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.

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.

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.

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.

[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.

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.

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.

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.

Hassall's corpuscles with cellular-senescence features maintain IFNα production through neutrophils and pDC activation in the thymus.

Hassall's corpuscles (HCs) are composed of cornifying, terminally differentiated medullary thymic epithelial cells (mTECs) that are developed under the control of Aire. Here, we demonstrated that HC-mTECs show features of cellular senescence and produce inflammatory cytokines and chemokines including CXCL5, thereby recruiting and activating neutrophils to produce IL-23 in the thymic medulla. We further indicated that thymic plasmacytoid dendritic cells (pDCs) expressing IL-23 receptors constitutively produced Ifna, which plays a role in single positive (SP) cell maturation, in an Il23a-dependent manner. Neutrophil depletion with anti-Ly6G antibody injection resulted in a significant decrease of Ifna expression in the thymic pDCs, suggesting that thymic neutrophil activation underlies the Ifna expression in thymic pDCs in steady state conditions. A New Zealand White mouse strain showing HC hyperplasia exhibited greater numbers and activation of thymic neutrophils and pDCs than B6 mice, whereas Aire-deficient B6 mice with defective HC development and SP thymocyte maturation showed significantly compromised numbers and activation of these cells. These results collectively suggested that HC-mTECs with cell-senescence features initiate a unique cell activation cascade including neutrophils and pDCs leading to the constitutive IFNα expression required for SP T-cell maturation in the thymic medulla.

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.

Combined effect of anti-high-mobility group box-1 monoclonal antibody and peramivir against influenza A virus-induced pneumonia in mice.

Human pandemic H1N1 2009 influenza virus causes significant morbidity and mortality with severe acute lung injury due to the excessive inflammatory reaction, even with neuraminidase inhibitor use. The anti-inflammatory effect of anti-high-mobility group box-1 (HMGB1) monoclonal antibody (mAb) against influenza pneumonia has been reported. In this study, we evaluated the combined effect of anti-HMGB1 mAb and peramivir against pneumonia induced by influenza A (H1N1) virus in mice. Nine-week-old male C57BL/6 mice were inoculated with H1N1 and treated with intramuscularly administered peramivir at 2 and 3 days post-infection (dpi). The anti-HMGB1 mAb or a control mAb was administered at 2, 3, and 4 dpi. Survival rates were assessed, and lung lavage and pathological analyses were conducted at 5 and 7 dpi. The combination of peramivir with the anti-HMGB1 mAb significantly improved survival rate whereas the anti-HMGB1 mAb alone did not affect virus proliferation in the lungs. This combination therapy also significantly ameliorated histopathological changes, neutrophil infiltration, and macrophage aggregation by inhibiting HMGB1, inflammatory cytokines, and oxidative stress. Fluorescence immunostaining showed that the anti-HMGB1 mAb inhibited HMGB1 translocation from type I alveolar epithelial cells. In summary, combining anti-HMGB1 with conventional anti-influenza therapy might be useful against severe influenza virus infection.

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.

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.

Maternal age-specific risk for trisomy 21 based on the clinical performance of NIPT and empirically derived NIPT age-specific positive and negative predictive values in Japan.

The data collected by nation-wide study of noninvasive prenatal genetic testing (NIPT) for trisomy 21 from 21,610 pregnant women with advanced maternal age in Japan were reported. Among 188 NIPT-positive cases, 180 cases were true positive. The incidence of aneuploidy according to maternal age was estimated using a state-space model. Although, the frequency of trisomy increased exponentially with maternal age as previously reported, the maternal age-specific risk for trisomy 21 that was based on the clinical performance of NIPT was lower than the predicted risk in previous Western cohorts based on the data from invasive prenatal testing (Bayesian two-sided tail-area probability P = 0.0156). The empirical positive predictive value (PPV) of NIPT is likely to turn out higher than that of the theoretical PPV calculated from the sensitivity/specificity of the test and the incidence of trisomy 21 from this study.

Correction: Maternal age-specific risk for trisomy 21 based on the clinical performance of NIPT and empirically derived NIPT age-specific positive and negative predictive values in Japan.

Since the advance online publication of this article, the authors of the above paper have noticed errors in the list of authors and affiliations. The article with correct author information now appears in this issue.

Correction: Nationwide survey for current clinical status of amniocentesis and maternal serum marker test in Japan.

Since the publication of this paper, the authors noticed that Yosuke Fujii was assigned to the incorrect affiliation. The affiliation information is provided correctly, above.

Prescription of Antidementia Drugs and Antipsychotics for Elderly Patients in Japan: A Descriptive Study Using Pharmacy Prescription Data.

BACKGROUND: Antipsychotics are commonly used for managing behavioral and psychological symptoms of dementia among elderly patients with dementia receiving antidementia drugs (ADDs). However, the use of antipsychotics among these patients has not been investigated since 3 ADDs were approved in 2011 in Japan. METHOD: We conducted a descriptive study using pharmacy prescription data and identified patients aged ≥65 years who were newly prescribed donepezil, memantine, rivastigmine, and galantamine between January 1, 2012, and September 30, 2014. We determined the proportion of antipsychotic prescription and the factors affecting antipsychotic prescription using multivariable Cox proportional hazard models. RESULT: Of 13 876 patients, 1705 were memantine users, and the proportion of antipsychotic prescription among them was the highest (11.1%). Adjusted hazard ratios for donepezil, rivastigmine, and galantamine were 0.66, 0.56, and 0.66, respectively, relative to that for memantine. CONCLUSION: Compared to other ADD users, new memantine users were most likely to be prescribed antipsychotics.

Epidemiology of Pediatric Acute Encephalitis/Encephalopathy in Japan.

We studied the etiology of pediatric acute encephalitis/encephalopathy (pAEE) using epidemiological data obtained from a nationwide survey in Japan. Two-step questionnaires were sent to the pediatric departments of hospitals throughout the country in 2007, querying the number of the cases during 2005-2006 as the first step, and asking for the details of clinical information as the second step. In all, 636 children with pAEE (age ≤ 15 years) were enrolled. For the known etiology of pAEE (63.5% of the total cases), 26 microbes and 2 clinical entities were listed, but the etiology of 36.5% remained unknown. Influenza virus (26.7%), exanthem subitum (12.3%), and rotavirus (4.1%) were the most common, and the incidence of pAEE peaked at the age of 1 year. This trend was common among all etiologies. Among the neurological symptoms observed at the onset of pAEE, seizures were observed more often in patients aged ≤ 3 years, although abnormal speech and behavior were also common in older children. Undesirable outcomes (death and neurological sequelae) occurred at high rates in patients with any known etiology other than mycoplasma. In conclusion, these findings provide comprehensive insight into pAEE in Japan.

Overall survival of first-line axitinib in metastatic renal cell carcinoma: Japanese subgroup analysis from phase II study.

Subgroup analyses of a randomized global phase II study of axitinib showed objective response rate of 66% and median progression-free survival of 27.6 months in treatment-naïve Japanese patients with metastatic renal cell carcinoma (RCC). This analysis evaluated overall survival (OS) and safety in 44 Japanese patients and compared the results with 169 non-Japanese patients. In addition, baseline characteristics for predictive factors that may influence OS in first-line metastatic RCC were explored in all patients using a Cox proportional hazard model. With median follow-up of 33 months, fewer than half (16 of 44) of the Japanese patients had died and median OS was not reached (95% confidence interval [CI], 38.8 months-not estimable), whereas 107 of 169 (63%) non-Japanese patients had died and median OS was 33.9 months (95% CI, 28.9-42.7). Estimated 1-year, 2-year and 3-year survival probability (95% CI) was 86.4% (76.2-96.5), 75.0% (62.2-87.8) and 68.2% (54.4-81.9), respectively, in Japanese patients, and was higher than that in non-Japanese patients (75.1% [68.4-81.8], 62.1% [54.5-69.7] and 47.2% [39.3-55.1], respectively). The updated safety analysis did not reveal any new adverse events of concern among Japanese or non-Japanese patients. The multivariate analysis identified that lower baseline Eastern Cooperative Oncology Group performance status, lower baseline tumor burden, and longer time from histopathological diagnosis to treatment were significant positive predictors of OS. The current analysis confirmed the clinical activity of axitinib in treatment-naïve Japanese patients with metastatic RCC, with an acceptable toxicity profile.

Phase I study of glasdegib (PF-04449913), an oral smoothened inhibitor, in Japanese patients with select hematologic malignancies.

The hedgehog signaling pathway regulates multiple morphogenetic processes during embryogenesis. Aberrant activation of the hedgehog pathway signal transduction in adult tissues is associated with the pathogenesis of hematologic malignancies and solid tumors. We report findings from an open-label, multicenter phase I trial of the selective, small-molecule hedgehog signaling inhibitor glasdegib (PF-04449913) in Japanese patients with select advanced hematologic malignancies. Glasdegib was administered as once-daily oral doses (25, 50 and 100 mg) in 28-day cycles after a lead-in dose on Day -5. The primary objectives were to determine first-cycle dose-limiting toxicities, safety, vital signs and laboratory test abnormalities. Secondary objectives included evaluation of pharmacokinetics, pharmacodynamics and preliminary evidence of clinical activity of glasdegib. No dose-limiting toxicities were noted in the 13 patients in the present study. All patients experienced at least one treatment-emergent, all-causality adverse event. The most frequent treatment-related adverse events (observed in ≥3 patients) were dysgeusia (n = 9), muscle spasms (n = 5), alopecia, decreased appetite (n = 4 each), and increased blood creatinine phosphokinase, constipation and diarrhea (n = 3 each). Two deaths occurred during the study and were deemed not to be treatment-related due to disease progression. Glasdegib demonstrated dose-proportional pharmacokinetics, marked downregulation of the glioma-associated transcriptional regulator GLI1 expression in normal skin, and evidence of preliminary clinical activity, although data are limited. Glasdegib was safe and well tolerated across the dose levels tested. It is confirmed that the 100-mg dose is safe and tolerable in Japanese patients, and this dose level will be examined in the future clinical trial.