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Abstract Extramammary Paget's disease (EMPD) is a skin cancer that can metastasize to distant lymph nodes and organs. However, there are no reports showing histological evidence of metastasis to the ureter. Here we report a case of EMPD that metastasized to the ureter in an 80‐year‐old man. The primary EMPD was resected and the right inguinal lymph node metastasis was dissected. Radiation therapy was administered around the right inguinal lymph nodes postoperatively. Four years later, a thickening of the wall of the right ureter was found, and a total right nephroureterectomy was performed due to suspicion of primary ureteral cancer. Histological examination showed nests of atypical cells in the renal adventitia and the surrounding lymphatic vessels, muscular layer and mucosal layer, but not in the ureteral epithelium. Immunohistochemical staining of tumour cells was positive for carcinoembryonic antigen, cytokeratin 7 and gross cystic disease fluid protein‐15 and was negative for cytokeratin 20. These results are consistent with a primary skin lesion. Although EMPD is not a frequent source of ureteral metastasis, EMPD can metastasize to the ureter. This case implies the feasibility of an accurate preoperative diagnosis through immunostaining, offering the potential to circumvent nephroureterectomy and instead facilitate appropriate management using a ureteral stent.

Abstract Aim To investigate the outcomes of cabozantinib in patients with unresectable hepatocellular carcinoma (uHCC), focusing on dose setting and modification. Methods We retrospectively analyzed 34 Japanese patients who received cabozantinib for uHCC. Trough concentrations (Ctrough) of cabozantinib were also measured weekly for 6 weeks in the 18 patients. Results Sixteen patients received ≥40 mg (high‐dose group), and 18 patients received 20 mg (low‐dose group). Dose escalations were performed in 27.8% of the patients in the low‐dose group. Although median duration of the first dose reduction or interruption in the low‐dose group was twice that in the high‐dose group (28 vs. 14 days, p

Background: The impact of the sex of bystanders who initiate cardiopulmonary resuscitation (CPR) on out-of-hospital cardiac arrest (OHCA) patients has not been fully elucidated. This study aims to investigate the association between the sex of bystanders who perform CPR and the clinical outcomes of OHCA patients in real-world clinical settings. Methods: We conducted a retrospective, observational study using data from the Okayama City Fire Department in Japan. Patients were categorized based on bystanders’ sex. Our primary outcomes were return of spontaneous circulation (ROSC). Our secondary outcome was 30-day survival and 30-day favorable neurological outcome, defined as Cerebral Performance Category score of 1 or 2. Multivariable logistic regression analysis was used to examine the association between these groups and outcomes. Results: The study included 3,209 patients with a comparable distribution of male (1,540 patients: 48.0%) and female bystanders (1,669 patients: 52.0%) between the groups. Overall, 221 (6.9%) ROSC at hospital arrival, 226 (7.0%) patients had 30-day survival, and 121 (3.8%) patients had 30-day favorable neurological outcomes. Bystander sex (female as reference) did not contribute to ROSC at hospital arrival (adjusted OR [aOR] 1.11, 95% CI: 0.76–1.61), 30-day survival (aOR 1.23, 95% CI: 0.83–1.82), or 30-day favorable neurological outcomes (aOR 0.66, 95% CI: 0.34–1.27). Basic life support education experience was a bystander factor positively associated with ROSC. Patient factors positively associated with ROSC were initial shockable rhythm and witness of cardiac arrest. Conclusion: There were no differences in ROSC, 30-day survival, or 30-day neurological outcomes in OHCA patients based on bystander sex.

Bacterial cellulose-based hydrogels with GM3 trisaccharides and those with Gg3 trisaccharides were constructed from commercially available nata de coco via NaIO4 oxidation, reductive amination using propargylamine, and click conjugation with the corresponding glycosyl azides. Since these hydrogels are visible to the naked eye, their assembly in aqueous media could be readily monitored without costly devices. This is the first naked-eye system for monitoring GM3-Gg3 interactions, which are deeply associated with tumor metastases. Reference experiments using bacterial cellulose-based hydrogels carrying lactosides or those carrying glucosides showed that each carbohydrate subunit of GM3 trisaccharide and Gg3 trisaccharide substantially contributes to GM3-Gg3 interactions.

Abstract Aims This study aimed to clarify the relationship between cardiovascular prognosis and left ventricular hypertrophy (LVH) in patients with severe aortic stenosis who underwent transcatheter aortic valve replacement (TAVR) and to investigate the relationship between cardiac sympathetic nerve (CSN) function and these factors using 123I‐metaiodobenzylguanidine scintigraphy. Methods and results In this single‐centre, retrospective observational study, 349 patients who underwent TAVR at our institution between July 2017 and May 2020 were divided into two groups: those with severe LVH pre‐operatively [severe LVH (+) group] and those without LVH pre‐operatively [severe LVH (−) group]. The rates of freedom from cardiovascular events (cardiovascular death and heart failure hospitalization) were compared. The relationship between changes in left ventricular mass index (LVMi) and changes in delay heart–mediastinum ratio (H/M) from before TAVR to 6 months after TAVR was also investigated. The event‐free rate was significantly lower in the severe LVH (+) group (87.1% vs. 96.0%, log‐rank P = 0.021). The severe LVH (+) group exhibited a significantly lower delay H/M value, scored by 123I‐metaiodobenzylguanidine scintigraphy, than the severe LVH (−) group (2.33 [1.92–2.67] vs. 2.67 [2.17–3.68], respectively, P

Abstract Background Composite hemangioendothelioma (CHE) is an intermediate group of tumors with features between hemangioma and angiosarcoma both histologically and biologically. CHE is predominant in young and middle-aged adults, but very infrequently affects the spine. We describe the case of primary CHE in the cervical spine exhibiting kaposiform hemangioendothelioma (KHE)-like components that was associated with cervical myelopathy with vertebral body destruction in an elderly woman. We retrospectively reviewed the case of a primary cervical spinal tumor, diagnosed as CHE with KHE-like components in pathological findings, associated with cervical myelopathy and cervical vertebral body destruction. Case presentation An 80-year-old woman presented with progressive cervical myelopathy caused by a cervical spine tumor. Preoperative cervical MRI revealed a neoplastic lesion invading the cervical spine that strongly compressed the spinal cord, causing right upper-limb paralysis. We performed partial tumor resection along with posterior decompression and fixation. Postoperatively, pathological findings showed that the tumor was CHE with KHE-like features. Following radiotherapy, no recurrences have been observed in 21 months. Conclusions This is the first report of CHE with features of KHE in the spine of an elderly patient. Posterior decompression and fusion of the cervical spine and subsequent radiotherapy resulted in a good outcome.

Background: Delayed hyponatremia after pituitary surgery can be treated with the V2-receptor antagonist, oral tolvaptan. We investigated the pharmacological effect of oral tolvaptan against SIAD in patients with hyponatremia after pituitary surgery. Methods: Thirty-nine patients with pituitary adenoma treated by endoscopic transsphenoidal surgery developed SIAD according to the major guidelines, and 7 patients (17.9%) were treated with tolvaptan. Tolvaptan was administrated orally half a tablet (3.75 mg) once in the first two cases, and half a tablet twice in the other five cases. Serum osmolality, urinary osmolality, urinary sodium concentration, urinary volume, and serum sodium and potassium concentration were evaluated before administration, and after the last oral administration of tolvaptan. Serum osmolality and urine osmolality were physically measured. Results: Serum sodium concentration was significantly increased from 132.1 ± 4.0 to 143.0 ± 2.9 mmol/L (mean ± standard deviation, n = 7, P < 0.001). Serum osmolality was significantly increased from 266.3 ± 7.7 to 289.6 ± 6.7 mOsm/kg (n = 7, P < 0.001). Urine osmolality was significantly reduced from 607.1 ± 240.4 to 262.7 ± 115.6 mOsm/kg (n = 7, P = 0.01). Urinary sodium concentration was significantly decreased from 121.3 ± 48.4 to 36.9 ± 35.0 mOsm/kg (n = 7, P = 0.001). Urine output (24-hour including the first administration) was significantly increased from 1384.2 ± 550.7 to 3291.3 ± 1710.9 mL/day (n = 6, P = 0.026). Conclusions: Oral tolvaptan administration corrects SIAD after pituitary surgery. Hyponatremia after pituitary surgery was confirmed to be due to SIAD.

Purpose: One of the major problems in revision total hip arthroplasty (THA) is severe acetabular bone loss. The aim of our study was to evaluate the clinical outcomes of revision THA using a Kerboull-type reinforcement device (KT plate) and allogeneic structural bone graft. Methods: This retrospective study evaluated 48 hips that underwent revision THA using a KT plate and allogeneic structural bone graft between 2008 and 2016, with a median follow-up of 6.2 years (range 3–12.6 years). Functional outcome was assessed using the Japanese Orthopaedic Association (JOA) hip score. Postoperative and follow-up radiographs were compared to assess migration and breakage of the implant. Results: The mean JOA hip score improved from 45.6 (±16.3) points before surgery to 72.1 (±11.9) points at the most recent follow-up examination ( p < 0.001). Two hips (4.2%) underwent re-revision THA because of cup loosening due to breakage of the KT plate. A total of 13 hips (27.1%) were classified as radiological failures. Binomial logistic regression analysis showed that a Kawanabe classification of stage 4, which indicates massive bone defects in the weight-bearing area, was a risk factor for radiological failure (odds ratio: 4.57; 95% confidence interval: 1.01–26.35). Conclusions: A KT plate with an allogeneic structural bone graft is a useful method of acetabular reconstruction in revision THA that restores bone stock and improves hip function. Our findings indicated that a Kawanabe classification of stage 4 was a risk factor for radiological failure of the implant.

Patients with peritoneal metastasis of gastric cancer have dismal prognosis, mainly because of inefficient systemic delivery of drugs to peritoneal tumors. We aimed to develop an intraperitoneal treatment strategy using amido-bridged nucleic acid (AmNA)-modified antisense oligonucleotides (ASOs) targeting synaptotagmin XIII (SYT13) and to identify the function of SYT13 in gastric cancer cells. We screened 71 candidate oligonucleotide sequences according to SYT13-knockdown efficacy, in vitro activity, and off-target effects. We evaluated the effects of SYT13 knockdown on cellular functions and signaling pathways, as well as the effects of intraperitoneal administration to mice of AmNA-modified anti-SYT13 ASOs. We selected the ASOs (designated hSYT13-4378 and hSYT13-4733) with the highest knockdown efficiencies and lowest off-target effects and determined their abilities to inhibit cellular functions associated with the metastatic potential of gastric cancer cells. We found that SYT13 interfered with focal adhesion kinase (FAK)-mediated intracellular signals. Intraperitoneal administration of hSYT13-4378 and hSYT13-4733 in a mouse xenograft model of metastasis inhibited the formation of peritoneal nodules and significantly increased survival. Reversible, dose- and sequence-dependent liver damage was induced by ASO treatment without causing abnormal morphological and histological changes in the brain. Intra-abdominal administration of AmNA-modified anti-SYT13 ASOs represents a promising strategy for treating peritoneal metastasis of gastric cancer.

Abstract We report the case of a patient with a giant Brunner's gland hamartoma that was pathologically diagnosed by endoscopic mucosal resection. A 69‐year‐old woman presented with intermittent abdominal pain, and imaging revealed a smooth saccular submucosal tumor, 40 mm in diameter, on the anterior wall of the duodenal bulb. Brunner's gland and smooth muscle tissue were observed on endoscopic ultrasound‐guided fine‐needle aspiration biopsy, which resulted in the preoperative diagnosis of a duplication cyst. However, subsequent endoscopic mucosal resection established a final histopathological diagnosis of Brunner's gland hamartoma.

Abstract Background Controlling metastasis is essential for improving the prognosis of patients with gastric cancer (GC). Here, we aimed to identify a molecule required for GC metastasis and to investigate its potential utility as a target for the development of therapeutic antibodies (Abs). Methods Transcriptome and bioinformatics analyses of human GC cell lines identified the neuronal pentraxin receptor (NPTXR) as a candidate molecule. NPTXR function was probed by modulating its expression in GC cells and assessing the effects on intracellular signaling and malignant behaviors in vitro and in mouse xenograft models. We also generated anti-NPTXR Abs and Nptxr −/− mice, and assessed the clinical significance of NPTXR expression in GC specimens. Results NPTXR mRNA expression in clinical specimens was associated with disease progression and was significantly higher in tissues from GC patients with distant metastasis compared with those without. NPTXR regulated expression of genes involved in metastatic behaviors as well as activation of the PI3K–AKT–mTOR, FAK–JNK, and YAP signaling pathways. NPTXR silencing promoted caspase-mediated apoptosis and attenuated GC cell proliferation, cell cycle progression, migration, invasion, adhesion, stem cell-like properties, and resistance to 5-fluorouracil in vitro, and also inhibited the tumorigenicity of GC cells in vivo. Anti-NPTXR Abs inhibited GC peritoneal metastasis in mice. Nptxr −/− mice showed no abnormalities in reproduction, development, metabolism, or motor function. Conclusions NPTXR plays an essential role in controlling the malignant behavior of GC cells in vitro and in vivo. NPTXR-targeting Abs may thus have utility as novel diagnostic tools and/or treatment modalities for GC.

Body cooling is recommended for patients with heat stroke and heat exhaustion. However, differences in the outcomes of patients who do or do not receive active cooling therapy have not been determined. The best available evidence supporting active cooling is based on a case series without comparison groups; thus, the effectiveness of this method in improving patient prognoses cannot be appropriately quantified. Therefore, we compared the outcomes of heat stroke patients receiving active cooling with those of patients receiving rehydration-only therapy. This prospective observational multicenter registry-based study of heat stroke and heat exhaustion patients was conducted in Japan from 2010 to 2019. The patients were stratified into the “severe” group or the “mild-to-moderate” group, per clinical findings on admission. After conducting multivariate logistic regression analyses, we compared the prognoses between patients who received “active cooling + rehydration” and patients who received “rehydration only,” with in-hospital death as the endpoint. Sex, age, onset situation (i.e., exertional or non-exertional), core body temperature, liver damage, renal dysfunction, and disseminated intravascular coagulation were considered potential covariates. Among those who received active cooling and rehydration-only therapy, the in-hospital mortality rates were 21.5% and 35.5%, respectively, for severe patients (n = 231) and 3.9% and 5.7%, respectively, for mild-to-moderate patients (n = 578). Rehydration-only therapy was associated with a higher in-hospital mortality in patients with severe heat illness (adjusted odds ratio [aOR], 3.29; 95% confidence interval [CI], 1.21–8.90), whereas the cooling methods were not associated with lower in-hospital mortality in patients with mild-to-moderate heat illness (aOR, 2.22; 95% CI, 0.92–5.84). Active cooling was associated with lower in-hospital mortality only in the severe group. Our results indicated that active cooling should be recommended as an adjunct to rehydration-only therapy for patients with severe heat illness.

Let G be a 4-connected graph, and let E ̃ (G) denote the set of those edges of G which are not contained in a triangle, and let E c (G) denote the set of 4-contractible edges of G . We show that if 3 ≤ | E ̃ (G) | ≤ 4 or | E ̃ (G) | ≥ 7 , then | E c (G) | ≥ (| E ̃ (G) | + 8) ∕ 4 unless G has one of the three specified configurations. Keywords: 4-connected graph, Contractible edge, Triangle

A conventional method for acoustic impedance eduction in a flow duct is proposed. This method is based on the straight forward method. Assuming that a single mode propagates in the duct and the flow is uniform, propagation constants for both forward and retreat waves are explicitly calculated from three transfer functions between four microphones aligned in a line parallel to the flow duct. Two values of acoustic impedance are separately obtained from either of the propagation constants. The test section of our flow duct has a square cross section whose three walls are rigid and the rest wall is the acoustic impedance wall of interest. To verify the present method, we performed numerical simulations and experiments. First, the boundary element method was employed to obtain the sound pressure field in the flow duct without grazing flow; the target acoustic impedance was prescribed. The acoustic impedance is successfully reproduced by the present method from the sound pressures at virtual four microphones even when the retreat wave is apparent. Then, the acoustic impedance of a perforated plate without grazing flow was experimentally educed. The value agrees with the value measured by the 2-microphone-method in an impedance tube. Third, the acoustic impedance of the perforated plate with grazing flow of Mach number around 0.12 was educed. The resistance increases and both of the reactance and the rate of change in the reactance with frequency decrease from those values without grazing flow. In consequence, when the grazing flow exists, the maximum value of the sound absorption coefficient and its frequency increase, and the frequency range where the sound absorption coefficient shows higher value expands.

Osteophytes are physiological bony outgrowths that develop at the margins of the articular surfaces during the progression of osteoarthritis; they are associated with active endochondral bone formation processes and expressions of various growth factors. We believe they could be a source of bone grafts as a result of a potentially strong osteoinductive effect. Moreover, osteophytes can be easily harvested by arthroscopy in patients undergoing open-wedge high tibial osteotomy (OW-HTO) for medial unicompartmental knee osteoarthritis. Therefore, we have been using osteophyte autografts for osteotomy gaps in OW-HTO with positive preliminary results indicating rapid bone healing of osteotomy sites. In this technical note, we introduce a technique for harvesting autologous osteophytes by arthroscopy and implanting them into the gap formed after OW-HTO. We expect that autologous osteophyte grafting can be a useful method for accelerating bone union and therefore enabling weight bearing from an early stage after surgery, which will lead to an early return to social activities.

Osteoid osteoma is a benign bone tumor and causes persistent pain that is usually treated by surgery or ablation therapy. Conservative management with non-steroidal anti-inflammatory drugs (NSAIDs) is also used to avoid the morbidity associated with surgery or ablation therapy; however, it usually takes several years for the condition to resolve using conservative treatment. Our patient, a 10-year-old boy, presented with a 3-month history of a painful lesion in his leg. Plain radiography, bone scanning, computed tomography and magnetic resonance images showed the presence of a lesion with radiological features consistent with an osteoid osteoma of the cortex in the tibial diaphysis. The patient was treated with a usual dose of ibuprofen for 3 weeks. Within 3 weeks, his symptoms were almost completely resolved; he no longer needed NSAIDs and returned to normal life. Repeat imaging studies showed complete disappearance of the nidus within 2.5 years after the resolution of symptoms.

The Hedgehog pathway is activated in various types of malignancies. We previously reported that inhibition of SMO or GLI prevents osteosarcoma growth in vitro and in vivo. Recently, it has been reported that arsenic trioxide (ATO) inhibits cancer growth by blocking GLI transcription. In this study, we analyzed the function of ATO in the pathogenesis of osteosarcoma. Real-time PCR showed that ATO decreased the expression of Hedgehog target genes, including PTCH1, GLI1, and GLI2, in human osteosarcoma cell lines. WST-1 assay and colony formation assay revealed that ATO prevented osteosarcoma growth. These findings show that ATO prevents GLI transcription and osteosarcoma growth in vitro. Flow cytometric analysis showed that ATO promoted apoptotic cell death. Comet assay showed that ATO treatment increased accumulation of DNA damage. Western blot analysis showed that ATO treatment increased the expression of γH2AX, cleaved PARP, and cleaved caspase-3. In addition, ATO treatment decreased the expression of Bcl-2 and Bcl-xL. These findings suggest that ATO treatment promoted apoptotic cell death caused by accumulation of DNA damage. In contrast, Sonic Hedgehog treatment decreased the expression of γH2AX induced by cisplatin treatment. ATO re-induced the accumulation of DNA damage attenuated by Sonic Hedgehog treatment. These findings suggest that ATO inhibits the activation of Hedgehog signaling and promotes apoptotic cell death in osteosarcoma cells by accumulation of DNA damage. Finally, examination of mouse xenograft models showed that ATO administration prevented the growth of osteosarcoma in nude mice. Because ATO is an FDA-approved drug for treatment of leukemia, our findings suggest that ATO is a new therapeutic option for treatment of patients with osteosarcoma.

The polycomb-group (PcG) proteins function as general regulators of stem cells. We previously reported that retrovirus-mediated overexpression of Bmi1, a gene encoding a core component of polycomb repressive complex (PRC) 1, maintained self-renewing hematopoietic stem cells (HSCs) during long-term culture. However, the effects of overexpression of Bmi1 on HSCs in vivo remained to be precisely addressed.In this study, we generated a mouse line where Bmi1 can be conditionally overexpressed under the control of the endogenous Rosa26 promoter in a hematopoietic cell-specific fashion (Tie2-Cre;R26Stop(FL)Bmi1). Although overexpression of Bmi1 did not significantly affect steady state hematopoiesis, it promoted expansion of functional HSCs during ex vivo culture and efficiently protected HSCs against loss of self-renewal capacity during serial transplantation. Overexpression of Bmi1 had no effect on DNA damage response triggered by ionizing radiation. In contrast, Tie2-Cre;R26Stop(FL)Bmi1 HSCs under oxidative stress maintained a multipotent state and generally tolerated oxidative stress better than the control. Unexpectedly, overexpression of Bmi1 had no impact on the level of intracellular reactive oxygen species (ROS).Our findings demonstrate that overexpression of Bmi1 confers resistance to stresses, particularly oxidative stress, onto HSCs. This thereby enhances their regenerative capacity and suggests that Bmi1 is located downstream of ROS signaling and negatively regulated by it.

Background/Aim: Squamous cell carcinoma is one of the major subtypes of esophageal carcinoma, and the 5-year overall survival rate of esophageal squamous cell carcinoma patients who underwent curative treatment remains below 40%. We aimed to detect and validate the prognosticators of esophageal squamous cell carcinoma in patients who underwent radical esophagectomy. Materials and Methods: Comprehensive analysis of transcriptome and clinical data from The Cancer Genome Atlas revealed OPLAH as one of the differentially expressed genes between esophageal squamous cell carcinoma tissues and normal esophageal mucosa. OPLAH expression changes were significantly associated with a patient prognosis. OPLAH protein levels were further evaluated by immunohistochemistry in esophageal squamous cell carcinoma tissues (n=177) as well as in serum samples (n=54) using ELISA. Results: OPLAH mRNA was significantly overexpressed in esophageal squamous cell carcinoma tissues compared to normal esophageal mucosa, and patients with high OPLAH mRNA expression have a significantly poorer prognosis, according to The Cancer Genome Atlas data. The high staining intensity of OPLAH protein in esophageal squamous cell carcinoma tissue clearly stratified patient prognosis. According to multivariable analysis, high OPLAH protein expression was an independent prognostic factor for survival after surgery. Pre-neoadjuvant chemotherapy serum OPLAH protein concentrations were significantly associated with clinical tumor depth and node positivity and, consequently, with advanced clinical stage. The serum OPLAH protein concentration was significantly decreased by neoadjuvant chemotherapy. Conclusion: OPLAH protein expression in cancerous tissue and serum may have clinical utility towards stratifying prognosis of patients with esophageal squamous cell carcinoma. [ABSTRACT FROM AUTHOR]