Citations

Abstract Background: Reductions in breast density with tamoxifen and aromatase inhibitors may be an intermediate marker of treatment response. We compare changes in volumetric breast density among breast cancer cases using tamoxifen or aromatase inhibitors (AI) to untreated women without breast cancer. Methods: Breast cancer cases with a digital mammogram prior to diagnosis and after initiation of tamoxifen (n = 366) or AI (n = 403) and a sample of controls (n = 2170) were identified from the Mayo Clinic Mammography Practice and San Francisco Mammography Registry. Volumetric percent density (VPD) and dense breast volume (DV) were measured using Volpara (Matakina Technology) and Quantra (Hologic) software. Linear regression estimated the effect of treatment on annualized changes in density. Results: Premenopausal women using tamoxifen experienced annualized declines in VPD of 1.17% to 1.70% compared with 0.30% to 0.56% for controls and declines in DV of 7.43 to 15.13 cm3 compared with 0.28 to 0.63 cm3 in controls, for Volpara and Quantra, respectively. The greatest reductions were observed among women with ≥10% baseline density. Postmenopausal AI users had greater declines in VPD than controls (Volpara P = 0.02; Quantra P = 0.03), and reductions were greatest among women with ≥10% baseline density. Declines in VPD among postmenopausal women using tamoxifen were only statistically greater than controls when measured with Quantra. Conclusions: Automated software can detect volumetric breast density changes among women on tamoxifen and AI. Impact: If declines in volumetric density predict breast cancer outcomes, these measures may be used as interim prognostic indicators. Cancer Epidemiol Biomarkers Prev; 26(6); 930–7. ©2017 AACR.

Background: Quantitative magnetic resonance (qMR) can be used to measure macromolecules in tissues and is a potential method of observing early cartilage changes in the development of posttraumatic osteoarthritis. Hypothesis/Purpose: We hypothesized that specific patient and surgical factors affecting cartilage matrix composition after anterior cruciate ligament (ACL) reconstruction (ACLR) can be detected using T1ρ and T2 relaxation times. Our purpose was to demonstrate this ability in a multicenter feasibility study. Study Design: Case series; Level of evidence, 4. Methods: A total of 54 patients who underwent ACLR underwent bilateral MRI at baseline before surgery and 6 months postoperatively. Operative findings were recorded. T1ρ and T2 relaxation times were calculated for 6 cartilage regions: the medial femur, lateral femur, medial tibia, lateral tibia, patella, and trochlea. A paired t test compared relaxation times at baseline and 6 months, univariate regression identified regions that influenced patient-reported outcome measures, and analysis of covariance was used to determine the surgical factors that resulted in elevated relaxation times at 6 months. Results: The injured knee had significantly prolonged T1ρ and T2 relaxation times in the tibiofemoral compartment at baseline and 6 months but had shorter values in the patellofemoral compartment compared with the uninjured knee. Prolonged T1ρ and T2 times at 6 months were noted for both the injured and uninjured knees. At 6 months, prolongation of T1ρ and T2 times in the tibial region was associated with lower patient-reported outcome measures. ACLR performed within 30 days of injury had significantly shorter T1ρ times in the tibial regions, and lateral meniscal tears treated with repair had significantly shorter T1ρ times than those treated with excision. Conclusion: Prolonged relaxation times in multiple regions demonstrate how the injury affects the entire joint after an ACL tear. Changes observed in the uninjured knee may be caused by increased loading during rehabilitation, especially in the patellofemoral articular cartilage and distal femur. Relaxation times in the tibial regions may be predictive of patient symptoms at 6 months. These same regions are affected by surgical timing as early as 30 days after injury, but this may partially be reflective of the severity of the preoperative injury and the choice of treatment of meniscal tears.

Background: The cases of patients with medial compartment osteoarthritis who were ≤55 years old and had a proximal tibial osteotomy (PTO) or medial unicompartmental knee arthroplasty (UKA) were compared. Outcomes included postoperative activity level, function, and survivorship free of revision to total knee arthroplasty. Methods: Between 1998 and 2013, data were available for 240 patients between 18 and 55 years old with medial compartment arthritis and varus malalignment who were treated either with PTO (57 patients) or with UKA (183 patients). The mean age was 42.7 years for the 57 patients (41 men and 16 women) in the PTO group versus 49.2 years for the 183 patients (82 men and 101 women) in the UKA group. The Tegner activity level and Lysholm knee scores were evaluated at 3 months and at 1, 2, and 5 years postoperatively as well as at the time of the final follow-up. The end point for survival was defined as revision to total knee arthroplasty. A Wilcoxon rank-sum test was used to evaluate the difference between the groups with respect to the Tegner and Lysholm scores at the respective follow-up intervals. Multivariate regression was used to assess potential confounders. Results: Preoperatively, the PTO and UKA groups had similar Tegner (3.0 ± 1.3 and 2.6 ± 0.09, respectively) and Lysholm scores (69.5 ± 7.3 and 71.6 ± 5.4). Postoperatively, the UKA group had significantly superior mean Tegner scores compared with the PTO group at 3 months (3.82 and 2.02, respectively), at 2 years (4.33 and 3.75), and at the time of the final follow-up (4.48 and 3.08), while the Lysholm scores were higher at 3 months (88.0 and 76.3) and at the final follow-up (90.0 and 80.2) (p < 0.01 for all). Multivariate analysis showed UKA to be an independent predictor of activity level at 3 months, 1 year, and 2 years, as well as at the final follow-up. The survivorship was 77% in the PTO group at an average of 7.2 years and 94% in the UKA group at an average of 5.8 years (p < 0.01). The average time to failure was 98 months (range, 38 to 169 months) in the PTO group and 42 months (range, 2 to 123 months) in the UKA group (p < 0.01). Conclusions: In this comparative cohort study of young patients with isolated unicompartmental arthritis, those treated with UKA reached a higher level of activity early after surgery and it persisted at mid-term follow-up. The UKA group had earlier, but less frequent, revision to total knee arthroplasty. Level of Evidence: Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.

OBJECTIVE Defects in the apoptotic machinery and augmented survival signals contribute to drug resistance in glioblastoma (GBM). Moreover, another complexity related to GBM treatment is the concept that GBM development and recurrence may arise from the expression of GBM stem cells (GSCs). Therefore, the use of a multifaceted approach or multitargeted agents that affect specific tumor cell characteristics will likely be necessary to successfully eradicate GBM. The objective of this study was to investigate the usefulness of sulforaphane (SFN)—a constituent of cruciferous vegetables with a multitargeted effect—as a therapeutic agent for GBM. METHODS The inhibitory effects of SFN on established cell lines, early primary cultures, CD133-positive GSCs, GSC-derived spheroids, and GBM xenografts were evaluated using various methods, including GSC isolation and the sphere-forming assay, analysis of reactive oxygen species (ROS) and apoptosis, cell growth inhibition assay, comet assays for assessing SFN-triggered DNA damage, confocal microscopy, Western blot analysis, and the determination of in vivo efficacy as assessed in human GBM xenograft models. RESULTS SFN triggered the significant inhibition of cell survival and induced apoptotic cell death, which was associated with caspase 3 and caspase 7 activation. Moreover, SFN triggered the formation of mitochondrial ROS, and SFN-triggered cell death was ROS dependent. Comet assays revealed that SFN increased single- and double-strand DNA breaks in GBM. Compared with the vehicle control cells, a significantly higher amount of γ-H2AX foci correlated with an increase in DNA double-strand breaks in the SFN-treated samples. Furthermore, SFN robustly inhibited the growth of GBM cell–induced cell death in established cell cultures and early-passage primary cultures and, most importantly, was effective in eliminating GSCs, which play a major role in drug resistance and disease recurrence. In vivo studies revealed that SFN administration at 100 mg/kg for 5-day cycles repeated for 3 weeks significantly decreased the growth of ectopic xenografts that were established from the early passage of primary cultures of GBM10. CONCLUSIONS These results suggest that SFN is a potent anti-GBM agent that targets several apoptosis and cell survival pathways and further preclinical and clinical studies may prove that SFN alone or in combination with other therapies may be potentially useful for GBM therapy.

Abstract Purpose: To determine the MTD and to assess the safety, tolerability, and potential activity of LB-100, a first-in-class small-molecule inhibitor of protein phosphatase 2A (PP2A) in adult patients with progressive solid tumors. Experimental Design: LB-100 was administered intravenously daily for 3 days in 21-day cycles in a 3 + 3 dose escalation design. Results: There were 29 patient entries over 7 dose escalations. One patient stopped treatment after one dose because of an acute infection and was reenrolled after recovery; each course was analyzed as a separate patient entry. Two patients had dose-limiting toxicity (reversible increases in serum creatinine or calculated serum creatinine clearance) at the 3.1 mg/m2 level. Probable or possible study drug-related grade 3 adverse events occurred in 6 (20.7%) patients [anemia (n = 2), decreased creatinine clearance, dyspnea, hyponatremia, and lymphopenia]. Ten (50%) of 20 response-evaluable patients had stable disease for four or more cycles. One patient with pancreatic adenocarcinoma had a partial response noted after 10 cycles, which was maintained for five additional cycles. The other patients achieving stable disease had one of the following: fibrosarcoma, chondrosarcoma, thymoma, atypical carcinoid of lung, or ovarian, testicular, breast (n = 2), and prostate cancer. The recommended phase II dose of LB-100 is 2.33 mg/m2 daily for 3 days every 3 weeks. Conclusions: The safety, tolerability, preliminary evidence of antitumor activity, and novel mechanism of action of LB-100 support its continued development alone and in combination with other therapies. Clin Cancer Res; 23(13); 3277–84. ©2016 AACR.