Glasdegib with intensive/nonintensive chemotherapy in Japanese patients with untreated acute myeloid leukemia or high-risk myelodysplastic syndromes.

Glasdegib is a potent, selective, oral inhibitor of the hedgehog signaling pathway. In this phase I study, previously untreated Japanese patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes were treated with glasdegib (100 mg once daily) combinations: low-dose cytarabine (20 mg twice daily; cohort 1, n = 6; expansion cohort, n = 15); daunorubicin and cytarabine (60 mg/m2 i.v.; cohort 2, n = 6); or azacitidine (100 mg/m2 i.v.; cohort 3, n = 6). Patients, except cohort 2, were ineligible for intensive chemotherapy. The primary end-point was dose-limiting toxicity in cohorts 1-3 and disease-modifying response in the expansion cohort. Disease-modifying response rate was tested with the null hypothesis of 6.8%, which was set based on the results from the phase II BRIGHT AML 1003 study (NCT01546038). No dose-limiting toxicities were observed in cohorts 1 or 3; one patient in cohort 2 experienced a dose-limiting toxicity of grade 3 erythroderma. The most common grade ≥3 treatment-related adverse events were neutropenia and thrombocytopenia (66.7% each) in cohort 1 and thrombocytopenia (60.0%) in the expansion cohort. In the expansion cohort, the disease-modifying response rate was 46.7% (90% confidence interval, 24.4-70.0; p < 0.0001), with all patients achieving either a complete response or complete response with incomplete blood count recovery. Median overall survival was 13.9 months. In this study, the primary disease-modifying response end-point with glasdegib plus low-dose cytarabine was met. The study confirms the safety and efficacy of glasdegib plus low-dose cytarabine in Japanese patients with AML ineligible for intensive chemotherapy.

Decreased levels of histidine-rich glycoprotein and increased levels of high-mobility group box 1 are risk factors for refractory Kawasaki disease.

OBJECTIVES: Histidine-rich glycoprotein (HRG) and high-mobility group box 1 (HMGB1) regulate the activation of neutrophils and vascular endothelium. The aim of this study was to quantify HRG and HMGB1 levels in patients with Kawasaki disease (KD) and evaluate their use in the clinical management of KD. METHODS: This study was prospectively performed. Patients were divided into two groups and analysed depending on whether KD symptoms improved by Day 10 of illness. HRG, HMGB1, and other laboratory variables were measured before the first treatment in all cases and, in most cases, afterwards for assessing trends. RESULTS: In this prospective study, we enrolled 60 patients with KD and 48 healthy controls. The HRG level in the KD group was significantly lower than that in the healthy control group; HMGB1 levels showed no obvious differences. In the KD group, HRG levels were negatively correlated with white blood cell and neutrophil counts. In the poor responders and responders groups, a tendency for a decrease in HRG and HMGB1 levels, respectively, was observed from pretreatment to post-treatment. CONCLUSIONS: HRG and HMGB1 are related to the pathogenesis of KD; low HRG and high HMGB1 levels cause resistance against KD treatment.

Trends in Prescribing Antipsychotics for Children and Adolescents in Japan: A Descriptive Epidemiological Study Using a Large-Scale Pharmacy Dataset.

Little is known about antipsychotic prescription patterns among children and adolescents in Japan, particularly in outpatient settings. We investigated the prevalence and trends of antipsychotic prescription for outpatients aged ≤ 17 years receiving a first antipsychotic prescription from 2006 to 2012 based on a large-scale dispensation dataset. Measurements included age, sex, department of diagnosis and treatment, type of prescription (monotherapy or polytherapy), antipsychotic dosage, and concomitant psychotropic drugs. Of the 10,511 patients, 65.1% were aged 13-17 years, and 52.9% were males. Second-generation antipsychotic monotherapy prescriptions increased from 53.8% in 2006 to 78.3% in 2012. Risperidone was the most frequently prescribed antipsychotic, followed by aripiprazole and olanzapine. Approximately 25.0% of patients were prescribed an initial dose less than recommended. Second-generation antipsychotic monotherapy is currently the most frequent prescription pattern among outpatients aged ≤ 17 years receiving an initial antipsychotic prescription.

Safety and tolerability of bosutinib in patients with amyotrophic lateral sclerosis (iDReAM study): A multicentre, open-label, dose-escalation phase 1 trial.

Background: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease caused by the loss of motor neurons, and development of effective medicines is urgently required. Induced pluripotent stem cell (iPSC)-based drug repurposing identified the Src/c-Abl inhibitor bosutinib, which is approved for the treatment of chronic myelogenous leukemia (CML), as a candidate for the molecular targeted therapy of ALS. Methods: An open-label, multicentre, dose-escalation phase 1 study using a 3 + 3 design was conducted in 4 hospitals in Japan to evaluate the safety and tolerability of bosutinib in patients with ALS. Furthermore, the exploratory efficacy was evaluated using Revised ALS Functional Rating Scale (ALSFRS-R), predictive biomarkers including plasma neurofilament light chain (NFL) were explored, and single-cell RNA sequencing of iPSC-derived motor neurons was conducted. Patients, whose total ALSFRS-R scores decreased by 1-3 points during the 12-week, received escalating doses starting from 100 mg quaque die (QD) up to 400 mg QD based on dose-limiting toxicity (DLT) occurrence, and all participants who received one dose of the study drug were included in the primary analysis. This trial is registered with ClinicalTrials.gov, NCT04744532, as Induced pluripotent stem cell-based Drug Repurposing for Amyotrophic Lateral Sclerosis Medicine (iDReAM) study. Findings: Between March 29, 2019 and May 7, 2021, 20 patients were enrolled, 13 of whom received bosutinib treatment and 12 were included in the safety and efficacy analyses. No DLTs were observed up to 300 mg QD, but DLTs were observed in 3/3 patients of the 400 mg QD cohort. In all patients receiving 100 mg-400 mg, the prevalent adverse events (AEs) were gastrointestinal AEs in 12 patients (92.3%), liver function related AEs in 7 patients (53.8%), and rash in 3 patients (23.1%). The safety profile was consistent with that known for CML treatment, and ALS-specific AEs were not observed. A subset of patients (5/9 patients) was found to respond well to bosutinib treatment over the 12-week treatment period. It was found that the treatment-responsive patients could be distinguished by their lower levels of plasma NFL. Furthermore, single-cell RNA sequencing of iPSC-derived motor neurons revealed the pathogenesis related molecular signature in patients with ALS showing responsiveness to bosutinib. Interpretation: This is the first trial of a Src/c-Abl inhibitor, bosutinib, for patients with ALS. The safety and tolerability of bosutinib up to 300 mg, not 400 mg, in ALS were described, and responsiveness of patients on motor function was observed. Since this was an open-label trial within a short period with a limited number of patients, further clinical trials will be required. Funding: AMED and iPS Cell Research Fund.

Clinical impact of physician staffing transition in intensive care units: a retrospective observational study.

BACKGROUND: Intensivists play an essential role in improving the outcomes of critically ill patients in intensive care units (ICUs). The transition of ICU physician staffing from low-intensity ICUs (elective intensivist or no intensivist consultation) to high-intensity ICUs (mandatory intensivist consultation or a closed ICU) improves clinical outcomes. However, whether a transition from high-intensity to low-intensity ICU staffing affects ICU outcomes and quality of care remains unknown. METHODS: A retrospective observational study was conducted to examine the impact of high- versus low-intensity staffing models on all-cause mortality in a suburban secondary community hospital with 400 general beds and 8 ICU beds. The ICU was switched from a high-intensity staffing model (high-former period) to low-intensity staffing in July 2019 (low-mid period) and then back to high-intensity staffing in March 2020 (high-latter period). Patients admitted from the emergency department, general ward, or operating room after emergency surgery were enrolled in these three periods and compared, balancing the predicted mortality and covariates of the patients. The primary outcome was all-cause mortality analyzed using hazard ratios (HRs) from Cox proportional hazards regression. An interrupted time-series analysis (ITSA) was also conducted to evaluate the effects of events (level change) and time. RESULTS: There were 962 eligible admissions, of which 251, 213, and 498 occurred in the high-former, low-mid, and high-latter periods, respectively. In the matched group (n = 600), the all-cause mortality rate comparing the high-former period with the low-mid period showed an HR of 0.88 [95% confidence interval (CI), 0.56, 1.39; p = 0.58] and that comparing the high-latter period with the low-mid period showed an HR of 0.84 [95% CI, 0.54, 1.30; p = 0.43]. The result for comparison between the three periods was p = 0.80. ITSA showed level changes of 4.05% [95% CI, -13.1, 21.2; p = 0.63] when ICU staffing changed from the high-former to the low-mid period and 1.35% [95% CI, -13.8, 16.5; p = 0.86] when ICU staffing changed from the low-mid to the high-latter period. CONCLUSION: There was no statistically significant difference in all-cause mortality among the three ICU staffing periods. This study suggests that low-intensity ICU staffing might not worsen clinical outcomes in the ICU in a medium-sized community hospital. Multiple factors, including the presence of an intensivist, other medical staff, and practical guidelines, influence the prognosis of critically ill patients.

Relationship between Onset of Sliding Behavior and Size of Droplet on Inclined Solid Substrate.

Whether a droplet slides or not on inclined solid surface is mainly influenced by a balance between the adhesion force at contact area and the gravitational force exerted on the droplet. Especially as the adhesion force is a key parameter for the determination of the sliding behavior of droplets. The adhesion force is mainly estimated by experimental observation for the sliding motion of the droplet. However, at present it is unknown whether the adhesion force is a constant value regardless of the droplet size or not. In the present study, focused on the onset for sliding of water-ethanol binary mixture droplets on inclined solid surface, experimental investigation on the sliding droplets is performed by considering the droplet volumes ranging from 7 to 600 µL in order to understand the effect of the size of the droplet on the adhesive property. The results are discussed using the existing analytical models. From the results, it is found that the adhesion force increases in the case of large droplet volume, while the force reaches constant value in the case of small droplet volume. This difference is related to the degree of the droplet shape deformation, which leads to a change in the contact angle. Finally, a simple empirical model for the adhesion force including the size effect is proposed.

[Early endoscopic diagnosis can save lives and reduce the extent of colon resection for acute fulminant amebic colitis: a case report with review].

A man in his 50s was referred to the hospital with fever, right lower abdominal pain, and bloody diarrhea. Based on computed tomography images and characteristic varioliform erosions observed during the colonoscopic examination, the patient was diagnosed with fulminant amebic colitis. Intravenous metronidazole was administered immediately. After symptom improvement, a second colonoscopic examination revealed inflammation localized to the right hemicolon. A right colectomy was performed on the 75th hospital day, and the patient was discharged without further problems. Prompt antiamebic therapy based on early endoscopic diagnosis was effective in quelling colonic inflammation in a life-threatening case of acute fulminant amebic colitis. Moreover, colonoscopic reexamination was useful in determining the extent of inflammation and minimizing colon resection.

Rapid detection of single nucleotide polymorphisms using the MinION nanopore sequencer: a feasibility study for perioperative precision medicine.

INTRODUCTION: Precision medicine is a phrase used to describe personalized medical care tailored to specific patients based on their clinical presentation and genetic makeup. However, despite the fact that several single nucleotide polymorphisms (SNPs) have been reported to be associated with increased susceptibility to particular anesthetic agents and the occurrence of perioperative complications, genomic profiling and thus precision medicine has not been widely applied in perioperative management. METHODS: We validated six SNP loci known to affect perioperative outcomes in Japanese patients using genomic DNA from saliva specimens and nanopore sequencing of each SNP loci to facilitate allele frequency calculations and then compared the nanopore results to those produced using the conventional dideoxy sequencing method. RESULTS: Nanopore sequencing reads clustered into the expected genotypes in both homozygous and heterozygous cases. In addition, the nanopore sequencing results were consistent with those obtained using conventional dideoxy sequencing and the workflow provided reliable allele frequency estimation, with a total analysis time of less than 4 h. CONCLUSION: Thus, our results suggest that nanopore sequencing is a promising and versatile tool for SNP genotyping, allowing for rapid and feasible risk prediction of perioperative outcomes.

Ten-year outcome of unilateral leg replantation after bilateral lower leg amputation following traumatic injury: A case report.

The absolute indications for lower limb replantation are not unequivocally established; rather, this procedure is still challenging and controversial. We report a case of a young male who underwent bilateral leg amputation, followed by unilateral replantation. The patient demonstrated good 10-year outcomes. A 23-year-old man had both of his lower legs crushed by heavy machinery that fell from the back of a truck, leading to amputation of bilateral lower limbs. Although bilateral amputation was recommended due to severe contusion on both sides, the patient and his family strongly requested replantation of the right leg, and surgery was started approximately 3 h after the injury. In addition to the emergency replantation, six surgeries were performed thereafter. Five months after the first surgery, the patient was fitted with a left lower leg prosthesis and started gait training. He was discharged 8 months later. Ten years after the replantation, the patient is satisfied with his leg. He has a normal gait with a prosthesis and has integrated into society with no functional deficit. There are still no clear standards for replantation after leg amputation, and individual decisions must be made based on the severity of the injury and the patient's general condition. In this case, we respected the patient's strong will to preserve the right leg and decided on the treatment plan. As a result, the patient was highly satisfied, and the spared right leg facilitated the patient's physical and mental recovery.

Avelumab in Combination with Axitinib as First-Line Treatment in Patients with Advanced Hepatocellular Carcinoma: Results from the Phase 1b VEGF Liver 100 Trial.

INTRODUCTION: Combining an immune checkpoint inhibitor with a targeted antiangiogenic agent may leverage complementary mechanisms of action for the treatment of advanced/metastatic hepatocellular carcinoma (aHCC). Avelumab is a human anti-PD-L1 IgG1 antibody with clinical activity in various tumor types; axitinib is a selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1, 2, and 3. We report the final analysis from VEGF Liver 100 (NCT03289533), a phase 1b study evaluating safety and efficacy of avelumab plus axitinib in treatment-naive patients with aHCC. METHODS: Eligible patients had confirmed aHCC, no prior systemic therapy, ≥1 measurable lesion, Eastern Cooperative Oncology Group performance status ≤1, and Child-Pugh class A disease. Patients received avelumab 10 mg/kg intravenously every 2 weeks plus axitinib 5 mg orally twice daily until progression, unacceptable toxicity, or withdrawal. Endpoints included safety and investigator-assessed objective response per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and modified RECIST (mRECIST) for HCC. RESULTS: Twenty-two Japanese patients were enrolled and treated with avelumab plus axitinib. The minimum follow-up was 18 months as of October 25, 2019 (data cutoff). Grade 3 treatment-related adverse events (TRAEs) occurred in 16 patients (72.7%); the most common (≥3 patients) were hypertension (n = 11 [50.0%]), palmar-plantar erythrodysesthesia syndrome (n = 5 [22.7%]), and decreased appetite (n = 3 [13.6%]). No grade 4 TRAEs or treatment-related deaths occurred. Ten patients (45.5%) had an immune-related AE (irAE) of any grade; 3 patients (13.6%) had an infusion-related reaction (IRR) of any grade, and no grade ≥3 irAE and IRR were observed. The objective response rate was 13.6% (95% CI: 2.9-34.9%) per RECIST 1.1 and 31.8% (95% CI: 13.9-54.9%) per mRECIST for HCC. CONCLUSION: Treatment with avelumab plus axitinib was associated with a manageable toxicity profile and showed antitumor activity in patients with aHCC.

Estimation of the Number of General Anesthesia Cases Based on a Series of Nationwide Surveys on Twitter during COVID-19 Pandemic in Japan: A Statistical Analysis.

Background and objectives: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread to more than 200 countries. In light of this situation, the Japanese Government declared a state of emergency in seven regions of Japan on 7 April 2020 under the provisions of the law. The medical care delivery system has been under pressure. Although various surgical societies have published guidelines on which to base their surgical decisions, it is not clear how general anesthesia has been performed and will be performed in Japan. Materials and Methods: One of the services provided by the social network service Twitter is a voting function-Twitter Polls-through which anonymous surveys were conducted. We analyzed the results of a series of surveys 17 times over 22 weeks on Twitter on the status of operating restrictions using quadratic programming to solve the mathematical optimizing problem, and public data provided by the Japanese Government were used to estimate the current changes in the number of general anesthesia performed in Japan. Results: The minimum number of general anesthesia cases per week was estimated at 67.1% compared to 2015 on 27 April 2020. The timeseries trend was compatible with the results reported by the Japanese Society of Anesthesiologists (correlation coefficient r = 0.69, p < 0.001). Conclusions: The number of general anesthesia was reduced up to two-thirds during the pandemic of COVID-19 in Japan and was successfully quantitatively estimated using a quick questionnaire on Twitter.

Predicting study duration in clinical trials with a time-to-event endpoint.

In event-driven clinical trials comparing the survival functions of two groups, the number of events required to achieve the desired power is usually calculated using the Freedman formula or the Schoenfeld formula. Then, the sample size and the study duration derived from the required number of events are considered; however, their combination is not uniquely determined. In practice, various combinations are examined considering the enrollment speed, study duration, and the cost of enrollment. However, effective methods for visually representing their relationships and evaluating the uncertainty in study duration are insufficient. We developed a graphical approach for examining the relationship between sample size and study duration. To evaluate the uncertainty in study duration under a given sample size, we also derived the probability density function of the study duration and a method for updating the probability density function according to the observed number of events (ie, information time). The proposed methods are expected to improve the operation and management of clinical trials with a time-to-event endpoint.

Critical Care Demand and Intensive Care Supply for Patients in Japan with COVID-19 at the Time of the State of Emergency Declaration in April 2020: A Descriptive Analysis.

Background and objectives: The coronavirus disease 2019 (COVID-19) pandemic is overwhelming Japan's intensive care capacity. This study aimed to determine the number of patients with COVID-19 who required intensive care and to compare the numbers with Japan's intensive care capacity. Materials and Methods: Publicly available datasets were used to obtain the number of confirmed patients with COVID-19 undergoing mechanical ventilation and extracorporeal membrane oxygenation (ECMO) between 15 February and 19 July 2020 to determine and compare intensive care unit (ICU) and attending bed needs for patients with COVID-19, and to estimate peak ICU demands in Japan. Results: During the epidemic peak in late April, 11,443 patients (1.03/10,000 adults) had been infected, 373 patients (0.034/10,000 adults) were in ICU, 312 patients (0.028/10,000 adults) were receiving mechanical ventilation, and 62 patients (0.0056/10,000 adults) were under ECMO per day. At the peak of the epidemic, the number of infected patients was 651% of designated beds, and the number of patients requiring intensive care was 6.0% of ICU beds, 19.1% of board-certified intensivists, and 106% of designated medical institutions in Japan. Conclusions: The number of critically ill patients with COVID-19 continued to rise during the pandemic, exceeding the number of designated beds but not exceeding ICU capacity.

Pulmonary vein thrombosis and cerebral infarction after video-assisted thoracic surgery of the left upper lobe: a case series.

BACKGROUND: Pulmonary vein thrombosis (PVT) and cerebral infarction are rare but critical complications after video-assisted thoracic surgery (VATS). CASE PRESENTATION: We experienced two cases of massive middle cerebral artery infarction after VATS for the left upper lobe. Although the precise source of their embolus was never identified, both cases were clinically suspected PVT. Unfortunately, case 2 died because of progressive cerebral herniation. We decided to perform contrast-enhanced computed tomography routinely after VATS for the left upper lobectomy (VATS-LUL) after these cases. Case 3, a 79-year-old female patient, underwent VATS-LUL for lung cancer. She developed PVT in the stump of the left upper pulmonary vein on postoperative day 4. Anti-coagulation therapy was begun immediately and continued for 3 months. She was free of complications 7 months after the operation. CONCLUSION: PVT and cerebral infarction may occur after VATS-LUL. Appropriate postoperative management is required to recognize PVT and to prevent life-threatening stroke.

Avelumab plus axitinib vs sunitinib for advanced renal cell carcinoma: Japanese subgroup analysis from JAVELIN Renal 101.

The phase 3 JAVELIN Renal 101 trial of avelumab + axitinib vs sunitinib in patients with treatment-naive advanced renal cell carcinoma (RCC) demonstrated significantly improved progression-free survival (PFS) and higher objective response rate (ORR) with the combination vs sunitinib. Japanese patients enrolled in the study (N = 67) were randomized to receive avelumab + axitinib (N = 33) or sunitinib (N = 34); 67% vs 59% had PD-L1+ tumors (≥1% of immune cells) and 6%/64%/27% vs 6%/82%/12% had International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) favorable/intermediate/poor risk status. In patients who received avelumab + axitinib vs sunitinib, median PFS (95% confidence interval [CI]) was not estimable (8.1 months, not estimable) vs 11.2 months (1.6 months, not estimable) (hazard ratio [HR], 0.49; 95% CI, 0.152, 1.563) in patients with PD-L1+ tumors and 16.6 months (8.1 months, not estimable) vs 11.2 months (4.2 months, not estimable) (HR, 0.66; 95% CI, 0.296, 1.464) in patients irrespective of PD-L1 expression. Median overall survival (OS) has not been reached in either arm in patients with PD-L1+ tumors and irrespective of PD-L1 expression. ORR (95% CI) was 60.6% (42.1%, 77.1%) vs 17.6% (6.8%, 34.5%) in patients irrespective of PD-L1 expression. Common treatment-emergent adverse events (all grade; grade ≥3) in each arm were hand-foot syndrome (64%; 9% vs 71%; 9%), hypertension (55%; 30% vs 44%; 18%), hypothyroidism (55%; 0% vs 24%; 0%), dysgeusia (21%; 0% vs 56%; 0%) and platelet count decreased (3%; 0% vs 65%; 32%). Avelumab + axitinib was efficacious and tolerable in treatment-naive Japanese patients with advanced RCC, which is consistent with results in the overall population.

Induced pluripotent stem cell-based Drug Repurposing for Amyotrophic lateral sclerosis Medicine (iDReAM) study: protocol for a phase I dose escalation study of bosutinib for amyotrophic lateral sclerosis patients.

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive and severe neurodegenerative disease caused by motor neuron death. There have as yet been no fundamental curative medicines, and the development of a medicine for ALS is urgently required. Induced pluripotent stem cell (iPSC)-based drug repurposing identified an Src/c-Abl inhibitor, bosutinib, as a candidate molecular targeted therapy for ALS. The objectives of this study are to evaluate the safety and tolerability of bosutinib for the treatment of patients with ALS and to explore the efficacy of bosutinib on ALS. This study is the first clinical trial of administered bosutinib for patients with ALS. METHODS AND ANALYSIS: An open-label, multicentre phase I dose escalation study has been designed. The study consists of a 12-week observation period, a 1-week transitional period, a 12-week study treatment period and a 4-week follow-up period. After completion of the transitional period, subjects whose total ALS Functional Rating Scale-Revised (ALSFRS-R) score decreased by 1-3 points during the 12-week observation period receive bosutinib for 12 weeks. Three to six patients with ALS are enrolled in each of the four bosutinib dose levels (100, 200, 300 or 400 mg/day) to evaluate the safety and tolerability under a 3+3 dose escalation study design. Dose escalation and maximum tolerated dose are determined by the safety assessment committee comprising oncologists/haematologists and neurologists based on the incidence of dose-limiting toxicity in the first 4 weeks of the treatment at each dose level. A recommended phase II dose is determined by the safety assessment committee on completion of the 12-week study treatment in all subjects at all dose levels. The efficacy of bosutinib is also evaluated exploratorily using ALS clinical scores and biomarkers. ETHICS AND DISSEMINATION: This study received full ethical approval from the institutional review board of each participating site. The findings of the study will be disseminated in peer-reviewed journals and at scientific conferences. TRIAL REGISTRATION NUMBER: UMIN000036295; Pre-results, JMA-IIA00419; Pre-results.

Inotuzumab ozogamicin versus standard of care in Asian patients with relapsed/refractory acute lymphoblastic leukemia.

Inotuzumab ozogamicin (InO) is a targeted treatment for adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). InO was previously studied in INO-VATE, an international, open-label, randomized phase 3 trial comparing InO against standard of care (SoC). In the present subgroup analysis, we evaluated outcomes in the 55 Asian patients who were randomized in INO-VATE (31 InO and 24 SoC). Complete remission (CR) or CR with incomplete hematologic recovery (CRi) was achieved in 22/31 patients treated with InO versus 5/24 treated with SoC. In the InO arm, more of the patients achieving CR/CRi were minimal residual disease (MRD)-negative (17/22 versus 1/5), and more patients proceeded directly to hematopoietic stem cell transplantation (15/31 versus 3/24). Median overall survival for the respective arms was 5.8 versus 3.9 months (hazard ratio 0.67; 97.5% CI 0.28, 1.62). In the safety analysis (n = 51), the most common adverse events were hematologic. Sinusoidal obstruction syndrome was reported in five InO patients and one SoC patient. In conclusion, Asian patients with relapsed or refractory B-cell ALL experienced improved efficacy with InO versus SoC, with an efficacy and safety profile consistent with results of the overall INO-VATE population.Clinical trial registration: ClinicalTrials.gov identifier: NCT01564784.

Observational Needs for Improving Ocean and Coupled Reanalysis, S2S Prediction, and Decadal Prediction.

Developments in observing system technologies and ocean data assimilation (DA) are symbiotic. New observation types lead to new DA methods and new DA methods, such as coupled DA, can change the value of existing observations or indicate where new observations can have greater utility for monitoring and prediction. Practitioners of DA are encouraged to make better use of observations that are already available, for example, taking advantage of strongly coupled DA so that ocean observations can be used to improve atmospheric analyses and vice versa. Ocean reanalyses are useful for the analysis of climate as well as the initialization of operational long-range prediction models. There are many remaining challenges for ocean reanalyses due to biases and abrupt changes in the ocean-observing system throughout its history, the presence of biases and drifts in models, and the simplifying assumptions made in DA solution methods. From a governance point of view, more support is needed to bring the ocean-observing and DA communities together. For prediction applications, there is wide agreement that protocols are needed for rapid communication of ocean-observing data on numerical weather prediction (NWP) timescales. There is potential for new observation types to enhance the observing system by supporting prediction on multiple timescales, ranging from the typical timescale of NWP, covering hours to weeks, out to multiple decades. Better communication between DA and observation communities is encouraged in order to allow operational prediction centers the ability to provide guidance for the design of a sustained and adaptive observing network.

Adherence and Concomitant Medication Use among Patients on Warfarin Therapy: Insight from a Large Pharmacy Dispensing Database in Japan.

Warfarin is a drug used for anticoagulation management, with a narrow therapeutic range and multiple drug-drug interactions. Adherence and proper use of concomitant medication are thus fundamental to the efficacy and safety of warfarin therapy. In 2012, we retrospectively analyzed data from three large-scale pharmacy chains in Japan. We included all adults (≥ 20 years old) with at least one record of warfarin dispensation. We examined patient demographic data, adherence as measured by medication possession ratio (MPR), and co-dispensation focusing on the number of concomitant dispensations and concurrent use of medications that increase bleeding risk. Thresholds of underadherence and overadherence were set at <0.9 and >1.1, considering the narrow therapeutic window. We reviewed 443007 warfarin dispensation records of 71340 individuals (median age, 73 years; 62% male). The MPR was 1.0 (interquartile range: 0.96-1.0), and underadherence and overadherence was found in 16.3 and 1.9% of individuals, respectively. The median number of co-dispensed drugs was eight at each pharmacy encounter, which did not differ by age group. Drugs associated with a high bleeding risk were dispensed in 40.0% of encounters and accounted for 16.4% of all co-dispensed drugs. In summary, we found optimal overall adherence, as assessed by MPR, among our Japanese study population, even when defining a strict cut-off value. However, polypharmacy was common in all age groups and medications with a high bleeding risk profile were often co-dispensed with warfarin. Future research addressing how these dispensation patterns affect patient outcome is warranted.

Patients with metastatic renal cell carcinoma who benefit from axitinib dose titration: analysis from a randomised, double-blind phase II study.

BACKGROUND: A prospective, randomised phase II study demonstrated clinical benefit of axitinib dose titration in a subset of treatment-naïve patients treated with axitinib for metastatic renal cell carcinoma. This analysis evaluated patient baseline characteristics that may impact overall survival (OS) with axitinib dose titration. METHODS: Following a 4-week lead-in period during which all patients received axitinib 5 mg twice-daily (bid); patients meeting the predefined randomisation criteria were randomly assigned to receive axitinib 5 mg bid plus either axitinib or placebo titration. In exploratory analyses, patients were grouped into those who achieved OS ≥24 versus < 24 months, and compared their baseline characteristics with Fisher's exact test or Cochran-Armitage trend exact test, with a 5% significance level. Potential predictive baseline characteristics associated with effect of axitinib dose titration on OS were investigated using a Cox proportional hazard model. RESULTS: Overall, 112 patients were randomised. Three of 56 patients receiving axitinib titration were censored; of the remaining 53, 33 (62%) achieved OS ≥24 months versus 20 (38%) with OS < 24 months. Patients with OS ≥24 vs. < 24 months, respectively, had significantly fewer metastatic sites (≤2 metastases: 52% vs. 10%; ≥3 metastases: 48% vs. 90%), fewer lymph node (45% vs. 75%) or liver (15% vs. 45%) metastases, higher haemoglobin level (i.e., ≥ lower limit of normal: 67% vs. 25%) at baseline, lower neutrophil (≤ upper limit of normal, 97% vs. 75%) and platelet (≤ upper limit of normal, 82% vs. 50%) levels at baseline and ≥ 1 year between histopathological diagnosis and treatment (64% vs. 15%). The primary reason for treatment discontinuation in both OS groups was disease progression. The frequency of toxicity-related discontinuation was comparable between the 2 groups, indicating that it was not a factor for a shorter OS. The multivariate analysis showed that ≥1 year from histopathological diagnosis to treatment and baseline haemoglobin level equal or greater than lower limit of normal were significant covariates associated with favourable OS in patients receiving axitinib titration. CONCLUSIONS: The current analyses identified potentially predictive factors that could help selecting patients who may benefit from axitinib dose titration. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT00835978. Registered prospectively, February 4, 2009.