[Low-Dose and Interval Administration of Imatinib in a Patient with Liver Metastasis of the Gastrointestinal Stromal Tumor of the Stomach - A Case Report].

A 69-year-old woman underwent proximal gastrectomy with distal pancreatectomy and splenectomy for a gastrointestinal stromal tumor of the stomach.Adjuvant imatinib was administered for a year.Two years after resection of the tumor, liver metastasis in S8 was detected.Therefore, imatinib was re-administered at 300mg/day.After a year of re-administration, the patient suffered muscle cramps in the hands, and therefore imatinib was administered with intervals, such as 4 weeks administration and 4 weeks rest.Re -administration of imatinib was effective and her liver metastasis decreased in size.It was not detected with CT after 1 year and 4 months and remained in complete response(CR)for 3 years and 8 months.After she suffered a brain infarction, imatinib administration was stopped for 4 months.Consequently, the liver metastasis was detectable in S8 again.This clinical course suggested that low-dose and interval administration of imatinib is effective in the treat- ment of GIST.

Caregiver Burden with Duchenne and Becker Muscular Dystrophy in Japan: A Clinical Observation Study.

Objective Skeletal muscle weakness and cardiomyopathy can be seen in carriers of dystrophinopathy. Therefore, the health management of caregivers of Duchenne/Becker muscular dystrophy (DMD/BMD) patients who are themselves carriers is an important issue. However, few studies have focused on caregivers who have dystrophin mutations. Methods In this cross-sectional study conducted at five hospitals, the daily living, situation medical treatment status, genetic testing, physical assessment, care burden, and quality of life of caregivers of DMD/BMD patients were surveyed. Results The subjects were 36 main caregivers (mean age 55.7±8.4 years old), of whom 52.8% were diagnosed as carriers, 8.3% were noncarriers, and 38.9% were not confirmed. In addition, half of the caregivers were not examined regularly at medical institutions. Of all caregivers, 54.3% had muscle or cardiac symptoms, and 75% had elevated serum creatine kinase levels. The mean Zarit Caregiver Burden Interview (ZBI) total score of current caregivers was 20.9±13.1. The frequency of a ZBI total score ≥25 was significantly higher in caregivers diagnosed as carriers than in caregivers unexamined as carriers (p=0.04). The health-related quality of life score (Short Form 36; SF-36) in caregivers was slightly lower than the Japanese standard scores in the sections of physical functioning, role limitations-physical, bodily pain, and social functioning. Conclusion Some caregivers of DMD/BMD patients can themselves have muscular or cardiac symptoms and a heavy care burden. It is therefore necessary for carrier caregivers, especially women, to undergo regular health checkups and receive appropriate health management.

An inhibitor of transforming growth factor beta type I receptor ameliorates muscle atrophy in a mouse model of caveolin 3-deficient muscular dystrophy.

Skeletal muscle expressing Pro104Leu mutant caveolin 3 (CAV3(P104L)) in mouse becomes atrophied and serves as a model of autosomal dominant limb-girdle muscular dystrophy 1C. We previously found that caveolin 3-deficient muscles showed activated intramuscular transforming growth factor beta (TGF-ß) signals. However, the cellular mechanism by which loss of caveolin 3 leads to muscle atrophy is unknown. Recently, several small-molecule inhibitors of TGF-ß type I receptor (TßRI) kinase have been developed as molecular-targeting drugs for cancer therapy by suppressing intracellular TGF-ß1, -ß2, and -ß3 signaling. Here, we show that a TßRI kinase inhibitor, Ki26894, restores impaired myoblast differentiation in vitro caused by activin, myostatin, and TGF-ß1, as well as CAV3(P104L). Oral administration of Ki26894 increased muscle mass and strength in vivo in wild-type mice, and improved muscle atrophy and weakness in the CAV3(P104L) mice. The inhibitor restored the number of satellite cells, the resident stem cells of adult skeletal muscle, with suppression of the increased phosphorylation of Smad2, an effector, and the upregulation of p21 (also known as Cdkn1a), a target gene of the TGF-ß family members in muscle. These data indicate that both TGF-ß-dependent reduction in satellite cells and impairment of myoblast differentiation contribute to the cellular mechanism underlying caveolin 3-deficient muscle atrophy. TßRI kinase inhibitors could antagonize the activation of intramuscular anti-myogenic TGF-ß signals, thereby providing a novel therapeutic rationale for the alternative use of this type of anticancer drug in reversing muscle atrophy in various clinical settings.

Rescue from respiratory dysfunction by transduction of full-length dystrophin to diaphragm via the peritoneal cavity in utrophin/dystrophin double knockout mice.

Duchenne muscular dystrophy (DMD) is an inherited severe muscle wasting disorder with, thus far, no effective therapy. DMD causes respiratory and cardiac failure as well as muscle wastage. Among the various symptoms, respiratory insufficiency is a major cause of death in DMD patients at about 20 years of age. So, naturally, the improvement of respiratory function will extend the patient's life. We report here, for the first time, a sensitive procedure using whole-body plethysmography to monitor respiratory parameters detected in the utrophin/dystrophin double knockout mouse (dko mouse), showing quite similar systemic symptoms to human DMD including restrictive ventilatory impairment. Furthermore, we show that a highly efficient dystrophin-transduction to the dko's diaphragm--achieved by simple intraperitoneal injection of a helper-dependent adenovirus vector (HDAdv) containing the full-length dystrophin expression cassette--provided beneficial results. In spite of dystrophin expression only in the diaphragm, this focal gene transfer could result in the rescue from ventilatory impairment (increased tidal volume (TV) and improvement of compensatory hyperpnea). Our result suggests that a DMD patient's mortal ventilatory impairment may be improved via technically easy means through the intraperitoneal injection of HDAdv.

Liver hemorrhage due to idiopathic peliosis hepatis successfully treated with hepatic artery embolization.

Peliosis hepatis is an extremely rare condition that may cause fatal hepatic hemorrhage and liver failure. We report a case of liver hemorrhage due to idiopathic peliosis hepatis. A 60-year-old woman was admitted to our hospital with slight right hypochondriac pain. She went into hemorrhagic shock, and computed tomography (CT) showed multiple low-density areas in the right liver with massive subcapsular blood collection. Selective transfemoral arteriography of the celiac artery revealed no signs of vascular malformation or tumor stain, but showed signs of pooling in the right posterior segmental artery. The artery was embolized with particles of gelatin sponge, and hemostatic control was successful. Although peliosis hepatis is extremely rare, the diagnosis is significant because of its urgent clinical status, and transarterial embolization is a useful and minimally invasive procedure for liver hemorrhage due to peliosis hepatis.

Renal function in amyotrophic lateral sclerosis patients on long-term treatment with edaravone.

ABSTRACT: Edaravone, a free radical-scavenger, was approved in Japan for the treatment of amyotrophic lateral sclerosis (ALS). However, the effect of the drug on renal function in ALS patients remains unclear. This study aimed to investigate renal function in ALS patients on long-term treatment with edaravone by measuring the serum estimated glomerular filtration rate based on cystatin C (eGFR-CysC).In a retrospective study, the data of ALS patients who were treated with over 10 cycles of intravenous edaravone treatment and were evaluated by eGFR-CysC before and after 10 cycles of treatment between July 2015 and June 2018 were analyzed. Then, the results were compared with those of a control ALS group that had never been treated with edaravone.There were 11 patients with ALS who received over 10 cycles of intravenous edaravone treatment. The mean interval between the first and final eGFR-CysC measurements was 18.7 ±â€Š7.9 months. Three patients (27.3%) had >20 mL/min/1.73 m2 decrease in serum eGFR-CysC. However, no patients discontinued edaravone treatment because of renal dysfunction. The average variation rate of eGFR-CysC was not different between the long-term edaravone group (0.29 ±â€Š1.07) and the control group (-0.34 ±â€Š0.40).This retrospective, single-center analysis showed no clinical exacerbation of renal function in ALS patients who received long-term treatment with edaravone.

A web-based questionnaire survey on the influence of coronavirus disease-19 on the care of patients with muscular dystrophy.

To clarify the influence of coronavirus disease-19 (COVID-19) on the care of muscular dystrophy patients, we performed a questionnaire survey that was posted on the internet on May 11, 2020. By the end of July 2020, 542 responses had been collected. Approximately 30% of patients postponed regular consultations, and one-quarter of patients who received consultation more than once a month used telephone consultations. Two of 84 patients with Duchenne muscular dystrophy had reduced their steroid doses. A shortage of ventilator accessories and infection protection equipment occurred following the onset of COVID-19, and this shortage had a serious impact on medical care and infection prevention measures. Reductions in rehabilitation and other services, and avoidance of outings, led to a decrease in exercise and an increase in caregiver burden. Inpatients were restricted from going out and visiting family members. More than 20% of patients reported physical or mental complaints; however, few required treatment. COVID-19 has seriously affected the activities and quality of life of patients with muscular dystrophy. We will continue this survey and analyze the longitudinal changes.

Transduction of full-length dystrophin to multiple skeletal muscles improves motor performance and life span in utrophin/dystrophin double knockout mice.

Duchenne muscular dystrophy (DMD) is a fatal, progressive, muscle-wasting disease caused by defects in the dystrophin. No viral vector except the helper-dependent adenovirus vector (HDAdv) can package 14-kilobase (kb) full-length dystrophin complementary DNA (cDNA), and HDAdv is considerably safer than old-generation adenovirus vectors because of the large-size deletion in its genome. We have generated HDAdv that carries myc-tagged murine full-length dystrophin cDNA (HDAdv-myc-mFLdys). We injected it into multiple proximal muscles of 7-day-old utrophin/dystrophin double knockout mice (dko mice) (which typically show symptoms quite similar to human DMD) because the proximal muscles are affected in DMD patients. Eight weeks after the injections, the transduced dystrophin was widely expressed, and we found a significant reduction in centrally nucleated myofibers and the restoration of the dystrophin-associated proteins, beta-dystroglycan (beta-DG) and alpha-sarcoglycan (alpha-SG), as well as neuronal nitric oxide synthase (nNOS). The injected dko mice also showed an increase in body weight, an improvement in motor performance, and a prolongation of life span. Using HDAdv, we could treat DMD model mice even by transferring the therapeutic gene into multiple skeletal muscles. Our results suggest that multiple intramuscular administrations of HDAdv carrying full-length dystrophin cDNA may reduce symptoms and compensate for lost functions in DMD patients.

Treatment of hyperinsulinemic hypoglycemia due to diffuse nesidioblastosis in adults: a case report.

An 82-year-old man was admitted to our hospital with a complaint of hypoglycemic syncope in the early morning. Insulinoma was suspected, but an abdominal CT showed no mass. Abdominal angiography showed a slight stain fed from the splenic artery. Arterial stimulation and venous sampling (ASVS) showed an abnormal insulin response only from the splenic artery. Under a provisional diagnosis of insulinoma, surgical treatment was undertaken. Although no pancreatic masses were palpable, we performed a distal pancreatectomy. Subsequently, a pathological examination revealed diffuse nesidioblastosis. Reported cases of diffuse nesidioblastosis have had common clinical features: postprandial hyperinsulinemic hypoglycemia, no abnormal findings in radiological examinations, and the presence of the ductulo-insular complex on histological examination. Surgical resection is recommended, but the extent of surgery is controversial. Our case had some clinical features of insulinoma but was diagnosed as diffuse nesidioblastosis according to histopathologic criteria. Because ASVS showed that the pancreatic body and tail had a lesion producing insulin abnormally, we performed a distal pancreatectomy to cure the hypoglycemia. Clinically, it is very difficult to distinguish diffuse nesidioblastosis from insulinoma. When we treat hyperinsulinemic hypoglycemia, ASVS can be an essential examination to decide the extent of pancreatectomy.

Regions downstream from the WW domain of dystrophin are important for binding to postsynaptic densities in the brain.

In order to investigate the mechanism of dystrophin localization in the central nervous system (CNS), we generated adenovirus vectors that contained minidystrophin or truncated minidystrophin cDNA. We infected a primary neuronal culture derived from mdx mouse hippocampus with these viruses. Minidystrophin was observed along the plasma membrane as punctate dots or very short segments. In double immunofluorescence staining with anti-dystrophin and anti-postsynaptic density-95 antibodies, we observed that these proteins entirely colocalized. On the other hand, the truncated minidystrophin, which has deleted WW, cysteine-rich and C-terminal domains, was homogenously expressed in cytoplasm, neurites and axons. These findings suggest that a binding site to postsynaptic densities exists in the region extending from the WW domain to the C-terminal domain of dystrophin and that this site is necessary for binding to membrane.

Mdx respiratory impairment following fibrosis of the diaphragm.

Duchenne muscular dystrophy (DMD) is a progressive muscle-wasting disease that causes respiratory or cardiac failure and results in death at about 20 years of age. An animal model of DMD, the mdx mouse, is commonly used to estimate dystrophic pathology. The pathological features of limb muscles are relatively mild, however the diaphragm is severely affected and exhibits a degenerative pattern similar to that observed in human DMD. Although, the muscle strength assay of the dystrophic diaphragm has been used to estimate mdx respiratory impairment, systemic functional assessments compared with histopathological analysis have not been demonstrated. Here, we report a sensitive procedure using whole-body plethysmography to monitor respiratory parameters detected during early respiratory insufficiency in the mdx mouse. The dystrophic changes in the diaphragm lead to respiratory dysfunctions. These methods may be useful to assess the therapeutic approaches for the mdx mouse.

[A case of myasthenia-like symptoms induced by cibenzoline overdosage].

The present patient was an 87-year-old man who had been taking cibenzoline for tachyarrhythmia. Five years after initiation of administration, he was referred to our hospital for ptosis that worsened from midday, as well as weakness of the facial and limb muscles. He tested negative for anti-acetylcholine receptor antibody but positive in the edrophonium test, suggesting that he had myasthenia gravis. He was admitted to our hospital 3 years later due to worsening symptoms of ptosis and muscle weakness. He had hypoglycemia, cardiac conduction defect, and renal dysfunction. In addition, blood concentration of cibenzoline was markedly high (1,850 ng/ml). We terminated the administration of cibenzoline, after which the patient's neurologic symptoms improved. Our findings suggest that cibenzoline toxicity must be considered in differentiating myasthenia gravis when a patient also presents with renal dysfunction.

Long-term effects of edaravone on survival of patients with amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: Oxidative stress has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Edaravone, a free radical scavenger, was approved as a therapeutic drug for ALS in 2015 in Japan. A phase 3 clinical trial demonstrated a smaller decline in ALS functional scale scores compared with placebo. However, the long-term effects of edaravone on ALS patients remain unclear. This study aimed to retrospectively investigate the long-term effects of edaravone on the survival of ALS patients. METHODS: We retrospectively analyzed 27 consecutive patients with ALS who were treated with edaravone and 30 consecutive ALS patients who were not treated with edaravone between 2010 and 2016. RESULTS: The differences of ALSFRS-R scores from baseline to 6 months was significantly reduced in the edaravone group, compared to the control group. The changes in serum creatinine, as a possible marker of ALS severity, from baseline to 6 and 12 months were significantly improved in the edaravone group, compared to the control group. The survival rate was significantly improved in the edaravone group compared with control patients. CONCLUSION: Our retrospective single-center analysis suggests slower progression and better prognosis of ALS patients with edaravone treatment. Further investigation, including prospective multicenter analysis, is warranted to confirm the usefulness of edaravone for a better prognosis of ALS.

Female dystrophinopathy: Review of current literature.

Skeletal muscle or cardiac symptoms are known to appear in a certain proportion of female patients carrying the dystrophin gene mutation. There is limited high-quality evidence to guide the treatment of female carriers of Duchenne muscular dystrophy/Becker muscular dystrophy (DMD/BMD). The available evidence is mainly based on expert opinions and clinical experience. To improve this situation, we reviewed 1002 reports published from 1967 to 2017 to assess the following themes: epidemiology, clinical symptoms, cardiomyopathy, burdens on parents or caregivers, pregnancy or delivery, and prognosis. We aimed to provide guidance for the provision of support, care, and education for patients, caregivers, and health care professionals. There were 271 reports before 1987, and 731 reports after 1987 when dystrophin was first recognized. In this review, we mainly selected 37 papers that were reported after 1987. In seven large research papers, the incidence of skeletal muscle damage among female carriers, including asymptomatic carriers, was reported as 2.5%-19%, and the incidence of dilated cardiomyopathy was 7.3%-16.7% for DMD and 0%-13.3% for BMD. We integrated and summarized the genetically definite manifesting carriers with skeletal muscle symptoms from 10 case series. In combined data, among 93 manifesting carriers, 16 (17.2%) presented with cardiac abnormalities. The frequency of manifesting carriers complicated by cardiomyopathy increased with age. Reports on cardiac magnetic resonance in female carriers and the burden on caregivers are increasing, whereas literatures concerning pregnancy, delivery, and prognosis in female carriers are limited. This represents a future direction for research.

Medical Attitudes Survey for Female Dystrophinopathy Carriers in Japan.

Objective This study attempted to clarify the current status of female dystrophinopathy carriers, including the numbers of patients, the status of genetic screening, the status of counseling, physicians' understanding, and barriers to registration. Methods We sent out questionnaires to 402 physicians registered in the Remudy dystrophinopathy registry. The total number of responses received was 130 (response rate: 32%). Result In total, 1,212 cases of Duchenne muscular dystrophy, 365 cases of Becker muscular dystrophy, and 132 cases of female dystrophinopathy with a confirmed genetic mutation were encountered, and genetic testing was performed in the mother in 137, 23, and 12 cases, respectively. With respect to the risk of the onset of health problems, 25% of physicians always explained, 29% usually explained, 29% sometimes explained, and 13% never explained the risk to the mothers and female siblings of dystrophinopathy patients. The most common reason for not explaining the risk was a lack of knowledge/information. Thirty-five percent were familiar with the guidelines for testing the heart function of carriers. Conclusion Fewer mothers of dystrophinopathy patients have undergone genetic testing in Japan than in other countries. A significant portion of doctors did not explain the risks of health problems due to a lack of knowledge. We hope this survey will lead to an increased discussion of female dystrophinopathy patients.

A case report of intracholecystic papillary neoplasm of the gallbladder resembling a submucosal tumor.

BACKGROUND: Intracholecystic papillary neoplasm (ICPN) is defined as papillary tumors detected macroscopically in the gallbladder. We report a case of ICPN which exhibited the atypical form like a submucosal tumor. CASE PRESENTATION: A 70-year-old man was admitted to our hospital because of hepatic disorder. Computed tomography and magnetic resonance imaging showed irregular thickening of the wall within the gallbladder fundus. Because the lesion might have been malignant, we performed laparoscopic cholecystectomy and liver bed resection. Macroscopic findings showed the mucosal surface of the tumor was smooth, and its form was similar to that of a submucosal tumor. Histopathological examination revealed papillary tumors within the mass with low-grade dysplasia; therefore, we diagnosed ICPN. CONCLUSION: In the present case, ICPN was resembling a submucosal tumor macroscopically because the tumors arose into the Rokitansky-Aschoff sinus and the adenomyomatous hyperplasia was merged with the ICPN. It is necessary to consider the possibility of tumor lesions within adenomyomatous hyperplasia.

Detection and management of cardiomyopathy in female dystrophinopathy carriers.

Regular health checkups for mothers of patients with Duchenne muscular dystrophy have been performed at National Hospital Organization Tokushima Hospital since 1994. Among 43 mothers participated in this study, 28 dystrophinopathy carriers were identified. Skeletal and cardiac muscle functions of these subjects were examined. High serum creatine kinase was found in 23 subjects (82.1%). Obvious muscle weakness was present in 5 (17.8%) and had progressed from 1994 to 2015. Cardiomyopathy was observed in 15 subjects (60.0%), including dilated cardiomyopathy-like damage that was more common in the left ventricular (LV) posterior wall. Late gadolinium enhancement on cardiac MRI was found in 5 of 6 subjects, suggesting fibrotic cardiac muscle. In speckle tracking echocardiography performed seven years later, global longitudinal strain was decreased in these subjects, indicating LV myocardial contractile abnormality. These results suggest that female dystrophinopathy carriers should receive regular checkups for detection and treatment of cardiomyopathy, even if they have no cardiac symptoms.

The effects of the Kumamoto earthquake on the clinical symptoms of patients with Parkinson's disease.

Our hospital is the designated treatment base for intractable neurological diseases in the Kumamoto Prefecture. It is located in the center of the prefecture where the major 7.3-magnitude Kumamoto earthquake was recorded in 2016. In order to examine whether this earthquake affected the clinical symptoms of patients with Parkinson's disease in this hospital, we investigated outpatients examined up to 4 weeks after the earthquake. The subjects were 26 consecutive patients without any changes in anti-Parkinson's disease treatment or their attending physician during the examination period. All of the items in Part III of the Unified Parkinson's Disease Rating Scale (UPDRS), which is a clinician-scored scale for monitoring and evaluating motor function, were confirmed with the subjects before and after the earthquakes. After the earthquakes, worsened symptoms were found in 7 patients and 7 patients felt better. On the UPDRS, worsened symptoms were most commonly found among the items examining "muscle rigidity" and "slowness of movement and decreased movement" among the 7 patients with exacerbated symptoms. After the earthquake, clinical symptoms worsened significantly in women (P = 0.0188), patients with mild symptoms (P = 0.0111), and those who suffered a high degree of personal loss, such as those whose homes were damaged, who were forced to take refuge, or who had to sleep in their car (P = 0.0184). The mental and emotional burden due to the earthquake might be particularly high in the group of patients with worsened symptoms, suggestive of a relationship between stress and the exacerbation of parkinsonian symptoms.

Utility of skinfold thickness measurement in non-ambulatory patients with Duchenne muscular dystrophy.

Nutritional disorders in Duchenne muscular dystrophy (DMD) worsen the medical condition. In particular, obesity is a serious problem that increases the risk of cardiomyopathy and affects nursing care. However, it is often difficult to evaluate body fatness in the advanced stages of DMD. Skinfold thickness measurement is a classical method to evaluate body fatness and is easily performed, even for bed-bound patients at home. We aimed to investigate the utility of skinfold thickness measurement in non-ambulatory DMD patients. Twenty-two patients with non-ambulatory, steroid-naive DMD ranging in age of 12-47 years were evaluated by body mass index (BMI), blood tests, measurement of triceps skinfold thickness (TSF), and abdominal computed tomography (CT) measurement of the areas of both subcutaneous and visceral fat. TSF showed good correlation with BMI (r = 0.80; p < 0.001), serum triglycerides (r = 0.67; p < 0.01), area of subcutaneous fat (r = 0.85; p < 0.0001), and area of visceral fat (r = 0.76; p < 0.0001). These results indicate the skinfold thickness measurement may be applicable as a screening tool in clinical practice where CT and magnetic resonance imaging assessment is often difficult in patients with advanced DMD.