tbuckley/cabot-search huggingface dataset:
Antitumor activity against GPR87-expressing non-small cell lung cancer cells in GPR87-suppressing adenoviral vector.
Authors: Takayuki Nakano, Dage Liu, Yusuke Kita, Yoshimasa Tokunaga, Kazuhito Nii, Natsumi Matsuura, Nariyasu Nakashima, Shintaro Tarumi, Xia Zhang, Tetsuhiko Go, Yoshiyuki Kakehi, Hiroyasu Yokomise
Journal: Journal of Clinical Oncology (2017)

e23152 Background: GPR87 is a newly deorphanized member of the G protein-coupled receptor family, it was suggested to contribute to the viability of human tumor cells, and overexpression of GPR87 was found in many malignant tumors including lung cancer. To explore effective gene therapies, we previously reported that adenoviral vector expressing short hairpin RNA targeting GPR87 (Ad-shGPR87) exerts a strong anti-proliferation activity against GPR87-overexprssing human bladder cancer cells. Here, the effect of Ad-shGPR87 was further examined in lung cancer cells. Methods: Human lung cancer cells of EBC, H358, LUDLU, MAC10 and RERF were investigated. Two cell of adenocarcinoma cell H358 (Ad) and squamous cell carcinoma cell LUDLU with an overexpression of GPR87 were selected for experiment. An adenoviral vector expressing short hairpin siRNA targeting GPR87 gene (Ad-shGPR87) was constructed by the COS-TPC method with Adenovirus Expression Vector kit (Takara Biomedicals). Real-time RT-PCR was performed to evaluate gene expressions. MTT assay was used to evaluate the cell viability. A human tumor xenograft model in nude mice was prepared by subcutaneously implanting tumors derived from H358 cells. Results: Transfection with Ad-shGPR87 effectively downregulated the GPR87 expression in both cells (more than 90% 3 days after transfection). MTT assay demonstrated the transfection of Ad-shGPR87 strongly suppressed the cell viability (less than 6.6 % for LUDLU cell and 20.0% for H358 cell at nine days after transfection). Furthermore, the treatment with Ad-shGPR87 exerted a significant antitumor effect against the GPR87-overexpressing H358 xenografts. Conclusions: The cancer gene therapy using Ad-shGPR87 has a strong anti-tumor effect both in vitro and in vivo against the GPR87-overexpressing lung cancer cells. GPR87 appear to be a promising target for cancer therapy.
Development and validation of a prognostic model for overall survival in chemotherapy-naïve men with metastatic castration-resistant prostate cancer
Authors: A.J. Armstrong, P. Lin, C.S. Higano, C.N. Sternberg, G. Sonpavde, B. Tombal, A.J. Templeton, K. Fizazi, D. Phung, E.K. Wong, A. Krivoshik, T.M. Beer
Journal: Annals of Oncology (2018)

BackgroundPrognostic models are needed that reflect contemporary practice for men with metastatic castration-resistant prostate cancer (mCRPC). We sought to identify predictive and prognostic variables for overall survival (OS) in chemotherapy-naïve men with mCRPC treated with enzalutamide.Patients and methodsPatients from the PREVAIL trial database (enzalutamide versus placebo) were randomly split 2 : 1 into training (n = 1159) and testing (n = 550) sets. Using the training set, 23 predefined variables were analyzed and a multivariable model predicting OS was developed and validated in an independent testing set.ResultsPatient characteristics and outcomes were well balanced between training and testing sets; median OS was 32.7 months in each. The final validated multivariable model included 11 independent prognostic variables. Median OS for low-, intermediate-, and high-risk groups (testing set) defined by prognostic risk tertiles were not yet reached (NYR) (95% CI NYR–NYR), 34.2 months (31.5–NYR), and 21.1 months (17.5–25.0), respectively. Hazard ratios (95% CI) for OS in the low- and intermediate-risk groups versus high-risk group were 0.20 (0.14–0.29) and 0.40 (0.30–0.53), respectively. Secondary outcomes of response and progression differed widely in model-defined risk groups. Enzalutamide improved outcomes in all prognostic risk groups.ConclusionsOur validated prognostic model incorporates variables routinely collected in chemotherapy-naïve men with mCRPC treated with enzalutamide, identifying subsets of patients with widely differing survival outcomes that provide useful information for external validation, patient care, and clinical trial design.Trial registrationClinicalTrials.gov: NCT01212991.
Relationship of minimal residual disease (MRD) in acute lymphocytic leukemia (ALL) and putative leukemia stem cells (LSCs).
Authors: Jonathan Michael Gerber, Elizabeth Jandrisevits, Lawrence Druhan, Amanda Lance, Andrea Price, Virginia Thurston, Jing Ai, Thomas Gregory Knight, Brittany K. Ragon, Mitchell Turner, Edward H. Lipford, Edward Alan Copelan, Michael Richard Grunwald, Belinda Rene Avalos, David Foureau
Journal: Journal of Clinical Oncology (2018)

7012 Background: MRD has emerged as a significant prognostic factor in ALL, but even levels < 0.1% still carry a risk of relapse. It is theorized that relapse is due to resistant LSCs, which survive after therapy. Consistent with this, MRD in acute myeloid leukemia patients was enriched for LSCs, which were CD34+CD38- with intermediate (int) levels of aldehyde dehydrogenase (ALDH) activity (CD34+CD38-ALDHint) [Gerber, et al. Blood, 2012]. A similar CD34+CD38-ALDHint putative LSC population was subsequently found in ALL [Gerber, et al. ASH, 2016]. We hypothesized that MRD in ALL would also be enriched for LSCs. Methods: Bone marrow specimens were collected on an IRB-approved protocol at diagnosis and/or post treatment from 32 patients with B cell ALL over a 3-year span. CD34+ cells were isolated by magnetic bead/column selection, then analyzed by flow cytometry (FACS) for CD19, CD34, CD38, and ALDH. Student’s t-test was used for statistical comparisons. Results: Twenty-four patients were followed post therapy, 5 of whom achieved complete remission with < 0.1% detectable MRD by clinical flow cytometry and/or PCR. Whereas clinical FACS detected a mean of 0.0164 ± 0.0116% MRD in the 5 cases, the LSCs constituted 31.95 ± 13.51% of the CD34+CD38- stem/progenitor cells, a nearly 2,000-fold increase (p < 0.05). In fact, in all cases with clinically detectable MRD by FACS and/or PCR, LSCs were reliably detected in the CD34+CD38- stem/progenitor population, at levels as low as 1 in 106 mononuclear marrow cells. Furthermore, while the CD34+CD38-ALDHint LSC population represented only 9.15 ± 4.07% of the total leukemic burden at diagnosis, it constituted 58.14 ± 18.63% in the MRD state (p < 0.01). Of note, CD19 was expressed on the CD34+CD38-ALDHint population in all cases, both at diagnosis and in MRD. Conclusions: MRD was enriched for CD34+CD38-ALDHint cells in ALL patients, implying that the putative LSCs are more resistant than the bulk leukemic cells to therapy. The LSCs expressed CD19, even in the MRD state, suggesting that therapies directed against CD19 could target LSCs and might prove curative. LSC detection may serve as a highly sensitive test for MRD. These findings merit validation in a larger cohort.
Influence of age and histologic subtype in outcome of operable liposarcoma.
Authors: Daniela Greto, Calogero Saieva, Mauro Loi, Francesca Terziani, Luca Visani, Pietro Garlatti, Monica Lo Russo, Cristina Muntoni, Carlotta Becherini, Juljana Topulli, Domenico Campanacci, Giovanni Beltrami, Guido Scoccianti, Francesco Muratori, Pierluigi Bonomo, Isacco Desideri, Giulio Francolini, Lorenzo Livi
Journal: Journal of Clinical Oncology (2018)

e23552 Background: A tailored approach of patients with liposarcoma (LPS) considering histologic subtypes and age, could be helpful in delineating therapeutic management. In this paper, we report a retrospective series of a single-institution cohort of patients with LPS undergoing surgery, radiotherapy and/or chemotherapy with curative intent. The aim is to evaluate whether clinical, tumor and treatment characteristics affect clinical outcome. Methods: Data of patients with locally advanced liposarcoma treated between 1990-2015 were retrospectively reviewed. Two patient subgroups were identified according to age ( < 65 years or > 65 years). Statistical analysis was performed to assess correlation between the clinical variables and local recurrence-free survival (DFS-LR), distant metastasis-free survival (DMFS) and overall survival (OS); moreover, differences in clinical outcome between the two age groups were identified. Results: Data of 186 patients were collected. At diagnosis 27.4% of patients were 65 years or older. At a median follow-up of 8.6 years (range, 0.1-27.3), Kaplan-Meier (KM) survival analysis showed that LR, DM and OS were 75.5%, 76.6% and 48.1%, respectively. KM analysis showed that age > 65, dedifferentiated liposarcoma (DDLPS) subtype were related to LR (p = 0,001, p = 0,0001). Age and DDLPS were independent prognostic factors of LR (p = 0,024, p = 0,002). Age and grading were independent prognostic factors affecting distant recurrence (p = 0,009, p 0,017). G3 disease and age > 65 were related with worse OS (p = 0,008, p = 0,0001). Age, DDLPS and Grade were related to OS at univariate (p = 0,0001, p = 0,0001 and p = 0,03, respectively) and multivariate CR analysis (p = 0,031, p = 0,0001 and p = 0,001, respectively). However, analyzing specific causes of death, elderly patients died more often due to other causes compared to younger population (p = 0.006). Conclusions: Histotype-driven schedules of treatment should be developed considering biological heterogeneity of LPS. Further studies are needed to stratify patient-subgroups and develop tailored treatment strategies. More prospective trials are needed to develop treatment guidelines in elderly STS, considering frailty and peculiarity of this subgroup.
Intertumoral Heterogeneity in SCLC Is Influenced by the Cell Type of Origin
Authors: Dian Yang, Sarah K. Denny, Peyton G. Greenside, Andrea C. Chaikovsky, Jennifer J. Brady, Youcef Ouadah, Jeffrey M. Granja, Nadine S. Jahchan, Jing Shan Lim, Shirley Kwok, Christina S. Kong, Anna S. Berghoff, Anna Schmitt, H. Christian Reinhardt, Kwon-Sik Park, Matthias Preusser, Anshul Kundaje, William J. Greenleaf, Julien Sage, Monte M. Winslow
Journal: Cancer Discovery (2018)

The extent to which early events shape tumor evolution is largely uncharacterized, even though a better understanding of these early events may help identify key vulnerabilities in advanced tumors. Here, using genetically defined mouse models of small cell lung cancer (SCLC), we uncovered distinct metastatic programs attributable to the cell type of origin. In one model, tumors gain metastatic ability through amplification of the transcription factor NFIB and a widespread increase in chromatin accessibility, whereas in the other model, tumors become metastatic in the absence of NFIB-driven chromatin alterations. Gene-expression and chromatin accessibility analyses identify distinct mechanisms as well as markers predictive of metastatic progression in both groups. Underlying the difference between the two programs was the cell type of origin of the tumors, with NFIB-independent metastases arising from mature neuroendocrine cells. Our findings underscore the importance of the identity of cell type of origin in influencing tumor evolution and metastatic mechanisms.Significance: We show that SCLC can arise from different cell types of origin, which profoundly influences the eventual genetic and epigenetic changes that enable metastatic progression. Understanding intertumoral heterogeneity in SCLC, and across cancer types, may illuminate mechanisms of tumor progression and uncover how the cell type of origin affects tumor evolution. Cancer Discov; 8(10); 1316-31. ©2018 AACR.See related commentary by Pozo et al., p. 1216This article is highlighted in the In This Issue feature, p. 1195.
Endothelial cell fitness dictates the source of regenerating liver vasculature
Authors: Mahak Singhal, Xiaoting Liu, Donato Inverso, Kai Jiang, Jianing Dai, Hao He, Susanne Bartels, Weiping Li, Ashik Ahmed Abdul Pari, Nicolas Gengenbacher, Eva Besemfelder, Lijian Hui, Hellmut G. Augustin, Junhao Hu
Journal: The Journal of Experimental Medicine (2018)

Neoangiogenesis plays a key role in diverse pathophysiological conditions, including liver regeneration. Yet, the source of new endothelial cells (ECs) remains elusive. By analyzing the regeneration of the liver vasculature in irradiation-based myeloablative and nonmyeloablative bone marrow transplantation mouse models, we discovered that neoangiogenesis in livers with intact endothelium was solely mediated by proliferation of resident ECs. However, following irradiation-induced EC damage, bone marrow–derived mononuclear cells were recruited and incorporated into the vasculature. Further experiments with direct bone marrow infusion or granulocyte colony–stimulating factor (G-CSF)–mediated progenitor cell mobilization, which resembles clinically relevant stem cell therapy, demonstrated that bone marrow–derived cells did not contribute to the regeneration of liver vasculature after two-thirds partial hepatectomy (PHx). Taken together, the data reconcile many of the discrepancies in the literature and highlight that the cellular source of regenerating endothelium depends on the fitness of the residual vasculature.
Use of adjuvant radiotherapy in women with stage I endometrioid adenocarcinoma of the uterus: A National Cancer Database study.
Authors: Nicholas Rydzewski, Anna Everett Strohl, Eric Donald Donnelly, Margaux Jenna Kanis, John Robert Lurain, Wilberto Nieves-Niera, Jonathan Blake Strauss
Journal: Journal of Clinical Oncology (2016)

e17107 Background: Randomized controlled trials have consistently shown that the use of post-operative radiotherapy in stage I endometrial cancer leads to a reduction in the incidence of pelvic recurrences without a corresponding reduction in mortality. We hypothesized that a reduction in mortality associated with the receipt of radiotherapy could be identified in a large dataset with greater statistical power. Methods: The National Cancer Database was queried to identify women with stage I endometrial adenocarcinoma diagnosed between 2003 and 2011 and treated with total hysterectomy. A Cox regression analysis was performed to determine the impact of known prognostic factors and receipt of radiotherapy (pelvic radiotherapy or vaginal brachytherapy) on mortality. Results: A total of 43,188 eligible women were identified (33,081 stage IA and 10,107 stage IB). Of these, 89.2% of women with stage IA and 55.8% of women with stage IB tumors received no radiotherapy. Older age, co-morbid disease, higher histologic grade and larger tumor size were independently associated with an increase in mortality. Receipt of vaginal brachytherapy was independently associated with a reduction in mortality in both stage IA (HR 0.81; 95% CI 0.67-0.97) and stage IB disease (HR 0.62; 95% CI 0.51-0.74). Conclusions: Analyses from this large database support the utility of post-operative radiotherapy for many women with stage I endometrial cancer. Radiotherapy appears to be underused in this population. Greater adherence to consensus guidelines may lead to improved outcomes.
Geriatric assessment to predict hospitalization frequency and long-term care utilization in older adult cancer survivors.
Authors: Grant Richard Williams, Lisette Dunham, YunKyung Chang, Allison Mary Deal, Mackenzi Pergolotti, Jennifer Leigh Lund, Emily Jean Guerard, Kelly Kenzik, Hyman B. Muss, Hanna Kelly Sanoff
Journal: Journal of Clinical Oncology (2018)

10036 Background: Geriatric assessments (GA) assess physiologic age in older adults; however, the association between GA identified impairments and long-term healthcare utilization in older cancer survivors remains unknown. Our objective was to evaluate whether a GA performed at cancer diagnosis was predictive of hospitalizations and long-term care [LTC] utilization in older adult cancer survivors. Methods: Older adults within the Carolina Senior Registry (NCT01137825) with GA performed between 3 months before and up to 6 months after diagnosis were included (n = 125). Patients with fee-for-service coverage were linked to Medicare claims. Hospitalizations and LTC utilization (skilled nursing or assisted living) were identified up to 5 years after their diagnosis, death, or 12/31/2013. GA risk measures (prefrail/frail status, impaired Instrumental Activities of Daily Living [IADL], limitations in climbing stairs, prolonged Timed Up and Go [TUG], > 5% unintended weight loss) were assessed in separate Poisson models estimating the relative risk (RR) for hospital and long-term care visits, controlling for person-time, age, and Charlson comorbidity score. Results: Participants median age of 74 years, majority female (80%), and white (89%). Most common malignancies were breast (64%) and lung cancer (8%); predominantly early stage disease (stage 0-III = 77%). During follow-up 41 (33%) participants were hospitalized and 20 (16%) received LTC. Prefrail/frail status (RR 2.5, p < 0.001), IADL impairment (RR 5.47, p < 0.001), and limitations in climbing stairs (RR 2.94, p < 0.001) were associated with increased hospitalizations. Prefrail/frail status (RR 1.86, p < 0.007), IADL impairment (RR 4.58, p < 0.001), presence of falls (RR 6.73, p < 0.001), prolonged TUG (RR 5.45, p < 0.001), and limitations in climbing stairs (RR 1.89, p < 0.005) were associated with LTC utilization. Conclusions: GA identified impairments were associated with increased hospitalizations and LTC utilization among older adults with cancer. GA-focused interventions, such as physical and occupational therapy, should be employed to potentially reduce long-term adverse health care utilization in this vulnerable population.
Intracellular targeting of the oncogenic MUC1-C protein with a GO-203 nanoparticle formulation overcomes MCL-1- and BFL-1-mediated resistance in human carcinoma cells.
Authors: Masayuki Hiraki, Caining Jin, Maroof Alam, Takahiro Maeda, Masaru Murata, Masahiro Hiratsuka, Yuichiro Doki, Surender Kharbanda, Masaki Mori, Donald W. Kufe
Journal: Journal of Clinical Oncology (2017)

e14053 Background: Aberrant expression of MCL-1 and BFL-1, the pro-survival members of the Bcl-2 family, is a major cause of drug resistance in human cancers. Mucin 1 (MUC1) is a heterodimeric oncoprotein that is aberrantly expressed in most human carcinomas. Notably, there is no known relationship between the oncogenic MUC1 C-terminal subunit (MUC1-C) and these anti-apoptotic proteins. Methods: MUC1-C was targeted in breast, lung and colon cancer cells by a stable shRNA, a tetracycline-inducible shRNA, or a pharmacologic peptide inhibitor GO-203. MCL-1 was inhibited by siRNA or the MS-1 peptide. In vitro and in vivo studies were conducted using our polymeric nanoparticles (NPs) for intracellular delivery of peptide cargos. Cells were selected for resistance to ABT-737 or ABT-263, which target BCL-2, BCL-XL and BCL-w, but not MCL-1 and BFL-1. Results: Targeting MCL-1 with MS-1/NPs inhibited the survival of parental cancer cells in vitro and in vivo, and was associated with upregulation of BFL-1 levels. In addition, MS-1/NPs treatment had limited effects on ABT-resistant cells because of increased BFL-1 expression. Importantly, we found that targeting MUC1-C is associated with suppression of both MCL-1 and BFL-1. Mechanistically, MUC1-C (i) stabilizes MCL-1 by activating the MEK→ERK and PI3K→AKT pathways, and (ii) induces BFL-1 through the NF-κB p65 pathway. Treatment with GO-203/NPs suppressed proliferation of parental and ABT-resistant cells. In addition, we show that combining GO-203 with ABT-737 is synergistic in inhibiting survival of parental and ABT-resistant cells. Conclusions: These findings demonstrate that targeting MUC1-C with GO-203/NPs is a potential strategy for abrogating MCL-1- and BFL-1-mediated resistance.
Use and Cost of Actinic Keratosis Destruction in the Medicare Part B Fee-for-Service Population, 2007 to 2015
Authors: Howa Yeung, Marissa L. Baranowski, Robert A. Swerlick, Suephy C. Chen, Jennifer Hemingway, Danny R. Hughes, Richard Duszak
Journal: JAMA Dermatology (2018)

Actinic keratosis is prevalent and has the potential to progress to keratinocyte carcinoma. Changes in the use and costs of actinic keratosis treatment are not well understood in the aging population.To evaluate trends in the use and costs of actinic keratosis destruction in Medicare patients.A billing claims analysis was performed of the Medicare Part B Physician/Supplier Procedure Summary Master Files and National Summary Data of premalignant skin lesion destructions performed from 2007 to 2015 among Medicare Part B fee-for-service beneficiaries.Mean number of actinic keratosis lesions destroyed and associated treatment payments in 2015 US dollars estimated per 1000 Medicare Part B fee-for-service beneficiaries. Data analysis was performed from November 2017 to July 2018.More than 35.6 million actinic keratosis lesions were treated in 2015, increasing from 29.7 million in 2007. Treated actinic keratosis lesions per 1000 beneficiaries increased from 917 in 2007 to 1051 in 2015, while mean inflation-adjusted payments per 1000 patients decreased from $11 749 to $10 942 owing to reimbursement cuts. The proportion of actinic keratosis lesions treated by independently billing nurse practitioners and physician assistants increased from 4.0% in 2007 to 13.5% in 2015.This study's findings suggest that actinic keratosis imposes continuously increasing levels of treatment burden in the Medicare fee-for-service population. Reimbursement decreases have been used to control rising costs of actinic keratosis treatment. Critical research may be warranted to optimize access to actinic keratosis treatment and value for prevention of keratinocyte carcinoma.
Costs and values of the immune check point inhibitors antibodies in non-small cell lung cancer.
Authors: Helmy M. Guirgis, Corey J. Langer
Journal: Journal of Clinical Oncology (2017)

e20644 Background: Costs (C) and values (V) of the check point inhibitors antibodies have not been compared. Our objectives were to weigh and compare C and V of Nivolumab (Nivo), Atezolizumab (Atezo) and Pembrolizumab (Pembro) vs. Docetaxel (Doc) in 2 nd -line non-small-cell lung cancer (NSCLC). Methods: Median overall survival gain over control (OS), hazard ratios (HR), doses and prices posted by parent companies were quoted. Probability of survival (PoS) was calculated as (1.0- HR). Values were computed at 4-week (w) as 4wC/PoS and one-year as C/life-year gain (LYG). Results: Doc OS was 72 days, HR not reported, generic 4wC &lt; $500 and C/LYG 26,896. In comparison, in non-enriched non-squamous (sq-) Nivo C/LYG was 558,313, Atezo 618,244, Pembro 659,059. Nivo OS was 84, HR 0.73, 4wC $10,021 and 4wV 37,115 improving in &gt; 10% PD-L1 positive to OS 264, HR 0.27 and 4wV 13,727. Atezo OS was 87, HR 0.73, 4wC $11,493 and 4wV 42,567 improving in medium- high PD-L1 to 150, 0.46 and 4wV 21,283 respectively. Pembro demonstrated OS 57, HR 0.71, 4wC $8,027 and 4wV 27,679 improving in &gt; 50% PD-L1 to 201, 0.54 and 4wV 17,450. Conclusions: Doc, without accounting for adverse events and quality of life, remains a valuable drug in 2 nd -line NSCLC. In PD-L1- enriched non-sq, Nivo, Atezo and Pembro consistently demonstrated marked V improvement to justify their C. The limited available data and the inherent problems of drug comparison preclude favoring one ICPIA over another. References: Doc: Shepherd FA et al. JCO 18:2095, 2000; Nivo: Checkmate 057, Brahmer JN et al. NEJM 373: 123, 2015; Atezo: POPLAR; Pembro: KEYNOTE-010.