Cytochrome P450 oxidoreductase deficiency: Rare congenital disorder leading to skeletal malformations and steroidogenic defects

Cytochrome P450 oxidoreductase (POR) deficiency (PORD) is a newly characterized disorder. PORD is caused by homozygous or compound heterozygous mutations in POR encoding an electron donor for several microsomal enzymes such as CYP21A2, CYP17A1, CYP19A1, CYP51A1, and CYP26A1‐C1. Molecular defects of PORD include a Japanese founder mutation p.R457H, as well as various missense, nonsense, frameshift, and splice‐site mutations and exonic deletions. PORD leads to unique skeletal malformations referred to as Antley–Bixler syndrome, in addition to 46,XX and 46,XY disorders of sex development, pubertal failure, adrenal dysfunction, and maternal virilization during pregnancy. Such clinical features are ascribable to impaired activities of the POR‐dependent microsomal enzymes. PORD represents one form of congenital adrenal hyperplasia, although it can occur as a congenital malformation syndrome and a disorder of sex development. Phenotypic severity of PORD is highly variable and only partly depends on the residual activity of the mutant proteins. It is possible that PORD remains undiagnosed in several patients. Detailed hormonal assessment and molecular analysis are useful for diagnosis of PORD.     

Laparoscopic pancreaticoduodenectomy for remnant pancreatic recurrence after laparoscopic distal pancreatectomy and hepatectomy for greater omentum leiomyosarcoma

Laparoscopic pancreatic surgery is one of the most difficult procedures, and the adoption of laparoscopic pancreaticoduodenectomy has been limited. The application of laparoscopic surgery has extended to advance cancer, but there have been no reports of laparoscopic pancreaticoduodenectomy after laparoscopic liver resection and distal pancreatectomy. In the present case, a 67‐year‐old woman was diagnosed with remnant pancreatic recurrence of metastatic greater omentum leiomyosarcoma. She had previously undergone laparoscopic distal pancreatectomy and left lateral liver sectionectomy in 2016. We performed laparoscopic subtotal stomach‐preserving pancreaticoduodenectomy in June 2017. The operation time was 274 minutes, and the estimated blood loss was 50 mL. There were no postoperative complications. In summary, laparoscopic pancreaticoduodenectomy is a safe and feasible procedure for a patient who had previously undergone pancreas and liver surgery.     

Silver-Russell syndrome in a girl born after <Emphasis Type="Italic">in vitro</Emphasis> fertilization: partial hypermethylation at the differentially methylated region of <Emphasis Type="Italic">PEG1</Emphasis>/<Emphasis Type="Italic">MEST</Emphasis>

Purpose: The prevalence of low birth weight (LBW) is increased in subjects born after assisted reproduction technology (ART), and defective imprinting has frequently been identified in patients with Beckwith-Wiedermann and Angelman syndromes conceived by ART. Thus, we examined methylation pattern in a girl born after ART who had Silver-Russell syndrome (SRS) which can be caused by maternal uniparental disomy for chromosome 7 and by hypomethylation of the differentially methylated region (DMR) of H19. Methods: We examined methylation status of 31 cytosines at the CpG dinucleotides in the DMR of PEG1/MEST on 7q32.2 and 23 cytosines at the CpG dinucleotides in the DMR of H19 on 11p15, using leukocyte genomic DNA. Results: Eight of the 31 cytosines in the patient and four of the 31 cytosines in the father were hypermethylated in the PEG1/MEST-DMR. In the H19-DMR, no abnormal methylation pattern was identified in the patient. Conclusion: The results suggest that hypermethylation of paternally expressed genes including PEG1/MEST, which usually have growth-promoting effects, may be relevant to LBW in subjects conceived by ART. Partial hypermethylation was identified at the differentially methylated region of paternally expressed PEG1/MEST in a girl with Silver-Russell syndrome born after in vitro fertilization.     

Obstetrical factors for death and brain injury among extremely-low-birth-weight infants

OBJECTIVE: To examine the obstetrical risk factors for death and brain injury among extremely-low-birth-weight (ELBW) infants (birth weight <1000 g). STUDY DESIGN: Study subjects were 121 ELBW infants born at a single tertiary perinatal center. Death among ELBW infants was considered to have occurred when subjects died within their corrected age of 40 weeks. In the sub-analysis of the 91 ELBW infants who survived their corrected age of 40 weeks, brain injury was defined as present when criteria based on ultrasound and/or MRI were substantiated. RESULTS: A birth weight of <800 g [adjusted odds ratio (OR), 14.57; 95% confidence interval (CI), 4.72-56.98], a younger gestational age of <26 weeks (adjusted OR, 4.64; 95% CI, 1.60-14.90), and a low Apgar score of <5 (adjusted OR, 3.88; 95% CI, 1.32-12.45) were significantly associated with death among ELBW infants. A maternal age of 30 years or older (adjusted OR, 3.71; 95% CI, 1.19-13.35) was only associated with brain injury among surviving ELBW infants. CONCLUSION: Obstetrical care should be aimed at preventing or predicting premature delivery especially at <26 weeks of gestation.     

Intra- and inter-examiner reliability and minimal detectable change for different methods of measuring toe grip strength in healthy adults

[Purpose] This study aimed to compare the inter- and intra-examiner reliabilities of toe grip strength measurements obtained just above the first interphalangeal joint with those of toe grip strength measurements obtained in the most comfortable position for the participant. The study also aimed to calculate the minimal detectable change for the more reliable method. [Participants and Methods] The participants for each test included 20 healthy adult males and females. Intra-class correlation coefficient (1,1) and (2,1) values were calculated for both tests. Bland–Altman analysis was used to determine the systematic error and calculate the minimal detectable change. [Results] The intra- and inter-examiner reliabilities of measurements obtained by setting the position of the toe-grasping bar to the first interphalangeal joint were better than those obtained in the most comfortable position for the participant. Measurement of the minimal detectable change showed a random error of 4.97 kg. [Conclusion] We considered that toe grip strength measurements just above the first interphalangeal joint were better. The minimal detectable change was 4.97 in healthy adults.     

Non–clinical efficacy,safety and stable clinical cell processing of induced pluripotent stem cell‐derived anti–glypican‐3 chimeric antigen receptor‐expressing natural killer/innate lymphoid cells

The use of allogeneic, pluripotent stem‐cell‐derived immune cells for cancer immunotherapy has been the subject of recent clinical trials. In Japan, investigator‐initiated clinical trials will soon begin for ovarian cancer treatment using human leukocyte antigen (HLA)‐homozygous‐induced pluripotent stem cell (iPSC)‐derived anti–glypican‐3 (GPC3) chimeric antigen receptor (CAR)‐expressing natural killer/innate lymphoid cells (NK/ILC). Using pluripotent stem cells as the source for allogeneic immune cells facilitates stringent quality control of the final product, in terms of efficacy, safety and producibility. In this paper, we describe our methods for the stable, feeder‐free production of CAR‐expressing NK/ILC cells from CAR‐transduced iPSC with clinically relevant scale and materials. The average number of cells that could be differentiated from 1.8‐3.6 × 10⁶ iPSC within 7 weeks was 1.8‐4.0 × 10⁹. These cells showed stable CD45/CD7/CAR expression, effector functions of cytotoxicity and interferon gamma (IFN‐γ) production against GPC3‐expressing tumor cells. When the CAR‐NK/ILC cells were injected into a GPC3‐positive, ovarian‐tumor‐bearing, immunodeficient mouse model, we observed a significant therapeutic effect that prolonged the survival of the animals. When the cells were injected into immunodeficient mice during non–clinical safety tests, no acute systemic toxicity or tumorigenicity of the final product or residual iPSC was observed. In addition, our test results for the CAR‐NK/ILC cells generated with clinical manufacturing standards are encouraging, and these methods should accelerate the development of allogeneic pluripotent stem cell‐based immune cell cancer therapies.     

Clinicopathological study of nonalcoholic fatty liver disease in Japan: the risk factors for fibrosis

Background/Aims: We evaluated patients with nonalcoholic fatty liver disease (NAFLD) and compared the clinical and pathological features to identify the risk factors for NAFLD with severe fibrosis. Methods: One hundred and eighty‐two patients with biopsy‐confirmed NAFLD from various medical centres were recruited into this study. Results: The variables that were significantly associated with severe steatosis were male gender (mild:severe=36%:53%, P=0.02), younger age (mild:severe=57%:82%, P>0.001) and absence of type 2 diabetes (mild:severe=43%:71%, P>0.001). There was no significant difference in the degree of inflammation among the clinical groups. The variables that were significantly associated with severe fibrosis were female gender (mild:severe=54%:84%, P=0.002), older age (≥60 years old) (mild:severe=29%:53%, P=0.020), type 2 diabetes (mild:severe=42%:71%, P=0.020) and hypertension (mild:severe=24%:53%, P=0.002). Although there were more obese patients in the group with severe fibrosis, the association was not statistically significant (mild:severe=67%:78%, P=0.229). The prevalence of high serum triglyceride levels was similar between the two groups. The N (Nippon) score (total number of risk factor) could significantly predict severe fibrosis in NAFLD patients (1.48 ± 1.14 vs. 2.66 ± 0.94, P<0.001). Conclusions: The N score can be used to predict severe fibrosis in cases of NAFLD.     

Dialysate Vascular Endothelial Growth Factor Is an Independent Determinant of Serum Albumin Levels and Predicts Future Withdrawal From Peritoneal Dialysis in Uremic Patients

Peritoneal protein loss due to high peritoneal permeability may contribute to hypoalbuminemia and early withdrawal from peritoneal dialysis (PD) therapy in end stage renal disease (ESRD) patients. We have found that pigment epithelium‐derived factor (PEDF) has anti‐vasopermeability properties both in cell culture and animal models by counteracting the biological actions of vascular endothelial growth factor (VEGF). However, it remains unknown which clinical variables, including dialysate VEGF and PEDF, are associated with decreased serum albumin levels and could predict early withdrawal from the PD in ESRD patients. We address these issues. Twenty‐seven ESRD patients undergoing PD were enrolled. Clinical variables were measured at 6 months after commencing PD. We examined the independent correlates of serum albumin in PD patients and then prospectively investigated the predictors of withdrawal from the PD therapy over 4 years. Dialysate VEGF was associated with peritoneal solute transport rate (P = 0.002), serum albumin (inversely, P < 0.001) and dialysate PEDF levels (P < 0.001). In multiple stepwise regression analysis, age (P = 0.002) and dialysate VEGF levels (P < 0.001) were independent determinants of serum albumin levels. High VEGF (>27 pg/mL), low serum albumin (≤3.31 g/dL) and low hemoglobin (≤11.2 g/dL) were correlated with withdrawal from the PD therapy during the 4 years. The odds ratio of dialysate VEGF for early withdrawal from the PD was 6.310 (P = 0.035). The present study demonstrated that increased dialysate VEGF was associated with decreased serum albumin and early withdrawal from the PD therapy. Inhibition of peritoneal VEGF production may be a therapeutic target in PD patients.