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2.  P31: Salvage surgery for PMGCT: beneficial for persistent positive-marker patients? 
Journal of Thoracic Disease  2015;7(Suppl 3):AB100.
Primary mediastinal germ cell tumors (PMGCT) are rare and high-grade malignant tumors. Mainstay treatment for PMGCT is systemic chemotherapy, and salvage surgery for residual tumor is considered in patients with normalized tumor makers. However, survival benefit of salvage surgery for persistent positive-marker patients remains unclear. The purpose is to clarify the outcome of salvage surgery for PMGCT.
A total of eight patients undergoing salvage surgery for PMGCT in our institution from July 2000 to February 2013 were enrolled. Surgical outcomes of these patients were retrospectively analyzed.
All patients were men and the median age was 25 years (range, 18–37 years). Histological type was seminoma in one and non-seminomatous germ cell tumor in seven. Serum alpha-fetoprotein (AFP) level was initially elevated in seven patients. All patients received primary chemotherapy consisting of bleomycin, etoposide, and cisplatin with a median cycle of 3 (range, 3–4). Four patients additionally received 2nd (n=2), 3rd (n=1), or 4th (n=1) line chemotherapy. AFP level normalized in five patients. Complete R0 resection was achieved and serum AFP level normalized in all patients. Median duration of postoperative hospital stay was 7 days (range, 5–11 days), and there was no morbidity or mortality. Pathological complete response was observed in four patients. The median recurrence-free and overall survival (RFS and OS) periods for all eight patients were 31 (range, 6–74) and 31 (range, 15–74) months, respectively. All of the five patients with preoperatively normalized AFP levels were alive without recurrence, with a median follow-up period of 56 (range, 26–74) months. Of the three persistent AFP-positive patients, two were alive without recurrence at 24 and 33 months after surgery.
We confirmed that complete resection of residual PMGCT achieved favorable prognosis in patients with preoperatively normalized AFP levels. This study suggests that salvage surgery might be beneficial even in persistent positive-marker patients if complete resection is deemed possible.
PMCID: PMC4700304
Primary mediastinal germ cell tumors (PMGCT); salvage surgery; alpha-fetoprotein (AFP); complete resection
3.  Does the Extent of Osteonecrosis Affect the Survival of Hip Resurfacing? 
The effect of the extent of osteonecrosis on the survival of hip resurfacing for osteonecrosis of the femoral head (ONFH) has not been well documented, but is a potentially important variable in the decision to perform resurfacing.
We examined (1) the relationship between the volume of osteonecrosis in the femoral head before surgery and the extent of the residual necrotic bone after femoral head machining, (2) how the extent of the residual necrotic bone relative to the resurfaced femoral head (after femoral head machining) affected the survival of total hip resurfacing for patients with ONFH, and (3) how the extent of the necrotic bone relative to the entire femoral head (before femoral head machining) affected the survival and clinical outcome scores of patients who underwent total hip resurfacing.
Thirty-three patients (39 hips) who underwent hip resurfacing were reviewed after a mean followup of 8 years. The extent of osteonecrosis in the femoral head and residual osteonecrosis in the implant bony bed after femoral head machining were estimated using a three-dimensional MRI-based templating system.
There was a statistically significant difference in the extent of osteonecrosis before and after femoral head machining, although the two were well correlated (r = 0.97). The mean percentage of osteonecrosis in the implant bony bed after femoral head machining was 5% smaller than that relative to the entire femoral head (range, −9% to 15%). There were no significant differences in implant survival between groups with small and large osteonecrosis classified by either the total amount of osteonecrosis before surgery or residual osteonecrosis after femoral head machining.
The extent of osteonecrosis in the femoral head significantly decreased after femoral head machining. Neither the residual osteonecrosis volume in the implant bony bed after femoral head machining nor the total amount of osteonecrosis before femoral head machining had significant influence on the survival of hip resurfacing.
Level of Evidence
Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.
PMCID: PMC3706687  PMID: 23397316
4.  Modular acetabular reconstructive cup in acetabular revision total hip arthroplasty at a minimum ten year follow-up 
International Orthopaedics  2013;37(4):605-610.
Modular acetabular reconstructive cups have been introduced in an attempt to offer initial rigid fixation by iliac lag screws and ischial pegs, to support bone grafts with a flanged metal socket, and to restore original hip center in acetabular revision. The purpose of this study was to clarify minimum ten year follow-up results of this cup system with morsellised allografts in revision cases.
We retrospectively investigated 54 acetabular revisions at a mean of 11 years (range, ten to 14 years). The indications were Paprosky’s type 2B (eight hip), 2C (eight hips), 3A (23 hips), 3B (nine hips), and 4 (six hips).
Using aseptic loosening as the endpoints, the survival rate was 89.3 % (95 % CI 81–98). Radiographically, one type 3A hip, three type 3B hips and one type 4 hip showed aseptic loosening while no type 2 hips or no cemented cups showed loosening.
The modular reconstructive cups for acetabular revision showed bone stock restoration and stable implantation.
PMCID: PMC3609976  PMID: 23423427
5.  Nucling, a novel protein associated with NF-κB, regulates endotoxin-induced apoptosis in vivo 
Journal of Biochemistry  2012;153(1):93-101.
Nucling is a proapoptotic protein that regulates the apoptosome and nuclear factor-kappa B (NF-κB) signalling pathways. Strong stimuli, such as Gram-negative bacterial lipopolysaccharide (LPS), induce the simultaneous secretion of cytokines following the activation of NF-κB. Proinflammatory cytokines can induce liver damage through several mechanisms such as increases in oxidative stress and apoptotic reactions leading to tissue necrosis. Herein, we show that Nucling-knockout (KO) mice are resistant to LPS that consistently caused mortality in wild-type (WT) counterparts. Although serum levels of cytokines such as tumour necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 did not differ significantly between WT and Nucling-KO mice after the LPS challenge, hepatocytes of Nucling-KO mice were refractory to LPS- or TNF-α-induced cell death. These results were consistent with the decreased expression of proapoptotic proteins including apoptosis-inducing factor and cleaved form of poly (ADP-ribose) polymerase and terminal deoxynucleotidyl transferase dUTP nick end-labelling positive cells in the liver of Nucling-KO mice after the administration of a lethal dose of LPS. Moreover, the upregulation of NF-κB-regulated anti-apoptotic molecules including cellular inhibitor of apoptosis (cIAP) 1 and cIAP2 was observed in the liver of Nucling-KO mice after LPS treatment. These findings indicate that the Nucling deficiency leads to resistance to apoptosis in liver. We propose that Nucling is important for the induction of apoptosis in cells damaged by cytotoxic stressors through the NF-κB signalling pathway.
PMCID: PMC3527998  PMID: 23071121
apoptosis; hepatocyte; lipopolysaccharide; nucling; NF-κB
6.  Does CT-Based Navigation Improve the Long-Term Survival in Ceramic-on-Ceramic THA? 
Although navigated THA provides improved precision in implant positioning and alignment, it is unclear whether these translate into long-term implant survival.
We compared survivorship, dislocation rate, and incidence of radiographic failures such as loosening and bearing breakage after THA with and without navigation at a minimum 10-year followup.
We retrospectively reviewed 46 patients (60 hips) and 97 patients (120 hips) receiving THA with or without a CT-based navigation system, respectively, using cementless THA ceramic-on-ceramic bearing couples. There were no differences in age, sex, diagnosis, height, weight, BMI, or preoperative clinical score between groups. We evaluated survivorship, mode of acetabular and femoral component fixation, osteolysis, and implant wear or breakage at a minimum followup of 10 years (average, 11 years; range, 10–13 years).
Survival at 13 years was 100% with navigation and 95.6% (95% CI, 88.4%–98.4%) without navigation. With navigation, all cups were placed within a zone of 40° (range, 30°–50°) of radiographic inclination and 15° (range, 5°–15°) of radiographic anteversion; without navigation, 31 cups (26%) were placed outside this zone. Hips treated without navigation had a higher rate of dislocation (8%) than the navigated cases (0%). Revision was performed in four nonnavigated cases, all of which showed evidence of neck impingement on the ceramic liner. Moreover, seven other cases without navigation showed posterior neck erosion on radiographs. These 11 impingement-related mechanical complications correlated with cup malorientation, and the incidence of impingement-related complications was higher in nonnavigated cases.
Navigation reduced the rates of dislocation and impingement-related mechanical complications leading to revision in cementless THA using ceramic-on-ceramic bearing couples over a minimum 10-year followup.
Level of Evidence
Level III, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.
PMCID: PMC3462880  PMID: 22569720
7.  High Survival of Dome Pelvic Osteotomy in Patients with Early Osteoarthritis from Hip Dysplasia 
The Chiari osteotomy reportedly has a 60% to 91% survival rate at a minimum 20 years followup. The dome pelvic osteotomy (DPO) has the advantage of allowing a larger weightbearing surface, and congruity in the sagittal plane presumably would reduce the joint contact stress and perhaps increase longevity.
We determined: (1) the survival after DPO at a minimum 25-year followup, (2) patient function, (3) acetabular coverage, and (4) factors influencing conversion to THA.
We retrospectively reviewed 50 patients (59 hips) with developmental dysplasia of the hip (DDH) treated with DPO. The preoperative radiographic stages were graded as prearthritis (18 hips), early osteoarthritis (25 hips), and advanced osteoarthritis (16 hips). We performed a Kaplan-Meier survival analysis with THA conversion as the end point. We determined various radiographic parameters reflecting coverage, and compared demographic information for hips without and with THA conversion using multivariate logistic regression analysis. The minimum followup was 25 years (mean, 27.5 years; range, 25–32 years).
Survival for all hips was 63.6% (95% CI, 51–76) at 27.5 years and that for hips with prearthritis and early osteoarthritis before the surgery was 79.1% (95% CI, 63–91). Twenty-one hips (36%) had undergone THAs at a mean 18.3 years (range, 2.5–25 years). At the last followup, pain, walking ability, and acetabular coverage improved. We identified four factors predicting THA conversion: greater age, presence of a preoperative Trendelenburg sign, higher preoperative radiographic osteoarthritis grade, and smaller postoperative acetabular head index (AHI) predicted conversion to THA.
DPO is a reasonable treatment option for patients with DDH and prearthritis or early osteoarthritis, with high survival at greater than 25 years.
Level of Evidence
Level IV, prognostic study. See the Guidelines for Authors for a complete description of levels of evidence.
PMCID: PMC3830085  PMID: 22354611
8.  Is the transverse acetabular ligament a reliable cup orientation guide? 
Acta Orthopaedica  2012;83(5):474-480.
Background and purpose
It is controversial whether the transverse acetabular ligament (TAL) is a reliable guide for determining the cup orientation during total hip arthroplasty (THA). We investigated the variations in TAL anatomy and the TAL-guided cup orientation.
80 hips with osteoarthritis secondary to hip dysplasia (OA) and 80 hips with osteonecrosis of the femoral head (ON) were examined. We compared the anatomical anteversion of TAL and the TAL-guided cup orientation in relation to both disease and gender using 3D reconstruction of computed tomography (CT) images.
Mean TAL anteversion was 11° (SD 10, range –12 to 35). The OA group (least-square mean 16°, 95% confidence interval (CI): 14–18) had larger anteversion than the ON group (least-square mean 6.2°, CI: 3.8 – 7.5). Females (least-square mean 20°, CI: 17–23) had larger anteversion than males (least-square mean 7.0°, CI: 4.6–9.3) in the OA group, while there were no differences between the sexes in the ON group. When TAL was used for anteversion guidance with the radiographic cup inclination fixed at 40°, 39% of OA hips and 9% of ON hips had more than 10° variance from the target anteversion, which was 15°.
In ON hips, TAL is a good guide for determining cup orientation during THA, although it is not a reliable guide in hips with OA secondary to dysplasia. This is because TAL orientation has large individual variation and is influenced by disease and gender.
PMCID: PMC3488173  PMID: 22974185
9.  Is Vertical-center-anterior Angle Equivalent to Anterior Coverage of the Hip? 
We investigated whether the vertical-center-anterior (VCA) angle measured on the false-profile view of the hip represents true anterior coverage by computer simulation using three-dimensional (3-D) computed tomography (CT) in 100 hips without osteoarthritic changes. True anterior coverage angle on the sagittal plane was measured in the pelvic coordinate system. Two types of VCA angle were measured on the digital reconstructed radiographs: the anterior point of the VCA angle was defined as the foremost aspect of the acetabulum, denoted VCA-1, whereas the anterior edge of the dense shadow of the subchondral bone of the acetabulum was defined as VCA-2. In the normal hips, VCA-1 was consistent with anterior coverage angle (r = 0.88, Spearman rank test), whereas VCA-2 underestimated the anterior coverage (r = 0.72). In the dysplastic hips, VCA-2 did not always indicate true anterior coverage (r = 0.64), whereas VCA-1 overestimated the anterior coverage (r = 0.002). Although VCA-1 in normal hips shows true anterior coverage, the VCA angle does not indicate true anterior coverage in dysplastic hips, and VCA angle measurement in dysplastic hips should be used carefully.
Level of Evidence: Level IV, diagnostic study. See Guidelines for Authors for a complete description of levels of evidence.
PMCID: PMC2758969  PMID: 19322617
10.  Proximal bone remodelling differed between two types of titanium long femoral components after cementless revision arthroplasty 
International Orthopaedics  2007;32(4):431-436.
In revision surgery with proximal femoral bone loss, progressive bone atrophy due to stress shielding remains a concern. We compared 2-year radiological results between two types of cementless long titanium stems with different configurations and surface coatings. Of 17 hips implanted with a wholly hydroxyapatite-coated stem, 12 (71%) exhibited stress shielding of the second degree or higher according to Engh’s criteria, and the mean relative bone mass index decreased from 22.1% pre-operatively to 14.6% at 2 years post-operatively. In 23 hips implanted with a sand-blasted, conically shaped stem, no hip showed stress shielding of the second degree or higher. The mean relative bone mass index increased from 21.6% to 31.4%. These results indicate that the configuration and surface coating of the stem have a significant influence on proximal bone remodelling after revision surgery.
PMCID: PMC2532259  PMID: 17464508
11.  Extent of Osteonecrosis on MRI Predicts Humeral Head Collapse 
Although MRI is useful for predicting progression of osteonecrosis (ON) of the femoral head or femoral condyle, predicting outcome of atraumatic osteonecrosis of the humeral head using MRI has not been previously examined. We asked whether the prognosis was related to the extent and location of necrotic lesions on MRI. We investigated 46 radiographically noncollapsed humeral heads in 27 patients, 24 steroid-related and three alcohol-related, using MRI and serial radiographs. The minimum followup was 24 months (mean, 84.9 months; range, 24–166 months). The necrotic lesion was typically located at the medial and superior aspect of the humeral head. The necrotic angle, which expressed the extent of the necrotic lesion, was measured on midoblique-coronal plane (range; 0°–134.7°) and on midoblique-sagittal plane (range; 0°–150.6°). Of the 46 lesions, 34 were less than 90° and did not collapse, whereas 11 of the other 12 lesions of more than 90° (92%) collapsed within 4 years. Of these 11 collapsed lesions, four of less than 100° did not progress, followed by reparative reaction on plain radiographs, whereas the other seven of more than 100° progressed to osteoarthritis. The extent of a necrotic lesion on MRI is useful to predict collapse of the humeral head.
Level of Evidence: Level IV, prognostic study. See the Guidelines for Authors for a complete description of levels of evidence.
PMCID: PMC2311460  PMID: 18350349
12.  Chk2 Is a Tumor Suppressor That Regulates Apoptosis in both an Ataxia Telangiectasia Mutated (ATM)-Dependent and an ATM-Independent Manner 
Molecular and Cellular Biology  2002;22(18):6521-6532.
In response to ionizing radiation (IR), the tumor suppressor p53 is stabilized and promotes either cell cycle arrest or apoptosis. Chk2 activated by IR contributes to this stabilization, possibly by direct phosphorylation. Like p53, Chk2 is mutated in patients with Li-Fraumeni syndrome. Since the ataxia telangiectasia mutated (ATM) gene is required for IR-induced activation of Chk2, it has been assumed that ATM and Chk2 act in a linear pathway leading to p53 activation. To clarify the role of Chk2 in tumorigenesis, we generated gene-targeted Chk2-deficient mice. Unlike ATM−/− and p53−/− mice, Chk2−/− mice do not spontaneously develop tumors, although Chk2 does suppress 7,12-dimethylbenzanthracene-induced skin tumors. Tissues from Chk2−/− mice, including those from the thymus, central nervous system, fibroblasts, epidermis, and hair follicles, show significant defects in IR-induced apoptosis or impaired G1/S arrest. Quantitative comparison of the G1/S checkpoint, apoptosis, and expression of p53 proteins in Chk2−/− versus ATM−/− thymocytes suggested that Chk2 can regulate p53-dependent apoptosis in an ATM-independent manner. IR-induced apoptosis was restored in Chk2−/− thymocytes by reintroduction of the wild-type Chk2 gene but not by a Chk2 gene in which the sites phosphorylated by ATM and ataxia telangiectasia and rad3+ related (ATR) were mutated to alanine. ATR may thus selectively contribute to p53-mediated apoptosis. These data indicate that distinct pathways regulate the activation of p53 leading to cell cycle arrest or apoptosis.
PMCID: PMC135625  PMID: 12192050
13.  Functional Replacement of the Intracellular Region of the Notch1 Receptor by Epstein-Barr Virus Nuclear Antigen 2 
Journal of Virology  1998;72(7):6034-6039.
The intracellular region (RAMIC) of the mouse Notch1 receptor interacts with RBP-J/CBF-1, which binds to the DNA sequence CGTGGGAA and suppresses differentiation by transcriptional activation of genes regulated by RBP-J. Epstein-Barr virus nuclear antigen 2 (EBNA2) is essential for immortalization of human B cells by the virus. EBNA2 is a pleiotropic activator of viral and cellular genes and is targeted to DNA at least in part by interacting with RBP-J. We found that EBNA2 and the Notch1 RAMIC compete for binding to RBP-J, indicating that their interaction sites on RBP-J overlap at least partially. EBNA2 and Notch1 RAMIC transactivated the same set of viral and host promoters, i.e., the EBNA2 response element of the Epstein-Barr virus TP1 and the HES-1 promoter. Furthermore, EBNA2 functionally replaced the Notch1 RAMIC by suppressing differentiation of C2C12 myoblast progenitor cells.
PMCID: PMC110408  PMID: 9621066

Results 1-13 (13)