Overcoming High Trabectedin Resistance of Soft-tissue Sarcoma With Recombinant Methioninase: A Potential Solution of a Recalcitrant Clinical Problem.

BACKGROUND/AIM: Drug resistance has been a recalcitrant problem for sarcoma patients for many decades. Trabectedin is a second-line chemotherapy for soft-tissue sarcoma that often leads to resistance and death of the patients. The objective of the present study was to address the issue of trabectedin-chemoresistance in HT1080 fibrosarcoma cells by combining recombinant methioninase (rMETase) with trabectedin and examining their efficacy on trabectedin-resistant fibrosarcoma cells in vitro. MATERIALS AND METHODS: Trabectedin-resistant HT1080 (TR-HT1080) cells were generated by subjecting HT1080 human fibrosarcoma cells to increasing trabectedin concentrations (3.3-8 nM). IC50 values for trabectedin and rMETase were compared for HT1080 and TR-HT1080 cells. TR-HT 1080 cells were placed into four groups to determine synergy of rMETase and trabectedin on TR-HT1080 cells: a control group with no treatment; a group treated with trabectedin (3.3 nM); a group treated with rMETase (0.75 U/ml); and a group treated with both trabectedin (3.3 nM) and rMETase (0.75 U/ml). RESULTS: The IC50 value of trabectedin- on TR-HT1080 cells was 42.9 nM, whereas the IC50 value of trabectedin on the parental HT1080 cells was 3.3 nM, indicating a 13-fold increase. The combination of rMETase (0.75 U/ml) and trabectedin (3.3 nM) was synergistic on TR-HT1080 cells resulting in an inhibition of 64.2% compared to trabectedin alone (5.7%) or rMETase alone (50.5%) (p<0.05). rMETase increased the efficacy of trabectedin 11-fold on trabectedin-resistant fibrosarcoma cells. CONCLUSION: The combined administration of trabectedin and rMETase was synergistic on the viability of TR-HT1080 cells in vitro. The combination of rMETase and trabectedin has promising clinical potential for overcoming chemo-resistance of soft-tissue sarcoma.

Central Sensitization Is a Risk Factor for Persistent Postoperative Pain and Dissatisfaction in Patients Undergoing Revision Total Knee Arthroplasty.

BACKGROUND: The objective of this study is to investigate whether central sensitization (CS) was associated with patient dissatisfaction after revision total knee arthroplasty (TKA). METHODS: Between 2012 and 2016, 68 cases (68 patients) of revision TKA performed by a single surgeon were included in this study with a minimum follow-up of 2 years. Patients were categorized into 2 groups by 40-point preoperative Central Sensitization Inventory (CSI) scores. The control group consisted of 48 patients (48 knees) with CSI scores of less than 40 points, while the CS group consisted of 20 patients (20 knees) with CSI scores of 40 points or more. Clinical outcomes were evaluated using an 11-point visual analog scale (VAS) and Western Ontario and McMaster Universities Osteoarthritis Index scores. Patient satisfaction was evaluated using the satisfaction items of the new Knee Society Scores, where scores ≥20 indicated satisfaction. RESULTS: Higher preoperative pain VAS scores in the CS group were maintained 3, 6, 12, and 24 months postoperatively (all P < .05). The CS group showed significantly worse pain, function subscores, and total scores of the Western Ontario and McMaster Universities Osteoarthritis Index preoperatively and at 2 years postoperatively. Forty-four (91.7%) patients in the control group and 3 (15.0%) patients in the CS group were satisfied with their revision TKAs (P < .001). Multivariate logistic regression analysis demonstrated that the odds of dissatisfaction after revision TKAs were increased 39.081 times (95% confidence interval 6.926-220.504, P < .001) in patients with CSI scores ≥40. Higher VAS intensity 2 years postoperatively also predicted dissatisfaction following revision TKA (odds ratio 1.864, 95% confidence interval 1.086-3.199, P = .024). CONCLUSION: CS is a risk factor for persistent postoperative pain and dissatisfaction in patients undergoing revision TKAs. LEVEL OF EVIDENCE: III.

Attitudes of Korean clinicians to postmenopausal hormone therapy after the Women's Health Initiative study.

OBJECTIVE: To assess the attitudes of Korean physicians toward hormone therapy (HT) after publication of the Women's Health Initiative (WHI) study. DESIGN: Self-administered questionnaires, consisting of 22 items, were sent by mail to the members of the Korean Society of Menopause. RESULTS: More than 95% of Korean physicians were aware of the WHI study. The HT prescription rate decreased by 16% after publication of the WHI report; approximately half of the physicians who continued prescribing HT changed their prescriptions. The largest decreases occurred in regimens using conjugated equine estrogens and medroxyprogesterone acetate, for which prescriptions of sequential and continuous-combined regimens decreased by 20.7% and 22.7%, respectively. In contrast, the prescription rate for tibolone increased by 3.6%. Approximately 30% of physicians changed from standard to low doses, and 67.8% shortened the duration of HT. After publication of the WHI report, the main reasons for not prescribing or discontinuing HT were patient refusal and increased risk of cardiovascular disease, rather than breast cancer risk. After publication of the WHI report, the number of physicians who prescribed alternative or complementary medicines increased, the rate of HT prescription for the prevention of osteoporosis decreased, and the number of postmenopausal outpatients decreased. CONCLUSIONS: Despite the results of the WHI report, most Korean physicians who participated in this study continued prescribing HT; however, approximately half of those who continued prescribing HT changed their prescriptions. The greatest change occurred in regimens using conjugated equine estrogens and medroxyprogesterone acetate.