PubMed | Red Cross, Toranomon Hospital, Sasebo City General Hospital, National Cancer Center Research Institute and 9 more.
Type: Journal Article | Journal: Nature | Year: 2016
Successful treatment of many patients with advanced cancer using antibodies against programmed cell death 1 (PD-1; also known as PDCD1) and its ligand (PD-L1; also known as CD274) has highlighted the critical importance of PD-1/PD-L1-mediated immune escape in cancer development. However, the genetic basis for the immune escape has not been fully elucidated, with the exception of elevated PD-L1 expression by gene amplification and utilization of an ectopic promoter by translocation, as reported in Hodgkin and other B-cell lymphomas, as well as stomach adenocarcinoma. Here we show a unique genetic mechanism of immune escape caused by structural variations (SVs) commonly disrupting the 3 region of the PD-L1 gene. Widely affecting multiple common human cancer types, including adult T-cell leukaemia/lymphoma (27%), diffuse large B-cell lymphoma (8%), and stomach adenocarcinoma (2%), these SVs invariably lead to a marked elevation of aberrant PD-L1 transcripts that are stabilized by truncation of the 3-untranslated region (UTR). Disruption of the Pd-l1 3-UTR in mice enables immune evasion of EG7-OVA tumour cells with elevated Pd-l1 expression in vivo, which is effectively inhibited by Pd-1/Pd-l1 blockade, supporting the role of relevant SVs in clonal selection through immune evasion. Our findings not only unmask a novel regulatory mechanism of PD-L1 expression, but also suggest that PD-L1 3-UTR disruption could serve as a genetic marker to identify cancers that actively evade anti-tumour immunity through PD-L1 overexpression.
PubMed | Kobe City Medical Center General Hospital, Sasebo City General Hospital, National Cancer Center, Inagi Municipal Hospital and 5 more.
Type: Journal Article | Journal: Medical physics | Year: 2017
In general, beam data of individual linac is measured for independent dose verification software program and the verification is performed as a secondary check. In this study, independent dose verification using golden beam data was compared to that using individual linacs beam data.Six institutions were participated and three different beam data were prepared. The one was individual measured data (Original Beam Data, OBD) .The others were generated by all measurements from same linac model (Model-GBD) and all linac models (All-GBD). The three different beam data were registered to the independent verification software program for each institute. Subsequently, patients plans in eight sites (brain, head and neck, lung, esophagus, breast, abdomen, pelvis and bone) were analyzed using the verification program to compare doses calculated using the three different beam data.1116 plans were collected from six institutes. Compared to using the OBD, the results shows the variation using the Model-GBD based calculation and the All-GBD was 0.0 0.3% and 0.0 0.6%, respectively. The maximum variations were 1.2% and 2.3%, respectively. The plans with the variation over 1% shows the reference points were located away from the central axis with/without physical wedge.The confidence limit (2SD) using the Model-GBD and the All-GBD was within 0.6% and 1.2%, respectively. Thus, the use of golden beam data may be feasible for independent verification. In addition to it, the verification using golden beam data provide quality assurance of planning from the view of audit. This research is partially supported by Japan Agency for Medical Research and Development(AMED).
Iwanaga M.,Nagasaki University |
Iwanaga M.,Kwassui Women's College |
Watanabe T.,Tokyo Medical University |
Utsunomiya A.,Imamura Bun in Hospital |
And 16 more authors.
Blood | Year: 2010
Definitive risk factors for the development of adult T-cell leukemia (ATL) among asymptomatic human T-cell leukemia virus type I (HTLV-1) carriers remain unclear. Recently, HTLV-1 proviral loads have been evaluated as important predictors of ATL, but a few small prospective studies have been conducted. We prospectively evaluated 1218 asymptomatic HTLV-1 carriers (426 males and 792 females) who were enrolled during 2002 to 2008. The proviral load at enrollment was signifi-cantly higher in males than females (median, 2.10 vs 1.39 copies/100 peripheral blood mononuclear cells [PBMCs]; P < .001), in those 40 to 49 and 50 to 59 years of age than that of those 40 years of age and younger (P = .02 and .007, respectively), and in those with a family history of ATL than those without the history (median, 2.32 vs 1.33 copies/100 PBMCs; P = .005). During follow-up, 14 participants progressed to overt ATL. Their baseline proviral load was high (range, 4.17-28.58 copies/100 PBMCs). None developed ATL among those with a baseline proviral load lower than approximately 4 copies. Multivariate Cox analyses indicated that not only a higher proviral load, advanced age, family history of ATL, and first opportunity for HTLV-1 testing during treatment for other diseases were independent risk factors for progression of ATL. © 2010 by The American Society of Hematology.
Ishida T.,Nagoya City University |
Hishizawa M.,Kyoto University |
Kato K.,Kyushu University |
Kato K.,Red Cross |
And 15 more authors.
Blood | Year: 2012
Adult T-cell leukemia-lymphoma (ATL) is an intractable mature T-cell neoplasm. We performed a nationwide retrospective study of allogeneic hematopoietic stem cell transplantation (HSCT) for ATL in Japan, with special emphasis on the effects of the preconditioning regimen. This is the largest study ofATL patients receiving HSCT. Median overall survival (OS) and 3-year OS of bone marrow or peripheral blood transplantation recipients (n = 586) was 9.9 months (95% confidence interval, 7.4-13.2 months) and 36% (32%-41%), respectively. These values for recipients of myeloablative conditioning (MAC; n = 280) and reduced intensity conditioning (RIC; n = 306) were 9.5 months (6.7-18.0 months) and 39% (33%-45%) and 10.0 months (7.2-14.0 months) and 34% (29%-40%), respectively. Multivariate analysis demonstrated 5 significant variables contributing to poorer OS, namely, older age, male sex, not in complete remission, poor performance status, and transplantation from unrelated donors. Although no significant difference in OS between MAC and RIC was observed, there was a trend indicating that RIC contributed to better OS in older patients. Regarding mortality, RIC was significantly associated with ATL-related mortality compared with MAC. In conclusion, allogeneic HSCT not only with MAC but also with RIC is an effective treatment resulting in long-term survival in selected patients with ATL. © 2012 by The American Society of Hematology.
Nakano T.,Sasebo City General Hospital |
Fujimoto T.,Sasebo City General Hospital |
Fukuda Y.,Sasebo City General Hospital |
Takahashi T.,Tohoku University |
Kanbayashi T.,Akita University
Clinical Neurology | Year: 2011
A 31-year-old woman with a 5-year history of recurrent optic neuritis and encephalomyelitis underwent repeated steroid therapy. She developed general malaise and fever in October 2009. Laboratory tests revealed marked reduction in serum Na (106 mEq/L). Because the plasma osmotic pressure was lower than the urinary osmotic pressure and the serum antidiuretic hormone (ADH) level was elevated, she was diagnosed with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Magnetic resonance imaging (MRI) revealed high signal intensities on symmetrical T2 weighted and fluid attenuated inversion recovery (FLAIR) images of both sides of the hypothalamus. The serum samples tested positive for the antibody to aquaporin-4 (AQP4). Previously conducted cervical MRI had revealed a longitudinally extending lesion in the cervical cord, and brain MRI had revealed brainstem lesions. We diagnosed the patient with neuromyelitis optica (NMO) according to the revised diagnostic criteria for NMO proposed by Wingerchuk in 2006. Furthermore, she complained of excessive daytime sleepiness. The concentration of orexin in the cerebrospinal fluid was mildly reduced and the orexin levels returned to normal when her sleepiness decreased. ADH and orexin neurons localized in the hypothalamus; hence, we considered the above-mentioned symptoms to be caused by bilateral hypothalamic lesions.
PubMed | National Hospital Organization Kumamoto Medical Center, Heart Life Hospital, Sasebo City General Hospital, University of Ryukyus and 11 more.
Type: Clinical Trial | Journal: Bone marrow transplantation | Year: 2016
Allogeneic hematopoietic SCT (allo-HSCT) is a curative treatment for aggressive adult T-cell leukemia/lymphoma (ATLL). Considering the dismal prognosis associated with conventional chemotherapies, early application of allo-HSCT might be beneficial for patients with ATLL. However, no previous study has addressed the optimal timing of allo-HSCT from related donors. Hence, to evaluate the impact of timing of allo-HSCT for patients with ATLL, we retrospectively analyzed data from patients with ATLL who received an allo-HSCT from a related donor. The median age was 52 years. Patients were grouped according to the interval from diagnosis to allo-HSCT: early transplant group, <100 days, n=72; late transplant group, 100 days, n=428. The corresponding constituents of disease status were not statistically different between the two groups (P=0.11). The probability of OS in the early transplant group was significantly higher than that in the late transplant group (4-year OS, 49.3% vs 31.2%). Multivariate analysis revealed that late allo-HSCT was an unfavorable prognostic factor for OS (hazard ratio, 1.46; 95% confidence interval (CI), 1.01-2.11; P=0.04). Despite the limitations of a retrospective study, it might be acceptable to consider early application of allo-HSCT for ATLL.
PubMed | Otemae Hospital, Sasebo City General Hospital, Kanagawa Cancer Center, National Cancer Center and 4 more.
Type: Journal Article | Journal: Medical physics | Year: 2017
Actual irradiated prescription dose to patients cannot be verified. Thus, independent dose verification and second treatment planning system are used as the secondary check. AAA dose calculation engine has contributed to lung SBRT. We conducted a multi-institutional study to assess variation of prescription dose for lung SBRT when using AAA in reference to using Acuros XB and Clarkson algorithm.Six institutes in Japan participated in this study. All SBRT treatments were planed using AAA in Eclipse and Adaptive Convolve (AC) in Pinnacle3. All of the institutes used a same independent dose verification software program (Simple MU Analysis: SMU, Triangle Product, Ishikawa, Japan), which implemented a Clarkson-based dose calculation algorithm using CT image dataset. A retrospective analysis for lung SBRT plans (73 patients) was performed to compute the confidence limit (CL, Average2SD) in dose between the AAA and the SMU. In one of the institutes, a additional analysis was conducted to evaluate the variations between the AAA and the Acuros XB (AXB).The CL for SMU shows larger systematic and random errors of 8.79.9 % for AAA than the errors of 5.74.2 % for AC. The variations of AAA correlated with the mean CT values in the voxels of PTV (a correlation coefficient : -0.7) . The comparison of AXB vs. AAA shows smaller systematic and random errors of -0.71.7%. The correlation between dose variations for AXB and the mean CT values in PTV was weak (0.4). However, there were several plans with more than 2% deviation of AAPM TG114 (Maximum: -3.3 %).In comparison for AC, prescription dose calculated by AAA may be more variable in lung SBRT patient. Even AXB comparison shows unexpected variation. Care should be taken for the use of AAA in lung SBRT. This research is partially supported by Japan Agency for Medical Research and Development (AMED).
Kitazaki T.,Red Cross |
Fukuda Y.,Sasebo City General Hospital |
Fukahori S.,Sasebo City General Hospital |
Oyanagi K.,Sasebo City General Hospital |
And 3 more authors.
Supportive Care in Cancer | Year: 2015
Purpose: The purpose of the study is to investigate the usefulness of the triplet regimen comprising aprepitant, palonosetron, and dexamethasone in patients treated with highly emetogenic chemotherapy (HEC) and moderately emetogenic chemotherapy (MEC).Methods: Patients with lung cancer (aged 65.8 ± 8.4 years) who received carboplatin-based MEC and those treated with cisplatin-based HEC were enrolled. The antiemetic regimen for both types of chemotherapy consisted of aprepitant, palonosetron, and dexamethasone based on the May 2010 guidelines prepared by the Japan Society of Clinical Oncology. The incidence of chemotherapy-induced nausea and vomiting (CINV) and the use of salvage treatment were assessed. The primary endpoints were the percentage of patients with a complete response (CR: no nausea and no salvage treatment) during the entire study period (5 days) after chemotherapy, during the acute phase (day 1), and during the delayed phase (days 2–5).Results: CR rates for the entire period were 86 and 71 % in patients receiving carboplatin-based and cisplatin-based chemotherapy, respectively. CR rates were respectively 98 and 100 % in the acute phase versus 87 and 71 % in the delayed phase. Most of the patients could ingest food throughout the entire period after chemotherapy. Assessment of various risk factors for acute and delayed CINV (gender, age, prior vomiting due to antineoplastic therapy, prior experience of motion sickness, and history of drinking) revealed no significant influence of these factors on the CR rate for the entire period in patients receiving either carboplatin-based or cisplatin-based chemotherapy.Conclusion: The present triple therapy can be recommended for supporting both carboplatin-based and cisplatin-based chemotherapy regimens. © 2014, Springer-Verlag Berlin Heidelberg.
Kawamura N.,Kyushu University |
Yamasaki R.,Kyushu University |
Yonekawa T.,Kyushu University |
Matsushita T.,Kyushu University |
And 7 more authors.
Neurology | Year: 2013
Objectives: We aimed to identify the target antigens for combined central and peripheral demyelination (CCPD). Methods: We screened target antigens by immunohistochemistry and immunoblotting using peripheral nerve tissues to identify target antigens recognized by serum antibodies from selected CCPD and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) cases. We then measured the level of antibody to the relevant antigen in 7 patients with CCPD, 16 patients with CIDP, 20 patients with multiple sclerosis, 20 patients with Guillain-Barré syndrome, 21 patients with other neuropathies, and 23 healthy controls (HC) by ELISA and cell-based assays using HEK293 cells. Results: At the initial screening, sera from 2 patients with CCPD showed cross-like binding to sciatic nerve sections at fixed intervals, with nearly perfect colocalization with neurofascin immunostaining at the node and paranode. ELISA with recombinant neurofascin revealed significantly higher mean optical density values in the CCPD group than in other disease groups and HC. Anti-neurofascin antibody positivity rates were 86% in patients with CCPD, 10% in patients with multiple sclerosis, 25% in patients with CIDP, 15% in patients with Guillain-Barré syndrome, and 0% in patients with other neuropathies and HC. The cell-based assay detected serum anti-neurofascin antibody in 5 of 7 patients with CCPD; all others were negative. CSF samples examined from 2 patients with CCPD were both positive. In anti-neurofascin antibody- positive CCPD patients, including those with a limited response to corticosteroids, IV immunoglobulin or plasma exchange alleviated the symptoms. Conclusion: Anti-neurofascin antibody is frequently present in patients with CCPD. Recognition of this antibody may be important, because patients with CCPD who are antibody positive respond well to IV immunoglobulin or plasma exchange. © 2013 American Academy of Neurology.