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Biomedical subjects

Hisao Ito

Publications and source records attributed to Hisao Ito.

At least 19 recordsLinked to original sources

ARPP protein is selectively expressed in renal oncocytoma, but rarely in renal cell carcinomas.

We have recently isolated a gene, Ankyrin-repeated protein with a proline-rich region (ARPP), that is highly expressed in the skeletal and cardiac muscle. Our previous immunohistochemical analysis revealed that ARPP expression was augmented in rhabdomyosarcoma but scarcely detectable in leiomyosarcoma, showing that ARPP is a useful marker for rhabdomyosarcoma. In the present study, we generated the anti-ARPP monoclonal antibody, YAS11, immunoreactive with the N-terminal region (amino-acids residues 1-145) of the ARPP protein. Further, we immunohistochemically analyzed 100 renal tumors including 14 oncocytomas, and 86 renal cell carcinomas (RCCs). We found that ARPP was highly expressed in 12 of the 14 (85.7%) oncocytomas, but was detectable in only four of the 86 (4.7%) RCCs. Interestingly, ARPP was not detected in any of 11 chromophobe RCCs, suggesting that ARPP may be useful for differential diagnosis between oncocytoma and chromophobe RCC. Furthermore, we found that ARPP was selectively expressed in part of the distal renal tubule in normal kidney. Immunoelectron microscopy with anti-ARPP antibody revealed that ARPP was localized in mitochondria and nuclei in both the normal distal renal tubule and oncocytoma, suggesting that oncocytoma may be derived from the distal nephron, and probably from part of the distal renal tubule.

Adenoma, Oxyphilic↗

Phase I study of oral S-1 and concurrent radiotherapy in patients with unresectable locally advanced pancreatic cancer.

PURPOSE: The primary objective of this study was to determine the maximum-tolerated dose (MTD) of S-1, an oral fluoropyrimidine derivative, with concurrent radiotherapy in patients with unresectable locally advanced pancreatic cancer. METHODS AND MATERIALS: Patients with histopathologically proven, unresectable, locally advanced pancreatic cancer were eligible. Radiotherapy was delivered in 1.8 Gy daily fractions to a total dose of 50.4 Gy over 5.5 weeks. S-1 was administered orally twice a day from Day 1 to 14 and 22 to 35 at escalating doses from 60 to 80 mg/m(2)/day. RESULTS: Sixteen patients were enrolled in this study. Three patients received S-1 at 60 mg/m(2)/day, 3 at 70 mg/m(2)/day, and 10 at 80 mg/m(2)/day. Though 1 patient at the final dose level (80 mg/m(2)/day) experienced a dose limiting toxicity (biliary infection with Grade 3 neutropenia), the MTD was not reached in this study. The most common toxicities were anorexia and leukocytopenia, with Grade 3 toxicity occurring in 31% and 6.3% of the patients, respectively. CONCLUSIONS: The recommended dose of S-1 with concurrent radiotherapy was determined to be 80 mg/m(2)/day from Day 1 to 14 and 22 to 35 in patients with locally advanced pancreatic cancer. Oral S-1 and radiotherapy is well tolerated and feasible and should be further investigated.

Aged↗

Characterization of a unique mutant lysE gene, originating from Corynebacterium glutamicum, encoding a product that induces L-lysine production in Methylophilus methylotrophus.

lysE24 is an allele of lysE encoding an L-lysine exporter of Corynebacterium glutamicum. The mutant gene is able to induce L-lysine production in Methylophilus methylotrophus. Although lysE24 has a mutation in the middle of lysE that results in chain termination, the entire lysE locus, including the region downstream of the short open reading frame, is necessary for L-lysine production. We propose that separate polypeptides are synthesized from the lysE24 locus due to reinitiation of translation utilizing an existing start codon beyond the site of the frameshift, and present evidence that translational coupling is required to form the functional lysE24 product. In addition, expression of lysE24 induces L-lysine production in another methylotroph, Methylobacillus glycogenes. These data suggest that the lysE24 product is a split protein and that this curious feature might be a structure necessary for its functioning in certain obligate gram-negative methylotrophs.

Amino Acid Sequence↗

Accumulation of Epstein-Barr virus (EBV) BMRF1 protein EA-D during latent EBV activation of Burkitt's lymphoma cell line Raji.

As a new model to elucidate molecular mechanisms in Epstein-Barr virus (EBV) activation, we tested the tetracycline-inducible (Tet-On)/BZLF1-oriP plasmid system in Raji cells. Cells transfected with this Tet-On plasmid did not activate EBV by doxycycline and surprisingly EBV latency was disrupted with large amounts of BMRF1 protein (EA-D) being accumulated in the cells. Brilliant EA-D fluorescence was markedly condensed in small sized cells, intra-cellular vesicles, and extra-cellular particles. Scanning electron microscopy demonstrated the extra-cellular particles to be covered with a membrane. EA-D molecules of 58, 50, 48, and 44kDa were expressed in the cells. The high (58 and 50kDa) and low (48 and 44kDa) EA-D molecules appeared in the early and late stages, respectively. Low EA-D molecules were detected mostly in EA-D positive cells separated into the heaviest density layer of a discontinuous Percoll gradient. Such molecules could be created from high EA-D molecules by protein phosphatase treatment. The EA-D molecules that appeared similar were detected in EBV-activated P3HR-1 and Akata cells. Several hypotheses concerning the accumulation of EA-D molecules of various polymorphic forms and their phosphorylation/dephosphorylation in this model system are presented, with possible biological and clinical relevance.

Antigens, Viral↗

Repair of potentially lethal damage in normal cells and ataxia telangiectasia cells; consideration of non-homologous end-joining.

When cell lines are held in a quiescent state after irradiation, survival rates are greater than those from cells that are stimulated to grow immediately after irradiation. These differences in survival rates correspond to rates of potentially lethal damage repair. The effects of confluent holding recovery after gamma-irradiation were investigated using normal human fibroblasts (AG1522) and ataxia telangiectasia fibroblasts (GM02052). Calyculin-A-induced premature chromosome condensation and fluorescent in situ hybridization were applied to study G2/M chromosomal aberrations. Survival results indicated normal capacity for PLDR in AG1522 cells but that PLDR was extremely compromised in GM02052 cells. The chromosomal aberration frequency decreased when AG1522 cells were allowed to repair for 24-h, whereas 24-hour incubation had little effect on the aberration frequency in GM02052 cells. Since the main mechanism for dsbs repair during G0/G1 phases of the cells cycle involve the non-homologous end-joining (NHEJ) process, our study indicates that for AG1522 cells the NHEJ repair process is more likely to induce accurate chromosome repair under quiescent G0 conditions than proliferating G1 phase, while in GM02052 cells the fidelity of NHEJ is similarly defective at either cell cycle phase. Reduced fidelity of NHEJ may be responsible for PLDR defect and its hyper-radiosensitivity in A-T cells.

Ataxia Telangiectasia↗

Enhancement of SPHK1 in vitro by carbon ion irradiation in oral squamous cell carcinoma.

PURPOSE: The purpose of this study was to assess the gene expression changes in oral squamous cell carcinoma (OSCC) cells after carbon ion irradiation. METHODS AND MATERIALS: Three OSCC cell lines (HSC2, Ca9-22, and HSC3) were irradiated with accelerated carbon ion beams or X-rays using three different doses. The cellular sensitivities were determined by clonogenic survival assay. To identify genes the expression of which is influenced by carbon ion irradiation in a dose-dependent manner, we performed Affymetrix GeneChip analysis with HG-U133 plus 2.0 arrays containing 54,675 probe sets. The identified genes were analyzed using the Ingenuity Pathway Analysis Tool to investigate the functional network and gene ontology. Changes in mRNA expression in the genes were assessed by real-time reverse transcriptase-polymerase chain reaction. RESULTS: We identified 98 genes with expression levels that were altered significantly at least twofold in each of the three carbon-irradiated OSCC cell lines at all dose points compared with nonirradiated control cells. Among these, SPHK1, the expression of which was significantly upregulated by carbon ion irradiation, was modulated little by X-rays. The function of SPHK1 related to cellular growth and proliferation had the highest p value (p = 9.25e-7 to 2.19e-2). Real-time reverse transcriptase-polymerase chain reaction analysis showed significantly elevated SPHK1 expression levels after carbon ion irradiation (p < 0.05), consistent with microarray data. Clonogenic survival assay indicated that carbon ion irradiation could induce cell death in Ca9-22 cells more effectively than X-rays. CONCLUSIONS: Our findings suggest that SPHK1 helps to elucidate the molecular mechanisms and processes underlying the biologic response to carbon ion beams in OSCC.

Adaptor Proteins, Signal Transducing↗

Runt-related transcription factor 3 expression in human oral squamous cell carcinomas; implication for tumor progression and prognosis.

Runt-related transcription factor 3 (RUNX3) is a tumor suppressor factor of gastric cancer and appears to be an important component of the transforming growth factor-beta (TGF-beta)-induced tumor suppression pathway. This study aimed to analyze the expression of the RUNX3 protein in human oral normal epithelia, dysplasia and squamous cell carcinomas (SCCs), comparing it with clinicopathological profiles. Western blot analysis revealed the RUNX3 protein as a single band at 44kDa in oral non-neoplastic mucosa and SCC. The expression of RUNX3 protein was also examined in 10 normal epithelia, 51 dysplasias and 108 oral SCCs. The labeling indices (LIs) of RUNX3, Ki-67, P21, P27 and the apoptotic index (AI) were evaluated using immunohistochemistry and the TUNEL method. The LI of RUNX3 was 7.7+/-1.6 in the normal epithelia, 20.8+/-2.7 in the dysplasias and 9.0+/-1.3 in the SCCs. The LI of RUNX3 was significantly highest in the dysplasias, followed by the SCCs (p<0.05) and normal epithelia (p<0.05). The RUNX3 LI correlated with the histological differentiation of SCCs, being the highest in the well differentiated SCCs (p<0.01). In addition, RUNX3 expression was significantly related to the lower Ki-67 LI, but not to LI of P21 and P27, and AI in the SCCs. The survival rate was significantly lower in the patients with lower RUNX3 expression (<5%) than in those with higher expression (5%) (p<0.05). These results indicate that the expression of RUNX3 is correlated with histological differentiation, and inversely with cellular proliferation of the oral SCCs, and might be a new prognostic marker in the patients with oral SCC.

Biomarkers, Tumor↗

[Assessment of whole body PET/MRI fusion imaging using automated software: usefulness of partial body fusion].

PURPOSE: In this study, we created a whole body fusion image of PET and MRI using automated software for fusion imaging, and assessed the accuracy of the software. MATERIALS AND METHODS: Twenty patients with abnormal FDG-PET findings underwent whole body MRI. Images from both modalities were automatically fused in two ways using software (Fusion Viewer, Nihon Medi-Physics Co., Ltd., Nishinomiya, Japan) with a registration algorithm based on maximum mutual information. One was to create a whole body fusion image at once, named whole body fusion (WBF). The other was to create fusion images of the head and body separately, named partial body fusion (PBF). Two radiologists measured the misregistration between PET and MRI in the fusion images at nine landmarks (brain, cervical spine, chest, heart, liver, right kidney, left kidney, vertebra, base of bladder). RESULTS: When fusion images were created using WBF at once, misregistration was observed in the head and neck area in approximately half of the cases, whereas almost no misregistration was observed in the body. When fusion images were created using PBF, the misregistration in the head and neck areas was significantly smaller than in those using WBF, and misregistration in the body was very small. CONCLUSION: The PBF technique that creates highly accurate whole body PET/MRI fusion images is easy to use and may provide clinically useful information.

Adult↗

Expression of polo-like kinase 1 (PLK1) protein predicts the survival of patients with gastric carcinoma.

OBJECTIVE: To assess the prognostic value of polo-like kinase 1 (PLK1), an important regulator of cell cycle progression, in patients with gastric carcinoma. METHODS: PLK1 expression was determined in 160 gastric carcinoma patients by immunohistochemistry and compared with p53 expression and the proliferating cell nuclear antigen-labeling index (PCNA-LI) to evaluate the effect of PLK1 on tumor progression. Furthermore, PLK mRNA expression was determined in 26 advanced gastric cancer patients by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: PLK mRNA expression was detected in 25 (96.2%) patients by RT-PCR. Immunohistochemical staining revealed PLK1 expression in 84 (52.5%) patients. There were no significant relationships between PLK1 expression and various clinicopathological factors. PLK1 expression was significantly correlated with the PCNA-LI, but not p53 expression. The prognosis of patients with PLK1-positive tumors was significantly worse than that of patients with PLK1-negative tumors (p < 0.05). Moreover, multivariate analysis revealed that PLK1 expression was an independent prognostic factor. Patients with PLK1-positive and high PCNA-LI tumors showed a significantly poorer prognosis than patients with PLK1-negative and/or low PCNA-LI tumors. Furthermore, the prognosis of patients with PLK1- and p53-positive tumors was significantly worse than that of patients with PLK1- and p53-negative or PLK1-negative and p53-positive tumors. CONCLUSION: PLK1 expression may be a critical indicator of a poor prognosis in patients with gastric carcinoma.

Biomarkers, Tumor↗

Interleukin-10 expression significantly correlates with minor CD8+ T-cell infiltration and high microvessel density in patients with gastric cancer.

We aimed to investigate the relationships between interleukin-10 (IL-10) expression and both the clinicopathological findings and prognoses in patients with gastric cancer and to compare IL-10 expression with microvessel (MV) density and CD8+ T lymphocyte infiltration to evaluate its effects on angiogenesis and immune responses in gastric cancer. IL-10 expression was determined in gastric cancer patients by reverse transcription-polymerase chain reaction (RT-PCR) or immunohistochemical procedures. Two of 7 normal gastric tissues showed IL-10 mRNA expression, while its expressions were confirmed in all advanced gastric carcinoma tissues examined (n=11) by RT-PCR. Immunohistochemical staining demonstrated that IL-10 expression was detected in 52 (47.7%) of 109 cases. There was a close correlation between IL-10 expression and MV density. IL-10 expression inversely correlated with CD8+ T-lymphocyte infiltration. The prognoses of patients whose tumors expressed IL-10 were significantly worse than those of patients whose tumors did not express IL-10. Multivariate analysis indicated IL-10 expression was an independent prognostic factor. IL-10 might be associated with tumor progression by stimulating angiogenesis and suppressing immune responses in gastric cancer.

Adenocarcinoma↗

Extranodal natural killer/T-cell lymphoma, nasal type: the significance of radiotherapeutic parameters.

BACKGROUND: The objective of this study was to investigate the correlation between local recurrence and radiotherapeutic parameters, including dose and RT radiotherapy (RT) field. METHODS: The current study included 35 patients who were diagnosed with immunohistochemically confirmed nasal natural killer (NK)/T-cell lymphoma between 1976 and 2004. There were 21 males and 14 females, and they ranged in age from 18 years to 76 years (median, 51 yrs). The primary tumor originated in the nasal cavity in 28 patients, and 32 patients had Stage I disease. Seventeen patients received treatment solely with RT, and the remaining 18 patients received a combination of chemotherapy and RT. The median tumor dose was 50 grays (Gy) (range, 22-60 Gy). Twenty-seven patients received RT to include all macroscopic lesions, all paranasal sinuses, the palate, and the nasopharynx. Eight patients received RT to all macroscopic lesions with generous margins. RESULTS: A complete remission (CR) or a CR/unconfirmed was achieved in 28 patients (80%). The 5-year overall survival (OAS) rate, disease-free survival (DFS) rate, and local control probability (LCP) were 47.3%, 42.9%, and 65.2%, respectively. Patients who received RT only to macroscopic lesions fared less well in terms of LCP (LCP 5 years, 71.9% vs. 41.7%; P=0.007). The difference in RT field also affected both the OAS rate and the DFS rate. Patients who received RT doses>or=50 Gy tended to achieve favorable local control. CONCLUSIONS: In the management of nasal NK/T-cell lymphoma, the RT field affected treatment outcomes. RT doses>or=50 Gy resulted in favorable local control.

Adolescent↗

Prospective trial of radiotherapy for patients 80 years of age or older with squamous cell carcinoma of the thoracic esophagus.

PURPOSE: To assess the safety and efficacy of external beam radiotherapy for elderly patients with esophageal cancer. METHODS AND MATERIALS: A trial testing external beam radiotherapy (66 Gy within 6.5 weeks) as a single-modality treatment was performed for biopsy-proven squamous cell carcinoma of the thoracic esophagus clinically staged as Stage I and IIA (T1-T3N0M0, International Union Against Cancer, 1987) in patients aged > or =80 years. RESULTS: From January 1999 through December 2002, 51 evaluable patients (35 men and 16 women) with a median age of 83 years (range, 80-91 years) were enrolled from 22 institutions. Of the 51 patients, 18 (35%) had Stage T1 and 33 (65%) had Stage T2-T3 disease. Radiotherapy could be completed in 47 patients (92%) within 43-58 days (median, 49). The actuarial incidence of Grade 3 or worse cardiopulmonary complications at 3 years was 26%, with 3 early deaths, and correlated significantly with the size of the anteroposterior radiotherapy portals. The median survival time and overall survival rate at 3 years was 30 months and 39% (95% confidence interval, 25-52%), respectively. CONCLUSION: The results of high-dose radiotherapy in octogenarians are comparable to those in younger patients, but meticulous treatment planning and quality control is required.

Aged, 80 and over↗

Postoperative radiation therapy for carcinoma of the uterine cervix.

Postoperative radiation therapy (PORT) for cervical cancer has been empirically performed for patients with pathologic risk factors for recurrence after surgery. The efficacy of PORT is mainly supported by retrospective studies. Despite convincing evidence demonstrating a reduction in pelvic recurrence rates when PORT is employed, there is no evidence that it eventually improves patient survival. Local recurrence, such as vaginal stump recurrence, is not always fatal if diagnosed earlier. Some patients, unfortunately, may develop distant metastases even after PORT. The positive effects of PORT also may be counterbalanced by increased toxicities that result from combining local therapies. These factors obscure the efficacy of PORT for cervical cancer patients. There has been no consensus on the predictive value of risk factors for recurrence, which renders indication of PORT for early-stage cervical cancer quite variable among institutions. Today, efforts have been made to divide patients into three risk groups based on the combination of risk factors present after radical hysterectomy. In Europe/USA and Japan, however, a fundamental difference exists in the indications for radical surgery, highlighting differences in the concept of PORT; "adjuvant pelvic irradiation for stage IB-IIA patients after complete resection" in Europe/USA and "pelvic irradiation after surgery irrespective of initial clinical stage and surgical margin status" in Japan. Thus, it is questionable whether scientific evidence established in Europe/USA is applicable to Japanese clinical practice. The purpose of this article is to review the role of PORT by interpreting the results of clinical studies.

Combined Modality Therapy↗

Dose-volume factors predicting radiation pneumonitis in patients receiving salvage radiotherapy for postlobectomy locoregional recurrent non-small-cell lung cancer.

BACKGROUND: The correlation between treatment-related factors and lung toxicity has not been sufficiently evaluated in salvage radiotherapy. METHODS: Twenty-one patients with recurrent non-small-cell lung cancer (NSCLC) after lobectomy received salvage radiotherapy to a total dose of 46-60 Gy. The effects of radiotherapy parameters on the development of radiation pneumonitis (RP) were examined using dose-volume histograms. RESULTS: Grade 1 RP was observed in 4, grade 2 in 2, and grade 3 in 1 patient. Patients who developed RP had a significantly higher value in V dose (V13, V20) parameters and mean lung dose (MLD) than those who did not develop RP. Concerning G2 or higher RP, 3 patients who developed > or = G2 RP had a significantly higher value in V20, V13, and MLD than the remaining patients with P values of 0.01, 0.015, and 0.016, respectively. The mean V20, V13, and MLD in these 3 patients were 27%, 29.3%, and 14.8 Gy, respectively, whereas the mean V20, V13, and MLD in the remaining 18 patients were 15.8%, 18.3%, and 8.8 Gy, respectively. Three of 6 patients with a V20 > or = 20% developed > or = G2 RP whereas this did not occur in the remaining patients (P = 0.015). Similarly, 3 of 6 patients with a V13 > or = 23% developed > or = G2 RP whereas this did not occur in the remaining patients (P = 0.015). CONCLUSIONS: These data suggest that a somewhat lower V dose value or MLD, as compared with the setting of definitive radiotherapy, could be a surrogate for RP in patients undergoing salvage radiotherapy for recurrent NSCLC.

Aged↗

A case of gastric lymphoma with marked interfractional gastric movement during radiation therapy.

Radiation therapy (RT) with or without chemotherapy has been a widely accepted treatment for patients with localized gastric lymphoma. We encountered a patient with gastric diffuse large B-cell lymphoma, whose stomach volume, and the position and location of the clips that had been endoscopically placed to define the gastric lesions clearly differed considerably at three simulation times. The positions of the clips moved between 5 and 35 mm (mean 24 mm) laterally on simulation films. The mean movement of these clips along the cephalocaudal directions was 8 mm (range 0-15 mm). There have been no published articles which systemically evaluated interfractional gastric motion between each treatment session. Therefore this is an important observation in the management of patients with gastric lymphoma with RT.

Aged↗

Trends in oncological CT imaging: clinical application of multidetector-row CT and 3D-CT imaging.

Computed tomography (CT) plays an essential role in oncological imaging as the modality of screening for malignancies, mapping out the treatment strategy at staging, assessing response to the treatment, and following up patient outcome after the treatment. The advent of multidetector-row CT (MDCT) has brought about dramatic changes in clinical oncological imaging. The very superior temporal and spatial resolution of MDCT has transformed CT imaging from a transaxial cross-sectional technique into an isotropic volume-imaging technique. MDCT facilitates multiphasic contrast-enhanced study for a wide range of body scanning in a single examination, as well as providing flexibility of multidirectional reconstruction and high-quality three-dimensional imaging. With increases in the number of detector rows year by year, systems with 64-detector rows have become commercially available in 2006. The purpose of this article is to review the status of CT imaging in oncological imaging: (1) to outline the impact of MDCT, focusing on oncological imaging and (2) to review the clinical applications of oncological CT imaging with MDCT.

Humans↗

Radiation therapy after breast-conserving surgery.

The authors critically reviewed previous articles concerning the significance of breast irradiation following breast-conserving surgery in terms of the following subject items: indications for breast-conserving therapy, the significance and complications of breast irradiation, the timing of the start of breast irradiation, the significance of boost irradiation, the potential improvement of survival with systemic therapy plus breast irradiation, the significance of axillary dissection, indications and the significance of regional nodal irradiation, accelerated hypofractionated radiotherapy, omission of breast irradiation in low-risk patients, and future directions. In addition, our previously reported results of breast irradiation following breast-conserving surgery at the Keio University Hospital are outlined. Our newly developed tangential irradiation technique directed to the axilla and a recently introduced three-dimensional simulation technique for radiotherapy treatment planning are also presented.

Breast↗