tbuckley/cabot-search huggingface dataset:
Abstract IA15: Promise and challenges of pediatric cancer PDX models
Authors: Peter J. Houghton, Raushan T. Kurmasheva
Journal: Clinical Cancer Research (2016)

Abstract The Pediatric Preclinical Testing Program (PPTP) has evaluated almost 97 single agents and several combinations over the last 10 years. A total of 89 xenograft models that encompass solid tumors, brain tumors, and acute leukemias have been used as a screen to identify novel agents that could be accelerated for clinical trial. With few exceptions, all models were directly established in mice from patient biopsies, and approximately half of the models were established from patients who were refractory or had relapsed. Expression analysis showed that tumor models clustered with their appropriate clinical histotype, and exome sequencing showed mutation frequency and identity to be similar to published genomic data for patient cancers. The models accurately identified known active agents that are used as standard of care therapy for solid tumors and leukemias, thus validating the models. Criteria for assessing response similar to clinical criteria were developed. Of the 97 agents tested, twenty-four signaling inhibitors (ligand or receptor binding antibodies, kinase inhibitors etc.) were evaluated. With the exception of inhibitors of Aurora kinase A, and Polo-like kinase 1, the overall objective response rate (ORR) was &amp;lt;2%. The low response rate is probably an accurate reflection of likely ORR in clinical trials, as the models identified selumetinib in an astrocytoma with BRAF (V600E) mutation, dasatinib in a Ph+ ALL, sorafenib in a Flt3 mutant ALL, and crizotinib in an ALK mutant neuroblastoma. The models identified several cytotoxic agents as having broad-spectrum antitumor activity (eribulin, alisertib, PR-104), with small molecule and antibody conjugated antimitotic agents showing high-level activity in many models (eribulin in sarcoma and ALL, glembatumab in osteosarcoma). The major issue is that the models overpredict drug activity due to tolerance of the host (mouse) compared to patients. Thus, it is imperative to adjust dose/schedule to accurately reproduce clinical exposures. Another issue to be addressed is whether the models adequately encompass genomic and epigenomic heterogeneity. With increasing evidence of molecular subtypes within histotypes previously considered as relatively homogeneous, it is clear that additional models need to be established. We have analyzed 2134 tumor/drug studies undertaken as part of the PPTP to determine whether alternative experimental designs can be used that would allow an increased genomic diversity to be interrogated using current resources. Citation Format: Peter J. Houghton, Raushan T. Kurmasheva. Promise and challenges of pediatric cancer PDX models. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr IA15.
Neoadjuvant treatment response as a tumor necrosis grade for patients with rectal cancer.
Authors: Byoungyong Shim, Ji Han Jung, Hyun Min Cho, Hyung Jin Kim, Ji Hyung Hong, Sung Whan Kim
Journal: Journal of Clinical Oncology (2013)

e14563 Background: Neoadjuvant chemoradiotherapy for rectal cancer results in prevention of local recurrence and may achieve sphincter conserving surgery. Association between pathologic response evaluated after radical tumor resection and patient prognosis was well established. The object of this study was to assess the association between the degree of tumor necrosis after chemoradiotherapy and oncologic outcomes. Methods: In all, 225 patients with locally advanced rectal cancer (stage II and III by endorectal ultrasonography, CT and MRI) had 50.4 Gy over 5.5 weeks, plus 5-fluorouracil and leucovorin and surgery was performed at 7 to 10 weeks after completion of all therapies. Pathologic tissue necrosis after chemoradiotherapy was reviewed and scored as follows: Grade 0, no response; Grade 1, necrosis or disappearance of tumor cells less than 2/3; Grade 2, necrosis or disappearance of tumor cells more than 2/3; and Grade 3, no viable cells (ypCR). Correlation analysis was performed using Pearson’s Chi square or Fisher’s exact test, as appropriate. Recurrence-free survival and overall survival were calculated using the Kaplan-Meier method. Results: This study included cStage II (101 patients) and cStage III (124 patients) rectal cancer patients, and down stage rate was 57.3% and pCR was 16.9%. The pathologic tumor response ( pStage 0 v I v II v III) was associated with 5-year RFS (97.4 % v 81.5% v 76.6% v 50.0%; p&lt;0.001). The tumor necrosis (Grade 0 &amp; 1 v 2 v 3) was associated with 5-year RFS (64.4% v 76.8 v 97.4%; p=.002). Conclusions: The tumor necrosis to neoadjuvant chemoradiotherapy is a surrogate marker for recurrence and oncologic outcomes in rectal cancer patients treated with 5 flurouracil and leucovorin neo-adjuvant chemoradiotherapy.
Clinical similarity of biosimilar ABP 501 to adalimumab in the treatment of patients with moderate to severe plaque psoriasis: A randomized, double-blind, multicenter, phase III study
Authors: Kim Papp, Herve Bachelez, Antonio Costanzo, Peter Foley, Melinda Gooderham, Primal Kaur, Joanna Narbutt, Sandra Philipp, Lynda Spelman, Jolanta Weglowska, Nan Zhang, Bruce Strober
Journal: Journal of the American Academy of Dermatology (2017)

BackgroundABP 501 is a biosimilar of adalimumab.ObjectiveWe sought to compare the efficacy and safety of ABP 501 with adalimumab.MethodsThis 52-week, double-blind study randomized patients with moderate to severe psoriasis to ABP 501 or adalimumab. At week 16, those with 50% or more improvement in Psoriasis Area and Severity Index score from baseline on ABP 501 continued the same treatment, whereas adalimumab-treated patients were rerandomized to adalimumab or ABP 501. Clinical similarity in Psoriasis Area and Severity Index percent improvement from baseline to week 16 (primary end point) was established if the point estimate of treatment difference and its 2-sided 95% confidence interval between groups was within equivalence margin of ±15. Patients, including those undergoing a single transition at week 16, were evaluated for safety and immunogenicity.ResultsPsoriasis Area and Severity Index percent improvement at week 16 was 80.9 for ABP 501 and 83.1 for adalimumab (least-square mean difference −2.18 [95% confidence interval −7.39 to 3.02]). Adverse events (67.2% [117/174] vs 63.6% [110/173]) and antidrug antibody incidence (55.2% [96/174] vs 63.6% [110/173]) for ABP 501 vs adalimumab were similar. Safety, including immunogenicity, was similar among groups after single transition (week 20).LimitationsThe 52-week data are not reported here.ConclusionsABP 501 was shown to be clinically similar to adalimumab. Safety and immunogenicity were not impacted immediately after single transition (adalimumab to ABP 501).
Erratum: Cutaneous adiaspiromycosis: A distinct dermatologic entity associated with Chrysosporium species (Journal of the American Academy of Dermatology (2004) 51 (S113-S117))
Authors: W. G. Stebbins, A. Krishtul, E. J. Bottone, R. Phelps, S. Cohen
Journal: Journal of the American Academy of Dermatology (2004)
Lack of chemopreventive activity of lycopene in the Wistar-Unilever rat prostate cancer model
Authors: Maarten C. Bosland, William D. Johnson, Michael J. Cwik, Ronald A. Lubet, Vernon E. Steele, David L. McCormick
Journal: Cancer Research (2004)

3906   Several epidemiology studies have identified an inverse association between consumption of tomato-based products and prostate cancer risk. Although this relationship has not been a universal finding, the possible activity of lycopene and/or other tomato components as inhibitors of prostate carcinogenesis remains a compelling hypothesis. The present study was conducted to evaluate the hypothesis that consumption of lycopene protects against prostate cancer induction in rats. A preliminary diet tolerance study identified no clinical evidence of toxicity when lycopene was administered at levels of up to 5000 mg/kg diet. In blood samples collected after six weeks of exposure, plasma lycopene demonstrated a linear increase with dose between 0 and 5000 mg/kg diet. Based on a multiple of presumed human exposure, lycopene doses of 500 and 2500 mg/kg diet were selected for use in the prostate cancer chemoprevention study. In the chemoprevention study, hormone-dependent prostate cancers were induced in male Wistar-Unilever rats by a sequential regimen of antiandrogen –androgen –chemical carcinogen –androgen. Rats were treated with cyproterone acetate (50 mg/kg/day for 21 days via gavage) followed by testosterone propionate (100 mg/kg/day for 3 days via subcutaneous injection). Sixty hours after the first dose of testosterone propionate, rats (40 to 42 per group) rats received a single intravenous injection of  N -methyl- N -nitrosourea [MNU; 30 mg/kg body weight]. Beginning one week post-MNU, chronic androgen stimulation was provided by 2 subcutaneous pellets containing 40 mg of crystalline testosterone; pellets were replaced at intervals of 6 months. Dietary administration of lycopene was initiated one week post-MNU, and was continued until the termination of the study at 13 months. Accessory sex glands were collected from all study animals at necropsy, and cancer incidence was determined by histopathologic evaluation of interrupted step sections prepared from all glands. Dietary administration of lycopene conferred no protection against prostate carcinogenesis in this study. In comparison to a total cancer incidence of 63% (all accessory sex glands) in dietary controls, total cancer incidences of 81% and 69% were observed in groups fed the low and high doses of lycopene. Similarly, cancers that were clearly limited to the dorsolateral/anterior prostate were found in 48% of dietary controls versus 60% and 43% of rats in groups fed the low and high doses of lycopene, respectively. None of these differences was significant at the 5% level of confidence. Cancer incidence in the seminal vesicle was less than 15% in all groups. These data do not support the hypothesis that lycopene is a potent inhibitor of prostate carcinogenesis. (Supported by NO1-CN-95113 from the NCI.)
Abstract B59: Mathematical Model of Oxygen Transport in Tuberculosis Granulomas
Authors: Meenal Datta, Laura Via, Wei Chen, James Baish, Lei Xu, Clfton Barry, Rakesh Jain
Journal: Cancer Research (2017)

Abstract Pulmonary granulomas—the hallmark of Mycobacterium tuberculosis (MTB) infection—are dense cellular lesions that, like solid tumors, often feature regions of hypoxia and necrosis partially due to limited transport of oxygen. Low oxygen in granulomas can impair the host immune response, while MTB are able to adapt and persist in hypoxic environments. Here, we used a physiologically based mathematical model of oxygen diffusion and consumption, based on models originally derived for avascular tumors, to calculate oxygen profiles within the granuloma, assuming Michaelis-Menten kinetics. An approximate analytical solution—using a priori and newly estimated parameters from experimental data in a rabbit model of tuberculosis—was able to predict the size of hypoxic and necrotic regions in agreement with experimental results from the animal model. Such quantitative understanding of transport limitations can inform future tuberculosis therapeutic strategies that may include adjunct host-directed therapies that facilitate oxygen and drug delivery for more effective treatment. Citation Format: Meenal Datta, Laura Via, Wei Chen, James Baish, Lei Xu, Clfton Barry, Rakesh Jain. Mathematical Model of Oxygen Transport in Tuberculosis Granulomas. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B59.
High Dose Valacyclovir Is Highly Effective to Prevent Cytomegalovirus and Other Herpes Viruses Viremia After Allogeneic Stem Cell Transplantation.
Authors: Marie Detrait, Guy Boivin, Robert Delage, Claire Béliveau, Annie-Claude Labbé, Sandra Cohen, Thomas Kiss, Lambert Busque, Denis-Claude Roy, Guy Sauvageau, Jean Roy
Journal: Blood (2009)
Relationship between Hypotension and Cerebral Ischemia during Hemodialysis
Authors: Clare MacEwen, Sheera Sutherland, Jonathan Daly, Christopher Pugh, Lionel Tarassenko
Journal: Journal of the American Society of Nephrology (2017)

The relationship between BP and downstream ischemia during hemodialysis has not been characterized. We studied the dynamic relationship between BP, real-time symptoms, and cerebral oxygenation during hemodialysis, using continuous BP and cerebral oxygenation measurements prospectively gathered from 635 real-world hemodialysis sessions in 58 prevalent patients. We examined the relationship between BP and cerebral ischemia (relative drop in cerebral saturation >15%) and explored the lower limit of cerebral autoregulation at patient and population levels. Furthermore, we estimated intradialytic exposure to cerebral ischemia and hypotension for each patient, and entered these values into multivariate models predicting change in cognitive function. In all, 23.5% of hemodialysis sessions featured cerebral ischemia; 31.9% of these events were symptomatic. Episodes of hypotension were common, with mean arterial pressure falling by a median of 22 mmHg (interquartile range, 14.3-31.9 mmHg) and dropping below 60 mmHg in 24% of sessions. Every 10 mmHg drop from baseline in mean arterial pressure associated with a 3% increase in ischemic events (P<0.001), and the incidence of ischemic events rose rapidly below an absolute mean arterial pressure of 60 mmHg. Overall, however, BP poorly predicted downstream ischemia. The lower limit of cerebral autoregulation varied substantially (mean 74.1 mmHg, SD 17.6 mmHg). Intradialytic cerebral ischemia, but not hypotension, correlated with decreased executive cognitive function at 12 months (P=0.03). This pilot study demonstrates that intradialytic cerebral ischemia occurs frequently, is not easily predicted from BP, and may be clinically significant.
Spatiotemporal genomic architecture informs precision oncology in glioblastoma
Authors: Jin-Ku Lee, Jiguang Wang, Jason K Sa, Erik Ladewig, Hae-Ock Lee, In-Hee Lee, Hyun Ju Kang, Daniel S Rosenbloom, Pablo G Camara, Zhaoqi Liu, Patrick van Nieuwenhuizen, Sang Won Jung, Seung Won Choi, Junhyung Kim, Andrew Chen, Kyu-Tae Kim, Sang Shin, Yun Jee Seo, Jin-Mi Oh, Yong Jae Shin, Chul-Kee Park, Doo-Sik Kong, Ho Jun Seol, Andrew Blumberg, Jung-Il Lee, Antonio Iavarone, Woong-Yang Park, Raul Rabadan, Do-Hyun Nam
Journal: Nature Genetics (2017)
Galectin-3 Is the Molecular Target for Overcoming Multidrug Resistance Due to the Cell Protection by Bone Marrow Leukemia Microenvironment in Chronic Myeloid Leukemia,
Authors: Mio Yamamoto, Junya Kuroda, Tsutomu Kobayashi, Nana Sasaki, Hisao Nagoshi, Yuji Shimura, Miki Kiyota, Ryuko Nakayama, Shigeo Horiike, Eishi Ashihara, Kenichi Akaji, Masafumi Taniwaki
Journal: Blood (2011)
Genetic predisposition in nonalcoholic fatty liver disease
Authors: Silvia Sookoian, Carlos J. Pirola
Journal: Clinical and Molecular Hepatology (2017)

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease whose prevalence has reached global epidemic proportions. Although the disease is relatively benign in the early stages, when severe clinical forms, including nonalcoholic steatohepatitis (NASH), cirrhosis and even hepatocellular carcinoma, occur, they result in worsening the long-term prognosis. A growing body of evidence indicates that NAFLD develops from a complex process in which many factors, including genetic susceptibility and environmental insults, are involved. In this review, we focused on the genetic component of NAFLD, with special emphasis on the role of genetics in the disease pathogenesis and natural history. Insights into the topic of the genetic susceptibility in lean individuals with NAFLD and the potential use of genetic tests in identifying individuals at risk are also discussed.
Characterization and cytotoxicity of novel polyethyleneglycol-modified liposome contained doxorubicin
Authors: Yasuyuki Sadzuka, Ikumi Sugiyama
Journal: Cancer Research (2007)

2264  Polyethyleneglycol (PEG)-modified liposomes are able to avoid from catch by the reticuloendothelial system. It has been clarified that the prolongation of liposome circulation in the blood and passive targeting to the tumor was achieved by PEG modification of the liposomal membrane. In our previous study, we reported that the mixed PEG-modified liposomes by a mixture of PEG-DSG with short polyoxyethylene chains (Mw : 500) and that with long ones(Mw : 2000) were useful. The mixed PEG modification with different PEG-molecular weights increased the fixed aqueous layer thickness (FALT) around the liposome, compared to that of single PEG modification. Furthermore, we confirmed that mixed PEG modification of the doxorubicin (DOX)-containing liposomes improved the biodistribution and increased in the antitumor activity compared to that of the single PEG modifications, and are superior. However, in this mixed PEG modified liposome, PEG ratio of PEG500 and PEG2000 on liposomal membranes was considered to be changed gradually in blood and tumor. In this study, we synthesized novel PEG lipid with different double arm (Mw of PEGs : 500 and 2000)-PEG (DDA-PEG) and was clarified the characterization and cytotoxicity of this DDA-PEG modified liposome contained doxorubicin.  All liposome was prepared by Bangham method, using DSPC : cholesterol : DSPG : PEG (DDA-PEG or PEG 500- and PEG 2000-DSG ). The FALT around the liposomes was increased with the increase of the PEG-molecular weight. In mixed PEG-modified liposomes with long polyoxyethylene chain and short polyoxyethylene chain, the FALT increased more than that of single PEG-modified liposomes. It was considered that the mushroom structure of long polyoxyethylene chains was transformed into a brush structure because the short polyoxyethylene chains full into the gap of the long polyoxyethylene chains. On the other hand, the FALT of DDA-PEG-modified liposomes was shown same level, compared to maximum level of mixed PEG-modified liposomes. Namely, it was expected that a part of long polyoxyethylene chains was changed to brush structure by short polyoxyethylene chains in one molecule. As the PEG ratio of PEG500 and PEG2000 in DDA-PEG-modified liposome does not change, the efficacy of DDA-PEG-modified liposome was speculated to be maintaining in the body. The cytotoxicity on P388 leukemia cells by this DDA-PEG-modified liposome contained doxorubicin was shown to be higher than those of unmodified liposome and mixed PEG-modified liposome, suggested to be superior novel PEG modification. In conclusion, it was clarified that DDA-PEG lipid as novel PEG lipid on liposome modification has outstanding properties in the physical character and the cytotoxicity.
John “Mickey” Nardo
Authors: Bob Roehr
Journal: BMJ (2017)

Pioneer in trial reanalysis



Credit: Abby Nardo

The name Mickey Nardo is not widely known, but it should be. Nardo played a yeoman’s role in the first-of-its-kind 2015 reanalysis of Study 329,1 which used industry data to show that the selective serotonin reuptake inhibitor paroxetine (Paxil, Seroxat) had no beneficial effect and caused substantial harm when used to treat major depression in adolescents.

Nardo always thought he wanted to do research, but his path ended up being long and circuitous, with many rewarding chapters along the way.

He focused on mathematics at the University of Tennessee, Knoxville, and continued at the university school of medicine in Memphis, obtaining his MD in 1967. Residencies in internal medicine, and immunology and rheumatology followed, with the aim of going into research. An offer from Stanford University to work on tissue typing for organ transplant was pending, when a letter from the Pentagon arrived.

As the war in Vietnam raged, Nardo was offered the choice of serving two years at a hospital in Abilene, Texas, or three years in England. “We didn’t have to think one nanosecond about that,” recalls his wife, Sharon. The young family, which by now included baby Abby, moved to RAF Lakenheath Hospital in Suffolk in 1971, where the paterfamilias served as chief of internal medicine.

The big revelation for Nardo was that he really …
Impact of Routine Surveillance Imaging on Outcomes in Patients with Diffuse Large B-Cell Lymphoma (DLBCL) Undergoing Autologous Hematopoietic Cell Transplantation (auto-HCT)
Authors: Narendranath Epperla, Namrata Shah, Kristin Richardson, Jonathan Kapke, George Carrum, Parameswaran Hari, Mehdi Hamadani, Sai Ravi Pingali, Reem Karmali, Timothy S. Fenske
Journal: Blood (2015)
Short Duration Filgrastim (G-CSF) Therapy (2–4 Days) Is Adequate To Maintain Dose Intensity in Hodgkin’s Lymphoma Patients Treated with Adriamycin, Bleomycin, Vinblastine and Dacarbazine (ABVD).
Authors: Lynne S. Kaminer, Seema Bavisi, Jessica Lawton, William Uhlig, George Carro, David L. Grinblatt
Journal: Blood (2006)
Philadelphia chromosome plus ve patients with adult acute lymphoblastic leukaemia (ALL), early results from the international ALL trial (MRC UKALL-XII/ECOG E2993).
Authors: A H Goldstone, S Richards, P H Wiernik, I M Franklin, A K Burnett, H M Lazarus, H G Prentice, D Neuberg, M S Tallman, G Harrison, J M Rowe
Journal: Blood (1999)
Increased Fetal Hemoglobin Levels Following Decitabine Treatment of Normal Baboons (P. anubis) are Achieved by Transcriptional Activation of the γ-Globin Gene.
Authors: Imo Akpan, Virryan Banzon, Vinzon Ibanez, Kestis Vaitkus, Joseph DeSimone, Donald Lavelle
Journal: Blood (2009)
Not All Middle Cerebral Artery M2 Segments Are the Same
Authors: Nicola Morelli, Eugenia Rota, Emanuele Michieletti
Journal: JAMA Neurology (2017)

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Abstract P2-01-30: Limited effectiveness of patent blue dye in addition to isotope scanning for identification of sentinel lymph nodes: Cross-sectional real-life study in 1024 breast cancer patients
Authors: J-L Merlin, P Rauch, L Leufflen, J Salleron, A Harlé, P Olivier, F Marchal
Journal: Cancer Research (2017)

Abstract This abstract was withdrawn by the authors.