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BACKGROUND Regulatory T cells (Tregs) play important roles in the suppression of immune responses, including antitumor immune responses. C-C chemokine receptor 4 (CCR4) is highly expressed on effector Tregs, and anti-CCR4 antibody is attracting attention as a novel immunotherapeutic agent for solid tumors. This study aimed to evaluate the expression of CCR4-positive Tregs (CCR4+Tregs) in prostate cancer and estimate the clinical potential of CCR4-targeting therapy for prostate cancer. METHODS A total of 15 radical prostatectomy (RP) specimens and 60 biopsy specimens from individuals diagnosed with prostate cancer were analyzed to evaluate the infiltration of CCR4+Tregs in prostate cancer. The relationships between the number of CCR4+Tregs and clinical parameters were investigated in RP and biopsy specimens. Moreover, the total number of Tregs, CCR4+Tregs, and T cells and the ratio of CCR4+Tregs to Tregs and T cells in biopsy specimens were compared between patients with poor prognosis who progressed to castration-resistant prostate cancer (CRPC) within 12 months (n = 13) and those with good prognosis who were stable with hormone-sensitive prostate cancer over 12 months (n = 47). Furthermore, biopsy specimens were divided into two groups: low and high CCR4+Treg expression groups and the prognosis was compared between them. RESULTS There was a higher expression of CCR4+Tregs in RP specimens with a higher (≥8) Gleason score than in those with a lower (

Introduction: The purpose of this study was to investigate the incidence of necrosis and insufficiency fracture of the hip and knee using magnetic resonance imaging (MRI) in renal transplant patients. Methods: We examined 300 consecutive renal transplant patients using MRI of the hips and knees (T1-weighted coronal MRI) preoperatively and at 3 and 6 months postoperatively. Oblique axial-plane T1-weighted MRI and short-tau inversion-recovery T2-weighted MRI were performed parallel to the femoral neck when distinguishing the osteonecrosis of the femoral head (ONFH) from subchondral insufficiency fracture (SIF) of the femoral head was difficult. Results: ONFH was observed in 3 hips (3 cases, 1.0%). Osteonecrosis of the knee was observed in 2 knees (1 case, 0.3%). SIF of the femoral head was observed in 5 hips (3 cases, 1.0%). Bilateral simultaneous onset of SIF of the femoral head was observed in 2 cases (0.7%). Insufficiency fracture of the knee was observed in 2 knees (1 case, 0.3%). Conclusions: When it was difficult to distinguish ONFH from SIF of the femoral head, oblique axial-plane T1-weighted MRI and the short-tau inversion-recovery T2-weighted MRI parallel to the femoral neck were useful to establish the correct diagnosis.

We have reported the usefulness of chondrocyte sheets on articular cartilage repair in animal experiments. Here, we investigated the regenerative effects of EP2 signalling with or without chondrocyte sheets. Forty-five rabbits were used, with six rabbits in each of the six groups and nine rabbits for chondrocytes and synovial cells harvesting to fabricate triple-layered chondrocyte sheets: osteochondral defect only (control, Group A), EP2 agonist (Group B), EP2 antagonist (Group C), chondrocyte sheets (Group D), EP2 agonist and chondrocyte sheets (Group E), and EP2 antagonist and chondrocyte sheets (Group F). After surgery, the weight distribution ratio was measured as an indicator of pain alleviation. Injections of the EP2 agonist or EP2 antagonist were given from 4 weeks after surgery. The rabbits were sacrificed at 12 weeks, and the repaired tissues were evaluated for histology. The weight distribution ratio and International Cartilage Repair Society grading were as follows: Group A: 40.5% ± 0.2%, 14.8 ± 0.5; Group B: 43.4% ± 0.7%, 25.4 ± 0.8; Group C: 38.7% ± 0.7%, 13.7 ± 0.3; Group D: 48.6% ± 0.6%, 40.2 ± 0.5; Group E: 49.1% ± 0.3%, 40.5 ± 0.4; and Group F; 46.8% ± 0.4%, 38.7 ± 0.5. Significant differences in histology and pain alleviation were observed between groups except between Groups A and C, between Groups D and E, and between Groups D and F. These findings show that the intra-articular administration of an EP2 agonist achieved pain alleviation and tissue repair. However, no synergistic effect with chondrocyte sheets was observed.

Background The Japanese Orthopaedic Association (JOA) has been surveying approximately 3000 orthopedic surgery hospitals and clinics with inpatient facilities nationwide to collect information on atypical femoral fractures (AFFs) and patient characteristics since 2010. The present study aims to examine radiographic images and clarify the relationship between radiographic and patient characteristics of patients with AFF and treatment status. Methods The study involved 1996 facilities certified as clinical training sites by the JOA and 912 clinics with inpatient facilities affiliated with the Japanese Clinical Orthopaedic Association (JCOA). Additional clinical data collection and radiographic image review were performed in patients aged 35 years or older who met the American Society for Bone and Mineral Research (ASBMR) case definition for AFF and received treatment at participating facilities registered with JOA in 2013. Radiographic images were evaluated in accordance with the ASBMR case definition. Results Radiographic images of 304 fractures in 304 patients were collected. Among them, 230 fractures were determined to be AFFs. The fracture site was the proximal third in 70 AFFs (30.4%), middle third in 157 AFFs (68.3%), and distal third in 3 AFFs (1.3%). Among patients with AFFs, 173 (75.2%) were treated with bisphosphonates (BPs) and 45 patients (19.6%) were not (unknown in 12 patients). Duration of use was three years or longer in 103 patients (59.5%) and between one and three years in 24 patients (13.9%). Radiographic beaking was observed in 149 fractures (86.1%) in patients treated with BPs and 17 fractures (37.8%) in patients who were not treated with BPs (odds ratio 11.3, 95% CI 5.7–22.3). Conclusions Radiographic beaking was observed more frequently in patients treated with BPs than in patients not treated with BPs.

The present study examined the clinical pharmacokinetics of pazufloxacin in prostate tissue and estimated the probability of target attainment for tissue-specific pharmacodynamic goals related to treating prostatitis using various intravenous dosing regimens. Patients with prostatic hypertrophy received prophylactic infusions of pazufloxacin (500 mg, n = 23; 1000 mg, n = 25) for 0.5 h prior to transurethral prostate resection. Drug concentrations in plasma (0.5–5 h) and prostate tissue (0.5–1.5 h) were measured by high-performance liquid chromatography and used for subsequent noncompartmental and three-compartmental analysis. Monte Carlo simulation was performed to evaluate the probability of target attainment of a specific minimum inhibitory concentration (MIC) in prostate tissue: the proportion that achieved both area under the drug concentration over time curve (AUC)/MIC = 100 and maximum concentration (Cmax)/MIC = 8. Prostatic penetration of pazufloxacin was good with mean Cmax ratios (prostate tissue/plasma) of 0.82–0.99 and for AUC, 0.80–0.98. The probability of reaching target MIC concentrations in prostate tissue was more than 90% for dosing schedules of 0.25 mg/L for 500 mg every 24 h (500 mg daily), 0.5 mg/L for 500 mg every 12 h (1000 mg daily), 1 mg/L for 1000 mg every 24 h (1000 mg daily), and 2 mg/L for 1000 mg every 12 h (2000 mg daily). Importantly, the 2000 mg daily regimen of pazufloxacin produced a profile sufficient to have an antibacterial effect in prostate tissue against clinical isolates of Escherichia coli and Klebsiella pneumonia with MIC values less than 2 mg/L.

The hip placement with a metal-on-metal (MOM) bearing has been used for both surface replacement and total hip arthroplasty (THA). Use of MOM bearing for hip replacement reduces the wear compared to conventional bearings. We prospectively assessed 30 patients who underwent unilateral MOM THA. A control group of 30 patients who underwent metal-on-polyethylene THA using the implants as the other group, except for bearing, were accessed. Blood samples were collected preoperatively and at 3- , 6- , 9- , 12- , 15- , 18- , and 24-month intervals. Changes in mean blood metal ion concentration were compared between the MOM and metal-on-polyethylene groups. A statistically significant positive correlation was observed between blood cobalt and chromium concentrations in all of the patients. The mean blood ion concentrations of the MOM were significantly higher than those of the metal-on-polyethylene. A statistically significant negative correlation was found between maximum blood cobalt concentration and cup version angle. The maximum blood chromium concentrations in the patients who had larger cup version angles were more likely to decrease. We considered that cup version angle is one of the factors that have the greatest effect on blood metal ion concentration, and the target cup version angle that did not induce an increase in blood metal ion concentrations was approximately 20°.

Purpose The purpose of this study was to compare the usefulness of measuring acetabular anterior coverage by tomosynthesis and false profile (FP) radiography. Methods 70 hips in 35 patients who were diagnosed with early stage osteoarthritis of the hip, and 60 hips from 30 healthy volunteers were analysed. Plain FP radiographs were taken, and vertical-centre-anterior margin (FP-VCA) angles were measured. Acetabular anterior coverage was measured in the natural standing position using a tomosynthesis imaging system in the sagittal plane. As with FP radiography, we measured vertical-centre-anterior margin (TS-VCA) angles. Results The median values of the FP-VCA angle, and TS-VCA angle were 43.8°, 54.4°, respectively. The TS-VCA angle was significantly larger than the FP-VCA angle. For FP radiographs, the intraobserver intraclass correlation coefficient (ICC) was 0.68, and the interobserver ICC was 0.79. For tomosynthesis sagittal images, the intraobserver ICC was 0.85, and the interobserver ICC was 0.92. There was a strong positive correlation between the TS-VCA angle and the FP-VCA angle. When the FP-VCA angle was 25°, the TS-VCA angle was 35° in regression analysis. Conclusions Measuring acetabular anterior coverage using sagittal plane tomosynthesis correlates well with FP radiography. Regardless of the presence of acetabular deformities, tomosynthesis demonstrated high reproducibility, simple posture setting, low effective doses, and high versatility. A cut-off value of 35° was useful for the detection of developmental dysplasia of the hip joint using the TS-VCA angle.

We studied the ability of collagen vitrigel material to repair cartilage in vivo when used alone or with transforming growth factor-β (TGF-β). We measured the time course and quantity of TGF-β1 released from the collagen vitrigel in vitro to quantify the controlled release of TGF-β1. Over 14 days, 0.91 ng of TGF-β was released from the collagen vitrigel. Osteochondral defects were made in the femoral trochlear groove in 36 Japanese white rabbits, which were divided into three groups: untreated group (group A), collagen vitrigel-implanted group (group B), and TGF-β1-incorporated collagen vitrigel-implanted group (group C). The weight distribution ratio between the affected and unaffected limbs served as an indicator of pain. Animals were sacrificed at 4 and 12 weeks after surgery, and their tissues were assessed histologically. The weight distribution ratio increased in all groups and did not differ significantly between groups at 12 weeks. Group A needed 6 weeks to attain maximum improvement, and groups B and C showed near-maximum improvement at 4 and 2 weeks, respectively. The International Cartilage Repair Society II score improved significantly in group C relative to the other groups. These findings suggest that sustained, slow release of TGF-β caused early pain mitigation and cartilage repair. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 2592-2602, 2017.

PurposeSeptic arthritis of the hip joint in adults often progresses to recurrent infections that require repeated surgeries for treatment. The purpose of the present study was to assess the risk of a recalcitrant hip infection and the usefulness of musculocutaneous flap transposition.Methods15 adult patients who underwent surgeries for the treatment of hip infections were retrospectively analysed. Patients who recovered from infection by undergoing arthroscopy, open irrigation, debridement, continuous irrigation, resection arthroplasty, and/or the placement of antibiotic-loaded acrylic cement were classified into Group A (n = 10). Patients who showed residual infection after multiple surgeries and ultimately recovered after undergoing musculocutaneous flap transposition were classified into Group B (n = 5). The age at onset, sex, incidence of multi-drug-resistant organisms, incidence of infection at other sites, compromising factors, peak pre-operative C-reactive protein level, and period from onset to initial surgery were compared between groups.ResultsThere was a statistically significant difference in the period from onset to initial surgery (p = 0.024). The infections remained chronic after multiple surgeries in most patients who had complications and/or a poor general or local condition. All of the patients recovered after musculocutaneous flap transposition without the need for additional surgery and did not experience recurrence during the follow-up period in Group B.ConclusionsDelayed diagnosis and/or treatment and compromised host caused recurrent septic arthritis of the hip in adults. Musculocutaneous flap transposition may be a useful method for the treatment of recalcitrant hip infection.

Background With the improvement in postoperative care for renal transplant patients, the number of patients requiring spinal surgery after renal transplantation has been increasing. However, there have been only a few reports describing the results of spinal surgery in renal transplant recipients. In this study, we investigated the results of spine surgery in renal transplant recipients. Methods A total of 37 renal transplant recipients who underwent spinal surgery in our hospital between April 2003 and July 2012 were included in this study. Results Perioperative complications were observed in 6 cases (16.2%). Two of them (5.3%) were general complications including duodenal ulcer and acute renal failure. The other four complications (10.8%) were directly related to surgery, namely, epidural hematoma, neurological deterioration and two surgical site infections. No patient required permanent hemodialysis postoperatively. Twenty-five fusion surgeries were performed and pseudoarthrosis was observed in 3 cases (12.0%). Conclusion Spinal surgery in renal transplant recipients can be performed without major complications or requirement for permanent hemodialysis postoperatively. Our data also showed a high rate of surgical site infection and pseudoarthrosis after fusion surgery.

Docetaxel (DOC) is one of the most effective chemotherapeutic agents against castration‑resistant prostate cancer (CRPC). Despite an impressive initial clinical response, the majority of patients eventually develop resistance to DOC. In tumor metabolism, where tumors preferentially utilize anaerobic metabolism, lactate dehydrogenase (LDH) serves an important role. LDH controls the conversion of pyruvate to lactate, with LDH‑A, one of the predominant isoforms of LDH, controlling this metabolic process. In the present study, the role of LDH‑A in drug resistance of human prostate cancer (PC) was examined by analyzing 4 PC cell lines, including castration‑providing strains PC3, DU145, LNCaP and LN‑CSS (which is a hormone refractory cell line established from LNCaP). Sodium oxamate (SO) was used as a specific LDH‑A inhibitor. Changes in the expression level of LDH‑A were analyzed by western blotting. Cell growth and survival were evaluated with a WST‑1 assay. Cell cycle progression and apoptotic inducibility were evaluated by flow cytometry using propidium iodide and Annexin V staining. LDH expression was strongly associated with DOC sensitivity in PC cells. SO inhibited growth of PC cells, which was considered to be caused by the inhibition of LDH‑A expression. Synergistic cytotoxicity was observed by combining DOC and SO in LN‑CSS cells, but not in LNCaP cells. This combination treatment induced additive cytotoxic effects in PC‑3 and DU145 cells, caused cell cycle arrest in G2‑M phase and increased the number of cells in the sub‑G1 phase of cell cycle in LN‑CSS cells. SO promoted DOC induced apoptosis in LN‑CSS cells, which was partially caused by the inhibition of DOC‑induced increase in LDH‑A expression. The results strongly indicated that LDH‑A serves an important role in DOC resistance in advanced PC cells and inhibition of LDH‑A expression promotes susceptibility to DOC, particularly in CRPC cells. The present study may provide valuable information for developing targeted therapies for CRPC in the future.

Objectives To compare perioperative, oncological and functional outcomes of robot-assisted radical prostatectomy between experienced and novice open radical prostatectomy surgeons in a laparoscopically naive center with a limited caseload. Methods Six surgeons carried out robot-assisted radical prostatectomy in 154 patients, which were divided into the following three groups: group 1 (n = 90), including patients operated on by a surgeon with experience in both open radical prostatectomy and robot-assisted radical prostatectomy; group 2 (n = 36), including patients operated on by two surgeons with experience in open radical prostatectomy only; and group 3 (n = 28), including patients operated on by three surgeons with limited experience in both open radical prostatectomy or robot-assisted radical prostatectomy. Results Groups 2 and 3 did not differ significantly in their median values of external blood loss (P = 0.165) or console time (P = 0.103). Positive surgical margin rates for pT2 patients were also similar in these two groups: 21.2% (7/33) in group 2 and 22.7% (5/22) in group 3 (P = 0.894). Kaplan–Meier analysis showed that 12 months after robot-assisted radical prostatectomy the prostate-specific antigen-free rate for pT2 patients was 96.0% in group 2 and 100% in group 3, but the pad-free continence rate was just 91.0% in group 1, 88.0% in group 2 and 75.5% in group 3 (group 1 vs group 3, P = 0.037; group 2 vs group 3, P = 0.239). The major complication rate after robot-assisted radical prostatectomy was 3.3% (3/90) in group 1, 11.1% (4/36) in group 2 and 17.9% (5/28) in group 3 (group 1 vs group 3, P = 0.008; group 2 vs group 3; P = 0.441). Conclusions Robot-assisted radical prostatectomy offers satisfactory postoperative outcomes even when carried out by surgeons with limited experience in open radical prostatectomy.

Antibiotic-loaded acrylic cement (ALAC) spacers are useful for treatment of infected prostheses in the course of a two-stage revision. Spacers are handmade or are made using a commercial template, with reportedly good treatment outcomes. This study aimed to confirm the usefulness of custom-made ALAC spacers shaped like bipolar hip prostheses using a dental silicone template for treatment of infected hip prostheses, and described their manufacture. This study evaluated 10 patients who underwent two-stage revision for treatment of infected hip prostheses. Custom-made ALAC spacers were used in all patients. Templates were made with dental silicone. We investigated the following in treatment of the infected hip prostheses: bacterial pathogens; antibiotic-cement mixtures; waiting time to revision; dislocation, breakage, and migration of custom-made ALAC spacers; current hip status; progress during follow-up; presence or absence of recurrence; and walking ability. Dislocation, breakage, and migration were not observed in custom-made ALAC spacers. All patients recovered after two-stage revision without additional surgery and showed no recurrence during the follow-up period. Custom-made ALAC spacers shaped like bipolar hip prostheses using a template made of dental silicone may be useful for treatment of infected hip prostheses.

A 61-year-old woman with metastatic renal carcinoma was treated with axitinib as a second-line tyrosine kinase inhibitor. Thirteen days after the treatment, the patient developed reversible posterior leukoencephalopathy syndrome (RPLS). Her symptoms and imaging findings resolved after withdrawal of axitinib, blood pressure control, and administration of glycerin and levetiracetam. RPLS should be kept in mind as a possible rare adverse event after axitinib administration.

A 35-year-old Japanese man presented with a 1-month history of limited flexion and radiating pain in the left middle and ring fingers. A physical examination revealed a hard nodular mass in his left palm. Magnetic resonance imaging showed a 2 × 1.5 × 1 cm mass of low intensity on T1-weighted images and high intensity on T2-weighted images and gadolinium enhancement. The tumor was marginally resected, adhering to the flexor digitorum profundus of both the third and fourth fingers. The histological diagnosis was fibroma of tendon sheath. After the surgery, the range of motion and hand function were improved. No recurrence has been observed. Fibroma of tendon sheath usually arises on the fingers and hands with strong attachment to the tendon or tendon sheath. The tumor in the present case probably limited the range of flexion of the fingers by obstruction of the transverse carpal ligament.

INTRODUCTION AND OBJECTIVES: Carbapenems (doripenem and meropenem) are a therapeutic option for bacterial prostatitis and antibacterial prophylaxis in prostatic surgery, especially in patients who are intolerant or resistant to quinolones. However, the clinical pharmacokinetics (PK) of the two carbapenems in prostate tissue and attainment of their pharmacodynamic (PD) targets at site of action had been unclear. This study thus examined, for the first time, the clinical PK of doripenem and meropenem in prostate tissue, and estimated their PD target attainment at this site. METHODS: Doripenem (0.25 g or 0.5 g) or meropenem (0.25 g or 0.5 g) was intravenously administered to 101 patients with benign prostatic hypertrophy prior to TURP. Blood samples and prostate tissue samples were collected 0.5, 1, 1.5, 2, 3, 4 and 5 h after starting a 0.5-h infusion. Drug concentrations in plasma and prostate tissue were measured using high-performance liquid chromatography, analyzed using a three-compartment population pharmacokinetic model, and used to estimate the probability of attaining a bactericidal target (40% of the time above the minimum inhibitory concentration [MIC] for bacteria). RESULTS: These carbapenems penetrated similarly into prostate tissue, independently of the dose, with mean prostate tissue/ plasma ratios of 0.166e0.173 (maximum drug concentration) and 0.177e0.187 (area under drug concentration-time curve). Despite this relatively low penetration by doripenem and meropenem, their usual regimens of 0.25 g three times daily and 0.5 g twice daily (0.5-h infusions) achieved a favorable target-attainment probability value of 90.8e95.9%, in prostate tissue, against clinical isolate populations of Escherichia coli and Klebsiella species (the two major causative bacteria in prostatitis). However, Pseudomonas aeruginosa isolate population needed 0.5 g three times daily for probability values of 55.9% for doripenem and 52.3% for meropenem. The prostatic pharmacodynamic-based breakpoint MIC (the highest MIC at which the targetattainment probability in prostate tissue was more than 90%) was 0.063 mg/L for 0.25 g three times daily and 0.125 mg/L for 0.5 g three times daily, for both drugs. CONCLUSIONS: These results define clinical pharmacokinetics of doripenem and meropenem in prostate tissue, while also rationalizing and optimizing their dosing regimens for prostatitis on the basis of site-specific pharmacodynamic target attainment.

Purpose Imaging criteria for diagnosing compressive ulnar neuropathy at the elbow (UNE) have recently been established as the maximum ulnar nerve cross-sectional area (UNCSA) upon magnetic resonance imaging (MRI) and/or ultrasonography (US). However, the levels of maximum UNCSA and diagnostic cutoff values have not yet been established. We therefore analyzed UNCSA by MRI and US in patients with UNE and in controls. Methods We measured UNCSA at 7 levels in 30 patients with UNE and 28 controls by MRI and at 15 levels in 12 patients with UNE and 24 controls by US. We compared UNCSA as determined by MRI or US and determined optimal diagnostic cutoff values based on receiver operating characteristic curve analysis. Results The UNCSA was significantly larger in the UNE group than in controls at 3, 2, 1, and 0 cm proximal and 1, 2, and 3 cm distal to the medial epicondyle for both modalities. The UNCSA was maximal at 1 cm proximal to the medial epicondyle for MRI (16.1 ± 3.5 mm 2 ) as well as for US (17 ± 7 mm 2 ). A cutoff value of 11.0 mm 2 for MRI and US was found to be optimal for differentiating between patients with UNE and controls, with an area under the receiver operating characteristic curve of 0.95 for MRI and 0.96 for US. The UNCSA measured by MRI was not significantly different from that by US. Intra-rater and interrater reliabilities for UNCSA were all greater than 0.77. The UNCSA in the severe nerve dysfunction group of 18 patients was significantly larger than that in the mild nerve dysfunction group of 12 patients. Conclusions By measuring UNCSA with MRI or US at 1 cm proximal to the ME, patients with and without UNE could be discriminated at a cutoff threshold of 11.0 mm 2 with high sensitivity, specificity, and reliability. Type of study/level of evidence Diagnostic III.

The purpose of this study was to investigate the causes of failure to return to the pre-fracture place of residence at hospital discharge following an operation for a hip fracture and to continue medical treatment for osteoporosis. Herein, we discuss methods for improving discharge protocols for these patients. We examined patients who sustained osteoporotic fractures and were operated on for a hip fracture between 2001 and 2003 (83 males and 386 females; 81.2 ± 9.0 years old) and between 2011 and 2013 (121 males and 462 females; 83.1 ± 9.3 years old). In a follow-up study, we examined patients who moved into our related rehabilitation institution over a 3-year period, from 2011 to 2013. The incidence of hip fractures had increased from 2001–2003 to 2011–2013 in both genders, and it tended to increase in patients greater than 80 years of age in male and 90 years of age in female. The most common destination residence after discharge from the rehabilitation institution was the pre-fracture place of residence. The Barthel Index at discharge from the rehabilitation institution was significantly lager in patients who returned to the pre-fracture place of residence compared to those who returned to nursing home and our hospital. These results suggest improved mobility and ADL level of patients enable them to return to the pre-fracture place of residence. We propose the construction of a feedback system that aids in a medical pass to increase the ambulant consultation rate for orthopedics and prevent fragile fractures.

We studied the ability of collagen vitrigel material to repair cartilage in vivo when used alone or with transforming growth factor-β (TGF-β). We measured the time course and quantity of TGF-β1 released from the collagen vitrigel in vitro to quantify the controlled release of TGF-β1. Over 14 days, 0.91 ng of TGF-β was released from the collagen vitrigel. Osteochondral defects were made in the femoral trochlear groove in 36 Japanese white rabbits, which were divided into three groups: untreated group (group A), collagen vitrigel-implanted group (group B), and TGF-β1-incorporated collagen vitrigel-implanted group (group C). The weight distribution ratio between the affected and unaffected limbs served as an indicator of pain. Animals were sacrificed at 4 and 12 weeks after surgery, and their tissues were assessed histologically. The weight distribution ratio increased in all groups and did not differ significantly between groups at 12 weeks. Group A needed 6 weeks to attain maximum improvement, and groups B and C showed near-maximum improvement at 4 and 2 weeks, respectively. The International Cartilage Repair Society II score improved significantly in group C relative to the other groups. These findings suggest that sustained, slow release of TGF-β caused early pain mitigation and cartilage repair. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 2592-2602, 2017.

Dislocation of the hip joint in adults is usually caused by high-energy trauma such as road traffic accidents or falls from heights. Posterior dislocation is observed in most cases. However, atraumatic anterior dislocation of the hip joint is extremely rare. We present a case of atraumatic anterior dislocation of the hip joint that was induced by an activity of daily living. The possible causes of this dislocation were anterior capsule insufficiency due to developmental dysplasia of the hip, posterior pelvic tilt following thoracolumbar kyphosis due to vertebral fracture, and acetabular anterior coverage changes by postural factor. Acetabular anterior coverage changes in the sagittal plane were measured using a tomosynthesis imaging system. This system was useful for elucidation of the dislocation mechanism in the present case.

Retrospective study for L5 radiculopathy due to foraminal stenosis with vacuum phenomena (VP) at the L5/S disc.To investigate the influence of the L5/S VP on L5 radiculopathy, due to L5/S foraminal stenosis.Foraminal stenosis has often been detected via images. However, although this condition is well known, it is occasionally overlooked during diagnosis, because spinal nerve compression is not always visible on stationary images.Patients who underwent lumbar spine surgery were examined to determine the presence of foraminal stenosis (n = 194). The presence of VP and the range of motion of the L5/S disc were assessed on radiography with the lumbar spine in the extended and flexed positions. The shapes of the L5/S foramina were confirmed using sagittal magnetic resonance imaging. Patients who showed VP were divided into 2 groups: patients with (group A) and without (group B) symptomatic foraminal stenosis. The relationship between the VP and symptomatic foraminal stenosis was examined.In total, 35 cases of VP at the L5/S disc were noted on lateral radiography. L5 radiculopathy due to L5/S foraminal stenosis was identified in 14 of these 35 cases. The ranges of L5/S angles were 10° ± 4° and 5° ± 3° in groups A and B, respectively, and these values were significantly different (P 0.01). 11 (48%) of 23 L5/S foramina that showed VP of the L5/S disc and were completely occupied by a disc below the caudal edge of the vertebra had symptomatic foraminal stenosis.Our results indicated that VP, which showed a large range of motion angle between flexion and extension, triggered symptoms of foraminal stenosis at the L5/S disc. The dynamic motion of the VP should thus be considered for the diagnosis of L5/S foraminal stenosis.3.

Objectives To compare various methods for measuring tumor extent in prostate biopsy specimens to identify small-volume prostate cancer. Methods A total of 100 radical prostatectomy specimens were retrospectively analyzed. Receiver operating characteristic analysis was used to compare the abilities of prostate-specific antigen density, and four measures of tumor extent in prostate biopsy specimens – positive core number, greatest percentage of cancer in a single core, greatest length of cancer in cores and total length of cancer in cores – to identify small volume prostate cancer. Four definitions of insignificant cancer volume were used in this analysis: index and total tumor volume

INTRODUCTION AND OBJECTIVES: Data regarding the expression of estrogen receptors (ER) and prostate cancer (PCa) outcomes are limited. We evaluated the relationship of expression profiles of ERb; isoforms and the membrane bound estrogen receptor GPR30 with patient factors and outcomes following radical prostatectomy (RP). METHODS: Tissue microarrays constructed from 566 men who underwent RP for localized PCa were analyzed with immunohistochemistry targeting ERb1, ERb2, ERb5 and GPR30. An experienced, blinded pathologist scored receptor distributions and staining intensities. Demographic and clinical data were evaluated with descriptive statistics. Correlations between PCa ERb; isoform and GPR30 expression and clinicopathologic data were analyzed with c2 tests. Cox proportional hazards models were used to examine associations between each ER’s staining pattern and time to recurrence and prostate cancer-specific mortality (PCSM). Receptor sub-type staining patterns found to have a significant association with recurrence or PCSM were further analyzed using the Kaplan-Meier method. Significance was set at a

This study intends to present the concept of a mechanism that will lead to generate active innovations that can change our society. We first analyze the general process of innovations and identify core elements that lead to innovations. We then analyze existing tools and systems that support the creation of innovations in relation to core elements. This analysis leads to the building of the innovation model. We propose an “innovation compass” based on the innovation model that is an integrative system that enhances human creativity to generate innovations. It supports both individual and group creativity. It not only supports rational aspects of innovation processes but also stimulates the motivation of innovators.

Introduction & Objective: Regulatory T cells (Treg) play important roles in suppression of the immune response, including anti-tumor immunity. C-C chemokine receptor 4 (CCR4) is highly expressed on effector Tregs, and the anti-CCR4 antibody is attracting attention as a novel immunotherapeutic agent for solid tumors. The purpose of this study was to evaluate the expression of CCR4-positive Tregs in biopsy specimens of men with prostate cancer with a poor prognosis and to estimate the clinical potential of CCR4-targeting therapy for prostate cancer. Material & Methods: Data for 60 men diagnosed with prostate cancer based on transrectal 12-core systemic biopsy were retrospectively analyzed. They were divided into two groups, a good prognosis group comprising men with no disease progression during the observation period and a poor prognosis group comprising men with progression to castration resistant prostate cancer. In the biopsy cores, the core with the highest tumor volume was selected for immunohistochemical evaluation. Tregs were evaluated using immunohistochemistry with double staining using anti-forkhead box protein 3 (FOXP3) antibodies and anti-CCR4 antibodies. The number of CCR4+/- FOXP3+ cells in the biopsy specimens were compared between the two groups. Furthermore, the correlation between the number of CCR4+ FOXP3+ cells and clinical stage, PSA at diagnosis, and Gleason score were evaluated. Results: The good prognosis group included 29 men and the poor prognosis group included 31 men. Approximately 70-80% of FOXP3+ cells were positive for CCR4. There was no significant difference in the ratio of number of CCR4+ FOXP3+ cells to the number of total FOXP3+ cells between the poor and good prognosis groups. However, the total number of FOXP3+ cells significantly increased in the poor prognosis group than in the good prognosis group (200.1 ± 174.8 vs. 38.1 ± 38.1, p < 0.01). Furthermore, the number of CCR4+ FOXP3+ cells significantly increased in the poor prognosis group than in the good prognosis group (123.6 ± 99.1 vs. 58.88 ± 26.4, p < 0.01). The number of CCR4+ FOXP3+ cells positively correlated with clinical stage (ρ = 0.558, p < 0.001) and Gleason score (ρ = 0.458, p = 0.006) in prostate cancer. However, there was no significant correlation between the number of CCR4+ FOXP3+ cells and PSA at diagnosis. The men with a lower number of CCR4+ FOXP3+ cells had a significantly longer median survival time than those with high expression (not reached vs. 69.0 months; p = 0.040). Conclusions: Our results suggest the clinical potential of CCR4-targeted therapy for poor prognosis prostate cancer. Citation Format: Masahito Watanabe, Kent Kanao, Susumu Suzuki, Hiroyuki Muramatsu, Shingo Morinaga, Keishi Kajikawa, Ikuo Kobayashi, Genya Nishikawa, Yoshiharu Kato, Kogenta Nakamura, Kazuhiro Yoshikawa, Ryuzo Ueda, Makoto Sumitomo. Increased CCR4-positive regulatory T cells in biopsy specimen of poor prognosis prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3961. doi:10.1158/1538-7445.AM2017-3961

Introduction and objectives: It is well known as Warburg effect that anaerobic glycolytic pathway is activated in various type of advanced cancers including prostate cancer (PC). Lactate dehydrogenase-A (LDH-A) controls the conversion of pyruvate to lactate and plays an important role in glucose metabolism. Since LDH-A pathways have been implicated in chemoresistance in various cancers, we investigated whether inhibition of LDH-A pathway could mediate the sensitivity to docetaxel (DOC) in human PC cells. Materials and Method: Four PC cell lines (PC3, DU145, LNCaP, LN-CSS ) were used. LN-CSS is one of the LNCaP-derived castration-resistant PC (CRPC) cell lines established in our laboratories. Sodium oxamate (SO) was used as a specific LDH-A inhibitor. The protein expression was detected by western blot analysis using specific antibodies. Cell growth and survival were evaluated by WST-1 assays. Cell cycle progression and apoptotic inducibility were evaluated by flow cytometry using propidium iodide and Annexin V. The cytotoxicity of SO/DOC combination on PC cells was evaluated using the Chou-Talalay combination index (CI) method which offers quantitative definition for additive effect (CI = 1), synergism (CI < 1), and antagonism (CI > 1) in drug combinations. Result: Western blot analysis showed that LDH-A protein was highly expressed in LN-CSS cells compared with other PC cell lines including the parental LNCaP. WST-1 assays showed that treatment with SO (50 mM) for 72 hours in PC cells resulted in growth inhibition (PC3; ~30%, DU145; ~55%, LNCaP; ~20%,LN-CSS; ~55% ), while SO has little growth inhibitory effects on normal lymphocytes in the concentrations between 1-100 mM. IC50 to DOC in PC cells were showed to be 4 nM, 1 nM, 1nM, and 4.5 nM in PC3, DU145, LNCaP and LN-CSS, respectively, suggesting that both PC3 and LN-CSS were relatively resistant to DOC compared with DU145 and LNCaP. Synergistic cytotoxicity was observed after the combination therapy with DOC and SO in LN-CSS (CI: 0.5) but not in PC3 (CI: 1.9), DU145 (CI: 2.0), or LNCaP (CI: 6.5). Cell cycle analyses revealed that the combination with DOC and SO for 72 hours resulted in the accumulation of cells in G2-M phase followed by sub-G1 accumulation in LN-CSS cells. Annexin V assays showed that 43% apoptosis was induced by the combination therapy in LN-CSS cells, while only 12% by DOC only in LN-CSS cells. Conclusion: Our results strongly suggest that LDH-A plays an important role in DOC resistance in advanced PC cells and inhibition of LDH-A promotes DOC-sensitivity especially in CRPC cells. Our study may provide valuable information for the future development of targeted therapies in patients with CRPC. Citation Format: Hiroyuki Muramatsu, Makoto Sumitomo, Shingo Morinaga, Hiroshi Saiki, Ikuo Kobayashi, Keishi Kajikawa, Genya Nishikawa, Yoshiharu Kato, Masahito Watanabe, Kent Kanao, Kogenta Nakamura, kazuhiro Yoshikawa. Targeting lactate dehydrogenase-A promotes docetaxel induced cytotoxicity predominantly in castration-resistant prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4400. doi:10.1158/1538-7445.AM2017-4400

e16581 Background: Active surveillance (AS) is now an accepted strategy for men with low-risk prostate cancer (PCa). A critical factor for successful AS is the best possible patient selection. We recently develop a novel 18-G biopsy instrument based on an existing instrument, by extending the side-notch length from 19 to 25 mm and the stroke length from 22 to 28 mm, to take a longer tissue core and to reach the anterior portion of the prostate.In this study, we evaluated utility of the novel biopsy instrument in the selection of patients for AS. Methods: A total of 167 PCa patients diagnosed with the long-notch needle (n = 62; long-notch group) or normal-notch needle (n = 105; normal-notch group), who subsequently underwent prostatectomy, were retrospectively analyzed. All patients were diagnosed with 12 transrectal ultrasound-guided standard cores.The sampled core length, correlation between total tumor length in biopsy specimens, and total tumor volume in prostatectomy specimens were compared between the two groups. Gleason score (GS) upgrading was also compared. Prostatectomy specimens of patients who met the criteria of the PRIAS study were compared for the two groups. Results: The mean length of tissue taken with the long-notch needle was significantly longer than that taken with the normal-notch needle (16.3 vs. 22.4 mm, p < 0.001). The correlation coefficient between total tumor length in biopsy specimens and total tumor volume in prostatectomy specimens of the long-notch group was higher (r = 0.701) than that in the normal-notch group (r = 0.611). GS upgrading in the long-notch group was significantly lower than that in the normal-notch group (25.8 vs. 41.0%, p = 0.0479).Only 1 patient with tumor volume > 0.5 cc and GS 4+3 or more was included among the 5 who met the criteria of the PRIAS study in the long-notch group, while 6 patients were included among the 10 who met the criteria in the normal-notch group. Conclusions: We developed a novel biopsy instrument with a 25 mm side-notch for longer tissue samples, increased correlation between tumor volume in biopsy and prostatectomy specimens, and decreased GS upgrading. These results suggested the utility of the long-notch needle in the selection of patients for AS.

e16530 Background: Docetaxel is the standard treatment for castration-resistant prostate cancer (CRPC). However, the role of chemical/surgical castration during docetaxel chemotherapy is unclear. The purpose of this study was to analyze the impact of castration during docetaxel chemotherapy. Methods: Data from 43 patients diagnosed with CRPC and treated at our institute with docetaxel chemotherapy, from January 2007 to September 2016, were analyzed retrospectively. They were divided into two groups according to the continuation of chemical castration during docetaxel chemotherapy: a continuation group and a discontinued group. Patients’ background data (age and serum prostate-specific antigen [PSA] level), PSA decline, progression-free survival, and overall survival were compared between the two groups. Results: The continuation group included 19 patients, and the discontinued group included 24 patients. Castration included surgical castration (15.8%), use of a luteinizing hormone-releasing hormone (LH-RH) agonist (68.4%), and use of an LH-RH antagonist (15.8%). There were no significant differences in patient age (73.5 years vs. 73.5 years; p = 0.878) and baseline serum PSA levels (14.25 ng/ml vs. 31.1 ng/ml, p = 0.745) between the two groups at the start of chemotherapy. PSA declines of ≥50% were observed in 7/14 patients and in 9/20 patients, respectively. There were no significant differences between the two groups with respect to the median progression-free survival (5.7 months vs. 9.9 months, p = 0.406) and overall survival. (52.1 months vs. 44.1 months, p = 0.776). Conclusions: Continuing chemical/surgical castration during docetaxel chemotherapy did not affect progression and prognosis of CRPC. Our results might suggest that chemical castration is not necessary during docetaxel chemotherapy.