Citations

Background Fremanezumab (formerly TEV‐48125) is a monoclonal antibody directed against calcitonin‐gene‐related peptide (CGRP), a validated target for migraine preventive therapy. In two previous phase 2 studies, fremanezumab administered once every 28 days for 12 weeks was found to be effective and safe as a preventive treatment for patients suffering from episodic migraine (EM) and chronic migraine (CM). Objective To evaluate the efficacy and safety of fremanezumab as an add‐on preventive therapy in individuals with EM and CM who are on stable doses of preventive migraine medications. Methods Two randomized placebo‐controlled studies tested once‐monthly subcutaneous injections of various dosing regimens of fremanezumab versus placebo in EM and CM. Headache information was captured daily using an electronic headache diary. For these post hoc analyses, data were pooled from patients who were on stable preventive medications and taking fremanezumab doses of 225 mg or 675/225 mg, or placebo. Results The sample consisted of 133 patients, (67 fremanezumab and 66 placebo). Total reduction in migraine days for the duration of the study was 12.4 for fremanezumab and 7.4 for placebo ( P = .0321). There were also decreases in moderate/severe headache days (12.5 vs 7.1, P = .0058), and days using acute medication for headaches relative to placebo (11.6 vs 7.5, P = .0414). Treatment emergent adverse events were generally mild and transient, and no serious adverse events were considered to be treatment‐related by the site investigators. Conclusions The findings from these post hoc analyses suggest that fremanezumab is a safe and effective add‐on treatment for migraine patients being concomitantly treated with other migraine preventive medications. Trials are registered at Clinicaltrials.gov NCT02025556 and NCT02021773.

Purpose The primary aims of this work were to (1) describe normal range of motion (ROM) profiles for elite pitchers, (2) describe the characteristics of shoulder and elbow injuries in professional pitchers over a 6‐year period in one Major League Baseball organization, and (3) identify ROM measures that were independently associated with a future shoulder or elbow injury. Methods Over 6 seasons (2010‐2015), a preseason assessment was performed on all pitchers invited to Major League Baseball Spring Training for a single organization. ROM measures included shoulder flexion, horizontal adduction, external rotation (ER), internal rotation, as well as elbow flexion and extension, were measured for both the dominant and nondominant arm, and total range of motion and deficits were calculated. All noncontact shoulder and elbow injuries were identified. Using multivariate binomial logistic regression analysis to control for age, height, weight, and all other ROM measures, the factors associated with an increased risk of subsequent shoulder or elbow injury were identified. Results A total of 53 shoulder (n = 25) and elbow (n = 28) injuries occurred during 132 pitcher seasons (n = 81 pitchers). The most significant categorical risk factor associated with increased elbow injury rates was the presence of a shoulder flexion deficit >5° (odds ratio [OR] 2.83; P = .042). For continuous variables, the risk of elbow injury increased by 7% for each degree of increased shoulder ER deficit (OR 1.07; P = .030) and 9% for each degree of decreased shoulder flexion (OR 1.09; P = .017). None of the measures significantly correlated with shoulder injuries. Conclusions Preseason shoulder ER and flexion deficits are independent risk factors for the development of elbow injuries during the upcoming season. Although prior work has supported the importance of reducing glenohumeral internal rotation deficits in pitchers, this study demonstrates that deficits in shoulder ER and flexion are more significant predictors of subsequent elbow injury. Level of Evidence Level III, retrospective comparative study.

Objective Olfactory preservation after resection of esthesioneuroblastoma (ENB) has been reported, however, the ability to predict tumor involvement of the olfactory system is critical to this surgical strategy. This study aims to answer the question: Can a surgeon predict, based on preoperative imaging, whether there is unilateral involvement of the olfactory system allowing for safe attempt of olfactory preservation? Methods This is a retrospective review of post-resection ENB meeting inclusion criteria of having bilateral olfactory tracts and bulbs submitted at the time of primary resection for pathologic margins. Five board-certified skull base surgeons blinded to the pathology individually reviewed the preoperative MRI scans to predict degree of tumor involvement. Results Olfactory bulb involvement occurred in both bulbs in 35% of cases and unilateral in 39% of cases, and there was no involvement in 26% of cases sampled. When comparing physician prediction of involved tracts or bulbs, involvement was appropriate or over-called (i.e., called positive when pathology was in fact negative) in 96% of cases. Conclusion This study demonstrates unilateral or no pathologic olfactory involvement of the olfactory system in 65% of cases. Our ability to predict this involvement, which may allow for a management strategy that attempts to preserve olfactory function, was accurate at 96%. Therefore, interpretation of imaging and proceeding with smell preservation in ENB appears reasonable in this cohort.Level of Evidence: Level 2b.

PurposeTo develop a fully automated trajectory and gradient waveform design for the non‐Cartesian shells acquisition, and to develop a magnetization‐prepared (MP) shells acquisition to achieve an efficient three‐dimensional acquisition with improved gray‐to‐white brain matter contrast.MethodsAfter reviewing the shells k‐space trajectory, a novel, fully automated trajectory design is developed that allows for gradient waveforms to be automatically generated for specified acquisition parameters. Designs for two types of shells are introduced, including fully sampled and undersampled/accelerated shells. Using those designs, an MP‐Shells acquisition is developed by adjusting the acquisition order of shells interleaves to synchronize the center of k‐space sampling with the peak of desired gray‐to‐white matter contrast. The feasibility of the proposed design and MP‐Shells is demonstrated using simulation, phantom, and volunteer subject experiments, and the performance of MP‐Shells is compared with a clinical Cartesian magnetization‐prepared rapid gradient echo acquisition.ResultsInitial experiments show that MP‐Shells produces excellent image quality with higher data acquisition efficiency and improved gray‐to‐white matter contrast‐to‐noise ratio (by 36%) compared with the conventional Cartesian magnetization‐prepared rapid gradient echo acquisition.ConclusionWe demonstrated the feasibility of a three‐dimensional MP‐Shells acquisition and an automated trajectory design to achieve an efficient acquisition with improved gray‐to‐white matter contrast. Magn Reson Med 79:2024–2035, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Abstract Reconstruction techniques for the anterior cruciate ligament (ACL) have evolved considerably over the past 3 decades. The femoral tunnel is most commonly made via a transtibial or separate anteromedial portal approach. Benefits and drawbacks for each of these techniques exist. Improper tunnel placement is the cause of failure for ACL reconstruction 70% of the time. We present a hybrid technique for femoral tunnel placement using the Pathfinder ACL guide, which attempts to give the surgeon many of the benefits of both the transtibial and anteromedial portal techniques without the drawbacks. Technique Video video See video under supplementary data.

Abstract Horizontal cleavage meniscus tears are a common orthopedic injury often treated with partial or total meniscectomy versus repair. This Technical Note presents a technique for all‐inside repair with uniform compression of the superior and inferior leaflets by placement of multiple circumferential compression stitches using an all‐inside self‐retrieving suture passing device. The currently described technique provides several advantages for all‐inside repair of a horizontal cleavage tear: (1) eliminates the need for a posterior incision, (2) minimizes the risk of neurovascular injury, (3) uses standard arthroscopy portals (or small modifications), and (4) requires only a single suture deployment with a self‐retrieving device for each circumferential compression stitch. The resulting circumferential stitch provides uniform compression to the superior and inferior leaflets, promoting meniscal healing. This configuration has been shown to have the highest load to failure of all repair patterns. Technique Video video See video under supplementary data.

Abstract Glioblastoma is the most common primary tumor of the CNS in adults, representing approximately 50% of all gliomas and 15% of primary brain tumors. The current standard of care for GBM is safe maximal surgical resection followed by radiotherapy and concurrent Temozolomide (TMZ), but median survival continues to be 15–16 months. Temozolomide is a second-generation DNA alkylating agent that induces thymine mispairing during DNA replication resulting in tumor cell G2/M phase arrest and autophagy, a standard care of therapy against GBM. While the success of TMZ in clinical trials showed great promise for its overall efficacy, emerging TMZ resistance make us to think more for the combination therapy. CD47, a tumor cell surface marker, plays as “don't eat me signal” through binding its receptor SIRPα on macrophages and the antibody against CD47, which blocks interactions of CD47 with SIRPα, has been shown to lead to tumor destruction. Furthermore, CD47 is a prognostic marker as its expression predisposes cancer patients to a poorer survival outcome. This has significant clinical implications since approximately more than 80% of patients with the most GBMs, overexpress CD47. Overexpression of CD47 is also associated with a decreased probability of survival in clinical cohorts of GBM. Our work and that of others demonstrate that CD47 blockade enables tumor cell phagocytosis by antigen presenting cells (APC), establishing this molecule as a viable therapeutic target in GBM. We additionally investigated the combinatorial effect of CD47 blockade with temozolomide. DNA alkylating agents induce sporadic tumor cell necrosis associated with the extracellular release of damage associated molecular patterns (DAMPs) such as calreticulin, a pro-phagocytic protein whose interaction with low density lipoprotein receptor-related protein 1 (LRP1) facilitates recognition by professional antigen-presenting cells (APCs) and acts as a critical molecular component in promoting immunogenic cell. Our results showed that tumor cell treatment with temozolomide induces plasma membrane expression of calreticulin. Combination therapy resulted in amplified tumor cell phagocytosis and antigen presentation by APC. In addition, preclinical assessment of combination therapy in a syngeneic murine model of GBM resulted in significantly improved survival, characterized by increased intra-tumor penetration of APC cells. These results suggest that the combination of CD47 blockade with temozolomide may enhance tumor immunogenicity, and can improve clinical outcomes demonstrated by mono-therapeutic approaches with conventional chemotherapy. Citation Format: Yaqing Qie, Christina Von Roemeling, Yuanxin Chen, Kevin Shih, Xiujie Liu, Wen Jiang, Joshua Knight, Charles Chan, Irving Weissman, Betty Kim. CD47 blockade with temozolomide can enhance the therapy in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-208. doi:10.1158/1538-7445.AM2017-LB-208

Abstract Metabolic reprogramming plays a critical role in carcinogenesis, in part due its ability to promote immune suppressive properties within tumors. Agents that specifically target crucial metabolic enzymes utilized by cancer are been actively investigated. However, it is unclear whether inhibition of fatty acid metabolism in tumors affects their immunogenicity. Here, we show for the first time that inhibition of stearoyl-CoA desaturase 1 (SCD1), a key enzyme involved in fatty-acid synthesis and a potential prognostic marker for human cancers, increases the immunogenicity of poorly immunogenic tumors. The enhanced immune activation is accompanied by upregulated endoplasmic reticulum (ER) stress and is dependent on the translocation of ER protein calreticulin to the tumor cell surface. Inhibition of SCD1 increased both recruitment and activation of immune cells in vivo, which when combined with PD-1 blockade resulted in potent and durable anti-tumor T cell responses. Together, our results indicate that inhibition of tumorigenic de novo lipogenesis represents a novel approach to enhance T cell based cancer immunotherapy. Citation Format: Christina Anna Elizabeth Von Roemeling, Thomas Caulfield, Yaqing Qie, Derek C. Radisky, Xiujie Liu, Yuanxin Chen, Joshua Knight, John Copland, Betty Kim. Blockade of stearoyl CoA desaturase 1 promotes immunogenic clearance of tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-189. doi:10.1158/1538-7445.AM2017-LB-189

Abstract Lung cancer is the leading cancer diagnosis worldwide and the number one cause of cancer deaths. Exposure to cigarette smoke, the primary risk factor in lung cancer, reduces epithelial barrier function and increases susceptibility to infections. Herein, we hypothesized that somatic mutations together with cigarette smoke create a dysbiotic microbiota that is associated with lung carcinogenesis. Using lung tissue from controls (n=33) or cancer cases (n=143), we conducted 16S rRNA gene sequencing (MiSeq), with RNA-seq data from lung cancer cases in The Cancer Genome Atlas (n=1112) serving as the validation cohort. We demonstrate a lower alpha diversity in normal lung as compared to non-tumor adjacent or tumor tissue, indicating a shift in the overall microbial community in lung cancer patients as compared to those without cancer. Lung cancer cases were classified by the relative abundance of two taxa, Variovorax and Streptococcus, with an increase in Variovorax abundance in tumors as compared to non-tumor adjacent paired lung tissue (FDR corrected P=0.013). The species of Variovorax was identified histologically, and also by two additional 16S rRNA strategies (Resphera Insight analysis and PacBio sequencing). A group of taxa were associated with squamous cell carcinoma (SCC), of which Acidovorax were enriched in smokers (P =0.0013). Further, these taxa, including Acidovorax, exhibited higher abundance among the subset of SCC cases with TP53 mutations, an association not seen in adenocarcinomas (AD). Therefore, we observed a microbiome-gene and a microbiome-exposure interaction in SCC lung cancer tissue. Together, these results open the door for future biomarker research that could be used to improve screening and direct mechanistic studies of lung cancer therapy. Citation Format: Leigh Greathouse, James White, Valery Bliskovsky, Ashley Vargas, Eric Polley, Elise Bowman, Mohammed Khan, Ana Robles, Brid Ryan, Amiran Dzutsev, Giorgio Trinchieri, Marbin Pineda, Sven Bilke, Paul Meltzer, Marina Walther-Antonio, Garth Ehrlich, Joshua Mell, Joshua Earl, Sergey Balashov, Archana Bhat, Alex Valm, Clayton Deming, Sean Conlan, Julia Oh, Julie Segre, Curtis Harris. Microbiome-TP53 gene interaction in human lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4925. doi:10.1158/1538-7445.AM2017-4925

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common monogenic hereditary disorders in humans characterized by fluid-filled cysts, primarily in the kidneys. Cux1, a cell cycle regulatory gene highly expressed during kidney development, is elevated in the cyst-lining cells of Pkd1 mutant mice, and in human ADPKD cells. However, forced expression of Cux1 is insufficient to induce cystic disease in transgenic mice or to induce rapid cyst formation after cilia disruption in the kidneys of adult mice. Here we report a double mutant mouse model that has a conditional deletion of the Pkd1 gene in the renal collecting ducts together with a targeted mutation in the Cux1 gene (Pkd1CD;Cux1tm2Ejn). While kidneys isolated from newborn Pkd1CDmice exhibit cortical and medullary cysts, kidneys isolated from newborn Pkd1CD;Cux1tm2Ejn−/−mice did not show any cysts. Because Cux1tm2Ejn−/−are perinatal lethal, we evaluated Pkd1CDmice that were heterozygote for the Cux1 mutation. Similar to the newborn Pkd1CD;Cux1tm2Ejn−/−mice, newborn Pkd1CD;Cux1tm2Ejn+/−mice did not show any cysts. Comparison of Pkd1CDand Pkd1CD;Cux1tm2Ejn+/−mice at later stages of development showed a reduction in the severity of PKD in the Pkd1CD;Cux1tm2Ejn+/−mice. Moreover, we observed an increase in expression of the cyclin kinase inhibitor p27, a target of Cux1 repression, in the rescued collecting ducts. Taken together, our results suggest that Cux1 expression in PKD is not directly involved in cystogenesis but promotes cell proliferation required for expansion of existing cysts, primarily by repression of p27.