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Prostate cancer is an androgen-dependent malignancy that presents a marked treatment challenge, particularly after progression to the castration-resistant stage. Traditional treatments such as androgen deprivation therapy often lead to resistance, necessitating novel therapeutic approaches. Previous studies have indicated that some of the azolato-bridged dinuclear platinum(II) complexes (general formula: [{ cis -Pt(NH 3 ) 2 } 2 (μ-OH)(μ-azolato)]X 2 , where azolato = pyrazolato, 1,2,3-triazolato, or tetrazolato and X = nitrate or perchlorate) inhibit androgen receptor (AR) signaling. Therefore, here we investigated the potential of 14 such complexes as agents for the treatment of prostate cancer by examining their antiproliferative activity in the human prostate adenocarcinoma cell line LNCaP. Several of the complexes, particularly 5-H-Y ([{ cis -Pt(NH 3 ) 2 } 2 (μ-OH)(μ-tetrazolato- N2 , N3 )](ClO 4 ) 2 ), effectively inhibited LNCaP cell growth, even at low concentrations, by direct modulation of AR signaling, and by binding to DNA and inducing apoptosis, which is a common mechanism of action of Pt-based drugs such as cisplatin ( cis -diamminedichloridoplatinum(II)). Comparative analysis with cisplatin revealed superior inhibitory effects of these complexes. Further investigation revealed that 5-H-Y suppressed mRNA expression of genes downstream from AR and induced apoptosis, particularly in cells overexpressing AR, highlighting its potential as an AR antagonist. Thus, we provide here insights into the mechanisms underlying the antiproliferative effects of azolato-bridged complexes in prostate cancer.

Recipients of cellular therapies, including hematopoietic cell transplant (HCT) and chimeric antigen receptor T-cell (CART) therapy, are at risk for poor outcomes from coronavirus disease 2019 (COVID-19). There are limited data describing outcomes among patients in the pre- and early post-cellular therapy period during the Omicron era when multiple antiviral therapeutics were widely available. The objective of this study is to describe COVID-19 treatment and outcomes in patients diagnosed with COVID-19 during the pre- or early post-cellular therapy period. This is a single-center retrospective cohort study of adult HCT and CART recipients diagnosed with COVID-19 in the pre- and early post-cellular therapy period who tested positive for COVID-19 at our cancer center between January 1, 2022 and March 1, 2023. Primary outcomes were 30-day COVID-19-related hospitalization and death. A secondary outcome was development of persistent COVID-19, defined by a positive SARS-CoV-2 polymerase chain reaction (PCR) 31 to 90 days after COVID-19 diagnosis. Among 65 patients included, 52 (80%) received at least one COVID-19 therapeutic. The most common treatment after initial COVID-19 diagnosis was nirmatrelvir/ritonavir (29%), followed by monoclonal antibody therapy (26%) and remdesivir (11%). Of the 64 patients with at least 30 days of follow-up, 8 (12%) had at least one COVID-19-related hospitalization and one patient died, though cause of death was not due to COVID-19. Of the 8 patients hospitalized for COVID-19, one had severe disease and 7 had mild or moderate infection. Persistent COVID-19 was observed in 13/65 (20%) patients, with 4 patients requiring additional antiviral therapy. Three pre-cellular therapy patients had delays in receiving cellular therapy due to persistent COVID-19. During the Omicron era, rates of 30-day COVID-19-related hospitalization and death were relatively low in this cohort of pre- and early post-HCT and CART recipients, the majority of whom received treatment with at least one antiviral agent. Persistent COVID-19 occurred in 1 in 5 patients in the peri-cellular therapy period and led to cellular therapy treatment delays in several patients, highlighting the need for new COVID-19 treatment strategies., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: This study assessed the association of pathological kidney lesions with cardiovascular events in biopsy-proven diabetic kidney disease (DKD) with type 2 diabetes., Methods: This multicenter, retrospective study involved 244 patients with no previous cardiovascular events before biopsy, estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m 2 at biopsy (baseline), and ≥ 1 year of observation after biopsy. The outcomes were the first occurrence of cardiovascular events (cardiovascular death, non-fatal myocardial infarction, coronary intervention, or non-fatal stroke), and non-cardiovascular deaths before cardiovascular events were considered competing events. The association between the severity of each pathological lesion and cardiovascular events was investigated., Results: During follow-up (median: 6.4 years), 43 patients experienced cardiovascular events. The baseline clinical characteristics did not differ according to cardiovascular events. The cumulative incidence of cardiovascular events was higher in patients with mesangiolysis, global glomerulosclerosis ≥ 50%, moderate/severe interstitial inflammation, and moderate/severe arteriolar hyalinosis than in those having less advanced each lesion. Fine-Gray regression models revealed that global glomerulosclerosis ≥ 50% (subdistribution hazard ratio [SHR]: 3.85; 95% confidence interval [95% CI] 1.28-11.52), moderate/severe interstitial inflammation (SHR: 2.49; 95% CI 1.18-5.29), and moderate/severe arteriolar hyalinosis (SHR: 3.51; 95% CI 1.15-10.69) were linked to increased risk of cardiovascular events, after adjusting for clinical variables including RAAS inhibitors use at baseline. Adding the severity of these lesions to clinical variables improved the predictive value for cardiovascular events., Conclusions: In DKD with type 2 diabetes, advanced glomerulosclerosis, interstitial inflammation, and arteriolar hyalinosis were associated with cardiovascular events, adding predictive value to clinical features., (© 2024. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

Aim: Recently, substantial studies have been accumulated to indicate the important role of gut microbiota in diabetic kidney disease (DKD). The abnormal change of bacterial-derived products could imply specific injuries or play beneficial or harmful roles in DKD progression. In this study, we examined the presence and contribution of the Klebsiella oxytoca gene in the circulation of patients with DKD., Method: We enrolled a total of 16 healthy participants, 17 patients with DKD, 5 patients with DKD requiring haemodialysis (HD), and 7 patients with CKD without diabetes. Bacterial-derived DNA (16S rDNA and a specific K. oxytoca gene) in the blood was detected using droplet digital PCR, then investigated the relationship with clinical characteristics., Results: We identified an increase in K. oxytoca genes in the blood of DKD patients. Interestingly, blood K. oxytoca copies and K. oxytoca/ 16S DNA ratio correlated with higher blood creatinine and BUN levels together with lower eGFR in DKD patients. K. oxytoca levels were also associated with higher neutrophil percentage, lower lymphocyte frequency, and increased neutrophil-to-lymphocyte ratio., Conclusion: Collectively, the presence of the K. oxytoca gene in the circulation could serve as a biomarker reflecting reduced renal function in DKD patients., (© 2024 Asian Pacific Society of Nephrology.)

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., (© 2024. The Author(s).)

Abstract: The Blood and Marrow Transplant (BMT) Clinical Trials Network conducted a phase 3 randomized trial comparing gilteritinib with placebo after allogeneic hematopoietic cell transplantation (HCT) for FLT3-ITD+ acute myeloid leukemia (AML). The primary analysis demonstrated no statistically significant difference in relapse-free survival (RFS); however, patients with FLT3-ITD measurable residual disease (MRD) peri-HCT had significantly longer RFS with gilteritinib. This analysis investigates the effect of post-HCT gilteritinib vs placebo on health-related quality of life (HRQOL). HRQOL was measured with Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT), FACT-Leukemia (FACT-Leu), and EuroQOL-5 Dimensions (EQ-5D-5L) at post-HCT randomization; day 29; months 3, 6, 12, 18, 24; and/or end of therapy. HRQOL and clinically meaningful differences were summarized using descriptive statistics and compared using mixed model repeated measures to evaluate longitudinal change from baseline and stratified Cox model to evaluate time to improvement. HRQOL completion rate was acceptable (>70%) across all time points and measures. There were no differences in HRQOL scores at any time point between cohorts. Clinically meaningful and time to improvement in HRQOL were similar in both arms. Despite higher treatment-emergent adverse effects with gilteritinib, response to the question of being "bothered by side effects of treatment" did not differ between groups. Subgroup analysis of MRD-positive and negative patients demonstrated no differences in HRQOL between arms. For patients with FLT3-ITD+ AML undergoing HCT, gilteritinib maintenance was not associated with any difference in HRQOL or patient-reported impact of side effects. This trial was registered at www.ClinicalTrials.gov as #NCT02997202., (Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution.)

How do regional brain volume ratios and cerebral blood flow (CBF, mL/min) change with aging, and are there sex differences? This study aimed to comprehensively evaluate the relationships between regional brain volume ratios and CBF in healthy brains. The study participants were healthy volunteers who underwent three-dimensional T1-weighted MRI, time-of-flight MR angiography, and four-dimensional (4D) flow MRI between 2020 and 2022. The brain was automatically segmented into 21 brain subregions from 3D T1-weighted MRI, and CBF in 16 major intracranial arteries were measured by 4D flow MRI. The relationships between segmented brain volume ratios and CBFs around the circle of Willis were comprehensively investigated in each decade and sex. This study included 129 healthy volunteers (mean age ± SD, 48.2 ± 16.8; range, 22-92 years; 43 males and 86 females). The association was strongest between the cortical gray matter volume ratio and total outflow of the intracranial major arteries distal to the circle of Willis (Pearson's correlation coefficient, r: 0.425). In addition, the mean flow of the total inflow and outflow around the circle of Willis were significantly greater in women than men, and significant left-right differences were observed in CBFs even on the peripheral side of the circle of Willis. Moreover, the correlation was strongest between the left cortical gray matter volume ratio and the combined flows of the left anterior and posterior cerebral arteries distal to the circle of Willis (r: 0.486). There was a trend toward greater total intracranial CBF, especially among women in their 40s and younger, who had a larger cortical gray matter volume. This finding may be one of the reasons for the approximately twofold higher incidence of cerebral aneurysms and subarachnoid hemorrhage, and a threefold higher incidence of migraine headaches.

Background: Robot-assisted radical prostatectomy (RARP) is a preferred minimally invasive surgical treatment for prostate cancer. The number of elderly patients and those with cardiovascular and/or cerebrovascular issues undergoing surgery is increasing, and many of them are taking antithrombotic (AT) agents. However, the effect of AT agents on postoperative urinary recovery has not been adequately studied. In this study, we analyzed the differences in the postoperative recovery of urinary continence and oncological outcomes in patients undergoing RARP for localized prostate cancer between AT agent adherents and non-adherents., Methods: A total of 394 patients who underwent conventional anterior RARP between February 2015 and February 2021 were categorized into two groups: those taking oral AT agents (AT group) and the control group. Urinary continence recovery, complications, and oncological outcomes were compared between the groups. A Cox proportional hazards analysis was performed to identify clinical factors that affect urinary continence recovery., Results: The background data and bleeding complications did not differ significantly between the groups. The recovery of continence was significantly poorer in the AT group in terms of complete pad free (HR: 0.53 [95% CI: 0.39-0.71]) and use of ≤ 1 safety pad (HR: 0.74 [95% CI: 0.59-0.94]). The rate of anastomotic leakage on cystography was significantly higher in the AT group (20.9% vs. 6.7%). A univariate analysis revealed that taking antithrombotic agents, higher prostate-specific antigen levels, and a more advanced clinical stage were associated with a poor urinary continence recovery; a multivariate analysis showed that taking AT agents was an independent factor negatively associated with urinary continence recovery. There was no significant difference between the groups in the positive surgical margin rate (19.0% vs. 23.8%) or the biochemical-recurrence-free rate., Conclusion: Taking oral AT agents may be associated with poor urinary continence recovery after RARP., (© 2024. The Author(s).)

Introduction: Peritoneal equilibration test (PET) has been used to monitor peritoneal function. A more convenient marker would be useful in clinical situations including home medical care. Autotaxin is known to leak into the interstitium as vascular permeability increases during the progression of tissue fibrosis. Therefore, we hypothesized that autotaxin concentrations in peritoneal dialysis (PD) effluent might reflect peritoneal function., Methods: This study enrolled 45 patients undergoing PD from 2016 to 2021. Autotaxin concentrations measured in PD effluent were evaluated for their associations with markers obtained from PET., Results: Mean age was 69 years, and 33 patients were men. Univariate and multivariate analyses revealed that autotaxin concentrations are associated with dialysate/plasma creatinine ratio, end/start dialysate glucose ratio, and the dip in the dialysate sodium concentration, a marker of ultrafiltration capacity, at baseline (all p < 0.05)., Conclusions: Autotaxin concentrations in PD effluent might be an adjunct marker that reflects peritoneal function., (© 2024 International Society for Apheresis and Japanese Society for Apheresis.)

Abstract: Cytomegalovirus (CMV) disease occurs occasionally before allogeneic hematopoietic cell transplantation (HCT) and is associated with poor post-HCT outcomes; however, the impact of pre-HCT CMV reactivation is unknown. Pre-HCT CMV reactivation was assessed in HCT candidates from the preemptive antiviral therapy (2007-2017) and letermovir prophylaxis (2018-2021) eras. CMV DNA polymerase chain reaction (PCR) surveillance was routinely performed during the pre-HCT workup period, and antiviral therapy was recommended according to risk of progression to CMV disease. Risk factors for pre-HCT CMV reactivation were characterized, and the associations of pre-HCT CMV reactivation with post-HCT outcomes were examined using logistic regression and Cox proportional hazard models, respectively. A total of 1694 patients were identified, and 11% had pre-HCT CMV reactivation 14 days (median; interquartile range [IQR], 6-23) before HCT. Lymphopenia (≤0.3 × 103/μL) was the strongest risk factor for pre-HCT CMV reactivation at multiple PCR levels. In the preemptive therapy era, patients with pre-HCT CMV reactivation had a significantly increased risk of CMV reactivation by day 100 as well as CMV disease and death by 1 year after HCT. Clearance of pre-HCT CMV reactivation was associated with a lower risk of post-HCT CMV reactivation. Similar associations with post-HCT CMV end points were observed in a cohort of patients receiving letermovir prophylaxis. Pre-HCT CMV reactivation can be routinely detected in high-risk HCT candidates and is a significant risk factor for post-HCT CMV reactivation and disease. Pre-HCT CMV DNA PCR surveillance is recommended in high-risk HCT candidates, and antiviral therapy may be indicated to prevent post-HCT CMV reactivation., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Intratumour heterogeneity has been shown to play a role in the malignant progression of cancer. The clonal evolution in primary cancer has been well studied, however, that in metastatic tumorigenesis is not fully understood. In this study, we established human colon cancer-derived organoids and investigated clonal dynamics during liver metastasis development by tracking barcode-labelled subclones. Long-term subclone co-cultures showed clonal drift, with a single subclone becoming dominant in the cell population. Interestingly, the selected subclones were not always the same, suggesting that clonal selection was not based on cell intrinsic properties. Furthermore, liver tumours developed by co-transplantation of organoid subclones into the immunodeficient mouse spleen showed a progressive drastic reduction in clonal diversity, and only one or two subclones predominated in the majority of large metastatic tumours. Importantly, selections were not limited to particular subclones but appeared to be random. A trend towards a reduction in clonal diversity was also found in liver metastases of multiple colour-labelled organoids of mouse intestinal tumours. Based on these results, we propose a novel mechanism of metastasis development, i.e. a subclone population of the disseminated tumour cells in the liver is selected by neutral selection during colonization and constitutes large metastatic tumours., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: We developed a 3D-printed phantom model for ultrasound-guided caudal block for educational or training purposes because there have been no reports of the 3D-printed phantom model for ultrasound-guided caudal block. This study aimed to identify the needs for the phantom model in a lecture and demonstration at hands-on training (HoT) to promote the use of caudal block for sufficient pain control during high-dose-rate intracavitary/interstitial brachytherapy for gynecological cancers., Materials and Methods: The sacrum and formwork were designed by computed tomography imaging. A 3D-modeling software program was used to create the sacrum and formwork. The phantom was solidified by injecting a gelatin-based gel. Ultrasonography was performed to visualize the sacral hiatus and puncture needle in the phantom. In October 2023, 10 radiation oncologists who did not perform caudal block in daily clinical practice from ten Japanese facilities participated in HoT on ultrasound-guided caudal block. After the HoT, questionnaires were distributed to each participant, and feedback was obtained through online channels., Results: After receiving a lecture and demonstration on ultrasound-guided caudal block, 90% of the respondents would like to practice the procedure in their daily clinical practice. Moreover, 100% of the respondents would like to use the 3D-printed phantom model for ultrasound-guided caudal block for educational or training purposes., Conclusion: The 3D-printed phantom model for ultrasound-guided caudal block can be used in training and is in demand for facilities introducing caudal block., (Copyright © 2024 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

DNA hypomethylating agents (HMAs) are used for the treatment of myeloid malignancies, although their therapeutic effects have been unsatisfactory. Here we show that CRISPR-Cas9 screening reveals that knockout of topoisomerase 1-binding arginine/serine-rich protein (TOPORS), which encodes a ubiquitin/SUMO E3 ligase, augments the efficacy of HMAs on myeloid leukemic cells with little effect on normal hematopoiesis, suggesting that TOPORS is involved in resistance to HMAs. HMAs are incorporated into the DNA and trap DNA methyltransferase-1 (DNMT1) to form DNA-DNMT1 crosslinks, which undergo SUMOylation, followed by proteasomal degradation. Persistent crosslinking is cytotoxic. The TOPORS RING finger domain, which mediates ubiquitination, is responsible for HMA resistance. In TOPORS knockout cells, DNMT1 is stabilized by HMA treatment due to inefficient ubiquitination, resulting in the accumulation of unresolved SUMOylated DNMT1. This indicates that TOPORS ubiquitinates SUMOylated DNMT1, thereby promoting the resolution of DNA-DNMT1 crosslinks. Consistently, the ubiquitination inhibitor, TAK-243, and the SUMOylation inhibitor, TAK-981, show synergistic effects with HMAs through DNMT1 stabilization. Our study provides a novel HMA-based therapeutic strategy that interferes with the resolution of DNA-DNMT1 crosslinks., (© 2024. The Author(s).)

Since 2005 there has been steady decline in chronic graft-versus-host disease (cGVHD) at Fred Hutchinson Cancer Center (FHCC). To better understand this phenomenon, we studied the risk of cGVHD requiring systemic immunosuppression (cGVHD-IS) as a function of hematopoietic cell transplantation (HCT)-date in 3066 survivors from 2005 through 2019. Cox regression models were fit to assess associations of HCT-date (as a continuous linear variable) with cause-specific hazards of cGVHD, using unadjusted and adjusted models. Median follow-up for study subjects was 7.0 years (range, 1.0-17.2). Two-year probabilities of cGVHD-IS declined among all survivors from 45-52% (2005-2007) to approximately 40% (2008-2012) and then further to ~26% by 2017. A decline was also observed when the analysis was restricted to 502 pediatric survivors, with cGVHD-IS probabilities being <10% since 2013. Among 305 adult and pediatric survivors who were transplanted for nonmalignant diseases, cGVHD rates showed greater fluctuation but remained <20% after 2016. Each 5-year increase in HCT-date was associated with a 27% decrease in the cause-specific hazard of cGVHD (unadjusted hazard ratio [HR] 0.73; 95% confidence interval [CI] 0.68-0.78, p<.0001); the HR was 0.81 (95% CI 0.75-0.87, p<.0001) even after adjusting for various factors (age, donor/stem-cell source, race, sex, conditioning intensity, GVHD prophylaxis, among others) that could lead to cGVHD reduction. The decline in cGVHD was not fully explained by demographic shifts and greater use of HCT approaches generally associated with lower cGVHD rates. This observation underscores that single-cohort cGVHD-prevention studies should use contemporaneous and not historical controls for comparisons., (Copyright © 2024 American Society of Hematology.)

Background: This study aimed to examine postoperative recurrence after curative pancreatic resection following neoadjuvant chemoradiotherapy (NACRT) in patients with resectable (R-) and borderline resectable (BR-) pancreatic ductal adenocarcinoma (PDAC), focusing on its relationship with the standardized uptake value (SUV) on 18 F-fluorodeoxyglucose-positron emission tomography (FDG-PET)., Method: The postoperative initial recurrence patterns were examined in patients with R- and BR-PDAC who underwent NACRT followed by curative pancreatic resection. Data collected from three prospective clinical trials were retrospectively analysed., Results: After a median follow-up of 29 months, 91 (60 %) of 151 patients experienced postoperative recurrence. The median recurrence-free survival (RFS) for all patients was 18 months. The sites of first recurrence were lung-only in 24 (26 %) patients, liver-only in 23 (25 %), local-only in 11 (12 %), peritoneum-only in 10 (11 %), other single site in 5 (5 %), and multiple sites in 19 (21 %) patients. Multivariate analysis identified the maximum standardized uptake value (SUVmax) on FDG-PET at diagnoses ≥5.40 (hazard ratio [HR], 1.62; 95 % confidence interval [CI], 1.01-2.61; p = 0.045) and node-positive pathology (HR, 2.01; 95 % CI, 1.32-3.08; p = 0.001) as significant predictors of RFS. Furthermore, the SUVmax at initial diagnosis and after NACRT correlated with liver metastasis., Conclusion: R- and BR-PDACs with high SUV on FDG-PET at diagnosis are risk factors for postoperative recurrence. Among patients who undergo surgery after NACRT, those with a high SUVmax at diagnosis or post-NACRT require careful attention for postoperative liver recurrence., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Hangeshashinto is a traditional Japanese herbal medicine that is widely recognized for its efficacy in relieving mucositis induced by chemotherapy and radiotherapy. We herein present the cases of two patients with head and neck cancer who were clinically diagnosed with severe drug-induced interstitial lung disease (DILD) following Hangeshashinto administration for radiation-induced mucositis. Although Hangeshashinto has beneficial properties, it is also associated with a relatively low incidence of DILD, including some reports of death. To ensure patient safety, greater attention should be paid when prescribing Hangeshashinto, especially for elderly patients with factors predisposing them to develop severe DILD.

A simple method for purifying water using household items has been developed. The solution containing an environmental pollutant was added to the PET bottle. The lid of the PET bottle was closed, and the bottle was then placed with the lid down in a freezer for 9 h. The pourer of the PET bottle was surrounded by shredded paper scraps as a lagging material. Before the solution was completely frozen, the sample was removed from the freezer. The unfrozen portion (liquid) was sampled. The pollutant was concentrated in the liquid. The remaining frozen portion was completely thawed. As results, the concentration of the pollutant (Congo Red, Cr (VI), Pb (II), pentachlorophenol, fluoride, nitrate, or phosphate) in the thawed liquid was decreased by more than 90% compared with the initial concentration (0.10 mM). PRACTITIONER POINTS: A pollutant in a water sample can be removed by freezing a portion of the solution using a PET bottle, shredder scrap, and household freezer. Fluorine and hexavalent chromium can be removed from water to levels that meet water quality standards. The present method can efficiently remove a wide range of contaminants from water, including azo dyes, heavy metals, and pentachlorophenol., (© 2024 Water Environment Federation.)

We report a case of a patient with distal bile duct cancer who presented with ocular pain and eye redness due to a liver abscess. The patient developed a liver abscess while waiting for surgery. Since Klebsiella pneumoniae with high viscosity was identified and imaging studies showed systemic infection, a diagnosis of klebsiella invasive syndrome was made. In addition, infectious intraocular inflammation was also observed at the same time. In addition to antibiotic therapy, vitrectomy and percutaneous transhepatic abscess drainage successfully normalized the inflammatory response and negative blood cultures were obtained. Thirty-four days after the start of treatment, surgery was performed and the postoperative course was uneventful, and the patient was discharged from the hospital on the 39th postoperative day. Forty-six months after that surgery, there has been no evidence of recurrence of cholangiocarcinoma or recurrence of infection, but unfortunately, vision loss in the right eye remains. Some Klebsiella pneumoniae are highly pathogenic and are often reported from Southeast Asia, and ocular pain and hyperemic symptoms are important physical findings., (© 2024. Japanese Society of Gastroenterology.)

Background/aim: 18 F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) is reportedly associated with the malignant potential of cancer. This study aimed to evaluate the association between FDG accumulation and tumor metabolism in pancreatic ductal adenocarcinoma (PDAC)., Patients and Methods: A prognostic analysis of data from 131 patients with PDAC who underwent FDG-PET/CT before curative-intent pancreatic surgery was performed. Capillary electrophoresis-mass spectrometry (CE-MS) was used to analyze the metabolome of tumor and non-neoplastic pancreas from 80 patients. These patients were divided into two groups: low SUVmax group (SUVmax <6.09) and high SUVmax group (SUVmax ≥6.09)., Results: Carbohydrate antigen 19-9 (CA19-9), maximum standardized uptake value (SUVmax) of PET, N stage, and postoperative chemotherapy were identified as significant prognostic factors by univariate analysis. SUVmax emerged as an independent prognostic factor for overall survival [hazard ratio (HR)=1.88, p<0.05] and disease-free survival (HR=2.01, p<0.05) in multivariate analysis. Metabolic analyses confirmed that 43 metabolites significantly differed depending on the accumulation of SUV in tumors. Metabolites involved in the removal of reactive oxygen species (e.g., hypotaurine, glutathione, Met), treatment resistance (UDP-N-acetylglucosamine), and proliferation (e.g., choline, leucine, isoleucine) were increased in the high SUVmax group., Conclusion: FDG accumulation is an important independent prognostic factor reflecting tumor activity associated with metabolic changes in cancer cells., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: KRAS mutations frequently occur in cancers, particularly pancreatic ductal adenocarcinoma, colorectal cancer, and non-small cell lung cancer. Although KRAS G12C inhibitors have recently been approved, effective precision therapies have not yet been established for all KRAS-mutant cancers. Many treatments for KRAS-mutant cancers, including epigenome-targeted drugs, are currently under investigation. Small ubiquitin-like modifier (SUMO) proteins are a family of small proteins covalently attached to and detached from other proteins in cells via the processes called SUMOylation and de-SUMOylation. We assessed whether SUMOylation inhibition was effective in KRAS-mutant cancer cells., Methods: The efficacy of the first-in-class SUMO-activating enzyme E inhibitor TAK-981 (subasumstat) was assessed in multiple human and mouse KRAS-mutated cancer cell lines. A gene expression assay using a TaqMan array was used to identify biomarkers of TAK-981 efficacy. The biological roles of SUMOylation inhibition and subsequent regulatory mechanisms were investigated using immunoblot analysis, immunofluorescence assays, and mouse models., Results: We discovered that TAK-981 downregulated the expression of the currently undruggable MYC and effectively suppressed the growth of MYC-expressing KRAS-mutant cancers across different tissue types. Moreover, TAK-981-resistant cells were sensitized to SUMOylation inhibition via MYC-overexpression. TAK-981 induced proteasomal degradation of MYC by altering the balance between SUMOylation and ubiquitination and promoting the binding of MYC and Fbxw7, a key factor in the ubiquitin-proteasome system. The efficacy of TAK-981 monotherapy in immunocompetent and immunodeficient mouse models using a mouse-derived CMT167 cell line was significant but modest. Since MAPK inhibition of the KRAS downstream pathway is crucial in KRAS-mutant cancer, we expected that co-inhibition of SUMOylation and MEK might be a good option. Surprisingly, combination treatment with TAK-981 and trametinib dramatically induced apoptosis in multiple cell lines and gene-engineered mouse-derived organoids. Moreover, combination therapy resulted in long-term tumor regression in mouse models using cell lines of different tissue types. Finally, we revealed that combination therapy complementally inhibited Rad51 and BRCA1 and accumulated DNA damage., Conclusions: We found that MYC downregulation occurred via SUMOylation inhibition in KRAS-mutant cancer cells. Our findings indicate that dual inhibition of SUMOylation and MEK may be a promising treatment for MYC-expressing KRAS-mutant cancers by enhancing DNA damage accumulation., (© 2024. The Author(s).)

Purpose of Review: The development of new antiaging medicines is of great interest to the current elderly and aging population. Aging of the hematopoietic system is attributed to the aging of hematopoietic stem cells (HSCs), and epigenetic alterations are the key effectors driving HSC aging. Understanding the epigenetics of HSC aging holds promise of providing new insights for combating HSC aging and age-related hematological malignancies., Recent Findings: Aging is characterized by the progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. During aging, the HSCs undergo both quantitative and qualitative changes. These functional changes in HSCs cause dysregulated hematopoiesis, resulting in anemia, immune dysfunction, and an increased risk of hematological malignancies. Various cell-intrinsic and cell-extrinsic effectors influencing HSC aging have also been identified. Epigenetic alterations are one such mechanism., Summary: Cumulative epigenetic alterations in aged HSCs affect their fate, leading to aberrant self-renewal, differentiation, and function of aged HSCs. In turn, these factors provide an opportunity for aged HSCs to expand by modulating their self-renewal and differentiation balance, thereby contributing to the development of hematological malignancies., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

We investigated the reduction in regional brain volume and cerebral blood flow (CBF) with aging and explored potential sex differences in healthy brains. Three-dimensional (3D) T1-weighted magnetic resonance imaging (MRI), time-of-flight magnetic resonance angiography, and four-dimensional (4D) flow MRI were performed on 129 healthy volunteers aged 22-92 years. The brains of healthy volunteers were segmented into 21 subregions using 3D T1-weighted MRI and CBFs in 16 major intracranial arteries were measured using 4D flow MRI. The cortical gray matter volume decreased linearly with aging, whereas the cerebral white matter volume increased until the 40s and then decreased, and the subcortical gray matter volume changed little with aging. The cortical gray matter volume was significantly associated with the total CBF of the major intracranial arteries distal to the circle of Willis; however, the cerebral white matter and subcortical gray matter volumes were not. Generally, women have higher total CBF than men, particularly in their 40s and younger, despite the smaller intracranial volume and smaller diameters of intracranial arteries than men. This may contribute to the higher incidence of subarachnoid hemorrhage due to cerebral aneurysms and migraine in women., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The mammalian neocortex is formed by sequential radial migration of newborn excitatory neurons. Migrating neurons undergo a multipolar-to-bipolar transition at the subplate (SP) layer, where extracellular matrix (ECM) components are abundantly expressed. Here, we investigate the role of the ECM at the SP layer. We show that TGF-β signaling-related ECM proteins, and their downstream effector, p-smad2/3, are selectively expressed in the SP layer. We also find that migrating neurons express a disintegrin and metalloproteinase with thrombospondin motif 2 (ADAMTS2), an ECM metalloproteinase, just below the SP layer. Knockdown and knockout of Adamts2 suppresses the multipolar-to-bipolar transition of migrating neurons and disturbs radial migration. Time-lapse luminescence imaging of TGF-β signaling indicates that ADAMTS2 activates this signaling pathway in migrating neurons during the multipolar-to-bipolar transition at the SP layer. Overexpression of TGF-β2 in migrating neurons partially rescues migration defects in ADAMTS2 knockout mice. Our data suggest that ADAMTS2 secreted by the migrating multipolar neurons activates TGF-β signaling by ECM remodeling of the SP layer, which might drive the multipolar to bipolar transition., (© 2024. The Author(s).)

Colorectal cancer (CRC), a widespread malignancy, is closely associated with tumor microenvironmental hydrogen peroxide (H 2 O 2 ) levels. Some clinical trials targeting H 2 O 2 for cancer treatment have revealed its paradoxical role as a promoter of cancer progression. Investigating the dynamics of cancer cell H 2 O 2 eustress at the single-cell level is crucial. In this study, non-contact hopping probe mode scanning ion conductance microscopy (HPICM) with high-sensitive Pt-functionalized nanoelectrodes was employed to measure dynamic extracellular to intracellular H 2 O 2 gradients in individual colorectal cancer Caco-2 cells. We explored the relationship between cellular mechanical properties and H 2 O 2 gradients. Exposure to 0.1 or 1 mmol/L H 2 O 2 eustress increased the extracellular to intracellular H 2 O 2 gradient from 0.3 to 1.91 or 3.04, respectively. Notably, cellular F-actin-dependent stiffness increased at 0.1 mmol/L but decreased at 1 mmol/L H 2 O 2 eustress. This H 2 O 2 -induced stiffness modulated AKT activation positively and glutathione peroxidase 2 (GPX2) expression negatively. Our findings unveil the failure of some H 2 O 2 -targeted therapies due to their ineffectiveness in generating H 2 O 2 , which instead acts eustress to promote cancer cell survival. This research also reveals the complex interplay between physical properties and biochemical signaling in cancer cells' antioxidant defense, illuminating the exploitation of H 2 O 2 eustress for survival at the single-cell level. Inhibiting GPX and/or catalase (CAT) enhances the cytotoxic activity of H 2 O 2 eustress against CRC cells, which holds significant promise for developing innovative therapies targeting cancer and other H 2 O 2 - related inflammatory diseases., (Copyright © 2024. Published by Elsevier B.V.)

Purpose: Analyzing dose distributions to regional lymph-node metastases (RLNMs) in locally advanced cervical cancer (LACC) patients undergoing intracavitary and interstitial hybrid brachytherapy (IC/IS)., Methods: Dose distributions of eleven LACC patients with 38 RLNMs, and who received 38 IC/IS sessions were analyzed in EQD 2 , considering RLNM positions and ipsilateral interstitial needles; these RLNMs, excepting the para-aortic region, were classified into four groups., Results: RLNMs had a median of two ipsilateral interstitial needles per session. Significant differences were observed in total RLNM D 90 , depending on whether the position was cranial or caudal of the uterine base (85.5 vs. 378.9 cGy, p < 0.0001), and whether the RLNM D 90 was associated with a number of ipsilateral interstitial needles between 0-1 or 2 or more (68.4 vs. 112.2 cGy, p = 0.006) per session. At each session, Group 1 RLNMs (cranial of the uterine base, 0-1 ipsilateral interstitial needle) had a mean D 90 of 21.1 cGy; Group 2 (cranial, 2 or more), 73.8; Group 3 (caudal, 0-1), 94.7; and Group 4 (caudal, 2 or more), 136.1., Conclusion: RLNMs located caudal of the uterine base associated with two or more ipsilateral interstitial needles in IC/IS had a higher dose contribution, which should be considered when calculating the RLNMs' dose of external beam boost irradiation.

Background: A chronic expanding hematoma is an uncommon entity described as an organized blood collection that increases in size after the initial hemorrhagic event without histological neoplastic features. The standard treatment is complete resection. To our knowledge, this is the first report of a chronic expanding hematoma mimicking a pancreatic cystic tumor that has been successfully resected utilizing a laparoscopic approach., Case Presentation: We report the case of a 32-year-old man with a 10-cm chronic expanding hematoma that was preoperatively diagnosed as a cystic pancreatic tumor. Dynamic computed tomography revealed a cyst at the inferior part of the uncinate process of the pancreas without contrast enhancement. His blood biochemical data were within normal limits. The operation initially utilized a laparoscopic approach; however, the procedure was converted to hand-assisted laparoscopic surgery due to capsule adherence to surrounding organs and finally, enucleation of the tumor was performed. Pathological findings revealed a chronic expanding hematoma in the retroperitoneal space., Conclusion: Chronic expanding hematoma in the retroperitoneal space is so rare and sometimes adheres to the surrounding tissue. It is difficult to distinguish hematoma attaching pancreas and pancreatic cyst preoperatively. In rare cases such as this, hand-assisted laparoscopic surgery is a feasible, less invasive procedure for facilitating complete resection and preventing recurrence., (© 2024. The Author(s).)

The underlying mechanisms of atherosclerosis, the second leading cause of death among Werner syndrome (WS) patients, are not fully understood. Here, we establish an in vitro co-culture system using macrophages (iMφs), vascular endothelial cells (iVECs), and vascular smooth muscle cells (iVSMCs) derived from induced pluripotent stem cells. In co-culture, WS-iMφs induces endothelial dysfunction in WS-iVECs and characteristics of the synthetic phenotype in WS-iVSMCs. Transcriptomics and open chromatin analysis reveal accelerated activation of type I interferon signaling and reduced chromatin accessibility of several transcriptional binding sites required for cellular homeostasis in WS-iMφs. Furthermore, the H3K9me3 levels show an inverse correlation with retrotransposable elements, and retrotransposable element-derived double-stranded RNA activates the DExH-box helicase 58 (DHX58)-dependent cytoplasmic RNA sensing pathway in WS-iMφs. Conversely, silencing type I interferon signaling in WS-iMφs rescues cell proliferation and suppresses cellular senescence and inflammation. These findings suggest that Mφ-specific inhibition of type I interferon signaling could be targeted to treat atherosclerosis in WS patients., (© 2024. The Author(s).)

Subsequent to a medical examination, a 61-year-old male was referred to our hospital with jaundice. He was diagnosed with intrahepatic cholangiocarcinoma involving the hepatic hilum and was referred to our department to undergo a left trisectionectomy of the liver, extrahepatic bile duct resection, and regional lymphadenectomy. He was discharged on postoperative day 39 without liver failure. Two months postoperatively, positron-emission tomography/computed tomography(PET/ CT)indicated recurrences in the bone, and paraaortic lymph node. Gemcitabine and cisplatin combination first-line therapy was administered. Disease progression occurred after 4 courses of therapy. Gene panel testing was performed and the patient was switched to pembrolizumab owing to high microsatellite instability. After 2 courses of pembrolizumab, notable shrinkage of the paraaortic lymph node recurrence was confirmed on computed tomography as well as a partial response. PET-CT revealed disappearance of abnormal accumulation in all lesions at 20 months postoperatively. This has been sustained for 24 months following surgery without remarkable immune-related side-effects.

Background: Bidirectional reciprocal motion of cerebrospinal fluid (CSF) was quantified using four-dimensional (4D) flow magnetic resonance imaging (MRI) and intravoxel incoherent motion (IVIM) MRI. To estimate various CSF motions in the entire intracranial region, we attempted to integrate the flow parameters calculated using the two MRI sequences. To elucidate how CSF dynamics deteriorate in Hakim's disease, an age-dependent chronic hydrocephalus, flow parameters were estimated from the two MRI sequences to assess CSF motion in the entire intracranial region., Methods: This study included 127 healthy volunteers aged ≥ 20 years and 44 patients with Hakim's disease. On 4D flow MRI for measuring CSF motion, velocity encoding was set at 5 cm/s. For the IVIM MRI analysis, the diffusion-weighted sequence was set at six b-values (i.e., 0, 50, 100, 250, 500, and 1000 s/mm 2 ), and the biexponential IVIM fitting method was adapted. The relationships between the fraction of incoherent perfusion (f) on IVIM MRI and 4D flow MRI parameters including velocity amplitude (VA), absolute maximum velocity, stroke volume, net flow volume, and reverse flow rate were comprehensively evaluated in seven locations in the ventricles and subarachnoid spaces. Furthermore, we developed a new parameter for fluid oscillation, the Fluid Oscillation Index (FOI), by integrating these two measurements. In addition, we investigated the relationship between the measurements and indices specific to Hakim's disease and the FOIs in the entire intracranial space., Results: The VA on 4D flow MRI was significantly associated with the mean f-values on IVIM MRI. Therefore, we estimated VA that could not be directly measured on 4D flow MRI from the mean f-values on IVIM MRI in the intracranial CSF space, using the following formula; e 0.2(f-85)  + 0.25. To quantify fluid oscillation using one integrated parameter with weighting, FOI was calculated as VA × 10 + f × 0.02. In addition, the FOIs at the left foramen of Luschka had the strongest correlations with the Evans index (Pearson's correlation coefficient: 0.78). The other indices related with Hakim's disease were significantly associated with the FOIs at the cerebral aqueduct and bilateral foramina of Luschka. FOI at the cerebral aqueduct was also elevated in healthy controls aged ≥ 60 years., Conclusions: We estimated pulsatile CSF movements in the entire intracranial CSF space in healthy individuals and patients with Hakim's disease using FOI integrating VA from 4D flow MRI and f-values from IVIM MRI. FOI is useful for quantifying the CSF oscillation., (© 2024. The Author(s).)

This study assessed the significance of hands-on-training (HoT) and questionnaire-based surveys on 3D image-guided brachytherapy (3D-IGBT) and a combination of intracavitary and interstitial brachytherapy, the so-called 'hybrid' BT (HBT), in uterine cervical cancer. In October 2023, 29 radiation oncologists, nurses, radiologic technologists and medical physicists from 10 Japanese facilities participated in an HoT on 3D-IGBT and HBT. Questionnaires were distributed to each participant before and after the HoT, and feedback was obtained through online channels. The questionnaire response rate was 83% (24/29), with at least one participant responding from each facility. 'Insertion of applicators and needles', 'human resource shortage' and 'pain relief and sedation' were the primary concerns of radiation oncologists. 'Applicator reconstruction', ' optimization of dwell positions', ' treatment planning' and ' human resource shortages ' were the primary concerns of radiological technologists and medical physicists. The HoT content was adjusted according to the results of preliminary surveys. The concerns expressed by the participants were addressed during the lectures and practical training. Significant reductions in anxiety were observed toward all items of the 10-point self-assessment after the HoT, regardless of the profession. The average score on satisfaction with the HoT (on a 10-point scale) was 9.52 (minimum of 8 and maximum of 10). In conclusion, HoT tailored in response to a pre-questionnaire-based survey effectively reduced participants' anxiety regarding the implementation of 3D-IGBT and HBT., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Background: d-alanine administration prevented kidney damage in a murine acute kidney injury model. Further data are needed on the influence of d-alanine on kidney function in humans., Objective: This study investigated the effects of d-alanine intake on amino acid metabolism and kidney function in healthy volunteers., Methods: This multicenter pilot study randomly assigned individuals from the general Japanese population to receive 3 g or 6 g of d-alanine intake per day for 7 d in a 1:1 ratio. The primary endpoint was the mean change in plasma and urine d-alanine levels from baseline to 7 d after intake. The secondary endpoints were mean changes in kidney function and other clinical factors. Safety was assessed by evaluating adverse events and clinical parameters., Results: We randomly assigned 24 participants to the 3-g ( n = 12) and 6-g d-alanine ( n = 12) groups. The mean baseline estimated glomerular filtration rate (eGFR) was 73 mL/min/1.73 m 2 . The mean plasma d-alanine concentration increased from baseline by 77.5 ± 34.3 and 192.1 ± 80.9 nmol/mL in the 3-g and 6-g d-alanine groups (both p < 0.0001), respectively, in a dose-dependent manner (between-group difference: 114.6 nmol/mL; 95% CI: 62.1-167.2; P = 0.0002). A similar increase was observed for the urine d-alanine to creatinine ratio. The mean eGFR was elevated by 5.7 ± 8.8 mL/min/1.73 m 2 in the 6-g d-alanine group ( P = 0.045) but did not significantly change in the 3-g d-alanine group. Nonserious adverse events were reported in 11 participants., Conclusions: d-alanine intake increased plasma and urine d-alanine levels and was well tolerated in participants with normal kidney function. These results will be useful in future trials investigating the effects of d-alanine intake on kidney disease progression in patients with chronic kidney disease.This trial was registered at the UMIN Clinical Trials Registry as UMIN000051466., (© 2024 The Authors.)

Purpose: Allogeneic hematopoietic cell transplantation (HCT) improves outcomes for patients with AML harboring an internal tandem duplication mutation of FLT3 ( FLT3-ITD ) AML. These patients are routinely treated with a FLT3 inhibitor after HCT, but there is limited evidence to support this. Accordingly, we conducted a randomized trial of post-HCT maintenance with the FLT3 inhibitor gilteritinib (ClinicalTrials.gov identifier: NCT02997202) to determine if all such patients benefit or if detection of measurable residual disease (MRD) could identify those who might benefit., Methods: Adults with FLT3-ITD AML in first remission underwent HCT and were randomly assigned to placebo or 120 mg once daily gilteritinib for 24 months after HCT. The primary end point was relapse-free survival (RFS). Secondary end points included overall survival (OS) and the effect of MRD pre- and post-HCT on RFS and OS., Results: Three hundred fifty-six participants were randomly assigned post-HCT to receive gilteritinib or placebo. Although RFS was higher in the gilteritinib arm, the difference was not statistically significant (hazard ratio [HR], 0.679 [95% CI, 0.459 to 1.005]; two-sided P = .0518). However, 50.5% of participants had MRD detectable pre- or post-HCT, and, in a prespecified subgroup analysis, gilteritinib was beneficial in this population (HR, 0.515 [95% CI, 0.316 to 0.838]; P = .0065). Those without detectable MRD showed no benefit (HR, 1.213 [95% CI, 0.616 to 2.387]; P = .575)., Conclusion: Although the overall improvement in RFS was not statistically significant, RFS was higher for participants with detectable FLT3-ITD MRD pre- or post-HCT who received gilteritinib treatment. To our knowledge, these data are among the first to support the effectiveness of MRD-based post-HCT therapy.

Tuning of protein homeostasis through mobilization of the unfolded protein response (UPR) is key to the capacity of pancreatic beta cells to cope with variable demand for insulin. Here, we asked how insulin-degrading enzyme (IDE) affects beta cell adaptation to metabolic and immune stress. C57BL/6 and autoimmune non-obese diabetic (NOD) mice lacking IDE were exposed to proteotoxic, metabolic, and immune stress. IDE deficiency induced a low-level UPR with islet hypertrophy at the steady state, rapamycin-sensitive beta cell proliferation enhanced by proteotoxic stress, and beta cell decompensation upon high-fat feeding. IDE deficiency also enhanced the UPR triggered by proteotoxic stress in human EndoC-βH1 cells. In Ide -/- NOD mice, islet inflammation specifically induced regenerating islet-derived protein 2, a protein attenuating autoimmune inflammation. These findings establish a role of IDE in islet cell protein homeostasis, demonstrate how its absence induces metabolic decompensation despite beta cell proliferation, and UPR-independent islet regeneration in the presence of inflammation., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

Background: Clinically relevant postoperative pancreatic fistula (CR-POPF) after pancreatic resection can lead to severe postoperative complications. POPF is defined based on postoperative day (POD) 3 drainage fluid amylase level. POPF correlates with inflammatory parameters as well as drainage fluid bacterial infection. However, a standardized model based on these factors for predicting CR-POPF remains elusive. We aimed to identify inflammatory parameter- and drainage fluid culture-related risk factors for CR-POPF on POD 3 after pancreatoduodenectomy (PD) and distal pancreatectomy (DP)., Methods: Data from 351 patients who underwent PD or DP between 2013 and 2022 at a single institution were retrospectively analyzed. Risk factors for CR-POPF were investigated using multivariate analyses, and a prediction model combining the risk factors for CR-POPF was developed., Results: Of the 351 patients, 254 and 97 underwent PD and DP, respectively. Multivariate analyses revealed that drainage fluid amylase level ≥722 IU/L, culture positivity, as well as neutrophil count ≥5473/mm 3 on POD 3 were independent risk factors for CR-POPF in PD group. Similarly, drainage fluid, amylase level ≥500 IU/L, and culture positivity on POD 3 as well as pancreatic thickness ≥11.1 mm were independent risk factors in the DP group. The model for predicting CR-POPF achieved the maximum overall accuracy rate when the number of risk factors was ≥2 in both the PD and DP groups., Conclusions: Inflammatory parameters on POD 3 significantly influence the risk of CR-POPF onset after pancreatectomy. The combined models based on these values can accurately predict the risk of CR-POPF after pancreatectomy., (© 2024 International Society of Surgery/Société Internationale de Chirurgie (ISS/SIC).)

Background: /Objective: Preoperative treatment of resectable pancreatic ductal adenocarcinoma (PDAC) is gaining popularity worldwide. However, the characteristics of tumors located in the pancreatic head (Ph), or those in the body or tail (Pbt), after surgery following neoadjuvant chemoradiotherapy (NACRT) remain unclear. This study aimed to evaluate and compare the clinicopathological features, perioperative outcomes, and prognosis of patients with resectable PDAC who underwent NACRT followed by curative pancreatic resection, focusing on distinguishing between Ph and Pbt PDACs., Methods: We included 107 patients with resectable PDAC who underwent curative resection following NACRT between 2009 and 2023. Clinicopathological features, perioperative and prognostic outcomes, recurrence patterns, and prognoses were compared between Ph and Pbt PDAC groups., Results: Tumors were found in the Ph and Pbt in 64 and 43 patients, respectively. Albumin levels and lymphocyte-to-monocyte ratios after NACRT were significantly lower in the Ph group than in the Pbt group. The Pbt group showed significantly higher rates of positive peritoneal lavage cytology and serosal, arterial, and portal vein invasion than the Ph group did. Overall and recurrence-free survival were similar between the two groups. The most common site of initial postoperative recurrence was the lung only in both groups; however, the rate of peritoneal dissemination only was significantly higher in the Pbt group than in the Ph group., Conclusions: The prognoses based on tumor locations in the Ph and Pbt after surgery following NACRT are similar. Following the resection of resectable Pbt PDAC, the possibility of peritoneal dissemination recurrence should be considered., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Endoscopic ultrasound-guided fine-needle aspiration has become the common procedure for the diagnosis of pancreatic mass, and cytological examination is usually the first approach. Solid pseudopapillary neoplasm (SPN) cytologically represents papillary structures of branching capillaries surrounded by discohesive neoplastic cells. However, it may present various degrees of tissue degeneration, causing diagnostic challenges. Here, we report a 21-year-old female who had a 2-cm-sized mass in the pancreas head. Cytological examination revealed clumps of small round/oval cells that represented microcystic configurations with mucus, mimicking adenoid cystic carcinoma or mucinous adenocarcinoma. Cercariform cells, nuclear grooves/folding, and cytoplasmic vacuoles were not observed. Histopathological examination revealed confluent small glandular structures containing acidic mucus. The tumor cells were positively stained for β-catenin, CD10, and CD56, and negative for chromogranin A and E-cadherin, suggesting SPN, micropseudocystic variant. This variant has been scarcely described, but we should recognize it for accurate cytological triage of pancreatic tumors., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Cell-cell interaction factors that facilitate the progression of adenoma to sporadic colorectal cancer (CRC) remain unclear, thereby hindering patient survival., Methods: We performed spatial transcriptomics on five early CRC cases, which included adenoma and carcinoma, and one advanced CRC. To elucidate cell-cell interactions within the tumour microenvironment (TME), we investigated the colocalisation network at single-cell resolution using a deep generative model for colocalisation analysis, combined with a single-cell transcriptome, and assessed the clinical significance in CRC patients., Findings: CRC cells colocalised with regulatory T cells (Tregs) at the adenoma-carcinoma interface. At early-stage carcinogenesis, cell-cell interaction inference between colocalised adenoma and cancer epithelial cells and Tregs based on the spatial distribution of single cells highlighted midkine (MDK) as a prominent signalling molecule sent from tumour epithelial cells to Tregs. Interaction between MDK-high CRC cells and SPP1+ macrophages and stromal cells proved to be the mechanism underlying immunosuppression in the TME. Additionally, we identified syndecan4 (SDC4) as a receptor for MDK associated with Treg colocalisation. Finally, clinical analysis using CRC datasets indicated that increased MDK/SDC4 levels correlated with poor overall survival in CRC patients., Interpretation: MDK is involved in the immune tolerance shown by Tregs to tumour growth. MDK-mediated formation of the TME could be a potential target for early diagnosis and treatment of CRC., Funding: Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for Science Research; OITA Cancer Research Foundation; AMED under Grant Number; Japan Science and Technology Agency (JST); Takeda Science Foundation; The Princess Takamatsu Cancer Research Fund., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024. Published by Elsevier B.V.)