Serum Laminin γ2 Monomer as a Diagnostic and Predictive Biomarker for Hepatocellular Carcinoma.

BACKGROUNDS AND AIMS: Structural dynamics of basement membrane components are still to be elucidated in the process of hepatocarcinogenesis. We evaluated the characteristics of HCC expressing laminin γ2 monomer (LG2m), a basement membrane component not detected in normal tissues, for HCC diagnosis. We further determined whether elevated serum LG2m is a risk factor for HCC development in patients with chronic hepatitis C (CHC). APPROACH AND RESULTS: In HCC cell lines, LG2m was expressed in alpha-fetoprotein (AFP)-negative, CD90-positive cells characterized by highly metastatic natures. Using 14 cell lines and 258 HCC microarray data, we identified that LG2m gene signature was associated with Hoshida's S1/Boyault's G3 molecular subclasses with poor prognosis, which could not be recognized by AFP. Serum LG2m was assessed in 24 healthy donors, 133 chronic liver disease patients, and 142 HCC patients, and sensitivity and specificity of LG2m testing for HCC diagnosis were 62.9% and 70.5%, respectively (cutoff, 30 pg/mL). We evaluated the consequence of LG2m elevation in two independent HCC cohorts (n = 47 and n = 81), and LG2m-high HCC showed poor prognosis with later development of distant organ metastasis (cutoff, 60 pg/mL). LG2m was slightly elevated in a subset of CHC patients, and Kaplan-Meier analysis indicated a high incidence of HCC (n = 70). For validation, we enrolled 399 CHC patients with sustained virological response (SVR) as a multicenter, prospective study, and serum LG2m elevation correlated with a high incidence of HCC in the CHC patients with SVR (P < 0.0001). CONCLUSIONS: LG2m is a predictive biomarker for the development of metastatic HCC. Elevated serum LG2m is an HCC risk in CHC patients who have achieved SVR.

Phase I/II clinical trial of high-dose [131I] meta-iodobenzylguanidine therapy for high-risk neuroblastoma preceding single myeloablative chemotherapy and haematopoietic stem cell transplantation.

PURPOSE: Paediatric high-risk neuroblastoma has poor prognosis despite modern multimodality therapy. This phase I/II study aimed to determine the safety, dose-limiting toxicity (DLT), and efficacy of high-dose 131I-meta-iodobenzylguanidine (131I-mIBG) therapy combined with single high-dose chemotherapy (HDC) and haematopoietic stem cell transplantation (HSCT) in high-risk neuroblastoma in Japan. METHODS: Patients received 666 MBq/kg of 131I-mIBG and single HDC and HSCT from autologous or allogeneic stem cell sources. The primary endpoint was DLT defined as adverse events associated with 131I-mIBG treatment posing a significant obstacle to subsequent HDC. The secondary endpoints were adverse events/reactions, haematopoietic stem cell engraftment and responses according to the Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST 1.1) and 123I-mIBG scintigraphy. Response was evaluated after engraftment. RESULTS: We enrolled eight patients with high-risk neuroblastoma (six females; six newly diagnosed and two relapsed high-risk neuroblastoma; median age, 4 years; range, 1-10 years). Although all patients had adverse events/reactions after high-dose 131I-mIBG therapy, we found no DLT. Adverse events and reactions were observed in 100% and 25% patients during single HDC and 100% and 12.5% patients during HSCT, respectively. No Grade 4 complications except myelosuppression occurred during single HDC and HSCT. The response rate according to RECIST 1.1 was observed in 87.5% (7/8) in stable disease and 12.5% (1/8) were not evaluated. Scintigraphic response occurred in 62.5% (5/8) and 37.5% (3/8) patients in complete response and stable disease, respectively. CONCLUSION: 131I-mIBG therapy with 666 MBq/kg followed by single HDC and autologous or allogeneic SCT is safe and efficacious in patients with high-risk neuroblastoma and has no DLT. TRIAL REGISTRATION NUMBER: jRCTs041180030. NAME OF REGISTRY: Feasibility of high-dose iodine-131-meta-iodobenzylguanidine therapy for high-risk neuroblastoma preceding myeloablative chemotherapy and haematopoietic stem cell transplantation (High-dose iodine-131-meta-iodobenzylguanidine therapy for high-risk neuroblastoma). URL OF REGISTRY: https://jrct.niph.go.jp/en-latest-detail/jRCTs041180030 . DATE OF ENROLMENT OF THE FIRST PARTICIPANT TO THE TRIAL: 12/01/2018.

Development of novel diagnostic system for pancreatic cancer, including early stages, measuring mRNA of whole blood cells.

Pancreatic ductal adenocarcinoma (PDAC) is the most life-threating disease among all digestive system malignancies. We developed a blood mRNA PDAC screening system using real-time detection PCR to detect the expression of 56 genes, to discriminate PDAC from noncancer subjects. We undertook a clinical study to assess the performance of the developed system. We collected whole blood RNA from 53 PDAC patients, 102 noncancer subjects, 22 patients with chronic pancreatitis, and 23 patients with intraductal papillary mucinous neoplasms in a per protocol analysis. The sensitivity of the system for PDAC diagnosis was 73.6% (95% confidence interval, 59.7%-84.7%). The specificity for noncancer volunteers, chronic pancreatitis, and patients with intraductal papillary mucinous neoplasms was 64.7% (54.6%-73.9%), 63.6% (40.7%-82.8%), and 47.8% (26.8%-69.4%), respectively. Importantly, the sensitivity of this system for both stage I and stage II PDAC was 78.6% (57.1%-100%), suggesting that detection of PDAC by the system is not dependent on the stage of PDAC. These results indicated that the screening system, relying on assessment of changes in mRNA expression in blood cells, is a viable alternative screening strategy for PDAC.

Randomized placebo-controlled double-blind phase II study of zaltoprofen for patients with diffuse-type and unresectable localized tenosynovial giant cell tumors: a study protocol.

BACKGROUND: A tenosynovial giant cell tumor (TGCT) is a locally aggressive benign neoplasm arising from intra- or extra-articular tissue. Diffuse TGCT (D-TGCT) most commonly develops in the knee, followed by the hip, ankle, elbow, and shoulder. Surgical removal is the only effective treatment option for the patients. However, a local recurrence rate as high as 47% has been reported. Recently, we revealed that zaltoprofen, a nonsteroidal anti-inflammatory drug possessing the ability to activate peroxisome proliferator-activated receptor gamma (PPARγ), can inhibit the proliferation of TGCT stromal cells via PPARγ. PPARγ is a ligand-activated transcription factor that belongs to the nuclear hormone receptor superfamily. It plays an important role in the differentiation of adipocytes from precursor cells and exhibits antitumorigenic effects on certain malignancies. Therefore, we are conducting this investigator-initiated clinical trial to evaluate whether zaltoprofen is safe and effective for patients with D-TGCT or unresectable localized TGCT (L-TGCT). METHODS: This study is a randomized, placebo-controlled, double-blind, multicenter trial to evaluate the safety and efficacy of zaltoprofen for patients with D-TGCT or L-TGCT. For the treatment group, zaltoprofen 480 mg/day will be administered for 48 weeks; the placebo group will receive similar dosages without zaltoprofen. Twenty participants in each group are needed in this trial (40 participants total). The primary outcome is the progression-free rate at 48 weeks after treatment administration. "Progression" is defined as any serious events (1. Repetitive joint swelling due to hemorrhage, 2. Joint range of motion limitation, 3. Invasion of adjacent cartilage or bone, 4. Severe joint space narrowing, 5. Increase in tumor size) requiring surgical interventions. We hypothesize that the zaltoprofen group will have a higher progression-free rate compared to that of the placebo group at 48 weeks. DISCUSSION: This is the first study to evaluate the efficacy of zaltoprofen in patients with D-TGCT or unresectable L-TGCT. We believe that the results of this trial will validate a novel treatment option, zaltoprofen, to stabilize disease progression for TGCT patients. TRIAL REGISTRATION: University Hospital Medical Information Network (UMIN) Clinical Trials Registry ( UMIN000025901 ) registered on 4/01/2017.

Safety and efficacy of sustained release of basic fibroblast growth factor using gelatin hydrogel in patients with critical limb ischemia.

As a form of therapeutic angiogenesis, we sought to investigate the safety and efficacy of a sustained-release system of basic fibroblast growth factor (bFGF) using biodegradable gelatin hydrogel in patients with critical limb ischemia (CLI). We conducted a phase I-IIa study that analyzed 10 CLI patients following a 200-µg intramuscular injection of bFGF-incorporated gelatin hydrogel microspheres into the ischemic limb. Primary endpoints were safety and transcutaneous oxygen pressure (TcO2) at 4 and 24 weeks after treatment. During the follow-up, there was no death or serious procedure-related adverse event. After 24 weeks, TcO2 (28.4 ± 8.4 vs. 46.2 ± 13.0 mmHg for pretreatment vs after 24 weeks, p < 0.01) showed significant improvement. Regarding secondary endpoints, the distance walked in 6 min (255 ± 105 vs. 318 ± 127 m, p = 0.02), the Rutherford classification (4.4 ± 0.5 vs. 3.1 ± 1.4, p = 0.02), the rest pain scale (1.7 ± 1.0 vs. 1.2 ± 1.3, p = 0.03), and the cyanotic scale (2.0 ± 1.1 vs. 0.9 ± 0.9, p < 0.01) also showed improvement. The blood levels of bFGF were within the normal range in all patients. A subanalysis of patients with arteriosclerosis obliterans (n = 7) or thromboangiitis obliterans (Buerger's disease) (n = 3) revealed that TcO2 had significantly improved in both subgroups. TcO2 did not differ between patients with or without chronic kidney disease. The sustained release of bFGF from biodegradable gelatin hydrogel may offer a safe and effective form of angiogenesis for patients with CLI.

Measuring motivation for medical treatment: confirming the factor structure of the Achievement Motivation Index for Medical Treatment (AMI-MeT).

BACKGROUND: Developments in chemotherapy have led to changes in cancer care in Japan, with the government promoting a transition to outpatient chemotherapy. This requires patients and their families to participate more actively in treatment than in the past. However, it remains unclear how patients' motivation for medical treatment affects clinical consultations with their physicians. To investigate this, we developed a psychological index called the Achievement Motive Index for Medical Treatment (AMI-MeT), which comprises self-derived achievement motivation (AMS) and achievement motivation derived from others (AMO). However, its factor structure has not yet been confirmed in populations other than healthy university students. Thus, the aims of this study were to confirm the factor structure of the AMI-MeT in other groups and to determine the convergent and divergent validity of the AMI-MeT. METHODS: The AMI-MeT was administered to university students (n = 414), apparently healthy workers (n = 154), and cancer patients (n = 51). Multi-group confirmatory factor analysis was conducted and the mean scores of the AMI-MeT were compared between the groups. Correlations between the AMI-MeT and the Self-Construal Scale, comprising independent self-construal (IndSC) and interdependent self-construal (InterSC) subscales, were investigated in another group of students (n = 335). RESULTS: The multi-group confirmatory factor analysis supported a two-factor structure of the AMI-MeT: the weak invariance model was the best fit for the data. The mean scores of the AMI-MeT in apparently healthy workers and cancer patients were significantly higher than that in students (P < .01). The correlation analysis revealed that AMS scores were associated with IndSC scores (r = .25, P < .01) and AMO scores with InterSC scores (r = .30, P < .01). CONCLUSION: The two-factor model of the AMI-MeT was deemed appropriate for all three groups, and the subscales of the AMI-MeT successfully reflected the self and other dimensions. The AMI-MeT appears to be an effective tool for measuring medical treatment motivation, making it useful in participant observational research on medical consultations for Japanese cancer treatment.

A pilot study of regenerative therapy using controlled release of recombinant human fibroblast growth factor for patients with pre-collapse osteonecrosis of the femoral head.

PURPOSE: We evaluated the safety and clinical outcomes of a single local administration of gelatin hydrogel impregnated with recombinant human fibroblast growth factor (rhFGF)-2 for the treatment of the precollapse stage of osteonecrosis of the femoral head (ONFH). METHODS: Patients with ONFH (precollapse stage ≤2) received a single local administration of 800 µg of rhFGF-2-impregnated gelatin hydrogel and were followed up for one year. The surgery was performed using a minimally invasive technique involving a 1-cm skin incision, and walking was allowed from day one postoperatively. The primary outcomes included occurrence of adverse events and complications. The secondary outcomes included changes in the Harris hip scores, visual analog scale for pain scores, University of California, Los Angeles (UCLA) activity scores, and radiological images. RESULTS: We included ten patients, of which five experienced 14 adverse events, including one complication from spinal anesthesia. However, patients completely recovered from all adverse events. The mean clinical scores significantly improved by one year postoperatively compared with the pre-operative scores (before vs. after: visual analog score for pain, 21.2 vs. 5.3 mm; UCLA activity score, 5.5 vs. 6.6; Harris hip score, 81.0 vs. 96.9 points). There was only one case of femoral head collapse; however, this occurred in a hip with extensive necrosis. Stage progression and collapse did not occur in the other nine cases. Computed tomography confirmed bone regeneration in the femoral heads. CONCLUSIONS: Clinical application of rhFGF-2-impregnated gelatin hydrogel for patients with precollapse ONFH was feasible and safe.

Clinical effects of ghrelin on gastrointestinal involvement in patients with systemic sclerosis.

The majority of patients with systemic sclerosis (SSc) have gastrointestinal (GI) tract involvement, but therapies using prokinetic agents are usually unsatisfactory. Ghrelin stimulates gastric motility in healthy human volunteers. In this study, we investigated whether ghrelin could improve gastric emptying in patients with gastrointestinal symptoms due to SSc. The study was performed in a randomized, double-blind, placebo-controlled crossover fashion on two occasions. Ten SSc patients with GI tract involvement received an infusion of either ghrelin (5.0 µg/kg) or saline, and gastric emptying rate was evaluated by ¹³C-acetic acid breath test. Gastric emptying was significantly accelerated by ghrelin infusion in patients with SSc (ghrelin vs. saline: 43.3 ± 11.4 min vs. 53.4 ± 5.4 min, P=0.03). No serious adverse effects were observed. Our results suggest that ghrelin might represent a new therapeutic approach for GI tract involvement in patients with SSc.

Evaluation of 68Ga-PSMA-11 PET/CT: a Phase 1 clinical study in Japanese patients with primary, recurrent, or suspected recurrent prostate cancer.

BACKGROUND: Prostate-specific membrane antigen (PSMA)-targeted radiopharmaceuticals allow whole-body imaging to detect prostate cancer (PC). Positron emission tomography imaging using gallium-68 (68Ga)-PSMA-11 has been shown to have a favorable safety and tolerability profile and high diagnostic performance. The study evaluates the safety and pharmacokinetics of 68Ga-PSMA-11 in Japanese patients with primary, recurrent, or suspected recurrent prostate cancer. METHODS: This single arm study enrolled Japanese patients with primary PC (n = 3), suspected recurrent PC following radical prostatectomy (n = 4), or suspected recurrent PC following radical radiotherapy (n = 3). All patients received a single intravenous dose of 68Ga-PSMA-11 2.0 MBq/kg (±10%) followed by PSMA PET imaging and safety and pharmacokinetic evaluations. Based on the blood concentrations of 68Ga-PSMA-11 and the radioactivity distribution rate in each organ/tissue, the absorbed doses in major organs/tissues and the whole-body effective dose were calculated by the Medical Internal Radiation Dose method. RESULTS: Ten patients were enrolled. Mean age was 73.3 ± 4.8 years, and median prostate-specific antigen was 8.250 ng/mL. Five patients (50%) experienced a total of 6 adverse events, and no grade ≥ 2 adverse events or serious adverse events were reported. No clinically significant changes in vital signs, haematology parameters, or blood chemistry or ECG abnormalities were observed. The estimated whole body effective dose of 68Ga-PSMA-11 (mean ± standard deviation) was 2.524 × 10-2 ± 2.546 × 10-3 mSv/MBq. Time to maximum concentration (1.16 × 10-4 ± 1.3 × 10-5% ID/mL) in whole blood was 2.15 ± 0.33 min. CONCLUSIONS: 68Ga-PSMA-11 has a favourable safety and tolerability profile in Japanese patients with primary, recurrent, or suspected recurrent prostate cancer, which is comparable to previous observations in other populations.

An international survey of physicians regarding clinical trials: a comparison between Kyoto University Hospital and Seoul National University Hospital.

BACKGROUND: International clinical trials are now rapidly expanding into Asia. However, the proportion of global trials is higher in South Korea compared to Japan despite implementation of similar governmental support in both countries. The difference in clinical trial environment might influence the respective physicians' attitudes and experience towards clinical trials. Therefore, we designed a questionnaire to explore how physicians conceive the issues surrounding clinical trials in both countries. METHODS: A questionnaire survey was conducted at Kyoto University Hospital (KUHP) and Seoul National University Hospital (SNUH) in 2008. The questionnaire consisted of 15 questions and 2 open-ended questions on broad key issues relating to clinical trials. RESULTS: The number of responders was 301 at KUHP and 398 at SNUH. Doctors with trial experience were 196 at KUHP and 150 at SNUH. Among them, 12% (24/196) at KUHP and 41% (61/150) at SUNH had global trial experience. Most respondents at both institutions viewed clinical trials favorably and thought that conducting clinical trials contributed to medical advances, which would ultimately lead to new and better treatments. The main reason raised as a hindrance to conducting clinical trials was the lack of personnel support and time. Doctors at both university hospitals thought that more clinical research coordinators were required to conduct clinical trials more efficiently. KUHP doctors were driven mainly by pure academic interest or for their desire to find new treatments, while obtaining credits for board certification and co-authorship on manuscripts also served as motivation factors for doctors at SNUH. CONCLUSIONS: Our results revealed that there might be two different approaches to increase clinical trial activity. One is a social level approach to establish clinical trial infrastructure providing sufficient clinical research professionals. The other is an individual level approach that would provide incentives to encourage doctors to participate in and conduct clinical trials.

A clinical assessment of portable point-of-care testing for quick cortisol assay during adrenal vein sampling.

This study assessed the clinical performance of point-of-care testing (POCT) for quick cortisol assay (QCA) during adrenal vein sampling (AVS) using a newly invented portable quantitative assay instrument. An observational study was conducted prospectively at two centres in Japan. Forty-eight patients with primary aldosteronism considered for adrenalectomy were enrolled in this study and underwent AVS. Three basal adrenal vein samples from each adrenal vein and two from the inferior vena cava were collected sequentially. The cortisol concentration of adrenal vein samples was measured by routine method and QCA. A total of 338 adrenal vein samples were analysed from 250 sites to determine AVS success or failure. The distribution of turnaround time of the QCA for AVS success or failure followed a normal distribution with an average of 20.5 min. A positive correlation between the routine method and QCA was observed regarding cortisol concentration or selectivity index. No significant difference between the two methods was observed regarding the success rate of AVS. Using the routine method as a reference, the sensitivity and specificity of AVS success or failure were 99.1% (210/212) and 81.6% (31/38), respectively. Easy, quick, portable, and precise POCT-QCA demonstrated its compatibility with routine methods regarding clinical performance.

Sonic hedgehog myocardial gene therapy: tissue repair through transient reconstitution of embryonic signaling.

Sonic hedgehog (Shh) is a crucial regulator of organ development during embryogenesis. We investigated whether intramyocardial gene transfer of naked DNA encoding human Shh (phShh) could promote a favorable effect on recovery from acute and chronic myocardial ischemia in adult animals, not only by promoting neovascularization, but by broader effects, consistent with the role of this morphogen in embryogenesis. After Shh gene transfer, the hedgehog pathway was upregulated in mammalian fibroblasts and cardiomyocytes. This resulted in preservation of left ventricular function in both acute and chronic myocardial ischemia by enhanced neovascularization, and reduced fibrosis and cardiac apoptosis. Shh gene transfer also enhanced the contribution of bone marrow-derived endothelial progenitor cells to myocardial neovascularization. These data suggest that Shh gene therapy may have considerable therapeutic potential in individuals with acute and chronic myocardial ischemia by triggering expression of multiple trophic factors and engendering tissue repair in the adult heart.

A use-case analysis of Clinical Data Interchange Standards Consortium/Study Data Tabulation Model in academia in an investigator-initiated clinical trial.

Submitting data compliant with the Clinical Data Interchange Standards Consortium (CDISC) standards is mandatory for new drug applications (NDAs). The standards set by CDISC are widely adopted in the pharmaceutical business world. Introduction of CDISC standards in academia can be necessary to reduce labor, resolve the shortage of data managers in academia, and gain new knowledge through standardized data accumulation. However, the introduction of CDISC standards has not progressed in communities within the academia that do not apply for NDAs. Therefore, herein, we created study data tabulation model (SDTM)-compliant datasets within the academia, without outsourcing, to reduce costs associated with investigator-initiated clinical trials. First, we input data from paper case report forms (CRFs) into an electronic data capture system with minimal function for paper CRFs, "Ptosh," which is compatible with SDTM. Then, we developed a generic program to convert data exported from Ptosh into fully SDTM-compliant datasets. The consistency was then verified with an SDTM validator, Pinnacle21 Community V3.0.1 (P21C). This resulted in generation of SDTM datasets, resolving all "Rejects" in P21C, thereby achieving the required quality level. Although Ptosh directly exports data in SDTM format, manual mapping of items on CRFs to SDTM variables prepared in Ptosh is necessary. SDTM mapping requires extensive knowledge and skills, and it was assumed that mapping is challenging for the staff without in-depth knowledge of CDISC standards and datasets. Therefore, for CDISC dissemination in academia, it is crucial to secure the staff, time, and funding to acquire the knowledge.

Severe Skin Toxicity Caused by Sequential Anti-PD-1 Antibody and Alectinib in Non-small-cell Lung Cancer: A Report of Two Cases and a Literature Review.

Immune checkpoint inhibitors (ICIs) have demonstrated marked efficacy in some cancer patients, but they may cause various severe immune-related adverse events. Alectinib is a second-generation anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitor (TKI) approved for ALK-rearranged non-small-cell lung cancer (NSCLC). Alectinib is said to be safer than other TKIs. We conducted an investigator-initiated trial of alectinib, which also has RET kinase-inhibitory activity, against RET-rearranged NSCLC. Two RET-rearranged NSCLC patients experienced severe skin toxicity with alectinib after first undergoing anti-PD-1 antibody treatment with an ICI. These findings suggest that we should carefully follow patients for adverse effects of targeted drugs following ICI treatment.

Randomized placebo-controlled double-blind phase II study of zaltoprofen for patients with diffuse-type and unresectable localized tenosynovial giant cell tumors: The REALIZE study.

Background: A tenosynovial giant cell tumor (TGCT) is a locally aggressive benign neoplasm arising from intra- or extra-articular tissue, categorized as localized (L-TGCT, solitary lesion) and diffuse (D-TGCT, multiple lesions) TGCT. Surgical excision is the mainstay of the treatment, and a high local recurrence rate of approximately 50% has been reported. We focused on zaltoprofen, a nonsteroidal anti-inflammatory drug that can activate peroxisome proliferator-activated receptor gamma (PPARγ) and inhibit the proliferation of TGCT stromal cells. Therefore, we conducted a randomized trial to evaluate the safety and effectiveness of zaltoprofen in patients with D-TGCTs or unresectable L-TGCTs. Methods: This randomized, placebo-controlled, double-blind, multicenter trial evaluated the safety and efficacy of zaltoprofen. In the treatment group, zaltoprofen (480 mg/day) was administered for 48 weeks; the placebo group received similar dosages without zaltoprofen. The primary outcome was progression-free rate (PFR) 48 weeks after treatment administration. Disease progression was defined as the following conditions requiring surgical intervention: 1) repetitive joint swelling due to hemorrhage, 2) joint range of motion limitation, 3) invasion of the adjacent cartilage or bone, 4) severe joint space narrowing, and 5) increased tumor size (target lesion). Results: Forty-one patients were allocated to the zaltoprofen (n=21) or placebo (n=20) groups. The PFR was not significant between the zaltoprofen group and the placebo group at 48 weeks (84.0% and 90.0%, respectively; p=0.619). The mean Japanese Orthopedic Association knee score significantly improved from baseline to week 48 in the zaltoprofen group (85.38 versus 93.75, p=0.027). There was a significant difference between the values at 48 weeks of placebo and zaltoprofen group (p=0.014). One severe adverse event (grade 3 hypertension) was observed in the zaltoprofen group. Discussion: This is the first study to evaluate the efficacy and safety of zaltoprofen in patients with TGCT. No significant differences in PFR were observed between the groups at 48 weeks. Physical function significantly improved after zaltoprofen treatment. The safety profile of zaltoprofen was acceptable. This less invasive and safer treatment with zaltoprofen, compared to surgical removal, could be justified as a novel approach to treating TGCT. Further analysis of long-term administration of zaltoprofen should be considered in future studies. Clinical Trial Registration: University Hospital Medical Information Network Clinical Trials Registry, identifier (UMIN000025901).

Safety and pharmacokinetics of recombinant human hepatocyte growth factor (rh-HGF) in patients with fulminant hepatitis: a phase I/II clinical trial, following preclinical studies to ensure safety.

BACKGROUND: Hepatocyte growth factor (HGF) stimulates hepatocyte proliferation, and also acts as an anti-apoptotic factor. Therefore, HGF is a potential therapeutic agent for treatment of fatal liver diseases. We performed a translational medicine protocol with recombinant human HGF (rh-HGF), including a phase I/II study of patients with fulminant hepatitis (FH) or late-onset hepatic failure (LOHF), in order to examine the safety, pharmacokinetics, and clinical efficacy of this molecule. METHODS: Potential adverse effects identified through preclinical safety tests with rh-HGF include a decrease in blood pressure (BP) and an increase in urinary excretion of albumin. Therefore, we further investigated the effect of rh-HGF on circulatory status and renal toxicity in preclinical animal studies. In a clinical trial, 20 patients with FH or LOHF were evaluated for participation in this clinical trial, and four patients were enrolled. Subjects received rh-HGF (0.6 mg/m2/day) intravenously for 12 to 14 days. RESULTS: We established an infusion method to avoid rapid BP reduction in miniature swine, and confirmed reversibility of renal toxicity in rats. Although administration of rh-HGF moderately decreased BP in the participating subjects, this BP reduction did not require cessation of rh-HGF or any vasopressor therapy; BP returned to resting levels after the completion of rh-HGF infusion. Repeated doses of rh-HGF did not induce renal toxicity, and severe adverse events were not observed. Two patients survived, however, there was no evidence that rh-HGF was effective for the treatment of FH or LOHF. CONCLUSIONS: Intravenous rh-HGF at a dose of 0.6 mg/m2 was well tolerated in patients with FH or LOHF; therefore, it is desirable to conduct further investigations to determine the efficacy of rh-HGF at an increased dose.

The status of central ethical reviewing and challenges regarding its introduction to non-interventional studies in Japan.

In 2018, we conducted a study on 121 ethics review committee offices in Japan to examine the state of "central review" in non-interventional studies and discern any challenges regarding its introduction. Of the 452 offices that were invited to participate, 121 responded (26.8% response rate), and 35 (28.9%) had records of furnishing contracting agreements with ethical reviews by other research institutions. The merits of central reviewing include easing the burden on ethics review committees, improving the quality level and consistency of ethical reviews, and enhancing the efficiency in conducting them. The demerits include increased administrative overheads and work for researchers, such as preparing application forms and checking institutional requirements, and a lack of clarity regarding who is responsible for conducting the research, which makes it is less desirable for institutions to have their own ethics review committees. This study revealed that the comprehensive introduction of central review in non-interventional studies continues to encounter many hurdles, and promoting central review requires overcoming these challenges one at a time. The Ethical Guidelines for Medical and Health Research Involving Human Subjects will be revised in 2021 to require central review as a part of ethical reviews for non-interventional studies. In the future, central reviews of non-interventional studies will need to be of high quality and conducted efficiently, and this will require research institutions to utilize relevant central review guidelines and checklists.

Phase 1/2 study of alectinib in RET-rearranged previously-treated non-small cell lung cancer (ALL-RET).

BACKGROUND: Rearranged during transfection (RET) rearrangements occur in 1-2% of non-small cell lung cancers (NSCLCs). Alectinib administered at doses of 300 mg and 600 mg twice daily (BID) is approved for. ALK: rearranged NSCLC in Japan and other countries, respectively. Since alectinib has activity against RET, we conducted a phase (P) 1/2 study of alectinib to determine its activity in Japanese patients with. RET: rearranged NSCLC. METHODS: This study was a single-arm, open-label, multi-institutional P1/2 trial. Previously treated patients with RET-rearranged NSCLC, screened by nation-wide network (LC-SCRUM-Japan), were recruited. In P1, alectinib (600 or 450 mg BID) was administered following a 3+3 design and its safety was assessed. During P2, alectinib was administered at the recommended dose (RD) determined in P1. The primary endpoint was the objective response rate (ORR) in RET inhibitor-naïve patients treated with the RD of alectinib. RESULTS: Thirty-four patients were administered alectinib. In cohort 1 (600 mg BID) of P1, we observed 5 dose-limiting toxicities (DLTs), including grade 3 rash and thromboembolic event, in 3 of 6 patients. In cohort 2 (450 mg BID), we observed no DLTs in 3 patients. Pharmacokinetic analysis revealed that AUC0-10 to 600 mg BID was higher than that previously reported in global trials. We determined 450 mg BID as the RD for P2. In 25 RET inhibitor-naïve patients, one achieved an objective response (4%) and 13 achieved disease control at 8 weeks (52%). The median progression-free survival (PFS) was 3.4 months (95% CI, 2.0-5.4), while the median overall survival was 19.0 months (5.4-NE). We observed grade 3 adverse events (AEs) (4%) including pneumonitis in P2. CONCLUSIONS: Alectinib exerts limited activity against RET-rearranged NSCLC. Further investigation to elucidate the mechanisms underlying sensitivity and resistance of RET inhibitors is required to improve outcomes for these patients.

Clinical trial of autologous adipose tissue-derived regenerative (stem) cells therapy for exploration of its safety and efficacy.

INTRODUCTION: Liver cirrhosis is the ultimate condition of chronic liver diseases. Non-alcoholic steatohepatitis and fatty liver diseases are emerging in association with metabolic syndrome largely due to excess nutrition. Stromal cells of adipose tissue are enriched mesenchymal stem cells which are pluripotent and immunomodulatory, which are expected to be applied for repairing/regenerative therapy of the impaired organs. METHODS: We conducted the multi-institutional clinical trial (Japanese UMIN Clinical Trial Registry: UMIN000022601) of cell therapy using freshly isolated autologous adipose tissue-derived regenerative (stem) cells (ADRCs), which are obtained by the investigational trial device, adipose tissue dissociation device, for liver cirrhosis patients due to non-alcoholic steatohepatitis or fatty liver disease, to exploratory assess efficacy as well as safety of this trial. We completed treatment and 24 weeks follow-up for 7 patients. RESULTS: We observed that 6 out of 7 patients' serum albumin concentration was improved. As for prothrombin activity, 5 out of 7 patients showed improvement. No trial-related adverse events, which were serious or non-serious, was observed. Besides, no malfunction of the investigational trial device was encountered. CONCLUSION: Thus, treatment with autologous ADRCs obtained with the investigational trial device in steatohepatitis-related cirrhosis was confirmed to be safely conductible and potentially promising for the retaining or improving the impaired hepatic reserve.