A role for alternative splicing in circadian control of exocytosis and glucose homeostasis.

The circadian clock is encoded by a negative transcriptional feedback loop that coordinates physiology and behavior through molecular programs that remain incompletely understood. Here, we reveal rhythmic genome-wide alternative splicing (AS) of pre-mRNAs encoding regulators of peptidergic secretion within pancreatic ß cells that are perturbed in Clock-/- and Bmal1-/- ß-cell lines. We show that the RNA-binding protein THRAP3 (thyroid hormone receptor-associated protein 3) regulates circadian clock-dependent AS by binding to exons at coding sequences flanking exons that are more frequently skipped in clock mutant ß cells, including transcripts encoding Cask (calcium/calmodulin-dependent serine protein kinase) and Madd (MAP kinase-activating death domain). Depletion of THRAP3 restores expression of the long isoforms of Cask and Madd, and mimicking exon skipping in these transcripts through antisense oligonucleotide delivery in wild-type islets reduces glucose-stimulated insulin secretion. Finally, we identify shared networks of alternatively spliced exocytic genes from islets of rodent models of diet-induced obesity that significantly overlap with clock mutants. Our results establish a role for pre-mRNA alternative splicing in ß-cell function across the sleep/wake cycle.

Requirement for NF-κB in maintenance of molecular and behavioral circadian rhythms in mice.

The mammalian circadian clock is encoded by an autoregulatory transcription feedback loop that drives rhythmic behavior and gene expression in the brain and peripheral tissues. Transcriptomic analyses indicate cell type-specific effects of circadian cycles on rhythmic physiology, although how clock cycles respond to environmental stimuli remains incompletely understood. Here, we show that activation of the inducible transcription factor NF-κB in response to inflammatory stimuli leads to marked inhibition of clock repressors, including the Period, Cryptochrome, and Rev-erb genes, within the negative limb. Furthermore, activation of NF-κB relocalizes the clock components CLOCK/BMAL1 genome-wide to sites convergent with those bound by NF-κB, marked by acetylated H3K27, and enriched in RNA polymerase II. Abrogation of NF-κB during adulthood alters the expression of clock repressors, disrupts clock-controlled gene cycles, and impairs rhythmic activity behavior, revealing a role for NF-κB in both unstimulated and activated conditions. Together, these data highlight NF-κB-mediated transcriptional repression of the clock feedback limb as a cause of circadian disruption in response to inflammation.

Community gender norms, mental health, and suicide ideation and attempts among older Japanese adults: a cross-sectional study.

OBJECTIVES: Gender norms embedded in communities may restrict opportunities and harm the mental health of older adults, yet this phenomenon has received little attention. This study investigates the connection between older adults' perceptions of community gender norms and mental health and suicide-related outcomes. DESIGN: Cross-sectional. SETTING: This study analyzed data from the 2019 wave of the Japan Gerontological Evaluation Study. PARTICIPANTS: In total, 25,937 participants aged 65 years or older in 61 municipalities. MEASUREMENTS: Perceptions of community gender norms were assessed by the respondents' perceptions of the gender-differentiating language used by those around them such as "You should/should not do XXX, because you are a man/woman." RESULTS: The prevalence of all mental health outcomes was higher among both men and women who perceived community gender norms as restrictive. These associations remained in fully adjusted multivariable analyses. Prevalence ratios for men were 1.36 [95% confidence interval: 1.13, 1.65] for psychological resistance to obtaining help, 1.85 [1.54, 2.23] for depressive symptoms, 1.99 [1.34, 2.96] for suicidal ideation, and 2.15 [1.21, 3.80] for suicide attempts. The corresponding figures for women were 1.39 [1.17, 1.65], 1.80 [1.55, 2.10], 2.13 [1.65, 2.74], 2.62 [1.78, 3.87]. There was a more pronounced association between perceiving community gender norms as restrictive and depressive symptoms and suicidal behaviors among those with nonconventional gender role attitudes compared to those with conventional attitudes. CONCLUSIONS: Considering the effects of community gender norms, in addition to individual gender role attitudes, may be critical in designing effective public health interventions for improving mental health.

The inter-prefectural regional disparity of healthcare resources and representative surgical procedures in orthopaedics and general surgery: a nationwide study in Japan during 2015-2019.

BACKGROUND: Few reports have examined the localized regional disparity in representative surgical procedures in orthopaedics and general surgery globally. This study aimed to clarify the inter-prefectural regional disparity and relationships between healthcare resources and representative surgical procedures using a nationwide database in Japan. METHODS: The number of medical specialists in orthopaedics, general surgery, and anaesthesiology, as well as the number of hospitals, and the incidence of representative surgical procedures in orthopaedics and general surgery were evaluated annually per 100,000 inhabitants/people by prefecture in Japan during 2015-2019. Medium-sized regional disparities were evaluated using the Gini coefficient. Correlation coefficients were calculated for the defined variables and ageing rate. We also compared the urban and rural regional disparities in all study variables. RESULTS: The annual average number/incidence and Gini coefficients were 110.6 and 0.11 for femur fracture surgery, 106.3 and 0.09 for cholecystectomy, 14.2 and 0.11 for orthopaedic surgeon specialists, 17.6 and 0.09 for general surgeon specialists, 5.9 and 0.13 for anaesthesiology specialists, and 8.1 and 0.21 for hospitals, respectively. The correlation coefficients by the incidence of femur fracture surgery were 0.74 for orthopaedic surgeon specialists (p < 0.001), 0.63 for hospitals (p < 0.001), and 0.62 for the ageing rate (p < 0.001); those by the incidence of cholecystectomy were 0.60 for general surgeon specialists (p < 0.001) and 0.59 for hospitals (p < 0.001). The number/incidence of orthopaedic surgeon specialists, hospitals, femur fracture surgery, and cholecystectomy, as well as the ageing rate, were significantly higher in rural prefectures than in urban prefectures (p < 0.05). CONCLUSIONS: Inter-prefectural regional disparity was small, although certain items were unevenly distributed in the rural prefectures, which is contrary to our expectations. Higher prevalence was recognised in rural prefectures due to the higher ageing rate; however, supply and demand are balanced. This study provides basic data for healthcare policy development in a medium-sized community. LEVEL OF EVIDENCE: III.

Antenatal corticosteroids and outcomes of small for gestational age infants born at 24-31 gestational weeks: a population-based propensity score matching analysis.

PURPOSE: To evaluate the effect of antenatal corticosteroid (ACS) treatment on neonatal outcomes in small for gestational age (SGA) infants born at 24-31 gestational weeks compared with non-SGA infants. METHODS: A population-based retrospective study was conducted that analyzed clinical data from the Neonatal Research Network of Japan database, which enrolls neonates born at < 32 gestational weeks and weighing 1500 g or less (n = 22,414). Propensity score matching (with the ratio of ACS to no-ACS groups of 1:1) was performed in SGA (n = 7028) and non-SGA (n = 15,386) infants, respectively. Univariate logistic and interaction analyses were performed to compare the short-term neonatal outcomes of infants with and without ACS treatment in utero. RESULTS: In the SGA and non-SGA infants, ACS treatment significantly reduced in-hospital mortality (odds ratio 0.67 95% confidence interval [0.50-0.88] and 0.62 [0.50-0.78], respectively), respiratory distress syndrome (0.77 [0.69-0.87] and 0.63 [0.58-0.68], respectively), and composite adverse outcomes (0.73 [0.58-0.91] and 0.57 [0.50-0.65], respectively). ACS treatment also significantly reduced intraventricular hemorrhage (grade III/IV), periventricular leukomalacia, and sepsis in the non-SGA infants, but not in the SGA infants. However, interaction analyses revealed no significant differences between the SGA and non-SGA infants in the efficacy of ACS treatment on short-term outcomes except for respiratory distress syndrome. CONCLUSIONS: ACS treatment was associated with beneficial effects on mortality, respiratory distress syndrome, and adverse composite outcomes in extremely and very preterm SGA infants, with similar efficacy on all neonatal outcomes except for respiratory distress syndrome observed in the non-SGA infants.

Trends and age- and sex-stratified analysis of hallux valgus correction surgery from 2014 to 2019: A nationwide population-based cohort study in Japan.

BACKGROUND: Epidemiological studies on hallux valgus (HV) are challenging owing to differences in sampling and diagnostic criteria across studies. This study aimed to indirectly clarify HV epidemiology using a national database. METHODS: The age- and sex-stratified annual number rate of HV correction (RHVC) per 100,000 people in Japan during 2014-2019 were examined. RESULTS: The average annual RHVC was 3.0. RHVC had unimodal (peak, 65-79 years) and bimodal (peaks, 15-19 and 70-74 years) distributions among males and females, respectively, and increased over time in males aged 50-54 and 75-79 years and females aged 80-84 years. CONCLUSIONS: RHVC increases with increasing age and occurs commonly in female teens. The recent RHVC in Japan was lower than that reported in Europe and the United States, with an increasing trend among elderly people. LEVEL OF EVIDENCE: III.

Detailed clinical features and genotype-phenotype correlation in an OTOF-related hearing loss cohort in Japan.

Mutations in the OTOF gene are a common cause of hereditary hearing loss and the main cause of auditory neuropathy spectrum disorder (ANSD). Although it is reported that most of the patients with OTOF mutations have stable, congenital or prelingual onset severe-to-profound hearing loss, some patients show atypical clinical phenotypes, and the genotype-phenotype correlation in patients with OTOF mutations is not yet fully understood. In this study, we aimed to reveal detailed clinical characteristics of OTOF-related hearing loss patients and the genotype-phenotype correlation. Detailed clinical information was available for 64 patients in our database who were diagnosed with OTOF-related hearing loss. As reported previously, most of the patients (90.6%) showed a "typical" phenotype; prelingual and severe-to-profound hearing loss. Forty-seven patients (73.4%) underwent cochlear implantation surgery and showed successful outcomes; approximately 85-90% of the patients showed a hearing level of 20-39 dB with cochlear implant and a Categories of Auditory Performance (CAP) scale level 6 or better. Although truncating mutations and p.Arg1939Gln were clearly related to severe phenotype, almost half of the patients with one or more non-truncating mutations showed mild-to-moderate hearing loss. Notably, patients with p.His513Arg, p.Ile1573Thr and p.Glu1910Lys showed "true" auditory neuropathy-like clinical characteristics. In this study, we have clarified genotype-phenotype correlation and efficacy of cochlear implantation for OTOF-related hearing loss patients in the biggest cohort studied to date. We believe that the clinical characteristics and genotype-phenotype correlation found in this study will support preoperative counseling and appropriate intervention for OTOF-related hearing loss patients.

A novel behavioral science-based health checkup program and subsequent metabolic risk reductions in a workplace: Checkup championship.

The effectiveness of general health checkups and lifestyle counseling has been questioned. This study examined whether a workplace health promotion program implemented during a health checkup was associated with metabolic syndrome-related indicators. Hakuhodo DY group, one of Japan's largest advertising agencies, implemented a behavioral science-based program called "Checkup Championship" (Kenshin-sen in Japanese) in 2019, in which all employees could voluntarily participate. We studied 3697 employees (2818 men and 879 women, mean age: 40.7 years), consisting of 1509 program participants and 2188 non-participants. The characteristics of participants and non-participants were balanced using inverse probability weighting. We used their data from the health checkups in 2018 and 2019 together with other covariates and performed a difference-in-differences analysis using a linear mixed model. After program implementation, greater reductions were observed among participants compared with non-participants in weight (-0.66 kg, 95% confidence interval: -0.84 to -0.47), body mass index (-0.23 kg/m2, -0.29 to -0.16), waist circumference (-0.67 cm, -0.91 to -0.43), systolic blood pressure (-1.13 mmHg, -2.10 to -0.16), and diastolic blood pressure (-0.84 mmHg, -1.53 to -0.15). In addition, we observed greater reductions in weight, body mass index, waist circumference, and low-density lipoprotein cholesterol among participants who were with two or more risk factors for metabolic syndrome than other participants. We found that participation in a health checkup program based on behavioral science was associated with reduced metabolic syndrome-related indicators. There may be room for improvement in the effectiveness of general health checkups.

Antenatal prediction models for short- and medium-term outcomes in preterm infants.

INTRODUCTION: In extremely and very preterm infants, predicting individual risks for adverse outcomes antenatally is challenging but necessary for risk-stratified perinatal management and parents' participation in decision-making about treatment. Our aim was to develop and validate prediction models for short-term (neonatal period) and medium-term (3 years of age) outcomes based on antenatal maternal and fetal factors alone. MATERIAL AND METHODS: A population-based study was conducted on 31 157 neonates weighing ≤1500 g and born between 22 and 31 weeks of gestation registered in the Neonatal Research Network of Japan during 2006-2015. Short-term outcomes were assessed in 31 157 infants and medium-term outcomes were assessed in 13 751 infants among the 31 157 infants. The clinical data were randomly divided into training and validation data sets in a ratio of 2:1. The prediction models were developed by factors selected using stepwise logistic regression from 12 antenatal maternal and fetal factors with the training data set. The number of factors incorporated into the model varied from 3 to 10, on the basis of each outcome. To evaluate predictive performance, the area under the receiver operating characteristics curve (AUROC) was calculated for each outcome with the validation data set. RESULTS: Among short-term outcomes, AUROCs for in-hospital death, chronic lung disease, intraventricular hemorrhage (grade III or IV) and periventricular leukomalacia were 0.85 (95% CI 0.83-0.86), 0.80 (95% CI 0.79-0.81), 0.78 (95% CI 0.75-0.80), and 0.58 (95% CI 0.55-0.61), respectively. Among medium-term outcomes, AUROCs for cerebral palsy and developmental quotient of <70 at 3 years of age were 0.66 (95% CI 0.63-0.69) and 0.72 (95% CI 0.70-0.74), respectively. CONCLUSIONS: Although the predictive performance of these models varied for each outcome, their discriminative ability for in-hospital death, chronic lung disease, and intraventricular hemorrhage (grade III or IV) was relatively good. We provided a bedside prediction tool for calculating the likelihood of various infant complications for clinical use. To develop these prediction models would be valuable in each country, and these risk assessment tools could facilitate risk-stratified perinatal management and parents' shared understanding of their infants' subsequent risks.

Response of intraductal carcinoma of the prostate to androgen deprivation therapy predicts prostate cancer prognosis in radical prostatectomy patients.

BACKGROUND: Intraductal carcinoma of the prostate (IDC-P) has a poor prognosis and is thought to be completely resistant to current therapies, including androgen deprivation therapy (ADT). However, to date, there are no data showing direct evidence of such resistance. METHODS: We retrospectively evaluated 145 patients with high-risk prostate cancer who underwent radical prostatectomy (RP) with neoadjuvant ADT between 1991 and 2005. All patient data were collected from slides prepared from needle biopsy (NB) samples of prostate tissue and RP specimens. Data were analyzed in terms of serum level of prostate specific antigen (PSA), Gleason score of NB samples, clinical T stage, the positive cancer core rate, maximum cancer extension rate, presence of Gleason pattern 5, and presence of IDC-P in both NB samples and RP specimens. RESULTS: The median initial PSA was 33.2 ng/mL (range, 2.4-296 ng/mL), and the median follow-up period was 109 months (range, 11-257 months). The preoperative median ADT period was 4 months (range, 1-20 months). IDC-P was present in 53 patients (37%) in NB samples and 65 (45%) in RP. The patients were divided into three groups based on the presence or absence of IDC-P in NB/RP samples (IDC-P-negative at biopsy: 92 cases, IDC-P-positive at biopsy with IDC-P disappearance: 15 cases, and IDC-P-positive at biopsy with IDC-P persistence: 38 cases). Overall, 28% of IDC-P-positive cases in NB samples showed the disappearance of IDC-P at RP. IDC-P persistence cases showed the poorest prognosis, while IDC-P disappearance cases had a similar prognosis to that of IDC-P-negative at biopsy cases in terms of disease-free survival, cancer-specific survival, and overall survival (P = .0018, P = .0087, and P = .0034, respectively). CONCLUSIONS: Some cases with IDC-P responded to ADT and demonstrated favorable clinical outcomes similar to those of cases without IDC-P. These findings indicate that cases with IDC-P are heterogeneous.

Effect of core needle biopsy number on intraductal carcinoma of the prostate (IDC-P) diagnosis in patients with metastatic hormone-sensitive prostate cancer.

BACKGROUND: The number of core needle biopsies in metastatic prostate cancer cases are sometimes reduced to avoid various complications. We analyzed whether core needle biopsy number influence IDC-P detection rate in patients with metastatic castration-sensitive prostate cancer (mHSPC). METHODS: We retrospectively evaluated data from 150 patients diagnosed with mHSPC. Subjects were allocated to three groups according to the number of core biopsies performed: ≤ 5, 6-9, and ≥ 10. The study endpoints were the cancer-specific survival (CSS) and overall survival (OS) rates. RESULTS: For patients who underwent ≥ 10 core biopsies, a significant difference on CSS was detected between with or without IDC-P (P = 0.016). On the other hand, the difference decreased as the number of core biopsies became smaller (6-9; P = 0.322 and ≤ 5; P = 0.815). A similar trend was identified for the OS outcome. A significant difference on OS was also found between with or without IDC-P in patients who underwent ≥ 10 and 6-9 core needle biopsies (P = 0.0002 and 0.017, respectively), but not in those who underwent ≤ 5 core biopsies (P = 0.341). IDC-P served as a stronger prognostic marker for CSS and OS than did the other factors included in the multivariate analysis for patients had ≥ 10 core biopsies (P = 0.016, and P = 0.0014, respectively). CONCLUSIONS: Given the IDC-P detection and its value as a prognostic marker, we propose the performance of ≥ 10 core biopsy procedures in patients diagnosed with mHSPC to minimize the sampling error of the IDC-P.

The influence of the presence of intraductal carcinoma of the prostate on the grade group system's prognostic performance.

BACKGROUND: Although the presence of intraductal carcinoma of the prostate (IDC-P) influences biochemical failure in radical prostatectomy patients, no data are available regarding the impact of its integration into the classification grade group system. Thus, the aim of this study was to enhance the utility of the grade group system by integrating the presence of IDC-P. METHODS: This study was a retrospective evaluation of 1019 patients with prostate cancer who underwent radical prostatectomy between 2005 and 2013 without neoadjuvant or adjuvant therapy. The data on age, prostate-specific antigen (PSA) level at diagnosis, pathological T stage (pT), presence of Gleason pattern 5 (GP5), presence of IDC-P, and surgical margin status were analyzed to predict PSA recurrence after prostatectomy. RESULTS: The median patient age was 67 (range, 45-80) years and the median initial PSA level was 6.8 (range, 0.4-82) ng/mL. The median follow-up period was 82 (range, 0.7-148) months. IDC-P was detected in 157 patients (15.4%). Among these patients, the increase in the positive rate of IDC-P correlated with tumor upgrading. The grade groups (GGs) were as follows: GG1 without IDC-P, 16.0% (n = 163); GG2 without IDC-P, 46.1% (n = 470); GG3 without IDC-P, 15.7% (n = 160); GG4 without IDC-P, 2.6% (n = 27); GG5 without IDC-P, 4.1% (n = 42); any GG with IDC-P, 15.4% [n = 157; GG 2 (n = 29); GG3 (n = 60); GG4 (n = 13); GG5 (n = 55)]. Any grade Group with IDC-P showed significantly worse prognosis than any other group without IDC-P (P < 0.0001). In a multivariate analysis, integration of the IDC-P into the Grade Groups, the PSA level at diagnosis, and the surgical margin status were significant prognostic predictors (P < 0.0001, < 0.0001 and < 0.0001, respectively). CONCLUSIONS: Integrating the presence of IDC-P into the grade group system will result in more accurate predictions of patient outcome.

Anticancer Agent-Induced Life-Threatening Skin Toxicities: A Database Study of Spontaneous Reporting Data.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are potentially life-threatening cutaneous and mucosal adverse reactions to drugs. Nevertheless, the connection to anticancer agents remains unclear. To provide insight into the association of such adverse reactions with anticancer agents, we analyzed the profile of anticancer agent-induced SJS and TEN in the Japanese population. Of the 9,738 SJS/TEN events recorded in a database of spontaneous reporting data, 485 (5%, further categorized as SJS, 384 events, 79%; TEN, 101 events, 21%) were identified as anticancer agent-induced, and 53 of these (11%) were fatal. Multivariate logistic regression analyses indicated that, compared with patients using other drugs, those using anticancer drugs had lower incident risk of death (hazard ratio [HR], 0.592; p = .0006), longer median time to onset of SJS/TEN (18 vs. 11 days; p < .0001; multivariate Cox regression: HR, 0.66; p < .0001), and a higher likelihood of developing SJS/TEN later than 70 days after initiation of the suspected causal agent (15% vs. 7%; p < .0001), highlighting the need for vigilance and continuous monitoring for SJS/TEN in patients treated with anticancer agents. IMPLICATIONS FOR PRACTICE: Life-threatening skin toxicities induced by anti-cancer agents indicated significantly lower incident risk of death and longer time to onset of symptoms than for those induced by other drugs.

Integrating tertiary Gleason pattern 5 into the ISUP grading system improves prediction of biochemical recurrence in radical prostatectomy patients.

Although the presence of tertiary Gleason pattern 5 is reportedly related to unfavorable prostate cancer characteristics, few data are available regarding the effects of tertiary Gleason pattern 5 on the new ISUP (International Society of Urological Pathology) grading system in radical prostatectomy patients. In this study, we evaluated the effect of tertiary Gleason pattern 5 on biochemical recurrence following radical prostatectomy in patients with prostate cancer. We retrospectively evaluated 1000 patients with prostate cancer who underwent radical prostatectomy. The ISUP Grades were as follows: Grade 1, 16.3%; Grade 2, 48.1% (with tertiary Gleason pattern 5, 8.0% and without tertiary Gleason pattern 5, 40.1%); Grade 3, 21.9% (with tertiary Gleason pattern 5, 9.1% and without tertiary Gleason pattern 5, 12.8%); Grade 4, 3.9%; and Grade 5, 9.8%. Biochemical recurrence-free survival differed significantly among the five groups (Grade 1-5) (P < 0.0001). Grade 2 with tertiary Gleason pattern 5 had a significantly worse prognosis than Grade 2 without tertiary Gleason pattern 5. Similarly, Grade 3 with tertiary Gleason pattern 5 demonstrated a significantly worse prognosis than Grade 3 without tertiary Gleason pattern 5. When Grade 2 and Grade 3 were divided with or without tertiary Gleason pattern 5, the survival curves differed significantly among Grade 1, Grade 2 without tertiary Gleason pattern 5, Grade 2 with tertiary Gleason pattern 5, Grade 3 without tertiary Gleason pattern 5, Grade 3 with tertiary Gleason pattern 5, and Grade 4 (P < 0.0001) (hazard ratios: 1, 1.14, 1.86, 2.23, 3.53, and 6.30). In a multivariate analysis, integrating tertiary Gleason pattern 5 into the ISUP Grade, PSA, and surgical margin status significantly predicted biochemical recurrence (P < 0.0001). Integrating tertiary Gleason pattern 5 into the ISUP grading system will improve the accuracy of patient outcome prediction following radical prostatectomy in patients with prostate cancer.

The safety and effectiveness profile of eldecalcitol in a prospective, post-marketing observational study in Japanese male patients with osteoporosis.

We conducted a post-marketing observational study to investigate the safety and effectiveness of eldecalcitol for the treatment of osteoporosis in a Japanese clinical setting. The observation period was 12 months for women and 36 months for men. The final results for the female patients have already been published. In this article, the final results for the male patients are reported. A total of 470 male osteoporosis patients were enrolled. The safety analysis set included 431 patients (mean age, 76.8 years; mean ± SD follow-up period, 631.0 ± 450.3 days), and 175 patients continued treatment throughout the 3-year observational period. Adverse drug reactions (ADRs) were reported in 28 patients (6.49%); the most common ADRs were hypercalcemia (1.16%) and renal impairment (1.16%). Serious ADRs were reported in 5 patients (1.16%). Mean serum calcium was within the normal range throughout the observation period. The cumulative incidence of new vertebral and nonvertebral fractures at 36 months, estimated by Kaplan-Meier analysis, was 10.23 and 4.06%, respectively. At the last observation, mean lumbar spine bone mineral density was 3.49% higher (P < 0.0001) than at baseline, and levels of the bone turnover markers BAP and TRACP-5b were reduced (-14.64%; P = 0.0009, and - 29.51%; P < 0.0001, respectively). In conclusion, the safety and effectiveness of eldecalcitol for the treatment of Japanese male osteoporosis patients was confirmed in clinical practice. Careful monitoring of serum calcium and estimated glomerular filtration rate, both before and during treatment, is necessary to minimize the risk of hypercalcemia and renal impairment while maximizing the effectiveness of eldecalcitol.

Validation of prognostic impact of number of extrathoracic metastases according to the eighth TNM classification: a single-institution retrospective study in Japan.

BACKGROUND: In the eighth edition of the TNM classification of lung cancer, the M1b and M1c descriptors are newly defined by the number of extrathoracic metastases. To verify the prognostic value of these descriptors in Japan, we reclassified our cases and re-evaluated prognosis in M1b and M1c patients. METHODS: All non-small cell lung cancer (NSCLC) patients with extrathoracic metastases who visited Saitama Medical Center from 2010 to 2016 were evaluated, divided according to the eighth edition of the TNM classification criteria into two groups (M1b, patients with single extrathoracic metastasis, and M1c, patients with multiple extrathoracic metastases), and followed up until December 31, 2017. Survival time analysis was performed using the Kaplan-Meier method, and between-group differences in overall survival time (OS) were evaluated by the log-rank test. RESULTS: A total of 231 NSCLC patients were divided into 57 patients with M1b and 174 with M1c. Median OS was 15.2 months (95% confidence interval [CI]: 9.3-19.9) and 7.3 months (95% CI 5.7-10.7) for M1b and M1c, respectively, with no significant between-group difference (P = 0.239). However, after excluding patients with epidermal growth factor receptor (EGFR) mutation or echinoderm microtubule-associated protein-like 4 and anaplastic lymphoma kinase (EML4-ALK) fusion gene, median OS was 12.9 months (95% CI 7.2-19.9) for M1b and 5.4 months (95% CI 3.8-6.3) for M1c, respectively, showing a significant difference (P = 0.029). CONCLUSIONS: The effect of therapy directed toward EGFR mutation or EML4-ALK fusion gene might obscure the significant prognostic difference between M1b and M1c.

[Serious S-1-Induced Lung Injury Diagnosed by Early Lung Biopsy-A Case Report].

The patient was a 65-year-old man who developed dyspnea after 6 courses of S-1 and oxaliplatin(SOX)chemotherapy for advanced stomach cancer. The chemotherapy regimen consisted of SOX chemotherapy. The patient developed hypoxemia, and chest radiography revealed ground-glass opacity in both lungs. Bronchoscopy and DLST led to a diagnosis of druginduced lung injury caused by S-1. Although steroid pulse therapy was administered, the patient's condition deteriorated rapidly and was ultimately fatal. Based on the clinical course and histopathological findings, a DAD-type lung disorder was diagnosed. This description of a DAD-type drug-induced lung injury caused by S-1, for which histopathological findings were available in the early stages, is clinically valuable. We report this case along with a review of the relevant literature.

Potential utility of a longitudinal relative dose intensity of molecularly targeted agents in phase 1 dose-finding trials.

Phase 1 trials of molecularly targeted agents (MTA) often do not use toxicity data beyond the first cycle of treatment to determine a recommended phase 2 dose (RP2D). We investigated the potential utility of longitudinal relative dose intensity (RDI) that may be a better new way of determining a more accurate RP2D as a lower dose that is presumably more tolerable over the long term without compromising efficacy. All consecutive patients who were initially treated using a single MTA at the conventional RP2D or at one level lower dose (OLLD) of that RP2D in 9 phase 1 trials sponsored by the National Cancer Institute were included. The associations between longitudinal RDI, time to first progression, and response rate were analyzed. The RDI of the conventional RP2D group were maintained a rate of ≥70% throughout 10 cycles, and were higher than those of the OLLD group, although in both groups the RDI gradually decreased with additional treatment cycles. The RP2D group was similar to the OLLD group with respect to time to first progression and response rate. In both groups, however, the decreasing RDI over time was significantly associated with shorter time to first disease progression; therefore, the longitudinal RDI, which takes into account lower grade toxicity occurrences, may be useful in determining a more desirable dose to use in phase 2 and 3 studies.