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Cabozantinib is an oral small-molecule tyrosine kinase inhibitor that has become a standard of care for advanced renal cell carcinoma (RCC). However, cabozantinib is associated with a high rate of adverse events. Therefore, individualised cabozantinib administration and monitoring could help maximise its therapeutic efficacy and avoid serious adverse events. This study developed and validated a method to determine cabozantinib concentration in plasma using HPLC-UV. Sorafenib, an internal standard, was added to the plasma sample containing cabozantinib. A calibration curve for cabozantinib showed good linearity (R 2  = 1.00), between 25 and 4,000 ng/ml. The recovery rate was above 92.1%, and the intra- and inter-day coefficients of variation were smaller than 5.2 and 6.8%, respectively. Then, we applied the method for monitoring cabozantinib blood levels in three patients with advanced RCC who were taking cabozantinib at a dose of 20, 40 or 60 mg/day. Grade 3 adverse events were more likely to occur in patients with high dosing and blood level of cabozantinib. Owing to its simplicity, the developed method can be used in general hospitals, and is expected to help maximise drug efficacy and minimise serious adverse events in many patients with RCC undergoing cabozantinib treatment., (© 2023 John Wiley & Sons Ltd.)

Rapamycin is an inhibitor of the mammalian target of rapamycin (mTOR) signaling pathway, plays an important role in multiple cellular functions. Our previous study showed rapamycin treatment in acute phase reduced the neural tissue damage and locomotor impairment after spinal cord injury (SCI). However, there has been no study to investigate the therapeutic effect of rapamycin on neuropathic pain after SCI. In this study, we examined whether rapamycin reduces neuropathic pain following SCI in mice. We used a mouse model of thoracic spinal cord contusion injury, and divided the mice into the rapamycin-treated and the vehicle-treated groups. The rapamycin-treated mice were intraperitoneally injected with rapamycin (1 mg/kg) 4 h after SCI. The rapamycin treatment suppressed phosphorylated-p70S6K in the injured spinal cord that indicated inhibition of mTOR. The rapamycin treatment significantly improved not only locomotor function, but also mechanical and thermal hypersensitivity in the hindpaws after SCI. In an immunohistochemical analysis, Iba-1-stained microglia in the lumbar spinal cord was significantly decreased in the rapamycin-treated mice. In addition, the activity of p38 MAPK in the lumbar spinal cord was significantly attenuated by rapamycin treatment. Furthermore, phosphorylated-p38 MAPK-positive microglia was relatively decreased in the rapamycin-treated mice. These results indicated rapamycin administration in acute phase to reduce secondary neural tissue damage can contribute to the suppression of the microglial activation in the lumbar spinal cord and attenuate the development of neuropathic pain after SCI. The present study first demonstrated that rapamycin has significant therapeutic potential to reduce the development of neuropathic pain following SCI. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:93-103, 2017., (© 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

The effects of yokukansan and donepezil on learning disturbance and aggressiveness were examined in amyloid β protein (Aβ)-injected mice. Intellicage tests showed that both yokukansan and donepezil ameliorated Aβ-induced learning disturbance, but the ameliorating effect of donepezil was not enhanced by concomitant administration of yokukansan. On the other hand, a social interaction test showed that Aβ-induced aggressiveness was ameliorated by yokukansan, but not by donepezil. Co-administration of both drugs also ameliorated aggressiveness, as did yokukansan alone. In vitro binding assays revealed that yokukansan did not bind to choline receptors or transporters. In vitro enzyme assays revealed that yokukansan did not affect choline acetyltransferase activity or inhibit acetylcholinesterase activity, as did donepezil. These results suggest that yokukansan might ameliorate aggressiveness without interfering with the pharmacological efficacy (antidementia effect) of donepezil and also that concomitant administration of yokukansan might be useful for amelioration of aggressiveness, which was not lessened by donepezil. The difference in the efficacies of both drugs may be due to a difference in their pharmacological mechanisms., (Copyright © 2010 John Wiley & Sons, Ltd.)

Background: Prevention of blood glucose elevation and insulin resistance could be more pronounced in patients undergoing laparoscopic rather than open gastrectomy., Methods: Fifty-seven patients underwent distal gastrectomy by either laparoscopy (n = 36) or an open approach (n = 21). Blood glucose, serum insulin, and the daily insulin secretion rate (urinary C-peptide) were measured. Insulin resistance was evaluated using an adapted homeostasis model assessment of insulin resistance (HOMA-R)., Results: Blood glucose levels were lower in the laparoscopy group than in the open group on the operative day and on postoperative days (POD) 1 and 3 (P < .001, P = .001, and P = .024, respectively). Serum insulin levels were lower in the laparoscopy group than in the open group on POD 1 and 3 (P = .045 and P = .027, respectively). HOMA-R was lower in the laparoscopy group than in the open group on POD 1 and 3 (P = .024 and P = .009, respectively). Daily insulin secretion rates were lower in the laparoscopy group than in the open group on POD 1 (P = .023)., Conclusions: Laparoscopic surgery prevents blood glucose elevation and improves insulin resistance compared with open surgery.

Background: The association of Epstein-Barr virus (EBV) and Hodgkin's disease (HD) has been suggested by serologic, epidemiologic, and molecular biologic studies. The high level of EBV association with HD in the developing countries was discussed in relation to the high HD incidence in these areas. Japanese HD shows a distinct peak incidence in older adults. In contrast, Western HD shows a bimodal pattern, the first peak in young adulthood and a second peak in older patients. In the present study, the EBV association with HD in Japan was investigated, and the results were compared with those reported from industrialized and developing countries., Methods: Fifty-seven patients with HD were studied for the presence or absence of the EBV genome by the polymerase chain reaction and in situ hybridization methods. Seven cases were excluded from the analysis for EBV because of poor preservation of nucleotides in the specimens., Results: EBV genomes were detected in the Reed-Sternberg (R-S) cells of 32 of the 50 patients examined (64%). The EBV association was independently affected by histologic subtype (84% in mixed cellularity and 44% in others), sex (76% in males and 31% in females), and age (76% in patients aged 40 years and older and 38% in patients younger than 40 years of age; P < 0.01). High EBV association is found at the peak in older adults predominantly with mixed cellularity type. Previous studies revealed that the high EBV was associated with the older peak of the bimodal peaks in Western HD, and a unimodal peak in childhood in developing countries. The EBV subtype was predominantly type A, which is identical to the immunocompetent type of HD reported previously., Conclusions: The results of the current study, together with those reported previously, showed that the presence of the Epstein-Barr virus correlated with mixed cellularity type, age older than 40 years, and male sex.

Background: Differential diagnosis of angiosarcoma, predominantly showing a non- or poorly vasoformative proliferation from other types of sarcomas, poorly differentiated carcinomas, and amelanotic melanoma, is often problematic., Methods: The use of antibodies directed against Factor VIII-related antigen (FVIIIRA), Ulex europaeus lectin type 1 (UEA-1), CD31, and vascular endothelial growth factor (VEGF) in the diagnosis of angiosarcoma was examined in 98 cases of autopsy-proven angiosarcoma diagnosed during 1974-1990 in a survey of 178 Japanese hospitals. Reactivity of angiosarcoma cells for epithelial membrane antigen, cytokeratin, and melanoma cell antigen (HMB45) also was examined., Results: Histologic specimens were formed exclusively by vasoformative areas in 32 cases and combined vasoformative and varying extents of non- or poorly vasoformative areas in another 66 cases. In vasoformative areas, the proliferating cells showed a diffuse positive reaction in the cytoplasm and/or cell surface for anti-FVII-IRA in 82 (84%) of 98 cases, for anti-CD31 in 78 (80%), and for UEA-1 in 69 (70%). In non- or poorly vasoformative areas, the positivity rate for FVIIIRA, CD31, and UEA-1 was 29%, 62%, and 46%, respectively. A positive reaction was found for either one of three endothelial markers in the non- or poorly vasoformative areas of 57 cases (86%). Epithelial membrane antigen and anticytokeratin antibody were positive in 4 and 11 cases, respectively, in the vasoformative areas and in 3 and 14 cases, respectively, in non- or poorly vasoformative areas with a simultaneous positive reaction for either one of three endothelial cell markers. None of the proliferating cells showed a positive reactivity for HMB45. The positivity rates of the angiosarcoma cells for each marker were different according to the primary tumor sites. The angiosarcoma cells in non- or poorly vasoformative areas showed the lowest positivity rate for anti-FVIIIRA in the heart (9%) and for anti-CD31 in the extremities (17%) and the highest positivity rate for anticytokeratin in the trunk (60%). Ulex europaeus lectin type 1 had almost the same reactivity rate (30-56%) in every organ. Angiosarcoma cells in 13 (36%) of 36 biopsy specimens and 8 (14%) of 56 autopsy specimens were positive for the anti-VEGF antibody., Conclusion: These findings suggest that the combined use of endothelial cell markers including FVIIIRA, UEA-1, and CD31 is useful in the diagnosis of angiosarcoma, especially in cases exclusively with a non- or poorly vasoformative pattern.

Background: Angiosarcoma is rare, and information about its clinical features are limited. Therefore, a large scale study of angiosarcoma was performed in Japan., Methods: Through a nationwide Japanese study, 99 cases of angiosarcoma were collected and their clinicopathologic findings were summarized relative to predisposing risk factors., Results: The patient age at diagnosis was 3-92 years, (mean, 62 years), with a two to one male to female ratio. The head and face were the most common primary site (29 cases); other sites were liver (17); trunk (13): pleural cavity (6), chest wall (2), abdominal wall (2), buttock (2), inguinal region (1); heart (12); and extremities (7). The proven predisposing risk factors included chronic pyothorax for angiosarcoma in the pleural cavity (six), thorotrast in the liver (five), radiotherapy to the abdominal wall and buttock (four), and chronic limb edema of the forearm (one). Irrespective of primary sites, the majority of cases had metastases to lung in 72 cases, bone in 42, liver in 36, regional lymph nodes in 30, and adrenal gland in 24. The 2-year survival rate was 17%., Conclusions: This study describes a different etiology in the development of angiosarcoma in patients from Japan compared with that of patients from Western countries, though the frequency of angiosarcoma among all soft-tissue sarcomas was similar in both areas. In Japan, chronic pyothorax, radiotherapy, and thorotrast proved to be distinctive causative factors of angiosarcoma.

Since 1977, mass screening for breast cancer has been conducted in Miyagi Prefecture, Japan. The main activities consist of itinerant screening in the communities and group screening at the workplace. In addition, examinations were also carried out at a detection center. The total number of subjects examined was 90,076 in mass screening, with 4172 (4.6%) of them requiring a second examination. The overall breast cancer detection rate was 0.12% in the mass screening. In contrast, it was 3.1% at the center examination. Cytologic studies of nipple discharge were performed on 31,833 subjects. Positive findings were seen in 4 (0.004%). The incidence of smaller tumors was higher and that of nodal metastasis was lower in subsequent examinations than in the initial screening. In the high-risk group, who also underwent mammography at first screening, the detection rate was higher than that among general subjects examined.

Six cases of hepatocellular carcinoma (HCC) and one case of metastatic liver carcinoma in which SGOT, SGPT, and SLDH were suddenly and markedly elevated immediately before death are described. All had a large blood loss and systemic hypotension in the preterminal period; autopsy disclosed irregularly shaped, patchy necrotic areas or infarcts, often clearly demarcated by hemorrhagic rims, in the noncancerous liver parenchyma. Tumor growths in the intrahepatic portal branches were extensive in all six cases with HCC; in the metastatic case, invasion and narrowing of the portal branches were extensive. The incidence of this terminal catastrophe was 3.3% (6 of 184 cases) for HCC and 1.15% (1 of 87) for metastatic carcinoma. The terminal liver necrosis was probably a result of sudden reduction in portal perfusion which had been inadequate because of tumor thrombosis, combined with hypotension of hepatic arteries.