tbuckley/cabot-search huggingface dataset:
The utility of integrative genomic profiling in sarcoma diagnosis and treatment.
Authors: Bo Zhang, Bixun Li, Zehua Wu, Fabo Qiu, Shuang Ren, Ye Qiu, Lei Mei, XiaoWei Dong, Jicheng Yao, Weifeng Wang
Journal: Journal of Clinical Oncology (2018)

e23545 Background: Sarcomas are rare and highly heterogeneous in histological subtypes with various management protocols and prognoses. Next generation sequencing (NGS) has already been used to identify potential actionable genetic alterations and chromosomal rearrangements for diagnostic purposes in sarcomas, however it’s still challenging to select an integrative genomic profiling panel to provide valuable genetic information with reasonable medical costs in sarcoma. Methods: FFPE tumor and matched blood samples from 82 Chinese sarcoma patients were collected for NGS-based 450 genes DNA panel assay. All classes of genomic alterations including single base substitutions, short and long insertions/deletions, copy number variations, gene rearrangements were assessed, and tumor mutational burden as well. Panel based RNAseq specially assessing gene rearrangements and expressions was performed. Results: TP53 gene mutation is the most common genomic alteration (30%) in the current Chinese sarcoma cohort including 13 cases of liposarcoma, 11 cases of osteosarcoma, 10 cases of Ewing sarcoma, 8 cases of gastrointestinal stromal tumor (GIST), 5 cases of myxoid fibrosarcoma and 14 other histologically different types. All were reviewed by two experienced pathologists. There were about 40% (33/82) of patients with at least one actionable mutations with a potential of treatment to FDA approved drugs, including PIK3CA, PTEN, KIT, MET amplifications, BRCA truncations, ROS1 and PDGFB fusions. In the 25 cases of FFPE samples underwent RNAseq, a number of gene fusions partnered with TFE3, SSX1, EWSR1, COL1A1 and FUS were detected by RNAseq, and all were validated by FISH. In addition, three out of four GIST samples underwent RNAseq showed elevated level of cKIT gene expression. A sixteen year old patient, who was diagnosed by NGS as alveolar soft part sarcoma featured by TFE3 fusion with primary lesion on left thigh and distal brain metastasis, achieved partial response after three months of pazopanib treatment. Conclusions: The preliminary data from a small cohort of Chinese sarcoma patients indicated the value of integrative genomic profiling combining both DNAseq and RNAseq in sarcoma diagnosis and potential treatment implications.
UBE2N Promotes Melanoma Growth via MEK/FRA1/SOX10 Signaling
Authors: Anushka Dikshit, Yingai J. Jin, Simone Degan, Jihwan Hwang, Matthew W. Foster, Chuan-Yuan Li, Jennifer Y. Zhang
Journal: Cancer Research (2018)

Abstract UBE2N is a K63-specific ubiquitin conjugase linked to various immune disorders and cancer. Here, we demonstrate that UBE2N and its partners UBE2V1 and UBE2V2 are highly expressed in malignant melanoma. Silencing of UBE2N and its partners significantly decreased melanoma cell proliferation and subcutaneous tumor growth. This was accompanied by increased expression of E-cadherin, p16, and MC1R and decreased expression of melanoma malignancy markers including SOX10, Nestin, and ABCB5. Mass spectrometry–based phosphoproteomic analysis revealed that UBE2N loss resulted in distinct alterations to the signaling landscape: MEK/ERK signaling was impaired, FRA1 and SOX10 gene regulators were downregulated, and p53 and p16 tumor suppressors were upregulated. Similar to inhibition of UBE2N and MEK, silencing FRA1 decreased SOX10 expression and cell proliferation. Conversely, exogenous expression of active FRA1 increased pMEK and SOX10 expression, and restored anchorage-independent cell growth of cells with UBE2N loss. Systemic delivery of NSC697923, a small-molecule inhibitor of UBE2N, significantly decreased melanoma xenograft growth. These data indicate that UBE2N is a novel regulator of the MEK/FRA1/SOX10 signaling cascade and is indispensable for malignant melanoma growth. Our findings establish the basis for targeting UBE2N as a potential treatment strategy for melanoma. Significance: These findings identify ubiquitin conjugase UBE2N and its variant partners as novel regulators of MAPK signaling and potential therapeutic targets in melanoma. Cancer Res; 78(22); 6462–72. ©2018 AACR.
Androgen content and BET bromodomain proteins influence enzalutamide agonism of mutant F876L androgen receptor.
Authors: Daniel J. Coleman, Kathryn Van Hook, Carly J. King, Jacob Schwartzman, Robert Lisac, Joshua Urrutia, Archana Sehrawat, Josha Woodward, Nicholas J. Wang, Roman Gulati, George V. Thomas, Tomasz M. Beer, Martin E. Gleave, James E. Korkola, Lina Gao, Laura M. Heiser, Joshi J. Alumkal
Journal: Journal of Clinical Oncology (2016)

e16538 Background: One emergent resistance mechanism to medical castration is intratumoral androgen synthesis that activates the androgen receptor (AR). This insight led to the development of the AR antagonist enzalutamide. One enzalutamide resistance mechanism is AR F876L mutations that lead to enzalutamide agonism in some cases. However, mechanisms that contribute to the agonist switch have not been fully clarified, and there are no therapies to block AR F876L. Methods: We usedenzalutamide-resistant cell lines harboring AR F876L mutations to determine mechanisms that contribute to enzalutamide activation of mutant F876L AR. Results: Using these cell line models, we determined that cellular androgen content influences enzalutamide agonism of mutant F876L AR. Further, enzalutamide treatment of AR F876L expressing cell lines recapitulated the effects of androgen activation of F876L AR or wild-type AR. Because the BET bromodomain inhibitor JQ1 was previously shown to block androgen activation of wild-type AR, we tested JQ1 in AR F876L-expressing CRPC models. We determined that JQ1 suppressed androgen or enzalutamide activation of mutant F876L AR and suppressed growth of mutant F876L AR CRPC tumors in vivo, demonstrating a new strategy to treat tumors harboring this mutation. Conclusions: Our data demonstrate that androgens interfere with enzalutamide-induced agonism of F876L mutant AR. Because androgens persist in enzalutamide-resistant CRPC, AR activation by androgens, rather than enzalutamide, may explain why enzalutamide discontinuation does not lead to anti-androgen withdrawal effects clinically. Further, our results provide a cautionary note on therapeutic efforts to deplete androgens concomitantly with enzalutamide treatment as this may accentuate AR agonism by enzalutamide in tumors harboring AR F876L mutations. Finally, targeting BET bromodomain proteins is a promising strategy to suppress mutant AR F876L function irrespective of whether the AR agonist is androgens or enzalutamide.
Outcomes based on age in the phase 3 CELESTIAL trial of cabozantinib (C) versus placebo (P) in patients (pts) with advanced hepatocellular carcinoma (HCC).
Authors: Lorenza Rimassa, Irfan Cicin, Jean-Frédéric Blanc, Heinz Josef Klümpen, Vittorina Zagonel, Albert Tran, Stefano Chong Hun Kim, Zhong-Zhe Lin, Vincent C. Tam, Saswati Hazra, Milan Mangeshkar, Anthony El-Khoueiry, Ann-Lii Cheng, Tim Meyer, Robin Kate Kelley, Ghassan K. Abou-Alfa
Journal: Journal of Clinical Oncology (2018)

4090 Background: The incidence of HCC generally increases with age, although the age of onset varies depending on disease etiology and geographic region (Yang, Nat Rev Gastroenterol Hepatol 2010). In the phase 3 CELESTIAL trial (NCT01908426), C, an inhibitor of MET, VEGF receptors, and AXL, improved overall survival (OS) and progression-free survival (PFS) compared with P in pts with previously-treated advanced HCC. Overall, median OS was 10.2 mo for C vs 8.0 mo for P (HR 0.76, 95% CI 0.63–0.92; p = 0.0049), and median PFS was 5.2 mo for C vs 1.9 mo for P (HR 0.44, 95% CI 0.36–0.52; p < 0.0001). Here, we evaluate clinical outcomes based on age in the CELESTIAL trial. Methods: 707 pts were randomized 2:1 to receive C (60 mg qd) or P. Eligible pts had pathologic diagnosis of HCC, Child-Pugh score A, ECOG PS ≤1, and must have received prior sorafenib. Randomization was stratified by disease etiology, geographic region, and extent of disease. Outcomes were analyzed for subgroups based on age ( < 65 years and ≥65 years). Results: Median age at baseline was 64 years; 51% of pts were < 65 years old. Etiology of HBV was more frequent in pts < 65 years vs ≥65 years old (52% vs 22%), while etiology of HCV occurred at a similar frequency in both age groups (24%). Asian race and enrollment in Asia were more frequent in pts < 65 years vs ≥65 years old (46% vs 21% Asian race; 35% vs 14% enrolled in Asia). Median OS was 9.6 mo for C vs 7.7 mo for P (HR 0.81, 95% CI 0.62–1.05) for pts < 65 years old and 11.1 mo for C vs 8.3 mo for P (HR 0.74, 95% CI 0.56–0.97) for pts ≥65 years old. Median PFS was 5.0 mo for C vs 1.9 mo for P (HR 0.45, 95% CI 0.35–0.57) for pts < 65 years old and 5.4 mo for C vs 2.0 mo for P (HR 0.46, 95% CI 0.35–0.59) for pts ≥65 years old. The discontinuation rate due to treatment-related adverse events in the C group was lower in pts < 65 years vs ≥65 years old (11% vs 22%), while the percentage of pts with any dose reduction (61% vs 64%) and the median average daily dose of C (37 mg vs 34 mg) were similar in both age groups. The most common grade 3/4 adverse events in both age groups were consistent with those in the overall population. Conclusions: C improved OS and PFS vs P in pts with previously-treated advanced HCC irrespective of age category. Clinical trial information: NCT01908426.
Inflammatory biomarkers in HIV-infected veterans with non-small cell lung cancer receiving anti–PD-1 immunotherapy.
Authors: Elaine Chang, Alison Yoder, Kathryn Royse, Jennifer Kramer, Donna L. White, Peter A. Richardson, Anita Lyn Sabichi, Elizabeth Chiao
Journal: Journal of Clinical Oncology (2018)

e21110 Background: Anti-programmed cell death (anti–PD-1) response in patients with advanced non-small cell lung cancer (NSCLC) varies greatly. Higher neutrophil/lymphocyte ratio (NLR) or lower advanced lung cancer inflammation index (ALI) predicted lower nivolumab response rates and survival in studies of immunocompetent patients with NSCLC. The distribution of these markers in people living with HIV (PLWH) is unknown. This is the first report describing inflammatory biomarkers among HIV-infected and -uninfected veterans. Methods: We searched the Corporate Data Warehouse (CDW) to identify all 46,916 PLWH who used the Veterans Health Administration 2000-2016 and a 4:1 age-matched HIV-negative control cohort. Within these 2 cohorts, we defined the anti–PD-1 NSCLC cohorts by the following inclusion criteria: 1) VA Cancer Registry NSCLC diagnosis; and 2) receipt of ≥ 3 doses of nivolumab or pembrolizumab monotherapy. We calculated ALI using BMI*albumin/NLR at anti–PD-1 initiation, as previously described. Overall survival (OS) was measured from first anti–PD-1 dose. We used Fisher’s exact, independent t-test, and log-rank to compare cohorts. Results: Nine PLWH and 62 HIV-negative controls met inclusion criteria. Baseline age was similar between the two groups (67 [PLWH] vs. 66 [controls], p = 0.83), as was albumin, NLR and ALI (p > 0.05). Mean BMI of PLWH was lower than BMI of controls (21.6 vs. 25.9, p = 0.02). Months of treatment (mean 10.1 vs. 13.8, p = 0.37) and median OS (12.3 vs. 13.9 months, p = 0.76) were similar among PLWH and controls. Clinical benefit rate (CBR, defined as complete/partial response or stable disease) was higher in PLWH with ALI < 18 vs. PLWH with ALI > 18 (CBRALI < 18 = 2/2 [100%], CBRALI > 18 = 2/7 [29%], p > 0.05); median OSALI < 18 was not reached among PLWH. OS among controls with ALI > 18 was significantly greater than controls with ALI < 18 (18.9 vs. 11.2 months, p = 0.048). Conclusion: Baseline NLR and ALI, and anti–PD-1–treated NSCLC survival, were comparable in HIV-infected and uninfected veterans.. There was an unexpected trend of improved CBR among PLWH with lower ALI. OS was significantly prolonged in HIV-negative patients with higher ALI.
Abstract IA31: Radiation therapy in lung cancer: Recent trends and future directions
Authors: Daniel R. Gomez
Journal: Clinical Cancer Research (2018)

Abstract Radiation techniques for lung cancer have evolved substantially over the past decade. While previously many patients were treated with 3D conformal therapy, with large uniform margins placed to estimate respiratory motion in the “average” tumor, patients are now simulated with sophisticated, real-time monitoring of internal motion such that treatment volumes can be individualized to maximize normal tissue sparing through image-guided radiation therapy (IGRT). In addition, many patients are now treated with intensity-modulated radiation therapy (IMRT), which has served to drastically improve conformality in select cases and increase the proportion of patients in which high doses are achievable. Concurrent with these advances, proton beam therapy (PBT) has been implemented in a limited number of centers, with the hope of utilizing the dosimetric distribution advantage of the Bragg Peak to further reduce toxicity. The role of PBT in both early-stage and locally advanced non-small cell lung cancer continues to be defined, as results from a phase II multicenter randomized trial predominantly in patients with stage II-III disease did not demonstrate superiority with PBT and concurrent chemotherapy when compared to similar regimens with IMRT. Finally, there have been much data produced with regard to dosing regimens. In early-stage disease, there has been increased implementation of stereotactic ablative body radiation (SABR), with prospective data emerging for both peripheral and central lesions. In the locally advanced setting, results from RTOG 0617 demonstrated no difference when comparing 60 Gy vs. 74 Gy in the setting of chemoradiation. There has also been a trend towards hypofractionation for patients who are unable to tolerate concurrent chemoradiation or those with oligometastatic disease, yet the benefit of hypofractionated radiation sequentially vs. combined modality treatment will need to be further assessed in prospective randomized trials, particularly in the era of immunotherapy. Citation Format: Daniel R. Gomez. Radiation therapy in lung cancer: Recent trends and future directions [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr IA31.
Maintenance (MT) treatment (Tx) after lenalidomide, bortezomib, and dexamethasone (RVD) induction and stem cell transplant (SCT) in high-risk (HR) patients (pts) with newly diagnosed multiple myeloma (NDMM): A real-world analysis.
Authors: Rafael Fonseca, Kejal Parikh, Brian Ung, Quanhong Ni, Amit Agarwal
Journal: Journal of Clinical Oncology (2018)

e20041 Background: In the US and Europe, lenalidomide (LEN or R) was the first approved drug for post-SCT MT in MM. RVD induction is common in NDMM, but real-world evidence of R-MT after RVD and SCT is limited, particularly in HR pts. Here we report results of a retrospective observational analysis comparing R-MT vs No-MT in this setting. Methods: This analysis used electronic health records from the Flatiron Health database. Eligible pts diagnosed with MM between Jan 2011 and Dec 2017 and ≥ 2 documented clinical visits were included. NDMM was defined as no MM treatment (Tx) > 14 days (d) prior to first diagnosis. Index date was defined as the earlier of SCT date + 90 d or start of R-MT. Pts were identified as HR by FISH at diagnosis using international standards (Table). Time to next Tx (TTNT; duration from the index date to start of a new Tx line) was analyzed by Kaplan-Meier method and Cox proportional hazards model. Results: Among 340 pts who received RVD induction and SCT, 85 pts were HR; 41 (48%) received R-MT and 44 (52%) did not (No-MT). Pts receiving R-MT vs No-MT were older (mean age 62 vs 58 yrs; P = .0285), and a higher proportion had an ECOG performance status of 0 (80% vs 41%; P = .0399). More R-MT pts had chromosome 1 abnormalities, and fewer had del17p13. Median follow-up was 21.9 vs 9.7 mos. A smaller proportion of R-MT pts advanced to second line (2L) Tx (24% vs 59%) and had a significantly longer median TTNT (SCT + 90 d) (38.8 vs 2.8 mos; hazard ratio, 3.5 [95% CI, 2.25-5.58]; P < .001). Conclusions: This analysis demonstrated that HR pts with NDMM receiving R-MT were less likely to progress to 2L and had a significantly longer TTNT. These real-world outcomes align with clinical trial outcomes, which showed improved PFS with R-MT vs placebo or observation in HR pts. While HR pts may benefit from the addition of a proteasome inhibitor to MT, this study shows the benefit of single-agent LEN. Future studies are needed to determine the impact on pt survival and healthcare costs. Table: FISH Data Genetic abnormality, % R-MT n = 41 No-MT n = 44 Chromosome 1 abnormality 83 64 Del17p13 20 39 t(14;16) 12 9 t(4;14) 10 23 t(14;20) 0 2
Pilot study of an online app to reduce cancer patients' financial burden.
Authors: Yousuf Zafar, Ian Manners, Jonathan Nicolla, Andrew Friedman, Greg P. Samsa, Kathryn Pollak
Journal: Journal of Clinical Oncology (2016)

e18271 Background: PAPNavigator is a web-based app designed to reduce out-of-pocket treatment costs by connecting patients to financial assistance programs specific to their treatment, insurance, and financial situation. Providing cancer patients direct access to online financial navigation might assist more patients in financial need. It was designed to be used by oncology financial counselors and has not been tested in a patient population. Methods: This was a pilot study of PAPNavigator to determine patient-reported usability and preliminary effectiveness. Eligible cancer patients were receiving anti-cancer treatment and had out-of-pocket treatment costs. Patients interacted with PAPNavigator, inputted personal and financial data, and reviewed personalized financial resource results. Usability was assessed via the validated System Usability Scale (SUS). Domains assessed included ease of learning, efficiency, perceived user burden, utility, and satisfaction. Effectiveness was assessed by two measures (responses on 1-5 Likert scale): “PAPNavigator improved my knowledge about financial aspects of cancer care and what can be done about it,” and, “Using this website was helpful with my financial concerns” (for both items, 1 = strongly disagree, 5 = strongly agree). Results: 19 of 20 patients completed pilot testing (95%, 1 withdrew due to illness). 53% of patients were male, 26% were non-white, 79% had greater than high school education, and 21% were employed full- or part-time. Median annual household income was $77,500. 47% had Medicare, Medicare plus supplemental, Medicaid, or Medicare plus Medicaid. The median SUS score was 75 out of 100 (with > 68 considered above average). In response to the statements, “PAPNavigator improved my knowledge about financial aspects of cancer care and what can be done about it,” and, “Using this website was helpful with my financial concerns,” the median score for each was 4. Conclusions: PAPNavigator was considered highly usable and feasible. Even in a cohort with higher than average income, these results suggest PAPNavigator’s preliminary effectiveness in improving knowledge about financial aspects of cancer care and potential interventions to reduce cost.
Abstract 11582: Skeletal Muscle Mass Determined by Bioelectrical Impedance Analysis is Associated With Exercise Capacity and Cardiac Events in Patients With Congenital Heart Disease
Authors: Masaki Sato, Kei Inai, Mikiko Shimizu, Daiji Takeuchi, Testuko Ishii, Keiko Toyohara, Tokuko Shinohara, Hisashi Sugiyama, Hirofumi Tomimatsu, Toshio Nakanishi
Journal: Circulation (2017)

Introduction: Exercise capacity of patients with heart failure (HF) was thought to entirely associate with oxygen supply as central hemodynamic factor. However, skeletal muscle disorders in patient...
Treatment patterns among elderly follicular lymphoma patients diagnosed between 2000 and 2011: An analysis of linked SEER-Medicare data.
Authors: Ebere Onukwugha, Madhu Nagarajan, Husam Albarmawi, James F. Gardner, Karen N. Keating, Adriana Valderrama, Jean Malacan, Avin Yaldo, Jean Yared
Journal: Journal of Clinical Oncology (2017)

7563 Background: There are multiple treatment regimens approved for the management of follicular lymphoma (FL). However, there is limited information available to describe the course of therapy (COT) that patients receive following FL diagnosis. Methods: Using the linked Surveillance, Epidemiology, and End Results (SEER) registry &amp; Medicare claims dataset, we analyzed patients 66 years and older diagnosed with FL from 2000 to 2011. In order to characterize FL treatments, we identified first, second and subsequent-lines of therapy listed in the National Comprehensive Cancer Network guidelines 2.2016. We identified the first COT (COT1) as the first regimen that a patient receives after diagnosis. We identified the second and third COT (COT2 and COT3) as new treatment received following/interrupting COT1 or COT2, respectively. Using visual analytics software, we investigated and reported the proportion of patients receiving each COT, the top three regimens within each COT, and the median time to starting a COT from diagnosis or end of a previous COT. Results: 10,836 FL patients were identified after applying the inclusion/exclusion criteria. Sixty-two percent (N=6,756) of the patients received FL-directed treatment. Among patients receiving COT1, 65% received COT2. Among patients receiving COT2, 79% received COT3. The table below provides additional information on the COT received. Conclusions: Analysis of real-world data indicates that almost 4 out of 10 elderly FL patients do not receive the listed FL-directed treatments. In contrast to rituximab, there was limited use of RCHOP and RCVP after COT1 during the study period. Additional research is needed to understand the differences across demographic groups and associated health outcomes. [Table: see text]
Abstract 12385: Past Alcohol Consumption and Incident Atrial Fibrillation
Authors: Shalini Dixit, Alvaro Alonso, Elsayed Z Soliman, Lin Y Chen, Gregory M Marcus
Journal: Circulation (2015)

Introduction: Although current alcohol consumption appears to be a risk factor for incident atrial fibrillation (AF), limitations related to self-reported alcohol use and confounding in observational studies limit the certainty of conclusions regarding causality. Whether cessation of alcohol consumption can protect against incident AF remains unknown. Methods: We examined all participants in the Atherosclerosis Risk in Communities (ARIC) study, a population-based cohort of 15,792 men and women aged 45-65, without prevalent AF. Past alcohol consumption was assessed via self-report during the baseline dietary intake assessment. Cases of incident AF were ascertained via study ECGs, hospital discharge ICD-9 codes, and death certificates. Results: Among 15,262 participants with complete survey data, 2,898 (19.0%) were former drinkers. During an average follow-up of 17.4 years, there were 380 cases of incident AF in former consumers. Both before and after adjustment for potential confounders, a longer duration of alcohol abstinence was associated with a lower risk of developing AF; previously consuming alcohol for a longer duration and consuming a greater quantity of alcohol were each associated with a higher risk of developing AF (Table). Conclusions: Among former drinkers, the number of years of drinking and the amount of alcohol consumed may each confer an increased risk of AF. Given that a longer duration of abstinence was associated with a decreased risk of AF, modification of alcohol use could potentially play a role in AF prevention.