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The prevalence of the phylogenetic groups of Mycobacterium tuberculosis Beijing genotype has been reported to be similar in different areas of Japan. However, recent reports from rural areas of Japan show a low prevalence of modern Beijing strains, suggesting that the distribution of modern Beijing strains may have changed recently. Therefore, multi-locus variable number of tandem repeats analysis (MLVA) and draft whole genome sequence (DWGS) analysis were carried out to investigate the prevalence of particular genotype strains.Nine hundred and ninety modern Beijing strains were studied using minimum spanning tree (MST) analysis and neighbor-net analysis of MLVA and WGS data.An MST of M. tuberculosis Beijing genotype strains reconstructed from 12 loci-MLVA data showed two large complexes with the JThe results of this study suggested that pECT07 and its variants were prevalent among M. tuberculosis modern Beijing strains in Chiba Prefecture, but the prevalence of those strains may not have been due to an earlier large-scale latent outbreak.

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Supplementary Figure S1. Diagram of the multicolor zebrafish tumor model

Supplementary Table S1. Clinical data of cancer patients

Cancer metastasis can occur at early stages of tumor development due to facilitative alterations in the tumor microenvironment. Although imaging techniques have considerably improved our understanding of metastasis, early events remain challenging to study due to the small numbers of malignant cells involved that are often undetectable. Using a novel zebrafish model to investigate this process, we discovered that tumor-associated macrophages (TAM) acted to facilitate metastasis by binding tumor cells and mediating their intravasation. Mechanistic investigations revealed that IL6 and TNFα promoted the ability of macrophages to mediate this step. M2 macrophages were particularly potent when induced by IL4, IL10, and TGFβ. In contrast, IFNγ-lipopolysaccharide–induced M1 macrophages lacked the capability to function in the same way in the model. Confirming these observations, we found that human TAM isolated from primary breast, lung, colorectal, and endometrial cancers exhibited a similar capability in invasion and metastasis. Taken together, our work shows how zebrafish can be used to study how host contributions can facilitate metastasis at its earliest stages, and they reveal a new macrophage-dependent mechanism of metastasis with possible prognostic implications. Cancer Res; 75(2); 306–15. ©2014 AACR.

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The objective of this study was to identify the prognostic factors and to propose a new risk model in metastatic castration-resistant prostate cancer (mCRPC) patients. The clinical data were retrospectively obtained for 102 mCRPC patients who received cancer treatment between 2005 and 2018 at the University of Tokyo Hospital. We investigated clinical and pathological parameters, including prostate-specific antigen (PSA) kinetic profiles under androgen deprivation treatment, and identified predictors of overall survival (OS). The median age and PSA were 73 (Interquartile range [IQR], 68–79) years and 5.00 (IQR, 2.77–13.6) ng/ml. The median follow-up was 34 (IQR, 17–56) months. In univariate analysis, ‘lymph node metastasis’, ‘Hemoglobin (Hb)’, ‘Time to nadir PSA (TNPSA)’, ‘PSA doubling time (PSADT)’, ‘Time to CRPC’, and ‘presence of pain’ were prognostic factors. Multivariate analysis identified ‘Hb P = 0.0004). The proposed risk stratification model may contribute to the prediction of survival and provide supportive information in treatment decision-making.

Background Combination therapy based on radiotherapy and immune checkpoint inhibitors (ICIs) was recently reported as effective for various cancers. The radiation-induced immune response (RIIR) is an essential feature in ICI-combined radiotherapy; however, the effects of drugs used concomitantly with RIIR remain unclear. We screened for drugs that can modify RIIR to understand the mutual relationship between radiotherapy and combined drugs in ICI-combined radiotherapy. Methods We established a high-throughput system with reporter gene assays for evaluating RIIR, focusing on factors acting downstream of the STING-IRF pathway, which can stimulate cancer cells, T cells, and dendritic cells. We further quantified the effects of 2595 drugs, including those approved by the Food and Drug Administration, on RIIR in vitro. Results The reporter assay results correlated well with the expression of immune response proteins such as programmed death-ligand 1. This high-throughput system enabled the identification of drugs including cytotoxic agents, molecular-targeted agents, and other agents that activate or suppress RIIR. Conclusions Our study provides an encyclopedic catalogue of clinically approved drugs based on their effect on RIIR. In ICIs combined radiotherapy, activation of STING-IFN may improve the therapeutic effect and our result could form a biological basis for further clinical trials combining radiotherapy with ICIs.

We performed bone histomorphometric analysis of biopsy specimens from two patients with hyper- and hypoparathyroidism and a history of long-term hemodialysis (HD) because of diabetes. Case 1, a 53-year-old man with hyperparathyroidism, had been on HD for 22 years, and Case 2, a 54-year-old woman with hypoparathyroidism, for 20 years. Intact parathyroid hormone levels were 1070 and 3 pg/mL, respectively. Case 1 had mixed renal osteodystrophy (fibrous tissue volume to total volume [Fb.V/TV], 5.21%; osteoid volume to bone volume [OV/BV], 19.8%), and Case 2 had adynamic renal osteodystrophy (Fb.V/TV, 0%; OV/BV, 0.54%). Case 1 showed cortical bone thinning (cortical width, 0.2 mm) and porosis (cortical porosity, 14.1%), but case 2 did not (cortical width, 0.84 mm; cortical porosity, 11.6%). Trabecular connectivity of cancellous bone was preserved in both patients, with a bone volume to total volume of 18.2% in case 1 and 35.1% in case 2. Both patients had been doing daily strength training and treadmill walking (2-3 h/day) for over 10 years. Although case I showed cortical thinning and porosis, we suggest that long-term loaded exercise therapy may help to preserve cancellous trabecular bone in both hyperparathyroidism and hypoparathyroidism.

Radiotherapy (RT) is an effective treatment option for cancer; however, its efficacy remains less than optimal in locally advanced cancer. Immune checkpoint inhibitor-based therapy, including the administration of anti-PD-L1 antibodies, is a promising approach that works synergistically with RT. Proton beam therapy and carbon-ion therapy are common options for patients with cancer. Proton and carbon ions are reported to induce an immune reaction in cancer cells; however, the underlying mechanisms remain unclear. Here, we aimed to compare the immune responses after irradiation (IR) with X-ray, protons, and carbon ions in an oesophageal cancer cell line and the underlying mechanisms. An oesophageal cancer cell line, KYSE450, was irradiated with 1 fraction/15 GyE (Gy equivalent) of X-ray, proton, or carbon-ion beams, and then, the cells were harvested for RNA sequencing and gene enrichment analysis. We also knocked out STING and STAT1 in the quest for mechanistic insights. RNA sequencing data revealed that gene expression signatures and biological processes were different in KYSE450 irradiated with X-ray, proton, and carbon-ion beams 6–24 h after IR. However, after 3 days, a common gene expression signature was detected, associated with biological pathways involved in innate immune responses. Gene knock-out experiments revealed that the STING-STAT1 axis underlies the immune reactions after IR. X-Ray, proton, and carbon-ion IRs induced similar immune responses, regulated by the STING-STAT1 axis.

This study aimed to evaluate the pathological findings and oncological outcomes of deferred radical prostatectomy in patients who initially elected for active surveillance in a Japanese cohort. We retrospectively analyzed data collected from a multi-institutional prospective observational cohort of the Prostate Cancer Research International: Active Surveillance-JAPAN study between January 2010 and September 2020. Triggers for radical prostatectomy were disease progression based on pathological findings of repeat biopsy and patients’ request. The primary end point was evaluation of prostate-specific antigen recurrence-free survival. Secondary end points were overall survival and comparison of pathological and oncological outcomes between patients stratified into immediate or late radical prostatectomy group by time to radical prostatectomy. Overall, 162 patients (15.7%) with prostate cancer underwent initial active surveillance followed by radical prostatectomy. The median time to radical prostatectomy was 18 months (interquartile range 14–43.3), and the median postoperative follow-up was 32 months (interquartile range 14–57.5). Prostate-specific antigen recurrence was observed in eight patients (4.9%). The 3-year prostate-specific antigen recurrence-free survival rate was 96.9%. The 5-year overall survival rate was 100%; however, one patient died of another cause. There were no significant differences in pathological findings between immediate and late radical prostatectomy groups. No significant difference in prostate-specific antigen recurrence-free survival was found between the two groups (log-rank p = 0.34). Radical prostatectomy after active surveillance, as an initial treatment option, does not lead to loss of curative chances in Japanese patients with early-stage prostate cancer in the short follow-up period.

Background Implant impingement and soft tissue tension are factors involved in dislocation after total hip arthroplasty (THA). Combined anteversion (CA) has been used as an indicator for implant placement; however, placing implants optimally remains challenging. Moreover, the effect of changes in offset on dislocation remains unclear. We aimed to clarify the effects of postoperative CA and pre- and postoperative changes in offset on dislocation. Methods We included patients who underwent primary cementless THA performed between 2013 and 2020. The mean values of CA and offset in the dislocation and non-dislocation groups were compared. The CA values within ± 10% of the recommended values were defined as good CA, and those outside the range were defined as poor CA. The dislocation rates in the good and poor CA groups and in the groups with and without increased offset were compared. Results A total of 283 hips were included. The mean values of CA in the dislocation and non-dislocation groups were significantly different (p

Glucocorticoid-induced osteoporosis is osteoporosis arising due to long-term use of glucocorticoids. Despite decades of intense research, the effects of long-term use of glucocorticoids in humans on bone cells and bone structural changes remain unclear. We performed post-mortem histomorphometric analysis of bone from two female patients with rheumatoid arthritis aged 64 and 85 years. Our two patients had been treated with glucocorticoids for 19 and 14 years, respectively. In Case 1, all markers of cancellous bone volume were markedly decreased compared with the age-matched reference range. Connectivity of cancellous bone trabecula was absent. Only a few island bones were noted. There was prominent thinning of the cortical bone and extension of the bone marrow cavity into the cortical bone with prominent cortical porosis. Cortical nodes between the endocortical surface and the trabecula disappeared due to endocortical resorption. Stoppage of lamellar structure was observed because the bone resorption by osteoclasts surpassed bone formation by osteoblasts. Empty lacunae characterised by disappearance of osteocytes were visible. In Case 2, all volume markers of cancellous bone were decreased to the same extent as Case 1. However, cortical porosis was more prominent than Case 1. These two cases suggest that use of glucocorticoid therapy >10 years can induce severe osteoporosis in elderly rheumatoid arthritis women with higher disease activity and that the disappearance of cancellous bone is the common characteristic. The 85-year-old woman was characterised by cortical porosis.

Introduction The popularity of robot‐assisted radical cystectomy over open radical cystectomy has been increasing because the former, a minimally invasive surgery, contributes to earlier recovery and shorter hospitalization. However, atypical recurrences may be more frequent after robot‐assisted radical cystectomy than after open radical cystectomy. We report a case of an atypical early recurrence of bladder cancer including the descending colon. Case presentation A 70‐year‐old Japanese man underwent robot‐assisted radical cystectomy for muscle‐invasive bladder cancer. Four months later, he was hospitalized for severe anemia (hemoglobin, 5.1 g/dL). Colonoscopy revealed a 4‐cm submucosal oozing tumor in the descending colon. Computed tomography revealed multiple recurrent lesions including recurrence in the descending colon, all of which disappeared completely after chemotherapy with six cycles of dose‐dense methotrexate, vinblastine, doxorubicin, and cisplatin. Conclusion We encountered a rare case of an atypical recurrence of bladder cancer in the colon after robot‐assisted radical cystectomy.

Endoscopic resection (ER) is performed for early esophageal squamous cell carcinoma (ESCC) cases. Additional esophagectomy or chemoradiotherapy is recommended for non-curative resection (NCR) even with pathologically negative vertical margins (pVM0); however, their clinical outcomes remain unknown. We examined the long-term clinical outcomes of NCR for ESCCs according to additional treatments.We retrospectively analyzed the data of patients who underwent ER for cT1N0M0 ESCC between 2009 and 2017 judged to have NCR, which defined when pathologically diagnosed as invading the submucosa (SM) or muscularis mucosae (MM) involving lymphovascular invasion (LVI), pVM0, and endoscopically judged as negative horizontal margin. Additional esophagectomy (involving three-field lymphadenectomy), chemoradiotherapy [mainly cisplatin and 5-fluorouracil with concurrent radiotherapy (41.4 Gy)], or observation was undertaken. Thereafter, computed tomography was performed every 6-12 months. The cumulative recurrence (CRR) and recurrence-free survival (RFS) rates were evaluated.Eighty-nine patients were included. Among them, 14 had pathologically diagnosed pMM with LVI; 9 and 6, and 32 and 28 patients had pSM1 and pSM2 without and with LVI. Twenty-one patients underwent observation, whereas 18 and 50 underwent esophagectomy and chemoradiotherapy. During the 60.6-month median follow-up period, nine patients had recurrence; among them, six patients had occurrence at 4 years after ER. The 5-year CRR/RFS rates were 35.7%/48.1%, 13.4%/80.4%, and 0.0%/98.0% in the observation, esophagectomy, and chemoradiotherapy groups, respectively (observation vs. chemoradiotherapy; P 0.001).Additional treatments showed better long-term outcomes than observation for patients with NCR. As recurrence may occur at 4 years after ER, careful long-term follow-up examinations are needed.

The role of previous thoracic radiation therapy as a risk factor of immune-related pneumonitis is unclear. Furthermore, some patients develop radiation recall pneumonitis, which is characterized by a radiation pneumonitis-like imaging pattern with consolidation progressing within a previous radiation field. In this multicenter retrospective study, we analyzed the relationship of previous thoracic radiation therapy with immune-related pneumonitis and the characteristics of radiation recall pneumonitis. The medical records of patients with non-small-cell lung cancer who had received nivolumab between December 2015 and March 2017 at five institutions were retrospectively reviewed. Incidence, imaging patterns, clinical course, and risk factors of immune-related pneumonitis and radiation recall pneumonitis were evaluated. A total of 669 patients were evaluated, and the incidences of all-grade and grade 3 or higher immune-related pneumonitis were 8.8% and 2.6%, respectively. The incidences of immune-related pneumonitis were 13.2% (34/257) and 6.1% (25/412) in patients with and those without previous thoracic radiation therapy, respectively. A history of previous thoracic radiation therapy was associated with immune-related pneumonitis (odds ratio, 2.11; 95% confidence interval, 1.21-3.69 in multivariate analysis). Among the patients with previous thoracic radiation therapy, 6.2% (16/257) showed radiation recall pattern. This study found an increased risk of nivolumab-induced immune-related pneumonitis associated with a history of thoracic radiation therapy. Radiation recall pattern was one of the major patterns of immune-related pneumonitis among the patients with previous thoracic radiation therapy. Incidence, risk factors, and clinical outcome of radiation recall pneumonitis were elucidated.

The number of the patients with chronic kidney disease is now increasing in the world. The pathophysiology of renal hyperparathyroidism is closely associated with Klotho-FGF-endocrine axes, which must be solved definitively as early as possible. It was revealed that the expression of fgf23 is activated by calciprotein particles, which induces vascular ossification. And it is well known that phosphorus overload directly increases parathyroid hormone and hyperparathyroid bone disease develops in those subjects. On the other hand, low turnover bone disease is often recently. Both the patients with chronic kidney disease suffering from hyperparathyroid bone disease or low turnover bone disease are associated with increased fracture risk. Micropetrosis may be one of the causes of increased fracture risk in the subjects with low turnover bone disease. In this chapter, we now describe the diagnosis, pathophysiology and treatments of renal hyperparathyroidism.

To assess the surgical outcomes of off-clamp open partial nephrectomy without renorrhaphy. In the era of robot-assisted surgeries, open partial nephrectomy remains a surgical option for ≥ T1b renal tumours. Although the necessity of renal pedicle clamping and renorrhaphy in open partial nephrectomy for larger tumours remains to be discussed, reports on this issue are rare. Twenty-seven open partial nephrectomies for ≥ T1b renal tumours were performed without renal pedicle clamping or renorrhaphy. A soft coagulation system was used to control bleeding from the resection bed. Surgical results, complications, and predictors of perioperative estimated glomerular filtration rate (eGFR) preservation at 1 month and 3 months after surgery were analysed. The median estimated volume of blood loss was 420 mL. The rates of perioperative eGFR preservation were 88.9 and 87.3% at 1 and 3 months after surgery, respectively. Tumour size was an independent predictor of perioperative eGFR preservation at 1 month after surgery, whereas age and exophytic/endophytic properties of the tumour were independent predictors of perioperative eGFR preservation at 3 months after surgery. Open partial nephrectomy without renal pedicle clamping or renorrhaphy could be safely performed for ≥ T1b renal tumours, even when tumours were entirely endophytic and located close to the renal pedicle. Mild perioperative eGFR reduction was observed. Although surgical indications should be carefully considered in these cases, off-clamp open partial nephrectomy without renorrhaphy is a feasible procedure for patients with ≥ T1b renal tumours.

Para-aortic lymph node (PAN) metastasis for gastric cancer is considered a distant lymph node metastasis. Meanwhile, multidisciplinary treatments have improved survival of patients with PAN metastases. We developed a novel technique of curative para-aortic lymph node dissection via infra-mesocolonic approach in laparoscopic gastrectomy (CAVING approach). This method minimizes the mobilization of the pancreas and the spleen and maximizes the view from the caudal side resembling cave exploration. After laparoscopic gastrectomy, PAN dissection is performed using the same ports setup. The retroperitoneum is widely exposed to ease anatomical cognition and for troubleshooting. The inferior vena cava, the left gonadal vein, the left renal vein, and the aorta are recognized under Gerota’s fascia. The retroperitoneum is then divided into four sections. We perform PAN dissection in the order of 16blat, 16b1int, 16a2lat, and then 16a2int. Using the CAVING approach, the caudal side of the root of the superior mesenteric artery can then be dissected below the pancreas, and only the cranial side of the SMA root requires a suprapancreatic approach. In three cases, preoperative chemotherapy and laparoscopic gastrectomy plus D2 with PAN dissection were performed for gastric cancer and esophagogastric junction cancer. The median operation totaled 484 min, 142 min for the PAN dissection. The median whole blood loss was 130 ml. The median harvested number of PAN was 25. The minimal mobilization of pancreas and the wide surgical fields by CAVING approach may facilitate safe and reliable PAN dissection.

Robotic subtotal gastrectomy (RsTG) with a small remnant stomach for treatment of gastric cancer (GC) in the upper stomach may have advantages over robotic TG (RTG). These may affect postoperative complications and postoperative nutritional status. This is a single-center retrospective study of 46 consecutive patients with GC who underwent RsTG (n = 10) and RTG (n = 36). The indication for RsTG included tumor located in the upper body of the stomach, in which the distance between the upper edge of the tumor and the junction was 2 cm or more and less than 5 cm, and no clinical evidence of lymph node metastasis. Operation time was significantly longer (384 min) and intraoperative blood loss was significantly larger (38 ml) in the RTG group than in the RsTG group (299.5 min, P = 0.021, and 25 ml P = 0.002). Two patients (5.6%) in the RTG group had complications, while no postoperative complications of higher than grade II were observed in the RsTG group. Serum albumin levels at 3 months after surgery were significantly higher in the RsTG group (3.85 g/dl) than in the RTG group (3.2 g/dl, P = 0.001). Postoperative recovery of bodyweight at 6 months after surgery was significantly better in the RsTG group (91.3%) than in the RTG group (84.25%, P = 0.001). RsTG for treatment of patients with GC in the upper body of the stomach is safe and feasible, and may enable improved postoperative nutritional status compared with RTG.

Purpose To describe two cases of paracentral acute middle maculopathy (PAMM) that occurred unilaterally after endovascular coil embolization. Methods Medical records including ophthalmic examinations of two PAMM cases were retrospectively reviewed. Results The first case was a 64-year-old woman with hyperlipidemia and chronic sinusitis. The second case was a 49-year-old man with hypertension, hyperlipidemia, tension headache, and vertigo. Both cases exhibited paracentral scotomas just after endovascular coil embolization. Ophthalmoscopy showed multiple faint white-yellow lesions in each affected eye. Optical coherence tomography showed hyper-reflective bands that were mainly observed in the inner nuclear layer and corresponded to the PAMM lesions. Optical coherence tomography angiography revealed variable degrees of abnormal vasculature from slight dilation, decreased visualization, to nonvisualization in the superficial capillary plexuses and similar capillary changes in deep capillary plexuses. Conclusion We described two cases with PAMM that occurred after endovascular coil embolization, which was a new precursor cause of PAMM. Our results demonstrate that optical coherence tomography angiography is especially useful for not only diagnosis, but also for follow-up evaluations in patients with PAMM.

Background and Objectives: Precise acetabular cup placement is essential for successful total hip arthroplasty (THA). In obese patients, its accuracy is often difficult to achieve because of the thickness of the soft tissues. This study aimed to determine the relationship between the accuracy of acetabular cup angle and body mass index (BMI) in posterolateral THA using the computed tomography-based navigation (CT-navi) system. Materials and Methods: We retrospectively reviewed 145 consecutive primary THAs using the CT-navi system between January 2015 and January 2018. All surgeries were performed using cementless cups employing the posterolateral approach with the patient in the decubitus position. We compared the radiographic inclination and anteversion obtained intraoperatively from the CT-navi with those measured by postoperative CT using three-dimensional templating software. We evaluated the relationship between the extent of errors and correlation with BMI. Results: In non-overweight patients (BMI < 25, 88 hips), the mean navigation errors for inclination were 2.8 ± 2.2° and for anteversion were 2.6 ± 2.3°. Meanwhile, in overweight patients (BMI ≥ 25, 57 hips), the mean navigation errors were 2.6 ± 2.4° for inclination and 2.4 ± 2.4° for anteversion. We found no significant difference between overweight and non-overweight patients in both inclination and anteversion. There was no correlation between the extent of errors and BMI. Conclusions: In posterolateral THA, CT-navi can aid the precise placement of the acetabular cup irrespective of a patient’s BMI.

Background Obtaining a larger theoretical range of motion (ROM) is crucial to avoid prosthetic impingement after total hip arthroplasty (THA); however, no reports have examined the permissible range values of combined anteversion (CA) satisfying targeted ROM without prosthetic impingement. This retrospective study aimed to evaluate the possible postoperative CA extent that would allow meeting target ROM criteria according to Yoshimine’s theory using computed tomography (CT)-based three-dimensional motion analysis after THA. Methods This study included 114 patients (133 hips) who underwent cementless primary THA using a CT-based navigation system and implants (oscillation angle ≥ 135°). Implant positions were determined using Yoshimine's CA formula. Postoperative evaluation was conducted using a three-dimensional templating software for CT data. The postoperative Yoshimine’s and Widmer’s CA was calculated, and the difference between the target and postoperative values was defined as the error of Yoshimine’s CA and Widmer’s CA. Prosthetic ROM was assessed by Yoshimine’s stringent criteria for activities of daily living. Based on fulfilling these criteria, all patients were divided into the ROM (+) and ROM (−) groups. Evaluation items were compared between the two groups. Results There were 111 and 22 hips in the ROM (+) and ROM (−) groups, respectively. A significant difference was noted in the absolute error of Yoshimine’s and Widmer’s CA between the two groups. Using receiver operating characteristic analysis, threshold values of 6.0 (higher values indicate greater disability; sensitivity 90.9%, specificity 72.1%) for the absolute Yoshimine’s CA difference (area under the curve [AUC] 0.87, P P Conclusions The target range of Yoshimine’s CA (90.8° ± 6.0°) and Widmer’s CA values (37.3° ± 6.9°) was crucial in implant orientation for obtaining theoretical ROM without prosthetic impingement after THA.

Background and purpose Ionising radiation causes mutations in the genomes of tumour cells and serves as a potent treatment for cancer. However, the mutation signatures in the cancer genome following ionising radiation have not been documented. Materials and methods We established an in vitro experimental system to analyse the presence of de novo mutations in the cancer genome of irradiated (60 Gy/20 fr/4 weeks) oesophageal cancer cell lines. Subsequently, we performed whole-genome, chromatin immunoprecipitation, and RNA sequencing using untreated and irradiated samples to assess the damage to the genome caused by radiation and understand the underlying mechanism. Results The irradiated cancer cells exhibited hotspots for the de novo 8502–12966 single nucleotide variants and 954–1,331 indels on the chromosome. These single nucleotide variants primarily originated from double-stranded break repair errors, as determined using mutation signature analysis. The hotspots partially overlapped with the sites of H3K9 trimethylation, which are regions characterised by a weak capacity for double-stranded break repair. Conclusion This study highlights the signature and underlying mechanism of radiation on the cancer genome.

Background/aim To investigate the usefulness of cell-free DNA (cfDNA) in patients with oligometastasis. Patients and methods This study included oligometastatic colorectal cancer (CRC) patients who underwent ablative irradiation using stereotactic body radiotherapy or proton beam therapy for metastatic lesions at a single institution. cfDNA was purified from the plasma of pretreated patients and gene mutations were analyzed by next-generation sequencing. Progression-free survival (PFS) was statistically compared according to gene mutation, clonality or allele frequency. Results A total of 20 patients were analyzed. Mutations were detected in the following genes; TP53 (45%), APC (40%), KRAS (15%), PIK3CA (15%), NF1 (5%), BRCA1 (5%), ERBB2 (5%), FBXW7 (5%), KIT (10%), and HRAS (10%). Patients with multi-clonality of gene mutation showed tendency for poor PFS (p=0.07). Among 7 patients whose metastatic site was the lung, those with no cfDNA detected had significantly better PFS than those with cfDNA (p=0.02). Conclusion cfDNA profiles could be predictive tools for early recurrence of oligometastatic CRC patients after ablative radiotherapy.

416 Background: Platinum-based definitive chemoradiotherapy (dCRT) is the standard treatment for patients (pts) with unresectable locally advanced esophageal squamous cell carcinoma (ESCC), invading the aorta, vertebral body, or trachea. However, complete response (CR) rates are low (11–25%), with a median overall survival (OS) of 9–10 months. We previously reported atezolizumab following dCRT indicated promising 42.1% of confirmed CR (cCR) rate and 65.8% of 12-months OS (Bando H, et al., ESMO Congress 2022 ). Methods: We investigated predictive biomarkers for cCR in this multicenter phase II study. PD-L1 tumor proportion score (TPS) was examined with VENTANA PD-L1. Immunological phenotypes of tumor microenvironments were assessed with multiplex immunohistochemistry (mIHC) and multi-color flow cytometry (FCM). Cancer gene aberrations and gene expression were investigated with whole exome and whole transcriptome sequencing (WES/WTS), respectively. Results: In 35 pts with an evaluable PD-L1 TPS, the cCR rates of +CD8+PD-1+ T cells and CD3+CD8-FOXP3+ T cells prior to CRT in tumor tissue were significantly correlated with cCR and non-cCR, respectively (both are P+CD8+ T cells prior to CRT, after CRT, and after atezolizumab were significantly correlated with cCR (P+FOXP3highCD45RA-CD4+ regulatory T cells (Treg cells) after CRT were significantly correlated with non-cCR (P+CD8+ T cells prior to CRT may be a predictive biomarker for cCR of CRT followed by atezolizumab, and that several driver gene abnormalities, cancer intrinsic signatures and tumor-infiltrating Treg cells are associated with treatment resistance. These findings could enable subsequent biomarker-selected clinical trials and lead to the development of novel cancer immunotherapeutic strategies. Clinical trial information: UMIN000034373 .

In the present study, we provide conditions for the existence of pushouts of signature morphisms in constructor-based order-sorted algebra, and then we prove that reducibility and termination of term rewriting systems are closed under pushouts. Under the termination assumption, reducibility is equivalent to sufficient-completeness, which is crucial for proving several important properties in computing for constructor-based logics such as completeness, existence of initial models and interpolation. In logic frameworks that are not based on constructors, sufficient-completeness is essential to establish the soundness of the induction schemes which are based on some methodological constructor operators. We discuss the application of our results to the instantiation of parameterized specifications.

We aimed to identify prognostic factors of cancer-specific survival (CSS) in non-metastatic castration-resistant prostate cancer (M0CRPC) patients. The final analysis of this retrospective cohort included 82 patients who were diagnosed as M0CRPC between 1998 and 2018 at the University of Tokyo Hospital. CRPC was defined as prostate-specific antigen (PSA) progression (increased PSA ≥ 25% and ≥ 2 ng/mL above the nadir or detection of a metastatic lesion). The median value of age and PSA at the time of CRPC were 76 (range 55–94) years and 2.84 (range 2.04–22.5) ng/mL, respectively. The median follow-up time from CRPC diagnosis was 38 (range 3–188) months. The prognostic factors of CSS were ‘PSA doubling time (PSADT) ≤ 3 months’, ‘time to CRPC diagnosis from the start of androgen deprivation therapy (TTCRPC) ≤ 12 months’, of which TTCRPC was a novel risk factor of CSS. In the multivariate analysis, ‘PSADT ≤ 3 months’ and TTCRPC ≤ 12 months’ remained as statistically significant predictors of CSS. Novel risk stratification was developed based on the number of these risk factors. The high-risk group showed a hazard ratio of 4.416 (95% confidence interval 1.701–11.47, C-index = 0.727).

This study aimed to describe the general public’s understanding and attitudes toward science compared to those toward humanities, focusing on the characteristics of Japanese people, through an international comparison with the United States and the United Kingdom.

Microsomal prostaglandin E synthase-1 (mPGES-1)/prostaglandin E2 (PGE2) induces angiogenesis through the prostaglandin E2 receptor (EP1-4). Among immune cells, regulatory T cells (Tregs), which inhibit immune responses, have been implicated in angiogenesis, and PGE2 is known to modulate function and differentiation of Tregs. We hypothesized that mPGES-1/PGE2-EP signaling could contribute to recovery from ischemic conditions by promoting the accumulation of Tregs.Wild-type (WT), mPGES-1-deficient (mPges-1-/-), and EP4 receptor-deficient (Ep4-/-) male mice 6-8 weeks old were used. Hindlimb ischemia was induced by femoral artery ligation. Recovery from ischemia was suppressed in mPges-1-/- mice and compared with WT mice. The number of accumulated forkhead box protein P3 (FoxP3)+ cells in ischemic muscle tissue was decreased in mPges-1-/- mice compared with that in WT mice. Expression levels of transforming growth factor-β (TGF-β) and stromal cell derived factor-1 (SDF-1) in ischemic tissue were also suppressed in mPges-1-/- mice. The number of accumulated FoxP3+ cells and blood flow recovery were suppressed when Tregs were depleted by injecting antibody against folate receptor 4 (FR4) in WT mice but not in mPges-1-/- mice. Recovery from ischemia was significantly suppressed in Ep4-/- mice compared with WT mice. Furthermore, mRNA levels of Foxp3 and Tgf-β were suppressed in Ep4-/- mice. Moreover, the numbers of accumulated FoxP3+ cells in ischemic tissue were diminished in Ep4-/- mice compared with Ep4+/+ mice.These findings suggested that mPGES-1/PGE2 induced neovascularization from ischemia via EP4 by promoting accumulation of Tregs. Highly selective EP4 agonists could be useful for treatment of peripheral artery disease (PAD).Although surgical treatment for PAD in patients improved, some patients with advanced disease have no other option for treatments other than amputation. In the present study, we revealed that endogenous mPGES-1/PGE2-EP4 signaling induced recovery from ischemia by promoting Tregs accumulation at the ischemic site. In addition, we showed that selective EP4 agonist, or transplantation of Tregs, induced recovery from ischemic conditions. These results indicate that the use of selective EP4 agonist, or cell therapy of Tregs, may be a potential treatment option for severe critical limb ischemia patients.

We report a case of lethal myocarditis and myositis after pembrolizumab treatment for advanced upper urinary tract urothelial carcinoma. A 69-year-old man underwent pembrolizumab therapy as a second-line treatment. He had myalgia and a slightly elevated creatinine kinase (CK) on the day of the second administration of pembrolizumab. Five days later, the patient was admitted with severe fatigue and an abnormal gait. Physical examination revealed reduced muscle reflexes and proximal muscle weakness. An electrocardiogram (ECG) demonstrated a wide QRS complex ventricular rhythm. A marked elevation of cardiac enzymes, including CK, myoglobin, and cardiac troponin I, was detected. Myocardial biopsy revealed inflammatory cell infiltration and the partial impairment of myocardial tissue. The electromyogram was normal, but inflammation in myofibers was noted in a muscle biopsy. Myocarditis and myositis as immune-related adverse events (irAEs) were suspected, and the patient began intravenous steroid therapy and plasma exchange. However, the patient underwent cardiac arrest three days after admission and began extracorporeal membrane oxygenation and intra-aortic balloon pumping therapy. Despite steroid pulse therapy, the patient demonstrated no sign of improvement and subsequently died 17 days after admission. Immune-mediated myocarditis is a rare but fatal irAE of an immune checkpoint inhibitor (ICI). The present case suggests that myositis precedes myocarditis. Therefore, if myositis is suspected, subsequent myocarditis may need attention. In conclusion, we found that myositis and myocarditis developed in a patient with advanced urothelial carcinoma after pembrolizumab treatment. A routine follow-up of CK and cardiac troponin I, as well as an ECG, should be performed to identify any possible ICI-induced myocarditis and myositis quickly.

Objectives: A regimen of S-1 combined with oxaliplatin (SOX) has been widely used as the first-line regimen for advanced gastric cancer. To further improve the antitumor efficacy for gastric cancer patients with peritoneal metastasis, we added nab-paclitaxel to the established SOX regimen (NSOX). Nab-paclitaxel (nanoparticle albumin-bound paclitaxel) has effective transferability to tumor tissues and strong antitumor effects for peritoneal metastasis. We performed a phase 1 study of this regimen to determine the maximum tolerated dose (MTD) and the recommended dose (RD) in patients with gastric cancer with peritoneal metastasis. Methods: The NSOX regimen involved 21-day cycles with escalated doses of nab-paclitaxel (50 [level 1] to 80 [level 4] mg/m2 on days 1 and 8) and fixed doses of oxaliplatin (100 mg/m2 on day 1) and S-1 (80 mg/m2/day for 2 weeks). Results: Six patients with gastric cancer with peritoneal metastasis were enrolled. The MTD was determined to be dose level 2, as 2 of 3 patients experienced dose-limiting toxicities (DLTs), grade 4 non-hematological toxicities. One patient experienced acute myocardial infarction, and the other patient developed jejunal perforation. There were no treatment-related deaths. No patients experienced DLTs, so the RD was determined to be dose level 1. Conclusions: The NSOX regimen was shown to be a tolerable regimen and may be a promising triplet therapy for patients with gastric cancer with peritoneal metastasis.

Prostate cancer is one of the most common malignancies, but a substantial portion remains latent throughout the patients’ lifetime. Analysis of temporal change in the latent prostate cancer pool would be beneficial for clinical decision-making, but longitudinal autopsy studies are rare. We conducted a hand-search of the Annual of Pathological Autopsy Cases in Japan from 1980 to 2016 for cases of latent prostate cancer. Of 570 997 males aged 30 or older, latent prostate cancer was detected in 12 562 patients (2.2%). Proportion of detected cases correlated strongly with ‘aging rate’, the percentage of population aged 65 or older (squared Pearson’s correlation coefficient r2 = 0.972, P value

Endoscopic submucosal dissection (ESD) is a standard treatment for early gastric cancers (EGCs), but because of the obscured view and difficulty in submucosal lifting it is time consuming and poses high risk of perforation and bleeding in large lesions. In endoscopic submucosal tunnel dissection (ESTD) technique, good visualization of the submucosal layer can be achieved in the tunnel, it is, therefore, easy to discern the muscularis propria and visualize the vessels in the submucosal area. This study aims to evaluate the technical feasibility, efficacy, and safety of ESTD in comparison with conventional ESD (cESD) technique for treatment of EGCs. This is a single-center retrospective study of 799 consecutive patients with EGCs who underwent ESD. ESTD (n = 141) were performed between 2015 and 2018 and cESD (n = 658) were performed between 2003 and 2015. Using propensity scores to strictly balance the significant variables, we compared treatment outcomes. After matching, we enrolled 444 patients (n = 111 in ESTD group, n = 333 in cESD group). The resection speeds for lesions of the ESTD were faster than those of cESD (19.3 mm2/min versus 17.7 mm2/min, P = 0.009). There was no need to use additional countertraction by clip-with-line technique or snare for the submucosal dissection in the ESTD procedure. The incidence of perforation was significantly higher in the cESD group (6.0%) than in the ESTD group (0.9%) (P = 0.035). Among 799 patients, four patients who received non-curative ESD had recurrence of gastric cancer. ESTD technique is a safe and feasible treatment procedure for EGCs. It presents many theoretical advantages and may have definite benefits over cESD. ESTD may, therefore, be considered as the standard endoscopic treatment for EGCs.