tbuckley/cabot-search huggingface dataset:
ABT-888 (veliparib) in combination with weekly carboplatin and paclitaxel in advanced solid tumors.
Authors: Jorge Arturo Rios-Perez, Jan H. Beumer, Leonard Joseph Appleman, Hussein Abdul-Hassan Tawbi, Edward Chu, Ronald G. Stoller, Chandra Prakash Belani, Yixing Jiang, Robert W. Sobol, Stacie Peacock Shepherd, Vincent L. Giranda, Alice P. Chen, Shannon Leigh Huggins-Puhalla
Journal: Journal of Clinical Oncology (2012)

TPS1138 Background: The combination of paclitaxel and carboplatin is widely used for the treatment of patients with advanced solid tumors of diverse histologies. In breast cancer patients, a weekly regimen of paclitaxel has shown greater efficacy with comparable safety, when compared to every-three-weeks dosing (ECOG 1199). ABT-888 (veliparib) is an oral inhibitor of poly-ADP-ribose polymerase (PARP). Inhibition of PARP has been shown in preclinical studies to potentiate the effect of cytotoxic agents which induce DNA damage, such as platinum agents. The preclinical synergy of carboplatin with veliparib and the efficacy of the combination of paclitaxel with carboplatin supports exploration of this triplet regimen. Methods: This 3+3 phase I trial will seek to determine the maximum tolerated dose (MTD) of the combination of carboplatin (AUC 2), paclitaxel (80 mg/m 2 ), and veliparib in patients with advanced solid tumors. Veliparib will be escalated beginning at 50 mg PO BID to a maximum of 200mg PO BID. Treatment will be given on a weekly basis over a 21-day cycle. There will be an expansion cohort of 6-12 patients with triple negative breast cancer at the maximum tolerated dose. This group of patients will undergo mandatory pre- and post-cycle 1 tumor biopsies. Secondary aims of the study include safety and toxicity of the combination, its pharmacokinetic and pharmacodynamic effects, documentation of any anti-tumor response, and assessment of the characteristics of the tumor specimens obtained in the expansion cohort that may contribute to efficacy. The latter will include whole genome microarray analysis to evaluate expression of genes involved in DNA repair pathways. Currently, the recommended phase II dose has not been determined and enrollment is ongoing on the last planned dose level (veliparib 200 mg BID).
Comparing actionable results for breast and colorectal cancer patients across multigene panels.
Authors: Kelly Fulk, Carin Espenschied, Jessica Profato, Patrick Reineke, Holly LaDuca, Robina Smith
Journal: Journal of Clinical Oncology (2017)

e13109 Background: Many multigene panel (MGP) options are available for hereditary cancer testing. Previously, management guidelines were only published for a few high-risk genes, but now such guidelines exist for most genes on MGPs. Many clinicians question which MGP(s) may be most appropriate for their patients. We examined the likelihood of a positive result for patients diagnosed with breast cancer (BC) or colorectal cancer (CRC) across several MGPs and assessed the potential impact of these results on patient care. Methods: Positive results, defined by the presence of at least one pathogenic or likely pathogenic variant, were assessed for patients with BC or CRC across various MGPs ordered 6/2012-6/2016 at one commercial laboratory. For BC, the MGPs used for comparison were a high-risk BC panel (up to 6 genes), a comprehensive BC panel (up to 17 genes), and a multi-cancer panel (up to 32 genes). For CRC, a comprehensive CRC panel (up to 17 genes) was compared to the 32 gene multi-cancer panel. Results: For both BC and CRC patients, the utilization of a MGP with more genes led to more positive results than a MGP with fewer genes, with the vast majority of additional findings occurring in genes with published management guidelines (Table). Conclusions: The majority of positive results occurring in genes on larger MGPs, but not smaller MGPs, are in genes with published management guidelines.These results can impact treatment decisions and cancer risk management, including earlier and/or more frequent screening, chemoprevention, and/or other measures. In some cases, positive results occurred in genes not associated with the patient’s cancer diagnosis, but may still impact risk management for other cancer(s). Further studies are needed to determine the impact of larger MGPs on clinical outcomes for patients and their families. [Table: see text]
Relationship between serum HBV-RNA levels and intrahepatic viral as well as histologic activity markers in entecavir-treated patients
Authors: Jing Wang, Yiqi Yu, Guojun Li, Chuan Shen, Zhefeng Meng, Jianming Zheng, Yanhong Jia, Shaolong Chen, Xiao Zhang, Mengqi Zhu, Jiangjiang Zheng, Zhangzhang Song, Jing Wu, Lingyun Shao, Peiyu Qian, Xiaona Mao, Xuanyi Wang, Yuxian Huang, Caiyan Zhao, Jiming Zhang, Chao Qiu, Wenhong Zhang
Journal: Journal of Hepatology (2017)
Macrophage inhibitory cytokine 1 plasma levels in testicular cancer patients during cisplatin combination treatment and their relation to endothelial damage.
Authors: Renske Altena, Rudolf S. N. Fehrmann, Hink Boer, Elisabeth G. E. de Vries, Coby Meijer, Jourik A. Gietema
Journal: Journal of Clinical Oncology (2012)

e15035 Background: Chemotherapy- (CTx) related endothelial damage contributes to cardiovascular morbidity in testicular cancer (TC) patients (pts). We used an unbiased translational approach to identify mechanisms of and potential biomarkers for this damage. Methods: During varying time periods human microvascular endothelial cells (HMEC-1) were in vitro exposed to bleomycin, cisplatin or left untreated. From 18k cDNA microarray expression signals were obtained, and quantified with an Affymetrix GMS428 scanner. Differences were analysed at single gene and pathway level, and validated by qRT-PCR. With ELISA, protein levels of 1 candidate biomarker were measured in TC pt plasma before, during and 1 month after bleomycin etoposide cisplatin CTx. Levels were related to endothelial damage plasma markers (von Willebrand Factor [vWF], high-sensitivity C-Reactive Protein [hs-CRP]). Results: Microarray data from 16k genes identified several genes with highly differential expression; Macrophage Inhibitory Cytokine 1(MIC-1), Activating Transcription Factor 3 (ATF3) and Amphiregulin (AREG) had strong differences in &gt;1 experimental setting. We regarded these plausible candidates, and confirmed changes by qRT-PCR. Pathway analysis showed a strong association with ‘P53’ and ‘Diabetes Mellitus’ gene sets. Based on known function, we chose to validate MIC-1 protein levels in 41 TC pts. Pre-CTx MIC-1 levels did not differ from healthy controls (TC pts median 383 pg/mL [range 187-1935] vs 340 pg/mL [range 213-504], p=0.06). During CTx levels of MIC-1, vWF and hsCRP significantly increased. MIC-1 levels correlated with vWF and hsCRP at baseline (vWF r s = 0.35, P=0.03; hsCRP r s = 0.39, P=0.01), during (hsCRP at cycle 1d 8 r s = 0.44, P=0.01; vWF at cycle 3 d8 r s = 0.40, P=0.02) and after CTx (vWF r s = 0.56; P&lt;0.01). Conclusions: An unbiased approach in a preclinical model revealed a set of genes related to bleomycin- and cisplatin-induced endothelial activation, such as MIC-1. The increases in plasma levels and the association with vWF and hsCRP suggest that MIC-1 may be a biomarker for CTx-related endothelial damage. Supported by Dutch Cancer Society grant 2009-4365.
In cases of serious injury “scoop and run” improves survival compared with ambulance
Authors: Zosia Kmietowicz
Journal: BMJ (2017)

Researchers have discovered what gang members have known all along—that you’re more likely to survive a serious injury if you get yourself to hospital than if you wait for an ambulance.1

“Scoop and run” describes the most basic form of prehospital trauma care—transportation with no intervention. A study from 2014 found that patients who used private transportation had improved survival compared with those who waited for an ambulance. But researchers from John Hopkins University School of Medicine …
Phase 1 trial of CA-170, a novel oral small molecule dual inhibitor of immune checkpoints PD-1 and VISTA, in patients (pts) with advanced solid tumor or lymphomas.
Authors: James J. Lee, John D. Powderly, Manish R. Patel, Joshua Brody, Erika Paige Hamilton, Jeffrey R. Infante, Gerald Steven Falchook, HongWei Wang, Lisa Adams, Lucy Gong, Anna W Ma, Timothy Wyant, Adam Lazorchak, Shefali Agarwal, David P. Tuck, Adil Daud
Journal: Journal of Clinical Oncology (2017)

TPS3099 Background: Programmed-death 1 (PD-1) and V-domain Ig suppressor of T-cell activation (VISTA) are independent immune checkpoints that negatively regulate T-cell function and are implicated in various malignancies. Preclinical studies have demonstrated that dual blockade of these pathways is synergistic. CA-170 is a first-in-class oral small molecule that directly targets both PD-1/PD-L1 and VISTA pathways and has shown anti-tumor activity in multiple preclinical models. Methods: The dose escalation phase has a target enrollment of 50 pts with advanced solid tumors or lymphomas onto escalating doses; the first four single-pt cohorts are accelerated titration but then switch to 3+3 design. The dose expansion phase has a target enrollment of 250 pts with select tumor types known to be responsive to anti-PD-1/L1 inhibitors and/or known to express PD-L1 or VISTA. Key eligibility criteria include: age ≥ 18 years, ECOG ≤1, adequate organ function, and ineligible for/did not respond to standard therapy including anti-PD-1/L1 inhibitors, where available. Primary objectives of this first-in-human study: safety, maximum tolerated dose, and recommended phase 2 dose. Secondary objectives: pharmacokinetics (PK) and anti-tumor activity. Exploratory endpoints: biomarkers and pharmacodynamic (PD) effects, which include changes in immune cell and peripheral cytokine populations in tumor (IHC/mRNA) and blood (flow cytometry/mRNA). Oral CA-170 is administered once daily in 21-day cycles. Response will be evaluated every other cycle per RECIST (v1.1) and Immune-related Response Criteria or by Cheson criteria (2007). Patients who discontinue treatment for reasons other than progressive disease will be followed for progression-free survival. Serial plasma, blood, and tumor samples will be collected for PK and PD evaluation. Clinical trial identifier: Clinical trial information: NCT02812875.
Challenges to Biosimilar Substitution—Reply
Authors: Aaron Hakim, Joseph S. Ross
Journal: JAMA (2017)

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Nasal protein profiles in work‐related asthma caused by different exposures
Authors: H. Suojalehto, I. Lindström, H. Wolff, A. Puustinen
Journal: Allergy (2017)

Abstract Background The mechanisms of work‐related asthma (WRA) are incompletely delineated. Nasal cell samples may be informative about processes in the lower airways. Our aim was to determine the nasal protein expression profiles of WRA caused by different kind of exposures. Methods We collected nasal brush samples from 82 nonsmoking participants, including healthy controls and WRA patients exposed to (i) protein allergens, (ii) isocyanates and (iii) welding fumes the day after relevant exposure. The proteome changes in samples were analysed by two‐dimensional difference gel electrophoresis, and the differentially regulated proteins found were identified by mass spectrometry. Immunological comparison was carried out using Western blot. Results We detected an average of 2500 spots per protein gel. Altogether, 228 protein spots were chosen for identification, yielding 77 different proteins. Compared to the controls, exposure to protein allergens had the largest effects on the proteome. Hierarchical clustering revealed that protein allergen‐ and isocyanate‐related asthma had similar profiles, whereas asthma related to welding fumes differed. The highly overrepresented functional categories in the asthma groups were defence response, protease inhibitor activity, inflammatory and calcium signalling, complement activation and cellular response to oxidative stress. Immunological analysis confirmed the found abundance differences in galectin 10 and protein S100‐A9 between the groups. Conclusions Work‐related asthma patients exposed to protein allergens and isocyanates elicit similar nasal proteome responses and the profiles of welders and healthy controls were alike. Revealed biological activities of the protein expression changes are associated with allergic inflammation and asthma.
What are NCI-designated cancer centers using for gastric and esophageal cancer HER2 testing?
Authors: Julia R. Trosman, Christine B. Weldon, Gregory J. Tsongalis, Julian C. Schink, Al Bowen Benson
Journal: Journal of Clinical Oncology (2013)

e15010 Background: HER2 testing in gastric and esophageal cancers (GEC) is a new area with evolving research on which testing methods are best. Based on the ToGA trial, guidelines recommend IHC/reflex to FISH, but studies show effectiveness of other protocols as well (e.g. Yan et al, J Clin Pathol 2011). Our study provides a benchmark on practices for GEC HER2 testing at NCI Cancer Centers. Methods: We conducted an IRB approved web survey of 58 NCI cancer centers (pathologists and oncologists) providing adult GEC care. The survey included 14 questions on HER2 testing methods, reflex and retest practices and awareness of institutional lab accreditation. Results: The study achieved a response rate of 93% (54/58 sites). In this cohort, 41% (22/54) of sites conduct HER2 GEC tests using concurrent FISH and IHC methods. An IHC testing method with reflex to FISH is used at 39% (21/54) of sites, of which all 21 sites reflex IHC 2+ results, and 9 of 21 automatically reflex IHC beyond 2+ (see table, results are not mutually exclusive). FISH only testing is done at 15% (8/54); concurrent FISH and CISH testing at 2% (1/54); concurrent SISH and IHC testing at 2% (1/54), and SISH only testing at 2% (1/54) of sites. The survey separately asked about HER2 testing methods for breast cancer (BC), which were compared by site to GEC HER2 practices: 65% (35/54) of sites conduct HER2 testing in a similar manner - analogous methods in similar order (p= 0.0471); 19% (10/54) of sites use primary IHC in GEC but primary FISH in BC, and 17% (9/54) of sites conduct primary or concurrent FISH testing in GEC but primary IHC in BC. Lab CAP certification for their sites was known by 89% (56/63) of GEC pathologists vs 34% (19/56) of GEC oncologists (p &lt; .0001). 67% (42/63) of GEC pathologists were aware of whether their lab underwent a HER2 IHC and/or FISH proficiency test, vs 4% (2/56) of GEC oncologists (p&lt;.0001). Conclusions: For gastric and esophageal HER2 testing, concurrent FISH and IHC and expanded reflex testing, beyond IHC 2+ results, are the common practice at the NCI cancer centers. [Table: see text]
UK government to reclassify pregabalin and gabapentin after rise in deaths
Authors: Gareth Iacobucci
Journal: BMJ (2017)

The UK government is to reclassify the prescription drug pregabalin as a class C controlled substance, after experts issued safety warnings following an increase in deaths linked to its use.

A Home Office consultation, which also proposes reclassifying gabapentin, has been launched in response to growing pressure for the drug to be reclassified to tackle misuse and addiction.

Last year the Advisory Council on the Misuse of …
Association of Paravalvular Regurgitation With 1-Year Outcomes After Transcatheter Aortic Valve Replacement With the SAPIEN 3 Valve
Authors: Philippe Pibarot, Rebecca T. Hahn, Neil J. Weissman, Marie Arsenault, Jonathan Beaudoin, Mathieu Bernier, Abdellaziz Dahou, Omar K. Khalique, Federico M. Asch, Oumhani Toubal, Jonathon Leipsic, Philipp Blanke, Feifan Zhang, Rupa Parvataneni, Maria Alu, Howard Herrmann, Raj Makkar, Michael Mack, Richard Smalling, Martin Leon, Vinod H. Thourani, Susheel Kodali
Journal: JAMA Cardiology (2017)

Moderate/severe and even mild paravalvular regurgitation (PVR) are associated with increased mortality following transcatheter aortic valve replacement (TAVR) with first and second generations of transcatheter valves.To examine the incidence, evolution, and effect on 1-year outcomes of PVR following TAVR with a third-generation balloon-expandable transcatheter heart valve.Prespecified analysis of PVR in the Placement of Aortic Transcatheter Valves (PARTNER) II SAPIEN 3 trial, conducted between October 1, 2013, and September 3, 2014. Multicenter, nonrandomized registry of 1661 patients at intermediate or high surgical risk undergoing TAVR with the SAPIEN 3. Patients with severe, symptomatic aortic stenosis and high/intermediate surgical risk were enrolled in the registry at 51 sites in the United States and Canada.Transcatheter aortic valve replacement with the SAPIEN 3 valve.Paravalvular regurgitation was assessed in a core laboratory at 30 days and 1 year according to a 5-class scheme: 0, none or trace; 1, mild; 2, mild to moderate; 3, moderate; 4, moderate to severe; and 5, severe. We assessed the effect of PVR on 1-year mortality and heart failure rehospitalization.Among the 1661 included in the registry, 1592 received a SAPIEN 3 valve and had assessment of PVR. Of these patients, 55.7% had none-trace PVR, 32.6% had mild, 8.2% had mild to moderate, and 3.5% had at least moderate PVR at 30 days. At 1 year, 9.3% of patients had died and 14.2% had been rehospitalized. Only patients with at least moderate PVR had higher 1-year mortality (hazard ratio [HR], 2.40; 95% CI, 1.30-4.43; P = .005) and composite of mortality/rehospitalization (HR, 2.35; 95% CI, 1.52-3.62; P < .001). In a paired comparison including 1213 patients, 73% of the patients with at least moderate PVR at 30 days showed a reduction in PVR severity of at least 1 PVR class at 1 year.In this series of patients undergoing TAVR with the SAPIEN 3 valve, at least moderate PVR was rare but associated with increased risk of death and heart failure rehospitalization at 1 year. Even the upper range of the mild class in the 3-class grading scheme (ie, mild to moderate in the 5-class scheme) had no significant effect on short-term mortality or rehospitalization. Most patients with at least moderate PVR at 30 days showed a decrease of PVR severity grade at 1 year.clinicaltrials.gov Identifier: NCT01314313.
FOXO1: Another avenue for treating digestive malignancy?
Authors: Feiyu Shi, Tian Li, Zhi Liu, Kai Qu, Chengxin Shi, Yaguang Li, Qian Qin, Liang Cheng, Xin Jin, Tianyu Yu, Wencheng Di, Jianwen Que, Hongping Xia, Junjun She
Journal: Seminars in Cancer Biology (2017)

Digestive malignancies are the leading cause of mortality among all neoplasms, contributing to estimated 3 million deaths in 2012 worldwide. The mortality rate hassurpassed lung cancer and prostate cancer in recent years. The transcription factor Forkhead Box O1 (FOXO1) is a key member of Forkhead Box family, regulating diverse cellular functions during tumor initiation, progression and metastasis. In this review, we focus on recent studies investigating the antineoplastic role of FOXO1 in digestive malignancy. This review aims to serve as a guide for further research and implicate FOXO1 as a potent therapeutic target in digestive malignancy.
Large germline next generation (NGS) sequencing panel of uterine serous carcinoma.
Authors: Ignacio Romero, Zaida Garcia-Casado, Raquel Lopez-Reig, Antonio Fernandez-Serra, Carmen Illueca, Andres Poveda, Jose Antonio Lopez-Guerrero
Journal: Journal of Clinical Oncology (2017)

e13106 Background: Genetic predisposition to uterine serous carcinoma (USC) remains unclear and has been related to Lynch Syndrome (LS) and BRCA1/2 mutations. Wide NGS panels for this condition are starting to be implemented and data remain scarce. Methods: Consecutive USC were identified from a prospective endometrial cancer database (ECD) in a single institution. Clinical information including stage, follow-up, a three-generation pedigree, Microsatellite Instability (MSI) with 8 markers and the Mismatch Repair Protein (MMRPro) staining status, was retrieved from the ECD. Germline genetic testing was performed using a commercially available NGS panel including 80 familial cancer genes (Onco-GeneSGKit) on a MiSeq sequencer. Pathogenic or likely pathogenic variants were confirmed by Sanger sequencing. Results: Twenty-one women out of a total of 150 (14%) cases contained in the ECD were diagnosed with a USC. Median age was 65 (40-84 yo), median Body Mass Index of 26 (19-40), and histologically 18 were defined as pure and 3 as mixed USC. FIGO 2009 stages were I/II and III/IV in 42% and 58% of cases respectively. Adjuvant Chemotherapy (CT) was administered to 76%. MSI-High and MMRPro loss was described in 5%, 19% fulfilled Bethesda criteria, 23% had previous breast cancer and 5% personal Lynch related cancer history, 28% presented with pathological features of Lynch Syndrome such as dedifferentiation, Tumor Infiltrating Lymphocytes (14%), peritumoral lymphocytes or lower uterine location (14%). A median of 5 [range: 2-8] genetic alterations (pathogenic, variants of uncertain significance (VUS) and not described) per patient were observed, including 3 (14.3%) pathogenic mutations, 18 VUS and 43 not described. Among the three pathogenic mutations one was in MSH6 (p.Glu255Ter), another one in DKC1 (p.S280A) and the last one in the recessive gene MUTYH (p.Glu466del). VUS were detected in 57% of cases among 12 different genes: ATM (n = 3), AXIN2 (n = 2), BARD1 (N = 2), RAD50 (n = 2), RET (n = 2) and one case each of BMPR1A, BRIP1, CHEK2, MLH1, MSH6, SLX4 and TSC2. Conclusions: In our series 14% of USC harbored mutations in cancer predisposition genes.VUS are as high as 57% and represent a clinical challenge.
Multiplexed Nucleic Acid Programmable Protein Arrays
Authors: Xiaobo Yu, Lusheng Song, Brianne Petritis, Xiaofang Bian, Haoyu Wang, Jennifer Viloria, Jin Park, Hoang Bui, Han Li, Jie Wang, Lei Liu, Liuhui Yang, Hu Duan, David N McMurray, Jacqueline M Achkar, Mitch Magee, Ji Qiu, Joshua LaBaer
Journal: Theranostics (2017)

Cell-free protein microarrays display naturally-folded proteins based on just-in-time