tbuckley/cabot-search huggingface dataset:
<i>RET</i> Aberrations in Diverse Cancers: Next-Generation Sequencing of 4,871 Patients
Authors: Shumei Kato, Vivek Subbiah, Erica Marchlik, Sheryl K. Elkin, Jennifer L. Carter, Razelle Kurzrock
Journal: Clinical Cancer Research (2016)

Purpose: Aberrations in genetic sequences encoding the tyrosine kinase receptor RET lead to oncogenic signaling that is targetable with anti-RET multikinase inhibitors. Understanding the comprehensive genomic landscape of RET aberrations across multiple cancers may facilitate clinical trial development targeting RETExperimental Design: We interrogated the molecular portfolio of 4,871 patients with diverse malignancies for the presence of RET aberrations using Clinical Laboratory Improvement Amendments-certified targeted next-generation sequencing of 182 or 236 gene panels.Results: Among diverse cancers, RET aberrations were identified in 88 cases [1.8% (88/4, 871)], with mutations being the most common alteration [38.6% (34/88)], followed by fusions [30.7% (27/88), including a novel SQSTM1-RET] and amplifications [25% (22/88)]. Most patients had coexisting aberrations in addition to RET anomalies [81.8% (72/88)], with the most common being in TP53-associated genes [59.1% (52/88)], cell cycle-associated genes [39.8% (35/88)], the PI3K signaling pathway [30.7% (27/88)], MAPK effectors [22.7% (20/88)], or other tyrosine kinase families [21.6% (19/88)]. RET fusions were mutually exclusive with MAPK signaling pathway alterations. All 72 patients harboring coaberrations had distinct genomic portfolios, and most [98.6% (71/72)] had potentially targetable coaberrations with either an FDA-approved or an investigational agent. Two cases with lung (KIF5B-RET) and medullary thyroid carcinoma (RET M918T) that responded to a vandetanib (multikinase RET inhibitor)-containing regimen are shown.Conclusions:RET aberrations were seen in 1.8% of diverse cancers, with most cases harboring actionable, albeit distinct, coexisting alterations. The current report suggests that optimal targeting of patients with RET anomalies will require customized combination strategies. Clin Cancer Res; 23(8); 1988-97. ©2016 AACR.
Arc/Arg3.1 governs inflammatory dendritic cell migration from the skin and thereby controls T cell activation
Authors: Friederike Ufer, Pablo Vargas, Jan Broder Engler, Joseph Tintelnot, Benjamin Schattling, Hana Winkler, Simone Bauer, Nina Kursawe, Anne Willing, Oliver Keminer, Ora Ohana, Gabriela Salinas-Riester, Ole Pless, Dietmar Kuhl, Manuel A. Friese
Journal: Science Immunology (2016)

Skin-migratory dendritic cells (migDCs) are pivotal antigen-presenting cells that continuously transport antigens to draining lymph nodes and regulate immune responses. However, identification of migDCs is complicated by the lack of distinguishing markers, and it remains unclear which molecules determine their migratory capacity during inflammation. We show that, in the skin, the neuronal plasticity molecule activity-regulated cytoskeleton-associated protein/activity-regulated gene 3.1 (Arc/Arg3.1) was strictly confined to migDCs. Mechanistically, Arc/Arg3.1 was required for accelerated DC migration during inflammation because it regulated actin dynamics through nonmuscle myosin II. Accordingly, Arc/Arg3.1-dependent DC migration was critical for mounting T cell responses in experimental autoimmune encephalomyelitis and allergic contact dermatitis. Thus, Arc/Arg3.1 was restricted to migDCs in the skin and drove fast DC migration by exclusively coordinating cytoskeletal changes in response to inflammatory challenges. These findings commend Arc/Arg3.1 as a universal switch in migDCs that may be exploited to selectively modify immune responses.
Tumor-Intrinsic PD-L1 Signals Regulate Cell Growth, Pathogenesis, and Autophagy in Ovarian Cancer and Melanoma
Authors: Curtis A. Clark, Harshita B. Gupta, Gangadhara Sareddy, Srilakshmi Pandeswara, Shunhua Lao, Bin Yuan, Justin M. Drerup, Alvaro Padron, José Conejo-Garcia, Kruthi Murthy, Yang Liu, Mary Jo Turk, Kathrin Thedieck, Vincent Hurez, Rong Li, Ratna Vadlamudi, Tyler J. Curiel
Journal: Cancer Research (2016)

PD-L1 antibodies produce efficacious clinical responses in diverse human cancers, but the basis for their effects remains unclear, leaving a gap in the understanding of how to rationally leverage therapeutic activity. PD-L1 is widely expressed in tumor cells, but its contributions to tumor pathogenicity are incompletely understood. In this study, we evaluated the hypothesis that PD-L1 exerts tumor cell-intrinsic signals that are critical for pathogenesis. Using RNAi methodology, we attenuated PD-L1 in the murine ovarian cell line ID8agg and the melanoma cell line B16 (termed PD-L1lo cells), which express basal PD-L1. We observed that PD-L1lo cells proliferated more weakly than control cells in vitro As expected, PD-L1lo cells formed tumors in immunocompetent mice relatively more slowly, but unexpectedly, they also formed tumors more slowly in immunodeficient NSG mice. RNA sequencing analysis identified a number of genes involved in autophagy and mTOR signaling that were affected by PD-L1 expression. In support of a functional role, PD-L1 attenuation augmented autophagy and blunted the ability of autophagy inhibitors to limit proliferation in vitro and in vivo in NSG mice. PD-L1 attenuation also reduced mTORC1 activity and augmented the antiproliferative effects of the mTORC1 inhibitor rapamycin. PD-L1lo cells were also relatively deficient in metastasis to the lung, and we found that anti-PD-L1 administration could block tumor cell growth and metastasis in NSG mice. This therapeutic effect was observed with B16 cells but not ID8agg cells, illustrating tumor- or compartmental-specific effects in the therapeutic setting. Overall, our findings extend understanding of PD-L1 functions, illustrate nonimmune effects of anti-PD-L1 immunotherapy, and suggest broader uses for PD-L1 as a biomarker for assessing cancer therapeutic responses. Cancer Res; 76(23); 6964-74. ©2016 AACR.
Evaluation of FOXP3 microsatellite polymorphisms in high-risk melanoma patients receiving adjuvant interferon.
Authors: H. Gogas, E. Wang, A. Monaco, L. Uccellini, C. S. Floudas, Y. Metaxas, U. Dafni, G. Fountzilas, M. Spyropoulou-Vlachou, F. Marincola
Journal: Journal of Clinical Oncology (2010)

8538 Background: Attempts to identify patients who benefit from adjuvant treatment with interferon alfa-2b (IFN) have been disappointing. The development of autoimmunity during adjuvant therapy with IFN cannot assist selection of patients for therapy at baseline. The FOXP3 is located at Xp11.23 within an area of autoimmune disease linkage and therefore is an excellent positional candidate gene for autoimmunity at this locus. Consequently we performed a microsatellite analysis of FOXP3 gene in the exon 0 region in high-risk melanoma patients enrolled in a study of two regimens of high-dose IFN. Methods: A fragmentanalysis was performed in the DNA of 259 stage IIb, IIc, and III melanoma patients. After amplification and electrophoresis run, data from each sample were analyzed using Genemapper software (Applied Biosystems), which objectively calls the fragments size. Results: Thirteen alleles were detected (size: 284, 286, 288, 290, 292, 298, 302, 304, 306, 310, 312, 314, 316). The tabular distribution of these alleles in melanoma patients is presented below. At a median follow-up of 71 months (range 7.1-138.7 months), 144 patients have recurred and 95 have died. There were no statistically significant differences in the incidence of FOXP3 alleles between melanoma patients who recurred and those with no evidence of recurrence. RFS did not differ significantly between patients with recurrence and those without for each of the alleles detected. Conclusions: No allele defined by the microsatellite analysis of the FOXP3 gene in exon 0 was correlated with improved RFS in this high-risk group of melanoma patients. Genes No relapse n=115 (%) Relapse n=144 (%) p value allele_284 2 (1.74) 2 (1.39) 1 allele_286 2 (1.74) 1 (0.69) 0.586 allele_288 79 (68.70) 90 (62.50) 0.358 allele_290 4 (3.48) 2 (1.39) 0.411 allele_292 0 (0.00) 1 (0.69) 1 allele_298 1 (0.87) 5 (3.47) 0.231 allele_302 1 (0.87) 3 (2.08) 0.632 allele_304 1 (0.87) 2 (1.39) 1 allele_306 6 (5.22) 11 (7.64) 0.463 allele_310 16 (13.91) 18 (12.50) 0.853 allele_312 1 (0.87) 5 (3.47) 0.231 allele_314 2 (1.74) 2 (1.39) 1 allele_316 0 (0.00) 2 (1.39) 0.504 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Schering-Plough
Neoadjuvant treatment with imatinib for locally advanced dermatofibrosarcoma protuberans.
Authors: R. Neves, S. A. Fateh, B. Saunders, E. Kimchi, E. Bannon, J. J. Drabick
Journal: Journal of Clinical Oncology (2010)

e20507 Background: We report the cases of five patients with locally advanced dermatofibrosarcoma protuberans (DFSP) of the head and neck and other regions that were treated successfully with neoadjuvant imatinib. The tumors of all patients had molecular evidence of the t(17;22) translocation by FISH and had associated over-expression of the PDGFR. More than 90% of DFSP are characterized by this chromosomal translocation which leads to over-expression of PDGFR. PDGFR is a target for oral imatinib which has been shown to induce significant responses in this entity. Imatinib has been used primarily in advanced DFSP as palliative therapy after the failure of resection and radiotherapy. Methods: These five patients had tumors for which initial surgery was felt to be potentially disfiguring and morbid given their locations and locally advanced nature. Given the known ability of imatinib to induce significant objective responses in unresectable DFSP, the patients were treated with 6 cycles (months) of imatinib therapy prior to surgical resection. Results: All had excellent partial responses. Subsequently, they went on to surgical interventions that were technically easier to perform and less disfiguring. Conclusions: We review these cases in the context of the published literature and conclude that neoadjuvant therapy of locally advanced DFSP with imatinib can lead to significant tumor reduction and hence less disfiguring yet successful resections with better cosmetic outcomes for patients with this uncommon malignancy. No significant financial relationships to disclose.
The role of radio-surgery in patients with metastatic melanoma to the brain.
Authors: M. C. Lowe, A. Cavitt, J. Shelton, I. R. Crocker, L. Pan, D. H. Lawson, G. W. Carlson, K. A. Delman, M. Rizzo
Journal: Journal of Clinical Oncology (2010)

e19023 Background: The brain is a frequent site of melanoma metastases (mets) and is associated with a poor prognosis. Therapeutic options are limited and include surgical resection, whole brain radiation therapy (WBRT), and stereotactic radio-surgery (SRS). The aim of this study was to analyze outcomes and prognostic factors in patients treated with SRS in a single institution. Methods: Patients with brain mets from melanoma were retrospectively identified by chart review from 1999 to 2006. All brain mets were diagnosed with contrast brain MRI. Overall survival (OS) was calculated from the time of the diagnosis of brain mets to death and calculated using Kaplan Meier estimates and Cox models adjusted for clinical factors. Age, sex, Breslow thickness, location, type, ulceration, sentinel node status, number of brain mets, WBRT, receiving temozolomide, neurologic progression of disease, LDH level within 3 months from death were also analyzed. Results: 73 patients (age 20-92, median = 49) were identified with brain mets; 60 (82.1 %) received 72 SRS sessions. 13 patients (17.9%) did not receive SRS because they presented with > 3 brain mets (n = 7) or required neurosurgical decompression as an emergency (n = 6). Age, sex, Breslow thickness, location, type, presence of ulceration, sentinel node status were not predictive of developing brain mets. Median interval from resection of the primary to diagnosis of brain mets was 25.7 months. Overall, 42 patients (57.5%) received Temozolomide and 20 (27.3%) had WBRT. The number of brain mets, WBRT, temozolomide, age, sex, neurologic progression of the disease was not associated with increased survival. SRS was associated with improved survival (p = 0.02). Elevated LDH > 200 mg/dL was associated with the time to death (p = 0.0003). Median survival from the development of brain mets was 6.3 months (range = 1.03-130.93 months). At 12/30/2009 when we completed the analysis, only 5 patients (6.8%) were alive: they had 1-2 brain mets and all received SRS. Conclusions: Our results suggest that patients with melanoma brain mets have overall a very poor prognosis. Patients with LDH level < 200 mg/dL have a longer survival. SRS of limited metastatic disease in the brain is occasionally associated with long-term survival. No significant financial relationships to disclose.
A study of sperm-associated antigen 5 (SPAG5) in predicting response to anthracycline (ATC)/platinum chemotherapies (CT) in breast (BC) and ovarian cancers (OVC).
Authors: Tarek M. A. Abdel-Fatah, Graham Ball, Stephanie McArdle, Catherine Johnson, Paul Moseley, Shama Hosnii, Andrew R. Green, Ian O. Ellis, Stephen Chan
Journal: Journal of Clinical Oncology (2012)

1098 Background: Recently TOP2A alteration was found to be a predictor for ATC-CT and our neural network analysis of BC gene expression array (GEA) data has revealed SPAG5 gene as a major hubs in both TOP2A and proliferation pathways. In this study the molecular and clinicopathological functions of SPAG5 was investigated in BC and OVC. Methods: (1) A series of 171 BC was evaluated for SPAG5 gene copy number (using aCGH) and mRNA expression (using GEA) which were validated in 5 independent databases. (2) The expression of SPAG5 protein was evaluated pre-clinically in BC and OVC cell lines and in both 40 normal breast tissues and a series of 1650 primary BC and was correlated to clinicopathological and other biomarkers. (3) The association between SPAG5 and response to CT was investigated in a) 350 ER negative BC treated with adjuvant ATC-CT, b) 250 BC treated with neoadjuvant (NEO-A)-ATC-CT, and c) 200 primary OVC treated with cisplatinum based adjuvant CT. Results: (1) 5% and 15% of the 171 BC showed amplification and gain of SPAG5 locus, respectively, at 17q11.2. SPAG5 mRNA expression displayed a significant correlation with its copy number (p&lt; 0.0001). (2) 30% and 20% of ovarian and BC respectively, showed overexpression of SPAG5 protein (+). In BC, SPAG5+ at both mRNA and protein levels showed a significant association with aggressive phenotypes, high mitosis, ER-, high grade, p53 mutation and epithelial mesenchymal transition phenotypes (ps &lt;0.0001). SPAG5 mRNA (+) was statistically associated with poor survivals (p&lt;0.0001). (3) In ER- BC treated with adjuvant ATC-CT, SPAG5 negative (-)had 7-times higher risk of progression compared with SPRAG+ BC (p&lt;0.0001). SPAG5+ BC received NEO-A-ATC based CT achieved 38% pathological complete response (pCR) vs. 6% of SPAG5- (p&lt;0.0001). After controlling to other predictors for pCR, SPAG5 was an independent predictor (HR; 2.4; p=0.001). Similarly, SPAG5- OVCs were resistant to platinum (p&lt;0.001) and independently associated with poor survival (p&lt;0.001). Conclusions: SPAG5 is an important novel gene implicated in the survival of BC and OVC cells and its protein expression is an independent predictor for anthracycline/ cisplatinum CT.
Validation of the Immunoscore (IM) as a prognostic marker in stage I/II/III colon cancer: Results of a worldwide consortium-based analysis of 1,336 patients.
Authors: Jerome Galon, Bernhard Mlecnik, Florence Marliot, Fang-Shu Ou, Carlo Bruno Bifulco, Alessandro Lugli, Inti Zlobec, Tilman T. Rau, Arndt Hartmann, Giuseppe V. Masucci, Eva Zavadova, Pam Ohashi, Michael H. A. Roehrl, Yutaka Kawakami, Toshihiko Torigoe, Paolo Antonio Ascierto, Franco Marincola, Daniel J. Sargent, Bernard A. Fox, Franck Pages
Journal: Journal of Clinical Oncology (2016)

3500 Background: Mounting evidence indicates an enhanced lymphocytic reaction as an informative prognostic indicator in colon cancer (CC). The IM methodology has been defined to quantify the in situ immune infiltrate. Methods: A Society for Immunotherapy of Cancer-led international consortium of 23 pathology expert centers from 17 countries was initiated to evaluate the standardized IM assay in routine clinical settings. Patient (pt) eligibility criteria were CC Stages I/II/III and no neo-adjuvant treatment. 1336 pts split into a training set (TS) and internal validation set (IVS) were quantified for IM using standardized procedure, immunohistochemistry using CD3 and CD8 antibodies, and quantification using digital pathology on whole slide section of primary CCs. Statistical analysis plan was pre-defined and all statistical analyses performed by blinded external statisticians. Primary study endpoint was time-to-recurrence (TTR); analyses were by Cox models stratified by enrolling center. Results: Median recurrent follow-up duration across centers was 5.9 years. Overall pts: 51% Male, median age 69 years, 19%/56%/25% stage I/II/III. Among pts with Stages I/II/III CC, in the TS TTR was shorter among 332 pts (48.1%) with Low-IM CC vs. 358 pts with High-IM CC (HR (95% CI), 0.35 (0.23-0.52); P < 0.0001). In the IVS (630 pts) TTR was also shorter among 303 pts with Low-IM CC vs. 327 pts with High-IM CC (HR (95% CI), 0.54 (0.34-0.84); P = 0.006). In both groups, results were independent of pt age, sex, tumor stage and sidedness. Among pts with Stage II CC, the difference in TTR between Low and High-IM was significant both in the TS (HR (95% CI), 0.27 (0.14-0.51); P < 0.0001) and in the IVS (HR (95% CI), 0.46 (0.24-0.87) P = 0.014); multivariate results similar (TS HR (95% CI), 0.28 (0.14-0.54); P < 0.0001) and IVS HR (95% CI), 0.46 (0.24-0.87); P = 0.0142)). Reproducibility of the standardized IM assay was validated across centers. Conclusions: The primary endpoint of the worldwide pre-specified IM study was reached. TTR was significantly longer in pts stages I/II/III with High-IM. Low-IM identified a subgroup of patients with high-risk stage II CC.
Kawasaki Disease at 50 Years
Authors: Ezra Cohen, Robert Sundel
Journal: JAMA Pediatrics (2016)

<h3>Importance</h3> Kawasaki disease (KD) is the most recognized vasculitis of childhood. The condition's characteristic high fever, rash, mucositis, conjunctivitis, lymphadenopathy, and extremity changes are superficially unexceptional, and resolve spontaneously within a mean of 12 days. It is the acuity and the potential for life-changing damage to the coronary arteries that distinguish KD from conditions that mimic it and exemplify the unique aspects and challenges of vascular inflammation in children. <h3>Observations</h3> Although KD is an orphan disease, its role as a leading cause of acquired heart disease in children has led to significant efforts to determine its etiology, optimize diagnosis, and customize treatment according to individuals' needs. The result is that KD can now be controlled without sequelae in more than 95% of cases. Furthermore, advances in stratifying patients according to measurable risk factors allow therapy to be personalized in increasingly effective ways. High-risk patients, such as infants younger than 6 months, those with early evidence of coronary artery dilatation, and those with extreme abnormalities in laboratory test results, are often identified at presentation. This early identification allows them to be treated with corticosteroids in addition to intravenous immunoglobulin to improve their outcomes. Children with similar findings on laboratory tests and echocardiography may be treated based on algorithms for managing "incomplete KD" despite falling short of fulfilling classic diagnostic criteria. Children who do not respond to intravenous immunoglobulin are the focus of trials to minimize the duration of inflammation and thereby protect their coronary arteries in ways never before considered. <h3>Conclusions and Relevance</h3> Kawasaki disease is a hybrid condition at the junction of infectious diseases, immunology, rheumatology, and cardiology. Rather than being left an orphan disease, KD is bringing disciplines together to identify its genetic, pathophysiological, and hemodynamic features. In turn, this work promises to shed light on many other inflammatory conditions as well.
EGFR mutation detection in ctDNA from NSCLC patient plasma: A cross-platform comparison of technologies to support the clinical development of AZD9291.
Authors: Kenneth Thress, Roz Brant, Hedley Carr, Helen Brown, Simon Patrick Dearden, Suzanne Jenkins, Tracey Hammett, Mireille Cantarini, Serban Ghiorghiu, J. Carl Barrett
Journal: Journal of Clinical Oncology (2014)

8092 Background: EGFR tyrosine kinase inhibitors are highly effective in treating EGFR mutant+ NSCLC. Patients invariably relapse and resistance is most often associated with an EGFR T790M mutation. AZD9291 is currently in clinical development to address this primary T790M-mediated resistance. Several highly sensitive technologies have been described for detection of EGFR mutations from tumor DNA (ctDNA) shed into the circulating plasma. ctDNA may provide an option for patients unable to provide tissue biopsies for AZD9291 patient selection and disease monitoring purposes. Methods: Using plasma from patients enrolled on the AZD9291 clinical study (NCT01802632), we undertook a cross-platform comparison of 4 methods for the detection of EGFR mutations in ctDNA: ARMS-based detection using 1) Roche Cobas and 2) Qiagen Therascreen EGFR mutation detection kits, and digital PCR-based (dPCR) approaches using 3) BioRad ddPCR (MolecularMD) and 4) BEAMing (Inostics). Results: To date, 38 pre-dose plasma samples have been evaluated. ctDNA was tested for 3 EGFR mutations (T790M, L858R, Exon 19 del). Matched tumor biopsies were available for most plasma samples to enable ctDNA-tumor concordance testing. Overall, concordance of mutation status was high for all ctDNA detection methods. The false positive rate was low across platforms with specificities >90%. In contrast, dPCR methods showed increased sensitivities for T790M compared with the ARMS-based methods (67-71% vs. 29-41%) whereas sensitivity for activating mutations was equivalent between dPCR and ARMS (80-90%). The sensitivity of dPCR for T790M allowed for preliminary correlations of baseline plasma T790M levels with clinical characteristics and AZD9291 response (unvalidated). T790M was more frequently detected in the plasma from patients with metastatic vs. local disease (77% vs. 25%). Moreover, patients with quantifiable T790M at baseline showed a 71% response rate (RR) compared to a 31% RR for patients with undetectable levels of T790M. Conclusions: The detection of EGFR mutations from ctDNA using sensitive dPCR methods will help to inform alternative patient selection strategies for AZD9291.