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Murata T.,Osaka Saiseikai Nakatsu Hospital | Murata T.,Osaka University | Mizushima H.,Osaka University | Chinen I.,Osaka University | And 9 more authors.
Cancer Research | Year: 2011

Tumor stroma drives the growth and progression of cancers. A heparin-binding epidermal growth factor-like growth factor, HB-EGF, is an EGF receptor ligand that stimulates cell growth in an autocrine or paracrine fashion. While elevated expression of HB-EGF in cancer cells and its contribution to tumor progression are well documented, the effects of HB-EGF expression in the tumor stroma have not been clarified. Here, we show that HB-EGF is expressed in stromal fibroblasts where it promotes cancer cell proliferation. In uterine cervical cancers, HB-EGF was detected immunohistochemically in the stroma proximal to the cancer epithelium. Proliferation of cervical cancer cells in vitro was enhanced by coculture with fibroblasts isolated from tumor tissues of patients with cervical cancer. Inhibition of HB-EGF function or treatment with platelet-derived growth factor (PDGF) inhibitors abrogated cancer cell growth enhanced by cervical cancer-associated fibroblast (CCF) coculture. Furthermore, tumor formation in a mouse xenograft model was enhanced by cotransplantation of CCF or mouse embryonic fibroblasts, but not with embryonic fibroblasts from HB-EGF-deficient mice. Conversely, conditioned medium from cancer cells induced HB-EGF expression in CCF. Mechanistic investigations established that PDGF was the primary factor responsible. Together, our findings indicate that HB-EGF and PDGF reciprocally mediate the interaction of cancer cells with cancer-associated fibroblasts, promoting cancer cell proliferation in a paracrine manner that has implications for novel combinatorial cancer therapies. ©2011 AACR.


Maehara A.,Columbia University Medical Center | Maehara A.,Cardiovascular Research Foundation | Ben-Yehuda O.,Columbia University Medical Center | Ben-Yehuda O.,Cardiovascular Research Foundation | And 13 more authors.
JACC: Cardiovascular Interventions | Year: 2015

Objectives The present study sought to determine whether optical coherence tomography (OCT) guidance results in a degree of stent expansion comparable to that with intravascular ultrasound (IVUS) guidance. Background The most important predictor of adverse outcomes (thrombosis and restenosis) after stent implantation with IVUS guidance is the degree of stent expansion achieved. Methods We compared the relative degree of stent expansion (defined as the minimal stent area divided by the mean of the proximal and distal reference lumen areas) after OCT-guided stenting in patients in the ILUMIEN (Observational Study of Optical Coherence Tomography [OCT] in Patients Undergoing Fractional Flow Reserve [FFR] and Percutaneous Coronary Intervention) (N = 354) and IVUS-guided stenting in patients in the ADAPT-DES (Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents) study (N = 586). Stent expansion was examined in all 940 patients in a covariate-adjusted analysis as well as in 286 propensity-matched pairs (total N = 572). Results In the matched-pair analysis, the degree of stent expansion was not significantly different between OCT and IVUS guidance (median [first, third quartiles] = 72.8% [63.3, 81.3] vs. 70.6% [62.3, 78.8], respectively, p = 0.29). Similarly, after adjustment for baseline differences in the entire population, the degree of stent expansion was also not different between the 2 imaging modalities (p = 0.84). Although a higher prevalence of post-PCI stent malapposition, tissue protrusion, and edge dissections was detected by OCT, the rates of major malapposition, tissue protrusion, and dissections were similar after OCT- and IVUS-guided stenting. Conclusions In the present post-hoc analysis of 2 prospective studies, OCT and IVUS guidance resulted in a comparable degree of stent expansion. Randomized trials are warranted to compare the outcomes of OCT- and IVUS-guided coronary stent implantation. © 2015 American College of Cardiology Foundation


PubMed | Toyohashi Municipal Hospital, Fukushima Medical University, Osaka Saiseikai Nakatsu Hospital, Tohoku University and 7 more.
Type: | Journal: Journal of gastroenterology | Year: 2017

The worlds first diagnostic criteria for early CP were proposed in 2009 in Japan. This study aimed to clarify the clinico-epidemiological features of early CP in Japan.Patients with early CP who were diagnosed according to the diagnostic criteria for early CP and had visited the selected hospitals in 2011 were surveyed. The study consisted of two-stage surveys: the number of patients with early CP was estimated by the first questionnaire and their clinical features were assessed by the second questionnaire.The estimated number of early CP patients was 5410 (95% confidence interval 3675-6945), with an overall prevalence of 4.2 per 100,000 persons. The number of patients who were newly diagnosed with early CP was estimated to be 1330 (95% confidence interval 1058-1602), with an annual incidence of 1.0 per 100,000 persons. Detailed clinical information was obtained in 151 patients in the second survey. The male-to-female sex ratio was 1.32:1. The mean age was 60.4 and the mean age at disease onset was 55.4. Idiopathic (47.7%) and alcoholic (45.0%) were the two most common etiologies. Proportions of female and idiopathic cases were higher in early CP than in definite CP. Hyperechoic foci without shadowing and stranding were the most common findings on endoscopic ultrasonography. The clinical profiles of early CP patients who showed lobularity with honeycombing on endoscopic ultrasonography or previous episodes of acute pancreatitis were similar to those of definite CP patients.We clarified the current status of early CP in Japan.


Okamoto Y.,Kyoto University | Yamamoto T.,Osaka Saiseikai Nakatsu Hospital | Kalaria R.N.,Northumbria University | Senzaki H.,Osaka Saiseikai Nakatsu Hospital | And 9 more authors.
Acta Neuropathologica | Year: 2012

Cortical microinfarcts (CMIs) observed in brains of patients with Alzheimer's disease tend to be located close to vessels afflicted with cerebral amyloid angiopathy (CAA). CMIs in Alzheimer's disease are preferentially distributed in the arterial borderzone, an area most vulnerable to hypoperfusion. However, the causal association between CAA and CMIs remains to be elucidated. This study consists of two parts: (1) an observational study using postmortem human brains (n = 31) to determine the association between CAA and CMIs, and (2) an experimental study to determine whether hypoperfusion worsens CAA and induces CMIs in a CAA mouse model. In postmortem human brains, the density of CMIs was 0.113/cm 2 in mild, 0.584/cm 2 in moderate, and 4.370/cm 2 in severe CAA groups with a positive linear correlation (r = 0.6736, p < 0.0001). Multivariate analysis revealed that, among seven variables (age, disease, senile plaques, neurofibrillary tangles, CAA, atherosclerosis and white matter damage), only the severity of CAA was a significant multivariate predictor of CMIs (p = 0.0022). Consistent with the data from human brains, CAA model mice following chronic cerebral hypoperfusion due to bilateral common carotid artery stenosis induced with 0.18-mm diameter microcoils showed accelerated deposition of leptomeningeal amyloid β (Aβ) with a subset of them developing microinfarcts. In contrast, the CAA mice without hypoperfusion exhibited very few leptomeningeal Aβ depositions and no microinfarcts by 32 weeks of age. Following 12 weeks of hypoperfusion, cerebral blood flow decreased by 26% in CAA mice and by 15% in wild-type mice, suggesting impaired microvascular function due to perivascular Aβ accumulation after hypoperfusion. Our results suggest that cerebral hypoperfusion accelerates CAA, and thus promotes CMIs. © 2011 The Author(s).


Fujita H.,Osaka Saiseikai Nakatsu Hospital
Journal of applied clinical medical physics / American College of Medical Physics | Year: 2011

The aim of the present study was to evaluate the clinical efficacy of the single-shot dual-energy subtraction technique for obtaining portal images. We prepared two storage phosphor plates for this study. A 1 mm thick tungsten sheet was placed between the two storage phosphor plates. A single use of the double-exposure technique provides two portal images simultaneously (i.e., a standard image and a low-contrast image), using the same patient position and with no additional radiation delivered to the patient. A bone-enhanced image is created by image subtraction between these two images. For evaluation of clinical efficacy, three treatment sites--the brain, lung, and pelvis--were imaged. Ten sets of images were obtained for each site, and five landmarks were selected for each treatment site. The visibility of each landmark and the ease of overall verification for the selected treatment sites were assessed separately for the standard and bone-enhanced images. Four observers consisting of one radiation oncologist and three radiation therapists participated in the present study. For most of the landmarks studied, the bone-enhanced images were significantly superior to the standard images. Regarding the ease of overall verification, the bone-enhanced images were significantly superior to the standard images at all sites. The p-values of mean rating for the brain, lung, and pelvis were 0.002, 0.012, and 0.003, respectively. The bone-enhanced images obtained using our technique increased the image quality in terms of bone visibility, and are considered useful for routine clinical practice.


Takeoka Y.,Osaka Saiseikai Nakatsu Hospital
[Rinshō ketsueki] The Japanese journal of clinical hematology | Year: 2011

Intravascular large B-cell lymphoma (IVLBCL) is a rare form of non-Hodgkin's lymphoma characterized by a proliferation of tumor cells within the lumina of small to medium-sized vessels. Because there are few or no concomitant solid lesions, a diagnosis of IVLBCL usually cannot be established by CT or MR imaging. Herein, we describe a case of IVLBCL involving the uterus, in which (18)F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) was useful for diagnosis. A 47-year-old woman was referred to our hospital because of fever and anemia. Laboratory examination demonstrated anemia and thrombocytopenia. Bone marrow aspiration and biopsy showed hemophagocytosis without involvement of lymphoma cells. Random skin biopsy did not demonstrate lymphoma involvement. FDG-PET/CT imaging showed FDG accumulation in the uterus. MR imaging demonstrated uterine leiomyoma only. Based on these findings, uterine endometrial biopsy was performed and histological diagnosis of IVLBCL involving the uterus was established. She received 6 courses of R-CHOP therapy and high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation. At present, she remains in complete remission after 33 months.


Hamaoka M.,Osaka University | Chinen I.,Osaka University | Murata T.,Osaka Saiseikai Nakatsu Hospital | Takashima S.,Osaka University | And 2 more authors.
Journal of Biochemistry | Year: 2010

HB-EGF is a member of the EGF family of growth factors that bind and activate the EGF receptor. HB-EGF is synthesized as a membrane-anchored protein (proHB-EGF), and then proteolytically cleaved, resulting in the mitogenically active soluble form. ProHB-EGF functions as the receptor for the diphtheria toxin (DT). HB-EGF plays pivotal roles in pathophysiological processes, including cancer. Monoclonal antibodies (mAbs) specific for HB-EGF could be an important tool in HB-EGF research. However, few such mAbs have been established to date. In this study, we newly generated seven clones of hybridoma-derived mAbs by immunizing HB-EGF null mice with recombinant human HB-EGF protein. All mAbs specifically bound to human HB-EGF but not to mouse HB-EGF. Epitope mapping analysis showed that most of the mAbs recognized the EGF-like domain. Although none of the newly isolated mAbs directly inhibited the mitogenic activity of HB-EGF for EGFR-expressing cells, some strongly inhibited DT-binding. Interestingly, some of the mAbs efficiently inhibited ectodomain shedding of proHB-EGF, and consequently prevented the cell growth of the EGFR-expressing cells in a co-culture system with proHB-EGF-expressing cells. Hence, these new anti-HB-EGF mAbs may advance clinical as well as basic research on HB-EGF. © 2010 The Authors.


Nishimura H.,Osaka Saiseikai Nakatsu Hospital
Nippon rinsho. Japanese journal of clinical medicine | Year: 2011

In type 2 diabetes, macroangiopathy manifests as atherosclerosis like in nondiabetic patients, characterized by formation of plaques that follows in stages but with an accelerated course due to the several risk factors. Atherosclerosis in diabetes begins earlier, is more markedly pronounced and progresses more rapidly. It is still a debated question whether antidiabetic therapy to target normal glycated hemoglobin levels would reduce cardiovascular events in patients with advanced type 2 diabetes. New findings result from ACCORD Study reveal that microvascular and macrovascular effects of intensive glucose lowering have to be considered separately. On the other hand, our NICE Study yielded better cardiovascular outcomes for those patients with intensive glucose-lowering therapy using rapid-acting insulin analogue reducing postprandial glucose levels with less hypoglycemia.


In total hip arthroplasty (THA) for dysplastic hip osteoarthritis, bony deformity makes it difficult to identify the correct cup height and medialization. The authors developed a new technique for registration and navigation of cup position for dysplastic hips using an imageless navigation system. Eighty dysplastic hips (Crowe type I, n=58; type II, n=18; type III, n=4) underwent THA. Thirty-four hips were operated on while in the supine position and 46 hips were operated on while in the lateral position. Before capsulectomy, the anterior pelvic plane and the position of the femur were registered. After exposure of the acetabulum, the teardrop, posterior rim, and medial wall of the acetabulum were registered. Then the cup height, cup medialization, cup inclination, anteversion, and leg lengthening were navigated. The difference between the navigated and radiographic cup heights was 4.5 ± 4.0 mm, the difference in cup medialization was 3.0 ± 2.5 mm, the difference in cup inclination was 4.3° ± 3.1°, the difference in cup anteversion was 5.5° ± 3.8°, and the difference in leg lengthening was 3.7 ± 3.0 mm. Comparison of the first 20 cases with the last 20 cases showed that the accuracy of cup medialization was significantly improved. These differences were not affected by Crowe type or surgical position. Because the correct cup height and medialization are key issues in THA for dysplastic hip osteoarthritis, the accuracy of cup height and medialization in this imageless navigation system were acceptable for clinical application. Copyright 2012, SLACK Incorporated.


Oonishi H.,Tominaga Hospital | Ohashi H.,Osaka Saiseikai Nakatsu Hospital | Kawahara I.,Tominaga Hospital
CiOS Clinics in Orthopedic Surgery | Year: 2016

Background: To augment cement-bone fixation, Dr. Hironobu Oonishi attempted additional physicochemical bonding through interposition of osteoconductive crystal hydroxyapatite (HA) granules at the cement-bone interface in 1982. He first used the interface bioactive bone cement (IBBC) technique in 12 selected patients (12 hips) in 1982 (first stage) and followed them for 2 years. In 1985, the technique was applied in 25 total hip arthroplasty (THA) patients (second stage) and the effects were investigated by comparing the side with the IBBC technique and the other side without the IBBC technique. He has employed this technique in all THA patients since 1987 (third stage). Methods: In the IBBC technique, HA granules (2 to 3 g) were smeared on the bone surface just before the acetabular and femoral components were cemented. In the first stage, 12 hips were operated using the IBBC technique in 1982. In the second stage, THA was performed without the IBBC technique on one side and with the IBBC technique on the other side within 1 year in 25 patients. In the third stage, THA was performed with the IBBC technique in 285 hips in 1987. Results: In the first stage patients, implant loosening was not detected at 30 years after operation. In the second stage patients, revision was required in 7 hips without the IBBC technique due to cup loosening (5 hips) and stem loosening (2 hips), whereas no hip was revised after THA with the IBBC technique at 26 years after operation. In the third stage patients, the incidence of radiolucent lines and osteolysis was very few at 25 years after operation. Conclusions: The long-term follow-up of THA performed around the inception of the IBBC technique has revealed low incidences of radiolucent lines, osteolysis, and revision surgery. © 2016 by The Korean Orthopaedic Association.

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