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Purpose: In patients with jaw bone atrophy, dental implant therapy requires bone augmentation on the alveolar ridge. Common methods are autologous bone transplantation or bone substitutes. The latter technique is less surgically invasive because it does not require bone harvesting; however, blood supply from the surrounding tissues and local differentiation of osteoblasts are not guaranteed, so adequate bone regeneration for dental implant therapy is often not achieved. Therefore, at our hospital we introduced a bone regenerative medicine technique that uses adipose stem cells (ASCs) from adipose tissue. The new approach is less surgically invasive and appears to have a better effect on bone regeneration. The current retrospective study aimed to demonstrate the efficacy of ASC transplantation in patients who underwent alveolar ridge bone augmentation at our hospital. Methods: We compared medical records, postoperative radiographic findings, and histological results from patients treated between January 2018 and March 2022 by augmentation of the jaw bone with bone substitutes (carbonate apatite) mixed with ASCs (ASCs+ group) and those treated with bone substitutes (carbonate apatite) alone (ASCs− group). Results: After 6 months, the survival rate of augmented bone and the gray scale value in dental cone beam computed tomography (a bone density index) were significantly higher in the ASCs+ group than in the ASCs− group. Histological analysis at 6 months showed more adequate bone tissue regeneration in the ASCs+ group. Conclusions: The findings suggest the effectiveness of using ASCs in bone augmentation on the alveolar ridge in patients with jaw bone atrophy. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Previous studies have suggested that glucose variability may accelerate atherosclerosis progression in people with type 2 diabetes. Current guidelines recommend assessing glycaemic control using continuous glucose monitoring (CGM), which provides a comprehensive glycaemic profile to supplement HbA1c measurement. However, the association between CGM-derived metrics and atherosclerosis progression is not entirely clear. Methods: This exploratory study used baseline data and data obtained after 104 weeks from an ongoing prospective, multicentre, observational study. Six hundred study participants with type 2 diabetes and no apparent history of symptomatic cardiovascular disease underwent CGM and ultrasonographic atherosclerosis measurements of the carotid arteries, including the intima–media thickness (IMT) and grey-scale median (GSM), at baseline and 104 weeks. Non-invasive ultrasonic tissue characterisation of the carotid artery wall or plaque using the GSM reflects vascular composition. Multivariate regression models were used to analyse the association between CGM-derived indices, mainly time in range (TIR) and CV, and changes in carotid atherosclerosis index values. Results: Over the 104-week study period, there were modest increases in mean IMT (from 0.759±0.153 to 0.773±0.152 mm, p<0.001) and thickened-lesion GSM (from 43.5±19.5 to 53.9±23.5 units, p<0.001), but no significant changes in common carotid artery maximum-IMT (from 1.109±0.442 to 1.116±0.469 mm, p=0.453) or mean GSM (from 48.7±19.3 to 49.8±20.8 units, p=0.092). In a linear regression model with adjustment for possible atherosclerotic risk factors, including HbA1c, TIR and CV at baseline were significantly associated with the annual change in mean GSM (regression coefficient per 10% increase in TIR 0.52; 95% CI 0.06, 0.98; Hochberg-adjusted p value 0.038; regression coefficient per 1% increase in CV −0.12; 95% CI −0.22, −0.02; Hochberg-adjusted p value 0.038). TIR and CV at baseline were also significantly associated with the annual change in thickened-lesion GSM (regression coefficient per 10% increase in TIR 0.95; 95% CI 0.12, 1.79; Hochberg-adjusted p value 0.038; regression coefficient per 1% increase in CV −0.19; 95% CI −0.36, −0.01; Hochberg-adjusted p value 0.038). Participants who achieved target CGM-derived metrics at baseline, as proposed by an international consensus, showed significant annual changes in mean GSM compared with those who did not (0.94±6.88 vs −0.21±6.19 units/year, p=0.007). Conclusions/interpretation: TIR and CV were significantly associated with changes in the tissue characteristics of the carotid artery wall. Trial registration: University Hospital Medical Information Network Clinical Trials Registry, number UMIN000032325 [ABSTRACT FROM AUTHOR]

Purpose: In patients with esophageal cancer, skeletal muscle mass has been reported to decrease progressively after surgery and be independently associated with a poor prognosis. The purpose of this study was to investigate perioperative changes in dysphagia, oral intake status, and nutritional status and identify factors related to sarcopenia 6 months after esophagectomy. Methods: A total of 134 patients who underwent radical resection for thoracic esophageal cancer between March 2016 and July 2019 were analyzed retrospectively. The diagnosis of sarcopenia was made by CT taken 6 months postoperatively using the cut-off criteria of skeletal muscle index (SMI) < 52.4 cm2/m2 for male and SMI < 38.5 cm2/m2 for female patients. As factors related to postoperative sarcopenia, dysphagia, oral intake status, nutritional status, and physical function were extracted from the medical records. Multivariate logistic regression analysis was performed to identify perioperative risk factors related to sarcopenia 6 months after surgery. Results: Of the 134 patients, 34.3% were judged to be unable to start oral intake on swallowing assessment. At discharge, 30.6% received tube feeding with or without oral intake. In the non-oral intake group on swallowing assessment, a significantly higher proportion of patients received tube feeding at discharge (p = 0.014). Preoperative BMI, postoperative handgrip strength, and tube feeding at discharge were independent risk factors for sarcopenia 6 months after esophagectomy in male patients. Conclusion: Tube feeding at discharge is significantly related to postoperative sarcopenia in patients with esophageal cancer. Identifying high-risk groups might allow early detection of malnutrition and provision of appropriate care. [ABSTRACT FROM AUTHOR]

Cancer relapse after chemotherapy remains a main cause of cancer-related death. Although the relapse is thought to result from the propagation of resident cancer stem cells1, a lack of experimental platforms that enable the prospective analysis of cancer stem cell dynamics with sufficient spatiotemporal resolution has hindered the testing of this hypothesis. Here we develop a live genetic lineage-tracing system that allows the longitudinal tracking of individual cells in xenotransplanted human colorectal cancer organoids, and identify LGR5+ cancer stem cells that exhibit a dormant behaviour in a chemo-naive state. Dormant LGR5+ cells are marked by the expression of p27, and intravital imaging provides direct evidence of the persistence of LGR5+p27+ cells during chemotherapy, followed by clonal expansion. Transcriptome analysis reveals that COL17A1—a cell-adhesion molecule that strengthens hemidesmosomes—is upregulated in dormant LGR5+p27+ cells. Organoids in which COL17A1 is knocked out lose the dormant LGR5+p27+ subpopulation and become sensitive to chemotherapy, which suggests that the cell–matrix interface has a role in the maintenance of dormancy. Chemotherapy disrupts COL17A1 and breaks the dormancy in LGR5+p27+ cells through FAK–YAP activation. Abrogation of YAP signalling prevents chemoresistant cells from exiting dormancy and delays the regrowth of tumours, highlighting the therapeutic potential of YAP inhibition in preventing cancer relapse. These results offer a viable therapeutic approach to overcome the refractoriness of human colorectal cancer to conventional chemotherapy.A genetic lineage-tracing system in human colorectal organoids identifies a population of dormant cancer cells that persists during chemotherapy and enables cancer regrowth, and the cell-adhesion molecule COL17A1 has a key role in the process of breaking dormancy. [ABSTRACT FROM AUTHOR]

Purpose: Although early prediction of mortality is useful for the management of patients with colorectal perforations, no significant perioperative predictive factors have been identified. The purpose of this study was to identify useful prognostic factors for patients with colorectal perforation. Methods: This single-center retrospective study included consecutive patients undergoing emergency surgery for colorectal perforation from January 2012 to December 2019. The primary outcome was combined 30 day and in-hospital mortality. Patient- and disease-related factors obtained perioperatively were evaluated for mortality prediction. A scoring system was developed to enhance clinical utility. Results: Overall, 146 patients were included and 20 (14%) died after surgery. Multivariate logistic regression identified five predictive factors: age, hemodialysis, uncommon perforation etiology, plasma albumin level, and decreased platelet count. The area under the receiver operating curve for the scoring system using these parameters was 0.894 (95% CI 0.835–0.952). Patients at high-risk of mortality were classified by the proposed score with a sensitivity of 90.0% and negative predictive value of 98.0%. Conclusion: This study identified five perioperative factors significantly associated with mortality of patients with colorectal perforation. Although these parameters predict mortality of patients with colorectal perforation using a score with high discrimination, further study is required to confirm these findings. [ABSTRACT FROM AUTHOR]

Introduction: Denosumab has been shown to be highly effective at suppressing the progression of giant cell tumor of bone (GCTB). However, recent studies have observed a potential increased risk of local recurrence after surgery following the use of denosumab, raising concerns on the use of this agent against GCTB in combination with surgery. Methods: We retrospectively reviewed the medical records of 234 patients with GCTB who were surgically treated at multiple institutions from 1990 to 2017. Patient background, tumor characteristics, treatment methods, local recurrence-free survival rate, distant metastasis rate, oncologic outcome, and limb function at final follow-up were analyzed and compared between cases treated with and without denosumab. Results: The 3-year local recurrence-free survival rate was significantly lower in patients who underwent preoperative denosumab therapy (35.3%) compared with those treated without denosumab (79.9%) (P < 0.001). Among patients who were preoperatively treated with denosumab, those who had a local recurrence all underwent curettage surgery. Conclusions: Preoperative denosumab therapy in combination with curettage surgery was significantly associated with an increased risk of local recurrence in Campanacci grade 3 tumors. Our data suggest that clinicians seeing GCTB patients should be aware to this increased risk when planning preoperative denosumab therapy. [ABSTRACT FROM AUTHOR]

This meta-analysis aimed to evaluate the device performance of conventional balloon catheters (POBA), drug-coated balloons (DCB), bare-metal stents (BMS), and drug-eluting stents (DES) in below-the-knee (BTK) ischemic lesions with regard to lesion characteristics. Online searches of PubMed, Web of Science, and Cochrane databases (2010–2019) were conducted for each of the test devices. Primary patency rates (pp) and major amputation rates 1 year after the use of each device were analyzed using a random-effects meta-analysis model. Meta-regression analysis was conducted to test associations between the outcomes and lesion characteristics. The analysis included 18 studies reporting on 24 separate cohorts comprising 2,438 patients. DES demonstrated the best pp among the test devices (83.6%; 95% confidence interval = 78.4–88.8%, studies = 8; I2 = 66%, P = 0.005). A negative coefficient between lesion length and pp (P = 0.002) was obtained. The ratio of critical limb ischemia (CLI) patients impacted the amputation rates (P = 0.031), whereas no statistically significant difference was found between the devices. DES showed favorable pp in BTK lesions; however, as the lesion lengths using DES were short, pp in long lesions still needs to be evaluated. Shorter lesions gained better pp. A higher ratio of CLI patients resulted in increased amputation rates. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the clinical utility of the Vesical Imaging-Reporting and Data System (VI-RADS) by comparing its diagnostic performance for muscle-invasive bladder cancer (MIBC) between radiologists and urologists based on multiparametric MRI, including three-dimensional (3D) fast spin-echo (FSE) T2-weighted acquisitions. Methods: This study included 66 treatment-naïve patients (60 men, 6 women; mean age 74.0 years) with pathologically proven bladder cancer who underwent multiparametric MRI, including 3D FSE T2-weighted imaging, before transurethral bladder tumour resection between January 2010 and November 2018. The MRI scans were categorised according to the five-point VI-RADS score by four independent readers (two board-certified radiologists and board-certified urologists each), blinded to the histopathological findings. The VI-RADS scores were compared with the postoperative histopathological diagnosis. Interobserver agreement was assessed using weighted kappa coefficients. ROC analysis and generalised estimating equations were used to evaluate the diagnostic performance. Results: Forty-nine (74.2%) and 17 (25.8%) tumours were confirmed to be non-MIBC and MIBC, respectively, based on pathological examination. The interobserver agreement was good-to-excellent between all pairs of readers (range, 0.73–0.91). The urologists' sensitivity/specificity values for DCE-MRI VI-RADS scores were significantly lower than those of radiologists. No significant differences were observed for the overall VI-RADS score. The AUC for the overall VI-RADS score was 0.94, 0.92, 0.89, and 0.87 for radiologists 1 and 2 and urologists 1 and 2, respectively. Conclusions: The VI-RADS score, based on multiparametric MRI including 3D FSE T2-weighted acquisitions, can be useful for radiologists and urologists to determine the bladder cancer muscle invasion status preoperatively. Key Points: • VI-RADS (using multiparametric MRI including 3D FSE T2-weighted acquisitions) achieves good to excellent interobserver agreement and has similar diagnostic performance for detecting muscle invasion by both radiologists and urologists. • The diagnostic performance of the overall VI-RADS score is high for both radiologists and urologists, particularly due to the dominant effect of diffusion-weighted imaging on the overall VI-RADS score. • The sensitivity and specificity values of the T2WI VI-RADS scores for four readers in our study (using 3D FSE T2-weighted acquisitions) were similar (with slightly higher specificity values) to previously published results (using 2D FSE T2-weighted acquisitions). [ABSTRACT FROM AUTHOR]

Preoperative prediction of molecular information of lower-grade gliomas (LrGGs) helps to determine the overall treatment strategy as well as the initial surgical strategy. This study aimed to detect magnetic resonance imaging (MRI) texture parameters to predict the molecular signature of LrGGs using a commercially available software and routine MR images. Forty-three patients treated at Keio University Hospital who had World Health Organization grade II or III gliomas were included. All patients having preoperative T1- and T2-weighted, fluid-attenuated inversion recovery (FLAIR) and diffusion-weighted (DW) images were also included. Texture analyses of T2, FLAIR, and apparent diffusion coefficient (ADC) histograms were performed using a commercially available software. Texture parameters including kurtosis, skewness, and entropy were investigated to determine any correlation with the presence or absence of isocitrate dehydrogenase (IDH) mutations, 1p/19q codeletion, and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation. ADC skewness and T2 skewness were significantly associated with 1p/19q codeletion status. ADC skewness of ≥ 0.25 predicted 1p/19q codeletion with a sensitivity and specificity of 80% and 65.2%, respectively (AUC = 0.728). T2 skewness of ≥ − 0.11 predicted 1p/19q codeletion with a sensitivity and specificity of 80% and 91.3%, respectively, (AUC = 0.866). None of the texture parameters were associated with IDH mutation and MGMT promoter methylation. MRI texture analysis using a commercially available software demonstrated that T2 skewness could predict 1p/19q codeletion with high sensitivity and specificity, suggesting a clinical utility. [ABSTRACT FROM AUTHOR]

With ageing, normal human tissues experience an expansion of somatic clones that carry cancer mutations1–7. However, whether such clonal expansion exists in the non-neoplastic intestine remains unknown. Here, using whole-exome sequencing data from 76 clonal human colon organoids, we identify a unique pattern of somatic mutagenesis in the inflamed epithelium of patients with ulcerative colitis. The affected epithelium accumulates somatic mutations in multiple genes that are related to IL-17 signalling—including NFKBIZ, ZC3H12A and PIGR, which are genes that are rarely affected in colon cancer. Targeted sequencing validates the pervasive spread of mutations that are related to IL-17 signalling. Unbiased CRISPR-based knockout screening in colon organoids reveals that the mutations confer resistance to the pro-apoptotic response that is induced by IL-17A. Some of these genetic mutations are known to exacerbate experimental colitis in mice8–11, and somatic mutagenesis in human colon epithelium may be causally linked to the inflammatory process. Our findings highlight a genetic landscape that adapts to a hostile microenvironment, and demonstrate its potential contribution to the pathogenesis of ulcerative colitis. Whole-exome sequencing of colon organoids derived from patients with ulcerative colitis identifies somatic mutations in components of the IL-17 signalling pathway, which may confer a growth advantage to cells under inflammatory conditions. [ABSTRACT FROM AUTHOR]

The anti-VEGF antibody bevacizumab has shown efficacy for the treatment of neurofibromatosis type 2 (NF2). Theoretically, vascular endothelial growth factor receptors (VEGFRs)-specific cytotoxic T lymphocytes (CTLs) can kill both tumor vessel cells and tumor cells expressing VEGFRs. Here we show an exploratory clinical study of VEGFRs peptide vaccine in seven patients with progressive NF2-derived schwannomas. Hearing improves in 2/5 assessable patients (40%) as determined by international guidelines, with increases in word recognition scores. Tumor volume reductions of ≥20% are observed in two patients, including one in which bevacizumab had not been effective. There are no severe adverse events related to the vaccine. Both VEGFR1-specific and VEGFR2-specific CTLs are induced in six patients. Surgery is performed after vaccination in two patients, and significant reductions in the expression of VEGFRs in schwannomas are observed. Therefore, this clinical immunotherapy study demonstrates the safety and preliminary efficacy of VEGFRs peptide vaccination in patients with NF2. The anti-vascular endothelial growth factor (VEGF) antibody bevacizumab has shown efficacy for the treatment of neurofibromatosis type 2 (NF2). Here, the authors show that VEGFRs peptide vaccination can improve hearing and reduce tumor volume in NF2 patients, including in previously bevacizumab resistant tumors. [ABSTRACT FROM AUTHOR]

In this paper, we report the experimental results of surface friction between thermoresponsive poly( N-isopropylacrylamide) gels in water. The static friction force was found to depend on the waiting period prior to slider movement after contact between gel surfaces, which was a result of two relaxation mechanisms: the stress decay process due to macroscopic deformation under a normal load and the microscopic conformational change in the real contact area of polymer networks. The sliding velocity and the normal load dependence of the kinetic friction force were extensively measured. The results suggested that the following two mechanisms depended on the sliding velocity: the friction force generated by direct contact of the solid-like behavior and the viscous resistance of the liquid-like behavior. The strong temperature dependence of kinetic friction was observed, which was a result of a change in the balance between hydrophobic and hydrophilic interactions. The experimental results are discussed in terms of the multi-asperity contacts between the swollen gel/gel interfaces (solid friction, depending on the waiting period) and the viscous resistance and lubricating effect between the gel/water interfaces (fluid friction, depending on the sliding velocity). [ABSTRACT FROM AUTHOR]