tbuckley/cabot-search huggingface dataset:
Treatment-free interval (TFI) after first-line therapy as a prognostic and predictive factor in malignant pleural mesothelioma (MPM): Findings from the NGR015 phase III trial with NGR-hTNF plus best investigator choice (BIC) versus placebo plus BIC.
Authors: Vanesa Gregorc, Domenico Ghio, Claudio Sallemi, Alessandra Bulotta, Gilda Rossoni, Maria G Viganò, Floriana Fontana, Gloria Rossoni, Scialini Colombi, Antonio Lambiase, Claudio Bordignon
Journal: Journal of Clinical Oncology (2015)

7557 Background: Historically, the TFI (time from end of first-line to start of second-line therapy) has been reported as a prognostic factor and predictive marker of benefit of next treatment line across various tumors. Prognostic and predictive TFI values were assessed on MPM patients failing a front-line pemetrexed-based regimen and randomly assigned to receive NGR-hTNF 0.8 μg/m2 (n = 200) or placebo (n = 200) both given with BIC (gemcitabine, vinorelbine, doxorubicin or supportive care). Methods: The prognostic value of TFI, treated as continuous variable or split at sample median (4.8 months; 95% CI 4.2-5.1), was tested exclusively in the NGR015 placebo arm. Multivariate Cox models for OS and PFS were adjusted for age, sex, PS, histology, EORTC score, prior disease control and neutrophil to lymphocyte ratio. To assess whether TFI was predictive of benefit with NGR-hTNF, treatment-by-covariate interaction tests were applied on the whole dataset. Results: Continuous TFI data were independently related to OS (p = .005). Compared with patients with long TFI ( ≥ median, n = 201), those with short TFI ( < median, n = 198) had a significantly worse OS (median, 6.3 vs 11.7 months; HR = 1.81; p < .0001). Poor prognostic effects of short TFI were confirmed in multivariate models (HR = 1.98; p < .0001) and persisted after stratifying for chemotherapy agent (HR = 1.96; p < .0001). Similar results were shown for PFS. A significant interaction test was reported only between treatment group and TFI for OS (p = .008) and, consistently, for PFS (p = .009). In patients with short TFI, NGR-hTNF plus BIC vs placebo plus BIC significantly improved OS (median, 9.0 vs 6.3 months; HR = 0.69; p = .02) and PFS (6-month rate, 25% vs 12%; HR = 0.71; p = .03). In sensitivity analyses, similar differences in outcome were detected by moving the TFI cutpoint from the median to a more practical 6-month threshold (OS HR = 0.74; p = .04). Conclusions: A short TFI is an independent poor prognostic factor and predictive clinical marker of benefit with NGR-hTNF in MPM patients with rapidly progressing disease after first-line therapy. Clinical trial information: NCT01098266.
LBP-33-Gelesis superabsorbent hydrogel prevents hepatic steatosis in a high fat diet-induced NAFLD pre-clinical model
Authors: Alessandra Silvestri, Alessandro Sannino, Milena Vitale, Juliette Mouriès, Ilaria Spadoni, Christian Demitri, Elaine Chiquette, Maria Rescigno
Journal: Journal of Hepatology (2019)
Results of vincristine, cyclophosphamide, and topotecan protocol in refractory/relapsed pediatric solid tumors: A single-center experience.
Authors: Ugur Demirsoy, Funda Corapcioglu, Meriban Karadogan, Asiye Gungormus, Umay Ozod
Journal: Journal of Clinical Oncology (2015)

e21019 Background: Despite the dramatic progress on treatment of pediatric solid tumors in the last 3 decades, confronting a relapsed or refractory patient is still challenging. We report our experience of refractory/relapsed pediatric solid tumor patients treated with vincristin + topotecan + cyclophosphamide (VTC) as salvage therapy. Methods: Eleven refractory/relapsed patients (5 neuroblastoma, 4 Ewing’s sarcoma, 1 rhabdomyosarcoma and 1 osteosarcoma) who were given VTC as a salvage therapy were evaluated. Median age at diagnosis was 12 years. They, all, were metastatic at diagnosis and received appropriate initial chemotherapy. VTC consisted of vincristin (1.5 mg/m2 on day 1), CYC (600 mg/m2/day with mesna, on days 1 and 2) and TOPO (1 mg/m2/day on days 1, 2 and 3). Eleven patients received a total of 53 courses of VTC with a median of 4 (range 2-14). Results: One patient achieved CR, 6 patients had SD, and 4 patients had PD after 2 courses of VTC (Table). Median survival duration is 28 months after diagnosis while it is 16 months after relapse. Median survival duration after first VTC is 5 months (2-21 mon). Myelosuppression was the primary dose limiting toxicity. Conclusions: We concluded VTC to have a clinically tolerable but non-satisfactory effect on relapsed/refractory solid tumors in children. # Number of VTC cycles Response after 2nd VTC Response after 4th VTC Response after 6th-10th VTC Follow-up time after first VTC Overall follow-up time after diagnosis Last status of patient #1 14 CR2 CR2 CR2 12mon 29 mon Alive #2 4 SD PD N/A 5 mon 38 mon DOD #3 8 SD SD PD 9 mon 66 mon DOD #4 2 PD N/A N/A 2 mon 10 mon DOD #5 2 PD N/A N/A 2 mon 10.5 mon DOD #6 2 PD N/A N/A 4 mon 13.5 mon DOD #7 2 PD N/A N/A 3 mon 20 mon DOD #8 4 SD PD N/A 14mon 26 mon DOD #9 4 SD PD N/A 3 mon 67 mon DOD #10 6 SD SD PD 11 mon 28 mon DOD #11 5 SD PD N/A 21mon 36 mon DOD
SAT-476-Discordance between clinical judgement and genetic differentiation of intrahepatic metastasis and multicentric occurrence in multinodular HCC
Authors: Yuji Iimuro, Atsushi Takano, Kenji Amemiya, Yosuke Hirotsu, Hitoshi Mochizuki, Toshio Oyama, Masao Omata
Journal: Journal of Hepatology (2019)
A phase II study of [fam-] trastuzumab deruxtecan (DS-8201a) in HER2-overexpressing or -mutated advanced non-small cell lung cancer
Authors: D. Planchard, B.T. Li, H. Murakami, R. Shiga, C.C. Lee, K. Wang, P.A. Jänne
Journal: Annals of Oncology (2019)

Background: Approximately 30% of non-small-cell lung cancers (NSCLC) are human epidermal growth factor receptor 2 (HER2)-overexpressing (immunohistochemistry [IHC] 2+ or 3+) and approximately 2% have HER2-activating mutations. However, no HER2-targeted therapies are approved for the treatment of NSCLC. [Fam-] trastuzumab deruxtecan (DS-8201a) is a novel HER2-targeted antibody-drug conjugate with a humanized HER2 antibody, a topoisomerase I inhibitor payload, cleavable peptide-based linker, and a high drug-to-antibody ratio of 7 to 8. In an ongoing phase 1 trial, [fam-] trastuzumab deruxtecan (6.4 mg/kg) had a confirmed objective response rate (ORR) of 58.8% (10/17) in HER2-expressing or -mutated NSCLC and 72.7% (8/11) in HER2-mutated NSCLC, with a manageable safety profile (Tsurutani et al, WCLC 2018). Trial design: This multicenter, open-label, 2-cohort, phase 2 study will assess the efficacy and safety of [fam-] trastuzumab deruxtecan (6.4 mg/kg once every 3 weeks) in HER2-overexpressing or -mutated unresectable and/or metastatic nonsquamous NSCLC that is relapsed/refractory to standard treatment or for which no standard treatment is available (NCT03505710). Approximately 80 subjects will be enrolled; 40 in each of 2 cohorts (cohort 1: HER2-overexpressing [IHC 3+ or IHC 2+]; cohort 2: HER2-mutated including exon 20 insertions and single-nucleotide variants in kinase, transmembrane, and extracellular domains [eg, L755S, V659E, S310F]). To be eligible for cohort 1, HER2-overexpression must be assessed and confirmed by central testing based on archival samples. To be eligible for cohort 2, any HER2-activating mutation must be documented based on archival tumor samples. Study treatment will be continued until progressive disease or unacceptable toxicity. The primary endpoint is ORR based on RECIST version 1.1 by an independent radiologic facility. Secondary efficacy endpoints include progression-free survival, duration of response, disease control rate, and overall survival. Safety assessments include serious and treatment-emergent adverse events. The study will enroll subjects in North America, Europe, and Japan. Recruitment began in May, 2018. Clinical trial identification: NCT03505710. Editorial acknowledgement: Editorial assistance was provided by Stefan Kolata, PhD, of AlphaBioCom, LLC. Legal entity responsible for the study: Daiichi Sankyo, Inc. Funding: Daiichi Sankyo, Inc. Disclosure: D. Planchard: Member on the speakers program, Advisory board: AstraZeneca, Boehringer Ingelheim, BMS, Merck, Celgene, Novartis, Pfizer, Roche. R. Shiga, C.C. Lee, K. Wang: Full-time employee: Daiichi Sankyo. P.A. Jänne: Consulting fees, research funding: Acea, Astellas, AstraZeneca, Araxes, ARIAD, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Eli Lilly, Ignyta, Loxo, Merrimack, Pfizer, PUMA, Genentech; Stock: Gatekeeper; Royalties: LabCorp. All other authors have declared no conflicts of interest.
Pyruvate-Carboxylase-Mediated Anaplerosis Promotes Antioxidant Capacity by Sustaining TCA Cycle and Redox Metabolism in Liver
Authors: David A. Cappel, Stanisław Deja, João A.G. Duarte, Blanka Kucejova, Melissa Iñigo, Justin A. Fletcher, Xiaorong Fu, Eric D. Berglund, Tiemin Liu, Joel K. Elmquist, Suntrea Hammer, Prashant Mishra, Jeffrey D. Browning, Shawn C. Burgess
Journal: Cell Metabolism (2019)
Dynamic changes of patelet-to-lymphocyte ratio predict efficacy of PD-1/PD-L1 inhibitors in NSCLC
Authors: F. Zhou, A. Xiong, C. Zhou
Journal: Annals of Oncology (2019)

Background: Baseline neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are markers of host inflammation and have been reported as prognostic factors in advanced cancer patients, but have not been analyzed extensively in lung cancer in the era of immunotherapy, especially the dynamic changes of these markers. Methods: Patients who were treated with immune checkpoint inhibitors (ICIs) either as a standard of care or on a clinical trial at Shanghai Pulmonary Hospital were enrolled. Baseline complete blood count [defined as the results obtained at the time (−3/0 days) of initiating ICIs, including white blood cell (WBC), absolute neutrophil count (ANC), platelet count and absolute lymphocyte count (ALC) to calculate the NLR and PLR] were extracted from medical records. Derived NLR (dNLR) was calculated as dNLR = ANC/(WBC−ALC). C3 complete blood count (defined as the results obtained before Cycle 3 of ICIs) was also collected and calculated. Results: Ninety-five patients were identified in the present study. 49 (51.6%) of patients received ICI monotherapy, and 46 (48.4%) received ICI-based combination therapy. Baseline NLR, dNLR, PLR were not associated with clinical outcomes of ICI therapy (ORR or PFS). Using 5 as a C3 NLR cut-off value, patients with C3 NLR <5 had better ORR and PFS than those with C3 NLR ≥5. Furthermore, patients who had increased NLR (n = 29) had inferior ORR (17.2% versus 41.0%, p = 0.026) and median PFS (5.5 versus 8.5 months, p = 0.022) than those who had decreased NLR (n = 61). Patients with C3 dNLR <3 had better ORR and median PFS than those with C3 dNLR ≥3. Patients who had increased dNLR (n = 26) had lower ORR (15.4% versus 40.3%, p = 0.027) and inferior median PFS (5.6 versus 8.4 months, p = 0.150) than those who had decreased dNLR. There was a trend towards better ORR and median PFS in patients lower C3 PLR. Interestingly, patients who had decreased PLR (n = 47) had better ORR (42.6% versus 23.3%, p = 0.052) and median PFS (11.8 versus 5.5 months, p = 0.003) than those who had increased PLR (n = 43). Multivariate analysis revealed dynamic changes of PLR as an independent predictive factor for PFS (HR: 2.27, 95% CI, 1.10-4.71, p = 0.027). Conclusions: Dynamic change of PLR has a potentially predictive role of the efficacy of ICI therapy. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
The acceleration of adoption of tumor profiling into routine clinical practice: An insight from review of the literature and the case for comprehensive profiling.
Authors: Rosa Conforti, Kenneth Russel, Olivier Lefevre, Andreas Voss, David Khayat
Journal: Journal of Clinical Oncology (2015)

e22224 Background: Personalized medicine aimed at finding the right drug for the right patient has been greatly facilitated by the growing availability of molecular tests to profile patients’ tumors. We searched for case reports illustrating where a treatment was selected on the basis of molecular findings to successfully treat patients with rare or refractory cancer. Methods: In December 2014, we conducted a comprehensive search of the major databases of all publications using a broad selection of keywords to identify case reports and case series where tumor profiling was used to direct treatment. Results: We identified 173 published manuscripts or posters describing 185 cases across all tumor types that detailed successful use of molecular profiling. These cases demonstrated the use of profiling to identify patients more likely to respond to a drug, or to find an explanation for resistance to a drug, which may help in the avoidance of such treatments for other patients. In the past 5 years, the number of published cases has risen over 600%, increasing from 10 in 2009 to 63 in 2014. Over the past year, next-generation sequencing (NGS) has been used in 54% of cases published, in situ hybridization (ISH) in 17%, and immunohistochemistry (IHC) in 29% of published reports. Conclusions: IHC and ISH testing are well established and retain critical value in helping cancer patients without definitive treatment options. The results of the review show that the adoption of tumor profiling in routine clinical practice is accelerating as it becomes more widely available and provide evidence of utility across a spectrum of cancers.
Abstract 16954: SCARB1 Gene Variants are Associated With the New Lipid Phenotype of Combined High HDL-C and Lp(a)
Authors: Xiaoping Yang, Amar Sethi, Lisa R Yanek, Rasika A Mathias, Borge G Nordestgaard, Anne Tybjaerg-Hansen, Becker M Diane, Alan T Remaley, Lewis Becker
Journal: Circulation (2015)

Introduction: Although lipoprotein(a) (Lp(a)) is atherogenic, little is known about how it is transported from the plasma. Scavenger receptor class B type 1 (SR-B1), encoded by the gene SCARB1, binds high density lipoproteins (HDL). Recently we found that SR-B1 is also a receptor for Lp(a), mediates cellular uptake of Lp(a) in vitro, and promotes clearance of Lp(a) in vivo in mice. Genetic variants in SCARB1 have been associated with HDL level in humans, but no SCARB1 variants affecting Lp(a) have been reported. We hypothesized that loss of function mutations in SCARB1 would be associated with a phenotype of combined high HDL-C and Lp(a). Methods and Results: An index subject was identified in the NIH Lipid Clinic with high levels of both HDL-C and Lp(a). SCARB1 was sequenced and demonstrated a missense mutation at c.386 resulting in an S129L substitution in exon 3. To follow up on this finding, two cohorts of subjects (n=543 in the Genetic Study of Atherosclerosis Risk (GeneSTAR) and n=5907 in the Copenhagen City Heart Study) were screened for combined elevations of HDL-C and Lp(a). Subjects having HDL &gt;80 mg/dl and Lp(a) &gt;100 nmol/L in GeneSTAR, n=8, and &gt;100 mg/dl in CCHS, n=9, underwent sequencing of all SCARB1 exons and splice junctions; 15 from the combined population of 18 were found to have variants predicted or demonstrated to have reduced function of the translated protein. Functional studies showed that 4 of the SCARB1 variants (c.386C&gt;T; c.631-14T&gt;G, c.4G&gt;A and c.631-53mC&gt;T &amp; c.726+55mCG&gt;CA, all heterozygous) had decreased receptor function in vitro, and the latter two were novel and not previously reported. Six of the subjects were homozygous for a common synonymous SCARB1 polymorphism (c.1050C&gt;T) which has been reported to be associated with reduced protein expression. Conclusion: Human SCARB1 gene variants are associated with a new lipid phenotype, characterized by increases in both HDL-C and Lp(a). We demonstrate that SCARB1 exonic variants often result in diminished function of the translated SR-B1 lipid receptor with reduced binding/intracellular transport of Lp(a).
Breast cancer subtypes and the risk of distant relapse after breast conserving surgery or mastectomy: An Anatolian Society of Medical Oncology study.
Authors: Muhammet Ali Kaplan, Zuhat Urakci, Dogan Uncu, Faysal Dane, Metin Ozkan, Tulay Akman, Hakan Harputluoglu, Berna Oksuzoglu, Mehmet Kucukoner, Nuriye Ozdemir, İbrahim Vedat Bayoglu, Yusuf Gunaydin, Meltem Baykara, Dogan Yazilitas, Erdem Cubukcu, Ali Suner, Mehmet Bilici, Abdurrahman Isikdogan
Journal: Journal of Clinical Oncology (2015)

e12052 Background: Previous important studies reported that breast conserving surgery (BCS) plus radiotherapy and modified radical mastectomy (MRM) were similar in breast cancer patients with tumors 5 cm or smaller and axillary node negative or positive disease. In these studies, distant metastases were higher (≈% 4-5) in the BCS group than MRM group, but not statistically significant. These studies did not have information about biological subtype. The aim of the study was to investigate the effect of the surgical method on distant metastases free survival (DMFS) in terms of biological subtype. Methods: We retrospectively evaluated clinical data from 2094 early breast cancer patients who performed curative surgery (BCS, n = 471 or MRM, n = 1623) with tumors 5 cm or smaller and axillary node negative or positive disease, and adequate knowledge about ER, PR and HER2 status, between 2000 to 2014 from referral centers of Turkey. Patients with clinically node 2 or 3 disease, ≥ 5 cm tumor, relapsed with localized disease, or treated with neoadjuvant chemotherapy were excluded from study. The primary endpoint was time to distant metastasis according to biological subtypes (triple negative, n = 362 or non-triple negative, n = 1732). Results: After a median follow-up of 109 months (95% CI; 98.9-120.7 months), 221 patients (46.9%) had distant metastases in the MRM group versus 548 (33.8%) in the BCS group. Furthermore, 288 patients (17.7%) died in the MRM group and 98 (20.8%) in the BCT group. In patients with non-triple negative disease, there was no differences between BCS and MRM in terms of time to distant metastasis (DMFS 61.5 months in MRM group vs. 61.0 months in BCS group, p = 0.150, figure 1). In patients with triple negative disease, DMFS was shorter in the BCS group than MRM group (26.8 months vs. 53.7 months, p = 0.018, figure 2). Overall survival was similar between two groups (126.1 months vs. 115.3 months, in MRM and BCS group, respectively, p = 0.730). Conclusions: İn patients with triple negative disease, BCS was shorter DMFS when compared with MRM.
Pulmonary tuberculosis: A hurdle to overcome for early lung cancer diagnosis in TB burden countries
Authors: M.S. Akter, S. Ahmed
Journal: Annals of Oncology (2019)

Background: Bangladesh is ranked 6th among the Tuberculosis high burden countries. Sometimes, pulmonary tuberculosis (PTB) mimics the early symptoms of lung cancer. Developing countries like Bangladesh, with limited diagnostic facilities, often misdiagnose early lung cancer as smear negative PTB. According to national guidelines for PTB, smear negative PTB is defined as the cases diagnosed on the basis of X-ray abnormalities or suggestive histology and extra pulmonary cases without laboratory confirmation. This observational study has been done to find out the ratio of misdiagnosis of lung cancer as Smear Negative PTB. Methods: This observational study was done between June, 2017 to January, 2018 at OPD of NIDCH (National Institute of Diseases the Chest & Hospital), Dhaka, Bangladesh. Inclusion criteria for the confirmation of PTB were: symptoms not improving after 3 weeks of anti-TB treatment; non-improving chest X-ray; new symptoms; no prior anti-TB treatment; smear negative PTB. For confirmation of AFB (Acid fast bacillus) smear test, CT scan of chest, GeneXpert of sputum, Mycobacterium culture and histological confirmation were performed. During this period, 172 cases were included in the study. After confirmation of the diagnosis, every case was treated according to national TB guidelines and refered to other tertiary specialized hospitals. After changing of the treatment protocol, 3-weekly follow up was done for 2 months with chest X-ray and other blood parameters. Results: The investigations mentioned above were performed in all cases included in the study: 35 cases (20.34%) were diagnosed as lung cancer by histological confirmation. 81 cases were (47.09%) diagnosed as multidrug-resistant TB and 2 cases (1.16%) were diagnosed as extensively drug-resistant TB. Other cases (31.39%) were confirmed as PTB. Conclusions: In countries with a high tuberculosis burden and lack of facilities for guided biopsy or fine needle aspiration, except in tertiary hospitals, plays an important role in delay of early diagnosis of lung cancer. In addition, flexible national guidelines and DOT (direct observed therapy) of anti-TB drugs are given at no cost to patients are also contributory factors. In this short observational study, it was found that a number of patients received anti-TB drug based on clinical diagnosis has been diagnosed as Lung cancer that were previously diagnosed as Smear negative PTB on clinical ground and Chest X-ray. This finding suggests that national policy makers should consider that patients with smear negative PTB (clinical diagnosed PTB) need close follow up and proper referral to specialized & tertiary hospitals where there are facilities for confirming the diagnosis. To make and change in national guideline this observational study should be run in multi center in the country. Legal entity responsible for the study: NIDCH. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
FRI-037-Change in lipids: Characteristics and response to obeticholic acid in TARGET-PBC, a diverse, large United States real-world cohort
Authors: Cynthia Levy, Marlyn J. Mayo, Elizabeth Carey, Ester Little, W. Ray Kim, Karen Deane, Richard Zink, Robert Sandefur, Christopher Bowlus
Journal: Journal of Hepatology (2019)
THU-323-Impact of genetic polymorphisms associated with NAFLD on hepatic and vascular complications in diabetes
Authors: Rosa Lombardi, Lorena Airaghi, Giovanni Targher, Gaetano Serviddio, Paola Dongiovanni, Gabriele Maffi, Marica Meroni, Alessandro Mantovani, Claudio Maffeis, Antonio Colecchia, Rosanna Villani, Luca Valenti, Silvia Fargion, Anna Ludovica Fracanzani
Journal: Journal of Hepatology (2019)