Pimitespib in patients with advanced gastrointestinal stromal tumor (CHAPTER-GIST-301): a randomized, double-blind, placebo-controlled phase III trial.

BACKGROUND: Prognosis of advanced gastrointestinal stromal tumors (GIST) refractory to tyrosine kinase inhibitors (TKIs) is poor. This randomized, placebo-controlled, phase III trial evaluated the efficacy and safety of pimitespib, a novel heat shock protein 90 inhibitor, in advanced GIST refractory to standard TKIs. PATIENTS AND METHODS: Patients with histologically confirmed GIST refractory to imatinib, sunitinib, and regorafenib were randomized 2 : 1 to oral pimitespib 160 mg/day or placebo for 5 consecutive days per week in 21-day cycles. Following disease progression by blinded central radiological review (BCRR), cross-over to open-label pimitespib was permitted. The primary endpoint was progression-free survival (PFS) by BCRR in the full analysis set. Secondary endpoints included overall survival (OS) adjusted using the rank-preserving structural failure time (RPSFT) method to reduce the expected confounding impact of cross-over. RESULTS: From 31 October 2018 to 30 April 2020, 86 patients were randomized to pimitespib (n = 58) or placebo (n = 28). Median PFS was 2.8 months [95% confidence interval (CI) 1.6-2.9 months] with pimitespib versus 1.4 months (0.9-1.8 months) with placebo [hazard ratio (HR) 0.51 (95% CI 0.30-0.87); one-sided P = 0.006]. Pimitespib showed an improvement in cross-over-adjusted OS compared with placebo [HR 0.42 (0.21-0.85), one-sided P = 0.007]. Seventeen (60.7%) patients receiving placebo crossed-over to pimitespib; median PFS after cross-over was 2.7 months (95% CI 0.7-4.1 months). The most common (≥30%) treatment-related adverse events (AEs) with pimitespib were diarrhea (74.1%) and decreased appetite (31.0%); the most common (≥10%) grade ≥3 treatment-related AE was diarrhea (13.8%). Treatment-related AEs leading to pimitespib discontinuation occurred in three (5.2%) patients. CONCLUSIONS: Pimitespib significantly improved PFS and cross-over-adjusted OS compared with placebo and had an acceptable safety profile in patients with advanced GIST refractory to standard TKIs.

Grain size dependent photoresponsivity in GaAs films formed on glass with Ge seed layers.

The strong correlation between grain size and photoresponsivity in polycrystalline GaAs films on glass was experimentally demonstrated using Ge seed layers with a wide range of grain sizes (1‒330 µm). The crystal evaluations using Raman spectroscopy, scanning electron microscopy, electron backscatter diffraction, and transmission electron microscopy revealed that 500-nm-thick GaAs films epitaxially grown from the Ge seed layers at 550 °C inherited the grain boundaries and crystal orientations in Ge. With increasing grain size, the photoresponsivity corresponding to GaAs increased from 0.01 to 3 A W-1 under a bias voltage of 0.3 V. The maximum value approached that of the GaAs film formed simultaneously on a single-crystal Ge wafer, indicating the high potential of the large-grained GaAs film. Knowledge gained from this study will be essential for designing advanced solar cells based on polycrystalline III-V compound semiconductors using inexpensive substrates.

Application of ultra-high voltage electron microscope tomography to 3D imaging of microtubules in neurites of cultured PC12 cells.

Electron tomography methods using the conventional transmission electron microscope have been widely used to investigate the three-dimensional distribution patterns of various cellular structures including microtubules in neurites. Because the penetrating power of electrons depends on the section thickness and accelerating voltage, conventional TEM, having acceleration voltages up to 200 kV, is limited to sample thicknesses of 0.2 µm or less. In this paper, we show that the ultra-high voltage electron microscope (UHVEM), employing acceleration voltages of higher than 1000 kV (1 MV), allowed distinct reconstruction of the three-dimensional array of microtubules in a 0.7-µm-thick neurite section. The detailed structure of microtubules was more clearly reconstructed from a 0.7-µm-thick section at an accelerating voltage of 1 MV compared with a 1.0 µm section at 2 MV. Furthermore, the entire distribution of each microtubule in a neurite could be reconstructed from serial-section UHVEM tomography. Application of optimised UHVEM tomography will provide new insights, bridging the gap between the structure and function of widely-distributed cellular organelles such as microtubules for neurite outgrowth. LAY DESCRIPTION: An optimal 3D visualisation of microtubule cytoskeleton using ultra-high voltage electron microscopy tomography The ultra-high voltage electron microscope (UHVEM) is able to visualise a micrometre-thick specimen at nanoscale spatial resolution because of the high-energy electron beam penetrating such a specimen. In this study, we determined the optimal conditions necessary for microtubule cytoskeleton imaging within 0.7-µm-thick section using a combination with UHVEM and electron tomography method. Our approach provides excellent 3D information about the complex arrangement of the individual microtubule filaments that make up the microtubule network.

Utility of the Eating Assessment Tool-10 (EAT-10) in Evaluating Self-Reported Dysphagia Associated with Oral Frailty in Japanese Community-Dwelling Older People.

OBJECTIVES: The aim of the present study was to verify the associations between dysphagia as screened by the Eating Assessment Tool-10 (EAT-10) and indicators in the 100-mL water swallowing test (WST) or medical history among community-dwelling older people. STUDY DESIGN: A cross-sectional study. SETTING AND PARTICIPANTS: The study participants were 202 community-dwelling older Japanese adults aged ≥65 years. MEASUREMENTS: We investigated the participants' basic attributes, including age, sex, body mass index, medical history (cerebrovascular disease, respiratory disease: chronic obstructive pulmonary disease [COPD], and history of pneumonia within the previous year), and number of prescribed medications. Dysphagia assessment was performed using the EAT-10 and the 100-mL WST as subjective and objective examinations, respectively. The 100-mL WST used four indicators (SC: swallowing capacity, VS: volume per swallow, TS: time per swallow, and choking signs). Patients with and without dysphagia according to the EAT-10 were divided into two groups according to a cutoff score of 3, and the two groups were then compared in terms of their characteristics including medical history and 100-mL WST indicators. A multiple logistic regression model was used to determine whether the indicators of the 100-mL WST or medical history were independently associated with dysphagia in the EAT-10. RESULTS: The multiple logistic regression analysis revealed that dysphagia in the EAT-10 was independently associated with male sex (odds ratio [OR] = 2.78; 95% confidence interval [CI] = 0.98-7.90), COPD (OR = 14.68; 95% CI = 3.14-68.85), and VS and TS in the 100-mL WST (OR = 0.85; 95% CI = 0.80-0.90 and OR = 3.03; 95% CI = 1.78-5.16, respectively). CONCLUSIONS: Our results revealed that the EAT-10 was independently associated with the 100-mL WST and respiratory disease. We propose that swallowing rehabilitation incorporating respiratory training could be effective for older people screened using the EAT-10.

High-electron-mobility (370 cm2/Vs) polycrystalline Ge on an insulator formed by As-doped solid-phase crystallization.

High-electron-mobility polycrystalline Ge (poly-Ge) thin films are difficult to form because of their poor crystallinity, defect-induced acceptors and low solid solubility of n-type dopants. Here, we found that As doping into amorphous Ge significantly influenced the subsequent solid-phase crystallization. Although excessive As doping degraded the crystallinity of the poly-Ge, the appropriate amount of As (~1020 cm-3) promoted lateral growth and increased the Ge grain size to approximately 20 µm at a growth temperature of 375 °C. Moreover, neutral As atoms in poly-Ge reduced the trap-state density and energy barrier height of the grain boundaries. These properties reduced grain boundary scattering and allowed for an electron mobility of 370 cm2/Vs at an electron concentration of 5 × 1018 cm-3 after post annealing at 500 °C. The electron mobility further exceeds that of any other n-type poly-Ge layers and even that of single-crystal Si wafers with n ≥ 1018 cm-3. The low-temperature synthesis of high-mobility Ge on insulators will provide a pathway for the monolithic integration of high-performance Ge-CMOS onto Si-LSIs and flat-panel displays.

Long-Term Results and Follow-Up Examinations after Endovascular Embolization for Unruptured Cerebral Aneurysms.

BACKGROUND AND PURPOSE: The appropriate period of follow-up examinations after endovascular embolization for cerebral aneurysms using time-of-flight MR angiography is not well-known. We retrospectively investigated long-term results after endovascular embolization for unruptured cerebral aneurysms and evaluated the periods from embolization to recanalization and retreatment. MATERIALS AND METHODS: Between April 2006 and March 2011, one hundred forty-eight unruptured aneurysms were treated with endovascular coil embolization. Among them, we investigated 116 unruptured aneurysms, which were followed up for >5 years. Time-of-flight MR angiography was performed at 1 day, 3-6 months, 1 year after the procedure, and every year thereafter. RESULTS: The mean follow-up period was 7.0 ± 1.4 years. Recanalization was observed in 19 (16.3%) aneurysms within 2 years. Among them, retreatment for recanalization was performed in 8 (6.8%) aneurysms. No recanalization was detected in any aneurysms that had been stable in the first 2 years after embolization. A larger maximum aneurysm size was significantly correlated with recanalization (P = .019). CONCLUSIONS: Aneurysms in which recanalization was not observed within 2 years after endovascular coil embolization were stable during a mean follow-up of 7 years. This result may be helpful in considering the appropriate span or frequency of follow-up imaging for embolized cerebral aneurysms.

Dual Gas Treatment With Hydrogen and Carbon Monoxide Attenuates Oxidative Stress and Protects From Renal Ischemia-Reperfusion Injury.

BACKGROUND: Hydrogen (H2) and carbon monoxide (CO) gas are both reported to reduce reactive oxygen species and alleviate tissue ischemia-reperfusion (I-R) injury. The present study was conducted to evaluate the effects of a mixture of H2 gas and CO gas (dual gas) in comparison with hydrogen gas (H2: 2%) alone on I-R renal injury (composition of dual gas; N2: 77.8%; O2: 20.9%; H2: 1.30%; CO: 250 parts per million). METHODS: Adult male Sprague-Dawley rats (body weight 250-280 g) were divided into 5 groups: (1) sham operation control, (2) dual gas inhalation (dual treatment) without I-R treatment, (3) I-R renal injury, (4) H2 gas alone inhalation (H2 treatment) with I-R renal injury, and (5) dual treatment with I-R renal injury. I-R renal injury was induced by clamping the left renal artery and vein for 45 minutes followed by reperfusion, and then contralateral nephrectomy was performed 2 weeks later. Renal function was markedly decreased at 24 hours after reperfusion, and thereafter the effects of dual gas were assessed by histologic examination and determination of the superoxide radical, together with functional and molecular analyses. RESULTS: Pathologic examination of the kidney of I-R rats revealed severe renal damage. Importantly, cytoprotective effects of the dual treatment in comparison with H2 treatment and I-R renal injury were observed in terms of superoxide radical scavenging activity and histochemical features. Rats given dual treatment and I-R renal injury showed significant decreases in blood urea nitrogen. Increased expression of several inflammatory cytokines (tumor necrosis factor-α, interleukin-6, intracellular adhesion molecule-1, nuclear factor-κB, hypoxia inducible factor-1α, and heme oxygenase-1) was attenuated by the dual treatment. CONCLUSIONS: Dual gas inhalation decreases oxidative stress and markedly improves I-R-induced renal injury.

The impact of external fixation on mortality in patients with an unstable pelvic ring fracture: a propensity-matched cohort study.

AIM: There is not adequate evidence to establish whether external fixation (EF) of pelvic fractures leads to a reduced mortality. We used the Japan Trauma Data Bank database to identify isolated unstable pelvic ring fractures to exclude the possibility of blood loss from other injuries, and analyzed the effectiveness of EF on mortality in this group of patients. PATIENTS AND METHODS: This was a registry-based comparison of 1163 patients who had been treated for an isolated unstable pelvic ring fracture with (386 patients) or without (777 patients) EF. An isolated pelvic ring fracture was defined by an Abbreviated Injury Score (AIS) for other injuries of < 3. An unstable pelvic ring fracture was defined as having an AIS ≥ 4. The primary outcome of this study was mortality. A subgroup analysis was carried out for patients who required blood transfusion within 24 hours of arrival in the Emergency Department and those who had massive blood loss (AIS code: 852610.5). Propensity-score matching was used to identify a cohort like the EF and non-EF groups. RESULTS: With the use of propensity-score matching using the completed data, 346 patients were matched. When the propensity-score matching was adjusted, EF was associated with a significantly lower risk of death (p = 0.047). In the subgroup analysis of patients who needed blood transfusion within 24 hours and those who had massive blood loss, EF was associated with a significantly lower risk of death in patients who needed blood transfusion within 24 hours (p = 0.014) and in those with massive blood loss (p = 0.016). CONCLUSION: The use of EF to treat unstable pelvic ring fractures was associated with a significantly lower risk of death, especially in patients with severe fractures. Cite this article: Bone Joint J 2018;100-B:233-41.

Adjunctive perampanel in partial-onset seizures: Asia-Pacific, randomized phase III study.

OBJECTIVES: To evaluate the efficacy, safety, and tolerability of perampanel, a selective, non-competitive, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, as an adjunctive treatment for patients with refractory partial-onset seizures (POS) from Asia-Pacific. MATERIALS & METHODS: This multicenter, randomized, double-blind, placebo-controlled trial (ClinicalTrials.gov identifier: NCT01618695) involved patients aged ≥12 years with refractory POS (receiving 1-3 antiepileptic drugs). Patients were randomized (1:1:1:1) to receive once-daily placebo or perampanel 4, 8, or 12 mg over a 6-week titration and 13-week maintenance double-blind period. Enzyme-inducing antiepileptic drugs were equally stratified between groups. The primary efficacy endpoint was percent change in POS frequency per 28 days (double-blind phase vs baseline). Other efficacy endpoints included ≥50% responder rate and seizure freedom. Treatment-emergent adverse events (TEAEs) were also monitored. RESULTS: Of 710 randomized patients, seizure frequency data were available for 704 patients. Median percent changes in POS frequency per 28 days indicated dose-proportional reductions in seizure frequency: -10.8% with placebo and -17.3% (P = .2330), -29.0% (P = .0003), and -38.0% (P < .0001) with perampanel 4, 8, and 12 mg, respectively. In total, 108 (15.3%) patients discontinued treatment; 44 (6.2%) due to TEAEs. TEAEs occurring in ≥5% of patients, and reported at least twice as frequently with perampanel vs placebo, included dizziness and irritability. CONCLUSIONS: Adjunctive perampanel (8 and 12 mg/d) significantly improved seizure control in patients with refractory POS. Safety and tolerability were acceptable at daily doses of perampanel 4-12 mg.

Timing of initiation of adjuvant chemotherapy for gastric cancer: A case-matched comparison study of laparoscopic vs. open surgery.

BACKGROUND: Laparoscopic gastrectomy (LG) is reported to be associated with faster recovery than open gastrectomy (OG); however, the influence of the surgical approach on initiation timing of adjuvant chemotherapy (AC) remains unclear. METHODS: This was a single-institutional retrospective observational study. Patients with pathological stage II/III gastric cancer undergoing LG with D2 lymphadenectomy (LG group: n = 74) were matched 1:1 with patients selected from 214 similar patients undergoing OG (OG group: n = 74), identically matching gender, age, pathological stage, and type of gastrectomy, and comparing AC initiation timing between the two groups. Factors associated with delayed initiation of AC were investigated in a multivariable analysis. RESULTS: AC was performed in 86.5% (LG) and 83.8% (OG) of patients (p = 0.64). The median time interval before AC was significantly shorter in the LG vs. OG group (5.7 vs. 6.6 weeks, respectively, p < 0.001), and significantly more patients received AC within 6 weeks (60.8% vs. 27.0%, p < 0.001). Independent factors associated with delayed initiation of AC (>6 weeks) were: morbidity (≥grade 3a; odds ratio (OR): 16.1, 95% confidence interval (CI): 1.86-143), open surgery (OR: 5.17, 95% CI: 2.50-13.1), and postoperative weight loss ≥ 8% (OR: 2.47, 95% CI: 1.07-5.71). CONCLUSIONS: LG may be associated with shorter intervals before AC. Postoperative morbidity should be reduced as much as possible.

Oncogenic signaling by Kit tyrosine kinase occurs selectively on the Golgi apparatus in gastrointestinal stromal tumors.

Gastrointestinal stromal tumors (GISTs) are caused by gain-of-function mutations in the Kit receptor tyrosine kinase. Most primary GIST patients respond to the Kit inhibitor imatinib, but this drug often becomes ineffective because of secondary mutations in the Kit kinase domain. The characteristic intracellular accumulation of imatinib-sensitive and -resistant Kit protein is well documented, but its relationship to oncogenic signaling remains unknown. Here, we show that in cancer tissue from primary GIST patients as well as in cell lines, mutant Kit accumulates on the Golgi apparatus, whereas normal Kit localizes to the plasma membrane (PM). In imatinib-resistant GIST with a secondary Kit mutation, Kit localizes predominantly on the Golgi apparatus. Both imatinib-sensitive and imatinib-resistant Kit (Kit(mut)) become fully auto-phosphorylated only on the Golgi and only if in a complex-glycosylated form. Kit(mut) accumulates on the Golgi during the early secretory pathway, but not after endocytosis. The aberrant kinase activity of Kit(mut) prevents its export from the Golgi to the PM. Furthermore, Kit(mut) on the Golgi signals and activates the phosphatidylinositol 3-kinase-Akt (PI3K-Akt) pathway, signal transducer and activator of transcription 5 (STAT5), and the Mek-Erk pathway. Blocking the biosynthetic transport of Kit(mut) to the Golgi from the endoplasmic reticulum inhibits oncogenic signaling. PM localization of Kit(mut) is not required for its signaling. Activation of Src-family tyrosine kinases on the Golgi is essential for oncogenic Kit signaling. These results suggest that the Golgi apparatus serves as a platform for oncogenic Kit signaling. Our study demonstrates that Kit(mut)'s pathogenicity is related to its mis-localization, and may offer a new strategy for treating imatinib-resistant GISTs.

Low-intensity pulsed ultrasound (LIPUS) treatment of cultured chondrocytes stimulates production of CCN family protein 2 (CCN2), a protein involved in the regeneration of articular cartilage: mechanism underlying this stimulation.

OBJECTIVE: CCN family protein 2/connective tissue growth factor (CCN2/CTGF) promotes cartilage regeneration in experimental osteoarthritis (OA) models. However, CCN2 production is very low in articular cartilage. The aim of this study was to investigate whether or not CCN2 was promoted by cultured chondrocytes treated with low-intensity pulsed ultrasound (LIPUS) and to clarify its mechanism. METHODS: Human chondrocytic cell line (HCS)-2/8, rat primary epiphyseal and articular cartilage cells, and Ccn2-deficient chondrocytes that impaired chondrocyte differentiation, were treated with LIPUS for 20 min at 3.0 MHz frequency and 60 mW/cm2 power. Expressions of chondrocyte differentiation marker mRNAs were examined by real-time PCR (RT-PCR) analysis from HCS-2/8 cells and Ccn2-deficient chondrocytes at 30 min and 1 h after LIPUS treatment, respectively. CCN2 production was examined by Western blotting after 5 h of LIPUS treatment. Moreover, Ca2+ influx was measured by using a Fluo-4 probe. RESULTS: The gene expression of chondrocyte differentiation markers and CCN2 production were increased in cultured chondrocytes treated with LIPUS. In addition, Ca2+ influx and phosphorylation of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK)1/2 were increased by LIPUS treatment, and the stability of TRPV4 and BKca channel mRNAs was decreased by siRNA against CCN2. Consistent with those findings, the LIPUS-induced the gene expressions of type II collagen (COL2a1) and Aggrecan (ACAN) observed in wild-type cells were not observed in the Ccn2-deficient chondrocytes. CONCLUSION: These data indicate that chondrocyte differentiation represented by CCN2 production was mediated via MAPK pathways activated by LIPUS-stimulated Ca2+ influx, which in turn was supported by the induced CCN2 molecules in articular chondrocytes.

Low-dose thymoglobulin as second-line treatment for steroid-resistant acute GvHD: an analysis of the JSHCT.

A nationwide retrospective study for the clinical outcomes of 99 patients who had received thymoglobulin at a median total dose of 2.5 mg/kg (range, 0.5-18.5 mg/kg) as a second-line treatment for steroid-resistant acute GvHD was conducted. Of the 92 evaluable patients, improvement (complete or partial response) was observed in 55 patients (60%). Multivariate analysis demonstrated that male sex and grade III and IV acute GvHD were associated with a lower improvement rate, whereas thymoglobulin dose (<2.0, 2.0-3.9 and ⩾4.0 mg/kg) was NS. Factors associated with significantly higher nonrelapse mortality included higher patient age (⩾50 years), grade IV acute GvHD, no improvement of GvHD and higher dose of thymoglobulin (hazard ratio, 2.55; 95% confidence interval, 1.34-4.85; P=0.004 for 2.0-3.9 mg/kg group and 1.79; 0.91-3.55; P=0.093 for ⩾4.0 mg/kg group). Higher dose of thymoglobulin was associated with a higher incidence of bacterial infections, CMV antigenemia and any additional infection. Taken together, low-dose thymoglobulin at a median total dose of 2.5 mg/kg provides a comparable response rate to standard-dose thymoglobulin reported previously, and <2.0 mg/kg thymoglobulin is recommended in terms of the balance between efficacy and adverse effects.

Insulin degludec versus insulin glargine, both once daily as add-on to existing orally administered antidiabetic drugs in insulin-naive Japanese patients with uncontrolled type 2 diabetes: subgroup analysis of a pan-Asian, treat-to-target phase 3 trial.

Insulin degludec (IDeg) is a novel basal insulin analogue with an ultralong duration of action that provides flat and stable reductions in blood glucose. The BEGIN ONCE ASIA trial was a phase 3 pan-Asian study examining the efficacy and safety of IDeg once daily (OD) versus insulin glargine (IGlar) OD in insulin-naive patients with type 2 diabetes (T2D). In this multinational, 26-week, open-label, treat-to-target trial, participants were randomised (2:1) to IDeg OD or IGlar OD, administered with one or more antidiabetic drugs (OAD) per os. Here we report the results from a post hoc analysis of Japanese patients enrolled in the trial [n = 133; 63.2 % male; mean age 61.0 years; mean body mass index 24.1 kg/m2; mean glycosylated haemoglobin (HbA1c) 8.5 %]. After 26 weeks, mean HbA1c levels were similar between the two groups [estimated mean treatment difference 0.11 %; 95 % confidence interval (CI) -0.09, 0.31]. Confirmed hypoglycaemia was reported in 53.4 and 61.4 % of patients in the IDeg OD and IGlar OD groups [rate ratio (IDeg/IGlar) 0.87; 95 % CI 0.51, 1.48]. Confirmed nocturnal hypoglycaemia was reported in 17.0 and 22.7 % of patients in the IDeg OD and IGlar OD groups, respectively [rate ratio (IDeg/IGlar) 0.50; 95 % CI 0.19, 1.32]. Adverse event rates were similar between treatment groups. Initiating insulin treatment with IDeg OD in Japanese patients with T2D, inadequately maintained on OADs and requiring treatment intensification, provided effective glycaemic control with low rates of confirmed and nocturnal confirmed hypoglycaemia.

A comparison of IDeg + IAsp versus IDet + IAsp in subjects with type 1 diabetes: subgroup analysis of Japanese subjects.

OBJECTIVE: Efficacy and safety were compared between insulin degludec (IDeg) once daily (OD) in combination with mealtime insulin aspart (IAsp) and insulin detemir (IDet) OD or twice daily (BID) in combination with mealtime IAsp in Japanese subjects with type 1 diabetes mellitus (T1DM). MATERIALS AND METHODS: This was a post hoc analysis of a multinational, controlled, open-label, parallel-group, treat-to-target trial that randomised adults [aged ≥18 years (≥20 years for Japan)] with T1DM for ≥12 months to basal IDeg OD (n = 124) or IDet (n = 62), both with mealtime bolus IAsp. The IDet dosing was adjusted to BID if required at ≥8 weeks. RESULTS: The estimated mean change in HbA1c from baseline to week 26 (the primary outcome measure) was -1.03 % in the IDeg + IAsp group and -0.94 % in the IDet + IAsp group (mean estimated treatment difference [ETD] -0.09; 95 % confidence interval [CI] -0.29, 0.10). Significantly greater reductions in fasting plasma glucose were observed in the IDeg + IAsp group (mean ETD -39.36 mg/dL; 95 % CI -56.04, -22.68). Both groups had similar rates of confirmed hypoglycaemia (59.9 and 59.2 per patient-year of exposure [PYE] with IDeg + IAsp and IDet + IAsp, respectively). Rates of nocturnal confirmed hypoglycaemia were significantly lower with IDeg + IAsp than with IDet + IAsp (5.2 vs 9.5 episodes per PYE; estimated ratio 0.48; 95 % CI 0.31, 0.75). Adverse event profiles were similar. CONCLUSION: The findings were consistent with those of the global trial population. IDeg + IAsp may represent an improvement on current standard treatments for Japanese patients with T1DM.

Comparison of insulin degludec with insulin detemir in type 1 diabetes: a 1-year treat-to-target trial.

The long-term safety and tolerability of insulin degludec (IDeg) was compared with that of insulin detemir (IDet), as basal treatment in participants with type 1 diabetes mellitus (T1DM). In the present multinational, 26-week core + 26-week extension, controlled, open-label, parallel-group trial, adults with T1DM were randomized to IDeg or IDet as basal insulin treatment combined with meal-time bolus insulin aspart. IDeg was administered once daily, whilst IDet was administered once or twice daily depending on patients' glycaemic control. After 1 year, IDeg provided a 33% lower rate of nocturnal hypoglycaemia compared with IDet: estimated rate ratio (IDeg : IDet) 0.67 [95% confidence interval (CI) 0.51; 0.88]; p < 0.05. IDeg improved glycated haemoglobin after 1 year of treatment, similarly to IDet, but IDeg also provided a significantly greater reduction in fasting plasma glucose compared with IDet: estimated difference (IDeg - IDet) -1.11 (95% CI -1.83; -0.40) mmol/l; p < 0.05. The present study confirmed the long-term safety and tolerability profile of IDeg in patients with T1DM. IDeg provided a lower risk of nocturnal confirmed hypoglycaemia than IDet.

Integration of humoral and cellular HLA-specific immune responses in cord blood allograft rejection.

In allo-stem cell transplantation (SCT), it is unclear whether donor-specific anti-HLA Abs (DSAs) can actually mediate graft rejection or if they are simply surrogate markers for the cellular immunity that causes graft rejection. Here, we first analyzed a case of cord blood allograft rejection in which DSA and cytotoxic T lymphocyte (CTL) specific for donor HLA-B*54:01 were detected at the time of graft rejection. Both the DSA and CTL inhibited colony formation by unrelated bone marrow mononuclear cells sharing HLA-B*54:01, suggesting that the humoral and cellular immune responses were involved in the graft rejection. Interestingly, the DSA and CTL were also detected in cryopreserved pre-transplant patient blood, raising a hypothesis that the presence of anti-HLA Abs could be an indicator for corresponding HLA-specific T cells. We then evaluated the existence of HLA-specific CD8(+) T cells in other patient blood specimens having anti-HLA class I Abs. Interferon-γ enzyme-linked immunospot assays clearly confirmed the existence of corresponding HLA-specific T-cell precursors in three of seven patients with anti-HLA Abs. In conclusion, our data demonstrate that integrated humoral and cellular immunity recognizing the same alloantigen of the donor can mediate graft rejection in DSA-positive patients undergoing HLA-mismatched allo-SCT. Further studies generalizing our observation are warranted.