Effects of intertrochanteric osteotomy plane and preoperative femoral anteversion on the postoperative morphology of the proximal femur in transtrochanteric anterior rotational osteotomy: 3D CT-based simulation study.

BACKGROUND: Transtrochanteric anterior rotational osteotomy (ARO) is joint-preserving surgery for patients with osteonecrosis of the femoral head (ONFH). During ARO, femoral neck-shaft varus angulation by changing intertrochanteric osteotomy plane is often designed to obtain a sufficient postoperative intact ratio. However, the effect of intertrochanteric osteotomy plane on postoperative femoral anteversion has not been well examined. Therefore, we performed a simulation study of ARO to determine how intertrochanteric osteotomy plane and preoperative femoral anteversion affect both femoral neck-shaft varus angle and postoperative femoral anteversion. HYPOTHESIS: Both femoral neck-shaft varus angle and postoperative femoral anteversion are predicted by intertrochanteric osteotomy plane and preoperative femoral anteversion in ARO. MATERIALS AND METHODS: Using CT-data obtained from 10 hips in 10 patients with ONFH, ARO was simulated. On anteroposterior view, basic intertrochanteric osteotomy line (AP-view line) was defined as the perpendicular line to the femoral neck axis. On lateral view, basic intertrochanteric osteotomy line (lateral-view line) made through the cut surface of greater trochanter was defined as the perpendicular line to the lateral axis of the femur. By changing either AP-view or lateral-view line, 49 ARO models/hip were produced, in which femoral neck-shaft varus angle and postoperative femoral anteversion were assessed. RESULTS: With increase in the vertically-inclined degree of AP-view line, both neck-shaft varus angle and postoperative femoral anteversion increased. With increase in the posteriorly-tilted degree of lateral-view line, neck-shaft varus angle increased, whereas postoperative femoral anteversion decreased. The approximation equations based on the multiple regression analyses were as follows: neck-shaft varus angle≈vertically-inclined degree of AP-view line×0.9+posteriorly-tilted degree of lateral-view line×0.8+preoperative femoral anteversion×0.7; postoperative femoral anteversion≈vertically-inclined degree of AP-view line×1.1-posteriorly-tilted degree of lateral-view line×0.8. DISCUSSION: The postoperative morphology of proximal femur was nearly defined by intertrochanteric osteotomy plane with preoperative femoral anteversion, which is useful for preoperative planning in terms of both achieving a sufficient postoperative intact ratio and maintaining femoral anteversion. LEVEL OF EVIDENCE: Level IV case series without control group.

Factors influencing progressive collapse of the transposed necrotic lesion after transtrochanteric anterior rotational osteotomy for osteonecrosis of the femoral head.

BACKGROUND: Transtrochanteric anterior rotational osteotomy (ARO) for osteonecrosis of the femoral head (ONFH) can preserve for a long-time collapsed femoral head. Progressive collapse of anteriorly-transposed necrotic lesion leads to secondary arthritic changes and clinical failure. Critical factors influencing collapse of the transposed necrotic lesion after ARO remain largely unknown. Therefore, we performed a retrospective study of ARO to determine: (1) if preoperative collapse influences collapse of the transposed necrotic area, (2) if any other factor may influence collapse of the transposed necrotic area. HYPOTHESIS: We hypothesized the degree of preoperative femoral head collapse influences progressive collapse of the transposed necrotic lesion after ARO. MATERIALS AND METHODS: We reviewed 47 hips in 42 patients with ONFH treated with ARO between 2000 and 2005 with a mean follow-up of 11.4 years (10-14 years). The occurrence of progressive collapse of the transposed necrotic lesion after ARO was examined using lateral radiographs taken at least once every year after ARO. The following factors were statistically analyzed: age, sex, body mass index, Harris Hip Score (HHS), preoperative level of collapse, extent of the necrotic lesion and postoperative intact ratio (ratio of the transposed intact articular surface of the femoral head). RESULTS: Progressive collapse of the transposed necrotic lesion (progressive collapse group) was seen in 17 hips (36%) during a mean period of 1.8 years (0.5-3.7 years) after ARO, which has developed within 4 years in all cases. Preoperative level of collapse in the progressive collapse group (4.4±1.4mm) was significantly larger than that in the non-progressive collapse group (2.1±1.0mm), which was independently associated with progressive collapse of the transposed necrotic lesion in multivariate analysis (P<0.0001) with cut off point of 2.98mm. In univariate analysis, lower preoperative HHS, severe extent of the necrotic lesion and the lower postoperative intact ratio were also associated with progressive collapse of the transposed necrotic lesion, but were not associated as independent factors in multivariate analysis. DISCUSSION: The current study suggests that progressive collapse of the transposed necrotic lesion after ARO depends mainly on the preoperative level of collapse (cut-off point=2.98mm). LEVEL OF EVIDENCE: IV; retrospective case series.

GEP oncogene promotes cell proliferation through YAP activation in ovarian cancer.

G-protein-coupled receptors (GPCRs) and their ligands function in the progression of human malignancies. Gα12 and Gα13, encoded by GNA12 and GNA13, respectively, are referred to as the GEP oncogene and are implicated in tumor progression. However, the molecular mechanisms by which Gα12/13 activation promotes cancer progression are not fully elucidated. Here, we demonstrate elevated expression of Gα12/13 in human ovarian cancer tissues. Gα12/13 activation did not promote cellular migration in the ovarian cancer cell lines examined. Rather, Gα12/13 activation promoted cell growth. We used a synthetic biology approach using chimeric G proteins and GPCRs activated solely by artificial ligands to selectively trigger signaling pathways downstream of specific G proteins. We found that Gα12/13 promotes proliferation of ovarian cancer cells by activating the transcriptional coactivator YAP, a critical component of the Hippo signaling pathway. Furthermore, we reveal that inhibition of YAP by short hairpin RNA or a specific inhibitor prevented the growth of ovarian cancer cells. Therefore, YAP may be a suitable therapeutic target in ovarian cancer.

Necrotic enlargement of cone photoreceptor cells and the release of high-mobility group box-1 in retinitis pigmentosa.

Retinitis pigmentosa (RP) refers to a group of inherited retinal degenerations resulting form rod and cone photoreceptor cell death. The rod cell death due to deleterious genetic mutations has been shown to occur mainly through apoptosis, whereas the mechanisms and features of the secondary cone cell death have not been fully elucidated. Our previous study showed that the cone cell death in rd10 mice, an animal model of RP, involves necrotic features and is partly mediated by the receptor interacting protein kinase. However, the relevancy of necrotic cone cell death in human RP patients remains unknown. In the present study, we showed that dying cone cells in rd10 mice exhibited cellular enlargement, along with necrotic changes such as cellular swelling and mitochondrial rupture. In human eyes, live imaging of cone cells by adaptive optics scanning laser ophthalmoscopy revealed significantly increased percentages of enlarged cone cells in the RP patients compared with the control subjects. The vitreous of the RP patients contained significantly higher levels of high-mobility group box-1, which is released extracellularly associated with necrotic cell death. These findings suggest that necrotic enlargement of cone cells is involved in the process of cone degeneration, and that necrosis may be a novel target to prevent or delay the loss of cone-mediated central vision in RP.

Antibody responses of Macaca fascicularis against a new inactivated polio vaccine derived from Sabin strains (sIPV) in DTaP-sIPV vaccine.

Antibody responses of Macaca fascicularis against a new tetravalent vaccine composed of diphtheria toxoid, tetanus toxoid, acellular pertussis antigens, and inactivated poliovirus derived from Sabin strains (sIPV) was investigated to predict an optimal dose of sIPV in a new tetravalent vaccine (DTaP-sIPV) prior to conducting a dose-defined clinical study. Monkeys were inoculated with DTaP-sIPVs containing three different antigen units of sIPVs: Vaccine A (types 1:2:3 = 3:100:100 DU), Vaccine B (types 1:2:3 = 1.5:50:50 DU), and Vaccine C (types 1:2:3 = 0.75:25:25 DU). There was no difference in the average titers of neutralizing antibody against the attenuated or virulent polioviruses between Vaccines A and B. The average neutralizing antibody titers of Vaccine C tended to be lower than those of Vaccines A and B. The sIPV antigens did not affect the anti-diphtheria or anti-tetanus antibody titers of DTaP-sIPV. Furthermore, the average neutralizing antibody titers of Vaccine A against the attenuated and virulent polioviruses were comparable between M. fascicularis and humans. These results suggest that M. fascicularis may be a useful animal model for predicting the antibody responses to sIPVs in humans, and that it may be likely to reduce the amount of sIPVs contained in DTaP-sIPVs, even for humans.

Magnetic resonance imaging-guided navigation with a thermoplastic shell for breast-conserving surgery.

BACKGROUND: The aim of this study was to evaluate the accuracy of a magnetic resonance imaging (MRI) marking technique with a drape-type thermoplastic shell for planning breast-conserving surgery (BCS). METHODS: A prospective review was performed on 35 consecutive patients who underwent MRI in the supine position and used the specified MRI marking technique. Eleven cases underwent pre-operative chemotherapy and 24 cases did not. After immobilizing the breast mound with a drape-type thermoplastic shell, patients underwent MRI, and the location of the lesion was marked on the shell. Resection lines were dyed blue by indigo carmine, which was pushed through the pores of the shell. Specimens obtained during BCS were sliced into 5-mm contiguous sections, and the margin was assessed for each specimen. Cancer foci less than 5 mm from the margin were classified as positive. RESULTS: Of 35 patients, 33 were included in the analysis; 2 were excluded due to a lack of effect of pre-operative chemotherapy. Of these 33 patients, 25 (75.8%) had negative margins and 7 (21.2%) had positive margins. CONCLUSIONS: Our MRI marking technique may be useful for evaluating the extent of tumors that were determined by MRI alone. Long-term outcomes of this technique should be evaluated further.

Novel therapeutic strategies to target RCAS1, which induces apoptosis via ectodomain shedding.

The expression of receptor-binding cancer antigen expressed on SiSo cells (RCAS1) is associated with aggressive characteristics and poor overall survival for 15 different human malignancies. The correlation between RCAS1 expression and several clinicopathological variables, including tumor size, clinical stage, invasion depth and lymph node metastasis highlights this molecule's clinical significance. RCAS1 is a biomarker because: (1) its concentration in serum or pleural effusion is significantly higher in cancer patients; (2) its level is associated with treatment response; and (3) high RCAS1-valued serum from cancer patients inhibits growth of RCAS1 putative receptor-expressing K562 cells. RCAS1 is secreted by ectodomain shedding and induces apoptosis in peripheral lymphocytes and natural killer (NK) cells. Although its putative receptor and mechanism of apoptosis induction remain undefined, RCAS1 is believed to help tumor cells evade immune surveillance. RCAS1 expression is also related to changes in extracellular matrix characteristics, reduction of vimentin-positive stromal cells, and increased microvessel density (MVD), all suggesting that RCAS1 may induce connective tissue remodeling. Further exploration of RCAS1 biological function will facilitate development of novel therapeutic strategies that target RCAS1.

Residual internal limiting membrane in epiretinal membrane surgery.

BACKGROUND/AIM: To examine the degree of the residual internal limiting membrane (ILM) after epiretinal membrane (ERM) peeling. METHODS: Sixty-one eyes of 59 patients with ERM were enrolled. After ERM peeling, residual ILM was visualised with Brilliant Blue G (BBG). The residual ILM pattern was divided into three groups: (1) residual type (ILM mostly remained), (2) half type (approximately half of ILM remained), (3) no residual type (ILM mostly removed with ERM). If ILM remained, residual ILM was removed in all cases and histologically examined using the flat mount method in 10 cases. The correlation between the degree of ERM evaluated by preoperative best-corrected visual acuity (BCVA) and residual ILM pattern was also examined. RESULTS: Twenty-eight eyes (45.9%) were of the residual type. Three eyes (4.9%) were of the half type, and 30 eyes (49.2%) were of no residual type. The mean preoperative BCVA showed no significant correlation with the residual ILM pattern. Flat mount immunohistochemistry revealed many remnant cells, both glial fibrillar acidic protein positive and negative, on residual ILMs in all specimens examined. No recurrence that needed surgical treatment was observed. CONCLUSION: Residual ILM with remnant cells seems to be frequent after ERM removal. Intraoperative staining with BBG may be helpful in determining the extent of ILM removal.

Analysis of corneal inflammation induced by cauterisation in CCR2 and MCP-1 knockout mice.

AIM: To elucidate the role of CCR2/MCP-1 in corneal inflammation. METHODS: A cauterisation induced corneal inflammation model was used. The corneas were cauterised with silver nitrate in CCR2 knockout (KO) mice, MCP-1 KO mice, and control mice. Clinical signs such as corneal oedema and opacity were examined 96 hours after cauterisation and the phenotypes of the cells infiltrating the cornea were analysed by flow cytometry. Corneal inflammation in neutrophil depleted mice was also analysed. RESULTS: After cauterisation both CCR2 KO and MCP-1 KO mice showed the same levels of corneal oedema and opacity as control mice. Flow cytometry revealed that in control mice most of the infiltrating cells were neutrophils and macrophages, whereas in both CCR2 KO mice and MCP-1 KO mice, the number of macrophages infiltrating the cornea were markedly reduced. However, prominent infiltrates of neutrophils were still observed in the cornea in CCR2 KO mice and MCP-1 KO mice. The depletion of neutrophils significantly reduced the oedema and opacity induced in the cornea by cauterisation. CONCLUSION: The CCR2 and MCP-1 molecules are not essential for cauterisation induced corneal inflammation. Neutrophils, rather than migrated macrophages, are the final effector cells involved in inducing inflammation in this model.

Clinical significance of heparin-binding epidermal growth factor-like growth factor in peritoneal fluid of ovarian cancer.

Epidermal growth factor receptor (EGFR) has been implicated in tumour growth and extension of ovarian cancer. Peritoneal fluid in ovarian cancer patients contains various growth factors that can promote tumour growth and extension. In order to investigate the clinical significance of EGFR ligands as activating factors of ovarian cancer, we examined the cell proliferation-promoting activity and the level of EGFR ligands in peritoneal fluid obtained from 99 patients. Proliferation-promoting activity in peritoneal fluid from 63 ovarian cancer patients (OVCA) was much higher than peritoneal fluid from 18 ovarian cyst patients (OVC) and 18 normal ovary patients (NO), and the activity was suppressed only by antibodies against EGFR or heparin-binding epidermal growth factor (HB-EGF). A large difference was observed in the level of EGFR ligands between HB-EGF and TGF-alpha or amphiregulin. The concentration of HB-EGF in OVCA significantly increased compared to that in OVC or NO (P<0.01). No significant difference in the concentration of TGF-alpha and amphiregulin was found between the OVCA and NO or OVC groups. In peritoneal fluid, HB-EGF is sufficiently elevated to activate cancer cells even at an early stage of OVCA. These results suggested that HB-EGF in peritoneal fluid might play a key role in cell survival and in the proliferation of OVCA.

The characterisation of hyalocytes: the origin, phenotype, and turnover.

AIM: To determine the characterisation of hyalocytes: the origin, phenotype, and turnover in the rodent. METHODS: To characterise the ultrastructure and distribution of hyalocytes, transmission and scanning electron microscopy was performed in rat eyes. Immunophenotypical analysis was performed by either anti-ED1 or ED2 antibodies. To examine the origin of the hyalocytes, the chimeric mice were created and were used to transplant the bone marrow (BM) cells from enhanced green fluorescent protein (EGFP) transgenic mice. The turnover of hyalocytes was examined at 0, 4, 6, 7, and 12 months after BM transplantation. RESULTS: Hyalocytes were distributed especially in the vitreous cortex and had an irregular shape with a spherical granule. Immunophenotypical studies demonstrated that most of the hyalocytes in rat eyes expressed ED2 but not ED1. In the chimeric mice, the hyalocytes were GFP negative right after BM transplantation. Interestingly, more than 60% of hyalocytes were replaced within 4 months and approximately 90% within 7 months after BM transplantation. CONCLUSIONS: The rodent hyalocytes were shown to express tissue macrophage marker, were derived from BM, and totally replaced within 7 months. These data provide the characterisation of hyalocytes in physiological conditions, especially their origin, distribution, and turnover, and may contribute to the better understanding of the pathogenesis of vitreoretinal disease.

The relative contributions of each subset of ocular infiltrated cells in experimental choroidal neovascularisation.

AIM: Choroidal neovascularisation (CNV) is a major cause of blindness in adults. The aim of this study was to investigate the role of infiltrating cells in the development of experimental CNV. METHODS: CNV was induced in C57BL/6 (B6) mice by laser photocoagulation (PC). After PC, the numbers of each subset of infiltrated cells were analysed by flow cytometry at multiple time points. Each subset (except for macrophages) was depleted by the specific antibodies in vivo. Thereafter, the area of CNV was compared between the control B6 mice and the specific antibody treated mice 7 days after PC. The CNV formation in neutrophil depleted CC chemokine receptor-2 (CCR2) knockout mice was also examined to minimise the effects of macrophages. RESULTS: In the early phase of CNV formation, a large number of neutrophils and macrophages infiltrated to the eyes. Natural killer (NK) cells and T lymphocytes were barely detected while no B lymphocytes were detected. The CNV areas did not significantly change compared between the control B6 mice and the specific antibody treated mice. However, the neutrophil depleted CCR2KO mice resulted in a reduction of CNV. CONCLUSION: Although lymphocytes and NK cells had little effect on CNV formation, neutrophils partially contributed to CNV in the absence of macrophages.

Laparoscopically assisted distal gastrectomy for early gastric cancer in the elderly.

BACKGROUND: Open gastrectomy is associated with increased morbidity and a longer hospital stay than laparoscopically assisted gastrectomy. The aim of this study was to clarify the value of laparoscopically assisted distal gastrectomy (LDG) in the elderly, in whom co-morbid disease is generally more common. METHODS: Forty-five elderly patients (aged 70 years or more) and 57 younger patients who underwent LDG, and 28 elderly patients who underwent open distal gastrectomy (ODG) for early gastric cancer between January 1994 and April 2003 were studied. Demographics and postoperative outcomes were compared. RESULTS: : Co-morbidity was more common in elderly patients than in younger patients who underwent LDG (25 of 45 versus 16 of 57; P = 0.004). The postoperative complication rate, time to solid diet and postoperative hospital stay were similar in these two groups. Elderly patients who underwent LDG had a significantly reduced medical complication rate (two of 45 versus six of 28; P = 0.023), time to first flatus (3.7 versus 4.2 days; P = 0.042), time to solid diet (4.6 versus 5.5 days; P = 0.011) and postoperative hospital stay (16.3 versus 23.9 days; P = 0.011) than elderly patients who had ODG. CONCLUSION: LDG offers particular advantages to elderly patients with early gastric cancer, including rapid return of gastrointestinal function, fewer complications and a shorter hospital stay.

Pars plana vitrectomy assisted by triamcinolone acetonide for refractory uveitis: a case series study.

AIM: To examine the outcome of a triamcinolone acetonide (TA) assisted pars plana vitrectomy (PPV) for refractory uveitis. METHODS: Six patients suffering from proliferative vitreoretinopathy (PVR) with refractory uveitis underwent a TA assisted PPV. The patients consisted of one with Vogt-Koyanagi-Harada disease, one with acute retinal necrosis, one with Behçet's disease, and three with sarcoidosis. TA was inoculated into the vitreous cavity to visualise the vitreous. In four of six patients, 4 mg of TA were intentionally left in the vitreous cavity to reduce the degree of postoperative inflammation. RESULTS: The vitreous body was clearly seen using TA during surgery, which greatly helped us to perform a posterior hyaloid resection safely and thoroughly. As we previously observed in other disease, TA allowed us to visualise the transparent vitreous and thus was helpful in removing the vitreous cortex from the retina completely in uveitis. One patient (Behçet's disease, in whom TA was intentionally left) showed an elevated intraocular pressure (IOP) transiently after surgery which was controllable by topical eye drops. The remaining TA diminished day by day and had almost completely disappeared within a month from operation. CONCLUSION: TA improved the visibility of the hyaloid and the safety of the surgical procedures and no serious complications were observed after TA assisted PPV in uveitis. Although the long term effects are still unknown, this method appears to be potentially useful as an improved treatment for PVR associated with refractory uveitis.

Association between RCAS1 expression and clinical outcome in uterine endometrial cancer.

RCAS1, which acts as a ligand for a putative receptor on immune cells such as peripheral lymphocytes and natural killer cells, is strongly expressed in human cancers. RCAS1 can induce these cells to undergo apoptotic cell death, which suggests that RCAS1 expression may prohibit the stromal reaction occurring in a tumour. To clarify the clinical significance of RCAS1 expression in uterine endometrial cancer, we analysed the association between RCAS1 expression and clinicopathologic variables by statistical methods. With the use of immunohistochemical techniques, we performed a retrospective study of RCAS1 expression in resected tumour tissue from 147 patients with uterine endometrial cancer. We evaluated the statistical correlation between RCAS1 expression and clinicopathologic variables. RCAS1 was expressed in 106 of 147 patients with uterine endometrial cancer; 30 of these 147 patients showed RCAS1 overexpression. Overexpression of RCAS1 was significantly correlated with age at surgery, stage, extent of myometrial invasion, and positive peritoneal cytologic results. Multivariate analysis revealed that RCAS1 expression and metastasis were clinically significant prognostic factors for the overall survival. These findings indicated that analysis for RCAS1 expression can provide crucial information about the clinical behaviour of uterine endometrial cancer, which may be valuable for the management of patients with this disease.

T lymphocyte subsets and Th1/Th2 balance after laparoscopy-assisted distal gastrectomy.

BACKGROUND: Laparoscopic surgery provides for a less invasive procedure than open surgery in patients with gastric cancer, but the immune responses after laparoscopic surgery for early gastric cancer remain unknown. METHODS: Peripheral blood mononuclear cells from 20 patients with early gastric cancer who underwent laparoscopy-assisted distal gastrectomy (LADG) or open distal gastrectomy (ODG) were obtained; the cell surface molecules and intracellular cytokines (IFN-gamma and IL-4) were measured by flow cytometry. RESULTS: The populations of T lymphocytes after LADG, including CD3-, 4-, 8-, 57-, and HLA-DR-positive lymphocytes, showed patterns similar to those after ODG. The production of IFN-gamma as Th1 cell function decreased significantly on the third postoperative day after ODG but increased after LADG. The production of IL-4, representing Th2 cell function, increased postoperatively after ODG but not after LADG. CONCLUSIONS: When compared with ODG, LADG contributes to the preservation of postsurgical Th1 cell-mediated immune function.