Citations

Purpose The purpose of this study was to investigate the influence of multiple demographic and radiographic findings on the size of labral tears identified at the time of hip arthroscopy. Methods Data were prospectively collected for patients treated with arthroscopic labral repair or debridement from February 2008 to August 2011. Preoperative radiographic and demographic data were collected for 392 patients during the study period. Exclusion criteria included revision surgery and previous hip conditions. An anteroposterior pelvic view, 45° Dunn view, and false‐profile view were used to measure Tönnis grade, neck‐shaft angle, alpha angle, lateral center edge angle (LCEA), anterior center edge angle (ACEA), acetabular inclination, and the extent of crossover sign when present. At the time of surgery, labral tear size and location were documented for all patients, using traditional acetabular clock face nomenclature for sizing. A multiple linear regression analysis was then performed to assess the correlation of radiographic and demographic findings with the size of the labral tear. Results Regression analysis displayed statistical significance for sex ( P < .0001), age ( P < .0001), and alpha angle ( P = .005) with labral tear size. For female patients, Tönnis grade ( P = .0004) and neck‐shaft angle ( P = .004) correlated with labral tear size. This model accounted for only 26% of variation in labral tear size. Conclusions Preoperative risk factors for the extent of labral tear size are male sex, increasing age, and increasing alpha angle. Labral tears were larger in female patients with higher Tönnis grades and lower neck‐shaft angles. Measurements of acetabular coverage and version showed no correlation with labral tear size. The majority of labral tear size variation was not accounted for in this model. Level of Evidence Level IV, therapeutic case series.

Mantle cell lymphoma (MCL) is a unique type of lymphoma with a prognosis intermediate between indolent and aggressive types. The purpose of this study was to study blood cytokine levels in newly diagnosed and relapsed MCL patients with respect to patterns of abnormalities and relationship to the MCL International Prognostic Index (MIPI) score. We analyzed blood levels of 30 cytokines using a multiplex ELISA in 88 patients with newly diagnosed MCL (pre‐treatment levels) and 20 with relapsed MCL and compared them with controls without known lymphoma. Elevated cytokine levels were compared with clinical outcome and the MIPI score. In the 88 newly diagnosed MCL patients, we found significantly elevated levels compared with controls of IL‐12, IP‐10, sIL‐2Rα, MIG, IL‐1RA, IL‐8, MIP‐1α, and MIP‐1β (all P < 0.05). Of these elevated cytokines, sIL‐2Rα, IL‐8, MIG, MIP‐1α, and MIP‐1β were predictive of inferior event‐free survival, and sIL‐2Rα (HR = 1.94; P = 0.038), IL‐8 (HR = 2.17; P = 0.015), and MIP‐1β (HR = 2.10; P = 0.016) were independent of MIPI score; only sIL‐2Rα (HR = 2.35; P = 0.041) was associated with overall survival after adjustment for MIPI. In the relapsed MCL patient group, the only significantly elevated plasma cytokines that predicted EFS were sIL‐2Rα (HR = 2.90; P = 0.04) and IL‐8 (HR = 3.75; P = 0.02). Elevated blood levels of sIL‐2Rα and the pro‐inflammatory cytokines IL‐8 and MIP‐1β are poor prognostic factors in MCL patients and independent of MIPI score. These factors, if validated, will provide important additions to the MIPI and guide the development of new therapies for patients with elevated levels of these cytokines. Am. J. Hematol. 89:E223–E227, 2014. © 2014 Wiley Periodicals, Inc.

Abstract Poly (ADP-ribose) polymerase (PARP) plays an important role in several DNA repair processes, and previous studies with various PARP inhibitors have demonstrated robust enhancement of sensitivity to temozolomide (TMZ) chemotherapy in pre-clinical models of glioblastoma multiforme (GBM). The focus of this study was to evaluate the antitumor effects of a novel PARP inhibitor, BMN 673, as a single agent and in combination with TMZ in the established U251 glioma cell line, neurosphere cultures from the primary Mayo GBM xenograft line GBM12, and TMZ-resistant cells derived from either line (U251TMZ, GBM12TMZ(MGMT high) and GBM12TMZ(MGMT low)). In a biochemical assay of PARP inhibition, BMN 673 potently suppressed poly-ADP-ribosylation of cellular proteins at concentrations of 3 nM following hydrogen peroxide treatment of U251 cells. Single agent treatment had modest anti-tumor activity with 30 nM BMN 673 reducing absorbance in a CyQUANT cell proliferation assay relative to control treatment in both U251 and U251TMZ cells (Table 1). BMN 673 co-treatment also enhanced the efficacy of TMZ in both U251-derivative lines at a clinically relevant concentration of TMZ. Similarly, treatment with BMN673 alone or in combination with TMZ inhibited primary neurosphere formation in all three GBM12 models. Notably, the addition BMN 673 clearly re-sensitized both resistant GBM12 sub-lines to relatively low concentrations of TMZ. Consistent with a mechanism involving disruption of DNA repair, combined treatment with BMN 673 and TMZ resulted in robust activation of ATM-mediated KAP1 phosphorylation (Ser824) and ATR-mediated Chk1 phosphorylation (Ser345) as compared to TMZ or BMN 673 alone 24 hours after treatment. In conclusion, BMN673 is a promising PARP inhibitor with high potency and cytotoxicity in vitro against both TMZ sensitive and TMZ resistant GBM cells. Table 1 - In vitro antitumor effects of TMZ combined with BMN673 TMZ, microM 0 nM BMN673 30 nM BMN673 CyQUANT U251 Relative absorbance Relative absorbance 0 1.00 0.58 30 0.80 0.30 U251TMZ 0 1.00 0.69 30 1.02 0.21 Primary Neurosphere Assay GBM12 Relative Count Relative Count 0 1.00 0.66 5 0.32 0 10 0.01 0 GBM12TMZ (MGMT high) 0 1.00 0.32 5 1.11 0.02 10 1.04 0.01 GBM12TMZ (MGMT low) 0 1.00 0.25 5 0.86 0.03 10 0.75 0 Citation Format: Sani H. Kizilbash, Ryo Kawashima, Shiv Gupta, Ann C. Mladek, Yuqiao Shen, Jann N. Sarkaria. BMN 673 potentiates efficacy of temozolomide in sensitive and resistant glioblastoma models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2067. doi:10.1158/1538-7445.AM2013-2067

Summary The presence of clonal circulating plasma cells (c PC s) remains a marker of high‐risk disease in newly diagnosed multiple myeloma (MM) patients. However, its prognostic utility in MM patients with previously treated disease is unknown. We studied 647 consecutive patients with previously treated MM seen at the Mayo Clinic, Rochester who had their peripheral blood evaluated for c PC s by multi‐parameter flow cytometry. Of these patients, 145 had actively relapsing disease while the remaining 502 had disease that was in a plateau and included 68 patients in complete remission (CR) and 434 patients with stable disease. Patients with actively relapsing disease were more likely to have clonal c PC s than those in a plateau ( P < 0·001). None of the patients in CR had any clonal c PC s detected. Among patients whose disease was in a plateau, the presence of clonal c PC s predicted for a worse median survival (22 months vs. not reached; P = 0·004). Among actively relapsing patients, the presence of ≥100 c PC s predicted for a worse survival after flow cytometry analysis (12 months vs. 33 months; P < 0·001). Future studies are needed to determine the role of these findings in developing a risk‐adapted treatment approach in MM patients with actively relapsing disease.

Key Points Survival of patients with primary plasma cell leukemia has improved in recent years, but is still inferior to those patients with multiple myeloma. This survival benefit appears to be mainly in patients older than 65 years of age.

Key Points Weekly oral proteasome inhibitor ixazomib appears generally well tolerated with manageable toxicity, limited grade 1/2 neuropathy. Data show that more than 25% of 30 evaluable relapsed/refractory myeloma patients who received the MTD had clinically meaningful responses.

Abstract Purpose: Effective sensitizing strategies potentially can extend the benefit of temozolomide (TMZ) therapy in patients with glioblastoma (GBM). We previously demonstrated that robust TMZ-sensitizing effects of the [poly (ADP-ribose) polymerase] (PARP) inhibitor veliparib (ABT-888) are restricted to TMZ-sensitive GBM xenografts. The focus of this study is to provide an understanding for the differential sensitization in paired TMZ-sensitive and -resistant GBM models. Experimental Design: The impact of veliparib on TMZ-induced cytotoxicity and DNA damage was evaluated in vitro and in vivo in models of acquired TMZ resistance (GBM12TMZ-mgmtHigh, GBM12TMZ-mgmtLow, and U251TMZ), inherent TMZ resistance (T98G), and TMZ-sensitive (U251 and GBM12). In vivo drug efficacy, pharmacokinetics, and pharmacodynamics were analyzed using clinically relevant dosing regimens. Results: Veliparib enhanced TMZ cytotoxicity and DNA-damage signaling in all GBM models in vitro with more pronounced effects in TMZ-resistant lines at 3 to 10 μmol/L veliparib. In vivo, combined TMZ/veliparib, compared with TMZ alone, significantly delayed tumor growth and enhanced DNA-damage signaling and γH2AX levels in the sensitive GBM12 xenograft line but not in the resistant GBM12TMZ lines. The pharmacokinetic profile of veliparib was similar for GBM12 and GBM12TMZ tumors with Cmax (∼1.5 μmol/L) in tissue significantly lower than concentrations associated with optimal in vitro sensitizing effects for resistant tumors. In contrast, robust suppression of PARP-1 expression by shRNA significantly increased TMZ sensitivity of U251TMZ in vitro and in vivo. Conclusions: In vitro cytotoxicity assays do not adequately model the therapeutic index of PARP inhibitors, as concentrations of veliparib and TMZ required to sensitize TMZ-resistant cancer cells in vivo cannot be achieved using a tolerable dosing regimen. Clin Cancer Res; 20(14); 3730–41. ©2014 AACR.

ABSTRACT We present a case of disseminated Neosartorya pseudofischeri infection in a bilateral lung transplant patient with cystic fibrosis. The organism was originally misidentified from respiratory specimens as Aspergillus fumigatus using colonial and microscopic morphology. DNA sequencing subsequently identified the organism correctly as N. pseudofischeri .

Hemophagocytic syndrome (HPS) is an extremely rare condition arising from the overactivation of one’s own immune system. It results in excessive inflammation and tissue destruction. Prompt initiation of treatment is warranted in either scenario in order to decrease mortality. Most cases are triggered by infectious agents, malignancy, or drugs. We describe the first case of a CLL patient presenting with HPS due to acquisition of EBV-related large cell lymphoma in the setting of profound immunodeficiency.