p53-independent tumor suppression by cell-cycle arrest via CREB/ATF transcription factor OASIS.

CREB/ATF transcription factor OASIS/CREB3L1 is upregulated in long-term-cultured astrocytes undergoing cell-cycle arrest due to loss of DNA integrity by repeated replication. However, the roles of OASIS in the cell cycle remain unexplored. We find that OASIS arrests the cell cycle at G2/M phase after DNA damage via direct induction of p21. Cell-cycle arrest by OASIS is dominant in astrocytes and osteoblasts, but not in fibroblasts, which are dependent on p53. In a brain injury model, Oasis-/- reactive astrocytes surrounding the lesion core show sustained growth and inhibition of cell-cycle arrest, resulting in prolonged gliosis. We find that some glioma patients exhibit low expression of OASIS due to high methylation of its promoter. Specific removal of this hypermethylation in glioblastomas transplanted into nude mice by epigenomic engineering suppresses the tumorigenesis. These findings suggest OASIS as a critical cell-cycle inhibitor with potential to act as a tumor suppressor.

Effect of PARP Inhibitors as Maintenance Treatment on Restricted Mean Survival Time in Platinum-Sensitive Recurrent Ovarian Cancer: A Systematic Review and Meta-analysis.

BACKGROUND: Earlier trials on the efficacy of poly (ADP-ribose) polymerase (PARP) inhibitors in platinum-sensitive relapsed ovarian cancer used the hazard ratio (HR) as an efficacy parameter. OBJECTIVE: The present meta-analysis was focused on improving the robustness and clinical interpretability of the efficacy evaluation of PARP inhibitors using the restricted mean survival time (RMST). METHODS: A search for relevant studies published up to July 31, 2020, was performed in electronic databases to identify eligible trials comparing PARP inhibitors with placebo. The difference in RMST was used as a PARP inhibitor efficacy parameter. Combined differences in RMST with 95% CIs across studies were calculated using a random-effects model. RESULTS: Four trials (6 articles) were assessed, including 1079 patients treated with PARP inhibitors and 598 with placebo. The combined RMST differences for up to 360 days (PARP inhibitors minus placebo: point estimate and 95% CI) among all patients and the patients of subgroups with BRCA mutations, homologous recombination-deficient (HRD) carcinoma, and BRCA wild-type carcinoma were 87 days (95% CI = 71, 102), 112 days (95% CI = 96, 129), 99 days (95% CI = 80, 119), and 69 days (95% CI = 47, 92), respectively. The combined RMST differences for up to 660 and 720 days were also larger among patients with BRCA mutations than among those with HRD carcinoma. CONCLUSION AND RELEVANCE: Based on using the RMST difference as an alternative measure to the HR, this meta-analysis suggests that PARP inhibitors are the most effective for patients with BRCA mutations, followed by patients with HRD carcinoma.

Factors associated with successful phase III trials for solid tumors: A systematic review.

BACKGROUND: It is known that the success rates of phase III trials for solid cancers are low. The aim of this study was to investigate factors related to trial design and operation that were associated with the probability of the success of phase III trials for solid cancers based on the latest comprehensive data. METHODS: Relevant clinical trials, started between September 2007 and December 2017, were retrieved from ClinicalTrials.gov. Then, variables related to the selected trials such as types of primary endpoint and duration of trial enrollment were collected from the literature and ClinicalTrials.gov. Based on the collected data, a multivariate logistic regression analysis was conducted to find factors associated with the successful results. RESULTS: Four hundred phase III trials were found eligible for the study. Unsuccessful trials were 207 and successful trials were 193. As a result of multivariate logistic regression analysis, factors that presented a statistically significant relationship were primary endpoint (Odds ratio [OR]: 2.79 [95% CI: 1.59-4.89]), control arm (OR: 3.06 [95% CI: 1.39-6.73]), start year of trial (OR: 3.28 [95% CI: 1.87-5.77]), and duration of trial enrollment (OR: 0.77 [95% CI: 0.60-0.99]). CONCLUSION: Type of primary endpoints (time-to-event endpoints other than overall survival), control arm (treatments with lower evidence level, placebo or best supportive care), and duration of trial enrollment (faster enrollment speed) were associated with phase III trial success.

Predictability of Severe Adverse Events in Phase 3 Trials from Safety Information on Phase 1 Trials in Oncology Drug Development.

PURPOSE: Safety information obtained in phase 1 trials is becoming increasingly important with the recent changes in the development strategy of oncology drugs, including the skipping of phase 2 or 3 trials before regulatory approval. This study aimed to investigate the predictive factors for severe adverse events (AEs) in phase 3 trials based on phase 1 trial data. METHODS: The data on phase 1 and phase 3 trials applied for their marketing approval of the newly approved anticancer drugs in Japan were used for analysis. Regression analyses were performed to investigate factors related to the predictability of the occurrence of severe AEs in phase 3 trials based on phase 1 trial data. RESULTS: Thirty-two drugs (80 phase 1 trials and 40 phase 3 trials) were selected for the analyses. As a result of multivariate regression analyses, immune therapy agents (P = 0.009) and a pair of monotherapy in the phase 1 trials and combination therapy in the phase 3 trials (P = 0.017) were associated with low predictability of severe AEs in the phase 3 trials; signal inhibitor agents (P = 0.002) and large number of subjects in phase 1 trials (P = 0.008) were associated with high predictability. A significant relationship between the actual number of subjects in phase 1 trials and the predictability of severe AEs was observed when trials for immune checkpoint inhibitors were excluded (P < 0.001). CONCLUSION: These results should be effectively utilized for the strategic design of early-stage oncology drug development.

Impact of Advantage in Tumor Response on the Correlation Between Progression-Free Survival and Overall Survival: Meta-Analysis of Clinical Trials in Patients with Advanced Non-Small Cell Lung Cancer.

BACKGROUND: Progression-free survival (PFS) has not been validated as a surrogate endpoint for overall survival (OS) in patients with advanced non-small cell lung cancer. OBJECTIVE: This study aimed to investigate an impact of advantage in tumor response on the correlation between PFS and OS in advanced non-small cell lung cancer. METHODS: Based on a literature search, we identified randomized controlled trials of first-line therapy for advanced non-small cell lung cancer. The impact of absolute difference in objective response rate between treatment arms on the correlation between hazard ratios (HRs) for PFS and OS was evaluated based on Spearman rank correlation coefficients. RESULTS: Sixty trials with a total of 29,134 patients were identified. The HR for PFS showed a relatively higher correlation with HR for OS (rs = 0.75) when the trials were limited to those that demonstrated a larger advantage in objective response rate, compared with the case for trials that demonstrated a smaller advantage (rs = 0.66). This tendency was also observed in the subgroup analysis stratified by the types of treatment agents (non-targeted, anti-angiogenic, and immunotherapy) except for the group of epidermal growth factor receptor-targeted agents. CONCLUSIONS: The magnitude of advantage in tumor response was suggested to contribute to a better prediction of OS-HR based on PFS-HR in clinical trials in patients with advanced non-small cell lung cancer.

Comparison of efficacy outcomes of anticancer drugs between Japanese patients and the overall population.

BACKGROUND: It is important to recognize regional and racial differences in drug efficacy and safety when performing multi-regional clinical trials (MRCTs). To understand regional differences, we compared the efficacy results in Japanese patients and the overall population in the MRCTs of anticancer drugs. METHODS: All new approvals of oncology drugs in Japan from January 2009 to December 2018 were searched using the Pharmaceuticals and Medical Devices Agency web site to find phase 3 MRCTs for the analysis. As the supporting data source, a literature search was performed in PubMed and Google Scholar. Linear regression analysis was performed and Pearson correlation coefficients (r) were calculated to compare the overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) between Japanese patients and the overall population. RESULTS: Seventy MRCTs were identified. The correlation of hazard ratios (HRs) for OS between Japanese patients and the overall population was moderate (r = 0.45), and OS was 1.31 times longer in Japanese patients than in the overall population, although the correlation of median OS was strong (r = 0.91). The HRs for PFS were moderately correlated (r = 0.70) and the correlation of median PFS was strong (r = 0.90). The correlation of ORR was very strong (r = 0.96). CONCLUSION: The PFS and ORR were consistent between Japanese patients and the overall population. A longer median OS was observed in Japanese patients. Our results would be a useful reference when planning and conducting MRCTs that include Japan for global simultaneous drug development.

Factors associated with high placebo response in clinical studies of hot flashes: a meta-analysis.

IMPORTANCE: High placebo response can often mask the evaluation of active treatment in clinical studies for women with hot flashes and potentially undermine the evaluation of new treatments. OBJECTIVE: The aim of this meta-analysis was to determine the factors associated with high placebo response (defined as the reduction in the mean number of hot flash frequency from baseline) in randomized, controlled, double-blind studies enrolling women with hot flashes. EVIDENCE REVIEW: To identify eligible studies, Embase, MEDLINE, and BIOSIS Previews were searched for English-language articles published between April 1975 and August 2020. Placebo-controlled, double-blind, randomized studies that assessed changes in hot flash frequency were included if they satisfied the defined criteria. We conducted univariate and multivariate analyses using categorical and numerical data. Categorical data included the following variables and levels in brackets: active treatment type (hormone therapy /non- hormone therapy /complementary and alternative medicine), administration route (oral/non-oral), study region (in/excluded the US), breast cancer population (in/excluded), entry criteria of hot flash severity (moderate to severe only/all included), parallel or crossover study, placebo run-in period before treatment (yes/no), and menopausal status (postmenopausal only/include perimenopausal/include premenopausal). Numerical data included published year, pretreatment period duration, treatment period duration, number of sites, number of total participants, number of placebo participants, number of treatment arms, mean age, BMI, and hot flash frequency at baseline. FINDINGS: Forty-three of the 802 identified publications were included in the review. Multivariate analysis identified three individual factors associated with high placebo response: treatment period duration, number of treatment arms, and BMI. CONCLUSIONS AND RELEVANCE: We identified several factors associated with high placebo response in clinical studies of women with hot flashes. Knowing these factors may enable proactive implementation of operational and analytic strategies that further aid in determining the true treatment effect of an intervention.

Factors Related to Conversion from Accelerated to Full Approval for Drugs Approved in the United States Between 2000 and 2016.

BACKGROUND: Accelerated approval (AA) is a program that grants approval to drugs based on clinical trial data for a surrogate endpoint or an intermediate clinical endpoint. Pharmaceutical companies are required to conduct a confirmatory trial to demonstrate true clinical benefit of the drug to obtain full approval (FA) for the AA. This study aimed at clarifying the points that should be considered by examining the characteristics of AA indications in all disease areas and the factors related to the status of conversion from AA to FA. METHODS: AA indications granted from January 1, 2000, to June 30, 2016, were investigated from the aspects of the characteristics of AAs and the status of conversion from AA to FA. RESULTS: Eighty-nine AAs were examined, of which 65 were converted to FA and 24 were not. A significant association was found between the FA status and period in which AA was granted, disease area, availability of IA data of a confirmatory trial for FA at the time of AA, and sales ranking of the company. CONCLUSIONS: To successfully convert from AA to FA, a development plan that focuses not only on AA but also on future FA needs to be considered and implemented from the early stage of development in line with the FDA guidance. In particular, for companies with insufficient experience in the development of AA indications and for products/indications without an established endpoint, more active discussion with the regulatory authorities from an early stage of development should be encouraged.

Characteristics of Drug Intervention Clinical Trials and Scientific Impact of the Trial Outcome: A Bibliometric Analysis Using the Relative Citation Ratio in Non-small Cell Lung Cancer from 2007 to 2016.

BACKGROUND: Although a large number of clinical trials have been conducted, the types of clinical trials that are scientifically influential, frequently utilized by society, and contribute to the progress of evidence-based medicine (EBM) have not been studied. Thus, we aimed to investigate the relationship between the characteristics of clinical trials and the scientific impact of the outcome in non-small cell lung cancer (NSCLC) by performing a bibliometric analysis using relative citation ratio (RCR), a newly developed bibliometric index by the National Institutes of Health (NIH). METHODS: Primary publications of drug intervention clinical trials for NSCLC between 2007 and 2016 were included in the study. The characteristics of clinical trials were compared among four RCR categories with 50 trials in each [LOW50, 50 NIH percentile (50NIH%ile), 95 NIH percentile (95NIH%ile), and TOP50], totaling to 200 trials. RESULTS: Median RCRs of LOW50, 50NIH%ile, 95NIH%ile, and TOP50 were 0.03, 1.00, 5.76, and 26.89, respectively. Publications of Phase 3, randomized, blinded, for-profit-company supported/sponsored, multi-center trials, and trials with a larger number of subjects were shown to have a higher scientific impact. Publications of clinical trials of newly developed molecular target drugs, including epidermal growth factor receptor-tyrosine kinase inhibitors, anaplastic lymphoma kinase inhibitors, and immune checkpoint inhibitors demonstrated a higher scientific impact than those of traditional chemotherapies. CONCLUSION: Clinical trials designed to have a high evidence level would improve the scientific impact of the outcome, and novel interventions would be another factor to improve the clinical trials' influence.

The Role of Tissue-Specific Ubiquitin Ligases, RNF183, RNF186, RNF182 and RNF152, in Disease and Biological Function.

Ubiquitylation plays multiple roles not only in proteasome-mediated protein degradation but also in various other cellular processes including DNA repair, signal transduction, and endocytosis. Ubiquitylation is mediated by ubiquitin ligases, which are predicted to be encoded by more than 600 genes in humans. RING finger (RNF) proteins form the majority of these ubiquitin ligases. It has also been predicted that there are 49 RNF proteins containing transmembrane regions in humans, several of which are specifically localized to membrane compartments in the secretory and endocytic pathways. Of these, RNF183, RNF186, RNF182, and RNF152 are closely related genes with high homology. These genes share a unique common feature of exhibiting tissue-specific expression patterns, such as in the kidney, nervous system, and colon. The products of these genes are also reported to be involved in various diseases such as cancers, inflammatory bowel disease, Alzheimer's disease, and chronic kidney disease, and in various biological functions such as apoptosis, endoplasmic reticulum stress, osmotic stress, nuclear factor-kappa B (NF-κB), mammalian target of rapamycin (mTOR), and Notch signaling. This review summarizes the current knowledge of these tissue-specific ubiquitin ligases, focusing on their physiological roles and significance in diseases.

Magnitude of advantage in tumor response contributes to a better correlation between treatment effects on overall survival and progression-free survival: a literature-based meta-analysis of clinical trials in patients with metastatic colorectal cancer.

BACKGROUND: Although it is suggested that the endpoints originated from the concept of tumor shrinkage dynamics, such as early tumor shrinkage and depth of response, are strongly associated with overall survival (OS) in patients with metastatic colorectal cancer (mCRC), they are yet to be validated as a single surrogate endpoint of OS by themselves. This study aimed to investigate the impact of advantage in tumor response on the correlation between treatment effects on progression-free survival (PFS) and OS in mCRC patients. METHODS: Based on an electronic search, we identified randomized controlled trials of first-line therapy for mCRC. The impact of advantage in objective response rate (ORR) on the correlation between treatment effects on PFS and OS was evaluated based on Spearman correlation coefficients (rs). RESULTS: Forty-seven trials with a total of 24,018 patients were identified. The hazard ratio for PFS showed a relatively higher correlation with that for OS (rs = 0.63) when the trials were limited to those that demonstrated a larger difference in ORR, compared to the case for trials that demonstrated a smaller difference (rs = 0.32). This tendency was also observed in the subgroup analysis stratified by the types of treatment agents (targeted or non-targeted). CONCLUSIONS: The magnitude of advantage in tumor response was suggested to contribute to a better prediction of OS benefit based on PFS in patients with mCRC. The accuracy of OS estimation in mCRC is expected to be improved by considering the degree of tumor shrinkage in conjunction with PFS.

Hypertonicity-responsive ubiquitin ligase RNF183 promotes Na, K-ATPase lysosomal degradation through ubiquitination of its ß1 subunit.

We previously reported that RNF183, a member of the RING finger (RNF) protein family, is specifically expressed in the renal collecting duct and that RNF183 mRNA is induced by the activity of nuclear factor of activated T cells 5 (NFAT5), which regulates the transcription of essential proteins for adaptation to hypertonic conditions. The renal medulla is the only tissue that is continuously hypertonic; therefore, RNF183 possibly plays an important role in adaptation to continuous hypertonic conditions. However, the mechanism of how cells adapt to long-term hypertonicity via RNF183 remains unclear. In this study, the Na, K-ATPase α1 subunit was identified as a candidate substrate of RNF183 by the BirA proximity-biotinylation technique. The Na, K-ATPase α1 subunit acts as an ion transporter along with the Na, K-ATPase ß1 subunit at the plasma membrane. We confirmed that RNF183 interacted with both α1 and ß1 subunits; however, we found that RNF183 ubiquitinated only the ß1 subunit, not the α1 subunit. Furthermore, RNF183 translocated both α1 and ß1 subunits from the plasma membrane to lysosomes. In addition, the expression levels of α1 and ß1 subunits in HEK293 cells stably expressing RNF183 were significantly decreased compared with mock control cells, and were restored by siRNA-mediated knockdown of RNF183. Moreover, in RNF183-expressing cells, chloroquine treatment increased the protein levels of the α1 and ß1 subunits. Therefore, our results suggest that Na, K-ATPase α1 and ß1 subunits are degraded in lysosomes by RNF183-mediated ubiquitination of ß1 subunit.

Regulatory characteristics and pivotal study design of US Food and Drug Administration approval of drugs for major vs. minor cancer.

PURPOSE: We aimed to investigate the regulatory approval of drugs for cancers by the US Food and Drug Administration based on the cancer type (major vs. minor), including the use of expedited development programs and duration from Investigational New Drug application (IND) to marketing approval. METHODS: From publicly available records and through a Freedom of Information Act request, we gathered data to evaluate regulatory characteristics and pivotal study design for 115 anticancer drug approvals between 2012 and 2017 and the data were analyzed based on cancer incidence (major vs. minor cancers) and how expedited programs, orphan drug designation, and pivotal study design contribute to expedited approval was studied. RESULTS: Drugs targeting minor cancers more frequently (67%; P = 0.0155) utilized breakthrough therapy designation and/or accelerated approval, both of which significantly contributed to expedited drug approval (median time from IND to approval, 6.4 years; P = 0.0008, 6.2 years; P < 0.0001). Drug approvals for pivotal study design without a comparator arm took significantly less time from IND to approval (median time from IND to approval, 6.2 years; P < 0.0001). CONCLUSIONS: Drugs targeting minor cancers have frequently utilized the expedited development programs; thus, efficiently shortening time to approval. As many of such drugs are approved based on non-comparative pivotal studies, meticulous evaluation and follow-up should be performed for such drugs after their approval.

Calnexin promotes the folding of mutant iduronate 2-sulfatase related to mucopolysaccharidosis type II.

Mucopolysaccharidosis type II (MPS II) is one of the most common mucopolysaccharidoses, which is caused by mutation of the gene encoding iduronate 2-sulfatase (IDS). The loss of function of IDS leads to the accumulation of heparan sulfate and dermatan sulfate of glycosaminoglycans throughout the body, resulting in skeletal deformities, mental retardation, rigid joints, and thick skin. Recently, enzyme replacement therapy has become a common strategy for treating this condition. However, its effectiveness on the central nervous system (CNS) is limited because intravenously administered recombinant IDS (rIDS) cannot pass through the blood brain barrier. Therefore, several methods for delivering rIDS to the CNS, using anti-human transferrin receptor antibody and adeno-associated virus 9, have been explored. To investigate additional approaches for treatment, more cognition about the intracellular dynamics of mutant IDS is essential. We have already found that mutant IDS accumulated in the endoplasmic reticulum (ER) and was degraded by ER-associated degradation (ERAD). Although the dynamics of degradation of mutant IDS was revealed, the molecular mechanism related to the folding of mutant IDS in the ER remained unclear. In this research, we confirmed that mutant IDS retained in the ER would be folded by binding with calnexin (CNX). Thus, knockdown of CNX reduced the translocation of mutant IDS from ER to lysosome and its enzyme activity, indicating that the correct folding of this protein via interaction with CNX ensures its functional activity. These findings reveal the possibility that modifying the interaction of mutant IDS and CNX could contribute to alternative therapeutic strategies for MPS II.

Functional evaluation of PDGFB-variants in idiopathic basal ganglia calcification, using patient-derived iPS cells.

Causative genes in patients with idiopathic basal ganglia calcification (IBGC) (also called primary familial brain calcification (PFBC)) have been reported in the past several years. In this study, we surveyed the clinical and neuroimaging data of 70 sporadic patients and 16 families (86 unrelated probands in total) in Japan, and studied variants of PDGFB gene in the patients. Variant analyses of PDGFB showed four novel pathogenic variants, namely, two splice site variants (c.160 + 2T > A and c.457-1G > T), one deletion variant (c.33_34delCT), and one insertion variant (c.342_343insG). Moreover, we developed iPS cells (iPSCs) from three patients with PDGFB variants (c.160 + 2T > A, c.457-1G > T, and c.33_34 delCT) and induced endothelial cells. Enzyme-linked immunoassay analysis showed that the levels of PDGF-BB, a homodimer of PDGF-B, in the blood sera of patients with PDGFB variants were significantly decreased to 34.0% of that of the control levels. Those in the culture media of the endothelial cells derived from iPSCs of patients also significantly decreased to 58.6% of the control levels. As the endothelial cells developed from iPSCs of the patients showed a phenotype of the disease, further studies using IBGC-specific iPSCs will give us more information on the pathophysiology and the therapy of IBGC in the future.

Time-Matched Evaluation of Cardiovascular Risks Associated with Drugs for Type 2 Diabetes Mellitus.

BACKGROUND AND OBJECTIVE: The results of large placebo-controlled clinical trials to evaluate cardiovascular risks associated with drugs for type 2 diabetes mellitus indicated different cardiovascular effects among these drugs, but the detailed design of each trial was not completely the same. The aim of this study was to perform time-matched evaluation of cardiovascular risks of drugs for type 2 diabetes. METHODS: We used the difference in restricted mean survival time (RMST) as a measure of cardiovascular risks. Regarding drugs for type 2 diabetes used currently, this study included all 10 clinical trials in patients with type 2 diabetes at high cardiovascular risk the results of which have been published as of 30 November 2018. Since the shortest study follow-up time was about 672 days in SUSTAIN-6, we chose 672 days as a common time point to estimate the RMSTs regarding each safety event. RESULTS: The differences of RMSTs (drugs for type 2 diabetes minus placebo: point estimate and 95% confidence interval) for major adverse cardiovascular events (MACE) were 8 days (1, 15) for semaglutide, 5 days (1, 9) for liraglutide, and 7 days (2, 13) for empagliflozin. Those for death from cardiovascular causes were 5 days (2, 8) for empagliflozin and 2 days (1, 4) for canagliflozin. Those for death from any cause were 4 days (1, 8) for empagliflozin. CONCLUSIONS: Through the evaluation up to 672 days, semaglutide, liraglutide, and empagliflozin decreased the risk of MACE. Concerning the risk of each cardiovascular event, risk reduction was seen with empagliflozin and canagliflozin.

Inflammatory bowel disease-associated ubiquitin ligase RNF183 promotes lysosomal degradation of DR5 and TRAIL-induced caspase activation.

RNF183 is a ubiquitin ligase containing RING-finger and transmembrane domains, and its expression levels are increased in patients with inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, and in 2,4,6-trinitrobenzene sulfonic acid-induced colitis mice. Here, we further demonstrate that RNF183 was induced to a greater degree in the dextran sulfate sodium (DSS)-treated IBD model at a very early stage than were inflammatory cytokines. In addition, fluorescence-activated cell sorting and polymerase chain reaction analysis revealed that RNF183 was specifically expressed in epithelial cells of DSS-treated mice, which suggested that increased levels of RNF183 do not result from the accumulation of immune cells. Furthermore, we identified death receptor 5 (DR5), a member of tumour necrosis factor (TNF)-receptor superfamily, as a substrate of RNF183. RNF183 mediated K63-linked ubiquitination and lysosomal degradation of DR5. DR5 promotes TNF-related apoptosis inducing ligand (TRAIL)-induced apoptosis signal through interaction with caspase-8. Inhibition of RNF183 expression was found to suppress TRAIL-induced activation of caspase-8 and caspase-3. Thus, RNF183 promoted not only DR5 transport to lysosomes but also TRAIL-induced caspase activation and apoptosis. Together, our results provide new insights into potential roles of RNF183 in DR5-mediated caspase activation in IBD pathogenesis.

Evaluation of the Implementation of Additional Risk Minimization Activities in Europe, the USA, and Japan.

BACKGROUND: Risk minimization activities are planned and conducted as part of a drug's risk management plan; additional risk minimization activities are implemented as needed in consideration of the regulations and medical environment in each country/region, as well as drug-specific factors. OBJECTIVE: The present study was conducted with the aim of investigating the status of implementing additional risk minimization activities in Europe, the USA, and Japan and understanding the characteristics of such activities commonly conducted in these countries/regions. METHODS: For new drugs approved between 2013 and 2017, the status of implementing the additional activities was investigated based on the information published on each of the regulatory agencies' websites. Next, we identified drugs approved in all three countries/regions and investigated drug-specific factors such as indications and safety concerns. Furthermore, the contents of the activities were analyzed from the viewpoint of whether they intended risk mitigation or risk prevention. RESULTS: The status of implementing additional activities was 26.4% (42/159 drugs) in Europe, 7.6% (15/197 drugs) in the USA, and 64.8% (92/142 drugs) in Japan. Forty-five drugs that were approved in all three countries/regions were identified. Many drugs with additional activities displayed novel mechanisms of action in therapeutic areas such as oncology. Common additional activities were implemented for only three drugs and for two of these drugs, "teratogenicity" was identified as a safety concern subjected to additional activities. CONCLUSIONS: Risk minimization activities were considered to be largely influenced by differences in regulatory thinking, medical systems, such as the number of healthcare providers per patient and the insurance system, and cultural differences. For drugs with a risk for teratogenicity and those with side effects that differ from conventional therapies, there was a tendency to commonly implement additional activities.

Cancer of the mandibular gingiva metastasizing to the small intestine.

Head and neck cancer metastasizing to the small intestine is very rare. Here we report a case of cancer of the mandibular gingiva metastasizing to the small intestine. The patient was an 82-year-old man who had squamous cell carcinoma of the mandibular gingiva staged as T2N2bM0. Two months after surgery, he presented with lower abdominal pain accompanied by signs of peritoneal irritation. Urgent abdominal surgery was performed, during which a crater-shaped perforation was noted on the wall of the ileum. Microscopic findings at this site confirmed a diagnosis of metastatic squamous cell carcinoma in the small intestine from the mandibular gingiva. To our knowledge, this is the first case report of oral cancer metastasizing to the small intestine. If gastrointestinal symptoms appear in a patient with advanced oral cancer, a differential diagnosis of metastasis to the gastrointestinal tract should be kept in mind.