Cost-utility analysis of second-line axicabtagene ciloleucel versus standard of care in Japan based on the ZUMA-7 trial.

Aim: To perform a cost-effectiveness analysis comparing axicabtagene ciloleucel (axi-cel) with standard of care (SoC; salvage chemoimmunotherapy, followed by high-dose therapy with autologous stem cell rescue for responders) for second-line (2L) treatment of adults with relapsed or refractory large B-cell lymphoma (r/r LBCL) in the pivotal ZUMA-7 trial data from a Japanese payer perspective. Materials & methods: A three-state partitioned survival model was utilized using population and clinical inputs from the ZUMA-7 trial data over a lifetime horizon. Results: Axi-cel was associated with greater incremental quality-adjusted life-years (2.06) and higher incremental total costs ($48,685.59/¥6.9 million) leading to an incremental cost-effectiveness ratio of $23,590.34/¥3.3 million per quality-adjusted life-years compared with SoC. Conclusion: Axi-cel is a cost-effective treatment alternative to SoC for 2L treatment of adults with r/r LBCL.

[Box: see text].

The usefulness of super-selective arterial spin labeling for postoperative evaluation of pediatric moyamoya disease: technical note.

Moyamoya disease is characterized by progressive internal carotid artery (ICA) occlusion. Extracranial-intracranial bypass surgery is effective, particularly in pediatric patients; imaging plays a crucial role in evaluating intracranial perfusion pre- and post-surgery. Arterial spin labeling (ASL) is a magnetic resonance technique employed for noninvasive, whole-brain perfusion assessment by magnetically labeling inflowing blood. However, ASL cannot evaluate the territories and development of each vessel perfusion compared with digital subtraction angiography (DSA). Recently, super-selective ASL (SS-ASL) has been developed, performing pinpoint labeling on a specific artery at a time, and offering a tomographic view that distinctly displays blood supply areas for each vessel. Unlike DSA, SS-ASL is noninvasive and can be repeatedly performed in pediatric patients. In conclusion, SS-ASL is useful for evaluating bypass development over time and understanding the pathophysiology of pediatric moyamoya disease.

Cost-effectiveness analysis 3L of axicabtagene ciloleucel vs tisagenlecleucel and lisocabtagene maraleucel in Japan.

Aim: Cost-effectiveness analysis (CEA) was performed to compare axicabtagene ciloleucel (axi-cel) with tisagenlecleucel (tisa-cel) and lisocabtagene (liso-cel) for treatment of relapsed or refractory large B-cell lymphoma in adult patients after ≥2 lines of therapy in Japan. Materials & methods: Cost-effectiveness analysis was conducted using the partition survival mixture cure model based on the ZUMA-1 trial and adjusted to the JULIET and TRANSCEND trials using matching-adjusted indirect comparisons. Results & conclusion: Axi-cel was associated with greater incremental life years (3.13 and 2.85) and incremental quality-adjusted life-years (2.65 and 2.24), thus generated lower incremental direct medical costs (-$976.29 [-¥137,657] and -$242.00 [-¥34,122]), compared with tisa-cel and liso-cel. Axi-cel was cost-effective option compared with tisa-cel and liso-cel from a Japanese payer's perspective.

[Box: see text].

T2 hypointense signal discovered incidentally at the posterior edge of the adenohypophysis on MRI: its prevalence and morphology and their relationship to age.

PURPOSE: T2 hypointense signal at the posterior edge of the adenohypophysis (T2HSPA) on magnetic resonance imaging (MRI) is incidentally encountered. We aimed to investigate the prevalence and morphology of T2HSPA and their relationship to age. METHODS: A total of 212 cases between 3 and 88 years old were examined. Sagittal T2-weighted image (T2WI) was evaluated for the presence of T2HSPA, which classified by its morphology into two types (belt-like or nodal). The Wilcoxon rank sum test and chi-square test were used to evaluate the differences between the groups. The T2HSPA was extracted by ImageJ software and measured as a cross-sectional area (CSA) quantitatively by threshold setting. We examined the relationship between CSA of T2HSPA and age, and Spearman's correlation coefficients were used for statistical analysis. RESULTS: Of the 212 cases, 80 (37.7%) were identified with T2HSPA. The groups with T2HSPA were significantly younger than the groups without it (p = .01). Groups with belt-like T2HSPA were significantly younger than the groups with nodal T2HSPA (p = .01). There was a weak negative correlation between CSA of T2HSPA and age (p = .02). CONCLUSION: T2HSPAs were incidentally detected in 37.7% of all cases, tended to be more common in younger cases, and their morphology was related to age. They seem to have little clinical significance as they tend to decrease in size with age.

Magnetic Resonance Spectroscopy in the Ventral Tegmental Area Distinguishes Responders to Suvorexant Prior to Treatment: A 4-Week Prospective Cohort Study.

Background: The ventral tegmental area (VTA; a dopaminergic nucleus) plays an important role in the sleep-wake regulation system including orexin system. In addition to neuronal activity, there is increasing evidence for an important role of glial cells (i.e., astrocytes and microglia) in these systems. The present study examined the utility of magnetic resonance spectroscopy (MRS) for detecting neural and/or glial changes in the VTA to distinguish responders from non-responders before treatment with the orexin receptor antagonist suvorexant. Methods: A total of 50 patients were screened and 9 patients were excluded. The remaining 41 patients with insomnia who have or not a psychiatric disease who were expected to receive suvorexant treatment were included in this study. We compared MRS signals in the VTA between responders to suvorexant and non-responders before suvorexant use. Based on previous reports, suvorexant responders were defined as patients who improved ≥3 points on the Pittsburgh Sleep Quality Index after 4 weeks of suvorexant use. MRS data included choline (reflects non-specific cell membrane breakdown, including of glial cells) and N-acetylaspartate (a decrease reflects neuronal degeneration). Results: Among 41 examined patients, 20 patients responded to suvorexant and 21 patients did not. By MRS, the choline/creatine and phosphorylcreatine ratio in the VTA was significantly high in non-responders compared with responders (p = 0.039) before suvorexant treatment. There was no difference in the N-acetylaspartate/creatine and phosphorylcreatine ratio (p = 0.297) between the two groups. Conclusions: Changes in glial viability in the VTA might be used to distinguish responders to suvorexant from non-responders before starting treatment. These findings may help with more appropriate selection of patients for suvorexant treatment in clinical practice. Further, we provide novel possible evidence for a relationship between glial changes in the VTA and the orexin system, which may aid in the development of new hypnotics focusing on the VTA and/or glial cells.

Merestinib monotherapy or in combination for japanese patients with advanced and/or metastatic cancer: A phase 1 study.

This phase 1, multi-center, nonrandomized, open-label, dose-escalation study consisted of Part A wherein merestinib 80 or 120 mg (40-mg tablets) was administered orally QD during a 28-day cycle to patients diagnosed with solid tumors and Part B wherein merestinib 80 mg (40-mg tablets) was administered orally QD, and cisplatin 25 mg/m2  + gemcitabine 1000 mg/m2 administered IV on Day 1 and Day 8 of a 21-day cycle (for a maximum of eight cycles) to patients diagnosed with biliary tract carcinoma (BTC). Nineteen patients were screened and 18 patients were (Part A, n = 10; Part B, n = 8) enrolled in the trial and received treatment. All patients in Parts A and B were from Japan and were within an age range of 43-73 years, with an ECOG PS of 0.1. No dose-limiting toxicity or deaths were experienced in the study. Dose-limiting toxicity equivalent toxicity of Grade 4 platelet count decreased (n = 1) and was observed in Part B. In Part A, treatment-related Grade ≥3 TEAEs were reported in one patient (PT: ALT increased and AST increased), while in Part B, five patients reported treatment-related Grade ≥3 TEAEs with four of the five patients reporting an event of neutrophil count decreased. No complete response was reported in either Part. One patient in Part B reported partial response while four patients in each part reported stable disease. Merestinib monotherapy was concluded to be tolerable in Japanese patients, and its combination with cisplatin and gemcitabine is a tolerable regimen for Japanese patients with BTC. Trial registration: NCT03027284 (ClinicalTrials.gov) registered on 23 January 2017.

A post-marketing observational study of ramucirumab in patients with gastric cancer in Japan.

BACKGROUND: This study evaluated the safety and effectiveness of ramucirumab monotherapy and combination therapy for advanced gastric cancer in the real-world setting. METHODS: This single-arm, prospective, multicenter, non-interventional, observational, post-marketing study was conducted in Japan from August 2015 to March 2019. Patients with unresectable advanced or recurrent gastric cancer and newly prescribed ramucirumab were followed for up to 12 months after first treatment. Data on adverse events and survival were collected via Electronic Data Capture. RESULTS: Of 687 enrolled patients, 658 were eligible for analysis. Most patients received either ramucirumab monotherapy (123/658; 18.7%) or ramucirumab plus paclitaxel combination therapy (528/658; 80.2%). The majority of patients reported ≥ 1 adverse events in both the combination therapy (any grade, 479/528; 90.7%; ≥ Grade 3, 321/528; 60.8%) and monotherapy groups (any grade, 77/123; 62.6%; ≥ Grade 3, 42/123; 34.2%). The most common any grade adverse events were neutropenia (combination: 49.6%; monotherapy: 8.9%), fatigue (combination: 19.5%; monotherapy: 13.8%), and decreased appetite (combination: 18.2%; monotherapy: 10.6%). Grade 5 adverse events were reported in 4 patients, including metastases to meninges, pneumonia aspiration, death, and gastric perforation; of these, gastric perforation was deemed treatment-related. Median survival time was 5.7 months (95% confidence interval: 4.1-6.8 months) following monotherapy and 11.0 months (95% confidence interval: 9.8-12.2 months) following combination therapy. CONCLUSIONS: This analysis adds to the limited data available on ramucirumab use in a real-world setting, demonstrating similar safety and effectiveness for ramucirumab in treating advanced gastric cancer in routine clinical practice in Japan to that of global clinical trials.

Comparison between turbo spin-echo and echo planar diffusion-weighted imaging of the female pelvis with 3T MRI.

BACKGROUND: Echo-planar imaging (EPI)-diffusion-weighted imaging (DWI) may take unclear image affected by susceptibility, geometric distortions and chemical shift artifacts. PURPOSE: To compare the image quality and usefulness of EPI-DWI and turbo spin echo (TSE)-DWI in female patients who required imaging of the pelvis. MATERIAL AND METHODS: All 57 patients were examined with a 3.0-T MR scanner. Both TSE- and EPI-DWI were performed with b values of 0 and 1000 s/mm2. We compared geometric distortion, the contrast ratio (CR) of the myometrium to the muscle and the apparent diffusion coefficient (ADC) values for the myometrium and lesion. Two radiologists scored the TSE- and EPI-DWI of each patient for qualitative evaluation. RESULTS: The mean percent distortion was significantly smaller with TSE- than EPI-DWI (p = 0.00). The CR was significantly higher with TSE- than EPI-DWI (p = 0.003). There was a significant difference in the ADC value for the uterus and lesions between the EPI- and TSE-DWI (p < 0.05). Finally, the ADC values of cancer were significantly different from those for the uterus and benign with both the two sequences (p < 0.05). The scores for ghosting artifacts were higher with TSE- than EPI-DWI (p = 0.019). But there were no significant differences between TSE- and EPI-DWI with regard to image contrast and overall image quality. CONCLUSION: TSE-DWI on the female pelvis by 3T MRI produces less distortion and higher CR than EPI-DWI, but there is no difference in contrast and image quality.

Characteristics of interstitial lung disease in patients from post-marketing data on metastatic breast cancer patients who received abemaciclib in Japan.

BACKGROUND: This study evaluated characteristics of patients treated with abemaciclib and diagnosed with interstitial lung disease (ILD), using 12-month post-marketing data from the real-world setting in Japan. METHODS: Spontaneous reports of adverse events in patients receiving abemaciclib were collected regularly from healthcare providers (HCPs) from November 30, 2018, to November 29, 2019. Detailed follow-up was requested on suspected ILD cases via questionnaires and/or interviews. Radiological images (when available) were reviewed by an ILD adjudication committee of specialists. The age distribution of patients prescribed abemaciclib in Japan was estimated based on insurance claims data. RESULTS: Of 4700 patients estimated to be exposed to abemaciclib, 82 cases of ILD were reported (46 serious, 13 fatal). Most (91%) had ≥ 1 symptom at diagnosis, commonly dyspnea/shortness of breath (59%), cough (44%), and/or fever (37%). The majority (68%) received steroid therapy (24 [56%] recovered/recovering; 5 [12%] not recovered; 13 [30%] deaths, 1 [2.3%] unknown). No specific imaging patterns or sites of predilection were identified, but a diffuse alveolar damage (DAD) pattern was observed at outcome in 3 of 4 evaluated fatal cases (16 in total evaluated). Features of fatal cases included advanced age, pre-existing interstitial change, and advanced Eastern Cooperative Oncology Group Performance Status. CONCLUSION: Advanced age and a DAD pattern were identified as potential risk factors for cases with poorer outcomes, as previously reported for drug-induced ILD. HCPs should consider the benefit-risk profile when prescribing abemaciclib, informing patients of risks and regularly monitoring treated patients to ensure early detection and treatment of ILD.

A phase 1 study of crenigacestat (LY3039478), the Notch inhibitor, in Japanese patients with advanced solid tumors.

Background This phase 1, single-center, nonrandomized, single-arm, open-label, dose-escalation study, evaluated the tolerability of crenigacestat, a γ-secretase inhibitor as an oral Notch inhibitor in Japanese patients with advanced solid tumors. Methods The study consisted of 2 dose levels of crenigacestat (25 mg and 50 mg), administered orally 3 times per week (TIW) over a 28-day cycle until disease progression, development of unacceptable toxicity, or any other discontinuation criteria were met. The primary objective was to evaluate the tolerability and determine the recommended dose of crenigacestat for Japanese patients. Secondary objectives were to characterize the safety and toxicity, the pharmacokinetic parameters, and to document any antitumor activity of crenigacestat. Results Eleven Japanese patients with advanced solid tumors were enrolled; 4 patients (median age of 64 years) received 25 mg of crenigacestat, and 7 patients (median age of 72 years) received 50 mg of crenigacestat. Median treatment duration was 8 weeks in the 25-mg treatment arm and 4 weeks in the 50-mg treatment arm. There were no dose-limiting toxicities or dose-limiting equivalent toxicities observed. None of the patients had a complete or partial response to the treatment. One patient (14.3%) with a desmoid tumor in the 50-mg treatment arm showed tumor size shrinkage of 22.4% and had stable disease for 22.5 months. Frequent (>14%) treatment-related-adverse events in both treatment arms included diarrhea, malaise, and vomiting. Conclusions Crenigacestat was tolerated in Japanese patients but with limited clinical activity. The recommended crenigacestat dose in Japanese patients is 50 mg TIW.Trial registration: NCT02836600 ( ClinicalTrials.gov ) registered on July 19, 2016.

Correction to: Phase 1 dose-escalation study of a novel oral PI3K/mTOR dual inhibitor, LY3023414, in patients with cancer.

The article Phase 1 dose-escalation study of a novel oral PI3K/mTOR dual inhibitor, LY3023414, in patients with cancer, written by Shunsuke Kondo, Masaomi Tajimi, Tomohiko Funai, Koichi Inoue, Hiroya Asou, Vinay Kumar Ranka, Volker Wacheck, Toshihiko Doi, was originally published electronically on the publisher's internet portal on 23 June 2020 without open access.

Phase 1 dose-escalation study of a novel oral PI3K/mTOR dual inhibitor, LY3023414, in patients with cancer.

LY3023414 is an oral, selective adenosine triphosphate-competitive inhibitor of class I phosphatidylinositol 3-kinase isoforms, mammalian target of rapamycin, and DNA-protein kinase in clinical development. We report results of a 3 + 3 dose-escalation Phase 1 study for twice-daily (BID) dosing of LY3023414 monotherapy in Japanese patients with advanced malignancies. The primary objective was to evaluate tolerability and safety of LY3023414. Secondary objectives were to evaluate pharmacokinetics and to explore antitumor activity. A total of 12 patients were enrolled and received 150 mg (n = 3) or 200 mg (n = 9) LY3023414 BID. Dose-limiting toxicities were only reported at 200 mg LY3023414 for 2 patients with Grade 3 stomatitis. Common treatment-related adverse events (AEs) across both the dose levels included stomatitis (75.0%), nausea (66.7%), decreased appetite (58.3%), diarrhea, and decreased platelet count (41.7%), and they were mostly mild or moderate in severity. Related AEs Grade ≥ 3 reported for ≥1 patient included anemia, stomatitis, hypophosphatemia, and hyperglycemia (n = 2, 16.7%). Two patients discontinued due to AEs (interstitial lung disease and stomatitis). No fatal events were reported. The pharmacokinetic profile of LY3023414 was characterized by rapid absorption and elimination. Five patients had a best overall response of stable disease (150 mg, n = 3; 200 mg, n = 2) for a 55.6% disease control rate. LY3023414 up to 200 mg BID is tolerable and safe in Japanese patients with advanced malignancies.

Kasumi leukemia cell lines: characterization of tumor genomes with ethnic origin and scales of genomic alterations.

Kasumi-1 has played an important role in an experimental model with t(8;21) translocation, which is a representative example of leukemia cell lines. However, previous studies using Kasumi-1 show discrepancies in the genome profile. The wide use of leukemia cell lines is limited to lines that are well-characterized. The use of additional cell lines extends research to various types of leukemia, and to further explore leukemia pathogenesis, which can be achieved by uncovering the fundamental features of each cell line with accurate data. In this study, ten Kasumi cell lines established in Japan, including five that were previously unknown, have been characterized by SNP microarray and targeted sequencing. SNP genotyping suggested that the genetic ancestry in four of the ten Kasumi cell lines was not classified as Japanese but covered several different east-Asian ethnicities, suggesting that patients in Japan are genetically diverse. TP53 mutations were detected in two cell lines with complex array profiles, indicating chromosomal instability (CIN). A quantitative assessment of tumor genomes at the chromosomal level was newly introduced to reveal total DNA sizes and Scales of Genomic Alterations (SGA) for each cell line. Kasumi-1 and 6 derived from relapsed phases demonstrated high levels of SGA, implying that the level of SGA would reflect on the tumor progression and could serve as an index of CIN. Our results extend the leukemia cellular resources with an additional five cell lines and provide reference genome data with ethnic identities for the ten Kasumi cell lines.

Automated determination of cardiac rest period on whole-heart coronary magnetic resonance angiography by extracting high-speed motion of coronary arteries.

PURPOSE: The aim of the present study was to develop an automated system for determining the cardiac rest period during whole-heart coronary magnetic resonance angiography (CMRA) examination. MATERIALS AND METHODS: Ten healthy male volunteers (25-51 years old, 50-77 beats/min heart rate) were enrolled in this prospective study. A motion area map was generated from a cine image set by extracting high-speed component of cardiac motion, and it was used to specify the rest period in the proposed CMRA. In conventional CMRA, the rest period was determined based on the visual inspection of cine images. Agreement of the start time, end time, and trigger time between the two methods was assessed by the Bland-Altman plot analysis. Two observers visually evaluated the quality of the curved planar reformation (CPR) image of the coronary arteries. RESULTS: The proposed method significantly prolonged the start time (mean systematic difference 37.7 ms, P < 0.05) compared with the conventional method. Good agreement was observed for the end time (mean systematic difference 8.9 ms) and trigger time (mean systematic difference -28.8 ms) between the two methods. A significantly higher image quality (P < 0.05) was provided for the left circumflex artery in the proposed CMRA (mean grading score 3.88) than in conventional CMRA (mean grading score 3.68). CONCLUSION: Our system enabled detection of the rest period automatically without operator intervention and demonstrated somewhat higher image quality compared with conventional CMRA. Its use may be useful to improve the imaging workflow for CMRA in clinical practice.

Dose-finding study of the checkpoint kinase 1 inhibitor, prexasertib, in Japanese patients with advanced solid tumors.

Prexasertib is a novel inhibitor of checkpoint kinase 1. The primary objective of this study was to evaluate prexasertib tolerability in Japanese patients with advanced solid tumors. This nonrandomized single-arm open-label phase 1 study of prexasertib consisted of 2 dose levels, 80 mg/m2 and the global-recommended dose based on a US study of 105 mg/m2 , administered intravenously once every 14 days (n = 6 for each dose). Transition to the higher dose proceeded if the frequency of dose-limiting toxicity observed in cycle 1 was <33% at the lower dose. Safety measures, pharmacokinetics and antitumor activity were assessed. A total of 12 patients were treated. Two patients, one in each dose group, experienced dose-limiting toxicities of febrile neutropenia, one grade 4 and the other grade 3; both patients recovered and continued the study treatment. The grade 4 treatment-emergent adverse events related to study treatment were neutropenia (6 patients [50.0%]), leukopenia (4 patients [33.3%]), and 1 instance each (8.3%) of anemia, febrile neutropenia and thrombocytopenia. Neutropenia was generally transient and reversible; 11 patients (91.7%) required granulocyte colony-stimulating factor treatment during the study. There were no discontinuations due to adverse events or deaths. The prexasertib pharmacokinetics displayed dose-independent and time-independent behavior across both dose levels, similar to the profile observed in the US-based phase 1 study. Eight patients had a best overall response of stable disease. These data are consistent with the known safety profile for prexasertib and confirm its tolerability in Japanese patients with advanced solid tumors.

Phase 1 study of abemaciclib, an inhibitor of CDK 4 and 6, as a single agent for Japanese patients with advanced cancer.

PURPOSE: To confirm the safety and tolerability, evaluate the pharmacokinetics (PK), and investigate the antitumor activity of abemaciclib in Japanese patients with advanced cancer. METHODS: We conducted a non-randomized, single-arm, open-label, dose-escalation phase 1 study of abemaciclib administered orally every 12 h (Q12H) on a 28-day cycle at doses of 100 mg (Cohort 1, n = 3), 150 mg (Cohort 2, n = 3), or 200 mg [Cohort 3, n = 6, maximum tolerated dose (MTD)]. Dose escalation was based on the frequency of dose-limiting toxicity (DLT). MTD, as established in the previous phase 1 study in non-Japanese patients, was the highest dose level at which <33 % of patients experienced DLT. RESULTS: Eleven of the 12 patients who received treatment with abemaciclib discontinued: 10 patients due to progressive disease, and 1 due to a DLT (Cohort 3, grade 2 nausea). Diarrhea, the most common treatment-emergent adverse event (AE), was managed supportively and did not require study treatment discontinuation. There were no drug-related serious AEs and no patients with corrected QT (QTc) > 480 ms or QTc change of >60 ms from baseline. The abemaciclib PK profile was characterized by slow absorption and high PK variability after single or repeated doses. Two patients, one with breast cancer and one with neuroendocrine tumor, experienced >30 % decrease in tumor size from baseline. CONCLUSIONS: In Japanese patients with advanced cancer, single-agent abemaciclib has an acceptable safety profile and demonstrates antitumor activity at a dose of 200 mg Q12H. These findings support ongoing development of abemaciclib for diverse populations with advanced cancer.

Dose-escalation study of tabalumab with bortezomib and dexamethasone in Japanese patients with multiple myeloma.

B-cell activating factor (BAFF) promotes the survival and adhesion of multiple myeloma (MM) cells. Tabalumab (LY2127399) is an anti-BAFF monoclonal antibody. This phase 1, multicenter, open-label, nonrandomized, dose-escalation study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of tabalumab in combination with bortezomib and dexamethasone in Japanese patients with relapsed or refractory MM (RRMM). Sixteen patients received intravenous i.v. tabalumab 100 mg (Cohort 1, n = 4) or i.v. tabalumab 300 mg (Cohort 2, n = 12) in combination with oral dexamethasone 20 mg/day and i.v. or s.c. bortezomib 1.3 mg/m(2) . All patients had treatment-emergent adverse events (TEAE) possibly related to study treatment; the most common TEAE were thrombocytopenia (81.3%), lymphopenia (43.8%) and increased alanine aminotransferase (43.8%). Two (20.0%) dose-limiting toxicities were observed, both in Cohort 2 (tabalumab 300 mg), which was below the predefined cutoff for tolerability (<33%). The pharmacokinetics of tabalumab were similar when bortezomib was coadministered i.v. versus s.c. The overall response rate was 56.3%, suggesting that the combined treatment was effective. In conclusion, combined treatment with these three agents was well tolerated in this population of Japanese patients with RRMM. The study was registered at www.clinicaltrials.gov (NCT01556438).

Phase 1 study of galunisertib, a TGF-beta receptor I kinase inhibitor, in Japanese patients with advanced solid tumors.

PURPOSE: Inhibition of transforming growth factor-beta receptor I (TGF-beta RI)-mediated signaling pathways blocks tumor growth and metastases in nonclinical studies. Galunisertib (LY2157299), a small molecule inhibitor of TGF-beta RI serine/threonine kinase, had antitumor effects with acceptable safety/tolerability in a first-in-human dose (FHD) study conducted mainly in Caucasian patients with glioma. In this nonrandomized, open-label, dose-escalation study, we assessed safety/tolerability, pharmacokinetics (PK), and tumor response in Japanese patients. METHODS: Patients with advanced and/or metastatic disease refractory were assigned sequentially to Cohort-1 (80 mg) or Cohort-2 (150 mg) of galunisertib, administered twice daily and treated using 2-week on, 2-week off treatment cycles. Dose escalation was guided by predefined PK criteria and dose-limiting toxicities (DLT). Safety assessments included treatment-emergent adverse events (TEAEs) and cardiac safety (ultrasound cardiography/Doppler imaging, electrocardiogram, chest computed tomography, and cardiotoxicity serum biomarkers). RESULTS: Twelve patients (Cohort-1, n = 3; Cohort-2, n = 9) were enrolled and the most common types of cancer were pancreatic (n = 5) and lung cancer (n = 3). Seven patients (Cohort-1, n = 2; Cohort-2, n = 5) experienced possibly galunisertib-related TEAEs. The most frequent related TEAEs were brain natriuretic peptide increased (n = 2), leukopenia (n = 2), and rash (n = 2). No cardiovascular toxicities or other DLTs were reported. PK profile of galunisertib was consistent with the FHD study. Maximum plasma concentration was reached within 2 h post-dose, and the mean elimination half-life was 9 h. CONCLUSIONS: Galunisertib had an acceptable tolerability and safety profile in Japanese patients with advanced cancers. CLINICATRIALS.GOV. IDENTIFIER: NCT01722825.

[Chemotherapy using gemcitabine hydrochloride for malignant lymphoma].

This report summarizes the use of gemcitabine for the treatment of malignant lymphoma. Gemcitabine is a deoxycytidine antagonist that has characteristics different from those of the deoxycytidine antagonist cytarabine(Ara-C). International guidelines based on the results of recent clinical studies recommend the use of gemcitabine as monotherapy and in combination therapy, particularly for relapsed and refractory malignant lymphomas. Clinical studies on gemcitabine monotherapy up to 2012 reported response rates of 51-75% for peripheral T -cell lymphoma and cutaneous T-cell lymphoma. Regarding combination therapy, the GDP regimen consisting of gemcitabine, dexamethasone, and cisplatin was associated with response rates of 62-70% for relapsed or refractory Hodgkin lymphoma and 45-53% for relapsed or refractory non-Hodgkin lymphoma, thereby displaying comparable efficacy to existing salvage chemotherapy regimens. The GDP regimen has a favorable safety profile and is also associated with favorable autologous transplantation rates, which suggests its potential as induction chemotherapy before autologous transplantation. Concerning adverse reactions requiring clinical caution, lung disorder was reported in 8 of 27 patients(30%)who received a regimen of gemcitabine in combination with bleomycin.

Haploinsufficiency of SAMD9L, an endosome fusion facilitator, causes myeloid malignancies in mice mimicking human diseases with monosomy 7.

Monosomy 7 and interstitial deletion of 7q (-7/7q-) are well-recognized nonrandom chromosomal abnormalities frequently found among patients with myelodysplastic syndromes (MDSs) and myeloid leukemias. We previously identified candidate myeloid tumor suppressor genes (SAMD9, SAMD9-like = SAMD9L, and Miki) in the 7q21.3 subband. We established SAMD9L-deficient mice and found that SAMD9L(+/-) mice as well as SAMD9L(-/-) mice develop myeloid diseases resembling human diseases associated with -7/7q-. SAMD9L-deficient hematopoietic stem cells showed enhanced colony formation potential and in vivo reconstitution ability. SAMD9L localizes in early endosomes. SAMD9L-deficient cells showed delays in homotypic endosome fusion, resulting in persistence of ligand-bound cytokine receptors. These findings suggest that haploinsufficiency of SAMD9L and/or SAMD9 gene(s) contributes to myeloid transformation.