Moyamoya disease (MMD) is a chronic steno‐occlusive arteriopathy involving the development of abnormal collateral vessels. Ring finger protein (RNF213) on the 17q25.3 locus was identified as an ...MMD‐susceptibility gene in East Asian populations. We report a 5‐year‐old Japanese boy diagnosed with cerebral infarction and unilateral MMD. Magnetic resonance angiography (MRA) showed severe stenosis of the left internal carotid artery (ICA), terminal portion of the left ICA, and left origin of the posterior cerebral artery. Genetic testing indicated a heterozygous c.14429G > A (formerly described as c.14576G > A) variant in RNF213. The boy's mother had no neurological symptoms, but sequencing of RNF213 showed the same variant, and MRA indicated stenosis of the terminal bilateral ICA. This is the first report, to our knowledge, of different MMD phenotypes in a familial case involving the same heterozygous c.14429G > A variant in RNF213. Genetic testing for RNF213 is suggested for family member screening.
Objectives
To report our experience with intravesical injection of botulinum toxin type A into the detrusor muscle of patients with neurogenic detrusor overactivity secondary to suprasacral spinal ...cord lesions or multiple sclerosis.
Methods
Between January 2003 and March 2011, 11 patients (aged 23–75 years) were treated with 40 injections of botulinum toxin type A 300 U. The patients were followed up for 4, 8 and 12 weeks after treatment. The King's Health Questionnaire was administered and cystometric studies were carried out at baseline and 8 weeks after treatment.
Results
A total of six women and five men were treated. Analysis of the King's Health Questionnaire showed a significant improvement in eight of the nine domain scores at 8 weeks from baseline. On cystometric studies, the mean maximum cystometric capacity increased significantly in all patients at 8 weeks from baseline (P < 0.001). Bladder compliance also increased significantly (P < 0.001). The number of urinary incontinence episodes per day improved significantly from baseline after injection (4 weeks, P < 0.001; 8 weeks, P < 0.001; 12 weeks, P < 0.001). Lack of efficacy appeared 7.15 ± 3.4 months after treatment.
Conclusions
Injection of botulinum toxin type A into the detrusor muscle of patients with neurogenic detrusor overactivity secondary to suprasacral spinal cord lesions or multiple sclerosis consistently improves bladder control and quality of life.
Aim
To determine risk factors associated with hepatocellular carcinoma (HCC) development following direct‐acting antiviral (DAA) therapy.
Methods
We enrolled patients with chronic hepatitis C who ...underwent direct‐acting antiviral therapy and achieved sustained virologic response at 12 weeks between 2012 and 2018. Subsequently, patients were followed up. The primary endpoint was the development of HCC or the date of the last follow up when the absence of HCC was confirmed. Uni‐ and multivariate Cox proportional hazards models were used to identify factors contributing to HCC development, including gadoxetic acid‐enhanced magnetic resonance imaging findings. The cumulative incidence rates of HCC development were calculated using the Kaplan–Meier method, and differences between groups were assessed using the log‐rank test.
Results
The final study cohort comprised 482 patients (median age 70.5 years; 242 men). The median follow‐up period was 36.8 months. Among 482 patients, 96 developed HCC (19.9%). The 1‐, 3‐, and 5‐year cumulative rates of HCC development were 4.9%, 18.6%, and 30.5%, respectively. Multivariate analysis revealed that age, male sex, history of HCC, and hepatobiliary phase hypointense nodules without arterial phase hyperenhancement were independent risk factors significantly associated with HCC development (p < 0.001–0.04). The highest risk group included patients with both a history of HCC and the presence of hepatobiliary phase hypointense nodules without arterial phase hyperenhancement (the 1‐ and 3‐year cumulative HCC development rates were 14.2% and 62.2%, respectively).
Conclusion
History of HCC and presence of hepatobiliary phase hypointense nodules without arterial phase hyperenhancement were strong risk factors for HCC development following direct‐acting antiviral therapy.
According to the multivariate analysis, age, male sex, history of hepatocellular carcinoma, and hepatobiliary phase hypointense nodule without arterial phase hyperenhancement were independent risk factors significantly associated with the development of hypervascular hepatocellular carcinoma (p < 0.001–0.04). The incidence rate of hypervascular hepatocellular carcinoma was significantly higher among patients with a history of hepatocellular carcinoma than in those without a history of hepatocellular carcinoma (p < 0.001). The 1‐, 3‐, and 5‐year cumulative hypervascular hepatocellular carcinoma development rates were 11.7%, 46.9%, and 71.9%, respectively, among patients with a history of hepatocellular carcinoma, whereas the rates were 2.0%, 8.0%, and 9.7%, respectively, in the patients without a history of hepatocellular carcinoma. The incidence rate of hypervascular hepatocellular carcinoma was significantly higher among patients with hepatobiliary phase hypointense nodule without arterial phase hyperenhancement than in those without that nodule (p < 0.001). The 1‐, 3‐, and 5‐year cumulative hypervascular hepatocellular carcinoma development rates were 10.9%, 44.2%, and 61.6%, respectively, in the patients with hepatobiliary phase hypointense nodule without arterial phase hyperenhancement, whereas the rates were 2.5%, 9.9%, and 15.9%, respectively, in the patients without that nodule.
Abstract
Skin is the largest organ system and is exposed to ultraviolet (UV) or sun light, a well-known mutagenic insult in various skin cancers, depending on the body site. A previous study showed ...that keratinocytes in sun-exposed eyelids harbor a high number of somatic mutations affecting a number of common driver mutations found in skin cancers, including NOTCH1, NOTCH2, NOTCH3, FAT1, TP53, and RBM10, suggesting pervasive expansion of clones before the development of skin cancer. However, clonal expansion in other skin sites in association not only with UV but also other insults, such as chronic inflammation is yet to be evaluated.
Thus, to fully characterize the clonal expansion in the skin, we performed sequencing analysis of apparently normal skin, as well as that affected by chronic inflammatory conditions such as psoriasis and atopic dermatitis. We analyzed small fragments (0.2mm2) of epidermal samples accrued from surplus biopsy materials using exome sequencing.
Analysis of bulk epidermal samples revealed a median of ~30 mutations/exome. Sun-exposed skin was notable for a high mutation burden (>200 mutations/exome). On the basis of the analysis of their variant allele frequencies, the median clone size was estimated to be ~0.1mm2. Several cases harbored large of clones that spanned multiple samples, which were invariably found in sun-exposed skin. In one of such cases, a clone spanned a region having more than 2mm in diameter. Skin affected by chronic inflammation showed a higher number of mutations. dN/dS analysis revealed positively selected driver genes that were similar to the previous report. Diseased skin showed a similar mutation profile that is seen in apparently normal sun-exposed skin. Analysis of mutational signature disclosed signatures that are related ageing (SBS1) and UV light exposure (SBS7). The contribution of SBS7 was prominent in the sun-exposed area but also detected in areas not exposed to sun light, such as the back, buttock, or thighs. By contrast, inflammation-affected skin samples are characterized by a large contribution of the SBS1 signature, likely reflecting increased cell cycles.
In conclusion, our analysis shows UV light is a relevant driver of clonal expansion of skin keratinocytes. Chronic inflammation accelerates an accumulation of somatic mutations in and/or clonal expansion of keratinocytes.
Citation Format: Yoshihiro Ishida, Nobuyuki Kakiuchi, Yoichi Fujii, Tomonori Hirano, Yoshikage Inoue, Tomomi Nishimura, Tatsuki Ogasawara, Hirona Maeda, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Satoru Miyano, Atsushi Otsuka, Kenji Kabashima, Seishi Ogawa. Clonal expansion of skin keratinocyte abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2675.
Background
Donor mixed chimerism (MC) is an increasing problem after hematopoietic stem cell transplantation (HSCT) for nonmalignant diseases.
Procedure
In this study, a self‐administered ...questionnaire was used to retrospectively compare efficacy and safety in 49 patients undergoing second HSCT (n = 13) or donor lymphocyte infusion (DLI; n = 36) as treatment for MC.
Results
The response rate to DLI of patients with secondary graft failure (GF) (25.0%) was significantly lower than that of patients without secondary GF (81.3%; P = 0.041). Among patients undergoing DLI, the rates of successful response were significantly higher in patients having at least 30% donor chimerism (94.1%) than in patients having less than 30% donor chimerism (61.1%; P = 0.041). Furthermore, the rates of successful response were significantly higher in patients receiving larger first or maximum doses of DLI. Sixteen (50.0%) of 32 patients without secondary GF attained complete chimerism after DLI. The cumulative incidence of grade II–IV acute graft‐versus‐host disease and cytopenia was 37.6 and 26.1%, respectively.
Conclusions
DLI yields promising response rates in most patients with higher donor chimerism levels, whereas second HSCT is more likely to benefit patients with lower donor chimerism levels.
Aim
Daclatasvir, a non‐structural (NS)5A replication complex inhibitor, is a potent and promising direct antiviral agent (DAA) for hepatitis C virus (HCV), being most effective in genotype 1b ...infection. Although it is known that genotype 1b viruses with Y93H and/or L31M/V/F mutations have strong resistance to daclatasvir, it is not known whether there are some clinical background conditions that favor the occurrence of HCV carrying those NS5A mutations.
Methods
In this study, we carried out deep sequencing analysis of stored sera to determine the presence and significance of daclatasvir‐resistant mutants in 110 genotype 1b HCV‐infected patients with no previous daclatasvir treatment.
Results
Deep sequencing analysis revealed that the NS5A L31M/V/F and Y93H mutations were present in 13 (11.8%) and 34 (30.9%) of the 110 patients, respectively, and significantly more frequently than in the control plasmid. Simultaneous L31M/V/F and Y93H mutations were detected in four of the 110 patients (3.6%). When the clinical relevance of NS5A resistance was investigated, Y93H was significantly correlated with the IL28B major (TT) genotype of the host (P = 0.042).
Conclusion
Y93H was detected frequently by deep sequencing in daclatasvir treatment‐naïve patients. Importantly, it seems that the IL28B status of the patients may influence the presence of Y93H mutations, resulting in different treatment responses to daclatasvir.
Aims
To assess the efficacy and safety of once‐daily lixisenatide versus placebo in Asian patients with type 2 diabetes insufficiently controlled on basal insulin ± sulfonylurea.
Methods
In this ...24‐week, randomized, double‐blind, placebo‐controlled, parallel‐group, multicentre study, participants (mean baseline HbA1c 8.53%) from Japan, Republic of Korea, Taiwan and the Philippines received lixisenatide (n = 154) or placebo (n = 157) in a stepwise dose increase to 20 µg once daily. The primary endpoint was HbA1c change from baseline to week 24.
Results
Once‐daily lixisenatide significantly improved HbA1c versus placebo (LS mean difference vs. placebo = −0.88% 95%CI= −1.116, −0.650; p < 0.0001), and allowed more patients to achieve HbA1c <7.0% (35.6 vs. 5.2%) and ≤6.5% (17.8 vs. 1.3%). Lixisenatide also significantly improved 2‐h postprandial plasma glucose and glucose excursion, average 7‐point self‐monitored blood glucose and fasting plasma glucose. Lixisenatide was well tolerated; 86% of patients on lixisenatide completed the study versus 92% on placebo. Ten (6.5%) lixisenatide and 9 (5.7%) placebo patients experienced serious adverse events. More lixisenatide patients 14 (9.1%) discontinued for adverse events versus placebo 5 (3.2%), mainly with gastrointestinal causes. Nausea and vomiting were reported in 39.6 and 18.2% of patients on lixisenatide versus 4.5 and 1.9% on placebo. Symptomatic hypoglycaemia was more frequent with lixisenatide (42.9%) versus placebo (23.6%), but was similar between groups (32.6 vs. 28.3%, respectively), in those not receiving sulfonylureas. No severe hypoglycaemia was reported.
Conclusions
In an Asian type 2 diabetes population insufficiently controlled by basal insulin ± sulfonylurea, once‐daily lixisenatide significantly improved glycaemic control, with a pronounced postprandial effect, and was well tolerated.
The revised core curriculum for pharmaceutical education requires pharmacy students to gain experience during the pharmacy and hospital clinical clerkships in medication counseling of patients with a ...major disease. However, since some pharmacies do not treat all of these diseases, we created a new education method for pharmacy clerkships. This trial’s primary purpose was to provide opportunities for students in medication counseling with as many kinds of diseases as possible. The preceptor pharmacists received assistance from cooperating pharmacists of other pharmacies for educating the pharmacy students on specific diseases that could not be covered at the original training pharmacy. The cooperating pharmacists provided three days of practical education at three-week intervals throughout the eleven-week clerkship. Thirteen students participated in this program and gave medication counseling to patients with the diseases such as a psycho-neurologic disease, hypertension, or other diseases that could not be covered at the original training pharmacy. During the three days, the median number of patients treated by each student was five, with a range of two to 23 patients. The students also learned how to make a record of the patient’s medication history. This cooperative method among pharmacies was an effective measure in providing the required learning for the clinical clerkships.
Background
Physicians rarely select surgery a second time as the treatment for octogenarians with hepatocellular carcinoma (HCC) recurrence.
Methods
We encountered eight male and three female ...octogenarians underwent surgery a second time as the treatment for HCC recurrence (octo group). We studied these cases clinically and compared them with 25 younger people underwent surgery a second time (young group). All patients of octo group have resectable HCC according to the Japanese guideline, that is HCC patients with Child‐Pugh status A or B and who have solitary or only a few HCC nodules, in addition, no serious comorbidities, no serious dementia, a performance status of 0–1 and the will to receive hepatectomy.
Results
The average maximum tumour size at the first hepatectomy was significantly larger than that at the second hepatectomy (P < 0.05). The extent of the first hepatectomy was significantly greater than that of the second one (P < 0.05). There were no mortalities at either hepatectomy. The morbidities of the first and the second hepatectomies were 9.1% and 18.2%, respectively. All complications were bile leakage. Furthermore, there were no significant differences in the clinical features, including the prognosis, between the octo and young groups.
Conclusion
Selected octogenarians who received a second hepatectomy showed a relatively good post‐operative course after the first and second hepatectomies. Repeated hepatectomy for octogenarians seems to have same positive influence on the prognosis in comparison to the young group. But on the data analysed, we have not shown repeated hepatectomy is superior to non‐surgical treatments.
Repeated hepatectomy for octogenarians have same positive influence on the prognosis in comparison to the young group.
Pod size of soybean is an important factor in the determination of seed weight. However, little is known about pod growth of soybean. Brassinosteroid, a group of phytohormones, regulate the pod ...growth of faba bean. We therefore investigated the role of brassinosteroid in pod growth of soybean. We measured pod length and cell number and cell area in pods treated with a brassinosteroid biosynthesis inhibitor. The inhibitor suppressed pod growth through the reduction of cell area. We then examined pod morphology and the expression of brassinosteroid biosynthesis (
GmCYP450 85A1
,
2
and
3
) and response (
GmBZR1
,
GmBES1
and
GmBRU1
) genes in the pods of two cultivars that differ in pod size. The difference in pod size was attributable to cell area, and the expression of brassinosteroid biosynthesis and response genes in pods was higher in the cultivar that has large pods. These results suggest that pod size of soybean is regulated through cell hypertrophy caused by brassinosteroid.
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