Threshold Core Temperatures for Tail Vasodilation During General Warming in Spontaneously Hypertensive Rats (SHR) and Stroke-prone SHR (SHRSP)

In order to study heat dissipation ability of spontaneously hypertensive rats, threshold core temperatures for occurrence of the tail vasodilation were compared among adult male spontaneously hypertensive rats (SHR), stroke-prone SHR (SHRSP) and Wistar-Kyoto rats (WKY). Mean age of month (M.) and mean systolic blood pressure were 8.4±0.5 M; 205±5 mmHg for SHR, 7.2±0.6 M; 240±8 mmHg for SHRSP and 7.6±1.1 M; 140±6 mmHg for WKY. For the measurement, each rat was placed into a small wire-mesh cage for a loose restraint. Rectal temperature, tail skin temperature and air temperature were simultaneously recorded by means of thermistor probes or copper-constantan thermocouples. Air temperature was gradually raised at a constant rate of 0.17℃/min. Stepwise changes in the tail skin temperature were observed during the gradual elavation of the air temperature. The beginning of the tail vasodilation was detected by the 1st increase in tail skin temperature. Mean threshold core temperature for the 1st vasodilation in SHR, SHRSP and WKY were, 38.9±0.1℃, 38.4±0.1℃ and 38.0±0.1℃, respectively. Threshold core temperatures for the 1st vasodilation in SHR and SHRSP were significantly high compared to that in WKY, while the threshold in SHRSP was significantly lower than SHR. Mean values of threshold Ta for the 1st tail vasodilation in SHR, SHRSP and WKY were 30.1±0.5℃, 29.9±0･6℃ and 29.7±0.5℃, respectively. There was no statistical significance among these values. These results are consistent with the fact that the core temperature in adult SHRSP is not always high as SHR, even though blood pressure of SHRSP is higher than SHR. And these facts also suggest that high systemic blood pressure itself may not cause developing high core temperature in these genetically hypertensive rats

Early prediction of histopathological tumor response to preoperative chemotherapy by Tc-99m MIBI imaging in bone and soft tissue sarcomas

金沢大学附属病院核医学診療科PURPOSE: Tc-99m-methoxyisobutylisonitrile (MIBI) accumulates in only viable cells. In patients with bone and soft tissue sarcomas, preoperative chemotherapy is essential and the early prediction of the tumor response to chemotherapy would be beneficial for the planning of treatment strategy. The purpose of this study was to assess whether the change of Tc-99m-MIBI images from the prechemotherapy state to the early to midportion of chemotherapy can predict the final histopathological tumor response as accurately as the change of imaging after completion of chemotherapy. METHODS: Seventy-three patients with bone and soft tissue sarcomas underwent Tc-99m-MIBI scintigraphy before chemotherapy and at least 2 times after the second or third or fifth course of chemotherapy. The changes of the tracer uptake (ΔUR) and perfusion (ΔPI) from prechemotherapy to postchemotherapy were compared with histologic response. RESULTS: The sensitivity, specificity, and accuracy for the prediction of effective chemotherapy in ΔPI were 88%, 83%, 85% after second, 85%, 72%, 78% after third, and 81%, 71%, 76% after 5th chemotherapy, and those in ΔUR were 88%, 83%, 85% after 2nd, 85%, 92%, 89% after 3rd, and 94%, 77%, 85% after fifth chemotherapy, respectively. The area under the receiver operator characteristic curve of the ΔPI after second, third, and fifth chemotherapy were similarly good (0.842, 0.858, 0.811, respectively) and those of ΔUR were similarly excellent (0.915, 0.936, 0.931, respectively). CONCLUSION: In patients with bone and soft tissue sarcomas, the change of Tc-99m-MIBI images from prechemotherapy to early to middle of chemotherapy can predict the final histopathological tumor response to chemotherapy as accurately as the change of Tc-99m-MIBI images from prechemotherapy to the completion of the preoperative chemotherapy. © 2010 by Lippincott Williams & Wilkins

Prediction of myocutaneous adverse side effect due to intra-arterial chemotherapy by intra-arterial 99mTc-macroaggregated albumin administration in patients with bone and soft-tissue tumors

金沢大学大学院医学系研究科In malignant bone and soft-tissue tumors, intra-arterial chemotherapy and limb-saving surgery have become popular. Myocutaneous inflammatory change and necrosis are the major local side effects of intra-arterial chemotherapy. 99mTc-macroaggregated albumin (MAA) imaging with intra-arterial tracer administration was performed to evaluate drug distribution, and the ability of 99mTc-MAA imaging to predict local side effects was assessed. Methods: In 24 patients, 42 99mTc-MAA images were obtained with tracer injection through an intra-arterial catheter that was inserted into the proximal portion of the tumor-feeding artery. Abnormal uptake other than by tumor was assessed visually and quantitatively. Results: In visual analysis, abnormal 99mTc-MAA accumulation was observed in 21 of 42 images. In the first consecutive 13 of these 21 images, intra-arterial chemotherapy with cisplatin, doxorubicin, and caffeine was administered, and myocutaneous inflammation or necrosis in the area corresponding to the abnormal 99mTc-MAA uptake was observed in 11. In contrast, none of the 21 images without abnormal 99mTc-MAA uptake demonstrated any local adverse effect from intra-arterial chemotherapy. In the last consecutive 8 images with abnormal 99mTc-MAA uptake, intra-arterial chemotherapy was initiated with only cisplatin, and doxorubicin and caffeine administration was changed to the intravenous route. In all 8 of these images, no local adverse effects from chemotherapy were observed. Overall, the sensitivity, specificity, and accuracy of 99mTc-MAA imaging for the detection of myocutaneous damage were 100% (11/11), 91% (21/23), and 94% (32/34), respectively, and positive and negative predictive values were 85% (11/13) and 100% (21/21), respectively. In quantitative analysis, when the diagnostic threshold of the uptake ratio was set at 2.5, sensitivity, specificity, and accuracy for the detection of myocutaneous complications were 91% (10/11), 96% (22/ 23), and 94% (32/34), respectively, and positive and negative predictive values were 91% (10/11) and 96% (22/23), respectively. Conclusion: 99mTc-MAA imaging with intra-arterial infusion before intra-arterial chemotherapy for bone and soft-tissue tumors can facilitate prediction of local myocutaneous adverse effects due to chemotherapy

Prognostic value of Tc-99m-MIBI performed during middle course of preoperative chemotherapy in patients with malignant bone and soft-tissue tumors

Purpose: This study was aimed to determine whether Tc-99m-hexakis-2- methoxyisobutylisonitrile (MIBI) scintigraphy performed in the middle of preoperative chemotherapy has a prognostic value in patients with malignant bone and soft tissue tumors (MBST). Materials and Methods: In 90 patients with MBST, Tc-99m-MIBI scintigraphy was performed 15 minutes after tracer injection before the first and after the third chemotherapy cycles. After 5 cycles of chemotherapy and tumor resection, therapeutic effect was assessed by histopathology. The percent reduction of uptake ratio (AUR) was calculated according to the following equation: 100 × ([prechemotherapy UR - post-middle course of chemotherapy UR]/prechemotherapy UR). Results: The average follow-up for the entire population was 52 months. Twenty-one patients had clinically detectable metastases at initial presentation (primary metastasis). Kaplan-Meier analysis demonstrated that absence of metastasis was associated with good survival in all patients, in patients with bone tumor, and those with soft tissue tumor (P < 0.0001, P < 0.0001, and P = 0.0003, respectively), and AUR ≥30% was also associated with survival in all patients and patients with bone tumor (P = 0.011 and P = 0.047, respectively), but was marginal in those with soft tissue tumor (P = 0.091). Multivariate analysis showed that primary metastasis was the most powerful independent predictor of a lethal clinical outcome in all patients, in both patients with bone and soft tissue tumors (hazard ratio [HR]: 4.9, 95% confidence interval [CI]: 2.61-9.08, P < 0.0001; HR: 15.1, CI: 4.86-52.7, P < 0.0001; HR: 3.7, CI: 1.45-8.94, P = 0.0069, respectively) and showed that Tc-99m-MIBI scintigraphy had a good independent long-term prognostic value in all patients and patients with bone tumor (HR: 2.2, CI: 1.14-4.43, P = 0.017; HR: 6.0, CI: 2.01-21.6, P = 0.0009, respectively) but not in those with soft tissue tumor (HR: 1.5, CI: 0.61-4.09, P = 0.38). Good disease-free survival was associated with ΔUR §30% in all patients and patients with soft tissue tumor (P = 0.0093 and P = 0.017, respectively) but not in those with bone tumor (P = 0.19). Conclusions: Tc-99m-MIBI scintigraphy at the middle course of preoperative chemotherapy could be used as a prognostic indicator in patients with MBST. Copyright © 2012 by Lippincott Williams & Wilkins.Thesis of Hiroshi Wakabayashi / 博士学位論文 若林 大

Safety analysis of two different regimens of uracil–tegafur plus leucovorin as adjuvant chemotherapy for high-risk stage II and III colon cancer in a phase III trial comparing 6 with 18 months of treatment: JFMC33-0502 trial

PURPOSE: The JFMC33-0502 trial is a phase III clinical study designed to determine the most appropriate duration of postoperative adjuvant chemotherapy with uracil–tegafur (UFT) plus leucovorin in patients with stage IIB or III colon cancer. We report the interim results of preplanned safety analyses. METHODS: Patients with stage IIB or III colon cancer who had undergone curative resection were randomly assigned to receive UFT (300 mg/m(2)) plus leucovorin (75 mg/day) for 6 months (control group, 4 weeks of treatment followed by a 1-week rest, five courses) or for 18 months (study group, 5 days of treatment followed by a 2-day rest, 15 courses). Treatment status and safety were evaluated. RESULTS: A total of 1,071 patients were enrolled, and 1,063 were included in safety analyses. Treatment completion rate at 6 months was 74.0 % in the control group and 76.7 % in the study group. Treatment completion rate in the study group at 18 months was 56.0 %. The overall incidence of adverse events (AEs) was 75.3 % in the control group and 77.6 % in the study group. The incidences of grade 3 or higher AEs were low in both groups. During the first 6 months, the incidences of the subjective AEs were significantly lower in the study group. CONCLUSIONS: Oral UFT plus leucovorin given by either dosage schedule is a very safe regimen for adjuvant chemotherapy. In particular, 5 days of treatment followed by a 2-day rest was a useful treatment option from the viewpoint of toxicity even when given for longer than 6 months. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00280-014-2461-5) contains supplementary material, which is available to authorized users

JRAB shifts “dancing style” of cell clusters

In fundamental biological processes, cells often move in groups, a process termed collective cell migration. Collectively migrating cells are much better organized than a random assemblage of individual cells. Many molecules have been identified as factors involved in collective cell migration, and no one molecule is adequate to explain the whole picture. Here we show that JRAB/MICAL-L2, an effector protein of Rab13 GTPase, provides the “law and order” allowing myriad cells to behave as a single unit just by changing its conformation. First, we generated a structural model of JRAB/MICAL-L2 by a combination of bioinformatic and biochemical analyses and showed how JRAB/MICAL-L2 interacts with Rab13 and how its conformational change occurs. We combined cell biology, live imaging, computational biology, and biomechanics to show that impairment of conformational plasticity in JRAB/MICAL-L2 causes excessive rigidity and loss of directionality, leading to imbalance in cell group behavior. This multidisciplinary approach supports the concept that the conformational plasticity of a single molecule provides “law and order” in collective cell migration

The E3 Ubiquitin Ligase Activity of Trip12 Is Essential for Mouse Embryogenesis

Protein ubiquitination is a post-translational protein modification that regulates many biological conditions [1], [2], [3], [4]. Trip12 is a HECT-type E3 ubiquitin ligase that ubiquitinates ARF and APP-BP1 [5], [6]. However, the significance of Trip12 in vivo is largely unknown. Here we show that the ubiquitin ligase activity of Trip12 is indispensable for mouse embryogenesis. A homozygous mutation in Trip12 (Trip12mt/mt) that disrupts the ubiquitin ligase activity resulted in embryonic lethality in the middle stage of development. Trip12mt/mt embryos exhibited growth arrest and increased expression of the negative cell cycle regulator p16 [7], [8], [9], [10]. In contrast, Trip12mt/mt ES cells were viable. They had decreased proliferation, but maintained both the undifferentiated state and the ability to differentiate. Trip12mt/mt ES cells had increased levels of the BAF57 protein (a component of the SWI/SNF chromatin remodeling complex) and altered gene expression patterns. These data suggest that Trip12 is involved in global gene expression and plays an important role in mouse development