A phase II trial of stereotactic body radiotherapy in 4 fractions for patients with localized prostate cancer.

PURPOSE/OBJECTIVE(S): To report results from our phase II study of stereotactic body radiotherapy (SBRT) delivering 36 Gy in 4 fractions for patients with localized prostate cancer. MATERIALS/METHODS: We enrolled 55 patients treated with SBRT delivering 36 Gy in 4 fractions between 2015 to 2018. All patients were categorized as low-risk (n = 4), intermediate-risk (n = 31) or high-risk (n = 20) according to National Comprehensive Cancer Network criteria. Median age was 73 years (range 54-86 years). Two-thirds of patients (n = 37) had received androgen-deprivation therapy for 3-46 months (median, 31 months). Median duration of follow-up was 36 months (range 1-54 months). We used Radiation Therapy Oncology Group and National Cancer Institute-Common Toxicity Criteria version 4 for toxicity assessments. Quality of life (QOL) outcomes were also evaluated using the Expanded Prostate Cancer Index Composite (EPIC). RESULTS: Protocol treatments were completed for all patients. Six patients experienced biochemical failures. Among these six patients, three patients experienced clinical failure. One patient showed bone metastasis before biochemical failure. One patient died of gastric cancer. The 3-year biochemical control rate was 89.8%. Acute grade 2 genitourinary (GU) and gastrointestinal (GI) toxicities were observed in 5 patients (9%) and 6 patients (11%), respectively. No grade 3 or higher acute toxicities were observed. Late grade 2 GU and GI toxicities were observed in 7 patients (13%) and 4 patients (7%), respectively. Late grade 3 GU and GI toxicities were observed in 1 patient (1.8%) each. EPIC scores decreased slightly during the acute phase and recovered within 3 months after treatment. CONCLUSION: Our phase II study showed that SBRT delivering 36 Gy in 4 fractions was safe and effective with favorable QOL outcomes, although this regimen showed slightly more severe toxicities compared to current standards.

Comparison of early femoral bone remodeling and functional outcome after total hip arthroplasty using the SL-PLUS MIA stem with and without hydroxyapatite coating.

BACKGROUND: Few reports have evaluated the use of hydroxyapatite (HA) coating in SL-MIA-type stems in total hip arthroplasty (THA). Here, we compared early femoral bone remodeling after total hip arthroplasty using the SL-PLUS MIA stem with and without hydroxyapatite coating. METHODS: From February 2012 to March 2017, 132 patients (150 hips) (HA group: 48 patients [52 hips], non-HA group: 84 patients [98 hips]) underwent THA with an SL-PLUS MIA stem. The mean follow-up duration was 3.7 years (standard deviation 1.2, range: 1.0-6.1). The Harris Hip Score (HHS), postoperative bleeding volume measurements and plain radiographs were used for clinical and radiological follow-up evaluations. Peri-prosthetic bone mineral density changes were measured by dual-energy X-ray absorptiometry. RESULTS: At 1 year, the HHS improved from 44.4 points preoperatively to 89.2 points postoperatively and from 44.5 points to 89.7 points in the HA and non-HA groups, respectively. At 1 year postoperatively, subsidence (≧ 3 mm) occurred in 0% and 8.2% of the HA and non-HA groups, respectively. Stress shielding (≧ Grade 3) occurred in 0% and 6% of the HA and non-HA groups, respectively. The radiolucent line was significantly smaller in the HA than in the non-HA group. There was no significant difference in the bone mineral density distribution in the two groups. CONCLUSION: Addition of HA to the SL-MIA stem can help enhance the initial fixation and early osseointegration. Further studies are required on the long-term effects of adding HA to reduce stress shielding of the proximal area of the stem.

Clinical results of hemiarthroplasty using new bipolar cups for stage 3 or lower osteonecrosis of the femoral head: a retrospective study.

PURPOSE: The aim of this study was to evaluate clinical and radiographic findings of stage 3 or lower osteonecrosis of the femoral head (ONFH) with intact acetabular cartilage in patients treated with bipolar hemiarthroplasty (BHA). METHODS: A total of 79 hips that underwent BHA for ONFH were included in this study. The average observation period was 7.6 years. Clinical results were evaluated using the Harris hip score. We performed radiographic analysis to assess the migration of the outer cup, the permanent image around the outer cup, and loosening of the stem. RESULTS: The total Harris hip score improved from 50 points before surgery to 92 points at final follow-up, while pain improved from 14 points to 36 points. Flexion improved from 94° to 120° and abduction from 27° to 37°. One patient on dialysis showed progress in terms of inward migration, and revision surgery was performed on the patient 14 years after the original surgery. CONCLUSIONS: Midterm performance of BHA for stage 3 or lower ONFH at our hospital was good.

Relationship between pull-out strength and oscillation angle in bipolar cups: an in vitro study.

PURPOSE: To compare the past and present bipolar hip arthroplasty (BHA) models in terms of balance between pull-out strength and oscillation angle (OA). METHODS: The pull-out strength and OA of 8 BHA models were compared: UPF-II, IBC, and Tandem XLPE (Smith & Nephew); Ringloc x (Biomet); J-FX (DePuy); Bipolar (Nakashima Medical); Multipolar (Zimmer); and Centrax (Stryker). RESULTS: Respectively for the UPF-II, IBC, Tandem, Ringloc, J-FX, Nakashima Bipolar, Multipolar, and Centrax, the mean pull-out strength was 2219 N, 3303 N, 1503 N, 951 N, 1453 N, 1856 N, 1536 N, and 753 N, whereas the mean OA was 54.2°, 53.8°, 64.0°, 73.2°, 63.0°, 65.4°, 55.6°, and 75.4°. The OA was lower in the integrated types. For pull-out strength of the locking mechanism, the integrated type (IBC and Nakashima) was stronger than the metal or polyethylene ring-lock type (all others). The pull-out strength and OA were negatively correlated (r= -0.881, p=0.007), and the balance between the 2 varied for different models. CONCLUSION: There is a trade-off between the pullout strength and OA; optimal balance between the 2 should be based on each patient's need.

Characterization of ASKP1240, a fully human antibody targeting human CD40 with potent immunosuppressive effects.

Blocking the CD40-CD154 interaction is reported to be effective for transplantation management and autoimmune disease models in rodents and nonhuman primates. However, clinical trials with anti-CD154 mAbs were halted because of high incidence of thromboembolic complications. Thus, we generated and characterized a fully human anti-CD40 mAb ASKP1240, as an alternative to anti-CD154 mAb. In vitro ASKP1240 concentration-dependently inhibited human peripheral blood mononuclear cell proliferation induced by soluble CD154. In addition, ASKP1240 did not destabilize platelet thrombi under physiological high shear conditions while mouse anti-human CD154 mAb (mu5C8) did. And ASKP1240 itself did not activate platelet and endothelial cells. In vivo administration of ASKP1240 (1 or 10 mg/kg, intravenously) to cynomolgus monkeys, weekly for 3 weeks, significantly attenuated both delayed-type hypersensitivity and specific antibody formation evoked by tetanus toxoid. The immunosuppressive effect was well correlated with the CD40 receptor saturation. Thus, these results suggest that ASKP1240 is immunosuppressive but not prothromboembolic, and as such appears to be a promising therapeutic candidate for the management of solid organ transplant rejection and autoimmune diseases therapy.

Gene expression profiles in differentiating leukemia cells induced by methyl jasmonate are similar to those of cytokinins and methyl jasmonate analogs induce the differentiation of human leukemia cells in primary culture.

Jasmonates are potent lipid regulators in plants that play pivotal roles in their biological activities. Methyl jasmonate (MJ) is very effective at inducing the myelomonocytic differentiation of human myeloid leukemia HL-60 cells. We examined the gene expression profiles associated with exposure to MJ using cDNA microarrays, and compared the results with those obtained with other inducers of differentiation, such as all-trans retinoic acid (ATRA), 1alpha,25-dihydroxyvitamin D(3) (VD(3)), isopentenyladenine (IPA) and cotylenin A (CN-A). Many genes were upregulated, and only a small fraction was downregulated, upon exposure to the inducers. MJ, IPA and CN-A, but not ATRA or VD(3), immediately induced the expression of mRNA for the calcium-binding protein S100P. The gene expression profile induced by MJ resembled that induced by IPA, suggesting that these inducers share many common signal transduction systems for inducing the differentiation of leukemia cells. Methyl 4,5-didehydrojasmonate was about 30 times more potent than MJ and the natural form of the stereoisomer was more effective than the unnatural isomer. It significantly stimulated both the functional and morphological differentiation of leukemia cells that had been freshly isolated from patients with hematological malignancies. Jasmonate derivatives may be promising therapeutic agents for differentiation therapy of leukemia.

Alpha1-adrenoceptors are required for normal male sexual function.

BACKGROUND AND PURPOSE: Alpha(1)-adrenoceptor antagonists are extensively used in the treatment of hypertension and lower urinary tract symptoms associated with benign prostatic hyperplasia. Among the side effects, ejaculatory dysfunction occurs more frequently with drugs that are relatively selective for alpha(1A)-adrenoceptors compared with other drugs of this class. This suggests that alpha(1A)-adrenoceptors may contribute to ejaculation. However, this has not been studied at the molecular level. EXPERIMENTAL APPROACH: The physiological contribution of each alpha(1)-adrenoceptor subtype was characterized using alpha(1)-adrenoceptor subtype-selective knockout (KO) mice (alpha(1A)-, alpha(1B)- and alpha(1D)-AR KO mice) since the subtype-specific drugs available are only moderately selective. We analysed the role of alpha(1)-adrenoceptors in the blood pressure and vascular response as well as ejaculation by determining these variables in alpha(1)-adrenoceptor subtype-selective KO mice and in mice with all their alpha(1)-adrenoceptor subtypes deleted (alpha(1)-AR triple-KO mice). KEY RESULTS: The pregnancy rate was reduced by 50% in alpha(1A)-adrenoceptor KO mice, and this reduction was dramatically enhanced in alpha(1)-adrenoceptor triple-KO mice. Contractile tension of the vas deferens in response to noradrenaline was markedly decreased in alpha(1A)-adrenoceptor KO mice, and this contraction was completely abolished in alpha(1)-adrenoceptor triple-KO mice. This attenuation of contractility was also observed in the electrically stimulated vas deferens. CONCLUSIONS AND IMPLICATIONS: These results demonstrate that alpha(1)-adrenoceptors, particularly alpha(1A)-adrenoceptors, are required for normal contractility of the vas deferens and consequent sperm ejaculation as well as having a function in fertility.

Cooperation of oncogenic K-ras and p53 deficiency in pleomorphic rhabdomyosarcoma development in adult mice.

Human rhabdomyosarcomas (RMSs) frequently demonstrate genetic alterations in ras and p53. To investigate their possible involvement in the tumorigenesis, we generated a knock-in mouse line with oncogenic K-ras, conditionally expressed by Cre/LoxP system on a background of p53 alteration. Electroporation of Cre expression vector in skeletal muscle tissues resulted in the generation of tumor in adults with tumor incidences of 100% at 10 weeks and 40% at 15 weeks, in p53(-/-) and p53(-/+) backgrounds, respectively. The tumor histology was pleomorphic RMS with characteristic bizarre giant cells, positive for desmin and alpha-sarcomeric actin and exhibiting remarkable increase in total and phosphorylated extracellular signal-regulated protein kinase (ERK)1 and ERK2. Loss of the wild-type p53 was detected in K-rasG12V-expressed tumors of p53(-/+) mice. Early lesions 3 weeks after electroporation consisted of proliferating populations of myogenic progenitors, including stem cells positive for ScaI antigen, immature cells positive for desmin and neural cell adhesion molecule-positive myotubes. Thus, cooperation of oncogenic K-ras and p53 deficiency resulted in the development of pleomorphic RMS in adult mice, providing a useful mouse model for further detailed studies.

Three-dimensional finite element analysis of unicompartmental knee arthroplasty--the influence of tibial component inclination.

Aseptic loosening and failure of a tibial component are recognized problems in unicompartmental knee arthroplasty (UKA). Excessive stress on the supporting cancellous bone is thought to contribute to the loosening and failure. Of factors that could influence supporting cancellous bone stresses, we focused on the inclination of a unicompartmental tibial component by analyzing the effect of coronal plane and sagittal plane inclination. Detailed geometrically accurate, three-dimensional finite element models were constructed from computed tomography (CT) data of a typical adult male proximal tibia. The material properties for the models were obtained directly from the CT data to simulate the inhomogeneous distribution of cancellous bone properties. Placing the component in slight valgus inclination in the coronal plane reduced the cancellous bone stresses. Posterior inclination in the sagittal plane caused a moderate increase in the stresses. Our results suggest that slight valgus inclination of a UKA tibial component may be preferable to varus or square inclination in the coronal plane. An excessive posterior slope of a tibial component should be avoided.

Does the self-centering mechanism of bipolar hip endoprosthesis really work in vivo?

PURPOSES: To examine radiographically the component motion in a bipolar prosthesis and to determine whether the self-centering mechanism really works in vivo. METHODS: 38 patients with 41 bipolar hip endoprostheses (30 for coxarthrosis and 11 for osteonecrosis of femoral head) were included in this study. Two radiographs of each case were taken to evaluate the self-centering mechanism. The first anteroposterior radiograph of both hip joints was taken at the maximum abduction while the patient standing on the endoprosthetic leg. The second radiograph was taken after the patient returned to neutral position while standing on 2 legs. In the present study, the order in which the radiographs were taken differed from previously reported studies. The radiographs were analysed using the method similar to that of Drinker and Murray. The adductive motion from abduction to a neutral position is within the range of inner bearing oscillation. RESULTS: The outer head alignment changed from 23 degrees to 12 degrees in the patients with osteonecrosis. However, the valgus position of the outer head (36 degrees) remained unchanged in the patients with coxarthrosis standing on 2 legs in the neutral position. CONCLUSION: The self-centering mechanism of the bipolar endoprosthesis functioned in the patients with osteonecrosis, but did not work in the coxarthrosis group.

Debridement and continuous irrigation for the treatment of pyogenic arthritis caused by the use of intra-articular injection in the osteoarthritic knee: indications and outcomes.

PURPOSE: To discuss the indications and therapeutic outcomes of synovectomy, debridement, and continuous irrigation for the treatment of pyogenic arthritis caused by intra-articular injection used in the treatment of osteoarthritis of the knee. METHODS: Records of 41 patients with infectious arthritis of the knee who presented to our hospital from 1981 were reviewed. 11 of them had a history of intra-articular injection. They underwent synovectomy, debridement, and continuous irrigation using a Salem double-lumen tube after confirmation that one side of the femorotibial joint cartilage was basically healthy. RESULTS: The infection was successfully treated in 9 of the 11 patients. Of these 9 patients, one died after 3 years and 2 underwent total knee arthroplasty after 3 and 8 years. The remaining 6 patients were followed up for 5 to 15 years. Five of them had deteriorating arthropathy, and the condition was unchanged in the others. Two of these 6 patients had pain while walking, and their Japanese Orthopaedic Association scores were 70. The remaining 4 had good knee function and reduction of pain, with a mean Japanese Orthopaedic Association score of 91 and a mean range of motion of 131 degrees. CONCLUSION: Arthrodesis is frequently considered the treatment for osteoarthritis if the joint destruction has affected the weight-bearing surface. However, in our experience, even when inflammatory granulation develops in the cartilage surface of one side of the femorotibial joint, good results can still be obtained by synovectomy, debridement, and continuous irrigation. After the pyogenic arthritis has subsided, if osteoarthritis has advanced and bowleg has exacerbated, further treatment options are available, such as tibial resection and even joint replacement. Continuous irrigation should be considered a feasible treatment option for pyogenic arthritis.

Successful laparoscopic Ladd's procedure and appendectomy for intestinal malrotation with appendicitis.

We successfully performed a laparoscopic Ladd's procedure and an appendectomy in a 15-year-old girl with intestinal malrotation and appendicitis. She had tenderness and rebound pain in the umbilicus and left lower abdominal quadrant. Blood analysis revealed a moderate inflammatory response. Enhanced computerized tomography (CT) scanning revealed a whirl-like pattern and a superior mesentric vein (SMV) rotation sign in the mesentry of the small intestine. A swollen appendix was seen just below the umbilicus. An upper gastrointestinal (GI) radiological series confirmed agenesis of Treitz's arch. The patient was diagnosed as having a nonrotation type of malformation accompanied by acute appendicitis. She underwent a laparoscopic Ladd's procedure, an appendectomy, peritoneal lavage, and drainage. The technique for this procedure and its effectiveness are briefly discussed.

NOS and COX isoforms and abnormal microvessel responses to CO2 and H+ in hyperoxia-injured lungs.

The aim of the present study was to compare microvessel responses to hypercapnic and isocapnic acidosis in hyperoxia-injured lungs and to assess the role of constitutive and inducible forms of nitric oxide synthase (NOS) and cyclo-oxygenase (COX). Real-time confocal luminescence microscopy was used to measure changes in the diameter of acinar arterioles, venules and capillaries in response to stimulation with hypercapnic and isocapnic acidosis in isolated rat lungs injured by 90% oxygen exposure for 48 h. Observations were made with and without inhibition of constitutive (endothelial constitutive NOS (ecNOS) and COX-1) and inducible isoforms (iNOS and COX-2) of NOS and COX. Upregulation of NOS was assessed by measuring enzyme levels in lung homogenates by Western blot analysis and enhancement of the COX-related pathway was judged from perfusate concentrations of 6-ketoprostaglandin F1alpha. ecNOS and COX-1, but not iNOS and COX-2, were upregulated in hyperoxia-injured lungs. The nitric oxide produced by ecNOS attenuated COX-1 activity in injured arterioles and venules, but carbon dioxide enhanced it, leading to paradoxical dilatation of these microvessels under hypercapnic conditions with ecNOS inhibition. Although a high hydrogen ion concentration was unnecessary for excitation of COX-1, venule constriction in response to H+ was enhanced by COX-1 inhibition. Constitutive, but not inducible, isoforms of cyclo-oxygenase and nitric oxide synthase play an important role in abnormal microvessel responses to carbon dioxide and hydrogen ions in hyperoxia-injured lungs.

Production of active bovine cathepsin C (dipeptidyl aminopeptidase I) in the methylotrophic yeast Candida boidinii.

The heterologous production of active bovine cathepsin C (CTC; dipeptidyl aminopeptidase I) was investigated. Attempts to express CTC in Escherichia coli were hampered by formation of inclusion bodies that were partially degraded. To overcome this impediment, secretion of recombinant CTC was attempted in the methylotrophic yeast Candida boidinii. A DNA fragment encoding bovine procathepsin C was synthesized based on preferred codon usage in C. boidinii and placed downstream of the C. boidinii proteinase A signal sequence resulting in secretion of active CTC into the culture medium. The gene was expressed under the control of the methanol-inducible formate dehydrogenase gene promoter. Production levels were significantly improved by using a protease-deficient strain, changing medium composition, and by lowering the temperature of induction. When the recombinant C. boidinii was grown for 90 h in a jar-fermenter, active CTC was secreted with a yield of up to approximately 12 mg/l.

The effects of tibial component inclination on bone stress after unicompartmental knee arthroplasty.

Unlike the case with total knee arthroplasty, the femorotibial angle (FTA) after unicompartmental knee arthroplasty (UKA) does not directly depend on the inclination of the tibial component when the height of the joint line is maintained. This study analyzed the effects of the inclination of the tibial component in the coronal plane on the contact pressure of the implant-bone surface and the stresses on the proximal tibia. A two-dimensional, coronal plane model of the proximal tibia was subjected to finite-element analysis. Sixteen patterns of finite-element models of equal FTA were developed in which the inclination of tibial components ranged from 5 degrees valgus to 10 degrees varus in increments of 1 degrees. Stress concentration at the proximal medial diaphyseal cortex gradually increased as the inclination changed from valgus to varus. Maximum contact pressure on the metal-bone interface similarly changed and shifted from the lateral edge to the medial edge of the implant as the inclination changed to varus. It was found that even without changing FTA, the inclination of the tibial component might affect stress concentration and contact pressure in the proximal tibia after UKA. The results suggested that slight valgus inclination of the tibial component might be preferable to varus and even to 0 degrees (square) inclination so far as the stress distribution is concerned.

An assessment of histopathological criteria for infection in joint arthroplasty in rheumatoid synovium.

Intraoperative frozen section is reported to be a reliable means of identifying occult infection for preoperative evaluation of arthroplasty. The aim of this study was to determine whether the reported histopathological criteria--the existence of more than 10 polymorphonuclear cells (PMN) per high-power field--is valuable for determination of infection during the arthroplasty of patients with rheumatoid arthritis (RA). The permanent histological sections of RA synovium were analysed to study the degree of infiltration of PMNs. Furthermore, in order to examine the penetrative distribution of PMNs within the synovial tissues, immunohistochemical staining of PMNs was performed. In addition, the clinical history, from the postoperative period to the present, was investigated in 46 patients (60 joints). The presence of early- and/or late-stage postoperative infection, the development of postoperative fever, the progression of erythrocyte sedimentation rate (ESR) (more than 30 mm per hour) and the changes in CRP (more than 10 mg per litre) were further examined and compared with the histopathological tissue analyses and findings. The results demonstrated the presence of more than five PMNs per high-power field, excluding surface fibrin and inflammatory exudate in at least five separate microscopic fields in 10 joints (16.7%) of nine patients, out of 60 joints of 46 patients, in which no postoperative infection was evident. As to the magnitude of penetrative distribution of PMNs in 10 joints, there was a trend of deepening infiltration among the patients with intensive PMN infiltration. In addition, no development of postoperative fever, CRP or continuous indications of high ESR values were evident in this group. As the existence of more than 10 PMN per high-power field was not absolutely indicative of occult infection, investigation of frozen section during arthroplasty should be carefully managed.

Comparison of ultrasonically activated scalpel versus conventional division for the pancreas in distal pancreatectomy.

PURPOSE: The goal of this study was to compare the benefits and complications of using an ultrasonically activated scalpel and conventional division of the pancreas in patients undergoing a distal pancreatectomy. METHODS: A retrospective review was performed of all patients who underwent distal pancreatectomy at the Department of Surgery, Koshigaya Municipal Hospital. In the ultrasonically activated scalpel (US) group (n = 11), the pancreas was divided using coagulation shears. The stump of the pancreas was left open without parenchymal suturing. In the conventional surgical division (CV) group (n = 20), the pancreas was cut with a knife and the stump was oversewn with interrupted mattress sutures. The main pancreatic duct was ligated in all patients in both groups. The postoperative courses in the two groups were then compared in terms of postoperative serum amylase levels and the incidence of pancreatic fistulas. RESULTS: The postoperative serum amylase levels were significantly lower in the US group than in the CV group (P < 0.01 on the day of operation). The incidence of pancreatic fistulas was also significantly lower in the US group (0%) than in the CV group (30%) (P = 0.04). CONCLUSIONS: The use of the ultrasonically activated scalpel was found to reduce the incidence of pancreatic fistula in distal pancreatectomy. Furthermore, the use of this device without any clamping or parenchymal suturing may reduce the damage to the remnant pancreas.

Hepatic resection using the harmonic scalpel.

We describe herein our technique of performing extensive resection of the liver by blunt dissection in combination with excision using a harmonic scalpel. A ball coagulator was inserted at 3-cm intervals along the proposed cutting line in the liver, and the liver parenchyma between these holes was then cut using coagulation shears. Regardless of the condition of the liver, good coagulation and cutting were achieved using the harmonic scalpel without vascular occlusion when dividing the shallow layer of the liver, and no complications in association with the harmonic scalpel, such as postoperative bleeding, bile leakage, or abscess formation at the cut margins, occurred. In the deep layer below the main trunk of the hepatic vein, blunt dissection was used, since it was difficult to achieve sufficient control of bleeding from large vessels using the harmonic scalpel alone. Therefore, when used in combination with other techniques, the harmonic scalpel appears to be an effective device for liver surgery that minimizes bleeding and decreases the vascular clamping time.