Feasibility of novel PPP1R15A and proposed ANXA11 single nucleotide polymorphisms as predictive markers for bevacizumab regimen in metastatic colorectal cancer.

PURPOSE: Bevacizumab improves survival in patients with metastatic colorectal cancer (mCRC) under chemotherapy, but few predictive markers have been identified. METHODS: To investigate chemosensitive single nucleotide polymorphisms (SNPs) of mCRC, we performed exome sequencing and RNA sequencing in 19 patients. A clinical association analysis was performed with the other 116 patients who had received chemotherapy to bevacizumab regimens. In vivo biodistribution studies and [(18)F]FDG-PET imaging were performed on mice bearing human colorectal cancer (HCT116 and SW480) xenografts after injection of bevacizumab with 5-FU, leucovorin, and irinotecan (FOLFIRI). RESULTS: PPP1R15A rs557806 showed the most significant association with FRB-driven tumor IR in exome sequencing and the highest correlation (r = 0.74) with drug responses in RNA sequencing. Patients homozygous for the reference alleles (GG) of PPP1R15A rs557806 exhibited greater disease control rate and a tendency toward greater objective response rate (ORR) than those with homozygous or heterozygous substitution alleles (GC and CC; P = 0.027 and 0.073, respectively). In xenografted mice, HCT116 clones transfected with the G allele at PPP1R15A rs557806 were more sensitive to bevacizumab regimens than those with the C allele. Tumor volume of xenografts with the G allele was significantly lower than that of xenografts with the C allele (P = 0.004, day 13). [(18)F]FDG uptake decreased to 75 % in HCT116 xenograft-bearing mice with the G allele, whereas [(18)F]FDG uptake was 42 % in mice xenografts with the C allele (P = 0.032). ANXA11 rs1049550, a predictive biomarker of SNP described in our previous study, was validated using the xenograft model. Tumor volume and [(18)F]FDG uptake analyses showed that tumors in the SW480 xenografts expressing the substitution allele (T) at ANXA11 rs1049550 were more susceptible to FOLFIRI plus bevacizumab-induced suppression than those expressing the reference allele (C) (P = 0.001 and 0.026, respectively). CONCLUSION: ANXA11 rs1049550 and PPP1R15A rs557806 may improve the identification of mCRC patients sensitive to bevacizumab regimens, and further validation is required in large cohorts.

The Early Result of Cementless Arthroplasty for Femur Neck Fracture in Elderly Patients with Severe Osteoporosis.

PURPOSE: The purposes of the current study were to assess the early results of cementless hip arthroplasty (HA) for femoral neck fractures in elderly patients with severe osteoporosis and to compare the clinical outcomes between those who underwent total HA (THA) or bipolar hemiarthroplasty (BHA). MATERIALS AND METHODS: From April 2011 to May 2012, we performed 87 cementless HAs for displaced femoral neck fractures in elderly patients (≥65 years) with severe osteoporosis. Among them, we studied 70 hips that were able to be followed-up for >24 months. Of these, 34 underwent THA and 36 underwent BHA. Clinical results were evaluated using the Harris hip score (HHS), Koval classification, and radiographs. RESULTS: Only one instance of femoral stem loosening was observed. Additionally, no dislocations were observed and no revision surgeries were required. The mean changes in the functional items of the HHS scores were 2.8 and 5.2 for those who underwent THA and BHA, respectively (P<0.05). According to the Koval classification used for the ambulatory status analysis, the mean perioperative change in the grade was 0.8 (0-4), with no significant differences noted between the THA and BHA groups. CONCLUSION: The early results of cementless HA for femur neck fractures in elderly patients with osteoporosis were satisfactory, and THA was found to have a functional advantage over BHA.

Comparison of manual rasping and robotic milling for short metaphyseal-fitting stem implantation in total hip arthroplasty: a cadaveric study.

OBJECTIVE: The ROBODOC system offers the theoretical advantage of providing better fit and mechanical stability of the stem in total hip arthroplasty. However, there has been no previous study on short metaphyseal-fitting stem implantation using the ROBODOC system. The aim of the present study was to compare the implant position and primary stability of short metaphyseal-fitting stems implanted by robotic milling and manual rasping in a human cadaveric femoral model. METHODS: Eight matched pairs of human cadaveric femora were randomly assigned to a robotic milling group or manual rasping group. Operative time and intraoperative femoral fractures were monitored, and radiographic evaluation of stem alignment was performed by comparison of preoperative planning and postoperative CT data. Stability testing was performed on six matched pairs of femora, excluding two specimens in which intraoperative fractures occurred. RESULTS: The robotic milling procedures took an average of 27 minutes longer than the manual rasping procedures (p < 0.001). The robotic milling group exhibited significantly better anteroposterior alignment and vertical seating, and also showed a significantly reduced variability in both alignment and vertical seating. No intraoperative femoral fracture was detected in the robotic milling group, whereas two femoral fractures and one femoral stem tip perforation were detected in the manual rasping group. Stability testing showed no significant difference in translational and rotational migrations between the two groups, although the robotic milling group showed a trend towards reduced variability of stability. CONCLUSIONS: Our cadaveric study suggests that the use of the ROBODOC system for short metaphyseal-fitting stem implantation may have advantages in improving implant fit and reducing the risk of intraoperative femoral fractures without compromising primary stability.

Cementless total hip arthroplasty in renal transplant patients.

We present our experience of contemporary cementless total hip arthroplasty (THA) conducted at a single institution to treat advanced avascular necrosis (AVN) in renal transplant patients. Between October 1997 and October 2008, 45 consecutive primary cementless THAs were performed in 30 patients with advanced AVN after renal transplantation. There were 18 males (27 hips) and 12 females (18 hips) (patient group) with an overall mean age 44 years (22 to 68). The clinical and radiographic results were compared with those of 96 sex and age-matched osteonecrotic hips in 72 patients that had not undergone organ transplantation or long-term steroid therapy (the control group). Patients were evaluated at surgery and at a mean of 7.2 years (2 to 13 years) postoperatively. The mean Harris hip score of patients improved from 48 points preoperatively to 94 points at last follow-up (p<0.05). Three hips in the patient group had massive osteolysis with polyethylene wear requiring revision surgery. One hip in the patient group underwent revision surgery because of recurrent dislocation at 11 years postoperatively. No intergroup differences in overall rates of complications or revisions were observed. However, transplant patients had a significantly higher rate of ectopic ossification. Despite diffuse osteopenia and chronic immunosuppression in renal transplant patients with osteonecrotic hips, cementless THA showed durable implant fixation to bone and no increased risk of complications.

Open repair and arthroscopic follow-up of severely delaminated femoral head cartilage associated with traumatic obturator fracture-dislocation of the hip.

This article describes an unusual case of a young adult with traumatic obturator fracture-dislocation of the hip, involving a large femoral head fragment and severe delamination of articular cartilage. The dislocation was irreducible by closed reduction because of interposing soft tissues, including the rectus femoris and iliopsoas muscles, and torn joint capsules, and therefore, open reduction was performed using an anterolateral approach in the lateral decubitus position. The large femoral head fragment was released from the ligamentum teres and fixed to the dislocated femoral head with headless screws. The severely delaminated femoral head cartilage was repaired with suture anchors and absorbable sutures. The patient was kept nonweight bearing for 6 weeks postoperatively, and was then allowed to resume full weight bearing gradually. He returned to normal activities of daily living at 14 weeks. At 9 months postoperatively, arthroscopic examination showed complete healing of the fracture and cartilage lesions, and at 12-month follow-up, there was no clinical or radiographic evidence of arthritis or osteonecrosis. The patient had no pain or limp, and achieved an excellent result according to Epstein's clinical evaluation criteria. To our knowledge, no previous report exists on the arthroscopic follow-up of a repaired femoral head cartilage in patients with obturator fracture-dislocation of the hip along with a large femoral head fragment and severe delamination of articular cartilage.

A comparative study of the posterolateral and anterolateral approaches for isolated acetabular revision.

PURPOSE: Although isolated revision of the acetabular component has become an increasingly common option for revision hip surgery, opinions differ regarding the ideal surgical approach for reducing postoperative instability. The purpose of this study was to compare the clinical and radiographic results of isolated acetabular revision performed using a posterolateral and an anterolateral approach. MATERIALS AND METHODS: The authors retrospectively compared the clinical and radiographic results of isolated acetabular revision performed in 33 hips using a posterolateral approach with those performed in 36 hips using an anterolateral approach. All procedures were performed by a single surgeon and all patients received the same postoperative protocol. Mean duration of follow-up was 4.6 years (range 2-13.2). RESULTS: Mean postoperative Harris hip scores were similar in the posterolateral and anterolateral groups (86.5 and 87.2 points, respectively). In the entire series of 69 hips, 6 (9%) underwent re-revision of the acetabular component because of aseptic cup loosening in 4, recurrent dislocation in 1, and deep infection in 1. No significant difference was found between the two groups with respect to complication or re-revision rates, but the dislocation rate in the anterolateral approach group was significantly lower than that in the posterolateral group (0 vs. 12%, p = 0.047). CONCLUSION: Isolated acetabular revision performed using an anterolateral approach seems to be the more viable option in selected patients, and in particular, it has a significantly lower postoperative dislocation rate than posterolateral acetabular revision.

TXNIP regulates germinal center generation by suppressing BCL-6 expression.

The detailed mechanism driving the germinal center (GC) reaction to B cell lymphomagenesis has not been clarified. Thioredoxin interacting protein (TXNIP), also known as vitamin D3 up-regulated protein 1 which is an important tumor repressor, is involved in stress responses, redox regulation, and cellular proliferation. Here, we report that TXNIP has a potential role in the formation of GC in peripheral lymphoid organs where B lymphocytes divide rapidly. First, we compared changes in GC from wild type mice and Txnip(-/-) mice. After immunization, Txnip(-/-) mice exhibited higher expression level of BCL-6 and larger percentage of GC B cells with the reduction in antibody production and plasma cell numbers. In addition, Txnip(-/-) spleens had a much larger population which expressed Ki-67, a marker of cell proliferation, in the red pulp border than WT spleens. Furthermore, the expression of BCL-6 was decreased in TXNIP overexpressing cells and elevated in TXNIP deficient cells. Taken together, we conclude that TXNIP may contribute to the formation of GCs after immunization. During this process, TXNIP suppresses BCL-6 expression.