myelogenous leukemia.

Tyrosine kinase inhibitors (TKIs) are widely used to treat patients with chronic myelogenous leukemia in the chronic phase (CML-CP), and outcomes of TKI treatment for patients with CML-CP have been excellent. Since multiple TKIs are currently available, second-line or third-line TKI therapy is considered for patients who are intolerant of or resistant to the previous TKI treatment. Therefore, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is considered only for patients with disease progression or for patients after treatment failure with multiple TKIs. To reflect the current clinical situation of patients with CML-CP, we tried to clarify whether prior TKI treatment affects the outcome of allo-HSCT. Data from 237 patients for whom the number of pretransplant TKIs varied from one to three were used for analysis. Before allo-HSCT, 153 patients were treated with one TKI, 49 patients were treated with two TKIs and 35 patients were treated with three TKIs. In addition to conventional risk factors, i.e., disease status at transplantation and patient's age, the use of three TKIs before transplantation was identified as a significant adverse factor for prognosis. Nonrelapse mortality rate was higher in patients treated with three TKIs than in patients treated with one or two TKIs. Our results suggest that allo-HSCT could be considered for young patients with CML-CP who manifest resistance to second-line TKI therapy and who have an appropriate donor.

[Successful treatment of an overwhelming infection with granulocyte transfusion in severe aplastic anemia patient undergoing allogeneic peripheral blood stem cell transplantation].

A 19-year-old woman complaining of fever and a sore throat was diagnosed with very severe aplastic anemia (AA) by bone marrow examination at a local hospital. Despite administration of antibiotics and granulocyte-colony stimulating factor to treat the soft tissue infection in her neck, her neutrophil count showed no increase. Because emergent allogeneic stem cell transplantation (SCT) was necessary, she was referred to our hospital. On admission, computed tomography revealed right-sided severe pharyngitis and lymphadenitis causing tracheal stenosis, and emergent intubation was required the next day. Granulocyte transfusion therapy (GTX) from related donors coupled with broad-spectrum antibiotic administration controlled the otherwise overwhelming infection. The patient received allogeneic peripheral blood SCT using a reduced-intensity conditioning regimen. After allogeneic SCT, successful engraftment was obtained. She was discharged from the hospital 59 days after allogeneic SCT. She remains alive and well, as of the latest follow up. This case clearly demonstrates that GTX is useful for controlling severe infection and enables patients with severe AA to receive allogeneic SCT safely.

Stabilization of a Silaaldehyde by its η(2) Coordination to Tungsten.

Treatment of pyridine-stabilized silylene complexes [(η(5)-C5 Me4R)(CO)2(H)W=SiH(py)(Tsi)] (R = Me, Et; py = pyridine; Tsi = C(SiMe3)3) with an N-heterocyclic carbene (Me)I(i)Pr (1,3-diisopropyl-4,5-dimethylimidazol-2-ylidene) caused deprotonation to afford anionic silylene complexes [(η(5)-C5Me4 R)(CO)2W=SiH(Tsi)][H(Me)I(i)Pr] (R = Me (1-Me); R = Et (1-Et)). Subsequent oxidation of 1-Me and 1-Et with pyridine-N-oxide (1 equiv) gave anionic η(2)-silaaldehydetungsten complexes [(η(5)-C5Me4R)(CO)2W{η(2)-O=SiH(Tsi)}][H(Me)I(i)Pr] (R = Me (2-Me); R = Et (2-Et)). The formation of an unprecedented W-Si-O three-membered ring was confirmed by X-ray crystal structure analysis.

Unexpected Formation of NHC-Stabilized Hydrosilylyne Complexes via Alkane Elimination from NHC-Stabilized Hydrido(alkylsilylene) Complexes.

N-heterocyclic carbene (NHC)-stabilized hydrosilylyne complex Cp*(CO)2WSiH((Me)IMe)2 (3a) ((Me)IMe = 1,3,4,5-tetramethylimidazole-2-ylidene) was formed by the reaction of an NHC-stabilized silylene complex Cp*(CO)2(H)WSiH((Me)IMe){C(SiMe3)3} (2a) with 1 equiv of (Me)IMe at 70 °C. In this reaction, HC(SiMe3)3 was unexpectedly eliminated from 2a. A C5Me4Et analogue of 3a, (C5Me4Et)(CO)2WSiH((Me)IMe)2 (3b), was also synthesized by the same method, and the structure of 3b was confirmed by X-ray crystallography. Although the silicon center of 3b is coordinated by two NHCs, the length of the W-Si bond of 3b [2.363(4) Å] is as short as that of the shortest W═Si double bond (∼2.36 Å). These complexes, 3a and 3b, are the first examples of a base-stabilized silylyne complex having only a hydrogen on the silicon atom.

Isolation of a hydrogen-bridged bis(silylene) tungsten complex: a snapshot of a transition state for 1,3-hydrogen migration.

A hydrogen-bridged bis(silylene) complex, which can be viewed as a snapshot of a transition state for 1,3-hydrogen migration, was isolated, and its unprecedented WSi2H four-membered-ring structure with a short diagonal Si-Si distance was revealed by X-ray crystallography. NMR studies including determination of the W-Si, Si-Si, and Si-H coupling constants and theoretical calculations suggest that a novel multicenter bond is formed in the WSi2H system, in which the bridging hydrogen takes on a hydridic nature.

The role of hematopoietic stem cell transplantation for relapsed and refractory Hodgkin lymphoma.

The optimal treatment strategy with the use of hematopoietic stem cell transplantation (HSCT) for relapsed and refractory Hodgkin lymphoma (HL) remains unclear. We performed a retrospective analysis using registry data from the Japanese Society for Hematopoietic Cell Transplantation. Adult patients with HL who underwent a first autologous or a first allogeneic HSCT between 2002 and 2009 were included. Patients who underwent HSCT in first complete remission (CR) were excluded. Autologous and allogeneic HSCT were performed in 298 and 122 patients, respectively. For autologous HSCT, overall survival at 3 years (3yOS) was 70%, and sex, age, disease status, and performance status (PS) at HSCT were prognostic factors. OS was favorable even in patients who underwent autologous HSCT in disease status other than CR. For allogeneic HSCT, 3yOS was 43%, and sex and PS at HSCT were prognostic factors. Disease status at HSCT, previous autologous HSCT, and conditioning intensity did not affect OS. Moreover, graft-versus-host disease did not affect progression-free survival or relapse/progression rate. A first allogeneic HSCT without a previous autologous HSCT was performed in 40 patients. 3yOS was 45%, and was significantly inferior to that in patients who underwent their first autologous HSCT. This result was retained after the correction by the different patient characteristics according to the type of HSCT. In conclusion, autologous HSCT is effective in prolonging survival in patients with relapsed and refractory HL. Allogeneic HSCT might be beneficial even to relapsed HL after autologous HSCT, although establishing the role of allogeneic HSCT remains a challenge.

Reactions of a tungsten-germylyne complex with α,ß-unsaturated ketones: complete cleavage of the W≡Ge bond and formation of two types of η3-germoxyallyl tungsten complexes.

Germylyne complex Cp*(CO)2W≡Ge{C(SiMe3)3} (1) reacted with two molecules of RC(O)CH═CH2 (R = Me, Et) to give η(3)-allyl complexes, in which an oxagermacyclopentene framework was bound to an η(3)-allyl ligand through an oxygen atom. In the reaction with α-Me-substituted MeC(O)C(Me)═CH2, 1 reacted with only one molecule of the substrate to give another type of η(3)-allyl complex, in which a five-membered oxagermacyclopentenyl ring was coordinated to the W center in an η(3) fashion. Both reactions resulted in unprecedented complete cleavage of a W≡Ge triple bond.

Serum IgA level, monocyte count, and international prognostic index are independently associated with overall survival in patients with HTLV-I-negative nodal peripheral T cell lymphoma.

Peripheral T cell lymphomas (PTCL) account for 10-15 % of non-Hodgkin's lymphomas and are associated with poor prognosis. Although many prognostic factors for PTCL have been proposed, the heterogeneity of PTCL seems to be an obstacle in the establishment of clinically useful prognostic system, such as the International Prognostic Index (IPI) in diffuse large B cell lymphoma. PTCL with nodal manifestation include the HTLV-I-negative histologic subtypes of PTCL not otherwise specified (PTCL-NOS), angioimmunoblastic T cell lymphoma (AITL), and anaplastic large cell lymphoma (ALCL). As PTCL-NOS encompasses a group of similar tumors and mostly shares their clinical pictures, we retrospectively analyzed clinical data from 77 patients diagnosed with ALCL, AITL, and PTCL-NOS at Kobe City Medical Center General Hospital from May 1994 to February 2012 to identify the prognostic factor for nodal PTCL. The median age of patients was 64 years, ranging from 23 to 83 years. With a median follow-up of 50 months, 5-year overall survival (OS) was 43 %. Multivariate analysis identified high-risk IPI (hazard ratio (HR), 4.04; P = 0.015), absolute monocyte count > 0.8 × 10(9)/L (HR, 3.44; P = 0.001), and serum concentration of IgA > 410 mg/dL (HR, 2.31; P = 0.013) as poor prognostic factors for OS. Thus, we have identified novel prognostic factors of monocyte count and serum IgA level for nodal PTCL. Although conventional prognostic models mainly reflect both tumor characteristics and host factors, the present model indicates the importance of host immune response as the unfavorable prognosis.

Phase II clinical trial of CD34+ cell therapy to explore endpoint selection and timing in patients with critical limb ischemia.

BACKGROUND: A prior phase I/IIa clinical trial provided evidence for safety, feasibility and potential efficacy of i.m. injection of granulocyte colony-stimulating factor (G-CSF)-mobilized CD34+ cells in patients with critical limb ischemia (CLI). METHODS AND RESULTS: A phase II trial of CD34+ cell therapy was conducted in patients with CLI to explore endpoint selection and timing. No-option CLI patients (n=11) underwent i.m. transplantation of G-CSF-mobilized CD34+ cells isolated by magnetic sorting. Ischemic rest pain scales improved from week 2 vs. baseline (P<0.05). Skin perfusion pressure (P=0.0175), transcutaneous partial oxygen pressure (P=0.0446) and pain-free walking distance (P=0.0056) improved from week 2, total walking distance from week 8 (P=0.0182) and toe brachial pressure index from week 12 (P=0.0174) vs. baseline. These parameters peaked at week 36 or 52. Rutherford's category improved from week 24 vs. baseline (P=0.0065). CLI-free ratio serially increased and peaked (85.7%) at week 36. Serial change in Rutherford's category correlated with that in Rest Pain Scale (P=0.0374), but not with that in any physiological parameters. CONCLUSIONS: Ischemic rest pain scales and physiological parameters improved relatively early after cell therapy, then plateaued later accompanied by recovery from the CLI state. Rutherford's category and CLI-free ratio at week 36 or later may be suitable endpoints in cell therapy clinical trials for CLI. Functional parameters should be evaluated independently of such clinical endpoints for ischemia severity. ( CLINICAL TRIAL REGISTRATION: URL: https://dbcentre3.jmacct.med.or.jp/jmactr/Default.aspx. Unique identifier: JMA-IIA00022)