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Abstract Background The clinical information housed within unstructured electronic health records (EHRs) has the potential to promote cancer research. The National Cancer Center Hospital (NCCH) is widely recognized as a leading institution for the treatment of thoracic malignancies in Japan. Information on medical treatment, particularly the characteristics of malignant tumors that occur in patients, tumor response evaluation, and adverse events, was compiled into the databases of each NCCH department from EHRs. However, there have been few opportunities for integrated analysis of data on both the hospital and research institute. Methods We developed a method for predicting tumor response evaluation and survival curves of drug therapy from the EHRs of lung cancer patients using natural language processing. First, we developed a rule-based algorithm to predict treatment duration using a dictionary of anticancer drugs and regimens used for lung cancer treatment. Thereafter, we applied supervised learning to radiology reports during each treatment period and constructed a classification model to predict the tumor response evaluation of anticancer drugs and date when the progressive disease (PD) was determined. The predicted response and PD date can be used to draw a survival curve for the progression-free survival. Results We used the EHRs of 716 lung cancer treatments at the NCCH and structured data of the cases as labels for the training and testing of supervised learning. The structured data were manually curated by physicians and CRCs. We investigated the results and performance of the proposed method. Individual predictions of tumor response evaluation and PD date were not extremely high. However, the final predicted survival curves were nearly similar to the actual survival curves. Conclusions Although it is difficult to construct a fully automated system using our method, we believe that it achieves sufficient performance for supporting physicians and CRCs constructing the database and providing clinical information to help researchers find out a chance of clinical studies.

Abstract Background Unresectable malignant bile duct stricture (often caused by unresectable pancreatic cancer and cholangiocarcinoma) can be drained via insertion of self-expandable metal stents (SEMS) during endoscopic retrograde cholangiopancreatography (ERCP). Because recurrent biliary obstruction (RBO) and complications following stent insertion can delay chemotherapy and other treatments, a longer time to RBO (TRBO) is desirable. Although a longer TRBO has been reported among patients who undergo insertion with larger diameter SEMS, patients who undergo insertion with smaller diameter fully covered SEMS (FCSEMS) may have a lower incidence of complications than those with larger diameter FCSEMS. The aim of this study is to determine the TRBO and incidence of complications with 6-mm FCSEMS vs 10-mm FCSEMS in patients with unresectable malignant distal bile duct stricture. Methods In this multicenter, open-label, randomized controlled, non-inferiority trial (COSMIC UNISON), a target of 250 patients over 23 locations in Japan will receive either the 6-mm FCSEM or the standard 10-mm FCSEM during ERCP, with 125 patients in each group. The observation period will be 24 months, and patients will be enrolled from 15 March 2024 and assessed until the date of RBO or the study end (31 March 2029). The primary endpoint is TRBO, with RBO defined as the coexistence of abnormal liver enzyme values and dilation of the common bile duct and intrahepatic bile duct upstream of the stent. The secondary endpoints are the incidence and rates (at 3, 6, and 12 months) of non-RBO events, overall survival, cause of RBO, and symptomatic stent deviation. Adverse events from endoscopic procedures will be classified by the Lexicon Classification from the American Society of Endoscopy, and all other adverse events will be classified per the Japanese translation of the Common Terminology Criteria for Adverse Events version 5.0. Discussion The COSMIC UNISON study is anticipated to provide evidence regarding the efficacy and safety of 6-mm vs 10-mm FCSEMS to inform the use of 6-mm FCSEMS for the treatment of unresectable malignant distal bile duct stricture. Trial registration Japan Registry of Clinical Trials identifier: jRCT1042230170. Prospectively registered on 15 March 2024.

Abstract Background Obsessive-compulsive disorder (OCD) present invasive thoughts and repetitive behaviors affecting 1–3% of the population, divided into 3–5 symptom dimensions. Self-contamination, a subtype within the contamination/washing dimension, remains poorly understood. This study aim is to investigate pathological features and treatment response in self-contamination subtype compared to other contamination subtype and checking symptoms. Method Seventy-one OCD patients were categorized into self-contamination (n = 15), contaminated (n = 25), and checking symptom (control, n = 31) groups. OCD symptom severity was assessed using the Japanese version of the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) Symptom Checklist. Comorbidities were evaluated using the Structured Clinical Interview for DSM-IV. Global functioning, anxiety, and depressive symptoms were measured using DSM-IV’s Global Assessment of Functioning Scale (GAFS), State-Trait Anxiety Inventory, and Zung’s Self-rating Depression Scale, respectively. Treatment involved a standardized combination of selective serotonin reuptake inhibitors and cognitive-behavioral therapy, with treatment response assessed after 1 year. Results Subjects in the self-contamination group showed significantly lower quality of life, GAFS scores, and higher comorbidities including major depressive disorder, social anxiety disorder, body dysmorphic disorder, and olfactory reference disorder. Treatment response was notably poorer in the self-contamination group. Multiple regression analysis identified four poor treatment outcome predictors: score on the Y-BOCS and the SDS, duration of illness, and prevalence of ORD. Conclusion The identification of the self-contamination subtype in OCD patients is crucial for understanding the pathophysiological and treatment response. Further research is needed to clarify the socio-cultural effects on the development of this putative subtype of OCD.

Objectives: This study aimed to evaluate the safety and long-term outcomes of a one-stage resection and anastomosis approach without preoperative decompression in patients with left-sided incomplete obstructive colorectal cancer. Methods: We conducted a retrospective analysis of 571 patients diagnosed with pT3-4NanyM0 left-sided colorectal cancer who underwent radical resection and primary anastomosis without preoperative decompression or a diverting stoma from April 2012 to December 2019. Of these, 97 (17%) patients presented with incomplete obstruction, while 474 (83%) had no obstruction. Incomplete obstruction was characterized by the inability of a small-caliber endoscope to pass through the tumor without necessitating emergency surgery or decompression due to bowel obstruction. We compared perioperative short-term outcomes, as well as the 5-year overall survival rate and the 5-year relapse-free survival rate between the two groups. Results: Patients in the incomplete obstruction group experienced significantly longer median intervals between admission and surgery (6 vs. 2 days, P

Objectives: Although curative resection for synchronous peritoneal carcinomatosis has been reported to improve prognosis, cases with positive intraoperative lavage cytology have not been reported. In this study, we investigated the prognostic value of potentially curative resection based on colorectal cancer and lavage cytology positivity in patients with synchronous peritoneal carcinomatosis. Methods: We retrospectively evaluated 72 patients who underwent intraoperative lavage cytology and one-stage potentially curative resection of primary and metastatic lesions (lavage cytology-positive, n = 21; lavage cytology-negative, n = 51) between July 2004 and December 2019. We compared the 5-year overall survival and 3-year recurrence rates between the lavage cytology-positive and lavage cytology-negative groups. Results: No significant differences were observed in the 5-year overall survival (48.2% vs. 45.5%, P = 0.924) or 3-year recurrence rates (74.5% vs. 62%, P = 0.143) between the two groups. Univariate analysis for 3-year recurrence revealed that lavage cytology-positive status was not an explanatory variable (hazard ratio: 1.552, 95% confidence interval: 0.83-2.902, P = 0.169). Multivariate analysis identified colon cancer as an independent risk factor of recurrence. Conclusions: In resectable cases, the resection of synchronous peritoneal carcinomatosis from colorectal cancer can be considered even if intraoperative lavage cytology is positive.

There are differences in the responsiveness to differential diagnostic tests for Cushing’s disease (CD), corticotroph tumor size, and the somatostatin receptor (SSTR) 5 expression in corticotroph tumors between CD patients. The differences in SSTR5 expression are particularly significant for identifying therapeutic targets for CD. However, prospective predictors of SSTR5 expression remain unclear. Thus, our objective was to elucidate the relationships among these clinical characteristics of CD, including SSTR5 expression. In 27 hospitalized patients with CD at Osaka University Hospital, Osaka, Japan, associations between corticotroph tumor diameter, the response of ACTH and cortisol to differential diagnostic tests for CD (CRH, desmopressin [DDAVP], and high-dose dexamethasone suppression test [HDDST]), the ACTH/cortisol index, and the SSTR5 immunoreactive score were retrospectively investigated. The response to differential diagnostic tests, ACTH/cortisol index, tumor diameter, and SSTR5 expression were significantly related (vs. tumor diameter [CRH: r = –0.54; DDAVP: r = –0.54; HDDST r = –0.67; ACTH/cortisol index: r = 0.76; SSTR5: r = –0.61], vs. CRH [DDAVP: r = 0.63, HDDST: r = 0.72, ACTH/cortisol index: r = –0.45; SSTR5: r = 0.56], vs. DDAVP [HDDST: r = 0.66; ACTH/cortisol index: r = –0.46; SSTR5: r = 0.76], vs. HDDST [ACTH/cortisol index: r = –0.62; SSTR5: r = 0.77], ACTH/cortisol index vs. SSTR5: r = –0.67). The areas under the receiver operating characteristic curve for the prediction of high SSTR5 expression via the CRH test, DDAVP test, HDDST, ACTH/cortisol index, and tumor diameter were 0.79, 0.87, 0.80, 0.71, and 0.71, respectively. Tests for differential diagnosis of CD, the ACTH/cortisol index, and the corticotroph tumor diameter have the potential for identifying SSTR5 expression in corticotroph tumors. These parameters may reflect the biological characteristics of corticotroph tumors.

Abstract The collection of wildlife tracking information throughout a species’ entire life cycle is important for comprehensive ecological elucidation and the establishment of practical protected areas. Although streaked shearwater (SS) is a seabird species for which biologging techniques are highly developed, there have been no reports of successful global positioning system (GPS) tracking during the early breeding and non-breeding seasons, when recapture is difficult. In this study, we succeeded in long-term GPS tracking, obtaining highly accurate tracking data during the non-breeding season from November to March and the early breeding season from April to July. We discuss the relationship between prey distribution and the marine environment to understand the species’ foraging habitat preferences. In September 2018, we attached GPS tags to birds breeding on Toshima, in the Izu Islands, and recaptured two birds in August 2020 and 2022. The tags worked for 277 and 549 days and fixed 23,510 and 37,233 positions, respectively. During the early breeding season, the foraging area had low sea surface temperatures (SST) and high chlorophyll-a (Chl-a) concentrations and moved northward as the season progressed. During the non-breeding season, one bird wintered in the South China Sea and the other off northern New Guinea. In the South China Sea, SS preferred sea areas with an average SST of 26 °C and high Chl-a concentrations (> 0.8mg/m3), whereas off northern New Guinea, SS preferred an area with an average SST of 29 °C. The foraging area used during the early breeding season depended on the optimal water temperature zone for their primary prey—Japanese Anchovy. The foraging areas used during the non-breeding season matched the optimal water temperature zones of the main fish distributed in each sea area. The GPS tracking data obtained in this study, while not a statistically sufficient sample size, are valuable and provide new insights into the environmental preferences of SS during early breeding and non-breeding seasons; life stages for which little information is available.

Postoperative pancreatic fistulas (POPFs) are common adverse events that occur after pancreatic surgery. Endoscopic ultrasonography (EUS)-guided drainage (EUS-D) is a first-line treatment, similar to that for pancreatic fluid collection (PFCs) after acute pancreatitis. However, some POPFs do not develop fluid collections depending on the presence or location of the surgical drain, whereas others develop fluid collections, such as postoperative fluid collections (POPFCs). Although POPFCs are similar to PFCs, the strategy and modality for POPF management need to be modified according to the presence of fluid collections, surgical drains, and surgical type. As discussed for PFCs, the indications, timing, and selection of interventions or stents for EUS-D have not been fully elucidated for POPFs. In this review, we discuss the management of POPFs and POPFCs in comparison with PFCs due to acute pancreatitis and summarize the topics that should be addressed in future studies.

Abstract We carried out a retrospective observational investigation to explore the association of endotheliopathy with coagulofibrinolytic reactions and the progression of disseminated intravascular coagulation (DIC) in adult trauma patients. We measured syndecan-1 (SDC-1), an indicator of endotheliopathy, and biomarkers of coagulofibrinolysis in 100 trauma patients immediately transferred to Ehime University Hospital. We evaluated the correlations between the coagulofibrinolytic parameters and SDC-1. We also investigated the association between SDC-1 elevations and the development of DIC, and determined the discriminators of DIC development. The median SDC-1 concentration was 82.7 (43.5–178.1) ng/mL. DIC developed in 16 patients (16.0%), and SDC-1 concentrations were significantly higher in DIC patients than in non-DIC patients (218.8 [134.5–798.2] ng/mL vs. 67.2 [39.6–114.5] ng/mL, p 92.5 ng/mL was significantly correlated with DIC progression (odds ratio [OR], 31.67; 95%CI: 3.97–252.31, p = 0.001). Many coagulofibrinolytic parameters were significantly correlated with SDC-1. Estimating the discriminators of DIC development by the least absolute shrinkage and selection operator (LASSO) and elastic-net regression analysis identified markers of coagulofibrinolytic activation, such as thrombin-antithrombin complex (TAT) and tissue plasminogen activator (tPA). A multivariate logistic regression model using TAT, tPA, and SDC-1 demonstrated that TAT and tPA, but not SDC-1, were independent factors predicting the development of DIC (TAT per 10 µg/L: OR, 1.14, 95%CI: 1.05–1.24, p = 0.003; tPA per 100pg/mL: OR, 1.03, 95%CI: 1.01–1.05, p = 0.003; SDC-1 per 10ng/mL: OR, 1.00, 95%CI: 0.99–1.01, p = 0.973). Mediation analysis showed that SDC-1 elevation was predominantly associated with the development of DIC indirectly through the increase in TAT (proportion mediated = 96.1%, p

Abstract Background Peritoneal metastasis, a major complication of colorectal cancer (CRC), often leads to poor quality of life and unfavorable outcomes. Despite numerous studies characterizing its biological features in CRC, intratumor heterogeneity and interactions between cancer cells and tumor microenvironment cells remain poorly understood. Methods To explore these aspects, we performed single-cell transcriptome analysis of matched primary tumor and peritoneal metastasis samples from a treatment-naïve patient. Results Our analysis revealed enrichment of “tip” endothelial cells in the primary tumor, driving angiogenic sprouting, whereas these cells were absent in peritoneal metastases. Moreover, cancer cells in peritoneal metastasis displayed a distinct expression signature associated with epithelial–mesenchymal transition and tumor invasiveness. Analysis of cell–cell communication between endothelial and tumor cells revealed decreased VEGF signaling and increased CXCL–ACKR1 interactions in peritoneal metastasis. Conclusions Although limited by its N-of-1 design and requiring further validation, our study provides preliminary observations suggesting that alterations in cancer-endothelial cell interactions could reduce dependence on VEGF signaling and influence immune cell infiltration in CRC peritoneal metastasis.

Abstract Superdense phase between graphite and Li metal, $$\hbox {C}_{2}$$ C 2 Li, has been significant in the research on both lithium-ion batteries (LIBs) and graphite intercalated compounds (GICs). However, a detailed method for synthesizing $$\hbox {C}_{2}$$ C 2 Li remains unknown owing to the limited information regarding $$\hbox {C}_{2}$$ C 2 Li and difficulties in distinguishing $$\hbox {C}_{2}$$ C 2 Li from $$\hbox {C}_{6}$$ C 6 Li. Thus, we performed in situ X-ray diffraction measurements on samples with the nominal composition of $$\hbox {C}_{2}$$ C 2 Li under high pressures and temperatures of up to 10 GPa and 400 $$^{\circ }\hbox {C}$$ ∘ C , respectively. We employed two types of $$\hbox {C}_{2}$$ C 2 Li samples; one was a mixture of $$\hbox {C}_{6}$$ C 6 graphite powder and Li metal (C $$_{6}+3$$ 6 + 3 Li), and the other was a mixture of $$\hbox {C}_{6}$$ C 6 Li and Li metal in which the $$\hbox {C}_{6}$$ C 6 Li was prepared by the electrochemical discharge (reduction) reaction that occurs in LIBs. Considering changes in the d-value based on the 001 diffraction peak from $$\hbox {C}_{6}$$ C 6 Li or $$\hbox {C}_{2}$$ C 2 Li, C $$_{6}$$ 6 Li + 2Li is suitable for synthesizing $$\hbox {C}_{2}$$ C 2 Li, although the nonaqueous electrolyte used for the electrochemical reaction should be removed to avoid structural transformations to lower-stage compounds such as $$\hbox {C}_{12}$$ C 12 Li and $$\hbox {C}_{18}$$ C 18 Li during the heating. These findings pave the way toward a method for synthesizing C $$_{2}$$ 2 Li, which could increase the energy density of LIBs and establish GICs with novel physical and electronic properties.

Abstract Inherited retinal degenerations are blinding genetic disorders characterized by high genetic and phenotypic heterogeneity. In this retrospective study, we describe sixteen families with early-onset non-syndromic retinal degenerations in which affected probands carried rare bi-allelic variants in CFAP410, a ciliary gene previously associated with recessive Jeune syndrome. We detected twelve variants, eight of which were novel, including c.373+91A>G, which led to aberrant splicing. To our knowledge this is the first likely pathogenic deep-intronic variant identified in this gene. Analysis of all reported and novel CFAP410 variants revealed no clear correlation between the severity of the CFAP410-associated phenotypes and the identified causal variants. This is supported by the fact that the frequently encountered missense variant p.(Arg73Pro), often found in syndromic cases, was also associated with non-syndromic retinal degeneration. This study expands the current knowledge of CFAP410-associated ciliopathy by enriching its mutational landscape and supports its association with non-syndromic retinal degeneration.

Abstract Background Behavioural parent training (BPT) is a psychosocial intervention designed for children with attention deficit hyperactivity disorder (ADHD). BPT programs teach parents to use effective commands or rules whilst encouraging them to pay careful attention to their child’s appropriate behaviour. In this study, we will investigate the efficacy of BPT on parental stress, mothers’ sense of emotional closeness to their children, and children’s attachment security to their mothers. We will also examine the effects of BPT on children’s internalising and externalising symptoms, ADHD symptoms, and sensitivity to rewards and punishments compared to usual care alone. The use of bias-prone assessment tools limits the ability of previous studies to assess effectiveness. Therefore, in this study, the child’s attachment security will be assessed in a structured interview conducted by assessors blinded to group allocation, and brain changes will be assessed using magnetic resonance imaging. Methods This randomised controlled clinical trial will aim to compare the efficacy of BPT to routine clinical care for 60 children with ADHD. Participants will be randomised, with stratification by medication status for ADHD (medicated or non-medicated). The BPT intervention group will receive parent training weekly for 10 weeks in a group of six or less. The primary outcome measure will be changes in parental stress. Furthermore, the key secondary outcome measure will be the child’s attachment security, which will be assessed in an interview conducted by assessors blinded to group allocation. We will also evaluate changes in neural connectivity in both children and mothers using magnetic resonance imaging. Other secondary outcomes will include child behavioural problems, ADHD symptoms, emotional regulation, child sensitivity to rewards and punishments, parental behaviour, and the child and parent’s social support network following the completion of 10 sessions. Discussion This study represents the first randomised controlled trial exploring the efficacy of BPT on child attachment security and mothers’ sense of emotional closeness to their children. It aims to provide robust evidence to assist parents of children with ADHD in making appropriate treatment decisions. Trial registration UMIN000038693. Registered on November 9, 2019.

Abstract Background Platelet-rich plasma (PRP), which is prepared by concentrating platelets in autologous blood, shows efficacy in chronic skin wounds via multiple growth factors. However, it exhibits heterogeneity across patients, leading to unstable therapeutic efficacy. Human induced pluripotent stem cell (iPSC)-derived megakaryocytes and platelets (iMPs) are capable of providing a stable supply, holding promise as materials for novel platelet concentrate-based therapies. In this context, we evaluated the effect of iMPs on wound healing and validated lyophilization for clinical applications. Methods The growth factors released by activated iMPs were measured. The effect of the administration of iMPs on human fibroblasts and human umbilical vein endothelial cells (HUVECs) was investigated in vitro. iMPs were applied to dorsal skin defects of diabetic mice to assess the wound closure rate and quantify collagen deposition and angiogenesis. Following the storage of freeze-dried iMPs (FD-iMPs) for three months, the stability of growth factors and their efficacy in animal models were determined. Result Multiple growth factors that promote wound healing were detected in activated iMPs. iMPs specifically released FGF2 and exhibited a superior enhancement of HUVEC proliferation compared to PRP. Moreover, an RNA-seq analysis revealed that iMPs induce polarization to stalk cells and enhance ANGPTL4 gene expression in HUVECs. Animal studies demonstrated that iMPs promoted wound closure and angiogenesis in chronic wounds caused by diabetes. We also confirmed the long-term stability of growth factors in FD-iMPs and their comparable effects to those of original iMPs in the animal model. Conclusion Our study demonstrates that iMPs promote angiogenesis and wound healing through the activation of vascular endothelial cells. iMPs exhibited more effectiveness than PRP, an effect attributed to the exclusive presence of specific factors including FGF2. Lyophilization enabled the long-term maintenance of the composition of the growth factors and efficacy of the iMPs, therefore contributing to stable supply for clinical application. These findings suggest that iMPs provide a novel treatment for chronic wounds.

Objectives: Peritoneal metastasis indicates a poor prognosis in patients with colorectal cancer (CRC). Studies have shown improved prognosis in patients after removal of peritoneal dissemination, and this surgery is recommended if not excessively invasive. The aim of this study was to examine clinical outcomes and prognostic factors for R0 resected CRC with synchronous peritoneal metastasis. Methods: We analyzed data retrospectively from 250 patients with stage IV CRC who underwent R0 resection at our hospital. The patients were divided into three groups according to the type of surgery: non-resected (N), palliative primary tumor resection (P), and R0 resection (R0) groups. Overall survival (OS) and recurrence-free survival (RFS) were investigated and clinicopathological parameters were analyzed for prognostic significance. Results: The 3-year OS was 57.2% in the R0 group. The R0 group had a significantly higher 3-year OS than that in the other groups (p < 0.0001). Multivariate analysis revealed that histological type, lymphatic and venous invasion, liver metastasis, R0 resection, and perioperative chemotherapy were independent prognostic factors. The 5-year RFS in the R0 group was 26.5%. Multivariate analysis revealed that the number of peritoneal metastases and surgical procedure were independent prognostic factors. Laparoscopic surgery had better 5-year RFS in the R0 group compared with that in the open surgery group (p = 0.0044). Conclusions: R0 resection of colorectal cancer with synchronous peritoneal metastasis should be considered for improving long-term survival. The laparoscopic approach for this disease is another promising method to prolong survival in patients with R0 resection.

Abstract Protein turnover is crucial for cell survival, and the impairment of proteostasis leads to cell death. Aging is associated with a decline in proteostasis, as the progressive accumulation of damaged proteins is a hallmark of age-related disorders such as neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). We previously discovered that the declining function of the ubiquitin-proteasome system (UPS) in motor neurons contributes to sporadic ALS pathologies, such as progressive motor neuron loss, protein accumulation, and glial activation. However, the mechanisms of UPS dysfunction-induced cell damage, such as cell death and aggregation, are not fully understood. This study used transcriptome analysis of motor neurons with UPS dysfunction and found that the expression of N-myc downstream regulated 1 (NDRG1) gets upregulated by UPS dysfunction. Additionally, the upregulation of NDRG1 induces cell death in the Neuro2a mouse neuroblastoma cell line. These results suggest that NDRG1 is a potential marker for UPS dysfunction and may play a role in neurodegeneration, such as that seen in ALS.