Determining the changes in morphology and loading status following medial displacement calcaneal osteotomy for flatfoot using patient-specific finite element models.

Medial displacement calcaneal osteotomy (MDCO) is the standard procedure for flatfoot. We investigated the effect of MDCO on the foot using a finite element analysis. Foot models were created from computed tomography data of 8 patients with flat feet. MDCO was performed on each model with bone translation distance of 4, 8, and 12 mm. The morphological changes, plantar pressures, and stress percentage on the talocrural and subtalar joints were evaluated before and after surgery. Morphological evaluation showed improvement in the medial longitudinal arch. The stress percentage of plantar pressure in the medial area decreased, and the stress percentage of plantar pressure in the mid- and lateral forefoot area increased. At the talocrural joint, the medial and middle stress percentage increased, while the lateral and posterior stress percentage decreased. In the subtalar joint, the stress percentage in the middle subtalar joint increased and that in the posterior subtalar joint decreased. Within the posterior subtalar joint, the anterior and medial stress percentage increased, while the posterior and lateral stress percentage decreased. Preoperative simulation using the finite element analysis may be useful in understanding postoperative morphological changes and loading conditions to perform patient-specific surgery.

Childhood fever and hearing loss associated with CAPOS syndrome.

CAPOS (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss) syndrome is a rare genetic disorder caused by the heterozygous mutation, c.2452G > A, in the ATP1A3 gene. CAPOS syndrome involves a characteristic episode in which neuropathy develops after a fever in childhood, and here, we describe the case of a patient with CAPOS syndrome. The patient had repeated episodes of a fever around 74 months of age. Although he could speak at 23 months of age, he presented with hearing difficulty after the fever. Pure-tone audiometry revealed moderate-to-severe bilateral sensorineural hearing loss, and auditory brainstem response (ABR) showed poor response in the both ears. Auditory stead-state response (ASSR) produced relatively consistent results compared to pure-tone audiometry. A mutation in the ATP1A3 gene was detected through genetic testing. In CAPOS syndrome, a genetic mutation leads to desynchronization during neural firing. We believe that this desynchronization in neural firing is responsible for the lack of response in the ABR and the presence of a response in the ASSR. In this patient, we attribute the response detection in ASSR to its greater tolerance for errors in the timing of neural firing compared to ABR.

Phase II Study of Durvalumab Immediately after Completion of Chemoradiotherapy in Unresectable Stage III Non-small Cell Lung Cancer: TORG1937 (DATE Study).

PURPOSE: Concurrent chemoradiotherapy (CCRT) followed by durvalumab consolidation for up to 12 months is the standard of care for patients with unresectable stage III non-small cell lung cancer (NSCLC). However, exactly when to initiate durvalumab therapy after chemoradiation completion remains unknown. We evaluated the efficacy and safety of durvalumab, administered immediately after CCRT completion, for patients with unresectable stage III NSCLC. PATIENTS AND METHODS: This study was a prospective, single-arm, open-label phase II clinical trial. Patients without disease progression after definitive CCRT (two cycles of platinum-based doublet chemotherapy with 60 Gy/30 Fr radiotherapy) received durvalumab (every 2 weeks for up to 12 months) from the next day (up to 5 days) after the final radiation dose. The primary endpoint was the 1-year progression-free survival (PFS) from registration before the start of CCRT. RESULTS: From January 2020 to August 2020, 47 of 50 enrolled patients were evaluable for treatment efficacy and safety. The 1-year PFS from registration was 75.0% [60% confidence interval (CI), 69.0-80.0 and 95% CI, 59.4-85.3]. The objective response rate throughout the study treatment and median PFS from registration were 78.7% and 14.2 months (95% CI, 13.4 to not reached), respectively. Grade 3/4 pneumonitis and febrile neutropenia were each 4.3%. CONCLUSIONS: Our study met the primary endpoint. The incidence of pneumonitis was similar to that of a Japanese subset in the PACIFIC study. Our data support the efficacy and safety of durvalumab administered immediately after the completion of CCRT for patients with unresectable stage III NSCLC.

Impact of Locoregional Therapies for Brain Lesions on Survival in Patients With Non-small Cell Lung Cancer With Multiple Extrathoracic Metastases.

BACKGROUND/AIM: The treatment of brain metastases in patients with non-small cell lung cancer (NSCLC) typically involves surgery, irradiation, and chemotherapy (single or combination therapy). However, the impact of these therapies on the survival of patients with NSCLC with multiple extrathoracic metastases has not yet been determined. Therefore, in the present study, we examined the prognostic effect of multimodal treatment for brain metastases in patients with NSCLC with multiple extrathoracic metastases in the absence of driver mutations. PATIENTS AND METHODS: Patients with NSCLC with multiple extrathoracic metastases (including at least one brain metastasis), who visited Saitama Medical Center, Saitama Medical University from January 1, 2010 to December 31, 2016, were enrolled in this study; follow-up was conducted until December 31, 2021. RESULTS: A total of 56 patients were enrolled, including 12 and 44 patients with single and multiple brain metastases, respectively. The median overall survival (OS) for all patients was 4.9 months, and did not differ significantly between patients with single and multiple brain metastases (3.0 vs. 4.9 months, respectively). The selection of locoregional treatment for brain metastases did not depend on Karnofsky performance status (p=0.0862). Among patients with multiple brain metastases, the OS for those who underwent craniotomy followed by whole brain radiation therapy (WBRT), those who received only WBRT, and those treated without locoregional therapy was 47.7, 3.9, and 15.9 months, respectively (p=0.00382). CONCLUSION: Surgical resection followed by radiation therapy is an effective treatment option for brain metastases in patients with multiple metastases. However, WBRT alone did not improve prognosis.

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.

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.

P2Y1 purinergic receptor identified as a diabetes target in a small-molecule screen to reverse circadian ß-cell failure.

The mammalian circadian clock drives daily oscillations in physiology and behavior through an autoregulatory transcription feedback loop present in central and peripheral cells. Ablation of the core clock within the endocrine pancreas of adult animals impairs the transcription and splicing of genes involved in hormone exocytosis and causes hypoinsulinemic diabetes. Here, we developed a genetically sensitized small-molecule screen to identify druggable proteins and mechanistic pathways involved in circadian ß-cell failure. Our approach was to generate ß-cells expressing a nanoluciferase reporter within the proinsulin polypeptide to screen 2640 pharmacologically active compounds and identify insulinotropic molecules that bypass the secretory defect in CRISPR-Cas9-targeted clock mutant ß-cells. We validated hit compounds in primary mouse islets and identified known modulators of ligand-gated ion channels and G-protein-coupled receptors, including the antihelmintic ivermectin. Single-cell electrophysiology in circadian mutant mouse and human cadaveric islets revealed ivermectin as a glucose-dependent secretagogue. Genetic, genomic, and pharmacological analyses established the P2Y1 receptor as a clock-controlled mediator of the insulinotropic activity of ivermectin. These findings identify the P2Y1 purinergic receptor as a diabetes target based upon a genetically sensitized phenotypic screen.

Circadian rhythms ­ 'inbuilt' 24-hour cycles ­ control many aspects of behaviour and physiology. In mammals, they operate in nearly all tissues, including those involved in glucose metabolism. Recent studies have shown that mice with faulty genes involved in circadian rhythms, the core clock genes, can develop diabetes. Diabetes arises when the body struggles to regulate blood sugar levels. In healthy individuals, the hormone insulin produced by beta cells in the pancreas regulates the amount of sugar in the blood. But when beta cells are faulty and do not generate sufficient insulin levels, or when insulin lacks the ability to stimulate cells to take up glucose, diabetes can develop. Marcheva, Weidemann, Taguchi et al. wanted to find out if diabetes caused by impaired clock genes could be treated by targeting pathways regulating the secretion of insulin. To do so, they tested over 2,500 potential drugs on genetically modified beta cells with faulty core clock genes. They further screened the drugs on mice with the same defect in their beta cells. Marcheva et al. identified one potential compound, the anti-parasite drug ivermectin, which was able to restore the secretion of insulin. When ivermectin was applied to both healthy mice and mice with faulty beta cells, the drug improved the control over glucose levels by activating a specific protein receptor that senses molecules important for storing and utilizing energy. The findings reveal new drug targets for treating forms of diabetes associated with deregulation of the pancreatic circadian clock. The drug screening strategy used in the study may also be applied to reveal mechanisms underlying other conditions associated with disrupted circadian clocks, including sleep loss and jetlag.

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.

Initial rapidity of tumor growth as a prognostic factor for the therapeutic effect of immune-checkpoint inhibitors in patients with non-small cell lung cancer: evaluation for linear and non-linear correlation.

BACKGROUND: Immune-checkpoint inhibitors (ICIs) have been increasingly used for non-small cell lung cancer (NSCLC) treatment in recent years. Although insufficient, the rate of programmed death-ligand 1 expression has been adopted as a predictor of ICI efficacy. We evaluated tumor growth rate as a clinically easy-to-use predictor of the therapeutic effect of ICIs. METHODS: This study is a single-institution retrospective study in Japan. NSCLC patients treated with nivolumab, pembrolizumab, or atezolizumab at Saitama Medical Center from January 1, 2016 to December 31, 2018 were enrolled, and followed until December 31, 2020. We defined and calculated the initial rapidity of tumor progression (IRP) as: the increase in the sum of the diameters of intrathoracic tumors and lymph nodes on two series of chest computed tomography (CT) scans (one obtained at an initial checkup and the other obtained immediately before the first treatment) divided by the number of days between these CT scans. Two coefficients were calculated: the maximal information coefficient (MIC) between IRP and time to treatment failure (TTF) using the Python package with minepy library, and the Spearman's rank correlation coefficient. RESULTS: A total of 55 patients (median age, 70 years; 47 men) were enrolled. The median TTF with ICIs was 126 days, and four patients continued to receive ICI treatment at the end of the follow-up. The MIC between IRP and TTF was 0.302 with weak correlation, and the Spearman's rank correlation coefficient was -0.347 (P=0.00938). CONCLUSIONS: The initial tumor growth rate had a negative linear correlation with the therapeutic effect of ICIs.

Mortality and neurological outcomes in extremely and very preterm infants born to mothers with hypertensive disorders of pregnancy.

To evaluate the impact of maternal hypertensive disorders of pregnancy (HDP) on mortality and neurological outcomes in extremely and very preterm infants using a nationwide neonatal database in Japan. This population-based retrospective study was based on an analysis of data collected by the Neonatal Research Network of Japan from 2003 to 2015 of neonates weighing 1,500 g or less at birth, between 22 and 31 weeks' gestation. A total of 21,659 infants were randomly divided into two groups, HDP (n = 4,584) and non-HDP (n = 4,584), at a ratio of 1:1 after stratification by four factors including maternal age, parity, weeks of gestation, and year of delivery. Short-term (neonatal period) and medium-term (3 years of age) mortality and neurological outcomes were compared between the two groups by logistic regression analyses. In univariate analysis, HDP was associated with an increased risk for in-hospital death (crude odds ratio [OR], 1.31; 95% confidence interval, 1.04-1.63) and a decreased risk for severe intraventricular haemorrhage (0.68; 0.53-0.87) and periventricular leukomalacia (0.60; 0.48-0.77). In multivariate analysis, HDP was significantly associated with a lower risk for in-hospital death (adjusted OR, 0.61; 0.47-0.80), severe intraventricular haemorrhage (0.47; 0.35-0.63), periventricular leukomalacia (0.59; 0.45-0.78), neonatal seizures (0.40; 0.28-0.57) and cerebral palsy (0.70; 0.52-0.95) at 3 years after adjustment for covariates including birth weight. These results were consistent with those of additional analyses, which excluded cases with histological chorioamnionitis and which divided the infants into two subgroups (22-27 gestational weeks and 28-31 gestational weeks). Maternal HDP was associated with an increased risk for in-hospital death without adjusting for covariates, but it was also associated with a lower risk for mortality and adverse neurological outcomes in extremely and very preterm infants if all covariates except HDP were identical.

Functional inhibition of heat shock protein 70 by VER-155008 suppresses pleural mesothelioma cell proliferation via an autophagy mechanism.

BACKGROUND: Pleural mesothelioma, a devastating asbestos-associated malignancy, urgently requires a novel effective therapy. Heat shock protein 70 (HSP70), which is synthesized in the cell response to protein damage, is expected to be a new target for antitumor treatment. In addition to its well-known protein refolding function, HSP70 regulates cell proliferation through different pathways, including PI3K/AKT/mTOR, and autophagy in malignant cells. In this study, we attempted to clarify the effects of VER-155008, an HSP70 inhibitor, on pleural mesothelioma. METHODS: Human pleural mesothelioma cell lines 211H, H2452 and H28 were cultured with VER-155008, and protein expression, cell proliferation, colony formation, cell cycle, synergistic effect with cisplatin, and autophagy induction were analyzed. RESULTS: In mesothelioma cell lines, VER-155008 (5.0 µM or more) inhibited cell growth and colony formation, accompanied by G1 cell cycle arrest. According to western blot analysis, VER-155008 reduced p-AKT expression. However, VER-155008 failed to show a synergistic effect with cisplatin on cell growth. Mesothelioma cells transfected with the novel plasmid pMRX-IP-GFP-LC3-RFP-LC3ΔG, which was developed for the quantitative and statistical estimation of macroautophagy, showed enhanced macroautophagy upon treatment with VER-155008 and gefitinib which is an EGFR-tyrosine kinase inhibitor. In addition, fetal bovine serum deprivation induced macroautophagy was further enhanced by VER-155008. CONCLUSIONS: On the basis of these results, functional HSP70 inhibition by VER-155008 suppressed cell growth in pleural mesothelioma cells, accompanied by enhanced macroautophagy. HSP70 inhibition is thus expected to become a new strategy for treating mesothelioma. KEY POINTS: Significant findings of the study In pleural mesothelioma cells, inhibition of HSP70 function by VER-155008 suppressed cell proliferation accompanied by induction of autophagy which was synergistically enhanced under the starvation condition, whereas gefitinib, an EGFR-TKI, did not show the same synergistic effect in autophagy. What this study adds The inhibition of HSP70 induced autophagy and suppressed cell proliferation in mesothelioma cells.

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.

Genome-wide association meta-analysis identifies GP2 gene risk variants for pancreatic cancer.

Pancreatic cancer is the fourth leading cause of cancer-related deaths in Japan. To identify risk loci, we perform a meta-analysis of three genome-wide association studies comprising 2,039 pancreatic cancer patients and 32,592 controls in the Japanese population. Here, we identify 3 (13q12.2, 13q22.1, and 16p12.3) genome-wide significant loci (P < 5.0 × 10-8), of which 16p12.3 has not been reported in the Western population. The lead single nucleotide polymorphism (SNP) at 16p12.3 is rs78193826 (odds ratio = 1.46, 95% confidence interval = 1.29-1.66, P = 4.28 × 10-9), an Asian-specific, nonsynonymous glycoprotein 2 (GP2) gene variant. Associations between selected GP2 gene variants and pancreatic cancer are replicated in 10,822 additional cases and controls of East Asian origin. Functional analyses using cell lines provide supporting evidence of the effect of rs78193826 on KRAS activity. These findings suggest that GP2 gene variants are probably associated with pancreatic cancer susceptibility in populations of East Asian ancestry.

Evaluation of segment 4 portal vein embolization added to right portal vein for right hepatic trisectionectomy: A retrospective propensity score-matched study.

BACKGROUND: Adding segment 4 (S4) portal vein embolization (PVE) to right PVE before right hepatic trisectionectomy is controversial. We retrospectively examined the effect of S4 PVE on segments 2 and 3 (S2 + 3) hypertrophy. METHODS: We reviewed patients with biliary carcinoma who underwent right PVE with (R3PVE) or without (R2PVE) S4 PVE using gelatin sponge particles and coils (2010-2019). Propensity score matching balanced the cohort for baseline characteristics, including total liver volume and S2 + 3 volume before PVE. We compared the groups regarding the S2 + 3 volume changes after PVE. RESULTS: Of 178 enrolled patients, 38 underwent R3PVE for right hepatic trisectionectomy and 140 underwent R2PVE for right hepatectomy. Twenty-eight patients from each group were respectively matched. The median absolute volume increase in (146 cm3 vs 70 cm3 ), hypertrophy rate of (52.4% vs 32.3%), and kinetic growth rate of (3.1%/wk vs 2.0%/wk) S2 + 3 were significantly higher in the R3PVE group than in the R2PVE group. In the pre-matched cohort, the rate of posthepatectomy liver failure and postoperative hospital stay did not significantly differ between the patients who underwent right hepatic trisectionectomy and right hepatectomy. CONCLUSION: R3PVE increased the S2 + 3 volume more effectively than R2PVE in patients with biliary carcinoma.

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.

[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.

Comprehensive analysis of syndromic hearing loss patients in Japan.

More than 400 syndromes associated with hearing loss and other symptoms have been described, corresponding to 30% of cases of hereditary hearing loss. In this study we aimed to clarify the mutation spectrum of syndromic hearing loss patients in Japan by using next-generation sequencing analysis with a multiple syndromic targeted resequencing panel (36 target genes). We analyzed single nucleotide variants, small insertions, deletions and copy number variations in the target genes. We enrolled 140 patients with any of 14 syndromes (BOR syndrome, Waardenburg syndrome, osteogenesis imperfecta, spondyloepiphyseal dysplasia congenita, Stickler syndrome, CHARGE syndrome, Jervell and Lange-Nielsen syndrome, Pendred syndrome, Klippel-Feil syndrome, Alport syndrome, Norrie disease, Treacher-Collins syndrome, Perrault syndrome and auditory neuropathy with optic atrophy) and identified the causative variants in 56% of the patients. This analysis could identify the causative variants in syndromic hearing loss patients in a short time with a high diagnostic rate. In addition, it was useful for the analysis of the cases who only partially fulfilled the diagnostic criteria.

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.

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.