Anti-Inflammatory Actions of Expectorants in a Rat Carrageenan-Induced Footpad Edema Model.

S-Carboxymethyl-L-cysteine (SCMS) exhibits sputum-regulating and anti-inflammatory actions. Previous studies reported the anti-inflammatory effects of SCMS on chronic inflammatory diseases, but no study has examined these effects on acute inflammatory diseases. In this study, we investigated the anti-inflammatory effects of SCMS in a rat carrageenan-induced footpad edema model, which is routinely used as an acute inflammation model. Expectorants were administered to rats with footpad edema induced by subcutaneously administering 1%λ-carrageenan to the footpad of the left posterior limb, and the dose dependency of the anti-inflammatory effects was evaluated. As a result, even when the dose of SCMS was increased to 400 mg/kg, there were no inhibitory effects on edema. Furthermore, we examined the inhibitory effects of other expectorants (ambroxol hydrochloride, N-acetyl-L-cysteine, L-cysteine ethylester hydrochloride, and L-cysteine methylester hydrochloride), which were reported to exhibit anti-inflammatory effects on chronic inflammation, on edema. However, none of these expectorants inhibited edema.

Classification of osteonecrosis of the femoral head: Who should have surgery?

OBJECTIVES: Using a simple classification method, we aimed to estimate the collapse rate due to osteonecrosis of the femoral head (ONFH) in order to develop treatment guidelines for joint-preserving surgeries. METHODS: We retrospectively analyzed 505 hips from 310 patients (141 men, 169 women; mean age 45.5 years (sd 14.9; 15 to 86)) diagnosed with ONFH and classified them using the Japanese Investigation Committee (JIC) classification. The JIC system includes four visualized types based on the location and size of osteonecrotic lesions on weightbearing surfaces (types A, B, C1, and C2) and the stage of ONFH. The collapse rate due to ONFH was calculated using Kaplan-Meier survival analysis, with radiological collapse/arthroplasty as endpoints. RESULTS: Bilateral cases accounted for 390 hips, while unilateral cases accounted for 115. According to the JIC types, 21 hips were type A, 34 were type B, 173 were type C1, and 277 were type C2. At initial diagnosis, 238/505 hips (47.0%) had already collapsed. Further, the cumulative survival rate was analyzed in 212 precollapsed hips, and the two-year and five-year collapse rates were found to be 0% and 0%, 7.9% and 7.9%, 23.2% and 36.6%, and 57.8% and 84.8% for types A, B, C1, and C2, respectively. CONCLUSION: Type A ONFH needs no further treatment, but precollapse type C2 ONFH warrants immediate treatment with joint-preserving surgery. Considering the high collapse rate, our study results justify the importance of early diagnosis and intervention in asymptomatic patients with type C2 ONFH.Cite this article: Y. Kuroda, T. Tanaka, T. Miyagawa, T. Kawai, K. Goto, S. Tanaka, S. Matsuda, H. Akiyama. Classification of osteonecrosis of the femoral head: Who should have surgery?. Bone Joint Res 2019;8:451-458. DOI: 10.1302/2046-3758.810.BJR-2019-0022.R1.

The use of a bioactive bone cement containing apatite-wollastonite glass-ceramic filler and bisphenol-a-glycidyl methacrylate resin for acetabular fixation in total hip arthroplasty: long-term follow-up results of a clinical trial.

AIMS: In the 1990s, a bioactive bone cement (BABC) containing apatite-wollastonite glass-ceramic (AW-GC) powder and bisphenol-a-glycidyl methacrylate resin was developed at our hospital. In 1996, we used BABC to fix the acetabular component in primary total hip arthroplasty (THA) in 20 patients as part of a clinical trial. The purpose of this study was to investigate the long-term results of primary THA using BABC. PATIENTS AND METHODS: A total of 20 patients (three men and 17 women) with a mean age of 57.4 years (40 to 71), a mean body weight of 52.3 kg (39 to 64), and a mean body mass index (BMI) of 23.0 kg/m2 (19.8 to 28.6) were evaluated clinically and radiologically. Survival analyses were undertaken, and wear analyses were carried out using a computer-aided method. RESULTS: The mean follow-up was 17.6 years (1.5 to 21.1). Radiological loosening occurred in four sockets with aseptic loosening at a mean of 7.8 years (1.5 to 20.7). Kaplan-Meier survival analyses using revision of the acetabular component, radiological loosening of the acetabular component, and the worst-case scenario with revision of the acetabular component to include the two patients lost to follow-up as endpoints yielded survival rates of 94.7%, 84.4%, and 85.0% at ten years, and 70.0%, 84.4%, and 62.8% at 20 years, respectively. Wear analysis revealed a mean linear wear rate of 0.068 mm per year. CONCLUSION: The long-term results of primary THAs using BABC were unsatisfactory. Its brittle nature and poor handling properties need to be improved before it becomes an alternative method of fixing the acetabular component in cemented THA. Cite this article: Bone Joint J 2019;101-B:787-792.

Erratum: iPS-derived MSCs from an expandable bank to deliver a prodrug-converting enzyme that limits growth and metastases of human breast cancers.

[This corrects the article DOI: 10.1038/cddiscovery.2016.64.].

iPS-derived MSCs from an expandable bank to deliver a prodrug-converting enzyme that limits growth and metastases of human breast cancers.

One attractive strategy to treat cancers is to deliver an exogenous enzyme that will convert a non-toxic compound to a highly toxic derivative. The strategy was tested with viral vectors but was disappointing because the efficiency of transduction into tumor cells was too low. Recent reports demonstrated that the limitation can be addressed by using tissue-derived mesenchymal stromal cells (MSCs) to deliver enzyme/prodrug systems that kill adjacent cancer cells through bystander effects. Here we addressed the limitation that tissue-derived MSCs vary in their properties and are difficult to generate in the large numbers needed for clinical applications. We prepared a Feeder Stock of MSCs from induced pluripotent stem cells (iPSs) that provided an extensively expandable source of standardized cells. We then transduced the iPS-derived MSCs to express cytosine deaminase and injected them locally into a mouse xenogeneic model of human breast cancer. After administration of the prodrug (5-fluorocytosine), the transduced iPS-MSCs both limited growth of preformed tumors and decreased lung metastases.

A Distinct Subpopulation of Bone Marrow Mesenchymal Stem Cells, Muse Cells, Directly Commit to the Replacement of Liver Components.

Genotyping graft livers by short tandem repeats after human living-donor liver transplantation (n = 20) revealed the presence of recipient or chimeric genotype cases in hepatocytes (6 of 17, 35.3%), sinusoidal cells (18 of 18, 100%), cholangiocytes (15 of 17, 88.2%) and cells in the periportal areas (7 of 8, 87.5%), suggesting extrahepatic cell involvement in liver regeneration. Regarding extrahepatic origin, bone marrow mesenchymal stem cells (BM-MSCs) have been suggested to contribute to liver regeneration but compose a heterogeneous population. We focused on a more specific subpopulation (1-2% of BM-MSCs), called multilineage-differentiating stress-enduring (Muse) cells, for their ability to differentiate into liver-lineage cells and repair tissue. We generated a physical partial hepatectomy model in immunodeficient mice and injected green fluorescent protein (GFP)-labeled human BM-MSC Muse cells intravenously (n = 20). Immunohistochemistry, fluorescence in situ hybridization and species-specific polymerase chain reaction revealed that they integrated into regenerating areas and expressed liver progenitor markers during the early phase and then differentiated spontaneously into major liver components, including hepatocytes (≈74.3% of GFP-positive integrated Muse cells), cholangiocytes (≈17.7%), sinusoidal endothelial cells (≈2.0%), and Kupffer cells (≈6.0%). In contrast, the remaining cells in the BM-MSCs were not detected in the liver for up to 4 weeks. These results suggest that Muse cells are the predominant population of BM-MSCs that are capable of replacing major liver components during liver regeneration.

Pim-2 kinase is an important target of treatment for tumor progression and bone loss in myeloma.

Pim-2 kinase is overexpressed in multiple myeloma (MM) cells to enhance their growth and survival, and regarded as a novel therapeutic target in MM. However, the impact of Pim-2 inhibition on bone disease in MM remains unknown. We demonstrated here that Pim-2 expression was also upregulated in bone marrow stromal cells and MC3T3-E1 preosteoblastic cells in the presence of cytokines known as the inhibitors of osteoblastogenesis in MM, including interleukin-3 (IL-3), IL-7, tumor necrosis factor-α, transforming growth factor-ß (TGF-ß) and activin A, as well as MM cell conditioned media. The enforced expression of Pim-2 abrogated in vitro osteoblastogenesis by BMP-2, which suggested Pim-2 as a negative regulator for osteoblastogenesis. Treatment with Pim-2 short-interference RNA as well as the Pim inhibitor SMI-16a successfully restored osteoblastogenesis suppressed by all the above inhibitory factors and MM cells. The SMI-16a treatment potentiated BMP-2-mediated anabolic signaling while suppressing TGF-ß signaling. Furthermore, treatment with the newly synthesized thiazolidine-2,4-dione congener, 12a-OH, as well as its prototypic SMI-16a effectively prevented bone destruction while suppressing MM tumor growth in MM animal models. Thus, Pim-2 may have a pivotal role in tumor progression and bone loss in MM, and Pim-2 inhibition may become an important therapeutic strategy to target the MM cell-bone marrow interaction.

Phase II trial of preoperative chemotherapy for breast cancer: Japan Breast Cancer Research Network (JBCRN)-02 trial.

BACKGROUND: Neoadjuvant chemotherapy (NAC) is one of the main strategies for patients with locally advanced breast cancer. In our previous study, biological markers such as estrogen receptor (ER), progesterone receptor (PgR), and HER2 were essential predictors of the effectiveness of NAC to help individualize treatment. This study examined the effect of NAC on the disease-free survival (DFS) of breast cancer patients. Furthermore, the study was expanded by adding Ki-67 as a biological marker, and examined the correlation between Ki-67 and the prognosis. PATIENTS AND METHODS: Between September 2005 and September 2007, 43 patients with breast cancer received NAC and surgery. Four cycles of DC (doxorubicin: 60 mg/m(2) and cyclophosphamide: 500 mg/m(2)) were administered intravenously (i.v.) on day 1 every 21 days, followed by 12 cycles of paclitaxel i.v. (80 mg/m(2)) every 7 days, prior to surgery. The primary endpoint was the pathological complete response (pCR) rate and the secondary endpoint was DFS; the pCR rate was estimated for each groups stratified by the presence or absence of different factors (PcR, ER/PgR, and Ki-67). RESULTS: The clinical response (cCR+cPR) rate was 81.0%, and the pCR rate was 25.6%. The pCR rate was 75, 50, 9 and 0% in HER2(+)/ER(-), HER2(+)/ER(+), HER2(-)/ER(-), and HER2(-)/ER(+) patients, respectively. The 4-year DFS rate was estimated at 78% for all patients. The HER2 status was an independent predictor of pathological complete response (pCR). The DFS rate of patients with lower Ki-67 values (<15%) was higher than that of patients with higher Ki-67 values (≥15%). The treatment-related adverse events were manageable: the majority were mild, but five patients experienced grade 3 (neutropenia and sensory neuropathy) adverse events. CONCLUSION: DC followed by weekly paclitaxel is an active and manageable preoperative regimen for breast cancer patients. HER2 overexpression may be a good predictive marker of pCR, and the Ki-67 value after NAC may be a prognostic factor for DFS.

Efficacy of S-1 in patients with capecitabine-resistant breast cancer-Japan Breast Cancer Research Network (JBCRN) 04-1 trial.

BACKGROUND: S-1 is an orally administered fluorinated pyrimidine with high activity in metastatic breast carcinoma (MBC) and in chemotherapy-pretreated metastatic breast carcinoma. PATIENTS AND METHODS: Forty patients with MBC who did not respond to capecitabine-based chemo-therapy and then received S-1 were identified from our data base of records between 2006 and 2008. The clinico-pathological data and outcomes of these patients were then reviewed. RESULTS: The overall response rate was 27.8%. The median survival was 19.2 months, and the median time to disease progression was 6.2 months. The most common treatment-related adverse events (all grades) were hand-foot syndrome (15%), nausea (15%), vomiting (7.5%), disorder of taste (7.5%), and diarrhea (5%). However, the majority were mild to moderate in intensity, and only one patient experienced grade 3 (according to the National Cancer Institute of Canada Common Toxicity criteria) adverse events. Myelosuppression and alopecia were rare, and there were no reported treatment-related deaths. CONCLUSION: The results of the current study demonstrate that S-1 is an effective and well-tolerated treatment in patients with capecitabine-resistant MBC. In addition, it is a convenient, orally administered drug, which makes it an attractive agent for use in outpatient treatment.

Insulin-mediated regulation of decidual protein induced by progesterone (DEPP) in adipose tissue and liver.

We analyzed the profile of the genes expressed in human adipose tissue and identified the fat-derived molecules, adiponectin and aquaporin 7, which modulate glucose and lipid metabolism. The same Bodymap analysis revealed abundant expression of the decidual protein induced by progesterone (DEPP) in the white adipose tissue. Northern blot analysis confirmed that human DEPP mRNA was highly expressed in white adipose tissue. Mouse DEPP mRNA was detected in heart, lung, skeletal muscle, and white adipose tissue under feeding state. In contrast, under fasting state, mouse DEPP mRNA was enhanced in lung, skeletal muscle, and white adipose tissue and it appeared also in the liver and kidney, suggesting up regulation of DEPP by fasting. Because fasting-induced DEPP expression was observed in insulin-sensitive organs, we investigated the regulation of DEPP in white adipose tissue and liver. During adipogenesis of mouse 3T3-L1 cells, DEPP mRNA increased in a differentiation-dependent manner similar to adiponectin and aquaporin 7. Treatment of cultured 3T3-L1 mature adipocytes, rat H4IIE, and human HepG2 hepatoma cells with insulin significantly decreased DEPP mRNA levels in dose- and time-dependent manners. IN VIVO experiments showed significant decrease of hepatic and adipose DEPP mRNA levels in refed mice, compared to fasted animals, and also showed significant increase in DEPP mRNA in streptozotocin-induced insulin-deficient diabetic mice. These results indicate that DEPP is a novel insulin-regulatory molecule expressed abundantly in insulin-sensitive tissues including white adipose tissue and liver.

[Aortic valve replacement through right thoracotomy; report of a case].

A 78-year-old female was admitted to our hospital with a diagnosis of severe aortic valve regurgitation. She had had dyspnea on effort and syncope twice in 5 months. She had also suffered from right pneumonia 8 years before, and her respiratory function was severely constrictive. Chest X-ray showed her mediastinum significantly shifted toward the right side. Chest computed tomography (CT) revealed the main pulmonary artery, right atrium (RA) and right pulmonary veins also shifted toward the right. We planned right thoracotomy at 4th intercostals space to obtain a good surgical field. A cardiopulmonary bypass was established by RA appendage drainage and femoral artery perfusion. Aortic valve replacement(AVR) was performed successfully after aortic clamp. Though defibrillator pads were placed on her back and the anterior wall of the left chest during operation, no ventricular fibrillation occurred. AVR via right thoracotomy is considered to be a good option for such a mediastinum shifted case.

[Metastatic lung cancer origin from osteosarcoma of mandible invading tracheal lumen].

A 52-year-old woman underwent the surgical treatment for osteosarcoma of the left mandible in 2003 and was followed up afterward. She suffered from dry cough and bloody sputum, and was admitted to our hospital in April 2007. Computed tomography (CT) revealed several nodules in bilateral lung, and bronchofiberscopy showed the endobronchial tumor obstructing in the right main bronchus. The metastatic tumor progressed in the right main bronchus from the right S6 lung segment. The tumor rapidly progressed in the right bronchus in comparison with the CT findings in about 2 weeks, and the possibility of the tracheal obstruction was considered. She underwent the right middle and lower lobectomy, and the endobronchial tumor was pulled through the right main bronchus. The postoperative course was uneventful, the patient was discharged on 14th postoperative day, and the chemotherapy using cisplatin (CDDP) and adriamycin (ADR) is on-going.

[Infective endocarditis with acute embolism to the lower extremity artery caused by a vegetation: report of a case].

Successful surgical treatment of a case of infective endocarditis with embolism to a lower extremity artery is reported. A 71-year-old man was referred to our hospital for the treatment of infective endocarditis. Echocardiography showed a vegetation on the non-coronary cusp of the aortic valve measuring 19 mm in diameter. We planned surgical treatment, including aortic valve replacement, however, embolism of a lower extremity artery by the vegetation occurred during the waiting period for the operation. We removed the offending vegetation from the popliteal artery and replaced the peccant aortic valve with a prosthetic valve in separate operations. The postoperative course was uneventful and the patient was transferred to another hospital on the 33rd day after the valve replacement surgery.

Hypermethylation-mediated reduction of WWOX expression in intraductal papillary mucinous neoplasms of the pancreas.

We have previously shown that WW domain-containing oxidoreductase (WWOX) has tumour-suppressing effects and that its expression is frequently reduced in pancreatic carcinoma. In this study, we examined WWOX expression in intraductal papillary mucinous neoplasm of the pancreas (IPMN) to assess the function of WWOX in pancreatic duct tumourigenesis using immunohistochemistry and methylation-specific polymerase chain reaction analysis. Among 41 IPMNs including intraductal papillary mucinous adenomas (IPMAs) and intraductal papillary mucinous carcinomas (IPMCs), loss or reduced WWOX immunoreactivity was detected in 3 (15%) of 20 IPMAs and 17 (81%) of 21 IPMCs. In addition, hypermethylation of the WWOX regulatory site was detected in 1 (33%) of 3 WWOX(-) IPMAs and 9 (53%) of 17 WWOX(-) IPMCs, suggesting that hypermethylation may possibly be important in the suppression of WWOX expression. Reduction of WWOX expression was significantly correlated with a higher Ki-67 labelling index but was not correlated with the ssDNA apoptotic body index. Interestingly, decreased WWOX expression was significantly correlated with loss of SMAD4 expression in these IPMNs. The results indicate that downregulation of WWOX expression by the WWOX regulatory region hypermethylation is critical for transformation of pancreatic duct.

Present status of pancreas transplantation in Japan--donation predominantly from marginal donors and modified surgical technique: report of Japan pancreas transplantation registry.

In Japan, organ donation has been still limited because of the strict donor criteria. The aim of this study was to show the effectiveness of pancreas transplantation (PTx) by analyzing the outcomes even under poor donor conditions. Thirty-six cases of PTx (32 simultaneous pancreas and kidney transplantations [SPK], 4 pancreas after kidney transplantations) performed during the last 8 years were examined especially for donor characteristics. Mean donor age of 41.4 +/- 11.9 years was considerably older compared with that in the United States and Europe; donors aged over 40 years comprised 67% of the total. According to the criteria described by Kapur, 29 cases (81%) in our series would be considered marginal. Thus, to increase blood supply into the pancreatic head, the gastroduodenal artery (GDA) was anastomosed using donor artery to common hepatic artery or iliac Y graft. These procedures were performed in 16 of the 24 cases in which there was liver procurement. Eventually, 34 cases (94%) preserved GDA continuity. Mean total cold ischemic time of pancreatic grafts was 12 hours 15 minutes. Of 214 registrants, 17 patients on the waiting list for SPK died of diabetic complications. To date, patient survival remains 100% with a mean follow-up period of 33 months. Pancreas graft survivals at 1, 3, and 5 years posttransplantation were 92%, 80%, and 80%, respectively. In contrast, kidney survivals were 91%, 91%, and 91%, respectively. The integrity of the pancreas head and duodenum by preservation of the GDA continuity might have decreased the risk associated with the marginal donors.

[Right lung cancer with right aortic arch].

An abnormal shadow was detected on chest X-ray mass screening in an asymptomatic 63-year-old man. The further examinations revealed the shadow to be primary lung cancer (Rt. S6. adenocarcinoma, cT2N0M0, c-stage IB) with right aortic arch. We used 3 dimentional-computed tomography (3D-CT) to assess an anatomical feature of vessels in detail. The right lower lobectomy and the dissection of medi astinal lymph nodes was performed. We confirmed no abnormal anatomy of pulmonary artery and vein at surgery, and it was possible to perform right lower lobectomy with the common procedure. Since lymph node was found by intraopetrative pathological examination, since no metastasis from interlobar to subcarinal lymph node was found, we did not perform dissection of upper mediastinal dissection, which was equivalent to ND2a lymph nodes dissection of the left lung cancer in General Rule for Clinical and Pathological Record of Lung Cancer. The patient with right aortic arch is known to have variant anatomy of other intrathoracic vessels occasionally. 3D-CT was quite useful in assessing anatomical feature, and enabled us to perform safe operation.