Overall survival and objective response in advanced unresectable hepatocellular carcinoma: A subanalysis of the REFLECT study.

BACKGROUND & AIMS: Validated surrogate endpoints for overall survival (OS) are important for expediting the clinical study and drug-development processes. Herein, we aimed to validate objective response as an independent predictor of OS in individuals with unresectable hepatocellular carcinoma (HCC) receiving systemic anti-angiogenic therapy. METHODS: We investigated the association between objective response (investigator-assessed mRECIST, independent radiologic review [IRR] mRECIST and RECIST v1.1) and OS in REFLECT, a phase III study of lenvatinib vs. sorafenib. We conducted landmark analyses (Simon-Makuch) of OS by objective response at 2, 4, and 6 months after randomization. RESULTS: Median OS was 21.6 months (95% CI 18.6-24.5) for responders (investigator-assessed mRECIST) vs. 11.9 months (95% CI 10.7-12.8) for non-responders (hazard ratio [HR] 0.61; 95% CI 0.49-0.76; p <0.001). Objective response by IRR per mRECIST and RECIST v1.1 supported the association with OS (HR 0.61; 95% CI 0.51-0.72; p <0.001 and HR 0.50; 95% CI 0.39-0.65; p <0.001, respectively). OS was significantly prolonged for responders vs. non-responders (investigator-assessed mRECIST) at the 2-month (HR 0.61; 95% CI 0.49-0.76; p <0.001), 4-month (HR 0.63; 95% CI 0.51-0.80; p <0.001), and 6-month (HR 0.68; 95% CI 0.54-0.86; p <0.001) landmarks. Results were similar when assessed by IRR, with both mRECIST and RECIST v1.1. An exploratory multivariate Cox regression analysis identified objective response by investigator-assessed mRECIST (HR 0.55; 95% CI 0.44-0.68; p <0.0001) and IRR-assessed RECIST v1.1 (HR 0.49; 95% CI, 0.38-0.64; p <0.0001) as independent predictors of OS in individuals with unresectable HCC. CONCLUSIONS: Objective response was an independent predictor of OS in individuals with unresectable HCC in REFLECT; additional studies are needed to confirm surrogacy. Participants achieving a complete or partial response by mRECIST or RECIST v1.1 had significantly longer survival vs. those with stable/progressive/non-evaluable disease. GOV NUMBER: NCT01761266. IMPACT AND IMPLICATIONS: This analysis of data taken from a completed clinical trial (REFLECT) looked for any link between objective response and overall survival time in individuals with unresectable HCC receiving anti-angiogenic treatments. Significantly longer median overall survival was found for responders (21.6 months) vs. non-responders (11.9 months). Overall survival was also significantly longer for responders vs. non-responders (based on objective response status at 2, 4, and 6 months) in the landmark analysis. Our results indicate that objective response is an independent predictor of overall survival in this setting, confirming its validity as a rapid marker of efficacy that can be applied in phase II trials; however, further validation is required to determine is validity for other systemic treatments (e.g. immunotherapies), or as a surrogate of overall survival.

Impact of bodyweight-based starting doses on the safety and efficacy of lenvatinib in primarily Japanese patients with hepatocellular carcinoma.

AIM: The phase III REFLECT study utilized bodyweight-based lenvatinib dosing in patients with unresectable hepatocellular carcinoma, based on results of the phase II Study 202. This post hoc analysis compared efficacy and safety in patients with lower and higher bodyweights. METHODS: This comparison included patients from Study 202 (Japanese, n = 43; Korean, n = 3) and Japanese patients from REFLECT (n = 81) who received lenvatinib. In Study 202, all patients received a starting dose of lenvatinib 12 mg/day; in REFLECT, patients received starting doses based on bodyweight (patients <60 kg, 8 mg/day; ≥60 kg, 12 mg/day). Safety and efficacy were assessed in both studies according to bodyweight. RESULTS: In Study 202, treatment-related, treatment-emergent adverse events (TEAEs) led to dose reductions in 80.8% and 55.0% of patients in the lower and higher bodyweight groups, respectively. In REFLECT, treatment-related TEAEs led to dose reductions in 52.5% and 70.7% of patients in the 8 and 12 mg groups, respectively. In Study 202, median overall survival (OS) was 16.2 months (95% confidence interval [CI], 9.8-25.1) and 21.3 months (95% CI, 10.1-not estimable) in the lower and higher bodyweight groups, respectively. In REFLECT, median OS was 15.8 months (95% CI, 10.4-27.6) and 18.2 months (95% CI, 11.3-26.9) in the 8 and 12 mg groups, respectively. CONCLUSIONS: Comparison between patients in Study 202 and REFLECT demonstrates efficacy was maintained with improved safety in patients with lower bodyweights who received lenvatinib 8 mg/day in REFLECT versus patients who received lenvatinib 12 mg/day in Study 202.

Imaging individual neurons in the retinal ganglion cell layer of the living eye.

Although imaging of the living retina with adaptive optics scanning light ophthalmoscopy (AOSLO) provides microscopic access to individual cells, such as photoreceptors, retinal pigment epithelial cells, and blood cells in the retinal vasculature, other important cell classes, such as retinal ganglion cells, have proven much more challenging to image. The near transparency of inner retinal cells is advantageous for vision, as light must pass through them to reach the photoreceptors, but it has prevented them from being directly imaged in vivo. Here we show that the individual somas of neurons within the retinal ganglion cell (RGC) layer can be imaged with a modification of confocal AOSLO, in both monkeys and humans. Human images of RGC layer neurons did not match the quality of monkey images for several reasons, including safety concerns that limited the light levels permissible for human imaging. We also show that the same technique applied to the photoreceptor layer can resolve ambiguity about cone survival in age-related macular degeneration. The capability to noninvasively image RGC layer neurons in the living eye may one day allow for a better understanding of diseases, such as glaucoma, and accelerate the development of therapeutic strategies that aim to protect these cells. This method may also prove useful for imaging other structures, such as neurons in the brain.

Preoperative hand-grip strength can be a predictor of stair ascent and descent ability after total knee arthroplasty in female patients.

BACKGROUND: Hand-grip strength was reported to be important predictor of functional limitation and disability related to low muscle strength in old people. The purpose of this study was to determine whether preoperative hand-grip strength predicts stair ascent and descent ability after total knee arthroplasty (TKA). METHODS: A total of 83 female patients (mean age 75.6 ± 7.2 years) who underwent unilateral TKA were included in this study. We measured body mass index, range of motion of both knees, bilateral quadriceps strength and hand-grip strength before and one year after TKA. One year after TKA, we had the subjects ascend and descend some stairs and recorded the gait pattern (step-to-step or step-over-step) and pain in both knees using a numerical rating scale. We divided the subjects into two groups according to gait pattern. These factors were compared between groups. Receiver Operating Characteristics (ROC) analysis was performed to estimate the preoperative hand-grip strength cut off point for the stair gait pattern. RESULTS: Pre- and postoperative mean hand-grip strengths were 20.1 ± 5.0 kg and 20.7 ± 5.4 kg, respectively, and there was a strong positive correlation between them (r = 0.82, P < 0.001). Quadriceps strength of both limbs significantly improved after TKA (P < 0.001). After TKA, all patients were able to perform both stair ascent and descent. The gait patterns of 27 patients were step-to-step, and 56 patients were step-over-step. Preoperative and postoperative quadriceps strength of both limbs and preoperative and postoperative hand-grip strength were significantly different between the groups. According to the ROC curve, the optimal cut off values of preoperative hand-grip strength for which female patients could ascend and descend the stairs by step-over-step after TKA was set at 19 kg. CONCLUSION: Preoperative hand-grip strength can be used in preoperative screening for stair ascent and descent ability after TKA.

Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial.

BACKGROUND: In a phase 2 trial, lenvatinib, an inhibitor of VEGF receptors 1-3, FGF receptors 1-4, PDGF receptor α, RET, and KIT, showed activity in hepatocellular carcinoma. We aimed to compare overall survival in patients treated with lenvatinib versus sorafenib as a first-line treatment for unresectable hepatocellular carcinoma. METHODS: This was an open-label, phase 3, multicentre, non-inferiority trial that recruited patients with unresectable hepatocellular carcinoma, who had not received treatment for advanced disease, at 154 sites in 20 countries throughout the Asia-Pacific, European, and North American regions. Patients were randomly assigned (1:1) via an interactive voice-web response system-with region; macroscopic portal vein invasion, extrahepatic spread, or both; Eastern Cooperative Oncology Group performance status; and bodyweight as stratification factors-to receive oral lenvatinib (12 mg/day for bodyweight ≥60 kg or 8 mg/day for bodyweight <60 kg) or sorafenib 400 mg twice-daily in 28-day cycles. The primary endpoint was overall survival, measured from the date of randomisation until the date of death from any cause. The efficacy analysis followed the intention-to-treat principle, and only patients who received treatment were included in the safety analysis. The non-inferiority margin was set at 1·08. The trial is registered with ClinicalTrials.gov, number NCT01761266. FINDINGS: Between March 1, 2013 and July 30, 2015, 1492 patients were recruited. 954 eligible patients were randomly assigned to lenvatinib (n=478) or sorafenib (n=476). Median survival time for lenvatinib of 13·6 months (95% CI 12·1-14·9) was non-inferior to sorafenib (12·3 months, 10·4-13·9; hazard ratio 0·92, 95% CI 0·79-1·06), meeting criteria for non-inferiority. The most common any-grade adverse events were hypertension (201 [42%]), diarrhoea (184 [39%]), decreased appetite (162 [34%]), and decreased weight (147 [31%]) for lenvatinib, and palmar-plantar erythrodysaesthesia (249 [52%]), diarrhoea (220 [46%]), hypertension (144 [30%]), and decreased appetite (127 [27%]) for sorafenib. INTERPRETATION: Lenvatinib was non-inferior to sorafenib in overall survival in untreated advanced hepatocellular carcinoma. The safety and tolerability profiles of lenvatinib were consistent with those previously observed. FUNDING: Eisai Inc.

AK106-001616, a Potent and Selective Inhibitor of Cytosolic Phospholipase A2: In Vivo Efficacy for Inflammation, Neuropathic Pain, and Pulmonary Fibrosis.

3-[3-Amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)-phenyl]-propionic acid (AK106-001616) is a novel, potent, and selective inhibitor of the cytosolic phospholipase A2 (cPLA2) enzyme. Unlike traditional nonsteroidal anti-inflammatory drugs and selective cyclooxygenase-2 inhibitors, AK106-001616 reduced prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) production by stimulated cells. The suppression of PGE2 and LTB4 production was also confirmed using an air pouch model in rats administered a single oral dose of AK106-001616. AK106-001616 alleviated paw swelling in a rat adjuvant-induced arthritis (AIA) model. The maximum effect of the inhibitory effect of AK106-001616 was comparable with that of naproxen on paw swelling in a rat AIA model. Meanwhile, the inhibitory effect of AK106-001616 was more effective than that of naproxen in the mouse collagen antibody-induced arthritis model with leukotrienes contributing to the pathogenesis. AK106-001616 dose dependently reversed the decrease in paw withdrawal threshold not only in rat carrageenan-induced hyperalgesia, but also in a rat neuropathic pain model induced by sciatic nerve chronic constriction injury (CCI). However, naproxen and celecoxib did not reverse the decrease in the paw withdrawal threshold in the CCI model. Furthermore, AK106-001616 reduced the disease score of bleomycin-induced lung fibrosis in rats. In addition, AK106-001616 did not enhance aspirin-induced gastric damage in fasted rats, increase blood pressure, or increase the thromboxane A2/ prostaglandin I2 ratio that is thought to be an underlying mechanism of thrombotic cardiovascular events increased by selective cyclooxygenase-2 inhibitors. Taken together, these data demonstrate that oral AK106-001616 may provide valuable effects for wide indications without attendant gastrointestinal and cardiovascular risks.

Younger patients with high varus malalignment of the contralateral knee may be candidates for simultaneous bilateral total knee arthroplasty.

PURPOSE: Bilateral total knee arthroplasty (TKA) is being performed more frequently. However, a consensus on whether simultaneous or staged procedures should be performed is not available. This study reviewed the clinical course of contralateral knees in patients who underwent unilateral TKA (UTKA) to determine which patients are candidates for simultaneous bilateral TKA (BTKA). METHODS: One hundred eighty-six patients with osteoarthritis who underwent UTKA at a single hospital between 2006 and 2009 (follow-up mean, 10.1 years) were retrospectively investigated. Age, sex, obesity, contralateral knee pain, Hospital for Special Surgery score, femorotibial angle (FTA), and Kellgren-Lawrence grades at the time of initial surgery were used to evaluate the risk for requiring contralateral TKA. Survival analysis and receiver-operating characteristic (ROC) analysis were performed. RESULTS: Ninety-one patients (48.9%) underwent contralateral TKA. The FTA of the contralateral knee (CFTA) was an independent related factor (hazard ratio, 1.15; p < 0.001), and the CFTA cut-off value for the next surgery was 183° (area under the curve, 0.85; sensitivity, 80.7%; specificity, 76.2%). The 10-year Kaplan-Meier survival rates for the CFTA < 183° group and the CFTA ≥ 183° group were 79.1% and 27.0%, respectively. In the CFTA ≥ 183° group, age was the predictor of future TKA, and elderly patients tended to not require a second procedure. The age cut-off value for the next surgery was 76 years. CONCLUSIONS: Varus deformities in the contralateral knee predicted additional contralateral TKA. Patients with CFTA ≥ 183° and aged 75 years or younger are considered reasonable candidates for simultaneous BTKA. LEVEL OF EVIDENCE: III.

Magnetic Resonance Imaging Diagnosis of Medial Meniscal Ramp Lesions in Patients With Anterior Cruciate Ligament Injuries.

PURPOSE: To prospectively evaluate the sensitivity and specificity of magnetic resonance imaging (MRI) for diagnosing ramp lesions, to compare them between 1.5- and 3-T MRI, and to evaluate whether bone contusion of the posterior lip of the medial tibial plateau was associated with ramp lesions. METHODS: For 155 knees that underwent primary ACL reconstruction, we prospectively examined for ramp lesions and medial meniscal body tears on MRI. MRI diagnosis of ramp lesions required high signal irregularity of the capsular margin or separation in the meniscocapsular junction of the medial meniscus posterior horn on sagittal images. Bone contusion of the posterior lip of the medial tibial plateau was verified in 105 knees with MRI performed within 6 weeks after injury. All ramp lesions were identified by transcondylar observation during surgery. The sensitivity and specificity of MRI for ramp lesions and body tears were measured. Furthermore, we evaluated whether bone contusion of the medial tibial plateau was associated with ramp lesions. The χ-square test was used for statistical analysis. RESULTS: During surgery, ramp lesions were observed in 46 knees and medial meniscal body tears were seen in 35 knees. The sensitivity of MRI for ramp lesions was 71.7% and specificity was 90.5%. The sensitivity for ramp lesions was significantly lower than that for meniscal body tears (94.3%) (P = .01). The sensitivity of 3-T MRI (83.3%) was superior to that of 1.5-T MRI (67.6%), but not significantly different. The incidence of bone contusions was not significantly different among ramp lesions (38.5%), body tears (40.0%), or no tears (30.5%). CONCLUSIONS: The sensitivity of MRI for diagnosing ramp lesions was significantly lower than that for medial meniscal body tears. Bone contusion of the posterior lip of the medial tibial plateau on MRI was not associated with ramp lesions. LEVEL OF EVIDENCE: Level III, comparative trial.

Predictive Evaluation of Pharmaceutical Properties of Ulinastatin-Containing Vaginal Suppositories as a Hospital Preparation by Near-Infrared Spectroscopy.

A vaginal suppository containing ulinastatin (UTI) was developed as a hospital pharmacy product from UTI injection solution and Witepsol® S-55. After mixing at 50°C for 0-8 h, UTI suppositories were prepared, which had good UTI content uniformity. Because 2% surfactant was contained in S-55, the UTI injection solution formed a water-in-oil type emulsion as a suppository base. The measured residual moisture content (loss on drying (LOD)) in the prepared vaginal suppositories decreased as the mixing time increased, but their hardness (hardness test (HT)) increased. Near (N) IR spectra of UTI suppositories were measured after mixing for 0-8 h. The best calibration models to predict the HT and LOD of the suppositories were determined based on the NIR spectra by the leave-one-out method in a partial least-squares regression analysis (PLS). The validation result indicated that PLS models for HT and LOD were obtained based on the spectra treated by a combination of smoothing and normalized, respectively, and the model consisted of three latent variables. The plots between the predicted and measured pharmaceutical properties (HT and LOD) based on the calibration data were superimposed with those of the external validation data. The developed NIR spectroscopy method was applied to the preparation process monitoring for UTI vaginal suppositories. In the prepared vaginal suppositories, the predicted LOD decreased as the mixing time increased, and the measured LOD values superimposed well with the predicted values. In contrast, the predicted HT increased as the mixing time increased, and the measured values superimposed with the predicted values.

Factors Associated With Posterior Cruciate Ligament Tightness During Cruciate-Retaining Total Knee Arthroplasty.

BACKGROUND: The purpose of our study was to identify factors affecting posterior cruciate ligament (PCL) tightness during cruciate-retaining total knee arthroplasty. METHODS: A total of 225 varus osteoarthritic knees that underwent cruciate-retaining total knee arthroplasty were included in this study. When the flexion gap was tighter than the extension gap after all bone resection and the lift-off sign was positive during surgery, the PCL was released. The association between PCL release and potential risk factors, such as age, gender, body mass index, preoperative range of motion, anterior cruciate ligament status, preoperative hip-knee-ankle angle (HKA), decrease in posterior condylar offset, and also change in tibial posterior slope angle (TPSA) from preoperative to postoperative measurement, was evaluated by univariate and multivariate logistic regression analyses. RESULTS: The PCL was released in 68 of 225 knees (30.2%). According to the univariate logistic regression analysis, preoperative knee flexion angle (odds ratio [OR], 0.98), anterior cruciate ligament status (OR, 3.94), the decrease in medial (OR, 0.73) and lateral posterior condylar offset (OR, 0.76), preoperative HKA (OR, 1.1), preoperative (OR, 1.15) and postoperative TPSA (OR, 0.77), and the decrease in TPSA (OR, 1.23) were associated with PCL release. Multivariable stepwise logistic regression analysis demonstrated that preoperative HKA (P < .001), postoperative TPSA (P = .02), and the decrease in TPSA (P < .001) were independently associated with PCL release. CONCLUSION: Many factors are associated with PCL tightness. The change in TPSA between preoperative and postoperative measurements was a higher risk factor than postoperative TPSA.

Discovery of novel 2-(4-aryl-2-methylpiperazin-1-yl)-pyrimidin-4-ones as glycogen synthase kinase-3ß inhibitors.

We herein describe the results of further evolution of glycogen synthase kinase (GSK)-3ß inhibitors from our promising compounds containing a 3-methylmorpholine moiety. Transformation of the morpholine moiety into a piperazine moiety resulted in potent GSK-3ß inhibitors. SAR studies focused on the nitrogen atom of the piperazine moiety revealed that a phenyl group afforded potent inhibitory activity toward GSK-3ß. Docking studies indicated that the phenyl group on the piperazine nitrogen atom and the methyl group on the piperazine make cation-π and CH-π interactions with GSK-3ß respectively. 4-Methoxyphenyl analogue 29 showed most potent inhibitory activity toward GSK-3ß with good in vitro and in vivo pharmacokinetic profiles, and 29 demonstrated a significant decrease in tau phosphorylation after oral administration in mice.

Discovery of novel 2-(3-phenylpiperazin-1-yl)-pyrimidin-4-ones as glycogen synthase kinase-3ß inhibitors.

We herein describe the results of further evolution of glycogen synthase kinase (GSK)-3ß inhibitors from our promising compounds containing a 2-phenylmorpholine moiety. Transformation of the morpholine moiety into a piperazine moiety resulted in potent GSK-3ß inhibitors. SAR studies focused on the phenyl moiety revealed that a 4-fluoro-2-methoxy group afforded potent inhibitory activity toward GSK-3ß. Based on docking studies, new hydrogen bonding between the nitrogen atom of the piperazine moiety and the oxygen atom of the main chain of Gln185 has been indicated, which may contribute to increased activity compared with that of the corresponding phenylmorpholine analogues. Effect of the stereochemistry of the phenylpiperazine moiety is also discussed.

Phase 2 study of eribulin in patients with previously treated advanced or metastatic soft tissue sarcoma.

Objective: Eribulin, a microtubule dynamics inhibitor, is approved for the treatment of patients with breast cancer and soft tissue sarcoma. We investigated the efficacy and safety of eribulin in Japanese patients with soft tissue sarcoma. Methods: This open-label, multicenter, nonrandomized, Phase 2 study enrolled Japanese patients with measurable, advanced/metastatic soft tissue sarcoma of high/intermediate grade and ≥1 prior chemotherapy for advanced disease. Patients received eribulin mesilate 1.4 mg/m2 intravenously over 2­5 minutes on Days 1 and 8 of a 21-day cycle. The primary endpoint was progression-free rate at 12 weeks. Secondary endpoints included overall survival, progression-free survival and safety. Efficacy analyses were stratified by histology (liposarcoma or leiomyosarcoma, and other subtypes). Results: Overall, 52 patients were enrolled and 51 patients were treated. Patients with liposarcoma/leiomyosarcoma (n = 35) had similar characteristics to those with other subtypes (n = 16), except for a higher proportion of women (63% vs 38%, respectively) and patients with Eastern Cooperative Oncology Group performance status 0 (57% vs 44%). Progression-free rate at 12 weeks was 60% in liposarcoma/leiomyosarcoma patients, 31% in other subtypes and 51% overall. Median progression-free survival was 5.5 months in liposarcoma/leiomyosarcoma patients, 2.0 months in other subtypes and 4.1 months overall. Median overall survival was 17.0 months in liposarcoma/leiomyosarcoma patients, 7.6 months in other subtypes and 13.2 months overall. The most common Grade 3­4 adverse events were neutropenia (86%), leukopenia (75%), lymphopenia (33%), anemia (14%) and febrile neutropenia (8%). Conclusion: Eribulin showed clinical activity with a manageable safety profile in previously treated Japanese patients with advanced/metastatic soft tissue sarcoma.

Angiomatoid fibrous histiocytoma: a series of seven cases including genetically confirmed aggressive cases and a literature review.

BACKGROUND: Angiomatoid fibrous histiocytoma (AFH) is a rare soft tissue tumor of intermediate biologic potential. Because of its rarity and nonspecific radiological and diverse pathological findings, AFH is often clinically misdiagnosed. However, few clinical reports have described this tumor. As reported herein, we analyzed the clinical and radiological features and clinical outcomes of AFH. METHODS: We retrospectively reviewed the medical records of seven cases histopathologically diagnosed as AFH. We examined clinical features, MRI findings, histopathological diagnoses, treatments, and outcomes. RESULTS: These seven cases comprised five male and two female patients with ages ranging from 8 to 50 years old. The primary locations included upper extremities in 2, lower extremities in 4, and the inguinal region in one patient. Of the tumors, 4 occurred in subcutaneous tissues and 3 occurred in deep tissues. No cases were diagnosed as AFH from MRI and needle biopsy results. All cases were diagnosed histopathologically after excision. After treatment, 2 patients (29%) had tumor recurrence and metastasis, one of whom died from disease progression. These 2 aggressive cases involved both EWSR1 and CREB1 gene rearrangements as determined by FISH. The other patients were alive and well without recurrence or metastasis. CONCLUSION: AFH is a rare tumor that is difficult to diagnose. Therefore, it tends to be misdiagnosed and to be treated inadequately by referring physicians. Surgeons must therefore be mindful of the presence of AFH, learn about appropriate treatment necessary for this tumor, and conduct careful follow-up because AFH can engender poor outcomes.

Does Residual Varus Alignment Cause Increasing Varus Laxity at a Minimum of Five Years After Total Knee Arthroplasty?

BACKGROUND: The purpose of this study is to investigate whether varus-valgus laxity of cruciate-retaining (CR) total knee arthroplasty (TKA) changes between 1 year and >5 years after surgery based on postoperative limb alignment. METHODS: One hundred twenty-one varus osteoarthritic knees that underwent CR TKA were included. The minimum follow-up was 5 years. Weight-bearing full-leg radiographs were obtained postoperatively and the hip-knee-ankle (HKA) angle was measured. Knees were grouped in varus (HKA angle ≤ -3°, 47 knees) and neutral groups (-3° < HKA angle < 3°, 70 knees). The range of motion was measured and a Hospital for Special Surgery score was obtained at the last follow-up. Varus-valgus laxity at 15° of knee flexion was measured with stress radiographs after 1 year and at the last follow-up. RESULTS: No knees required revision surgery. The mean knee flexion angle (121.0° vs 117.1°) and Hospital for Special Surgery score (90.3 vs 90.4) at the last follow-up were not significantly different between the varus and neutral groups. In both groups, there was no significant change in varus or valgus laxity between 1 year and at the last follow-up. CONCLUSION: Postoperative residual varus limb alignment did not lead to increasing varus laxity after CR TKA in the mid-term.

[General Anesthesia for Magnetic Navigation System-guided Catheter Ablation in a Patient with Persistent Atrial Tachycardia and an Extracardiac Total Cavopulmonary Connection].

Atrial arrhythmia is an important prognostic factor in patients undergoing the Fontan operation. Although catheter ablation is considered to be a curative treat- ment the anatomical constraints produced by extra- cardiac total cavopulmonary connection make it diffi- cult to insert catheters towards the right atrium. Mag- netic navigation systems enable safer catheter delivery to the target site in such cases. Catheter ablation was carried out under the guidance of a magnetic naviga- tion system after the Fontan conversion operation in a 39-year-old female patient with persistent atrial tachy- cardia for the first time in Japan. During a 3-hr period of atrial tachycardia (AT), the patient's hemodynamic status was severely compromised ; her systemic blood pressure fell below 80 mmHg, and her central venous pressure increased to 26 mmHg. After the termination of AT, the patient's hemodynamic status was normal- ized without any complications. The procedure was successful, and the patient was discharged as sched- uled. The number of catheter ablation procedures in patients with arrhythmia after the Fontan procedure is expected to increase as patients with complex congen- ital heart defects are surviving longer. It is important to clarify the issues associated with this procedure and establish a safe anesthetic management strategy based on hemodynamic data.

The morphologic change of the ulnar collateral ligament of elbow in high school baseball pitchers, with and without symptoms, by sonography.

BACKGROUND: Few reports in the literature relate morphologic changes of the ulnar collateral ligament (UCL) to prior elbow symptoms. This study used ultrasonography (US) to assess the ulnohumeral joint space width, with and without stress, and elucidate morphologic changes of the UCL of the elbow in high school pitchers with and without a history of elbow symptoms. METHODS: Each of 122 high school baseball pitchers who underwent US of the medial aspect of both elbows completed a self-administered questionnaire related to the self-satisfaction score (0-100) for pitching performance and throwing-related elbow joint pain sustained during the prior 3 years. We conducted gravity stress US elbow examination with 30° of flexion with and without valgus stress. Comparisons of the UCL thickness and ulnohumeral joint space width, with and without valgus stress, were made among the 122 high school pitchers with and without a history of elbow symptoms. RESULTS: Pitchers with an elbow symptom history exhibited a greater difference between the UCL thickness on the throwing side than those with no elbow symptom history (P = .0013). A negative significant association was found between UCL thickness on the pitching side and the self-evaluation score for pitching performance (r = -0.20, P = .04). CONCLUSIONS: US assessment demonstrated that the UCL in the dominant side with elbow symptom history was thicker than that with no elbow symptom history. The UCL thickness might reflect the prior pitching condition of high school baseball pitchers.

Tibial Tubercle in Valgus Osteoarthritic Knees Is More Laterally Positioned Than in Varus Knees.

BACKGROUND: The tibial tubercle (TT) is the most reliable landmark of the tibial component rotation in total knee arthroplasty. However, there is no report comparing the position of the TT between valgus and varus osteoarthritic knees. METHODS: Using preoperative computed tomography, we measured the TT-posterior cruciate ligament (PCL) distance representing the degree of lateralization of the TT and the angle between Akagi's anteroposterior (AP) axis and the dorsal condylar line (DCL) of the tibia in 36 valgus and 40 varus osteoarthritic knees and compared them. RESULTS: The mean TT-PCL distances in valgus and varus knees were 26.1 (18.2-36.8) and 17.2 mm (10.3-22.6), respectively, with a significant difference (P < .001). Twenty-four of 36 valgus knees (67%) had abnormal TT-PCL (>24 mm). The mean AP-DCL angles in valgus and varus knees were 103° (95.8°-114.8°) and 93.2° (85.3°-99.6°), respectively, with a significant difference (P < .001). CONCLUSION: The TT in valgus knees was significantly more laterally positioned than in varus knees. Also, Akagi's AP axis in valgus knees was significantly more externally rotated relative to the DCL of the tibia than in varus knees. Attention is necessary to correct rotational alignment without posterolateral overhang of the tibial component during total knee arthroplasty, particularly for valgus knees.

Relation between the stand-up test and gait speed, knee osteoarthritis, and osteoporosis using calcaneal quantitative ultrasound - Cross-sectional study.

OBJECTIVE: The aim of the present study was to clarify the relationship between the stand-up test and gait speed, knee osteoarthritis (OA), and osteoporosis using calcaneal quantitative ultrasound. STUDY DESIGN: Cross-sectional study. METHODS: A total of 185 subjects (55 men, 130 women) aged ≥40 years (mean age, 63.7 years; range, 40-79 years) were evaluated using the stand-up test to screen for locomotive syndrome. We also assessed OA of the knee using X-rays and a subjective questionnaire, physical characteristics, 6-m gait speed (m/s), and bone density. If results on the stand-up test were worse than benchmarks by age group (i.e., the height at which 50% of each age group could stand-up), the subject was defined as having a risk for locomotive syndrome (L group). We analyzed the relationship between the stand-up test and other variables. RESULTS: Of 185 subjects, 50 (27.0%) were classified into the L group. In univariate analysis, there were significant differences between the L group and non-L group in bone density (p < 0.001), gait speed (p < 0.001), osteoporosis (p < 0.001), slow gait speed group (SGSG) (cut off 1 m/s), and Japanese knee osteoarthritis measure score. Multivariate logistic regression analysis adjusted for age, height, weight, and gender showed a significant association between the stand-up test and bone density (OR 0.960, 95% confidence interval (95% CI) 0.927-0.994), gait speed (m/s) (OR 0.073, 95% CI 0.016-0.342), osteoporosis (OR 3.710, 95% CI 1.410-9.764), and SGSG (OR 7.849, 95% CI 1.628-37.845). CONCLUSIONS: The stand-up test to screen for the risk for locomotive syndrome was associated with bone density, gait speed, osteoporosis, SGSG. The stand-up test is an easy test to use to screen for possible disability among the elderly.

Relationship between knee osteoarthritis and the locomotive syndrome risk tests: A cross-sectional study.

OBJECTIVE: To determine the relationship between locomotive syndrome (LS) risk tests and knee osteoarthritis (KOA). STUDY DESIGN: Cross-sectional cohort study. METHODS: In 2015, 225 people (male 84, females 141, mean age 67.9, range 30-90) were examined using LS risk tests, including the stand-up test, the two-step test, and the 25-question risk assessment, in Katashina Village in Gunma prefecture. The Japanese orthopaedic association defined LS risk test stage 1, difficulty with standing from a 40-cm-high seat using one-leg in the stand-up test, two-step test <1.3, the 25-question risk assessment ≧7, and defined stage 2, difficulty with standing from a 20-cm-high seat using both legs in the stand-up test, two-step test <1.1, the 25-question risk assessment ≧16. Persons with two or more of the following on the ultrasound (US) assessment were defined as having KOA: peripheral joint space (PJS) < 5 mm during weight-bearing; medial radial displacement (MRD) > 5 mm during weight-bearing; and osteophytes > 2 mm. If the residents had KOA in either knee, they were defined as having KOA. RESULTS: 45 residents had KOA in either knee. Logistic regression analysis adjusted for age, height, weight, gender, and knee pain was performed with stage 0 as reference. On the stand-up test, the odds ratio was 5.484 (95% confidence interval (CI) 1.966-15.297) for stage 1 and 2.067 (95% CI 0.426-10.017) for stage 2. On the two-step test, the odds ratio was 1.497 (95% CI 0.557-4.021) for stage 1 and 0.71 (95% CI 0.210-2.395) for stage 2. On the 25-question risk assessment, the odds ratio was 1.73 (95% CI 0.646-4.631) for stage 1 and 1.5 (95% CI 0.508-4.433) for stage 2. CONCLUSIONS: A stand-up test of stage 1 had a significant relationship with KOA. This might suggest that proper care of KOA is needed to prevent progressive disability.