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Naomi Sasaki - Top 30 Publications

Long-term Outcomes of a Dose-reduction Trial to Decrease Late Gastrointestinal Toxicity in Patients with Prostate Cancer Receiving Soft Tissue-matched Image-guided Intensity-modulated Radiotherapy.

We experienced an unexpected high incidence of gastrointestinal (GI) toxicity in patients undergoing image-guided intensity-modulated radiotherapy (IG-IMRT) using helical tomotherapy in our initial 2.2 Gy/fraction schedule for prostate cancer; hence, a dose-reduction trial from 2.2 Gy to 2 Gy/fraction was conducted using modified planning target volume (PTV) contouring.

Palliative Reirradiation for Painful Bone Metastases: Clinical Cases and Literature Review.

Reirradiation to previously irradiated peripheral bone metastases for pain has been shown to be safe and effective, but no specific trial has been completed to define the indications for reirradiation of patients with recurrent symptoms of metastatic bone disease. Thus, we aimed to assess the effectiveness and prognostic factors of reirradiation for painful bone metastases. To do so, we reviewed the cases of 14 patients with painful bone metastases who had undergone reirradiation at our hospital. A favorable pain response after reirradiation wasachieved in 50% (7/14) of the patients. An interval from initial radiotherapy >6 months was a significant prognostic factor for pain response (p = 0.03). Performance status was correlated with pain response, with borderline significance (p = 0.06). No severe adverse events were reported. We conclude that reirradiation of painful bone metastases is effective in providing pain relief, especially for patients with a long interval from initial radiation and good performance status.

Clinical Usefulness of the Platelet-to Lymphocyte Ratio in Patients with Angiosarcoma of the Face and Scalp.

Angiosarcoma of the face and scalp (ASFS) is an extremely aggressive tumor that frequently metastasizes, often leading to death. The neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) are inflammatory markers that predict outcome of various cancers. We aimed to examine the relationship between pretreatment inflammatory markers and ASFS outcome. We included 17 patients with ASFS and a control group of 56 age- and gender-matched healthy individuals. Total white blood counts, neutrophil, lymphocyte, monocyte, and platelet counts were recorded; NLR, PLR, and LMR were calculated. Kaplan-Meier curves were used to calculate overall survival (OS) and distant metastasis-free survival (DMFS). Optimal cut-off values for each inflammatory marker were calculated using receiver operating curve analysis. Median follow-up was 22 months (range, 6-75). There was a statistically significant difference in absolute neutrophil counts and NLR between patient and control groups. Two-year OS and DMFS rates were 41% and 35%, respectively. In patients with tumors < 10 cm, PLR was highly correlated with DMFS, with the 2-year DMFS for those with a high PLR being 50% compared with 100% for those with a low PLR (p = 0.06). This study suggests that PLR is superior to NLR and LMR, and is a clinically useful marker in patients with ASFS with small tumors.

Interfractional Rectal Displacement Requiring Repeated Precaution Did Not Correlate to Biochemical Control and Rectal Toxicity in Patients with Prostate Cancer Treated with Image-guided Intensity-modulated Radiation Therapy.

To investigate the correlation between frequency of action level of interfractional rectal displacement requiring repeated precaution in patients with prostate cancer and late toxicity from image-guided intensity-modulated radiation therapy (IG-IMRT) using helical tomotherapy.

Measurement of exhaled nitric oxide and serum surfactant protein D levels for monitoring radiation pneumonitis following thoracic radiotherapy.

The present study aimed to examine the role of exhaled nitric oxide (eNO) and serum surfactant protein D (SP-D) level in the determination of radiation pneumonitis (RP) after thoracic radiotherapy (RT). The study included 34 treatments for 33 patients, including 16 three-dimensional conformal and 18 stereotactic body RT treatments. eNO levels were measured prior to RT, immediately subsequent to RT, every week during the RT course and at 1, 3, 6, 9 and 12 months following the treatment. The therapy reduced the eNO from 24.3±12.8 ppb prior to RT to 19.0±10.4 ppb immediately subsequent to RT (P=0.04). A total of 5 patients (14%) developed symptomatic RP of grade 2 or higher 3-5 months later, and exhibited an eNO elevation of 2.1±0.68-fold the minimum value, whereas the RP- group exhibited 1.4±0.6-fold elevation (P=0.02). The sensitivity of a cut-off of a 1.4-fold increase in the eNO ratio at the onset of RP was 100%; however, the specificity was 52%, and no predictive alterations to eNO levels were observed prior to the onset of RP. RT was associated with an elevated serum SP-D level at 3-6 months after RT. There was a statistically significant difference in the initial serum SP-D level between RP+ and RP- patients. In conclusion, obtaining the eNO ratio was a useful RP monitoring tool but did not predict RP occurrence in the present setting, whereas serum SP-D level may be a potential predictor for the detection of RP risk.

Local field radiotherapy without elective nodal irradiation for postoperative loco-regional recurrence of esophageal cancer.

Radiotherapy is an effective treatment for the postoperative loco-regional recurrence of esophageal cancer; however, the optimal treatment field remains controversial. This study aims to evaluate the outcome of local field radiotherapy without elective nodal irradiation for postoperative loco-regional recurrence of esophageal cancer.

T cells bearing anti-CD19 and/or anti-CD38 chimeric antigen receptors effectively abrogate primary double-hit lymphoma cells.

Patients with B cell lymphomas bearing MYC translocation combined with translocation involving other genes, such as BCL2, BCL3, or BCL6, defined as double-hit lymphoma (DHL), have a poor prognosis. Recent studies expanded the concept to include double-expressing lymphoma (DEL) that co-overexpresses MYC protein with either of those proteins. Accordingly, we defined cytogenetic DHL and DEL as primary DHL. An adoptive T cell immunotherapy with a chimeric antigen receptor (CAR) has been clinically shown to exhibit cytotoxicity in refractory neoplasias. We revealed the marked cytotoxicity of anti-CD19- and/or anti-CD38-CAR T cells against primary DHL cells from patients. CD19- and/or CD38-specific T cells were co-cultured with cytogenetic DHL (n = 3) or DEL (n = 2) cells from five patients for 3 days. We examined whether T cells retrovirally transduced with each vector showed cytotoxicity against DHL cells. Anti-CD19- and/or anti-CD38-CAR T cells were co-cultured with primary DHL cells at an E:T ratio of 1:2 for 3 days. Anti-CD19- and anti-CD38-CAR T cells completely abrogated these DHL cells, respectively. Anti-CD19-CAR T cells synergistically exerted collaborative cytotoxicity against these primary DHL cells with anti-CD38-CAR T cells. Therefore, refractory DHL cells can be efficiently abrogated by the clinical use of T cells with anti-CD19- and/or anti-CD38-CAR.

Clinical outcome of patients treated with re-irradiation for spine or pelvic bone metastasis: A multi-institutional analysis of 98 patients.

The present study aimed to describe the clinical results of re-irradiation (Re-RT) for spine or pelvic bone metastasis at the same initial irradiated area. Between April 2010 and March 2014, cases involving 98 patients with spine or pelvic bone metastasis who had undergone Re-RT at five institutions were reviewed. The clinical outcomes following Re-RT were evaluated, including overall survival (OS) and severe adverse events. The median time interval from initial radiation therapy (RT) to Re-RT was 439 days (range, 23-4,993 days), and the median duration of patient follow-up was 256 days (range, 11-2,284 days). The median biological effective dose for the Re-RT was 150 Gy2 (range, 17-240 Gy2; α/β = 2). Severe late adverse events occurred in two patients who underwent three-dimensional conformal radiotherapy for lumbar spine or pelvic bone metastases, which may be associated with tumor progression. The median survival time following Re-RT was 255 days, and the actuarial OS rate at 1 year was 36%. The interval between initial RT and Re-RT, and their performance statuses (PS) were significant independent prognostic factors for OS rates in multivariate analysis. Re-RT for spine or pelvic bone metastases is a relatively acceptable option with low risk of anticipated severe adverse events, particularly for patients with good PS following a long disease-free interval.

Palliative Radiotherapy in the Local Management of Stage IVB Esophageal Cancer: Factors Affecting Swallowing and Survival.

To clarify the role of external-beam radiotherapy in the local management of state IVB esophageal cancer.

Clinicopathological study of 5 cases of renal cell carcinoma with t(6;11)(p21;q12).

Renal cell carcinoma (RCC) with t(6;11)(p21;q12) has been incorporated into the recent WHO classification. We performed a clinicopathological study of 5 cases with such a tumor. The patients consisted of 4 males and 1 female. The age of patients ranged from 17 to 57 years with a mean age of 38.6 years. Tumor sizes ranged from 2.8 to 11 cm with a mean value of 6.5 cm. Despite immunotherapy and molecular-targeted therapy, one patient died of the disease 28 months after the surgery. Grossly, the cut surface of this tumor showed grayish white color in at least the focal area of all tumors. Furthermore, hemorrhage, daughter nodules and cystic changes were observed in two, three, and two tumors, respectively. Morphologically, all the tumors consisted of two components of large cells and small cells, and the latter surrounded basement membrane-like materials, forming rosette-like structures. Immunohistochemically, nuclei of tumor cells in all cases were positive for TFEB. Fluorescence in situ hybridization study confirmed the TFEB gene break in two tumors. Finally, urologists and pathologists should bear in mind that this tumor may occur in young adults to adults and might behave in an aggressive fashion. Break-apart FISH is useful for the definite diagnosis.

Solitary plasmablastic lymphoma in the esophagus.

Regulation of the chitin degradation and utilization system by the ChiX small RNA in Serratia marcescens 2170.

Serratia marcescens 2170 produces three different types of chitinases and chitin-binding protein CBP21. We found that transposon insertion into the 5' untranslated region (5' UTR) of chiPQ-ctb led to defective chitinase and CBP21 production. ChiX small RNA possessed the complementary sequence of the 5' UTRs of the chiPQ-ctb and chiR and repressed the expression of chiP and chiR. ChiX was detected in a medium containing glucose, glycerol, GlcNAc, and (GlcNAc)2, but the expression of both chiP and chiR was only observed in a medium containing (GlcNAc)2. ∆chiX mutant produced chitinases, CBP21, and chitobiase without induction. chiP transcripts were more abundant than those of chiR or chiX in a medium containing (GlcNAc)2. These results suggest that the constitutively expressed ChiX binds to the highly abundant chiP 5' UTR, thereby leading to the induction of chiR mRNA translation and the subsequent expression of chitinases and CBP21.

Platelet-Rich Plasma with Basic Fibroblast Growth Factor for Treatment of Wrinkles and Depressed Areas of the Skin.

There are several treatments for wrinkles and depressed areas of the face, hands, and body. Hyaluronic acid is effective, but only for 6 months to 1 year. Autologous fat grafting may cause damage during tissue harvest.

Selection of infants who potentially have congenital anomalies of the kidney and urinary tract from a large cohort for a more thorough examination.

Although congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of pediatric end-stage renal disease (ESRD), little is known about the characteristics exhibited in the infantile period by CAKUT patients who develop ESRD. Further, an efficient screening method for CAKUT diagnosis is not available currently. In the present study, we aimed to develop a method to select infants who potentially have CAKUT from a large group of infants.

Establishment of a vascular endothelial cell-reactive type II NKT cell clone from a rat model of autoimmune vasculitis.

We previously generated a rat model that spontaneously developed small vessel vasculitis (SVV). In this study, a T cell clone reactive with rat vascular endothelial cells (REC) was established and named VASC-1. Intravenous injection of VASC-1 induced SVV in normal recipients. VASC-1 was a TCRαβ/CD3-positive CD4/CD8 double-negative T cell clone with expression of NKG2D. The cytokine mRNA profile under unstimulated condition was positive for IL-4 and IFN-γ but negative for IL-2 and IL-10. After interaction with REC, the mRNA expression of IL-2, IL-5 and IL-6 was induced in VASC-1, which was inhibited by blocking of CD1d on the REC surface. Although the protein levels of these cytokines seemed to be lower than the detection limit in the culture medium, IFN-γ was detectable. The production of IFN-γ from the VASC-1 stimulated with LPS-pre-treated REC was inhibited by the CD1d blockade on the REC. These findings indicated VASC-1 as an NKT cell clone. The NKT cell pool includes two major subsets, namely types I and II. Type I NKT cells are characterized by expression of semi-invariant TCRs and the potential to bind to marine sponge-derived α-galactosylceramide (α-GalCer) loaded on CD1d; whereas, type II NKT cells do not manifest these characteristics. VASC-1 exhibited a usage of TCR other than the type I invariant TCR α chain and did not bind to α-GalCer-loaded CD1d; therefore, it was determined as a type II NKT cell clone. The collective evidence suggested that REC-reactive type II NKT cells could be involved in the pathogenesis of SVV in rats.

Efficacy and safety of eldecalcitol, a new active vitamin D3 analog, in the bone metabolism of postmenopausal women receiving maintenance hemodialysis.

Eldecalcitol (ELD), a new active vitamin D3 analog developed in Japan, has attracted attention as an effective osteoporotic therapeutic drug. However, because ELD leads to greater calcium absorption than does conventional active vitamin D3, it has yet to be used in patients with renal insufficiency. Therefore, we evaluated the efficacy and safety of ELD treatment in 27 postmenopausal women receiving maintenance dialysis in our institution and underwent ELD treatment (starting at 0.5 μg/day) for 6 months. The mean serum albumin-corrected calcium (Caalb) level was significantly increased following treatment (9.01 ± 0.60 before versus 9.56 ± 0.55 after treatment, mean ± SD). Severe hypercalcemia was prevented through cessation or adjustment of the dosage of calcium-containing phosphate binders or existing active vitamin D. The mean serum phosphorus and intact parathyroid hormone levels were well-controlled throughout. The median levels of bone turnover markers, bone-specific alkaline phosphatase and tartrate-resistant acid phosphatase-5b were significantly decreased. The mean lumbar spine bone mineral density (BMD) was increased, a significant difference being observed in age-matched Z-scores (-0.60 ± 1.6 versus -0.36 ± 1.5, p = 0.018). The average change in lumbar spine BMD after ELD treatment was 3.10%, and in patients with a T-score of <-4.0, it was 5.63%. There was no effect on forearm BMD. Although this study is based on short-term observation in a single institution, our results suggest that ELD could be used to increase bone density in dialysis patients.

Clinical significance of sIL-2R levels in B-cell lymphomas.

Elevated soluble interleukin-2 receptor (sIL-2R) in sera is observed in patients with malignant lymphoma (ML). Therefore, sIL-2R is commonly used as a diagnostic and prognostic marker for ML, but the mechanisms responsible for the increase in sIL-2R levels in patients with B-cell lymphomas have not yet been elucidated. We first hypothesized that lymphoma cells expressing IL-2R and some proteinases such as matrix metalloproteinases (MMPs) in the tumor microenvironment can give rise to increased sIL-2R in sera. However, flow cytometric studies revealed that few lymphoma cells expressed IL-2R α chain (CD25) in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL), and most CD25-expressing cells in the tumor were T-cells. Distinct correlations between CD25 expression on B-lymphoma cells and sIL-2R levels were not observed. We then confirmed that MMP-9 plays an important role in producing sIL-2R in functional studies. Immunohistochemical (IHC) analysis also revealed that MMP-9 is mainly derived from tumor-associated macrophages (TAMs). We therefore evaluated the number of CD68 and CD163 positive macrophages in the tumor microenvironment using IHC analysis. A positive correlation between the levels of sIL-2R in sera and the numbers of CD68 positive macrophages in the tumor microenvironment was confirmed in FL and extranodal DLBCL. These results may be useful in understanding the pathophysiology of B-cell lymphomas.

Emerging effects of sevelamer in chronic kidney disease.

Sevelamer, a non-absorbable anion exchange resin, is used to control hyperphosphatemia in chronic kidney disease (CKD) by binding to dietary phosphate in the gastrointestinal tract. Lipid-lowering effect is a widely recognized pleiotropic effect of sevelamer. In addition, many studies have reported that sevelamer leads to reduced vascular calcification compared with calcium-containing phosphate binders, which is attributed to the improved lipid profiles and decreased calcium load. In addition, recent studies have suggested novel pleiotropic effects on bone structure, inflammation, oxidative stress, anemia, fetuin-A, and trace element metabolism in CKD patients. All of these effects have the potential to suppress the development/progression of cardiovascular lesions and reduce mortality. This review summarizes novel findings from recent studies and discusses the potential pleiotropic effects of sevelamer on non-traditional cardiovascular risk factors in CKD patients.

Review of renal carcinoma with t(6;11)(p21;q12) with focus on clinical and pathobiological aspects.

Recently, a new category of MiTF/TFE family translocation carcinomas of the kidney has been proposed. This category includes Xp11.2 renal cell carcinoma (RCC) and the t(6;11) RCC. These tumors share clinical, morphological, immunohistochemical and molecular genetic features. In this article, we review t(6;11) RCC. This tumor predominantly affects children and young adults. Macroscopically, the tumor generally forms a well circumscribed mass. Satellite nodules may be observed. Histologically, the tumor comprises large cells and small cells surrounded by basement membrane material. Immunohistochemically, tumor cells show nuclear immunolabeling for TFEB and usually express Cathepsin-K in the cytoplasm. Karyotyping detects the rearrangement between chromosome 6p21 and chromosome 11q12. Alpha-TFEB fusion can be detected by reverse transcriptase polymerase chain reaction (RT-PCR) or fluorescence in situ hybridization (FISH). Most cases affecting children and young adults seem to be indolent, but some adult cases have presented with metastasis or caused death. As previously reported cases remain limited to date, further examination in a large scale study will be needed in order to elucidate clinical behavior and molecular characteristics.

Splenectomy followed by administration of rituximab is useful to treat a patient with hairy cell leukemia-variant.

Beneficial effects of combination therapy of intradialytic parenteral nutrition and oral L-carnitine administration.

Lung involvement at initial presentation in blastic plasmacytoid dendritic cell neoplasm lacking cutaneous lesion.

Clinical factors associated with serum copper levels and potential effect of sevelamer in hemodialysis patients.

Copper is an essential mineral nutrient for humans. Serum copper levels of hemodialysis patients are higher than those of healthy subjects, but it remains to be elucidated whether increased serum copper may have harmful effects. In addition, a recent in vitro study has shown that sevelamer can adsorb copper. In the present study, we searched for clinical factors associated with serum copper levels in hemodialysis patients.

A case of mediastinal lymph node carcinoma of unknown primary site treated with docetaxel and cisplatin with concurrent thoracic radiation therapy.

Mediastinal lymph node carcinoma of unknown primary site is rare and may have a better prognosis if extensive treatment is performed. Case, A 69-year-old-male presented with a persistent cough. Chest computed tomography (CT) demonstrated a large tumor 9.5 × 8.2 cm, in the mediastinum, compressing the right main bronchus, the right pulmonary artery, and the superior vena cava. Because fiberoptic bronchoscopy was insufficient for diagnosis, mediastinoscopic tumor biopsy under general anesthesia was undertaken. Histological examination revealed adenocarcinoma. Extensive examinations revealed no other neoplastic lesion except in the mediastinum. Mediastinal lymph node carcinoma of unknown primary site was diagnosed. The patient was treated with docetaxel and cisplatin with concurrent thoracic radiation therapy. A month after the start of chemoradiotherapy, the mediastinal tumor regressed markedly. The patient remained free of symptoms without regrowth of the primary site. Exploration of the body showed no further abnormalities 20 months after disease onset.

Potential influence of sevelamer hydrochloride on responsiveness to erythropoiesis-stimulating agents in haemodialysis patients.

Vitamin D analogues, cinacalcet, and sevelamer play pivotal roles in the management of chronic kidney disease-mineral bone disorder, and are noted to have pleiotropic effects. We examined whether these agents might be associated with the responsiveness to erythropoiesis-stimulating agents (ESA).

Germline alterations in the CDH1 gene in familial gastric cancer in the Japanese population.

Germline point or small frameshift mutations of the CDH1 (E-cadherin) gene are known to cause familial gastric cancer (FGC), but the frequency of CDH1 mutations is low in Japanese patients with FGC. Because recent studies have reported germline large genomic deletions of CDH1 in European and Canadian patients with FGC, in the present study we examined DNA samples from 13 Japanese patients with FGC to determine whether similar germline changes were present in CDH1 in this population. Using a sequencing analysis, a 1-bp deletion (c.1212delC), leading to the production of a truncated protein (p.Asn405IlefsX12), was found in an FGC family; immunohistochemical analysis revealed the loss of CDH1 protein expression in the tumors in this family. Using a combination of multiplex ligation-dependent probe amplification (MLPA) and RT-PCR analyses, we also found a large genomic deletion (c.164-?_387+?del), leading to the loss of exon 3 and the production of a truncated protein (p.Val55GlyfsX38), in another FGC family. The functional effects of the detected mutations were examined using a slow aggregation assay. Significant impairment of cell-cell adhesion was detected in CHO-K1 cells expressing Ile405fsX12- and Gly55fsX38-type CDH1 compared with cells expressing wild-type CDH1. Our results suggest that the p.Asn405IlefsX12 and p.Val55GlyfsX38 mutations of the CDH1 gene contribute to carcinogenesis in patients with FGC. This is the first report of CDH1 germline truncating mutations in Japanese patients with FGC. Screening for large germline rearrangements should be included in CDH1 genetic testing for FGC.

Giant granulocytic sarcoma of the vagina concurrent with acute myeloid leukemia with t(8;21)(q22;q22) translocation.

Human endogenous retrovirus-R Env glycoprotein as possible autoantigen in autoimmune disease.

It has long been discussed whether endogenous retroviruses (ERVs) are involved in the pathogenesis of autoimmune diseases. Among various human endogenous retroviruses (HERVs), we have focused on HERV-R. To investigate the biological roles of HERV-R, we earlier established transgenic rats carrying the full sequence of the viral genome. In these HERV-R rats, however, no disease occurred. Another trigger that induces autoimmunity may be essential for the recognition of HERV-R products by the immune system. Thus, in this study, we mated HERV-R rats with env-pX rats (transgenic rats carrying the env-pX gene of human T cell leukemia virus type I) that develop autoimmune diseases, and generated double transgenic (DTG) rats. In DTG rats, autoimmune diseases occurred similarly in env-pX rats. Interestingly, deposition of rat IgM but not IgG was observed on the glomerular endothelial cells. Such IgM deposition was never seen in the parental HERV-R or env-pX rats. We considered that in situ formation of immune complexes consisted of the HERV-R env glycoprotein and anti-HERV-R env IgM antibodies (Abs) in DTG rats, according to the following evidence: (1) No dense deposit, representing deposition of circulating immune complexes, was seen on glomerular endothelial cells. (2) IgM Abs reactive with HERV-R env glycoprotein were generated in the serum. (3) HERV-R env glycoprotein was expressed in the kidney, specifically on glomerular endothelial cells. (4) IgM deposition was partly colocalized with the HERV-R env glycoprotein on the glomeruli. These findings strongly suggest that the HERV-R env glycoprotein is recognized as an autoantigen in the host with autoimmune diseases.

Angioimmunoblastic T-cell lymphoma complicated with EBV-associated B-cell lymphoma.

A 71-year-old man with high fever and enlargement of the bilateral submandibular, cervical and inguinal lymph nodes was hospitalized at Hiroshima University Hospital. The immunohistochemical and pathologic findings from the biopsy specimens led to the diagnosis of angioimmunoblastic T-cell lymphoma (AILT) with a cluster of CD20-positive cells. Flow cytometry analysis by two-color staining did not reveal any neoplastic B cells. Southern blot analysis showed rearrangement of both the IgH gene and the TCR gene. Furthermore, PCR of the IgH gene using DNA extracted from purified CD19-positive cells from the lymph nodes showed a monoclonal band, and it was different from that of purified CD138-positive cells from the bone marrow. Furthermore, monoclonal Epstein-Barr virus (EBV) infection was detected with PCR using the SL18 and SL19 primers of the LMP-1 gene. Numerous EBER-positive cells were detected diffusely in the lymph nodes. These findings indicated a diagnosis of angioimmunoblastic T-cell lymphoma complicated with EBV-associated B-cell lymphoma, and that immunodeficiency in AILT led to an expansion of EBV infected B-cells.

Study on the Wnt/beta-catenin pathway in autosomal dominant polycystic kidney disease--a cytobiological evaluation of pkd1 gene.