tbuckley/cabot-search huggingface dataset:
Abstract 3161: Development and implementation of a non-invasive NGS-based diagnostic test for precision medicine in prostate cancer
Authors: Pan Du, Amy Wang, Tak Cheng, Winston Patrick Kuo
Journal: Cancer Research (2016)

Abstract The growth and survival of prostate cancer tumors relies primarily on the functioning of the androgen receptor (AR) signaling pathway. Recent studies suggested that the presence of AR-V7, a c-terminal truncated form of AR, in circulating tumor cells (CTCs) of patients with castration-resistant prostate cancer (CRPC) is associated with inherent and/or acquired resistance to enzalutamide and abiraterone, the stand of care androgen deprivation therapies in prostate cancer. A series of data also indicate that AR-Vs (eg, including AR-V7, ARv567es, AR-T878A, AR-F876L, and Arv567es) may drive resistance in CRPC. Expression of AR-Vs has been shown to correlate with disease progression and shortened survival and AR-V7 is most abundant in CRPC specimens. Considering that truncated ARs with C-terminal loss (splice variants) lack a functional LBD and are constitutively active, C-terminal AR-directed therapies may not be effective, and novels agents are needed that target mutated ARs including AR-Vs. Circulating tumor cell (CTC)-based AR-V7 tests are currently being tested in the clinic. However, nearly half of the CRPC patients do not have enough CTCs for AR-V7 test, raising the request for a complementary, non-CTC platform to detect AR variants as well as other resistance markers in circulation. Here we report the successful development of a non-invasive, next generation sequencing-based diagnostics platform that offers comprehensive profiling of genomic alterations in prostate cancer, including splicing variants (such as AR-V7), point mutation, copy number, and translocation using biofluid samples (blood and urine) from CRPC patients. To the best of our knowledge, this is the first non-invasive diagnostic test that measures genetic alterations especially AR-V7 in all patients with prostate cancer, regardless of their status of CTC enumeration. The successful development and clinical validation of this test has potential to enable precision medicine in prostate cancer. Citation Format: Pan Du, Amy Wang, Tak Cheng, Winston Patrick Kuo. Development and implementation of a non-invasive NGS-based diagnostic test for precision medicine in prostate 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 3161.
Surgeon assessment of volume preservation (SAVP) performed before or after partial nephrectomy to predict post-operative renal function.
Authors: Michael Klingler, Brian R. Lane, Georgios Hatzichristodoulou, Alexander Kutikov, Francesco Sanguedolce, Bulent Akdogan, Umberto Capitanio, Marco Roscigno, Alessandro Volpe, Martin Marszalek, Riccardo Campi, Robert G. Uzzo, Alessandro Antonelli, Hans Langenhuijsen, Andrea Minervini
Journal: Journal of Clinical Oncology (2016)

e16065 Background: Partial nephrectomy (PN) is the gold standard for small renal masses, improving renal functional outcomes by preserving functioning renal parenchyma when compared with radical nephrectomy. Recent work (J Urol 2014;191:1218-24) demonstrated that postoperative surgeon assessment of volume preservation (postop-SAVP) is a reliable approximation when compared with formal measurements obtained with 3D imaging. We hypothesize that surgeons can anticipate the volume preserved with PN based on preoperative imaging (pre-SAVP) and that pre-SAVP (like postop-SAVP) will be a reliable indicator of renal function after surgery. Methods: Data were collected from 336 patients who underwent PN for suspected renal cancer at 12 centers in the US and Europe. Surgeons documented pre-SAVP/postop-SAVP for each patient and renal function was assessed pre and postop by CKD-EPI equations. Correlations between pre-SAVP and postop-SAVP and between pre-SAVP or postop-SAVP and postop GFR were assessed with linear regression models. Bland-Altman analysis was used to assess agreement between pre-SAVP and postop-SAVP with a significance cutoff of 5%. Results: Median pre-SAVP was 90% (interquartile range: 85-100%) and postop SAVP was 90% (IQR: 80-94%). Pre-SAVP and postop-SAVP were moderately correlated (R = 0.67, p < 0.0001) and were found to be “interchangeable” by Bland-Altman analysis at a 5% acceptable rate of difference (95% CI: -5.4, -3.1,). Median postop GFR was 85.3 (IQR: 68.9-97.1). Both pre-SAVP and postop-SAVP were correlated with postop GFR (R = 0.82, p < .0001; R = 0.83, p < .0001, respectively). Conclusions: Similar to postop-SAVP, pre-SAVP can be a strong indicator of functional outcome following PN. Renal function is closely linked to the volume of parenchyma preserved. Pre-SAVP can provide important and relatively accurate information for decision-making in patients considering PN. Linear regression analysis of factors associated with postoperative GFR. Estimate (Std Error) R (p-value) Age -0.94 (0.09) 0.52 ( < 0.0001) vGFR Pre-SAVP 0.98 (0.06) 0.26 ( < 0.0001) vGFR Postop SAVP 0.99 (0.04) 0.83 ( < 0.0001)
The PKC- Inhibitor Enzastaurin Inhibits MM Cell Growth, Survival and Migration in the Bone Marrow Microenvironment.
Authors: Klaus Podar, Marc S. Raab, Dean Abtahi, Yu-Tzu Tai, Boris Lin, Nikhil C. Munshi, Teru Hideshima, Dharminder Chauhan, Kenneth C. Anderson
Journal: Blood (2005)
Abstract 999: P16 DNA methylation inactivates transcription of IncRNA ANRIL
Authors: Ying Gan, Baozhen Zhang, Chenghua Cui, Dajun Deng
Journal: Cancer Research (2016)

Abstract The exonic ANRIL (P15AS) is a 3.8-kb lncRNA transcribed from the antisense strand of the P14 promoter and flanking regions. Recently, we have constructed a P16 promoter DNA methyltransferase (P16-Dnmt) using the pTRIPZ vector that can specifically methylate human P16 CpG islands and found that P16 methylation directly leads to gene transcription silence [Cui et al. Genome Biology 2015, 16:252]. However, whether ANRIL transcription is affected by P16 DNA methylation has not previously been reported. In the present study, correlation between endogenous P16, P15, P14 mRNA and ANRIL levels in a panel of cell lines were determined using quantitative RT-PCR. Unexpectedly, the results showed that ANRIL transcriptional level was positively and significantly correlated with the P16 mRNA level (r = 0.774, P = 0.003), but not correlated with the P15 or P14 mRNA levels (r = 0.09 or 0.30, P = 0.78 or 0.35). These phenomena were confirmed using the public available transcriptome data in the Broad-Novartis Cancer Cell Line Encyclopedia (CCLE). Furthermore, transcription of both ANRIL and P16 mRNA were observed only in cancer cell lines in which the P16 alleles are unmethylated (Caski, SGC7901, BGC823, GES1, Siha and HeLa), but not in these cell lines in which the P16 alleles are fully methylated (Colo205, PC3, MHCC97H, RKO, SW480 and AGS). These suggest the possibility that methylation of the P16 promoter may inactivate transcription of ANRIL as well as P16. To study the possible causality between P16 DNA methylation and transcriptional silence of ANRIL, we employed P16-Dnmt to induce P16-specific DNA methylation in gastric cancer BGC823 cells, and found that transcription levels of both P16 and ANRIL were significantly decreased by the induced P16 DNA methylation (P&amp;lt;0.001 and 0.024, respectively). Besides, transcription level of P14 was also reduced (P = 0.043) while the P14 promoter CpG islands remained to be unmethylated. In contrast, P16 DNA demethylation induced by an artificial P16-specific transcription factor [Zhang et al. Human Gene Therapy 2012, 23:1071-81] re-activated transcription of both ANRIL and P16 in H1299 cells (P&amp;lt;0.001). The mechanism of inactivation of ANRIL expression by P16 DNA methylation is under investigation. In conclusion, transcription of ANRIL is regulated by P16 DNA methylation. Citation Format: Ying Gan, Baozhen Zhang, Chenghua Cui, Dajun Deng. P16 DNA methylation inactivates transcription of IncRNA ANRIL. [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 999.
Abstract 1922: miR-301 expression is deregulated in rhabdomyosarcoma
Authors: Rossella Rota, Alberto Gualtieri, Cristina Cossetti, Silvia Pomella, Laura Adesso, Franco Locatelli
Journal: Cancer Research (2016)

Abstract Rhabdomyosarcoma (RMS) is an aggressive pediatric soft tissue sarcoma of myogenic derivation. Conversely to normal myoblasts, RMS cells are unable to differentiate, thus they proliferate indefinitely. MicroRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression by affecting both the stability and translation of mRNAs. They are fundamental regulators of myogenesis and their deregulation has been involved in the pathogenesis of RMS. We evaluate here the expression and regulation of miR-301, which has been related to tumorigenesis in other types of cancers. We report here that the expression of miR-301 is upregulated in primary samples of both the alveolar RMS, which bears the fusion protein PAX3-FOXO1 (P3F) (ARMS), and the fusion-negative embryonal RMS (ERMS) compared to normal muscle tissues. Similarly, it appears higher in RMS cell lines versus normal skeletal myoblasts. Using an inhibitor of miR-301 (CONTRAmiR) we demonstrate that this miRNA favors RMS cell mobility and down-regulates p21Cip1, PTEN and DICER1 levels. However, the inhibition of miR-301 with the CONTRAmiR does not reduce tumor cell proliferation suggesting that the regulation of cell cycle is not under the control of this miRNA in RMS. Interestingly, the expression of SKA2 (Spindle And Kinetochore Associated Complex Subunit 2), whose gene hosts miR-301, is also upregulated in our setting. Experiments are ongoing to determine whether miR-301 and SKA2 are associated with RMS pathogenesis and could be targets for an anti-RMS therapy. This work was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC). Citation Format: Rossella Rota, Alberto Gualtieri, Cristina Cossetti, Silvia Pomella, Laura Adesso, Franco Locatelli. miR-301 expression is deregulated in rhabdomyosarcoma. [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 1922.
HG-61MOLECULAR CHARACTERIZATION OF<i>IN VIVO</i>AND<i>IN VITRO</i>MODELS OF DIPG
Authors: Mojca Stampar, Amanda Saratsis, Kristy Brown, Sridevi Yadavilli, Eric Raabe, Kathy Warren, Madhuri Kambhampati, Mamta Giri, Nalin Gupta, Roger Packer, Javad Nazarian
Journal: Neuro-Oncology (2016)
Abstract 4187: Loss of SLFN11 or gain of TWIST1 promote chemotherapy resistance in small cell lung cancer
Authors: Eric E. Gardner, Benjamin H. Lok, Valentina E. Schneeberger, Elisa de Stanchina, John T. Poirier, Charles M. Rudin
Journal: Cancer Research (2016)

Abstract The majority of patients with small cell lung cancer (SCLC) who are treated with first-line platinum/etoposide chemotherapy develop therapeutic resistance, but little is mechanistically understood how resistance develops in patients. This is partly due to limited access to historic paired tissue samples, few investigational re-biopsy programs and the aggressive nature of this disease. In this study we used a collection of 10 treatment-naïve, patient-derived xenograft (PDX) models of SCLC to determine how resistance to chemotherapy can be acquired in vivo, by cycling weekly cisplatin and etoposide, followed by serial passaging of tumor cells capable of surviving and proliferating through treatment. Applying whole transcriptome (RNAseq), exome and high-depth targeted sequencing approaches to paired parental and resistant populations revealed minimal recurrent mutations; however, two consistent gene expression changes were observed, implicating either a decrease in SLFN11 or an increase in TWIST1 transcript levels may promote resistance. We validated both mechanisms in vitro using conditional gain and loss of function experiments in SCLC cell lines of human and mouse origin. Where suppression of SLFN11 was associated with resistance to select classes of DNA damaging agents, gaining TWIST1 produced a broad resistance phenotype, consistent with an epithelial-to-mesenchymal transition. Increased sensitivity to chemotherapy through overexpression of SLFN11 was observed only in cell lines with low levels of TWIST1. Importantly, TWIST1 knockdown or knockout did not dramatically change the sensitivity to chemotherapy in multiple TWIST1-high cell lines tested, suggesting that directly targeting TWIST1 may be of limited utility in SCLC. We extended these results by modeling acquired resistance to cisplatin and etoposide in a triple knockout (p53/Rb/p130) mouse allograft model of SCLC, finding that increased expression of TWIST1 was associated with chemotherapy resistance, but did not confer a greater metastatic potential in a tumor type with an already high predilection for metastasis. Understanding the relative expression of SLFN11 and TWIST1 at baseline and upon clinical relapse may be informative in determining therapeutic options for SCLC patients that no longer respond to platinum and etoposide. Citation Format: Eric E. Gardner, Benjamin H. Lok, Valentina E. Schneeberger, Elisa de Stanchina, John T. Poirier, Charles M. Rudin. Loss of SLFN11 or gain of TWIST1 promote chemotherapy resistance in small cell lung 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 4187.
Carfilzomib Combined with Thalidomide and Dexamethasone (CTD) Is an Highly Effective Induction and Consolidation Treatment in Newly Diagnosed Patients with Multiple Myeloma (MM) Who Are Transplant Candidate
Authors: Pieter Sonneveld, Emilie Asselbergs, Sonja Zweegman, Bronno Van der Holt, Marie Jose Kersten, Edo Vellenga, Marinus van Marwijk-Kooy, Okke de Weerdt, Sarah Lonergan, Henk Lokhorst
Journal: Blood (2012)
High-grade Dysplasia in Anogenital Warts of HIV-Positive Men
Authors: Alexander Kreuter, Christos Siorokos, Frank Oellig, Steffi Silling, Herbert Pfister, Ulrike Wieland
Journal: JAMA Dermatology (2016)

<h3>Importance</h3> Human papillomavirus (HPV)-induced anogenital lesions are very frequent in men who have sex with men (MSM) who are HIV-positive (HIV+). Anogenital warts (AGWs) are considered benign lesions caused by low-risk HPV-types, whereas anogenital dysplasias are potential cancer precursors associated with high-risk HPV-types. Both types of lesions can usually be distinguished clinically. <h3>Objective</h3> To describe a case series of HIV+ MSM with typical AGW that harbored different grades of dysplasia. <h3>Design, Setting, and Participants</h3> For this retrospective virological analysis, we recruited 25 HIV+ MSM with AGWs (n = 38) harboring areas of dysplasia and 22 patients who were HIV-negative (HIV−) with AGWs seen between February 2013 and March 2015 at a tertiary dermatological referral center for anal cancer screening. Dysplasia-containing AGW tissue of HIV+ MSM were compared with randomly selected AGWs of patients who were HIV−. <h3>Main Outcomes and Measures</h3> Histopathological analysis, immunohistochemical staining for p16<sup>INK4a</sup>and Ki67, HPV-typing, and viral load determination in AGWs of HIV+ compared with patients who were HIV−. <h3>Results</h3> Overall, 25 HIV+ MSM with AGWs (mean [SD] age, 47.3 [11.1] years) harboring areas of dysplasia and 22 patients who were HIV− (5 women, 17 men; mean [SD] age, 35.5 [12.8] years) with AGWs were included in this study. The 38 dysplasia-containing AGWs of HIV+ MSM harbored low-grade dysplasia in 6 cases (16%), high-grade dysplasia in 31 cases (81%), and areas of invasive anal carcinoma in 1 (3%) case. With the exception of 1 biopsy, all low-grade lesions were p16<sup>INK4a</sup>-negative, whereas 25 of 31 (81%) AGWs with high-grade lesions or an anal carcinoma were p16<sup>INK4a</sup>-positive. Only low-risk HPV-types were present in 11 samples (29%; 2 low-grade lesions and 9 high-grade lesions), low-risk and high-risk types were found in 19 samples (50%; 1 low-grade lesion and 18 high-grade lesions), and only high-risk HPV-types were present in 8 samples (21%; 3 low-grade lesions, 4 high-grade lesion, and 1 cancer-containing lesion). High low-risk HPV DNA loads were found in low-grade and high-grade lesions, while high high-risk HPV DNA loads were only found in AGWs harboring high-grade lesions. The 22 AGWs of patients who were HIV− showed no signs of dysplasia, and p16<sup>INK4a</sup>-staining was always negative. All of these samples carried low-risk HPV types, and in 2 cases high-risk HPV-types were detected additionally. <h3>Conclusions and Relevance</h3> In contrast to immunocompetent patients, AGWs of HIV+ MSM may harbor high-grade dysplasia or even invasive squamous cell carcinoma. A substantial proportion of theses lesions may only contain low-risk HPV-types. Anogenital warts in patients who are HIV+ should be evaluated histopathologically to exclude cancer precursors.
Abstract 3550: Activation of a novel form of regulated necrosis to eliminate extracellular matrix detached epithelial cells
Authors: Mark A. Hawk, Cassandra L. Buchheit, Luqun Shen, Patrick Fagan, Zachary T. Schafer
Journal: Cancer Research (2016)

Abstract The overwhelming majority of breast cancer deaths are caused by the metastasis of cancer cells from the primary tumor to distant sites in the body. For cancer cells to successfully metastasize, they must: detach from the primary tumor, move out of the original tissue into the circulatory or the lymphatic system, travel to a new site followed by arresting their movement, and then extravasate to begin colonizing a secondary site. When normal epithelial cells detach from the extracellular matrix (ECM), they induce caspase-dependent cell death which is known as anoikis. Anoikis can therefore serve as a critical barrier to metastasis as cancer cells are exposed to limited and variable matrix conditions during each step of the metastatic cascade. However, our previous studies suggest that anoikis evasion is not sufficient to protect ECM-detached cells from cell death. Using MCF10A mammary epithelial cells, we have previously shown that ECM-detachment induced metabolic changes can compromise the survival of detached cells, although the precise mechanism controlling cell death remains unclear. Here, we present data suggesting that ECM-detached cells can also be eliminated by regulated necrosis (RN), a genetically programmed, caspase-independent form of necrosis that is morphologically indistinguishable from classical necrosis. In general, the molecular mechanisms involved in RN are poorly understood. With this in mind, the current most appreciated subtype of RN, termed necroptosis, is dependent upon TNFα, RIP1K, RIP3K, MLKL, and PGAM5 to execute cell death. Our data in ECM-detached cells suggest that cells are being eliminated by a mechanism that is dependent on the kinase activity of RIP1K. Further studies have shown an increase in the expression of CYLD, a deubiquitinating enzyme that specifically removes ubiquitin chains from RIP1K, in turn stabilizing both RIP1K expression and activation. Upon analyzing other dependent executioners of necroptosis, we have strikingly found that TNFα, RIP3K, and MLKL are all dispensable for RN to occur in ECM-detachment. Furthermore, using a variety of molecular tools, such as 3D cell culture, we have found that PGAM5 is necessary for the execution of ECM-detachment induced RN. These findings uncover a novel and distinct RN pathway and highlight the need to more thoroughly understand RN as well as the mechanisms employed by ECM-detached cells to antagonize RN and promote their survival in detachment. Citation Format: Mark A. Hawk, Cassandra L. Buchheit, Luqun Shen, Patrick Fagan, Zachary T. Schafer. Activation of a novel form of regulated necrosis to eliminate extracellular matrix detached epithelial cells. [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 3550.
Late Relapse After Allogeneic Hematopoietic Cell Transplantation For Hematological Malignancies: A Nationwide Retrospective Study From The Late Complications and Quality-Of-Life Working Group Of The Japan Society For Hematopoietic Cell Transplantation
Authors: Takuya Yamashita, Hideyuki Kuwabara, Kazuteru Ohashi, Naoyuki Uchida, Takahiro Fukuda, Koichi Miyamura, Shin-ichiro Mori, Koji Kato, Junji Tanaka, Souichi Adachi, Yoshiko Atsuta
Journal: Blood (2013)
Screening for Skin Cancer
Authors: Edward H. Livingston
Journal: JAMA (2016)

US Preventive Services Task Force; Kirsten Bibbins-Domingo, PhD, MD, MAS; David C. Grossman, MD, MPH; Susan J. Curry, PhD; Karina W. Davidson, PhD, MASc; Mark Ebell, MD, MS; John W. Epling Jr, MD, MSEd; Francisco A. R. García, MD, MPH; Matthew W. Gillman, MD, SM; Alex R. Kemper, MD, MPH, MS; Alex H. Krist, MD, MPH; Ann E. Kurth, PhD, RN, MSN, MPH; C. Seth Landefeld, MD; Carol M. Mangione, MD, MSPH; William R. Phillips, MD, MPH; Maureen G. Phipps, MD, MPH; Michael P. Pignone, MD, MPH; Albert L. Siu, MD, MSPH
Correlation of genomic alterations with outcome in patients (pts) with urothelial carcinoma (UC).
Authors: Hamid Emamekhoo, Monali K. Vasekar, Monika Joshi, Sierra Min Li, Arnab Basu, JoAnn Hsu, Junjia Zhu, Garrett Michael Frampton, Siraj Mahamed Ali, Vincent A. Miller, Jeffrey S. Ross, Brian I. Rini, Jorge A. Garcia, Sumanta K. Pal, Petros Grivas
Journal: Journal of Clinical Oncology (2016)

e16021 Background: The genomic landscape of UC is complex and may differ between primary and metastatic disease sites. Potential correlation between the number & type of genomic alterations, treatment response and overall survival (OS) may inform treatment targets and predictive biomarkers. Methods: A retrospective analysis of genomic alterations, clinicopathological & treatment factors, and outcome for 83 UC pts from 3 academic institutions (CCF, COH, PSHMC) was performed. Number and type of alterations including variants of unknown significance (VUS) were collected (next generation sequencing in >300 genes; FoundationOne). Alteration frequency was calculated; heatmaps were plotted using the threshold of minimum frequency difference of 0.1 or 0.075 to select genes that differ among phenotypic groups. Results: Median age at diagnosis was 65, 77% men, 95% stage IV, (23%) never-, (55%) ex-, (22%) current smokers. Median number of gene alterations per report: 19 (7-47) total, 12 (0-36) VUS, 7 (2-17) non-VUS; the numbers appeared comparable between primary (63) and metastatic (20) tumors (non-paired). With 71/83 pts with available f/u data 31 died; median OS for all pts was 51.7 months (m), 24 m-OS was 51% with median follow up for surviving pts 17 m (0.4 - 45). The most frequently altered genes were ARID1A (57%), MLL2 (48%), KDR (46%), MDM2 (46%), CDKN2A/B(42%), RBM10 (42%). Specifically, the most common non-VUS alterations were MLL2 (20%), CDKN2A/B (19%), RBM10 (17%), PIK3CA (16%), CDH1 (16%); the most common VUS alterations ARID1A (43%), MDM2 (37%), KDR (33%), ATM (28%), MLL2 (28%), BAP1 (28%). No specific gene alteration frequency correlated with OS (p > .05). Higher number of VUS per report correlated with longer OS (Table). Conclusions: The number of VUS per report may have prognostic value. Evaluation of correlation between genomic alterations and treatment (e.g. chemotherapy, immunotherapy) response is pursued; further validation in larger cohort is needed. Alteration (number/report) OS at 18 m (%) Cox proportional hazard model Non-VUS (≤7 vs >7) 68.7 63.2 HR 1.15 95%CI(0.49−2.67) p= .75 VUS (≤12 vs >12) 54.1 79.9 HR 0.30 95%CI(0.12−0.72) p= .01 VUS & non-VUS (≤19 vs >19) 54.5 82.2 HR 0.30 95%CI(0.12−0.77) p= .01