Citations

Abstract Background: MIF is a pleiotropic cytokine involved in tumor proliferation, invasiveness, angiogenesis, and the proinflammatory microenvironment. oxMIF is the pathogenic form mainly in tumor and its surrounding stroma. Imalumab (BAX69) is a novel recombinant, fully-human, monoclonal antibody that targets oxMIF, inhibiting tumorigenesis. Preclinical data demonstrated that imalumab has antitumor activities and acceptable toxicities. Methods: The primary endpoint of this dose-escalation study (3+3 design) was to assess maximum tolerated dose (MTD). The secondary endpoints were to assess antitumor activity, safety, pharmacokinetics (PK), and pharmacodynamics (PD). Patients (pts) received intravenous (IV) imalumab [28-d cycles; 2 dose schedules (DS)]: biweekly in all solid tumors (DS1); weekly in metastatic colorectal cancer (mCRC), metastatic ovarian cancer (OvCa) and metastatic non-small cell lung cancer (NSCLC) (DS2). Results: As of July 1 2015, 48 pts were treated in this study. DS1 = 19 pts in 6 cohorts (1, 3, 10, 25, 37.5, and 50 mg/kg), and DS2 = 29 pts in 2 cohorts (10 and 25 mg/kg) including expansion (10 mg/kg) into mCRC, OvCa and NSCLC. AUC and Cmax increased with dose. Dose escalation was stopped at 50 mg/kg (DS1) and 25mg/kg (DS2). An MTD was not reached for either DS. One pt reported dose-limiting toxicities: hypersensitivity pneumonitis (DS1; 50 mg/kg). There were no other grade 3 and 4 treatment related adverse events (trAEs). Grade 2 trAEs include: fatigue (n = 2), constipation (n = 1), peripheral edema (n = 1), infusion reaction (n = 1), and urticaria (n = 1). Stable disease (SD) ?4 mo was seen in 7 heavily pre-treated pts, including 1 pt with NSCLC who achieved SD for 13.4 mo. In DS2; Pre- and on-therapy tumor biopsies showed satisfactory tissue penetration of imalumab resulting in target saturation in all biopsy evaluable patients in all 3 tumor types. Biopsies revealed regulation of PI3K-AKT-mTOR downstream signaling, TNF-α signaling, anti-inflammatory cytokines (IL-1 and IL-10), and apoptosis. Based on clinical PK and PD study, 10mg/kg weekly was considered a biologically active dose and sufficient to reach ?95% target binding by the end of first cycle. Conclusions: Imalumab was well tolerated and showed single agent antitumor activity in heavily pretreated pts. An MTD was not reached. Recommended phase II dose (RP2D) is 10 mg/kg IV weekly. NCT01765790 Citation Format: Devalingam Mahalingam, Manish R. Patel, Jasgit C. Sachdev, Lowell L. Hart, Niels Halama, Ramesh K. Ramanathan, John Sarantopoulos, Xiaochun Liu, Salim Yazji, Dirk Jaeger, Deyaa Adib, Randolf Kerschbaumer, Apostolia Maria Tsimberidou. First-in-human phase 1 study assessing imalumab (BAX69), an anti-oxidized macrophage migration inhibitory factor (oxMIF) antibody in advanced solid tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT046.

Abstract Background: KRAS gene mutations are present in approximately 40% of colorectal adenocarcinomas and predict for nonresponse to the anti-epidermal growth factor receptor antibodies used in routine clinical practice. The most common activating mutations in this malignancy occur in codons 12 and 13 of exon 2. Determination of KRAS mutational status from tumor samples is an essential tool for managing patients with colorectal cancer (CRC) but requires tissue obtained by invasive percutaneous or surgical biopsies. Recent advances allow for the isolation and analysis of cell-free DNA (cfDNA) from the peripheral blood. A highly sensitive multiplex technology that uses low amounts of input DNA is needed to establish cfDNA as a liquid biopsy to personalize care. Methods: Digital droplet PCR (ddPCR) is a particularly sensitive method for detecting rare and low copy targets. Related work led to 7 individual assays, and to companion 4-plex and 3-plex assays, to accommodate the 7 common KRAS mutations and internal controls. A single 7-plex assay is favored to maximize efficiency and minimize cost. We optimized the RainDrop Digital PCR System to collectively detect the G12/G13 KRAS mutations, given that documentation of a mutation (not the specific mutation) is the factor of clinical relevance. Commercially available cell lines and genomic DNA aliquots were used as reference standards and for determinations of sensitivity and limit of blank (LOB). Initial clinical validation samples included tumor DNA derived from FFPE tissue (n = 10), cfDNA from healthy donors (n = 10), and cfDNA from metastatic CRC patients with tumors of known KRAS mutation status (n = 4). All assays were run in triplicate to confirm reproducibility. Results: Custom Taqman MGB probes were selected for KRAS wild type (WT), G12A, G12C, G12D, G12R, G12S, G12V, and G13D to allow for testing in a single reaction. LOB was 9 per 1×10(6) droplets on the basis of WT controls, including cfDNA samples from healthy donors. Evaluation of cell line DNA, genomic DNA aliquots, and FFPE samples demonstrates that the assay detects mutant KRAS with 100% accuracy and 0.1% mutant DNA in a total input of 10 ng WT/mutant DNA. With the clinical samples, concordant KRAS findings between cfDNA and tissue were obtained for two patients with WT tumors and one patient with a KRAS G12S mutant tumor. cfDNA analysis did not detect the G12V mutation identified in the colon primary of the other patient. Evaluation of additional clinical samples is in progress. Conclusions: Our 7-plex G12/G13 KRAS assay has excellent accuracy and is able to detect the KRAS mutations of interest at low (0.1%) mutation frequencies. Additional studies are being performed on prospectively collected plasma samples from patients with metastatic CRC of known KRAS mutation status. Large scale correlation between tumor mutation status and cfDNA findings will be performed to validate our assay for clinical implementation. Citation Format: Rajeswari Avula, Benjamin R. Kipp, Jesse S. Voss, Keegan E. Haselkorn, W. Edward Highsmith, Kevin C. Halling, Jeremy C. Jones, Steven R. Alberts, Michael B. Campion, Cassandra J. Nelson, Jin Jen, Eric D. Wieben, Julie M. Cunningham, Minetta C. Liu. Optimized 7-Plex cell-free DNA assay for clinically relevant KRAS mutations in colorectal cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 505.

Abstract Despite the rapid progress in personalized cancer therapy (PCT) for breast cancer, no previous studies have used genomic predictors to choose among multiple chemotherapy regimens. It is unclear that given the current regimens how much PCT can improve the response rate for patients who will receive chemotherapy. In this study, we reanalyzed data from published studies of 1111 breast cancer patients who were treated with neoadjuvant chemotherapies. Those patients were divided into three regimen groups: an anthracycline alone, anthracycline plus paclitaxel, and anthracycline plus docetaxel. We developed a new strategy called PRES (Personalized REgimen Selection) to reassign the optimal regimen to each of the patients. First, a variable selection scheme was developed to identify significant genetic predictors for chemotherapy response. The selected genetic variables were then combined with clinical variables to build random forest models to predict the response of a patient to each regimen using pCR (pathological complete response) as the measure of response. The models were used to assign an optimal regimen to each patient to maximize the chance of pCR. We found that the expected rate of pCR was improved from 21.2% to 39.6% (95% CI: 34.6% - 43.0%). We also found that 31.1% of the patients may have been overtreated and 8.2% patients undertreated. A validation study on 21 cell lines showed that our prediction agrees with their paclitaxel-sensitivity profiles. We performed additional analysis on the Cancer Genome Atlas (TCGA) data and found that 18 of the 19 genes identified are significantly differentially expressed between normal and tumor tissues, and 2 of them, TAF6L and METRN (meteorin), are associated with overall survival. In conclusion, PRES could substantially increase response rates for breast cancer patients who will receive one of the widely-accepted chemotherapy regimens at present. Citation Format: Jinfeng Zhang, Kaixian Yu, Qingxiang Amy Sang, Winston Tan, Mayassa B. Dargham, Jun S. Liu, Ty Lively, Cedric Sheffield. Personalized chemotherapy regimen selection for breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2034.

Abstract Individual tumors, including the aggressive and difficult to treat triple-negative (ER-/PR-/HER2-) breast cancers (TNBCs) are heterogeneous collections of cells with multiple subclonal populations each contributing to the tumor. While subclonal heterogeneity is likely responsible for the development of drug resistance, identification of how tumor cell populations change over time has been difficult, largely because of the challenges in resampling tumor tissue at close time points. Here we quantify tumor evolution in human patient-derived xenografts implanted into NSG mice, which we use to test subclonal heterogeneity as a function of location within a tumor, propagation time, and drug treatment. We used high-depth (∼400x) sequencing of a targeted panel of 358 genes to quantify somatic mutation allele frequencies from 6 spatially-separated and 8 temporally-propagated xenograft samples derived from the same TNBC patient tumors. Samples ranged in age from 2-4 months post-engraftment. Although we observed a few low frequency mutations distinguishing samples, overall we found that allele frequencies of somatic mutations were well-preserved on this time scale. We then generated replicate xenografts from the same patient tumor and treated them respectively with cisplatin, doxorubicin, cyclophosphamide, docetaxel, or vehicle control for 25 days. Although again somatic mutations showed few differences in allele frequency across samples, substantial variations were seen when data were analyzed for copy number alterations. To confirm these effects we repeated the treatments for xenografts derived from two additional TNBC patients. Again we observed strong changes in tumor heterogeneity at the copy number level. This effect was particularly, but not exclusively, apparent in tumors with the greatest response to therapy. We further verified these measurements through Sanger and digital PCR sequencing on the treated mice and other mice in the same cohorts. Using a multi-sample xenograft propagation, dissection, sequencing, and computational analysis protocol, we have shown that tumor subpopulation changes in response to treatment can be quantified and distinguished from spatial or temporal effects, even for treatment time courses as short as 1 month. In triple negative breast cancer these variations are most apparent at the level of copy number variation. Our study demonstrates how patient-derived xenografts can provide detailed resolution of tumor population evolution during the manifestation of resistance. Citation Format: Hyunsoo Kim, Pooja Kumar, Francesca Menghi, Joshy George, Guru Ananda, Susan Mockus, Chengsheng Zhang, Nicholas Larson, Henry C. Chen, Yan Yang, James Keck, R. Krishnamurthy Karuturi, Charles Lee, Carol Bult, Edison Liu, Jeffrey H. Chuang. Evolution during propagation and treatment of patient-derived triple negative breast cancer xenografts. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2411.

Glaucoma is one of the leading causes of blindness worldwide. Recent studies suggest that intraocular pressure (IOP) fluctuations, peaks, and rhythm are important factors in disease advancement. Yet, current glaucoma management remains hinged on single IOP measurements during clinic hours. To overcome this limitation, 24-hour IOP monitoring devices have been employed and include self-tonometry, permanent IOP, and temporary IOP monitoring. This review discusses each IOP measuring strategy and focuses on the recently FDA-approved contact lens sensor (CLS). The CLS records IOP-related ocular patterns for 24 hours continuously. Using the CLS, IOP-related parameters have been found to be associated with the rate of visual field progression in primary open-angle glaucoma, disease progression in primary angle-closure glaucoma, and various clinical variables in ocular hypertension. The CLS has been used to quantify blink rate and limbal strain and measure the circadian rhythm in a variety of disease states including normal-tension glaucoma and thyroid eye disease. The effects of various IOP-lowering interventions were also characterized using the CLS. CLS provides a unique, safe, and well-tolerated way to study IOP-related patterns in a wide range of disease states. IOP-related patterns may help identify patients most at risk for disease progression and assist with the development of tailored treatments.

Ciliated muconodular papillary tumors (CMPTs) are rare peripheral lung lesions, characterized by papillary architecture and ciliated columnar cells admixed with mucinous cells and basal cells. They often have prominent surrounding intra-alveolar mucin, which can lead to diagnostic confusion with mucinous adenocarcinoma. Recognition of the ciliated component is the key to diagnosis of CMPT. The literature contains few reported cases to date, all occurring in East-Asian patients. Although follow-up data are limited, CMPT seems to be an indolent tumor with very good prognosis, leading some to question whether it is a reactive or hamartomatous lesion. However, a very recent molecular study has identified BRAF (40%) and EGFR (30%) alterations in CMPT, supporting a truly neoplastic process. Here for the first time, we report 4 cases of morphologically typical CMPT in western patients, occurring in 1 man (60 y) and 3 women (71 to 83 y). Interestingly, 1 case occurred in background of pronounced small airway disease with necrotizing bronchiolitis and multiple carcinoid tumorlets. We further analyzed 1 tumor using a 50 gene next-generation sequencing oncology panel that identified 2 pathogenic mutations (BRAF V600E and AKT1 E17K). Our study is the first to describe that CMPT can occur in western (non-Asian) patients. Our data confirm BRAF V600E mutation as a probable driver in a subset of these tumors, along with AKT1 mutation, which further supports that CMPT are indolent pulmonary neoplasms.

Purpose According to the lung cancer staging project, T1a (≤ 2 cm) non–small-cell lung cancer (NSCLC) should be additionally classified into ≤ 1 cm and > 1 to 2 cm groups. This study aimed to investigate the surgical procedure for NSCLC ≤ 1 cm and > 1 to 2 cm. Methods We identified 15,760 patients with T1aN0M0 NSCLC after surgery from the Surveillance, Epidemiology, and End Results database. Overall survival (OS) and lung cancer–specific survival (LCSS) were compared among patients after lobectomy, segmentectomy, or wedge resection. The proportional hazards model was applied to evaluate multiple prognostic factors. Results OS and LCSS favored lobectomy compared with segmentectomy or wedge resection in patients with NSCLC ≤ 1 cm and > 1 to 2 cm. Multivariable analysis showed that segmentectomy and wedge resection were independently associated with poorer OS and LCSS than lobectomy for NSCLC ≤ 1 cm and > 1 to 2 cm. With sublobar resection, lower OS and LCSS emerged for NSCLC > 1 to 2 cm after wedge resection, whereas similar survivals were observed for NSCLC ≤ 1 cm. Multivariable analyses showed that wedge resection is an independent risk factor of survival for NSCLC > 1 to 2 cm but not for NSCLC ≤ 1 cm. Conclusion Lobectomy showed better survival than sublobar resection for patients with NSCLC ≤ 1 cm and > 1 to 2 cm. For patients in whom lobectomy is unsuitable, segmentectomy should be recommended for NSCLC > 1 to 2 cm, whereas surgeons could rely on surgical skills and the patient profile to decide between segmentectomy and wedge resection for NSCLC ≤ 1 cm.

Interplay between cell polarity module Scribble‐Lethal Giant Larvae‐Discs Large 1 (DLG1) and Yes‐associated protein (YAP) appears critical in tumor metastasis. We identified zinc finger protein 191 (ZNF191) as a metastasis suppressor acting through DLG‐YAP crosstalk in hepatocellular carcinoma (HCC). Overexpression of ZNF191 in HCC cells impaired cell motility, while ZNF191 depletion promoted cell migration in vitro and metastasis in vivo through triggering YAP signaling. Chromatin immunoprecipitation‐sequencing revealed that ZNF191 specifically bound to the promoter of DLG1, a cell polarity maintainer and a negative regulator of YAP. The binding sequence of ZNF191 at the DLG1 promoter is a seven‐repeat of TCAT motif. Double‐knockdown experiments inferred that DLG1 was not only the mediator of the function of ZNF191 to suppress migration but also a link between ZNF191 and YAP signaling. Decreased expression of ZNF191 in human metastatic HCC specimens correlated positively with DLG1 levels but inversely with YAP activation. Our findings illustrate a YAP‐targeting, antimetastasis function of ZNF191, thereby representing a possible prognostic marker and a potential target for metastasis therapy. Conclusion: ZNF191 directly binds to the DLG1 promoter at a typical TCAT repeating motif and activates the expression of DLG1; through up‐regulating DLG1, ZNF191 inhibits cell migration and YAP activation in HCC cells and eventually inhibits metastasis. (Hepatology 2016;64:1148‐1162)

The concept of optimizing health care by understanding and generating knowledge from previous evidence, ie, the Learning Health-care System (LHS), has gained momentum and now has national prominence. Meanwhile, the rapid adoption of electronic health records (EHRs) enables the data collection required to form the basis for facilitating LHS. A prerequisite for using EHR data within the LHS is an infrastructure that enables access to EHR data longitudinally for health-care analytics and real time for knowledge delivery. Additionally, significant clinical information is embedded in the free text, making natural language processing (NLP) an essential component in implementing an LHS. Herein, we share our institutional implementation of a big data-empowered clinical NLP infrastructure, which not only enables health-care analytics but also has real-time NLP processing capability. The infrastructure has been utilized for multiple institutional projects including the MayoExpertAdvisor, an individualized care recommendation solution for clinical care. We compared the advantages of big data over two other environments. Big data infrastructure significantly outperformed other infrastructure in terms of computing speed, demonstrating its value in making the LHS a possibility in the near future.