The probability of successful drug discovery is declining, and research and development costs are increasing. To solve these problems, pharmaceutical companies tend to in-license seeds from venture companies and academia. Therefore, academia’s role in drug discovery is extremely important. Tottori University started a “Next-Generation Research Support Project (Strategic Research Support Project)” in 2020, developing a translational research system to promote drug discovery. In this project, we established a research and development infrastructure, such as seed registration, construction of drug research and development support, and research fund allocation. The registered seed were converted into project, and the project implemented this research and development system, and evaluated and verified its results. Twenty-two seeds were converted into projects and portfolios were constructed. Research funds were allocated to eight prioritized projects. Each project raised the research and development stages. From the overall portfolio, one project with the Japan Agency for Medical Research and Development (AMED) Drug Discovery Booster Project, and three projects with Seeds A of the AMED Translational Research Strategic Promotion Program were adopted. Additionally, a new low-molecular weight chaperone drug against GM1-gangliosidosis was out-licensed to an overseas pharmaceutical company. The strength of this system was the strategic allocation of research funds and the accompanying support that leveraged internal and external resources with the PM and researchers at its core. This system achieved certain results in promoting drug discovery; however, resource optimization of specialized personnel needs to be strengthened in the future. In this report, we summarized the efforts of translational research in Japan and around the world. In addition, the translational research efforts of Japanese academia and Tottori University were compared and the current status was summarized.
Background Burn injuries, particularly extensive severe burns, often have a fatal prognosis. However, many prognostic predictors are based on changes in the clinical course of treatment, and no prognostic predictors can be estimated in the early phases of injury. Using the Burn Index (BI) for evaluations requires familiarity with daily burn treatment, such as being able to evaluate the change from a second degree burn to a third degree burn appropriately. We sought to find a simpler and more quantitative prognostic prediction index.
Methods We hypothesized that, in addition to the current prognostic predictors, the number of neutrophils in severe burns may correlate with the prognosis, and analyzed its usefulness. The neutrophil and white blood cell counts were measured within 48 hours of injury in 35 burn patients who required inpatient treatment at our own institution. Mann–Whitney test was used to determine the significant of differences between the Survivor and Non-survivor groups.
Results Compared to the Survivor group, neutrophil (P = 0.038) and white blood cell counts were increased significantly in the Non-survivor group (P = 0.004). Neutrophil counts and white blood cell counts correlated positively with the length of hospital stay, total body surface area, Prognostic Burn Index (PBI), and BI. The BI and PBI correlated with patient prognosis, as did neutrophil and white blood cell counts.
Conclusion These results suggested that neutrophil and white blood cell counts in the early phases of burn injuries might be another factor in the prognosis of burn patients in addition to the current predictors.
Background In recent years, the number of neonatal surgeries has been on the rise despite the decline in the number of births, and we examined the actual trends and problems at Tottori University Hospital located in the Sanin region.
Methods Medical records were retrospectively searched for patients who underwent major surgery during the neonatal period (within 30 days of age) at the Tottori University Hospital over the past 10 years (Jan. 2011 to Dec. 2020).
Results Sixty-five cases were included. Early birth infants (< 37 gestational weeks) comprised 15 cases (23%) and low birth weight (< 2500 g) infants involved 27 cases (42%). In the latter half (2016–2020), early birth and low birth weight infants were significantly less than in the first half (2011–2015). The common diseases were anorectal malformation (14 cases), esophageal atresia (10), duodenal atresia (10), and diaphragmatic hernia (9). Prenatal diagnosis was obtained in 26 cases (40%), with high diagnostic rate obtained in duodenal atresia (100%), abdominal wall defect (100%), ileal atresia (75%), meconium peritonitis (67%), and diaphragmatic hernia (67%). Fifty-five cases (85%) were operated on within 7 days of age. Other major malformations were associated in 23 cases (35%). There were 6 deaths (9%), of which 3 cases were low birth weight infants with gastrointestinal perforation, 2 cases with severe chromosomal abnormalities (esophageal atresia, omphalocele), and 1 case with diaphragmatic hernia with severe pulmonary hypertension. Home medical care has been required with gastrostomy tube in 2 cases.
Conclusion Neonatal surgery at Tottori University has been well performed as required with acceptable results along with the progression of other perinatal care. However, further investigation for improvements in premature delivery or organ hypoplasia may be required.
Background Zoledronic acid reduces the risk of bone metastasis, but denosumab is a better option for treating bone metastases. However, few studies have evaluated the use of denosumab to treat bone metastasis originating from hepatocellular carcinoma. This study aimed to assess the clinical outcomes of switching from zoledronic acid to denosumab for treating bone metastasis in patients with hepatocellular carcinoma.
Methods This prospective study enrolled 10 patients with HCC and bone metastases. The levels of type 1 collagen cross-linked N-telopeptide (NTx) and tumor growth remained abnormal in these patients despite administration of zoledronic acid for over 3 months. We switched from zoledronic acid to 120 mg denosumab every 4 weeks and evaluated the clinical outcomes, including changes in the NTx level, pain level, and activities of daily living, as well as adverse events, after each administration.
Results Urinary NTx clearance was normal in all patients. The average urinary NTx clearance increased from 13.2 to 21.2 nmol BCE/nmol · Cre (P = 0.54) after the switch to denosumab. Serum NTx levels were abnormal in all cases. The serum NTx level decreased from 142 nmol BCE/L to 126 nmol BCE/L (P = 0.56). The answers to questionnaires on pain and activities of daily living did not change significantly. Some patients showed elevated transaminase levels, but this was not due to the drug switch.
Conclusion Switching to denosumab did not show a significant change of the pain and activity of daily living for the patients with severe bone metastasis from hepatocellular carcinoma, in whom the efficacy of zoledronic acid was limited.
Background Yokukansan, the Chinese Herbal Medicine, may be effective for treating postoperative delirium. However, there is no sufficient evidence supporting this notion. This study aimed to investigate whether yokukansan was effective for preventing delirium after gastrointestinal cancer surgery by the prospective randomized study.
Methods This was a double-blind, randomized, controlled trial. Patients aged 75 years or older who underwent surgery between May 2017 and December 2019 were randomized to the yokukansan or anchusan (another Herbal Medicine) group. They received treatments with oral intake of assigned medicine from the day before surgery until postoperative day 3. Then, the incidence of postoperative delirium was compared. A psychiatrist diagnosed patients with postoperative delirium.
Results Seventy-seven patients were enrolled in this study, and the full analysis set comprised 68 patients. In total, 25 of 68 (36.8%) patients presented with postoperative delirium. Specifically, 13 (37.1%) patients in the control group and 12 (36.4%) in the yokukansan group were diagnosed with postoperative delirium. However, the results did not differ significantly in both groups. Moreover, there was no remarkable difference in terms of delirium severity, and adverse events correlated with the medications were not observed.
Conclusion Yokukansan was ineffective in preventing delirium after gastrointestinal cancer surgery.
Background Cleft lip and/or palate (CL/P) can be accompanied by other congenital anomalies. We conducted a long-term evaluation of the associations between cleft patterns, sex distribution, and accompanying congenital anomalies of patients with CL/P.
Methods The medical records of 739 patients with CL/P, seen between January 1967 and December 2020, were retrospectively reviewed. Fisher’s exact test was used for statistical analysis.
Results Among the 739 patients with CL/P, the male-to-female ratio was 1.1. Regarding the cleft pattern, 121 (16.4%), 104 (14.1%), 280 (37.9%), 198 (26.8%), and 36 (4.9%) patients had cleft lip (CL), cleft lip and alveolus (CLA), cleft lip and palate (CLP), cleft palate (CP), and submucous cleft palate (SMCP), respectively. Congenital anomalies were identified in 107 (14.5%) cases, of which 53 (49.5%) had congenital heart disease. The frequencies of congenital anomalies patients with in CL/P were 14/225 (6.2%), 36/280 (12.9%), 43/198 (21.7%), and 14/36 (38.9%) for a combination of CL and CLA, CLP, CP, and SMCP, respectively. Accompanying syndromes and chromosomal anomalies were identified in 40 (5.4%) cases, in which Pierre Robin sequence (16 cases of CP and 4 cases of SMCP) was the most frequent.
Conclusion No sex differences were observed in CL/P, and CLP and CP were the most common cleft patterns. Congenital anomalies associated with CL/P were dominated by congenital heart disease and were most frequently identified in CP and SMCP cases. Notably, the Pierre Robin sequence, a complex syndrome characterized by micrognathia, glossoptosis, respiratory obstruction, and a U- or V-shaped CP, was found in cases of both CP and SMCP, and accounted for the symptoms in most cases.
Background Parents residing in the community have children with diverse neurodevelopmental disorders. Thus, developing online parent training that is effective for various types of neurodevelopmental disorders, not just for a single one, is essential. This study investigated the effects of real-time online group parent training developed for parents of children with various neurodevelopmental disorders.
Methods Twenty-two parents (two males and 20 females) of children with diagnosed or suspected neurodevelopmental disorders participated. We developed real-time online group parent training based on the Tottori University parent training (TUPT-ON), which can be implemented online as a pilot study. Parenting stress, parenting attitudes, mental health, and children’s inappropriate behavior scores were measured before and after the intervention and analyzed using paired t–test.
Results The average participation rate was 75.5%, and the average homework submission rate was 66.6%. The intervention significantly improved parents’ quality of life and negative parenting. Moreover, significant improvements were found in the total problems age-standardized scores (T-scores) of the Child Behavior Checkl List in participants’ children. In response to five questions about the acceptability of our online group parent training, participants rated most items as four or higher out of five.
Conclusion The implementation of TUPT-ON showed some improvements in children’s outcomes and brought about positive changes in parental outcomes across various neurodevelopmental disorders. This result suggests the potential effectiveness of this intervention for different types of neurodevelopmental disorders. TUPT-ON could provide parent training and support for parents dealing with their children’s various neurodevelopmental disorders, regardless of location, as long as they have a stable internet connection. However, the lack of a control group and the small sample size of certain diseases warrant caution in interpreting these findings, and a rigorous validation design should be employed and revalidated in the future.
Malignant pericardial effusion is an uncommon metastatic manifestation of ovarian carcinoma. Few cases of ovarian serous carcinoma have been previously reported. Ovarian clear cell carcinoma is the second most common histologic subtype in East Asian countries and is a relatively rare in Western countries. Here, we report the case of cardiac tamponade secondary to Ovarian clear cell carcinoma. A 46-year-old woman with recurrent Ovarian clear cell carcinoma presented with worsening cough, palpitations, and shortness of breath during chemotherapy. Chest radiography and computed tomography confirmed a pleural effusion with cardiac tamponade. The patient underwent pericardial fenestration and drainage for cardiac tamponade. Pericardial fluid cytology showed malignant cells forming papillary and ball-like clusters with irregular stacking. The cells had a mirror ball-like appearance and collagenous stroma, in which a homogenous hyaline core was observed in the center of most tumor cell clusters. Based on these findings, a diagnosis of Ovarian clear cell carcinoma metastasis was made. She received palliative care and died 5 months after the operation without recurrent cardiac tamponade. This case suggests that cytological findings from pericardial effusion are useful in diagnosing Ovarian clear cell carcinoma metastasis.
Noonan syndrome is an autosomal dominant disease characterized by multi-organ disorders caused by variants of genes involved in the RAS/MAPK signaling pathway. The nine causative genes including PTPN11 and CBL have been identified. Mastocytosis is a disease characterized by mast cell proliferation in skin, bone marrow, and other organs. To date, no previous cases of Noonan syndrome with mastocytosis caused by a pathogenic CBL variant have been reported. A boy was diagnosed with Noonan syndrome at 8 months of age with facial features and minor anomaly of his body. He presented with brown nodules of 5–10 mm on his body since the age of 2 months. The patient was diagnosed with mastocytosis by a biopsy specimen from brown nodules, which showed infiltration of mast cells. Whole-exome sequencing of the parent–patient trio revealed a de novo pathogenic CBL variant. The occurrence of mastocytosis may be a cue for the analysis of the CBL gene in Noonan syndrome. The CBL gene is involved in mastocytosis and various cancers. In the case of the pathogenic variant, long-term follow-up for the risk of cancers related to the CBL variant is necessary.
Hemophilia A is a recessive congenital deficiency of factor VIII that is characterized by normal bleeding time, normal prothrombin time, and prolonged activated partial thromboplastin time. In moderate and severe cases, abnormal bleeding is observed even after minor trauma, and the diagnosis is usually made by the age of 5–6 years, whereas in mild cases, abnormal bleeding is detected after major trauma or surgery. Herein, we present a case of hemophilia A that was discovered due to difficulties with hemostasis after tooth extraction.
Status epilepticus (SE) often causes neuronal death in the cerebrum and consequent long-term sequelae. Acute encephalopathy with biphasic seizures and late reduced diffusion is clinically characterized by SE associated with fever and seizure clusters that occur 3–9 days after symptom onset. MRI reveals reduced diffusion in the frontal or frontoparietal subcortical white matter, with sparing of the perirolandic region following seizure clusters. Kawasaki disease (KD) is an acute self-limited vasculitis secondary to activation of the immune system; KD is rarely complicated by acute encephalopathy. We report the case of a male infant who developed SE associated with KD and showed late reduced diffusion in the subcortical white matter beneath the bilateral motor cortices (primary motor, premotor and supplementary motor areas) and the right frontal cortex. The patient had characteristic neurological sequelae in the chronic phase, including clumsiness of fingers and forearms, impaired discrimination of tactile sensation and position sense on digits in his hands and feet, corresponding to the lesions with reduced diffusion at the acute phase.