tbuckley/cabot-search huggingface dataset:
Abstract 4025: Impact of Kras mutant subtypes on PD-L1 expression in lung adenocarcinoma
Authors: Marius Ilie, Laetitia Fazzalari, Nicolas Guibert, Nathalie Yazbeck, Laurie Signetti, Véronique Hofman, Elodie Long, Katia Zahaf, Julien Fayada, Virginie Lespinet, Olivier Bordone, Virginie Tanga, Kevin Washetine, Nicolas Vénissac, Jérôme Mouroux, Charles Hugo Marquette, Patrick Brest, Paul Hofman
Journal: Cancer Research (2016)

Abstract Clinical responses to immune checkpoint blockade by anti-PD-1/PD-L1 monoclonal antibodies in non-small-cell lung cancer (NSCLC) may be associated with PD-L1 expression. This study was undertaken to determine the expression profile of PD-L1 in patients with Kras-mutant lung adenocarcinoma (LUAD) and to investigate the activation of Kras codon subtypes as a mechanism of PD-L1 regulation. Immunohistochemistry analysis of PD-L1 expression (SP142 clone) on 117 LUAD (KrasWT, n = 51; KrasG12D, n = 25; KrasG12V, n = 14; KrasG12C, n = 27), showed significantly greater expression of PD-L1 in both tumor and immune cells compartments in Kras mutant LUAD compared with KrasWT wild-type tumors (37% vs. 18%; P = 0.005). PD-L1+ tumors had greater CD66b+ neutrophil infiltrate and lower CD8+ T-cell infiltrate than PD-L1− tumors, notably in KrasG12D tumors. To determine the effect of Kras codon subtypes on PD-L1 expression, stable cell lines were generated by transfection of KrasG12D, KrasG12V, KrasG12C and KrasWT plasmids into Beas2B bronchial cells. At basal level, mutant Kras led to significantly higher cell-surface PD-L1 expression and PD-L1 transcripts, notably in KrasG12C and KrasG12V cells, suggesting transcriptional regulation. Moreover, there was differential activation of NF-kB, ERK and Pi3k/Akt pathways between Kras mutant subtypes. In addition, PD-L1 was upregulated 3-fold by stimulation with IFNγ, independently of the Kras codon subtypes. Instead, hypoxia significantly increased PD-L1 expression in KrasG12C and KrasG12D cells. Co-culture experiments with human PBMCs from healthy patients were performed to determine the functional effect of altered PD-L1 expression. Increased PD-L1 expression by tumor cells induced by Kras mutations led to decreased PBMCs proliferation and increased apoptosis. PD-L1 is expressed in 37% of Kras mutant LUAD, suggesting PD-L1 as a therapeutic target in this subset. According to the Kras mutation subtype, potential drugs targeting the NF-kB, ERK or Pi3k/Akt pathways may increase the antitumor adaptive immune responses. Citation Format: Marius Ilie, Laetitia Fazzalari, Nicolas Guibert, Nathalie Yazbeck, Laurie Signetti, Véronique Hofman, Elodie Long, Katia Zahaf, Julien Fayada, Virginie Lespinet, Olivier Bordone, Virginie Tanga, Kevin Washetine, Nicolas Vénissac, Jérôme Mouroux, Charles Hugo Marquette, Patrick Brest, Paul Hofman. Impact of Kras mutant subtypes on PD-L1 expression in lung adenocarcinoma. [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 4025.
Abstract 4329: The consequence of obesity and obstructive sleep apnea in liver cancer
Authors: Nathan W. Sweeney, Cecil J. Gomes, Sairam Pathasarthasy, Jesse D. Martinez
Journal: Cancer Research (2016)

Abstract Primary liver cancer is the 3rd leading cause of cancer mortality worldwide. Eighty-five percent of liver cancers is comprised of hepatocellular carcinoma (HCC). Risk of developing HCC increases when patients have obesity related comorbidities, involving non-alcoholic steatohepatitis (NASH), hepatic inflammation, or lipid accumulation. Additionally, obesity is generally regarded as a prime risk factor for the development of obstructive sleep apnea (OSA), a repeated obstruction of the upper airway during sleep leading to oxygen deficiency (OD), which also increases the incidence of NASH. The connection of these morbidities presume that patients suffering from obesity induced OSA have an increased risk of developing HCC. To examine obesity and OSA's role in HCC we combined three generally accepted methods: A one-time injection of tumor initiator diethylnitrosamine followed by continuous administration of the promoter phenobarbital, a high fat diet, and a hypoxia chamber to house the mice for regulation of their oxygen intake, allowing us to mimic the OD seen in OSA. Utilizing these treatment methods and applying microCT imaging to non-invasively and repeatedly monitor the liver, we have been able to examine the effects of obesity and/or OD. Preliminary result indicate that a high fat diet results in obesity, lipidosis and liver damage. Interestingly, OD seems to inhibit obesity while still generating hepatic inflammation. Furthermore, we have observed that obesity and OD together cause severe damage to the liver, enhancing the risk of developing HCC. This study will be a significant preclinical step in distinguishing mechanisms that may explain obesities and OSA's combined consequence in HCC. Citation Format: Nathan W. Sweeney, Cecil J. Gomes, Sairam Pathasarthasy, Jesse D. Martinez. The consequence of obesity and obstructive sleep apnea in liver cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4329.
Abstract 5211: Trends in the incidence of retinoblastoma in the United States from 1973-2012
Authors: Arthur G. Fernandes, Benjamin D. Pollock, Aaron E. Hoffman
Journal: Cancer Research (2016)

Abstract Background: Retinoblastoma is a rare form of eye cancer that usually develops in early childhood, typically before the age of 5. This study aims to determine the incidence of retinoblastoma in the United States over a 40-year period from 1973 to 2012 using a review of existing databases. Methods: 882 patients with retinoblastoma (International Classification of Diseases for Oncology (ICD-O-3) codes C69.2 (retina) and C69.9 (eye, NOS)) were derived from the Surveillance, Epidemiology, and End Results (SEER) program database in the United States from 1973 to 2012, using the nine historical SEER registries with the earliest observation collections. Incidence rates were calculated per 1,000,000 children and age-adjusted using the United States Census Bureau data as the standard population. The significance of trend in the incidence rate over time was determined using the Chi-Square test, and 95% CIs were calculated. Descriptive statistics evaluated differences in incidence in terms of age group, gender, race and laterality. Surveillance was evaluated by analysis of diagnosis confirmation and reporting source. Results: There were a total of 882 cases of retinoblastoma, representing 6.1% of all childhood cancers under age 5 years. 49.1% of cases were males and 96% of all cases were children aged 0-4 years. The mean incidence of retinoblastoma was 12.14 cases per million children aged 0-4 years (95% CI 11.32 to 12.96) and 0.49 cases per million children aged 5-9 years (95% CI 0.36 to 0.65). There was no significant trend in the incidence for children aged 0-4 years old (Xsup2 = 35.455 p = 0.6324) or 5-9 years old (Xsup2 = 32.247 p = 0.7695) for all races/genders. The proportion of bilateral cases (28.9%) versus unilateral cases (71.1%) remained stable over the 40-year period. 85.6% of the cases were confirmed microscopically and hospitals represent 98.8% of the reporting sources. Conclusions: The incidence rate of retinoblastoma in the United States has remained stable for the last 40 years. The majority of the cases are unilateral, and hospitals are the main reporting source. Citation Format: Arthur G. Fernandes, Benjamin D. Pollock, Aaron E. Hoffman. Trends in the incidence of retinoblastoma in the United States from 1973-2012. [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 5211.
Abstract 1575: Intratumoral injection of interleukin-17 inhibits distant metastasis of radiation-induced recurrent tumor
Authors: Yi-Nan Li, Fang-Hsin Chen, Ji-Hong Hong, Chi-Shiun Chiang
Journal: Cancer Research (2016)

Abstract Interleukin-17 (IL-17) is a pro-inflammatory cytokine that leads to the production of GM-CSF, G-CSF, IL-1, IL-6, TNF-α. It can be secreted by various cells, including T cells, NKT cells, fibroblasts, and even tumor cells. In addition, reports have shown that IL-17 could also promote tumor growth by recruiting and expanding granulocytic myeloid suppressor cells (G-MDSCs). In our preliminary study, we found that Tramp-C1, a murine prostate cancer cell line, had remarkable IL-17 level when it grew in pre-irradiated (PreIR) stroma. In contrast, B16F0, a murine melanoma cell line, had much less IL-17 and stronger tumor bed effect, in terms of tumor growth delay, but lung metastasis were formed gradually as B16F0 developed. When the recombinant IL-17 was directly injected into the B16F0 tumors growing in PreIR stroma, we found that the probability of lung metastasis was decreased despite a slight increase of tumor growth at primary site. This indicates that IL-17 may have different effects on irradiated tumor bed and distant metastatic site. The influence of IL-17 on tumor microenvironments of distant metastatic sites and irradiated tumor bed is currently under investigation. In conclusion, we propose a new therapeutic approach of reducing distant metastasis following radiation therapy.. This work was kindly supported by MOST-104-2314-B-182 -024 grant to Fang-Hsin Chen. Citation Format: Yi-Nan Li, Fang-Hsin Chen, Ji-Hong Hong, Chi-Shiun Chiang. Intratumoral injection of interleukin-17 inhibits distant metastasis of radiation-induced recurrent tumor. [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 1575.
Abstract 3688: The C-terminal domain of tumor-derived mutant p53 is required for its oncogenic gain-of-function activity
Authors: Caleb C. Lee, James Manfredi
Journal: Cancer Research (2016)

Abstract p53 is the most commonly mutated gene in human cancers. Unlike other tumor suppressors in which loss of protein expression is common, the vast majority of changes in p53 arise as point mutations. Tumor associated mutation hotspots are localized to the DNA binding domain, either in residues involved in direct DNA contact or those that regulate its conformation. In either case, such mutations have been shown to confer gain of function activity. This was first shown in soft agar assays in which over-expression of mutant p53 increased transformation of cells on a p53 null background. Furthermore, knock-in mouse models of mutant p53 showed alterations in tumor spectrum with the development of carcinomas not seen in p53 null mice. However, the mechanism by which mutant p53 actively aids in tumorigenesis remains unclear. Although mutant p53 causes loss of sequence specific DNA binding via the core domain, it retains the ability to interact with multiple proteins including transcriptional cofactors shown to have tumor suppressor activity such as p300 and CBP. These interactions occur through multiple protein binding domains including the C-terminal domain of p53. Our laboratory and others have shown that C-terminal truncation of wildtype p53 results in multiple deficiencies. Binding of mutant p53 to p300/CBP via the C-terminus is therefore an attractive hypothesis to explain mutant p53 gain of function. To determine the role of the C-terminus in mutant p53 gain of function activity, we have expressed constructs containing a C-terminal truncation in combination with varying hotspot mutations. Transfection of mutant p53 into a p53 null cell line was required for the formation of colonies in a soft agar assay, indicating an increase in tumorigenicity. Furthermore, C-terminal truncation of the mutant p53 abrogated this phenotype suggesting that this domain is required for mutant p53 gain of function. This was independent of expression levels as shown by immunoblot. We have also extended the findings of mutant p53 interaction with p300 by IP analysis of a panel of cell lines with varying p53 hotspot mutations. To confirm the role of the C-terminus in mutant p53 gain of function, we are developing a xenograft model to detect changes in tumorigenicity in vivo. These results will therefore explore the mechanism by which mutant p53 acts as an oncogene. Citation Format: Caleb C. Lee, James Manfredi. The C-terminal domain of tumor-derived mutant p53 is required for its oncogenic gain-of-function activity. [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 3688.
Abstract 10818: Lomitapide Observational Worldwide Evaluation Registry (LOWER): One-Year Data
Authors: Dirk Blom, John J Kastelein, Dominique Larrey, Lukas Makris, Charles Schwamlein, Helen Phillips, LeAnne Bloedon, James Underberg
Journal: Circulation (2015)

Introduction: Lomitapide is a microsomal triglyceride transfer protein inhibitor indicated as an adjunctive therapy for adults with homozygous familial hypercholesterolemia (HoFH). LOWER is a global, long-term, prospective, observational registry of the long-term safety and effectiveness of lomitapide in clinical practice. At least 300 adult HoFH patients will be followed for a minimum of 10 years. Enrollment opened in March 2014 for adult HoFH patients with less than 15 months of lomitapide exposure. We present data from the first year of the registry. Results: As of March 1, 2015, 84 patients with mean age 55.4 (SD 11.5) years, were enrolled in LOWER; 6 (7%) have since discontinued. Exposure duration was up to 26 months, with 60% of patients receiving the drug for ≥12 months. Lomitapide dose ranged from 5 to 40 mg; dose increased over time to a median of 13.0 mg (mean 14.4 mg) after 2 years’ exposure. Mean LDL-C at baseline was 216.3 (SD 76.9) mg/dL which decreased by 42% at Month 4 and was maintained throughout the reporting period. Fifty-one (61%) and 30 (36%) respectively achieved an LDL-C value &lt;100 mg/dL or &lt;70 mg/dL, at least once while receiving lomitapide. Events of special interest (ESI) include: 1 major adverse cardiovascular event (MACE) resulting in death; 11 hepatic events; and 6 gastrointestinal events. No tumors, pregnancies, or coagulopathy events were reported. Elevated aminotransferase levels ≥3x upper limit of normal (ULN) were observed in 16 patients (20%); 4 of these patients experienced elevations of ≥5x - &lt;10x ULN. No cases of Hy’s Law were recorded. Diarrhea was the most common adverse event (AE), experienced by 24% of patients, and the only AE reported by &gt;10% of patients. Serious AEs occurred in 6 (7%) patients. Eight (10%) patients discontinued lomitapide because of an AE. Conclusions: Data from the first year of the LOWER registry demonstrate both safety and efficacy that are consistent with the product labeling. There were no new safety signals. Discontinuations because of aminotransferase or gastrointestinal ESIs were low. Future data from LOWER will provide further information about the real-world, long-term safety and effectiveness of lomitapide in HoFH.
PARP Inhibitor Activity Correlates with <i>SLFN11</i> Expression and Demonstrates Synergy with Temozolomide in Small Cell Lung Cancer
Authors: Benjamin H. Lok, Eric E. Gardner, Valentina E. Schneeberger, Andy Ni, Patrice Desmeules, Natasha Rekhtman, Elisa de Stanchina, Beverly A. Teicher, Nadeem Riaz, Simon N. Powell, John T. Poirier, Charles M. Rudin
Journal: Clinical Cancer Research (2016)

PARP inhibitors (PARPi) are a novel class of small molecule therapeutics for small cell lung cancer (SCLC). Identification of predictors of response would advance our understanding, and guide clinical application, of this therapeutic strategy.Efficacy of PARP inhibitors olaparib, rucaparib, and veliparib, as well as etoposide and cisplatin in SCLC cell lines, and gene expression correlates, was analyzed using public datasets. HRD genomic scar scores were calculated from Affymetrix SNP 6.0 arrays. In vitro talazoparib efficacy was measured by cell viability assays. For functional studies, CRISPR/Cas9 and shRNA were used for genomic editing and transcript knockdown, respectively. Protein levels were assessed by immunoblotting and immunohistochemistry (IHC). Quantitative synergy of talazoparib and temozolomide was determined in vitro In vivo efficacy of talazoparib, temozolomide, and the combination was assessed in patient-derived xenograft (PDX) models.We identified SLFN11, but not HRD genomic scars, as a consistent correlate of response to all three PARPi assessed, with loss of SLFN11 conferring resistance to PARPi. We confirmed these findings in vivo across multiple PDX and defined IHC staining for SLFN11 as a predictor of talazoparib response. As temozolomide has activity in SCLC, we investigated combination therapy with talazoparib and found marked synergy in vitro and efficacy in vivo, which did not solely depend on SLFN11 or MGMT status.SLFN11 is a relevant predictive biomarker of sensitivity to PARP inhibitor monotherapy in SCLC and we identify combinatorial therapy with TMZ as a particularly promising therapeutic strategy that warrants further clinical investigation. Clin Cancer Res; 23(2); 523-35. ©2016 AACR.
Abstract 432: Loss of MGMT promoter methylation and resistance to cisplatin in non-seminomatous germ cell tumors
Authors: Cátia Moutinho, Xavier Garcia-del-Muro, Elisabet Guino, August Vidal, Sara Puertas, Clara Muñoz, Josep Piulats, Alberto Villanueva, Manel Esteller
Journal: Cancer Research (2016)

Abstract To explore if MGMT promoter methylation changes have a role in cisplatin chemoresistance, first we study its methylation status in cisplatin sensitive and resistant paired human non-seminomatous germ cancer cell lines. Secondly in xenograft paired tumors and after in human non-seminomatous germ cell primary tumors, from patients treated with cisplatin based chemotherapy. In general we found that cisplatin sensitive samples are related with MGMT promoter hypermethylation associated with its loss of expression. Resistance is present when MGMT promoter is not methylated and expressed. Clinically, the presence of MGMT promoter methylation is related with better overall survival (p = 0.025) in patients with testicular germ cell cancer. Inhibition of MGMT with O6-benzylguanine in vitro or in vivo increases the sensitivity to cisplatin and temozolomide, being this a possible chemotherapeutic approach to re-sensibilize human non-seminomatous germ cell refractory tumors. Citation Format: Cátia Moutinho, Xavier Garcia-del-Muro, Elisabet Guino, August Vidal, Sara Puertas, Clara Muñoz, Josep Piulats, Alberto Villanueva, Manel Esteller. Loss of MGMT promoter methylation and resistance to cisplatin in non-seminomatous germ cell tumors. [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 432.
Psychological factors are associated with the outcome of physiotherapy for people with shoulder pain: a multicentre longitudinal cohort study
Authors: Rachel Chester, Christina Jerosch-Herold, Jeremy Lewis, Lee Shepstone
Journal: British Journal of Sports Medicine (2016)

Background/aim Shoulder pain is a major musculoskeletal problem. We aimed to identify which baseline patient and clinical characteristics are associated with a better outcome, 6 weeks and 6 months after starting a course of physiotherapy for shoulder pain. Methods 1030 patients aged ≥18 years referred to physiotherapy for the management of musculoskeletal shoulder pain were recruited and provided baseline data. 840 (82%) provided outcome data at 6 weeks and 811 (79%) at 6 months. 71 putative prognostic factors were collected at baseline. Outcomes were the Shoulder Pain and Disability Index (SPADI) and Quick Disability of the Arm, Shoulder and Hand Questionnaire. Multivariable linear regression was used to analyse prognostic factors associated with outcome. Results Parameter estimates (β) are presented for the untransformed SPADI at 6 months, a negative value indicating less pain and disability. 4 factors were associated with better outcomes for both measures and time points: lower baseline disability (β=−0.32, 95% CI −0.23 to −0.40), patient expectation of ‘complete recovery’ compared to ‘slight improvement’ as ‘a result of physiotherapy’ (β=−12.43, 95% CI −8.20 to −16.67), higher pain self-efficacy (β=−0.36, 95% CI −0.50 to −0.22) and lower pain severity at rest (β=−1.89, 95% CI −1.26 to −2.51). Conclusions Psychological factors were consistently associated with patient-rated outcome, whereas clinical examination findings associated with a specific structural diagnosis were not. When assessing people with musculoskeletal shoulder pain and considering referral to physiotherapy services, psychosocial and medical information should be considered. Study registration Protocol published at http://www.biomedcentral.com/1471-2474/14/192 .
Individualized Pazopanib Dosing: A Prospective Feasibility Study in Cancer Patients
Authors: Remy B. Verheijen, Sander Bins, Ron H.J. Mathijssen, Martijn P. Lolkema, Leni van Doorn, Jan H.M. Schellens, Jos H. Beijnen, Marlies H.G. Langenberg, Alwin D.R. Huitema, Neeltje Steeghs
Journal: Clinical Cancer Research (2016)

Pazopanib is a tyrosine kinase inhibitor approved for the treatment of renal cell carcinoma and soft tissue sarcoma. Retrospective analyses have shown that an increased median progression-free survival and tumor shrinkage appear in patients with higher plasma trough levels (Cmin). Therefore, patients with low Cmin might benefit from pharmacokinetically guided individualized dosing.We conducted a prospective multicenter trial in 30 patients with advanced solid tumors. Pazopanib Cmin was measured weekly by LC-MS/MS. At weeks 3, 5, and 7, the pazopanib dose was increased if the measured Cmin was <20 mg/L and toxicity was <grade 3.In total, 17 patients had at least one Cmin <20 mg/L at weeks 3, 5, and 7. Of these, 10 were successfully treated with a pharmacokinetically guided dose escalation, leading to daily dosages ranging from 1,000 to 1,800 mg. Cmin in these patients increased significantly from 13.2 (38.0%) mg/L [mean (CV%)] to 22.9 mg/L (44.9%). Thirteen patients had all Cmin levels ≥20.0 mg/L. Of these, 9 patients with a high Cmin of 51.3 mg/L (45.1%) experienced ≥grade 3 toxicity and subsequently required a dose reduction to 600 or 400 mg daily, yet in these patients, Cmin remained above the threshold at 28.2 mg/L (25.3%).A pharmacokinetically guided individualized dosing algorithm was successfully applied and evaluated. The dosing algorithm led to patients being treated at dosages ranging from 400 to 1,800 mg daily. Further studies are needed to show a benefit of individualized dosing on clinical outcomes, such as progression-free survival. Clin Cancer Res; 22(23); 5738-46. ©2016 AACRSee related commentary by Ornstein and Rini, p. 5626.