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Comprehensive cancer genome profiling (CGP) has been nationally reimbursed in Japan since June 2019. Less than 10% of the patients have been reported to undergo recommended treatment. Todai OncoPanel (TOP) is a dual DNA–RNA panel as well as a paired tumor–normal matched test. Two hundred patients underwent TOP as part of Advanced Medical Care B with approval from the Ministry of Health, Labour and Welfare between September 2018 and December 2019. Tests were carried out in patients with cancers without standard treatment or when patients had already undergone standard treatment. Data from DNA and RNA panels were analyzed in 198 and 191 patients, respectively. The percentage of patients who were given therapeutic or diagnostic recommendations was 61% (120/198). One hundred and four samples (53%) harbored gene alterations that were detected with the DNA panel and had potential treatment implications, and 14 samples (7%) had a high tumor mutational burden. Twenty‐two samples (11.1%) harbored 30 fusion transcripts or MET exon 14 skipping that were detected by the RNA panel. Of those 30 transcripts, 6 had treatment implications and 4 had diagnostic implications. Thirteen patients (7%) were found to have pathogenic or likely pathogenic germline variants and genetic counseling was recommended. Overall, 12 patients (6%) received recommended treatment. In summary, patients benefited from both TOP DNA and RNA panels while following the same indication as the approved CGP tests. (UMIN000033647). Todai OncoPanel (TOP) is a dual DNA‐RNA panel as well as a paired tumor‐normal matched test. Pharmaceuticals and Medical Devices Agency (PMDA) indications for comprehensive cancer genomic profiling were followed in this study. The percentage of patients who were given therapeutic or diagnostic recommendations was 61%, including patients with fusion or MET exon 14 skipping transcripts that led to recommendations.

Introduction: It remains unclear which surgery or radiofrequency ablation (RFA) is the more effective treatment for small hepatocellular carcinoma (HCC). We aimed to compare survival between patients undergoing surgery (surgery group) and patients undergoing RFA (RFA group). Methods: We conducted a randomized controlled trial involving 49 institutions in Japan. Patients with Child-Pugh scores ≤7, largest HCC diameter ≤3 cm, and ≤3 HCC nodules were considered eligible. The co-primary endpoints were recurrence-free survival (RFS) and overall survival (OS). The current study reports the final result of RFS, and the follow-up of OS is still ongoing. Results: During 2009–2015, 308 patients were registered. After excluding ineligible patients, the surgery and RFA groups included 150 and 151 patients, respectively. Baseline factors did not differ significantly between the groups. In both groups, 90% of patients had solitary HCC. The median largest HCC diameter was 1.8 cm (interquartile range [IQR], 1.5–2.2 cm) in the surgery group and 1.8 cm (IQR, 1.5–2.3 cm) in the RFA group. The median procedure duration (274 vs. 40 min, p < 0.01) and the median duration of hospital stay (17 days vs. 10 days, p < 0.01) were longer in the surgery group than in the RFA group. RFS did not differ significantly between the groups as the median RFS was 3.5 (95% confidence interval [CI], 2.6–5.1) years in the surgery group and 3.0 (95% CI, 2.4–5.6) years in the RFA group (hazard ratio, 0.92; 95% CI, 0.67–1.25; p = 0.58). Discussion/Conclusion: Our study did not show which surgery or RFA is the better treatment option for small HCC.

Preclinical studies have revealed that the elevation of nicotinamide adenine dinucleotide (NAD + ) upon the administration of nicotinamide mononucleotide (NMN), an NAD + precursor, can mitigate aging-related disorders; however, human data on this are limited. We investigated whether the chronic oral supplementation of NMN can elevate blood NAD + levels and alter physiological dysfunctions in healthy older participants. We administered 250 mg NMN per day to aged men for 6 or 12 weeks in a placebo-controlled, randomized, double-blind, parallel-group trial. Chronic NMN supplementation was well tolerated and caused no significant deleterious effect. Metabolomic analysis of whole blood samples demonstrated that oral NMN supplementation significantly increased the NAD + and NAD + metabolite concentrations. There were nominally significant improvements in gait speed and performance in the left grip test, which should be validated in larger studies; however, NMN exerted no significant effect on body composition. Therefore, chronic oral NMN supplementation can be an efficient NAD + booster for preventing aging-related muscle dysfunctions in humans.

AimWe investigated whether or not postoperative complications (POCs) themselves have a negative survival impact or indirectly worsen the survival due to insufficient adjuvant chemotherapy in a pooled analysis of two large phase III studies performed in JapanPatients and methodsThe study examined the patients who enrolled in 1304, phase III study comparing the efficacy of 6 and 12 months of capecitabine as adjuvant chemotherapy for stage III colon cancer patients and in 882, a phase III study to confirm the tolerability of oxaliplatin, fluorouracil, and l-leucovorin in Japanese stage II/III colon cancer patients. In our study, POCs were defined as the following major surgical complications: anastomotic leakage, pneumonia, bowel obstruction/ileus, surgical site infection, postoperative bleeding, urinary tract infection, and fistula. Patients were classified as those with POCs (C group) and those without POCs (NC group).ResultsA total of 2095 patients were examined in the present study. POCs were observed in 169 patients (8.1%). The overall survival (OS) rates at 5 years after surgery were 75.3% in the C group and 86.5% in the NC group (p = 0.0017). The hazard ratio of POCs for the OS in multivariate analysis was 1.70 (95% confidence interval, 1.19 to 2.45; p = 0.0040). The time to adjuvant treatment failure (TTF) of adjuvant chemotherapy was similar between the groups, being 68.6% in the C group and 67.1% in the NC group for the 6-month continuation rate of adjuvant chemotherapy. The dose reduction rate of adjuvant chemotherapy and adjuvant treatment suspension rate were also similar between the groups (C vs. NC groups: 45.0% vs. 48.7%, p = 0.3520; and 52.7% vs. 55.0%, p = 0.5522, respectively).ConclusionPOCs were associated with a poor prognosis but did not affect the intensity of adjuvant chemotherapy. These results suggested that POCs themselves negatively influence the survival.

Chronic endometritis (CE) and endometrial dysbiosis (ED) are major causes of recurrent implantation failure (RIF). CE is diagnosed via hysteroscopy or the endometrial CD138 test; ED is examined using endometrial microbiome testing with next-generation sequencing. ED is characterized by a reduction in Lactobacillus species . However, correlations between the results of the three tests and the efficacy of treatment against CE and ED in pregnancy outcomes remain unclear. We analyzed 73 patients with RIF who underwent all three tests (hysteroscopy, endometrial CD138 test, and endometrial microbiome test). Patients with CE received antibiotics, whereas those with ED received antibiotics and vaginal Lactobacillus probiotics. The incidences of CE diagnosed using hysteroscopy and the CD138 test were 56.2 and 49.3%, respectively, and the prevalence of ED was 53.4%. No correlations were observed among the test-positive individuals in these three tests. Among patients with ED, 88.9% had a post-treatment clinical pregnancy, a significantly higher rate than that in patients without ED (p = 0.021). Multivariate analysis demonstrated that ED was associated with clinical pregnancy (odds ratio (OR): 6.29, p = 0.031). In conclusion, the three tests detected different populations of patients with RIF. ED diagnosed using the endometrial microbiome test was associated with favorable pregnancy outcomes after testing.

Background Hypertensive disorders of pregnancy lead to a critically ill maternal/fetal state due to maternal organ failure and fetal dysfunction related to placental abruption or impaired placental circulation. No treatment with established efficacy for hypertensive disorders of pregnancy is currently available, and delivery is the only definitive treatment. This article describes the study protocol for a trial that aims to evaluate whether early pravastatin treatment is effective in preventing hypertensive disorders of pregnancy. Methods A randomized, open-label, parallel-group, three-arm trial will be conducted with aspirin administered as the baseline treatment across all groups. Pregnant women with a history of hypertensive disorders of pregnancy who are at high risk of developing hypertensive disorders of pregnancy will be recruited from four recruitment sites in Japan. The three interventions of the study comprise oral pravastatin 5 mg once daily with oral bayaspirin 100 mg once daily, oral pravastatin 10 mg once daily with oral bayaspirin 100 mg once daily, and oral bayaspirin 100 mg once daily alone. The primary outcome measure is the incidence of hypertension during pregnancy. The secondary outcome measures include incidence rates of preeclampsia and gestational hypertension, maternal serum soluble fms-like tyrosine kinase-1/placental growth factor ratio, as well as soluble fms-like tyrosine kinase-1 and placental growth factor levels, whether the mother is proteinuric, placental weight, umbilical cord blood lipid profile, the incidence of hypertensive disorders of pregnancy-related complications (placental abruption, hemolysis, elevated liver enzymes, and low platelet count syndrome, and eclampsia), week at diagnosis of hypertensive disorders of pregnancy, incidence of severe hypertensive disorders of pregnancy, and neonatal outcomes (birth weight, percentage of small for gestational age neonates, neonatal intensive care unit admission rate, and auditory brainstem response). Discussion The results of this study are expected to have wide-ranging implications given the effects of hypertensive disorders of pregnancy on long-term maternal and child health, as well as health economics. Trial registration Japan Registry of Clinical Trials (Trial ID: jRCTs031230067; registered May 11, 2023; https://jrct.mhlw.go.jp/en-latest-detail/jRCTs031230067 ).

PurposeAssociated factors for and the natural course of sacroiliac (SI) joint degeneration in the normal population are unknown. The purpose of this study was to determine associated factors for and the progression rate of SI joint degeneration.MethodsWe enrolled 553 healthy middle-aged subjects who underwent the first and second comprehensive health screening at an interval of 5.9 years (range 3.0–10.7 years). The medical checkup included blood tests and whole-body computed tomography. We investigated associated factors of SI joint degeneration, the relationship of the laterality of degeneration between the SI and L4/5 facet joint, L5/S facet joint, and the natural course of SI joint degeneration over time.ResultsAt the first checkup, 70 subjects (12.7%) showed substantial degeneration (type 2 or 3) of the SI joints. Multivariate analysis revealed that female sex; pubic symphysis degeneration, L4/5, and L5/S facet joint degeneration; high body mass index; and several blood parameters were associated factors for SI joint degeneration. Laterality of SI joint degeneration was significantly more frequent than that of L4/5 or L5/S facet joint degeneration. Kaplan–Meier survival analysis revealed that the progression rates of SI joint degeneration from type 0 (no degeneration) or type 1 (slight degeneration) to substantial degeneration amounted to 3.4% and 35.5% after 10 years, respectively.ConclusionWe found substantial SI joint degeneration in 12.7% of healthy middle-aged subjects and considered it to be part of the normal aging process. There may be individual factors associated with its occurrence.Graphic abstractThese slides can be retrieved under Electronic Supplementary Material.

Background Acute exacerbation of interstitial lung disease (AE-ILD) is the most serious complication in lung cancer patients with pre-existing ILD receiving chemotherapy. The role of vascular endothelial growth factor (VEGF) in pathogenesis of AE-ILD is conflicting. The influence of bevacizumab (Bev), a monoclonal antibody against VEGF, on lung cancer patients with pre-existing ILD remains unclear. We examined the effect of Bev on reducing AE-ILD risk in non-squamous non-small cell lung cancer (NSCLC) patients receiving chemotherapy. Methods We analysed incidence of AE-ILD and outcomes of 48 patients with advanced non-squamous NSCLC with ILD who received first-line chemotherapy with (Bev group, n  = 17) and without (non-Bev group, n  = 31) Bev between July 2011 and July 2016. Gray’s test, which was competing risk analysis during the study period, was performed for both groups. Results The most common regimen used for first-line chemotherapy was the combination of carboplatin plus pemetrexed (PEM) in both groups. The incidences of chemotherapy-related AE-ILD 120 days after first-line chemotherapy initiation were significantly lower in the Bev than in the non-Bev groups (0% vs. 22.6%, p  = 0.037, Gray’s test). However, there were no differences in development of progressive disease of lung cancer and other events as the competing risk factors of AE-ILD between the two groups. Only patients receiving PEM-containing regimens also showed a significant difference in the incidence of AE-ILD between the two groups ( p  = 0.044). The overall-cumulative incidence of AE-ILD during the first-line and subsequent chemotherapy was 29.2% (14 of the 48). The median progression-free survival was significantly longer in the Bev than in the non-Bev groups (8.0 vs. 4.3 months, p  = 0.026). Conclusions The addition of Bev to chemotherapy regimens may reduce the risk of chemotherapy-related AE-ILD in patients with lung cancer.

: This study aimed to assess the efficacy of adjuvant chemotherapy for T1-2 stage III colorectal cancer, a disease with a low recurrence rate. : The efficacies of fluorouracil-based adjuvant chemotherapy (5FU group) and oxaliplatin-based adjuvant chemotherapy (L-OHP group) were assessed and compared with that of surgery alone (surgery group) using data from seven clinical trials conducted by the Japanese Foundation for Multidisciplinary Treatment of Cancer. Propensity score matching was used to compare the three groups. Direct-adjusted survival curves were delineated with consideration of treatment periods. : A total of 604 patients with T1-2 stage III colorectal cancer were identified. After adjusting for the patient factors, the hazard ratio of relapse-free survival (RFS) was 0.79 (95% confidence interval (CI): 0.13-4.65, = 0.79) and 0.64 (95% CI: 0.06-6.40, = 0.70) in the 5FU and L-OHP groups, respectively. Adjusted 5-year RFS rate was 82.8% (95% CI: 67.2-100%), 86.2% (95% CI: 74.2-100%), and 88.6% (95% CI: 74.0-100%) in the surgery, 5-FU, and L-OHP groups, respectively. Overall and disease-specific survival showed similar trends without significant differences. : No significant improvement in prognosis was observed after adjuvant chemotherapy. The potential improvement in the 5-year RFS after adjuvant chemotherapy for resected T1-2 stage III colorectal cancer should be balanced with patient factors and adverse events.

Purpose The current definition of menstrual cycle length in a Japanese woman is different from those of WHO definition, and the original data are outdated. We aimed to calculate the distribution of follicular and luteal phases length in modern Japanese women with various menstrual cycles. Methods This study determined the lengths of the follicular and luteal phases of Japanese women using basal body temperature data collected via a smartphone application from 2015 to 2019, and the data were analyzed using the Sensiplan method. Over 9 million temperature readings from more than 80 000 participants were analyzed. Results The mean duration of the low‐temperature (follicular) phase averaged 17.1 days and was shorter among participants aged 40–49 years. The mean duration of the high‐temperature (luteal) phase was 11.8 days. The variance and maximum‐minimum difference of the length of the low temperature period were significant in women under 35 years old than women aged more than 35 years. Conclusions The shortening of the follicular phase in women aged 40–49 years implied a relationship with the rapid decline of ovarian reserve in these women, and the age 35 years old was turning point of ovulatory function.