tbuckley/cabot-search huggingface dataset:
Lung cancer autoantibody signature as indicator of early disease.
Authors: T. V. Pedchenko, R. Mernaugh, D. Pareh, P. P. Massion
Journal: Journal of Clinical Oncology (2010)

10569 Background: Non-small cell lung cancer (NSCLC) is the most prevalent form of lung cancer and, if not detected early, has a low survival rate. Autoantibody to tumor-associated antigens (TAAs) could be found in the circulation of cancer patients up to 5 years before symptomatic disease. As such, the autoantibody can serve as biomarkers for early diagnosis. An anti-idiotypic antibody (anti-Id) can be used in place of TAA. The idiotype (Id) could be preserved during an isotypic switch from IgM to IgG autoantibody. We hypothesize that anti-Ids, selected from a phage-displayed single chain fragment variable (scFv) antibody library, can be used in lieu of TAAs in non-invasive assays to detect lung cancer autoantibodies for the early diagnosis of disease. Methods: Normal and lung cancer IgM and IgG (Id) antibodies from patient serum (n=20) were used in biopanning with a large phage-displayed scFv library to obtain anti-Id scFv binding to NSCLC autoantibody. High throughput antibody-printing and fluorescent microvolume assay technology (FMAT) were used to screen for NSCLC-specific scFv. Candidate scFv were then assayed against an independent serum sample set to evaluate scFv specificity using FMAT and mesa-scale discovery (MSD) technology. A novel homogeneous bridging MSD assay was developed where biotin- and Sulfo-tag labeled scFv were used to detect autoantibody. Results: Bacterial clones producing scFv were selected in biopanning with IgG and IgM from the patient sera. Anti-Id scFv were purified and evaluated. Twelve scFv were identified that discriminate IgG purified from NSCLC and normal serum. Four of these scFv discriminate the whole serum samples from patients with and without cancer. Sixteen scFv were identified based on IgM reactivity. Importantly, 9 of them discriminate stage I lung adenocarcinoma serum from no-cancer serum (p<0.05). Conclusions: We have identified a total of 13 recombinant anti-Id scFv that detect circulating NSCLC-specific autoantibodies at early stage of disease. We will test this panel of autoantibody in an independent set of early stage lung cancer and matched controls. The overall goal is to identify a panel of autoantibodies that may yield a molecular signature for non-invasive early diagnosis. No significant financial relationships to disclose.
Virus Particles in Rat Mammary Tumors of Varying Origin&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: H. Chopra, D. Jane Taylor
Journal: JNCI Journal of the National Cancer Institute (1970)

Spontaneous and chemically induced mammary tumor tissues in various strains of rats were studied for virus particles, with the aid of the electron microscope. In Fischer/344 rats, the 7,12-dimethylbenz[a]anthracene-induced and transplantable tumors showed some C-type particles; mammary tumors induced by diethylstilbestrol-cholestrol pellets and methylcholanthrene showed only a few extracellular C-type particles; chemically induced primary tumors showed no such virus particles. In Wistar/Furth rats, the MT/W9 mammary tumor contained a few virus particles, but the mammosomatotropic tumor (MtT/W5) and its variant (MtT/W5/OM), which metastasized to the ovary, revealed a huge number of virus particles.
DNMT1 is a required genomic regulator for murine liver histogenesis and regeneration
Authors: Kosuke Kaji, Valentina M. Factor, Jesper B. Andersen, Marian E. Durkin, Akira Tomokuni, Jens U. Marquardt, Matthias S. Matter, Tanya Hoang, Elizabeth A. Conner, Snorri S. Thorgeirsson
Journal: Hepatology (2016)

DNA methyltransferase 1 (DNMT1) is an essential regulator maintaining both epigenetic reprogramming during DNA replication and genome stability. We investigated the role of DNMT1 in the regulation of postnatal liver histogenesis under homeostasis and stress conditions. We generated Dnmt1 conditional knockout mice (Dnmt1(Δalb) ) by crossing Dnmt1(fl/fl) with albumin-cyclization recombination transgenic mice. Serum, liver tissues, and primary hepatocytes were collected from 1-week-old to 20-week old mice. The Dnmt1(Δalb) phenotype was assessed by histology, confocal and electron microscopy, biochemistry, as well as transcriptome and methylation profiling. Regenerative growth was induced by partial hepatectomy and exposure to carbon tetrachloride. The impact of Dnmt1 knockdown was also analyzed in hepatic progenitor cell lines; proliferation, apoptosis, DNA damage, and sphere formation were assessed. Dnmt1 loss in postnatal hepatocytes caused global hypomethylation, enhanced DNA damage response, and initiated a senescence state causing a progressive inability to maintain tissue homeostasis and proliferate in response to injury. The liver regenerated through activation and repopulation from progenitors due to lineage-dependent differences in albumin-cyclization recombination expression, providing a basis for selection of less mature and therefore less damaged hepatic progenitor cell progeny. Consistently, efficient knockdown of Dnmt1 in cultured hepatic progenitor cells caused severe DNA damage, cell cycle arrest, senescence, and cell death. Mx1-cyclization recombination-driven deletion of Dnmt1 in adult quiescent hepatocytes did not affect liver homeostasis.These results establish the indispensable role of DNMT1-mediated epigenetic regulation in postnatal liver growth and regeneration; Dnmt1(Δalb) mice provide a unique experimental model to study the role of senescence and the contribution of progenitor cells to physiological and regenerative liver growth. (Hepatology 2016;64:582-598).
Outpatient Management of Pulmonary Embolism in Cancer: Data on a Prospective Cohort of 138 Consecutive Patients
Authors: Carme Font, Alberto Carmona-Bayonas, Aranzazu Fernández-Martinez, Carmen Beato, Andrés Vargas, Pere Gascon, Remedios Otero
Journal: Journal of the National Comprehensive Cancer Network (2014)

The purpose of this prospective cohort study was to assess the feasibility of outpatient treatment in patients with cancer and objectively confirmed pulmonary embolism (PE), and to compare the performance of the different prognostic scales available in this setting. Patients were selected for outpatient management according to a set of exclusion criteria. Outcomes at 30 and 90 days of follow-up included thromboembolic recurrences, major bleeding, and all-cause death. The performance of 4 prognostic scales (Pulmonary Embolism Severity Index, Geneva Prognostic Score, POMPE-C, and Registro Informatizado de Enfermedad Tromboembólica [RIETE registry]) was evaluated. Of 138 patients, 62 (45%) were managed as outpatients. Incidental PE constituted 47% of the sample. Most patients treated at home had an incidentally detected PE (89%). The rate of recurrence and major bleeding events was similar in both groups. Mortality rates were higher for patients admitted to the hospital compared with outpatients at 30 days (18% vs 3%; P=.06) and 90 days (34% vs 10%; P=.001) of follow-up. None of the patients selected for home treatment required further admission because of PE complications. None of the prognostic models developed for symptomatic PE was significantly associated with 30-day mortality. Improved survival outcomes were observed in incidentally detected PEs compared with acute symptomatic events (overall mortality rates, 3.2% vs 18.4%; P=.006). A large proportion of patients with cancer and PE may be safely treated as outpatients, especially those with incidental PE. Cancer-specific prognostic scales including incidental PE should be developed for the optimal management of PE in this setting.
Role of Somatostatin Analogues in the Treatment of Neuroendocrine Tumors
Authors: Sujata Narayanan, Pamela L. Kunz
Journal: Journal of the National Comprehensive Cancer Network (2015)

Neuroendocrine tumors (NETs) are rare epithelial neoplasms with neuroendocrine differentiation that most commonly originate in the lungs and gastrointestinal tract. Many patients have advanced disease not amenable to surgery or local management. Some tumors also secrete amines, such as serotonin, that lead to syndromes of hormone excess, such as diarrhea and flushing. Thus, management of patients with NETs often requires a dual approach, including hormone symptom management and systemic tumor control. Somatostatin analogues have long been a mainstay of managing the hormone-related symptoms, and increasing evidence also supports their use for tumor control in patients with well-differentiated NETs. This article reviews the role of somatostatin analogues in the treatment of NETs.
Different Growth Pattern and Biologic Behavior of Human Renal Cell Carcinoma Implanted Into Different Organs of Nude Mice&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Seiji Naito, Andrew C. von Eschenbach, Isaiah J. Fidler
 5
Journal: JNCI Journal of the National Cancer Institute (1987)

This study was designed to determine the influence of implantation site on the growth of local "primary tumors" and metastatic behavior of human renal cell carcinoma (HRCC) cells. HRCC lines were established in vitro from a surgical specimen (SN12C) or from a liver metastasis produced in BALB/c nude mice by cells from the original specimen implanted into their kidney (SN12L1). Cultured HRCC cells of both lines were injected into the subcutis and the renal subcapsule (RSC) of nude mice. Tumor growth and metastatic behavior were monitored. In both cell lines, tumor cells injected into the RSC displayed faster growth and produced more systemic metastases than did cells injected sc. The kidney tumors were large, invasive, highly vascularized, nonencapsulated, and with minimal central necrosis. In contrast, the subcutaneous tumors were highly encapsulated, with peripheral vascularization and extensive necrosis that developed as early as 2 weeks after sc implantation. The SN12L1 cells were also implanted into nude mice by iv, ip, and intrasplenic injections. The most dramatic production of metastasis occurred after the tumor cells were injected into the kidney. These results indicate that the biologic behavior of this HRCC is influenced by the implantation site in nude mice. At least for the HRCC tested, the kidney is the natural organ for growth. Implantation into the RSC is advantageous for the study of the biology and therapy of HRCC in nude mice.
Glioma-derived extracellular vesicles selectively suppress immune responses
Authors: Justin E. Hellwinkel, Jasmina S. Redzic, Tessa A. Harland, Dicle Gunaydin, Thomas J. Anchordoquy, Michael W. Graner
Journal: Neuro-Oncology (2015)

Glioma-related immunosuppression is well documented; however, the mechanisms of suppression are not fully understood. Here we explore a role for glioma extracellular vesicles (EVs) as a means of immune modulation. Healthy donor peripheral blood mononuclear cells (PBMCs) were incubated with mitogenic stimuli and various concentrations of glioma-derived EVs. Intracellular signaling and cytokine output were determined by protein microarrays, and phenotypic changes were assessed by flow cytometry. Recall antigen testing, mixed lymphocyte reactions, and migration assays analyzed PBMC functional capacity. Protein microarray data revealed induction of an immunosuppressive phenotype and cytokine output at high tumor-vesicle concentrations but an activated phenotype at low concentrations. T cell activation antigen expression confirmed differential activation profiles. Functional analyses revealed decreased migratory capacity of PBMCs after incubation with EVs; however, recall antigen and mixed lymphocyte tests indicated that activation capacity is still retained in EV-treated cells. The differential effects of high and low EV concentrations dictate modulatory effects on PBMCs. These data provide a role for EVs at high concentrations for inducing selective tolerance of an immune response in a tumor setting. This suggests that lymphocytes in patients' circulation are not irreparably impaired, as previously thought, but can be rescued to augment antitumor responses.
GENO-09LANDSCAPE OF GENOMIC ALTERATIONS IN PITUITARY ADENOMAS
Authors: Wenya Linda Bi, Peleg Horowitz, Pankaj K. Agarwalla, Malak Abedalthagafi, William J. Gibson, Sandro Santagata, Edward R. Laws, Rameen Beroukhim, Ian F. Dunn
Journal: Neuro-Oncology (2015)

BACKGROUND: The genetic underpinnings of sporadic pituitary adenomas remain incompletely understood, despite their prevalence in adults. We describe a comprehensive genetic characterization of the largest mixed cohort of pituitary macroadenomas, including hormonally active and atypical adenomas. METHODS: 42 pituitary adenomas were selected to represent a spectrum of histopathologic subtypes, de novo and recurrent tumors, and MIB-1 proliferative indices to interrogate the heterogeneity intrinsic to pituitary tumors. Whole-exome sequencing was performed on tumor and paired blood to identify somatic copy-number alterations, mutations, insertions and deletions. RESULTS: We appreciated two classes of pituitary tumors based upon the fraction of the genome disrupted. The first class (71% of tumors) had somatic copy-number alterations involving less than 6% of the genome; the other class (29%) had significantly greater levels of genomic disruption, up to 99% of the genome involved. The widespread genomic disruption observed in the second class was largely accounted for by arm-level events, with minimal involvement of focal events, which is rare among tumor types. Levels of genomic disruption were associated with phenotype. Among the less disrupted group, 87% (26/30) were clinically non-functional adenomas, whereas the majority of the disrupted group were functional or atypical null-cell adenomas. The high and low genomic disruption classes did not differ in mean MIB-1 proliferative index. Frequent loss of chromosomes 11 and 1p were observed, as well as significant recurrent amplifications of chromosome 5, 7, 9, 12, and 14q. On the whole, the tumors harbored a low rate of mutations, similar to other benign brain tumors. CONCLUSIONS: Genomic characterization of a large series of sporadic pituitary adenomas reveals two distinct classes of tumor, based on genomic disruption from broad copy-number alterations, and associates with tumor subtype.
The impact of age on clinical outcomes in men with hormone refractory prostate cancer
Authors: S. Halabi, E. J. Small, S. Ou, N. J. Vogelzang
Journal: Journal of Clinical Oncology (2005)

4622 Background: To determine if men 65 years of age and older have worse clinical outcomes than men younger than 65 years of age with hormone refractory prostate cancer (HRPC). Methods: Data from eight multicenter trials (four phase II and four randomized phase III studies) conducted by the Cancer and Leukemia Group B (CALGB) from 1992–2003 were combined. Eligible patients had progressive adenocarcinoma of the prostate after androgen ablation (with castrate testosterone levels), an ECOG performance status of 0–2, and adequate hematologic, renal and hepatic function. Endpoints were overall survival (OS) and progression-free survival (PFS). Age was analyzed as binary and continuous variables. The log-rank statistic was used to compare OS and PFS between the two groups. In addition, the proportional hazards model was used to assess the prognostic importance of age adjusting for baseline factors in predicting OS and PFS. Results: Of the 1,216 men, 910 (75%) were 65 years or older. Older men were more likely to have had prior radiation (55%) compared to younger men (47%, p=0.01) and had lower alkaline phosphatase levels (median= 153, inter-quartile range (IQR) =95–324) than younger men (median = 172, IQR=105–347, p=0.04). The median survival time was 14.1 months (95% Confidence Interval (CI) = 12.9–15.5) for older men compared to 13.9 months (95% CI=12.63–16.8, p=0.97). The median time to progression was 2.6 months (95% CI=2.4–2.8) compared to 2.4 months (95% CI= 2.1–2.8, p=0.37) for older and younger men, respectively. In multivariate analysis, the hazard ratio (HR) was 2.57 (95% CI= 0.59–11.30, p=0.21) for men 65 years of age and older compared to younger men. Age, on the other hand, was a statistically significant predictor of OS with a HR = 1.07 (95% CI= 1.00–1.1, p=0.023) when analyzed as continuous covariate. Conclusions: There were no statistical significance differences in OS and PFS between older (>=65 years) and younger men (<65 years) with HRPC enrolled on these clinical trials. However, age was a significant predictor of OS when modeled as a continuous variable. It is unknown if these results would hold true in a less selected patient population. No significant financial relationships to disclose.
Targeted/Emerging Therapies for Metastatic Non–Small Cell Lung Cancer
Authors: Leora Horn
Journal: Journal of the National Comprehensive Cancer Network (2015)

At one time, histology alone guided treatment decisions in non-small cell lung cancer (NSCLC), but now molecular diagnostics help to categorize patients with lung cancer by driver mutations. This additional information arms oncologists with the keys to selecting the right targeted agent with the best chance of success for different subgroups of patients with NSCLC. During her presentation at the NCCN 20th Annual Conference, Dr. Leora Horn focused attention on both approved and emerging therapies in metastatic disease that target an assortment of molecular subsets, such as EGFR mutations, ALK rearrangements, ROS1 rearrangements, and BRAF mutations.
C6 depletion reduces proteinuria in experimental nephropathy induced by a nonglomerular antigen.
Authors: W G Couser, R F Ochi, P J Baker, M Schulze, C Campbell, R J Johnson
Journal: Journal of the American Society of Nephrology (1991)

The role of the complement membrane attack complex, C5b-9, in mediating glomerular injury has been well defined in models of membranous nephropathy induced by antibody to endogenous glomerular epithelial cell membrane antigens. The effect of selective C6 depletion (to prevent C5b-9 formation) on morphologic characteristics and proteinuria in a model of in situ subepithelial immune complex nephritis induced by an exogenous cationized antigen (human immunoglobulin G (IgG)) followed by rabbit antibody to human IgG was studied. Selective C6 depletion was achieved by repeated administration of a goat antibody to rat C6. Other groups were treated with cobra venom factor to induce generalized complement depletion and with sublethal irradiation to deplete circulating leukocytes. In C6-depleted rats, C6 levels were reduced to less than 3% of baseline throughout the 2 days of the study compared with over 100% in controls. At 4 h after disease induction, glomerular deposition of antigen and antibody were similar in C6D and control groups by immunofluorescence and by direct measurement of glomerular deposition of radiolabeled antigen and antibody (cationized 131I human IgG, 9.1 +/- 0.1 micrograms/38,000 glomeruli in C6D versus 9.8 +/- 0.9 in controls; P = was not significant; rabbit 125I-labeled anti-human IgG, 104 +/- 10 ng in C6D versus 80 +/- 9 ng in controls; P = was not significant). Circulating C3 levels and glomerular C3 deposition were also similar in C6D and control groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Minimal Residual Disease (MRD) Detection By Deep Sequencing In Newly Diagnosed Multiple Myeloma Patients Treated With Carfilzomib, Lenalidomide and Dexamethasone
Authors: Sham Mailankody, Neha Korde, Malek Faham, Mary Kwok, Elisabet E. Manasanch, Manisha Bhutani, Nishant Tageja, Dickran Kazandjian, Li Weng, Martin Moorhead, Rene Costello, Yong Zhang, Adriana Zingone, Debbie Burton, Peter Wu, Marcia Mulquin, Diamond Zuchlinski, Roger Kurlander, Irina Maric, Katherine R Calvo, Raul C. Braylan, Constance Yuan, Maryalice Stetler-Stevenson, Diane C Arthur, Mark Roschewski, Ola Landgren
Journal: Blood (2013)
Risk-based treatment for synovial sarcoma in patients under 30 years of age: Children’s Oncology Group study ARST0332.
Authors: Rajkumar Venkatramani, James Robert Anderson, Lynn Million, Cheryl M. Coffin, Beth McCarville, R. Lor Randall, David Parham, Simon C Kao, Andrea Anita Hayes-Jordan, Suzanne L. Wolden, Stephanie Alicia Terezakis, Jennifer O Black, Fran Laurie, Rose Anne Speights, Stephen Skapek, Douglas S. Hawkins, Sheri L. Spunt
Journal: Journal of Clinical Oncology (2015)

10012 Background: Synovial sarcoma (SS) is the second most common soft tissue sarcoma in children. ARST0332 evaluated a risk-based treatment strategy for young soft tissue sarcoma patients designed to limit therapy for low-risk disease and to test neoadjuvant chemoradiotherapy for unresected high-risk disease. Methods: Newly diagnosed SS patients < 30 years old were assigned to 4 treatment arms based on disease features including POG grade: A (surgery only): grossly excised intermediate-grade and ≤ 5 cm widely excised high-grade tumor; B (55.8 Gy radiotherapy [RT]): ≤ 5 cm marginally resected high-grade tumor; C (ifosfamide/doxorubicin chemotherapy + 55.8 Gy RT): > 5 cm grossly resected high-grade tumor ± metastases; D (neoadjuvant ifosfamide/doxorubicin chemotherapy and 45 Gy RT, then surgery and RT boost based on margins): > 5cm unresected tumor ± metastases. Patients treated in Arm A and B were considered low-risk (LR), Arm C and D without metastases as intermediate-risk (IR) and those with metastases as high-risk (HR). Results: Of the 149 SS patients enrolled, 129 were eligible for analysis: LR (43), IR (66) and HR (20). Most (74%) were 10-19 years of age and 52% were female. Tumors were 79% extremity, 71% > 5 cm, 30% intermediate-grade, 70% high-grade, 63% invasive, 96% deep, and 16% metastatic. Thirty-nine patients (30%) did not receive RT. There were no toxic deaths and only 5 unexpected grade 4 adverse events. By risk group, at a median follow-up of 2.6 years, estimated 3-year event-free survival was: LR 83%, IR 79%, HR 16% and overall survival was: LR 97%, IR 93%, HR 29%. After accounting for risk category, none of the other patient or disease characteristics (age, gender, tumor site, neurovascular invasiveness, depth) were statistically significantly associated with outcome. Conclusions: The novel risk-based treatment strategy used in ARST0332 produced favorable outcomes in non-metastatic SS patients relative to historical controls using RT less frequently and at lower doses. The outcome for metastatic SS remains unsatisfactory and new therapies are urgently needed. Besides risk group, no other factors predictive of outcome were identified. Clinical trial information: NCT00346164.