Metastatic renal cell carcinoma (mRCC) is a tumor entity with poor prognosis due to limited therapy options. Tyrosine kinase inhibitors (TKIs), the novel targeted agents have been used for the treatment of mRCC and have shown efficacy. Interferon (IFN)-α is also one of the most frequently used agents in immunotherapy. However, drug resistance needs to be overcome to achieve a sufficiently positive effect. Interleukin-6 (IL-6), which induce suppressor of cytokine signaling-3 (SOCS3) expression, is one of the factors associated with poor prognosis of patients with renal cell carcinoma (RCC). To analyze the influence of IL-6 in drug resistance of RCC, anti-IL-6 receptor antibody was used in combination with IFN or TKIs. The SOCS3 mRNA expression level was significantly increased by IFN-α stimulation in 786-O RCC cells which were resistant to IFN, but not in ACHN cells that were sensitive to IFN. The overexpression of SOCS3 by gene transfection in ACHN significantly inhibited the growth-inhibitory effect of IFN-α. An in vivo study demonstrated that co-administration of SOCS3-targeted siRNA promoted INF-α-induced cell death and growth suppression in 786-O cell xenograft. SOCS3 could be a key component in the resistance to interferon treatment of renal cell carcinoma. Because SOCS3 is rapidly up-regulated by IL-6 and a negative regulator of cytokine signaling, IL-6 expression on RCC cells was also analyzed and the 786-O cells showed the high level of IL-6 mRNA expression under the condition of interferon stimulation. IL-6R antibody, tocilizumab, significantly suppressed cell proliferation in 786-O cells by interferon stimulation accompanied with phosphorylation of STAT1 and inhibited SOCS3 expression. The in vivo effects of combination therapy with tocilizumab and interferon showed significant suppression of 786-O tumor growth in a xenograft model. We also hypothesized that TKI resistance and IL-6 secretion are causally connected. And we found that 786-O RCC cells secrete high IL-6 levels after low dose stimulation with the TKIs sorafenib, sunitinib and pazopanib, inducing activation of AKT-mTOR pathway, NFκB, HIF-2α and VEGF expression. Tocilizumab neutralizes the AKT-mTOR pathway activation and results in reduced proliferation. A combination therapy with tocilizumab and TKI suppresses 786-O tumor growth and inhibits angiogenesis in vivo more efficient than TKI alone. Our findings suggest that IL-6 could induce drug resistance on RCC, and combination therapy of IL-6R inhibitors and IFN/TKIs may represent a novel therapeutic approach for RCC treatment.
Since the development of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) in the early 1990s, its application has been extended to various diseases. For pancreatic cancer (PC), EUS-FNA can obtain specimens from the tumor itself with fewer complications than other methods. EUS-FNA can also be more useful for TNM staging than other imaging modalities. Furthermore, EUS-FNA can contribute to precision medicine by obtaining tissue for immunohistochemical or genetic studies from primary or metastatic sites of diseases. This paper will focus on the role of EUS-FNA in PC.
Heart failure (HF) is a common disease with high prevalence, mortality in hospitalization and after discharge, readmission rates, and burden on healthcare system. Activation of the inflammatory systems is an important role for HF progression, and pentraxin 3 (PTX3) is one of the inflammatory markers. The plasma PTX3 levels increased with advancing the HF severity, and high levels of plasma PTX3 indicated poor prognosis in HF patients. Moreover, we demonstrated that PTX3 had the crucial role for cardiac remodeling under pressure overload using two different genotypes of mice: PTX3 systemic knockout mice and transgenic mice with cardiac-specific overexpression of PTX3.
Diuretics are the essential drug for HF treatment, and we designed multicenter, randomized study for evaluating the efficacy and safety of tolvaptan compared to carperitide. Daily urine volume and serum sodium levels were significantly higher, and cardiovascular events were significantly lower in the tolvaptan group than in the carperitide group. Moreover, we investigated the influence of great earthquake in HF patients, and found out that moving into temporary housing by earthquake might affect the incidence of re-hospitalization due to worsening HF.
In this review article, we would introduce our research on HF which has various aspects as described above.
In children, storytelling provides many psychological and educational benefits, such as enhanced imagination to help visualize spoken words, improved vocabulary, and more refined communication skills. However, the brain mechanisms underlying the effects of storytelling on children are not clear. In this study, the effects of storytelling on the brains of children were assessed by using near-infrared spectroscopy (NIRS). Results indicated significant decreases of the blood flow in the bilateral prefrontal areas during picture-book reading when the subjects were familiarized in comparison to the cases of the subject naïve to the stories. However, no significant differences in the blood flow were found during storytelling between the subjects naïve and familiarized to the stories. The results indicated more sustained brain activation to storytelling in comparison with picture-book reading, suggesting possible advantages of storytelling as a psychological and educational medium in children.
Objective: The efficacy of sedation during endoscopic injection sclerotherapy (EIS) for esophageal varices (EVs) in patients with liver cirrhosis remains unclear. The aim of this study is to compare the efficacy and safety between propofol- and midazolam-based sedation for EIS.
Methods: Twenty-three patients with EVs were prospectively and randomly assigned to midazolam-based (Midazolam group) or propofol-based (Propofol group) sedation. All patients underwent a number connection test (NCT) to evaluate minimal hepatic encephalopathy (MHE) on the day before and at 2 and 24 hours following EIS. The primary endpoint was exacerbation of MHE after EIS, which was defined as deterioration of the NCT. The secondary endpoints were postoperative awareness, technical success rate, frequency of body movement, patient and operator satisfaction, cardiorespiratory dynamics during EIS, and adverse events.
Results: Exacerbations of MHE at 2 hours after EIS compared with those before EIS were not significantly different between the two groups. In both groups, the deterioration of NCT scores before and 2 hours after EIS was observed (Propofol group: 60.0 vs. 70.0 s, P = 0.026; Midazolam group: 42.5 vs. 67.0 s, P = 0.002). There were no significant differences in awareness, technical success rate, or patient satisfaction. However, the frequency of body movement in the Propofol group was significantly lower than that in the Midazolam group (1 vs. 4, P = 0.045), and operator satisfaction in the Propofol group was significantly higher than that in the Midazolam group (P = 0.016). No adverse events were observed.
Conclusions: Propofol-based sedation exacerbated MHE after EIS similarly to midazolam-based sedation in patients with liver cirrhosis. However, propofol-based sedation provided stable sedation with a lower frequency of body movements and high operator satisfaction.
Background: To clarify the predictive factors for poor outcome in pediatric C3 glomerulonephritis (C3GN), we retrospectively evaluated the relationship between the clinico-pathological findings and prognosis in cases of pediatric C3GN. Methods: We enrolled 18 patients diagnosed with C3GN. These patients were divided into two groups, four patients in the end-stage renal disease (ESRD) group and 14 patients in non-ESRD group, based on clinical status at the last examination. Patients in the non-ESRD group were further divided into Subgroup A, consisting of 6 treatment responders, and Subgroup B, consisting of 8 non- responders. The clinical and laboratory findings, as well as the histological findings were investigated for each group. Results: The frequency of nephrotic syndrome at onset in the ESRD group was higher than that in the non-ESRD group. Before treatment and at 2 years after treatment, urinary protein excretion levels and serum creatinine levels in the ESRD group were higher than those in the non-ESRD group. The mean serum C3 and CH50 levels at 2 years after treatment in the ESRD group were lower than those in the non-ESRD group. The degree of renal injury, level of mesangial deposits and degree of alpha SMA staining at the time of the first renal biopsy in the ESRD group were all higher than those in the non-ESRD group. Conclusions: Our results suggest that the severity of C3GN at onset and persistent complements activity are associated with poor prognosis in C3GN.
Background: Atrial septal defect is the third most common type of congenital heart disease. Surgical closure was the standard treatment for atrial septal defects before transcatheter closure was approved as minimally invasive treatment in Japan in 2006. In our hospital, this procedure has been performed since 2015.
Objective: To evaluate the safety and effectiveness of transcatheter closure of atrial septal defects in our hospital.
Methods: Thirty patients (mean age 57.0 ± 19.7 years, 11 males), who underwent transcatheter closure of atrial septal defect between September 2015 and February 2018 at the Fukushima Medical University Hospital, were enrolled. All procedures were performed under general anesthesia with angiographic and transesophageal echocardiographic guidance. Safety and effectiveness were evaluated by the procedural results and complications.
Results: All 30 patients successfully underwent transcatheter closure of atrial septal defects and no patient developed complications. New York Heart Association functional class was improved, and the right ventricular area and right atrium area were decreased, postoperatively.
Conclusion: Transcatheter closure is a safe and effective treatment for atrial septal defects, and thus could be an alternative option to open heart surgery.
A 66-year-old man was diagnosed from colonoscopy as having a 40-mm elevated tumor in the cecum. With a preoperative diagnosis of intramucosal carcinoma, endoscopic submucosal dissection (ESD) was performed. The tumor was resected en bloc, yielding a specimen with a 66-mm diameter. No perforation was detected during the operation.
Although neither abdominal pain nor fever was observed immediately after ESD, abdominal pain developed on the following day. Two days after ESD, the abdominal pain ceased. The patient was managed conservatively with fasting and intravenous antibiotic treatment. Four days after ESD, abdominal X-ray revealed marked gas retention. Computed tomography revealed pneumoperitoneum and a pelvic abscess, leading to a diagnosis of delayed perforation after colonic ESD and paralytic intestinal obstruction. A decompression tube was then inserted transnasally into the small intestine. Because a gradual decrease occurred in intestinal gas, the decompression tube was removed. Oral ingestion was resumed 13 days post-ESD.
Delayed perforation after colonic ESD often requires emergency surgery. The present case was managed conservatively, despite paralytic intestinal obstruction. This approach is rarely employed for this condition and is therefore worth reporting.