tbuckley/cabot-search huggingface dataset:
Efficacy and cost of <i>nab</i>-paclitaxel (<i>nab</i>-P) in metastatic melanoma (mM).
Authors: Sanjiv S Agarwala, Scott Whiting, Gary Binder, Evan Hersh
Journal: Journal of Clinical Oncology (2013)

e20033 Background: A recent phase III trial of nab-paclitaxel (nab-P, 130 nm albumin-bound paclitaxel) vs dacarbazine (DTIC) in mM demonstrated a significant improvement in progression-free survival (PFS). An economic analysis was applied to the results of this trial. Methods: Chemotherapy naive stage IV mM patients received nab-P 150 mg/m 2 on days 1, 8, and 15 every 4 weeks or DTIC 1000 mg/m 2 every 3 weeks. 529 patients were randomized to nab-P (n = 264) or DTIC (n = 265). The primary endpoint was independently assessed PFS, with overall survival (OS) as a secondary endpoint. Costs of nab-P and DTIC were taken from published 2013 Medicare reimbursement rates. A literature review identified costs for expected adverse events (AE), administration, and recently approved mM treatments. Results: In the intent-to-treat population, median PFS was 4.8 and 2.5 months in the nab-P and DTIC arms, respectively (HR: 0.792; P = 0.044). Median OS at the time of an interim analysis was 12.8 months with nab-P and 10.7 months with DTIC (HR: 0.831; P = 0.094; determination of ultimate statistical significance is pending full analysis at study conclusion). The most common grade ≥3 treatment-related AEs were neuropathy (nab-P: 25% vs DTIC: 0%) and neutropenia (nab-P: 20% vs DTIC: 10%). Grade 4 neutropenia rates were similar between arms (nab-P: 3% vs DTIC: 4%). Median time to neuropathy improvement by &gt;1 grade was 28 days. Median treatment duration was 3 months with nab-P vs 2.1 months with DTIC. Incremental costs per patient were $23,359 ($24,663 for nab-P vs $1,304 for DTIC) including drug, infusion, and AE management costs. These costs compare favorably to incremental costs of over $50,000 for newly approved therapies with similar median OS gains vsDTIC. Conclusions: nab-P is the only chemotherapy in a phase III trial to demonstrate a significant and clinically meaningful delay in disease progression over dacarbazine. Total costs are attractive in the context of other agents recently approved for mM. Further analysis is merited when final OS is available. Clinical trial information: NCT00864253.
Phase 2 study of the CDK4 inhibitor abemaciclib in dedifferentiated liposarcoma.
Authors: Mark Andrew Dickson, Andrew Koff, Sandra P. D'Angelo, Mrinal M. Gounder, Mary Louise Keohan, Ciara Marie Kelly, Ping Chi, Cristina R. Antonescu, Jonathan Landa, Li-Xuan Qin, Aimee Marie Crago, Samuel Singer, William D. Tap
Journal: Journal of Clinical Oncology (2019)

11004 Background: The oncogene cyclin-dependent kinase 4 (CDK4) is amplified in &gt; 90% of de-differentiated liposarcomas (DDLS). We previously demonstrated that treatment with the CDK4 inhibitor palbociclib results in favorable progression-free survival (PFS) in DDLS. Abemaciclib is a newer and more potent CDK4 inhibitor. This single-arm phase 2 study was designed to test the activity of abemaciclib in DDLS. Methods: Participants were adults with advanced DDLS, measurable disease by RECIST 1.1, any (or no) priory therapy, and progression by RECIST in the 6 months prior to study entry. The primary endpoint was PFS at 12 weeks. Based on historical data, promising drugs have 12-week PFS of ≥ 40% and not promising ≤ 20%. This study would be positive if 12-week PFS was ≥ 60%. The study was approved by the Institutional Review Board of Memorial Sloan-Kettering Cancer Center and all patients provided written informed consent. The study was registered at Clinicaltrials.gov (NCT02846987) and study drug was provided by Eli-Lilly. Results: Treatment was abemaciclib 200 mg by mouth twice daily continuously. 30 patients were treated and 29 were evaluable for the primary endpoint. Patient characteristics: Median age 62 (range 39-88), 60% male. Lines of prior therapy: 0 (50%); 1 (33%); ≥ 2 (17%). The observed PFS at 12 weeks was 76% (95% CI 57-90%). Median PFS was 30.4 weeks (95% CI 28.9-NE). There was one partial response. A further 3 patients had &gt; 10% decrease in tumor size by RECIST but did not meet the criterion for partial response. Grade 3-4 toxicity included anemia (37%), neutropenia (20%), thrombocytopenia (17%) and diarrhea (7%). Conclusions: This study met its primary endpoint. In patients with advanced progressive DDLS, abemaciclib treatment results in favorable PFS and objective tumor response with manageable toxicity. Updated response data and results of paired tumor biopsies will be presented. Clinical trial information: NCT02846987.
Augmentation of Therapy for Combined Loss of Heterozygosity 1p and 16q in Favorable Histology Wilms Tumor: A Children’s Oncology Group AREN0532 and AREN0533 Study Report
Authors: David B. Dix, Conrad V. Fernandez, Yueh-Yun Chi, Elizabeth A. Mullen, James I. Geller, Eric J. Gratias, Geetika Khanna, John A. Kalapurakal, Elizabeth J. Perlman, Nita L. Seibel, Peter F. Ehrlich, Marcio Malogolowkin, James Anderson, Julie Gastier-Foster, Robert C. Shamberger, Yeonil Kim, Paul E. Grundy, Jeffrey S. Dome
Journal: Journal of Clinical Oncology (2019)

In National Wilms Tumor Study 5 (NWTS-5), tumor-specific combined loss of heterozygosity of chromosomes 1p and 16q (LOH1p/16q) was associated with adverse outcomes in patients with favorable histology Wilms tumor. The AREN0533/AREN0532 studies assessed whether augmenting therapy improved event-free survival (EFS) for these patients. Patients with stage I/II disease received regimen DD4A (vincristine, dactinomycin and doxorubicin) but no radiation therapy. Patients with stage III/IV disease received regimen M (vincristine, dactinomycin, and doxorubicin alternating with cyclophosphamide and etoposide) and radiation therapy.Patients were enrolled through the AREN03B2 Biology study between October 2006 and October 2013; all underwent central review of pathology, surgical reports, and imaging. Tumors were evaluated for LOH1p/16q by microsatellite testing. EFS and overall survival were compared using the log-rank test between NWTS-5 and current studies.LOH1p/16q was detected in 49 of 1,147 evaluable patients with stage I/II disease (4.27%) enrolled in AREN03B2; 32 enrolled in AREN0532. LOH1p/16q was detected in 82 of 1,364 evaluable patients with stage III/IV disease (6.01%) in AREN03B2; 51 enrolled in AREN0533. Median follow-up for 83 eligible patients enrolled in AREN0532/0533 was 5.73 years (range, 2.84 to 9.63 years). The 4-year EFS for patients with stage I/II and stage III/IV disease with LOH1p/16 was 87.3% (95% CI, 75.1% to 99.5%) and 90.2% (95% CI, 81.8% to 98.6%), respectively. These results are improved compared with the NWTS-5 updated 4-year EFS of 68.8% for patients with stage I/II disease (P = .042), and 61.3% for patients with stage III/IV disease (P = .001), with trends toward improved 4-year overall survival. The most common grade 3 or higher nonhematologic toxicities with regimen M were febrile neutropenia (39.2%) and infections (21.6%).Augmentation of therapy improved EFS for patients with favorable histology Wilms tumor and LOH1p/16q compared with the historical NWTS-5 comparison group, with an expected toxicity profile.
The Role of Molacular Genetic Examination in Differential Diagnosis and Prognostic Prediction in Patints with B-Cell Chronic Lymphoproliferative Disorders: A Restrospective Study of 1592 Patients
Authors: Yuting Yan, Wenjie Xiong, Shuhua Yi, Li Zengjun, Dehui Zou, Weiwei Sui, Wei Liu, Tingyu Wang, Lugui Qiu
Journal: Blood (2018)
The Genomic Landscape of Sporadic Prolactinomas
Authors: Sunita M C De Sousa, Paul P S Wang, Stephen Santoreneos, Angeline Shen, Christopher J Yates, Milena Babic, Leila Eshraghi, Jinghua Feng, Barbara Koszyca, Samuel Roberts-Thomson, Andreas W Schreiber, David J Torpy, Hamish S Scott
Journal: Endocrine Pathology (2019)
CRAF Methylation by PRMT6 Regulates Aerobic Glycolysis–Driven Hepatocarcinogenesis via ERK‐Dependent PKM2 Nuclear Relocalization and Activation
Authors: Tin‐Lok Wong, Kai‐Yu Ng, Kel Vin Tan, Lok‐Hei Chan, Lei Zhou, Noélia Che, Ruby L.C. Hoo, Terence K. Lee, Stéphane Richard, Chung‐Mau Lo, Kwan Man, Pek‐Lan Khong, Stephanie Ma
Journal: Hepatology (2019)

Most tumor cells use aerobic glycolysis (the Warburg effect) to support anabolic growth and promote tumorigenicity and drug resistance. Intriguingly, the molecular mechanisms underlying this phenomenon are not well understood. In this work, using gain-of-function and loss-of-function in vitro studies in patient-derived organoid and cell cultures as well as in vivo positron emission tomography-magnetic resonance imaging animal models, we showed that protein arginine N-methyltransferase 6 (PRMT6) regulates aerobic glycolysis in human hepatocellular carcinoma (HCC) through nuclear relocalization of pyruvate kinase M2 isoform (PKM2), a key regulator of the Warburg effect.We found PRMT6 to methylate CRAF at arginine 100, interfering with its RAS/RAF binding potential, and therefore altering extracellular signal-regulated kinase (ERK)-mediated PKM2 translocation into the nucleus. This altered PRMT6-ERK-PKM2 signaling axis was further confirmed in both a HCC mouse model with endogenous knockout of PRMT6 as well as in HCC clinical samples. We also identified PRMT6 as a target of hypoxia through the transcriptional repressor element 1-silencing transcription factor, linking PRMT6 with hypoxia in driving glycolytic events. Finally, we showed as a proof of concept the therapeutic potential of using 2-deoxyglucose, a glycolysis inhibitor, to reverse tumorigenicity and sorafenib resistance mediated by PRMT6 deficiency in HCC.Our findings indicate that the PRMT6-ERK-PKM2 regulatory axis is an important determinant of the Warburg effect in tumor cells, and provide a mechanistic link among tumorigenicity, sorafenib resistance, and glucose metabolism.
Academic and community PCPs underestimate benefits of systemic therapy for lung and breast cancer.
Authors: Alireza Abdolmohammadi, Shesh Rai, Jianmin Pan, Joseph Alexander, Goetz H. Kloecker
Journal: Journal of Clinical Oncology (2012)

e16545 Background: In previous studies primary care physicians (PCP) under-appreciated systemic therapy for breast cancer (BC) and even more for lung cancer (LC). Lack of knowledge and a possible bias against lung cancer patients were suggested as potential causes. This study evaluates if the unawareness about beneficial systemic therapy persists in the era of targeted therapy, and if academic PCPs have a different perception than community PCPs. Methods: 3444 surveys were sent out, (printed 2,497, electronic 947) to 1,993 Family Medicine (57%) and 1,451 Internal Medicine MDs (43%), in academic (13%) and non-academic centers (87%). Case scenarios asked if respondents believed in the potential curative and palliative role of chemotherapy in the early and advanced stage of either lung cancer (LC) or breast cancer (BC). The study was testing a 20% difference in response rate between academic and non-academic MDs with a power of 80% and alpha of 5%. Results: 316 physicians (9.1%) responded, 89 academic MDs (28%), 227 non-academic MDs (72%). The rate of returned surveys was equal by specialty. PCPs believed less in curative systemic therapy for LC than BC (42% vs. 72.6%, (p&lt;0.001). PCPs believed less in systemic therapy to improve DFS for LC than BC (58.2% vs. 75.5%, p&lt;0.001). PCPs believed palliative chemotherapy can prevent symptoms and prolong life in advanced asymptomatic disease, 79.5% in LC and 84.6% in BC (ns). Half of the PCPs refer patients with symptomatic advanced disease to palliative care before seeing medical oncology, 50.8% in LC and 53.1% in BC (ns). Academic and community MDs responded in the same pattern for all scenarios (p&gt;0.5). Conclusions: Academic and community PCPs are very often not aware of the curative and palliative benefits of systemic therapy. This persistent lack of awareness by PCPs requires more educational effort by medical oncologists and academic institutions.
Icare 1: A Prospective Clinical Trial to Predict Treatment Response Based on Mutanome-Informed Computational Biology in Patients with Acute Myeloid Leukemia (AML) and Myelodysplastic Syndromes (MDS)
Authors: Leylah M. Drusbosky, Kimberly E. Hawkins, Cesia Salan, Madeleine Turcotte, Glenda G. Anderson, Neeraj Kumar Singh, Saumya Radhakrishnan, Yashaswini Ullal, Anay Talawdekar, Huzaifa Sikora, Prashant Nair, Priyanka Bhowmick, Taher Abbasi, Shireen Vali, Fei Zou, Nosha Farhadfar, Hemant S. Murthy, Biljana N. Horn, Helen L. Leather, Paul Castillo, Barry Sawicki, Randy A. Brown, Maxim Norkin, John W. Hiemenz, Jack W. Hsu, William Slayton, John R. Wingard, Christopher R. Cogle
Journal: Blood (2017)
The epithelial architecture of ovarian cancer cells mediates resistance to oncolytic adenoviruses
Authors: R Strauss, P Sova, Y Liu, Z Li, S Tuve, D Pritchard, P Brinkkoetter, T Möller, O Wildner, S Pesonen, Akseli Eetu Hemminki, N Urban, S Drescher, A Lieber
Journal: Cancer Research (2009)
Oral Curcumin No More Effective Than Placebo in Preventing Recurrence of Crohn's Disease After Surgery in a Randomized Controlled Trial
Authors: Gilles Bommelaer, David Laharie, Stéphane Nancey, Xavier Hebuterne, Xavier Roblin, Maria Nachury, Laurent Peyrin-Biroulet, Mathurin Fumery, Damien Richard, Bruno Pereira, Marion Goutte, Anthony Buisson, Dilek Coban, Marie Dodel, Félix Goutorbe, Christophe Allimant, Maud Reymond, Michel Dapoigny, Olivier Rouquette, Emilie Vazeille, Florian Poullenot, Pauline Riviere, Gilles Boschetti, Jérôme Filippi, Emilie Del Tedesco, Pauline Veyrard, Benjamin Pariente, Pauline Wils, Camille Zallot, Clara Yzet, Franck Brazier
Journal: Clinical Gastroenterology and Hepatology (2019)
Sphingosine-1-Phosphate induced tumor growth and metastatic potential in multiple myeloma is mitigated with an anti-S1P mAb (Sphingomab™)
Authors: Xiaoping Sun, Enze Wang, Daniel M. Jones, Haifa Shen, Marcella M. Johnson, Jean-Pierre J. Issa, Hesham Amin, Cheryl F. Ginsberg, Hagop M. Kantarjian, Michael Andreeff, Steven M. Kornblau, Armand B. Glassman, Ralph B. Arlinghaus
Journal: Cancer Research (2006)

3034  Sphingosine-1-phosphate (S1P) is the bioactive signaling product of a novel oncogene, sphingosine kinase, which is up-regulated in a variety of solid tumor types. S1P regulates solid tumor proliferation, invasion and angiogenesis. We have developed a high affinity and specific monoclonal anti-S1P antibody (anti-S1P mAb, rmSphingomab™) to selectively adsorb extracellular S1P, thus lowering its effective concentration and depriving the S1P specific GPCRs of their tumorigenic ligand. While Sphingomab™ has shown to be efficacious in a variety of animal models of human solid tumors, its efficacy has not been demonstrated in any liquid tumor models. We report for the first time that the extracellular sphingolipid signaling molecule, S1P, plays a pivotal role in B cell type multiple myeloma (MM) growth while effecting important interactions between B cells and bone marrow-derived stromal cells, effects which are mitigated with Sphingomab™. We demonstrate the ability of S1P to increase detachment of RPMI8226, U266 and U937 MM cells from stromal cells as well as the associated enhanced cellular migration, all of which are reversed by Sphingomab™. Cell line-specific S1P receptor profiling using real time, quantitative PCR allowed us to predict which MM cells were S1P-dependent and, correspondingly, responsive to Sphingomab™. An in vivo model using S1P-dependent human MM cells has been developed to confirm the tumorigenic role of S1P and the ability of Sphingomab™ to delay the progression of disease. Taken together, this study not only establishes S1P as a pleiotropic tumor promoter in multiple myeloma, but suggests that Sphingomab™ may be clinically useful in reducing disease progression by neutralizing the proliferative, metastatic and angiogenic effects of S1P. Thus, Sphingomab™ may represent a novel and innovative approach to the treatment of hematological cancers. This work is supported by the National Institutes of Health R43 CA110298-01 to ALC and RAS, PO1 CA64602
The Infant Welfare Movement in the Eighteenth Century.
Journal: Annals of Internal Medicine (1931)

The author gives the story of the progress made in infant welfare in London during the eighteenth century. He gives in detail the reasons for the tremendous infant mortality at the beginning of the century, and develops this to the opening of the Foundling Hospital by Thomas Coram. He gives this movement in detail with the work of William Cadogan, Jonas Hanway and George Armstrong. Much of the literature of the time has been consulted, and there is a complete bibliography. This book fills a place in the history of the development of infant welfare. Strangely enough the beginning steps made in the eighteenth century have not been fully enough realized, and this justifies the writing of such a book. It is well written and bound attractively, and should have a place in the library of any one interested in the development of pediatrics.
Increased flux through the mevalonate pathway mediates fibrotic repair without injury
Authors: Jennifer L. Larson-Casey, Mudit Vaid, Linlin Gu, Chao He, Guo-Qiang Cai, Qiang Ding, Dana Davis, Taylor F. Berryhill, Landon S. Wilson, Stephen Barnes, Jeffrey D. Neighbors, Raymond J. Hohl, Kurt A. Zimmerman, Bradley K. Yoder, Ana Leda F. Longhini, Vidya Sagar Hanumanthu, Ranu Surolia, Veena B. Antony, A. Brent Carter
Journal: Journal of Clinical Investigation (2019)

Macrophages are important in mounting an innate immune response to injury as well as in repair of injury. Gene expression of Rho proteins is known to be increased in fibrotic models; however, the role of these proteins in idiopathic pulmonary fibrosis (IPF) is not known. Here, we show that BAL cells from patients with IPF have a profibrotic phenotype secondary to increased activation of the small GTPase Rac1. Rac1 activation requires a posttranslational modification, geranylgeranylation, of the C-terminal cysteine residue. We found that by supplying more substrate for geranylgeranylation, Rac1 activation was substantially increased, resulting in profibrotic polarization by increasing flux through the mevalonate pathway. The increased flux was secondary to greater levels of acetyl-CoA from metabolic reprogramming to β oxidation. The polarization mediated fibrotic repair in the absence of injury by enhancing macrophage/fibroblast signaling. These observations suggest that targeting the mevalonate pathway may abrogate the role of macrophages in dysregulated fibrotic repair.
Efficacy and safety of inhaled α1-antitrypsin in patients with severe α1-antitrypsin deficiency and frequent exacerbations of COPD
Authors: Jan Stolk, Naveh Tov, Kenneth R. Chapman, Pablo Fernandez, William MacNee, Nicholas S. Hopkinson, Eeva Piitulainen, Niels Seersholm, Claus F. Vogelmeier, Robert Bals, Gerry McElvaney, Robert A. Stockley
Journal: European Respiratory Journal (2019)

Patients with inherited α1-antitrypsin (AAT) deficiency (ZZ-AATD) and severe chronic obstructive pulmonary disease (COPD) frequently experience exacerbations. We postulated that inhalation of nebulised AAT would be an effective treatment. We randomly assigned 168 patients to receive twice-daily inhalations of 80 mg AAT solution or placebo for 50 weeks. Patients used an electronic diary to capture exacerbations. The primary endpoint was time from randomisation to the first event-based exacerbation. Secondary endpoints included change in the nature of the exacerbation as defined by the Anthonisen criteria. Safety was also assessed. Time to first moderate or severe exacerbation was a median of 112 days (interquartile range (IQR) 40–211 days) for AAT and 140 days (IQR 72–142 days) for placebo (p=0.0952). The mean yearly rate of all exacerbations was 3.12 in the AAT-treated group and 2.67 in the placebo group (p=0.31). More patients receiving AAT reported treatment-related treatment-emergent adverse events compared to placebo (57.5% versus 46.9%, respectively) and they were more likely to withdraw from the study. After the first year of the study, when modifications to the handling of the nebuliser were introduced, the rate of safety events in the AAT-treated group dropped to that of the placebo group. We conclude that in AATD patients with severe COPD and frequent exacerbations, AAT inhalation for 50 weeks showed no effect on time to first exacerbation but may have changed the pattern of the episodes.
Genetic background and risk of lung adenocarcinoma in never smokers.
Authors: Kazuya Takamochi, Shiaki Oh, Kenji Suzuki
Journal: Journal of Clinical Oncology (2013)

e18549 Background: The causative association between tobacco smoking and lung cancer is well-known. However, the mechanism underlying the pathogenesis of lung adenocarcinoma in never smokers remains unclear. Recently, several driver oncogenes, such as EGFR and EML4-ALK, have been identified in lung adenocarcinomas ofnever smokers. Methods: This was a retrospective review of 596 patients with surgically resected lung adenocarcinomas between February 2009 and October 2012. The clinicopathological factors (age, gender, and pathological stage), EGFR and KRASmutation status, past history of any cancer or benign tumor, family history of any cancer, and the presence of multiple primary lung cancers were compared between never smokers (n = 312) and smokers (n = 284). Results: Lung adenocarcinomas in never smokers were more frequently found in females (P &lt; 0.001) and in patients with early stage disease (P = 0.01) than those in smokers. EGFR mutations were detected in 183 (59%) never smokers and in 89 (31%) smokers (P &lt; 0.001). K-ras mutations were detected in nine (3%) never smokers and in 57 (20%) smokers (P &lt; 0.001). The proportion of patients with a past history of any cancer was higher in smokers than in never smokers (28% vs 21%, P = 0.03). This may reflect the fact that tobacco smoking can cause various types of cancers. In contrast, the proportions of patients with any benign tumor and a family history of any cancer were higher in never smokers than in smokers (14% vs 4%, P &lt; 0.001 and 20% vs 13%, P = 0.02). These findings may suggest that a certain genetic background is involved in the pathogenesis of lung adenocarcinoma in never smokers. The frequency of multiple primary lung cancers was not significantly different between never smokers and smokers (6% vs 5%, P = 0.6). In never smokers, the EGFR and KRASmutation status was not associated with the frequency of a past history of any cancer or benign tumor, a family history of any cancer or the presence of multiple primary lung cancers. Conclusions: A certain genetic predisposition is suspected to be involved in the pathogenesis of lung adenocarcinoma in never smokers. Further studies are thus needed to elucidate the genetic alterations associated with the susceptibility to lung adenocarcinoma in never smokers.