tbuckley/cabot-search huggingface dataset:
Abstract CT133: Association of programmed death-ligand 1 (PD-L1) and 2 (PD-L2) expression with nivolumab (NIVO) efficacy in advanced melanoma (MEL)
Authors: Scott J. Rodig, Evisa Gjini, Kaushal Desai, Chelsea Jin, Christine Horak, Mary Ruisi, Jeffrey Weber, Gordon J. Freeman, F. Stephen Hodi
Journal: Cancer Research (2016)

Abstract Background: NIVO inhibits the interaction of the PD-1 receptor with its ligands, PD-L1 and PD-L2. While high tumor PD-L1 expression results in greater clinical benefit with NIVO, MEL patients (pts) with low-to-no PD-L1 expression also benefit from NIVO. This may be partially attributed to PD-L2. Here, we analyzed the association between PD-L1/PD-L2 expression and efficacy from a phase II study (CheckMate 064) evaluating NIVO followed by ipilimumab (IPI) vs IPI followed by NIVO in MEL. Methods: Pts were randomized 1:1 to receive sequential treatment with NIVO (3 mg/kg IV Q2W x 6) then IPI (3 mg/kg IV Q3W x 4) (cohort A) or IPI then NIVO (cohort B). Pts were biopsied prior to treatment and at Wk 13; pts had only received one agent at Wk 13. PD-L1 and PD-L2 expression were assessed by immunohistochemistry on formalin-fixed, paraffin-embedded tumor samples with the Dako PD-L1 28-8 pharmDx assay and a novel PD-L2 assay (antibody clone 9E5). Dichotomization of the percent expression of PD-L1 and PD-L2 was optimized by ROC analyses. Results: In pre-treatment samples, 32/97 (33%) pts had PD-L1 expression ?5% and 38/83 (46%) pts had PD-L2 expression ?70%. No consistent change from baseline in PD-L1 or PD-L2 was observed in either cohort with treatment. The frequency of pts with PD-L2 expression ?70% was higher among pts with PD-L1 ?5% vs PD-L1 &amp;lt;5%: 63% (19/30) vs 36% (17/47). In cohort A, there was a greater mean tumor burden reduction and higher response rates at Wk 13 among pts with high vs low PD-L2 expression, even in pts with low-to-no PD-L1 (Table). No association between PD-L2 and efficacy was observed in cohort B. Conclusions: Similar to PD-L1, PD-L2 expression may enrich response to NIVO in MEL. PD-L2 expression may partially explain the efficacy of NIVO in pts with low-to-no PD-L1. However, NIVO is still active in pts with low-to-no expression of both ligands, suggesting other factors may explain the activity of NIVO. Further analysis is required to delineate these factors. ExpressionStatus, %NCheckMateCheckMate064064Cohort ACohort BPD-L1PD-L2Tumor response, n/N (%)Reduction in tumor burden, %Tumor response, n/N (%)Reduction in tumor burden, %≥5≥70197/13 (54)-26.62/6 (33)4.9≥5&amp;lt;70112/7 (29)-13.30/4 (0)49.8&amp;lt;5≥70174/10 (40)-28.40/7 (0)58.0&amp;lt;5&amp;lt;70304/18 (22)-2.80/12 (0)31.3 Citation Format: Scott J. Rodig, Evisa Gjini, Kaushal Desai, Chelsea Jin, Christine Horak, Mary Ruisi, Jeffrey Weber, Gordon J. Freeman, F. Stephen Hodi. Association of programmed death-ligand 1 (PD-L1) and 2 (PD-L2) expression with nivolumab (NIVO) efficacy in advanced melanoma (MEL). [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 CT133.
Sympathetic neural regulation of angiogenesis through Adrb2 in prostate cancer: A novel therapeutic target.
Authors: Ali Zahalka, Anna Arnal-Estape, Maria Maryanovich, Fumio Nakahara, Paul S Frenette
Journal: Journal of Clinical Oncology (2016)

11524 Background: The sympathetic nervous system (SNS) has been implicated in the pathogenesis of epithelial malignancies. Clinical studies have shown that elevated SNS activity is associated with increased prostate cancer risk and mortality, whereas use of sympathetic β-adrenergic receptor (bAR) blockers reduces the risk. The prostate stroma is highly innervated by the SNS, and depletion of bARs (Adrb2 + Adrb3) in this compartment inhibits tumor growth. We aim to identify the stromal populations that mediate SNS signaling in the tumor microenvironment, and elucidate the mechanism by which loss of bAR signaling inhibits prostate cancer progression. Methods: In vivo xenograft tumor growth was measured in Adrb2-/-; Adrb3-/- mice using an orthotopic PC3-luciferase model. Cancer progression in the transgenic HI-myc model was assessed after conditional Adrb2 deletion in stromal populations by intercrossing Adrb2fl/fl line to stromal Cre lines: endothelial Cdh5CreERT2, myeloid Csf1riCre, and pericyte NG2CreERTM. A novel prostate-specific collagen matrix transplantation assay was employed to assess angiogenesis. Results: Deletion of the SNS bAR neural receptors Adrb2 and Adrb3 in the microenvironment synergized to arrest tumor growth. Imaging the tumor vasculature revealed a defect in vessel branching, suggesting altered angiogenesis in the absence of bAR stimulation. Histology revealed that vascular innervation was greatest during the pre-neoplastic PIN stage, and that conditional Adrb2 deletion in endothelial cells, but not myeloid cells or pericytes, reduced progression to high-grade PIN, and maintained inhibition of disease progression throughout all histopathological cancer stages. In the orthotopic matrix assay, endothelial deletion of Adrb2 was confirmed to inhibit angiogenesis as did sympathetic denervation. Conclusions: The SNS mediates a pro-angiogenic switch during the early stages of prostate carcinogenesis. We identified endothelial cells as the stromal targets of the SNS, and that abrogation of bAR signaling in the vasculature inhibits angiogenesis and delays prostate cancer progression, suggesting a novel therapeutic avenue for prostate cancer treatment.
Abstract 1286: Cytokine response of stromal cells to prostate cancer chemotherapeutics
Authors: Dominique Gales, Clayton C. Yates, Temesgen Samuel
Journal: Cancer Research (2016)

Abstract Non-responsiveness to chemotherapeutic drugs presents a significant challenge to the effective treatment of advanced prostate cancer. Exploration of the therapeutic response in prostate cancer has largely focused on the epithelial tumor cells. However, evidence suggests that the tumor microenvironment may modulate response to chemotherapeutics. The tumor microenvironment consists of immune, fibroblastic, and vascular cells, as well as extracellular matrix (ECM) and stromal-derived soluble factors, all of which contribute to interactions within the tumor microenvironment. It has been demonstrated that tumor cells cross-talk with stromal cells, to establish a protective niche at primary and distant sites and to facilitate survival of cancer cells. Such tumor-stroma cell cross-talk often involves secreted factors, such as cytokines. Previous studies have illustrated the importance of cytokines and cytokine receptors as modulators of drug response. In this study, we sought to identify cytokine factors expressed in response to drugs clinically used to control prostate cancer. To obtain the expression profiles, we conducted a human cytokine and chemokine array, which consisted of 84 specific genes. Analysis of the prostate cancer and stromal cells treated with Docetaxel (4nM), Enzalutamide (30μM) and Bicalutamide (30μM) revealed differential expression patterns. The effect of chemotherapeutics on the expression of the cytokine IL-16 and its cognate receptors CD9 and CCR5 in prostate cancer and stromal cell lines was further examined. We found IL-16 expression increased several fold following chemotherapeutic treatment in stromal cell lines compared to prostate cancer cell lines. To validate gene expression, we examined the expression of IL-16 and its receptors by RT-PCR. All experiments were performed in triplicates. Student t- tests were used to determine the statistical significance between groups. IL-16 expression increased following exposure to chemotherapeutics in stromal cell lines. CCR5 expression showed a decrease in PC3 prostate cancer cells but no significant changes were observed in LNCaP cells. CD9 expression showed an increase in both LNCaP and PC3 cell lines. Collectively, these results indicate that chemotherapy of prostate cancer may alter the expression of IL-16 and its receptors. We hypothesize that IL-16 is a soluble stromal factor that is expressed in response to anticancer drugs, and may have paracrine activity on neighboring cells that express the cognate receptors. Citation Format: Dominique Gales, Clayton C. Yates, Temesgen Samuel. Cytokine response of stromal cells to prostate cancer chemotherapeutics. [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 1286.
Abstract 1133: Prevalence of activated NOTCH receptor in solid tumors and chronic lymphocytic leukemia
Authors: Gerard Oakley, Lisa Riegle, Karim Benhadji, Andrew Schade
Journal: Cancer Research (2016)

Abstract Recent reports identified high expression of Notch 1 receptor in various tumors including adenoid cystic carcinomas (ACC). Notch 1 receptor is activated by gamma secretase cleavage to exert transcriptional control of processes including cellular differentiation and proliferation. Notch is also known to be activated in approximately 60% of T-cell acute lymphoblastic leukemias. We investigated the prevalence of Notch 1, 2 and 3 activation in different tumors by immunohistochemistry (IHC) designed separately for Notch 1, 2 and 3. Our proprietary antibodies recognize the post-gamma secretase cleavage activated Notch intracellular domain (NICD) fragments of Notch 1, Notch 2 and Notch 3, allowing direct measurement of activation of these receptors, in addition to their expression level by the tumor cells. In total we tested 48 ACCs of the salivary glands, 19 breast cancer, 35 chronic lymphocytic leukemias (CLL), 7 glioblastomas, and 35 non-small cell lung carcinomas (NSCLC) We found that at least 65% (31 out of 48) of ACCs were positive for Notch 1 activation using our assay. Of other tumor types, 4 out of 7 glioblastomas (57%), 14 out of 35 CLLs (40%), 7 out of 35 NSCLC (20%) and 2 out of 19 breast cancer cases (11%) were positive for Notch 1. Within NSCLC, 5 of the 16 tested squamous cell carcinomas were positive for Notch 1 activation (31%). Notch 2 and Notch 3 showed only rare activation in these tumors. We conclude that high levels of Notch 1 activation are identifiable in different tumor types including high prevalence in ACC, CLL and glioma. These tumors may benefit from therapeutic Notch pathway inhibition. Citation Format: Gerard Oakley, Lisa Riegle, Karim Benhadji, Andrew Schade. Prevalence of activated NOTCH receptor in solid tumors and chronic lymphocytic leukemia. [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 1133.
Abstract 2435: Amplification of CDK4 and MDM2 is associated with atypical clinical features in high risk neuroblastoma patients
Authors: Susanne M. Fransson, Hanna Kryh, Niloufar Javanmardi, Inge M. Ambros, Ana P. Berbegall, Ingrid Ora, Rosa Noguera, Jurate Asmundsson, Bengt Sandstedt, Peter F. Ambros, Per Kogner, Tommy Martinsson
Journal: Cancer Research (2016)

Abstract MYCN-amplification and 11q-deletion are important, although incomplete, markers of high-risk neuroblastoma. Thus, characterization of additional genomic alterations that can be used as prognostic and/or predictive markers is of clinical importance in order to provide best treatment possible. By using SNP-microarrays we identified a small group of neuroblastomas with high grade amplification of one or multiple loci on 12q, commonly involving the potential oncogenic target genes CKD4 (12q13-14) and/or MDM2 (12q15). The CDK4 and MDM2 regions were co-amplified in 13/16 samples, two tumors had CDK4-amplification in absence of MDM2-amplification while one tumor had MDM2-amplification without CDK4-amplification. Exome sequencing was performed on seven tumors and whole genome sequencing (WGS) was performed on tumor and constitutional DNA from one patient with 12q-amplification. No novel protein altering SNVs were detected within the amplified regions except a rare INHBE mutation in one patient. The tumor examined with WGS show high degree of structural rearrangements including chromothriptic features on chromosome 12 leading to high grade amplification of CDK4 and MDM2. This sample displayed 21 somatic protein changing alterations although not in any gene with known function in chromatin stability or DNA repair. Interestingly, the majority of the 12q-amplified neuroblastomas were of abdominal origin, some with renal location with initial suspicion of Wilms’ tumor. Atypical metastatic pattern were also seen in this patient group showing low degree of bone marrow involvement favoring other metastatic sites such as lung. The consistent co-amplification of two separate chromosome 12 regions in this subset of neuroblastoma suggests that there are one or more genes with importance in tumor development/progression. Our study indicates that CDK4 appears as main target in this 12q-amplified neuroblastoma subgroup although other genes such as MDM2 and FRS2 also could provide proliferative advantages. The 12q-amplified neuroblastomas exhibit distinct clinical features and may benefit from targeted therapy using a small molecule CDK4/CDK6 inhibitor such as LEE011 (Novartis). Citation Format: Susanne M. Fransson, Hanna Kryh, Niloufar Javanmardi, Inge M. Ambros, Ana P. Berbegall, Ingrid Ora, Rosa Noguera, Jurate Asmundsson, Bengt Sandstedt, Peter F. Ambros, Per Kogner, Tommy Martinsson. Amplification of CDK4 and MDM2 is associated with atypical clinical features in high risk neuroblastoma patients. [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 2435.
Abstract 3702: Src phosphorylated Mdm2 requires MdmX to act as a neddylating ligase
Authors: Paula M. Hauck, Lindsey D. Mayo
Journal: Cancer Research (2016)

Abstract Mdm2 is an oncoprotein and, along with its family member MdmX, have been shown to be elevated in human cancers. Like Mdm2, MdmX, is a RING containing protein, yet it lacks intrinsic E3 ligase function. Mdm2 has been shown to facilitate ubiquitination as a monomer, a homodimer, and as a heterodimer with MdmX depending on the cellular stress. Our recent report establishes that under growth conditions that activate Src, Mdm2 functions as a neddylating enzyme. Whether MdmX is necessary for Mdm2 to neddylate p53 has yet to be shown. Here we demonstrate that Src phosphorylation results in increased levels of MdmX, increased binding between Mdm2 and MdmX, and increased neddylation of MdmX and p53. Interestingly, the lack of MdmX (in transient assays or in shRNA cell lines) results in decreased neddylation of p53. These data support a critical role for MdmX as part of the Mdm2 neddylating complex. Citation Format: Paula M. Hauck, Lindsey D. Mayo. Src phosphorylated Mdm2 requires MdmX to act as a neddylating ligase. [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 3702.
Is routine prostate biopsy needed prior to radical cystectomy?
Authors: Yasuhiro Hashimoto, Yuichiro Suzuki, Atsushi Imai, Akiko Okamoto, Hayato Yamamoto, Shingo Hatakeyama, Takahiro Yoneyama, Takuya Koie, Chikara Ohyama
Journal: Journal of Clinical Oncology (2013)

223 Background: Prostate cancer (Pca) can be detected coincidentally in radical cystoprostatectomy (RCP) specimens for invasive bladder cancer. However, there is no uniformity of opinion on the need for prostate biopsy prior to RCP. We evaluated the necessity of preoperative prostate biopsy in invasive bladder cancer. Methods: From 1998 through 2009, of 300 patients undergoing radical cystectomy for muscle-invasive bladder cancer, 252 were male. Of these, we focused 212 patients, whose prostate-specific antigen (PSA) was measured preoperatively. Results: The median age was 66years and median follow-up period was 46 months. Thirty-five patients with PSA &gt; 4.0 ng/mL or digital rectal examination (DRE) positive were all subjected to transrectal ultrasound (TRUS)-guided prostate biopsy (Pbx), and Pca was detected in 7 cases (20%) (Group I). Pca was also detected in 5 patients (17.9%) in RCP specimens of the 28 whose Pbx results were negative (Group II). Seventy-seven of the 177 patients with PSA ≤ 4.0ng/mL and DRE negative were underwent TRUS-guided Pbx, and Pca was detected in 1 case (1.3%) (Group III). Pca was detected in 10 patients (13.2%) out of the 76 whose Pbx results were negative (Group IV). Of the 177 patients, 100 underwent RCP without prostate biopsy, and Pca was detected in 16 cases (16%) (Group V). The average Gleason score of each Group, I, II, III, IV, and V were 6.6, 6.6, 7, 6.2, and 6.5, respectively. Tumor volumes of each Group, I, II, III, IV, and V were 3.12mL, 1.0mL, 0.65mL, 0.43mL, and 0.19mL, respectively. No patients experienced recurrence of PC, including biochemical recurrence. Conclusions: In cases with PSA ≤4.0 ng/mL and/or DRE negative, Pbx is not considered necessary. In cases with PSA &gt; 4.0 ng/mL or DRE positive, Pca with an average volume of 3.12 mL were detected by Pbx in 20% of the patients. However, most are localized Pca, and postoperative recurrence of the Pca is not seen during follow-up period. The question of whether all patients in this group require Pbx needs to be examined through further stratification.
Two Cycles of ABVD Followed by Involved Field Radiotherapy with 20 Gray (Gy) Is the New Standard of Care in the Treatment of Patients with Early-Stage Hodgkin Lymphoma: Final Analysis of the Randomized German Hodgkin Study Group (GHSG) HD10. Study Supported by the Deutsche Krebshilfe and in Part by the Competence Network Malignant Lymphoma.
Authors: Andreas Engert, Volker Diehl, Annette Pluetschow, Hans T. Eich, Richard Herrmann, Bernd Doerken, Lothar Kanz, Richard Greil, Jana Markova, Michael Fuchs, Peter Borchmann, Hans Konrad Mueller-Hermelink, Rolf Peter Mueller
Journal: Blood (2009)
From Kitchen Bench to Bedside
Authors: Reena George, Vatsala Srinivasan
Journal: Annals of Internal Medicine (2016)

On Being a Doctor2 August 2016From Kitchen Bench to BedsideReena George, MD and Vatsala Srinivasan, PhDReena George, MDFrom Christian Medical College, Vellore, India, and Bengaluru, India. and Vatsala Srinivasan, PhDFrom Christian Medical College, Vellore, India, and Bengaluru, India.Author, Article, and Disclosure Informationhttps://doi.org/10.7326/M15-2352 Audio Reading - "From Kitchen Bench to Bedside" Audio. Michael A. LaCombe, MD, Annals Associate Editor, reads "From Kitchen Bench to Bedside," by R. George and V. Srinivasan. Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Maggots have been the proverbial bee in my bonnet. They are always a concern of mine, and I worry how I might prevent them in the open wounds of our patients in India dying at home. Flies love the odious smell of necrotic cancer. They leave mango groves and rubbish dumps to descend on any open wound that can serve as a warm, nourishing nest for their eggs.Keeping the wound covered with a dressing would be the simple answer. Except that it is not so simple in India, where grotesque head and neck cancer soaks through multiple dressings, when ... Author, Article, and Disclosure InformationAffiliations: From Christian Medical College, Vellore, India, and Bengaluru, India.Note: Dr. Srinivasan is a volunteer at Kidwai Memorial Institute of Oncology in Bengaluru, India.Corresponding Author: Reena George, MD, Palliative Care Unit, Christian Medical College, Vellore 632004, Tamil Nadu, India; e-mail, reena.[email protected]com. PreviousarticleNextarticle Advertisement Audio Reading - "From Kitchen Bench to Bedside" Audio. Michael A. LaCombe, MD, Annals Associate Editor, reads "From Kitchen Bench to Bedside," by R. George and V. Srinivasan. Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ FiguresReferencesRelatedDetails Metrics Cited byLearning Curve, Survival CurveRegular Low-Dose Oral Metronidazole Is Associated With Fewer Vesicovaginal and Rectovaginal Fistulae in Recurrent Cervical Cancer: Results From a 10-Year Retrospective CohortImproving malodour management in advanced cancer: a 10-year retrospective study of topical, oral and maintenance metronidazole 2 August 2016Volume 165, Issue 3Page: 223-224KeywordsBeesEdemaMouthNursesPalliative careSmellStomachSulfatesTongueToxins ePublished: 2 August 2016 Issue Published: 2 August 2016 Copyright & PermissionsCopyright © 2016 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Enhanced HDL Functionality in Small HDL Species Produced Upon Remodeling of HDL by Reconstituted HDL, CSL112
Authors: Svetlana A. Didichenko, Alexei V. Navdaev, Alexandre M.O. Cukier, Andreas Gille, Patrick Schuetz, Martin O. Spycher, Patrice Thérond, M. John Chapman, Anatol Kontush, Samuel D. Wright
Journal: Circulation Research (2016)

CSL112, human apolipoprotein A-I (apoA-I) reconstituted with phosphatidylcholine, is known to cause a dramatic rise in small high-density lipoprotein (HDL).To explore the mechanisms by which the formation of small HDL particles is induced by CSL112.Infusion of CSL112 into humans caused elevation of 2 small diameter HDL fractions and 1 large diameter fraction. Ex vivo studies showed that this remodeling does not depend on lipid transfer proteins or lipases. Rather, interaction of CSL112 with purified HDL spontaneously gave rise to 3 HDL species: a large, spherical species composed of apoA-I from native HDL and CSL112; a small, disc-shaped species composed of apoA-I from CSL112, but smaller because of the loss of phospholipids; and the smallest species, lipid-poor apoA-I composed of apoA-I from HDL and CSL112. Time-course studies suggest that remodeling occurs by an initial fusion of CSL112 with HDL and subsequent fission leading to the smaller forms. Functional studies showed that ATP-binding cassette transporter 1-dependent cholesterol efflux and anti-inflammatory effects in whole blood were carried by the 2 small species with little activity in the large species. In contrast, the ability to inactivate lipid hydroperoxides in oxidized low-density lipoprotein was carried predominantly by the 2 largest species and was low in lipid-poor apoA-I.We have described a mechanism for the formation of small, highly functional HDL species involving spontaneous fusion of discoidal HDL with spherical HDL and subsequent fission. Similar remodeling is likely to occur during the life cycle of apoA-I in vivo.
Medicine’s solemn moments
Authors: Daniel Sokol
Journal: BMJ (2016)

More common than we think



Not so long ago, at the start of a trial I took part in, the opposing barrister was ruffling through his papers while my witness was swearing the oath: “I swear by almighty God that I will tell the truth [ruffling of papers] . . . the whole truth [more ruffling] . . .” At this point the judge, with a frown, told my opponent to stop at once.

I was surprised by this judicial rebuke. Many barristers, for whom the court procedure has become second nature, pay little attention during the swearing of the …