Radiotherapy plus cetuximab for locally advanced squamous cell head and neck cancer in patients with cisplatin-ineligible renal dysfunction: A retrospective study

Clinical trials have not fully demonstrated the efficacy and safety of radiotherapy plus cetuximab for locally advanced squamous cell head and neck cancer (LA-SCCHN) in patients with cisplatin-ineligible renal dysfunction. Patients who received radiotherapy plus cetuximab for LA-SCCHN at Chiba University Hospital (Chiba, Japan) between July 2013 and October 2018 were retrospectively reviewed. Background characteristics and locoregional control and overall survival rates were compared between patients with and without renal dysfunction. Survival was examined using Kaplan-Meier analysis and an adjusted Cox proportional hazards model. Kaplan-Meier analysis demonstrated that overall survival was shorter in patients with creatinine clearance of <45 ml/min (P=0.041; log-rank test). However, there was no difference in the locoregional control rate (P=0.477; log-rank test). Adjusted Cox analysis revealed that the risk of death was increased by 2.52-fold (hazard ratio, 2.52; 95% confidence interval, 1.01-6.30; P=0.048) if creatinine clearance was <45 ml/min. Moderate to severe renal dysfunction did not affect the locoregional control rate in patients with LA-SCCHN treated with radiotherapy plus cetuximab but was an adverse prognostic factor.     

Genetic variations and haplotype structures of the ABC transporter gene ABCC1 in a Japanese population

Multidrug resistance-related protein 1 (MRP1), an ATP-binding cassette transporter encoded by the ABCC1 gene, is expressed in many tissues, and functions as an efflux transporter for glutathione-, glucuronate- and sulfate-conjugates as well as unconjugated substrates. In this study, the 31 exons and their flanking introns of ABCC1 were comprehensively screened for genetic variations in 153 Japanese subjects to elucidate the linkage disequilibrium (LD) profiles and haplotype structures of ABCC1 that is necessary for pharmacogenetic studies of the substrate drugs. Eighty-six genetic variations including 31 novel ones were found: 1 in the 5'-flanking region, 1 in the 5'-untranslated region (UTR), 20 in the coding exons (9 synonymous and 11 nonsynonymous variations), 4 in the 3'-UTR, and 60 in the introns. Of these, eight novel nonsynonymous variations, 726G>T (Trp242Cys), 1199T>C (Ile400Thr), 1967G>C (Ser656Thr), 2530G>A (Gly844Ser), 3490G>A (Val1164Ile), 3550G>A (Glu1184Lys), 3901C>T (Arg1301Cys), and 4502A>G (Asp1501Gly), were detected with an allele frequency of 0.003. Based on the LD profiles, the analyzed regions of the gene were divided into five LD blocks (Blocks -1 and 1 to 4). The multiallelic repeat polymorphism in the 5'-UTR was defined as Block -1. For Blocks 1, 2, 3 and 4, 32, 23, 23 and 13 haplotypes were inferred, and 9, 7, 7 and 6 haplotypes commonly found on > or = 10 chromosomes accounted for > or = 91% of the inferred haplotypes in each block. Haplotype-tagging single nucleotide polymorphisms for each block were identified to capture the common haplotypes. This study would provide fundamental and useful information for the pharmacogenetic studies of MRP1-dependently effluxed drugs in Japanese.     

Successful allogeneic stem cell transplantation in two patients with acute myelogenous leukaemia and invasive aspergillosis by antifungal combination therapy

Invasive aspergillosis (IA) is an important cause of infectious morbidity and mortality in patients who undergo haematopoietic stem cell transplantation (HSCT). History of IA before allogeneic HSCT is still challenging because of the high risk of recurrence after HSCT. Recent advances in early‐stage diagnosis and new, more effective classes of antifungal agents have improved the management of IA in the HSCT recipients. We report two cases with acute myelogenous leukaemia after primary failure of induction chemotherapy with the patients developing pulmonary IA. They responded well to a combination of voriconazole (VCZ) and micafungin, resulting in a remarkable reduction of pulmonary IA lesions at short intervals. Thereafter, antifungal therapy was switched to liposomal amphotericin B (L‐AmB), followed by conditioning regimen for allogeneic HSCT, because of the possibility of VCZ altering the metabolism of chemotherapeutic agents and calcineurin inhibitors. Successful engraftment was achieved without severe adverse side‐effects or aggravation of IA after HSCT. Combining VCZ with micafungin followed by L‐AmB throughout HSCT could be advantageous in stabilising IA in HSCT patients.     

Association of dietary and genetic factors related to one‐carbon metabolism with global methylation level of leukocyte DNA

Global hypomethylation of leukocyte DNA has been associated with an increased risk of cancer. As dietary and genetic factors related to one‐carbon metabolism may influence both the methylation and synthesis of DNA, we investigated associations between these factors and the global methylation level of peripheral blood leukocyte DNA based on a cross‐sectional study of 384 Japanese women. Dietary intake of folate and vitamins B2, B6, and B12 was assessed with a validated semiquantitative food frequency questionnaire. Five polymorphisms in methylenetetrahydrofolate reductase (MTHFR) ( rs1801133 and rs1801131 ), methionine synthase (MTR) ( rs1805087 ), and methionine synthase reductase (MTRR) ( rs10380 and rs162049 ) were genotyped. Global DNA methylation of leukocyte DNA was quantified using Luminometric Methylation Assay. A linear trend of association between methylation and dietary and genetic factors was evaluated by regression coefficients in a multivariable linear regression model. Mean global methylation level (standard deviation) was 70.2% (3.4) and range was from 59.0% to 81.2%. Global methylation level significantly decreased by 0.36% (95% confidence interval, 0.03–0.69) per quartile category for folate level. Subgroup analysis suggested that alcohol drinking modified the association between folate intake and global methylation level (P_interaction = 0.01). However, no statistically significant association was observed for intake of vitamins B2, B6, and B12, alcohol consumption, or five single nucleotide polymorphisms of MTHFR, MTR, and MTRR. We found that higher folate intake was significantly associated with a lower level of global methylation of leukocyte DNA in a group of healthy Japanese females.     

Prospective study of intramuscular ergometrine compared with intramuscular oxytocin for prevention of postpartum hemorrhage

AIM: To compare the efficacy and safety of intramuscular oxytocin with intramuscular ergometrine in the management of postpartum hemorrhage during the third stage of labor. METHODS: Women who had been pregnant for more than 35 weeks and delivered cephalic singletons vaginally without predelivery administration of oxytocics were included. The cases considered to be at high risk were excluded, such as those who had uterine fibroids, a previous cesarean section, previous postpartum hemorrhage, or severe anemia. Five units of oxytocin or 0.2 mg of methylergometrine were administered intramuscularly immediately after delivery of the baby. RESULTS: Compared with intramuscular ergometrine, the use of intramuscular oxytocin was associated with a significant reduction in mean total postpartum blood loss (288.16 g vs 354.42 g, P = 0.004), frequency of postpartum hemorrhage (> or=500 mL: 10.9% vs 20.32%, relative risk [RR] = 0.54, 95% confidence interval [CI] = 0.32-0.91), and need for therapeutic oxytocics (5.13% vs 12.3%, RR = 0.42, 95% CI = 0.19-0.91). There were no differences between the groups in terms of the mean duration of the third stage, the mean level of hemoglobin on the second postpartum day, and the frequency of postpartum hemorrhage (> or =1000 mL), or manual removal of placenta. Few side-effects were found, with no significant differences between the groups. CONCLUSIONS: The routine use of intramuscular oxytocin is more effective than the use of intramuscular ergometrine for prevention of postpartum hemorrhage in the third stage of labor.     

Uterine artery embolization should not be recommended without careful consideration in the treatment of symptomatic uterine fibroids

AIM: To evaluate convalescence and the incidence of adverse symptoms associated with uterine artery embolization (UAE) in the treatment of uterine fibroids, several parameters after UAE were compared with those after laparoscopic surgery. METHODS: For the treatment of uterine fibroids, 78 patients underwent UAE and 58 received laparoscopic surgery (31 were laparoscopic myomectomy [LM] and 27 were laparoscopy-assisted myomectomy [LAM]) during the period July 2001 to July 2004. The length of hospitalization, and the periods until the beginning of a normal daily life, work and exercise, long-term follow up data in the UAE and laparoscopy groups were compared, and the incidence of adverse symptoms after each procedure was compared. RESULTS: The length of hospitalization for the UAE group 2.1 +/- 0.1 (mean +/- S.E) was significantly shorter than those for the LM and LAM groups (2.6 +/- 0.1 and 3.8 +/- 0.2 days, respectively; P < 0.0001 and P < 0.0001). The period until beginning of normal daily life and work were similar between the UAE and LM groups. The degree of improved symptoms after each procedure were similar among the three groups, but the incidence of adverse symptoms after UAE was significantly higher than after laparoscopic surgery. CONCLUSIONS: The UAE group showed a significantly shorter period of hospitalization, but the convalescence of the UAE group was similar to the LA group, with a higher incidence of adverse symptoms than laparoscopic surgeries. Therefore, UAE should not be recommended without careful consideration, in the treatment of symptomatic uterine fibroids.     

Mealtime Regularity Is Associated with Dietary Balance among Preschool Children in Japan—A Study of Lifestyle Changes during the COVID-19 Pandemic

The novel coronavirus-19 (COVID-19) pandemic has considerably impacted children’s lives. The aim of this study was to determine whether the pandemic affected mealtime regularity among preschool children and whether maintaining regular mealtimes or changes in mealtime regularity during the pandemic were related to dietary balance, including chronological relationships. This online cross-sectional survey involving individuals registered with a company that provides meals to children aged 2−6 years was conducted in February 2021. Using a 40-point scale, a healthy diet score (HDS) was developed to evaluate children’s dietary balance. The participants were divided into four groups based on their responses, and multiple regression analyses were performed with the HDS as the dependent variable. Maintaining regular mealtimes was associated with practices such as waking and going to bed earlier, less snacking, and eating breakfast every day. Even after adjusting for basic attributes, lifestyle habits, household circumstances, and other factors, regular mealtimes were still positively correlated with the HDS. These findings indicate that maintaining regular mealtimes is associated with higher HDS scores and better lifestyle habits. Furthermore, as the changed HDS was higher in the group whose mealtimes became regular during the pandemic, adopting regular mealtimes may lead to a more balanced diet.     

Erk pathways negatively regulate matrix mineralization

Skeletal mineralization is an important step regulating the mechanical properties of the calcified tissues, but molecular events underlying mineralization still remain elusive. We examined the role of extracellular signal-regulated kinase (Erk) pathways in matrix mineralization of osteogenic cells both in vitro and in vivo. Matrix mineralization by preosteocytic MLO-A5 cells and osteoblastic MC3T3-E1 cells was increased by either PD98059 Mek inhibitor treatment or adenovirus vector-mediated dominant negative Ras (Ras(DN)) expression and was suppressed by Erk activation by platelet-derived growth factor (PDGF) treatment or constitutively active Mek1 (Mek(CA)) expression. Administration of adenovirus vectors carrying Ras(DN) gene onto the calvaria of 1-day-old mice increased the mineralization of the tissues, while that of the Mek(CA) adenovirus suppressed it. These results suggest that the Erk pathway is a negative regulator of the matrix mineralization both in vitro and in vivo.