Adverse Drug Reaction Relief System in Japan: From Clinical Perspective.

Adverse drug reaction (ADR) relief system in Japan is comprehensively described in this article. Particularly, review process during ADR relief evaluation is focused from clinical perspective. The significance of clinical review process and roles of a physician medical reviewer in the ADR relief system in Japan are also discussed. The current ADR Relief Service in Japan requires criteria for compensation eligibility including the "proper" use of the medication associated with the adverse event, and reasonably plausible association between the drug and the adverse event. The criteria are primarily reviewed at the ADR relief department of Pharmaceuticals and Medical Devices Agency (PMDA). In this article, after introducing framework of the ADR relief system in Japan including review processes at PMDA, actual process of the ADR relief assessment is described. In more details, we explain appropriate indication and appropriate usage in the ADR relief evaluation and unexpected/unwritten ADR in the Japanese package insert. Also described are time period for the payment, causality assessment between ADRs and the death, and pitfalls during the evaluation of the ADR relief system in Japan. In the last part, current issues and future directions are referred.

A rare case of focal multiple medullary venous malformations with ipsilateral cerebral surface varix.

We report here a rare case of focal multiple venous malformations (VMs) in the white matter, via a draining vein arising from each VM, connecting with an ipsilateral cerebral surface venous varix. The male teen was asymptomatic neurologically. A diagnostic process using of MRI/MRDSA in this extremely rare entity is important as the more incidental discovery is expected with increasing opportunities of performing brain CT/MRI for various indications.

The role of the Pharmaceuticals and Medical Devices Agency and healthcare professionals in post-marketing safety.

The development of drugs and medical devices is necessary for medical progress; however, safety measures need to be put in place to protect the health of the population. In order to ensure the safety of drugs and medical devices, it is important to determine measures for appropriate management of risks at any time during the development phase, the regulatory review and the post-marketing phase. Adverse events detected in clinical trials are limited due to the restricted numbers of patients enrolled in the trials. Therefore, it is almost impossible to predict rare serious adverse events during the post-marketing phase. The revised Pharmaceutical Affairs Act was established in Japan in November 20, 2013. The new act focuses on increased safety of drugs and medical devices. The Pharmaceuticals and Medical Devices Agency (PMDA) is the regulatory authority in Japan that promotes safety measures from the development phase through to the post-marketing phase. In the post-marketing phase, the PMDA collects information from the medical product companies and healthcare professionals, as well as instructing and advising them with regard to post-marketing safety measures for each drug and medical device. Since Japan has a national health insurance system, a new drug or a medical device is available throughout the country when the drug price or medical fee is listed in the National Health Insurance price list. Healthcare professionals in medical institutions must learn about the drugs and medical devices they handle, and should make an effort to maintain patient safety. The PMDA medi-navi is a very useful electronic mail delivery service that provides critical information for protecting patients from health hazards caused by adverse events. The 'risk management plan' is also important as it contains important information about safety profile and post-marketing measures of a new drug.

Intrafractional setup errors in patients undergoing non-invasive fixation using an immobilization system during hypofractionated stereotactic radiotherapy for lung tumors.

Intrafractional setup errors during hypofractionated stereotactic radiotherapy (SRT) were investigated on the patient under voluntary breath-holding conditions with non-invasive immobilization on the CT-linac treatment table. A total of 30 patients with primary and metastatic lung tumors were treated with the hypofractionated SRT with a total dose of 48-60 Gy with four treatment fractions. The patient was placed supine and stabilized on the table with non-invasive patient fixation. Intrafractional setup errors in Right/Left (R.L.), Posterior/Anterior (P.A.), and Inferior/Superior (I.S.) dimensions were analyzed with pre- and post-irradiation CT images. The means and one standard deviation of the intrafractional errors were 0.9 ± 0.7mm (R.L.), 0.9 ± 0.7mm (P.A.) and 0.5 ± 1.0 mm (I.S.). Setup errors in each session of the treatment demonstrated no statistically significant difference in the mean value between any two sessions. The frequency within 3mm displacement was 98% in R.L., 98% in P.A. and 97% in I.S. directions. SRT under the non-invasive patient fixation immobilization system with a comparatively loose vacuum pillow demonstrated satisfactory reproducibility of minimal setup errors with voluntary breath-holding conditions that required a small internal margin.

Stereotactic body radiotherapy for metachronous multisite oligo-recurrence: a long-surviving case with sequential oligo-recurrence in four different organs treated using locally radical radiotherapy and a review of the literature.

Stereotactic body radiotherapy (SBRT) for oligometastases represents a recent trend in radiation oncology. While abundant data are available regarding the use of SBRT for the treatment of lung or liver oligometastases from various retrospective series and prospective trials, relatively little information has been accumulated for the treatment of oligometastases at sites other than the lungs and liver, particularly for sequential oligometastases in multiple organs. Oligometastases with primary lesions controlled is called "oligo-recurrence." We describe herein the case of a lung cancer patient who developed repeated oligo-recurrence at multiple sites that were each controlled by radical radiotherapy and achieved long-term survival and discuss the merits of locally aggressive radiotherapy for this type of disease condition with reviewing the literature. Although further investigation should be undertaken to clarify the benefits, objectives, and methods of SBRT for the treatment of oligometastases, we believe utilization of SBRT may be worthwhile for patients with remote metastases who hope for treatment to acquire better local control and possible longer survival.

Collapse of Viabahn stent-graft secondary to rheolytic thrombectomy: a rare complication of the AngioJet device.

There is increased use of percutaneous mechanical thrombectomy for treatment of occluded dialysis access. The AngioJet rheolytic thrombectomy device is one such device available. Reports have shown safety and efficacy of these techniques with relatively few complications. We describe a case report of a collapsed Viabahn endoprosthesis in an arteriovenous fistula during treatment with an AngioJet device.

Renal pseudoaneurysm following laser lithotripsy: endovascular treatment of a rare complication.

Hemorrhagic complications of renal transplantation can be life threatening and require prompt and timely intervention. This brief report describes the exceedingly rare formation of an extrarenal pseudoaneurysm of a transplant renal artery following laser lithotripsy for nephrolithiasis in a teenage male. The pseudoaneurysm ruptured into the renal collecting system. Transarterial coil embolization of the wide-neck saccular pseudoaneurysm of the extraparenchymal renal artery with the assistance of a 'safety microguidewire' was successfully performed and the allograft was preserved.

Transfer of regulatory T cells generated ex vivo modifies graft rejection through induction of tolerogenic CD4+CD25+ cells in the recipient.

Certain CD4+CD25+ T cells can induce and maintain T-cell non-responsiveness to donor alloantigens and have therapeutic potential in solid organ transplantation. Peripheral CD4+CD25- cells alloactivated with IL-2 and transforming growth factor beta (TGF-beta) ex vivo express the transcription factor FoxP3, and become potent antigen-specific CD4+CD25- suppressor cells. Here we report that the transfer of TGF-beta-induced regulatory CD4+ and CD8+ T cells (Tregs) co-incident with transplantation of a histoincompatible heart resulted in extended allograft survival. To account for this result, we injected non-transplanted mice with a single dose of CD4+ and CD8+ Tregs and transferred donor cells every 2 weeks to mimic the continuous stimulation of a transplant. We observed increased splenic CD4+CD25+ cells that were of recipient origin. These cells rendered the animals non-responsive to donor alloantigens by an antigen-specific and cytokine-dependent mechanism of action. Both the increased number of CD4+CD25+ cells and their tolerogenic effect were dependent on continued donor antigen boosting. Thus, Tregs generated ex vivo can act like a vaccine that generates host suppressor cells with the potential to protect MHC-mismatched organ grafts from rejection.

Transforming growth factor-beta/interleukin-2-induced regulatory CD4+ T cells prolong cardiac allograft survival in rats.

BACKGROUND: Treatment of naive CD4+ T cells in vitro with transforming growth factor-beta (TGF-beta) or TGF-beta/interleukin-2 (IL-2), combined with stimulation in a mixed lymphoid culture (MLC), has been shown to generate CD4+ CD25+ regulatory T cells. However, little is known about the effect of these regulatory T cells on cardiac allograft survival in vivo. METHODS: CD4+ CD25+ T cells were generated from Lewis (LEW) rat spleen through a primary MLC with TGF-beta (10 ng/ml) or TGF-beta/IL-2 (10 U/ml). The effect of adoptive transfer of the CD4+ CD25+ T cells (5.0 x 10(7)) was evaluated using an animal model of ACI rat cardiac allograft survival in LEW recipients. RESULTS: The MLC with TGF-beta or TGF-beta/IL-2 generated CD4+ CD25+ regulatory T cells, which suppressed the cytotoxic activity of LEW spleen T cells against irradiated ACI spleen cells in vitro. Adoptive transfer of the CD4+ CD25+ regulatory T cells intravenously to naive syngeneic recipients significantly prolonged the ACI cardiac allograft survival (N = 6, 13.5 +/- 3.4 days) compared with the control group (N = 6, 5.0 +/- 0.6 days). CONCLUSIONS: Intravenous administration of CD4+ CD25+ regulatory T cells, successfully generated by TGF-beta/IL-2 treatment, had a significant effect on cardiac allograft survival in this rat model. Adoptive transfer of regulatory T cells may represent a novel approach for preventing allograft rejection.

BCR/ABL P190 transgenic mice develop leukemia in the absence of Crkl.

The Bcr/Abl fusion protein directly causes chronic myelogenous leukemia and Philadelphia-chromosome positive acute lymphoblastic leukemia. Multiple independent studies have implicated Crkl, a small adapter protein, in transduction of oncogenic signals of Bcr/Abl and Crkl tyrosine-phosphorylation is used as a diagnostic tool for Philadelphia-positive leukemia. To evaluate the contribution of Crkl to this type of leukemia, we generated mutant mice that lack Crkl expression. We found that the overall survival of P190 BCR/ABL crkl-/- mice was comparable to that of genetically matched P190 BCR/ABL crkl +/+ mice. Both genotypes developed lymphoid lineage leukemia/lymphoma. Western blot analysis of -/- and +/+ lymphomas showed that the related Crk protein was tyrosine phosphorylated and could be found complexed with Bcr-Abl P190. These data indicate that possible therapeutic approaches that target Crkl may be complicated by the presence of pathways that compensate for lack of Crkl function.