tbuckley/cabot-search huggingface dataset:
Efficacy of bevacizumab and temozolomide in locally advanced and metastatic hemangiopericytoma (HPC) and malignant solitary fibrous tumor (SFT).
Authors: Mario De Lemos, Isabell Kang, Adeline Markarian, Nadine Badry
Journal: Journal of Clinical Oncology (2017)

e22535 Background: Patients with locally advanced, recurrent or metastatic HPC/SFT are often treated with a combination of BEV/TEM based on the clinical efficacy reported in a cases series of 14 patients (Park MS, et al. Cancer 2011). BEV is costly and this regimen should ideally be supported with further data. Given the rarity of HPC/SFT, large trials are not feasible. We report the efficacy of this regimen based on population-based analysis. Methods: This was a population-based retrospective, multi-centre analysis using patient data from the BC Cancer Agency, a government funded, integrated care organization which delivers cancer drug therapy through a network of cancer centres in the province of British Columbia, Canada. Cases from June 2006 through October 2016 were identified from the provincial registry and systemic therapy drug database for patients receiving at least one treatment of BEV/TEM for histologically diagnosed locally advanced, recurrent or metastatic HPC/SFT. The primary outcome was overall response rate (ORR) based on changes of lesion size in computerized tomography scan and clinical assessment through chart review. Secondary outcomes included time to response, progression free survival (PFS) and overall survival (OS), estimated using the Kaplan-Meir method. Results: Fourteen patients were identified: median age 59 (range 44-70), male 78.6%. Diagnoses were HPC 4 (28.6%) and SFT 10 (71.4%), with metastatic disease in 10 (72.7%) patients. Primary sites were: meninges 4 (28.6%), lung/pleura 2 (14.3%), pelvis 3 (21.4%), abdominal wall 2 (14.3%), gluteal regional 1 (7.1%), others 2 (14.3%). Eleven (78.6%) patients had no prior drug therapy. The median follow-up was 15.5 months, with median treatment of 4 months. ORR was 21.4% with median time to response of 4 months (3 [21.4%] partial response, 10 [71.4%] stable disease, 1 [7.1%] progressive disease). Median PFS, 6-month PFS and OS were 17 months, 65.0%, and 45 months, respectively. Conclusions: Efficacy of BEV/TEM in HPC/SFT appeared to be similar to that previously reported. PFS and OS were longer in our patients, probably reflected by having most patients with SFT and less heavily pretreated.
Preliminary results of ENCORE 601, a phase 1b/2, open-label study of entinostat (ENT) in combination with pembrolizumab (PEMBRO) in patients with non-small cell lung cancer (NSCLC).
Authors: Melissa Lynne Johnson, Alex A. Adjei, Suresh S. Ramalingam, Pasi A. Janne, George Dominguez, Dmitry Gabrilovich, Laura Deleon, Jeannette Lynne Hasapidis, Scott J. Diede, Peter Ordentlich, Matthew David Hellmann
Journal: Journal of Clinical Oncology (2016)

e20659 Background: Treatment with single agent PD-1 blockade improves survival in patients with chemotherapy-refractory NSCLC, yet only a minority respond. Rational combination approaches are needed to improve frequency, depth, and durability of response. ENT is an oral, class I selective histone deacetylase (HDAC) inhibitor. In animal models, ENT selectively reduces immunosuppressive myeloid derived suppressor cells (MDSCs) and enhances response to immune checkpoint blockade. ENCORE 601 is a Ph1b/2 study designed to evaluate ENT in combination with PEMBRO in patients with advanced NSCLC or melanoma. Methods: Patients with Stage III/IV NSCLC previously treated with platinum-based chemotherapy were enrolled in the 3+3 dose escalation phase. ENT 3mg qW and 5mg qW PO + PEMBRO 200mg q3W IV in 21-day cycles were explored to determine the safety and MTD or RP2D. Planned correlates included tumor PD-L1 expression and change in MDSCs and regulatory T cells in peripheral blood. Results: To date, 9 patients have been enrolled (6 @ 3mg qW and 3 @ 5mg qW). No DLTs have been observed in 8 of 9 patients. One patient, treated at ENT 3mg, developed grade 3 elevated alkaline phosphatase and bilirubin during cycle 2, which were considered manifestations of immune-mediated hepatitis; this was successfully and rapidly managed by holding study drugs and administering systemic corticosteroids. Stable disease has been observed in 3 of 6 patients thus far evaluated. The longest ongoing patient is in cycle 8. In 2 of 3 patients with paired peripheral blood samples, decreases in MDSCs from baseline were observed. Nine (9) additional patients are being enrolled in the dose confirmation phase of 1b; updated safety, efficacy, and correlative data will be reported. Conclusions: ENT combined with PEMBRO appears to be well tolerated and has preliminary immunomodulatory activity as hypothesized. Clinical trial information: NCT02437136.
Multiple testing strategies for clinical trials with co-primary endpoints in all comers and a subgroup.
Authors: Jiaheng Qiu, Vivian Ng, Yan Li, Qi Xia
Journal: Journal of Clinical Oncology (2016)

e14041 Background: In this new era of precision medicine, subgroup analyses have become increasingly critical for the success of oncology drug development. When the treatment benefit is still uncertain in the subgroup, sometimes registrational trials are designed to have co-primary endpoints, e.g. the same endpoint tested in both the all comer population and a (biomarker specified) subgroup with the family-wise Type 1 error being strongly controlled. Many multiple testing methods have been proposed and applied to address multiplicity issues for such designs. In this work we did a comprehensive review of current methods and compared their advantages and disadvantages. Methods: In a simple scenario of testing one endpoint in an oncology trial, assuming known sample size, randomization ratio and hazard ratio in subgroup and all comers, respectively, we reviewed six alpha spending methods including Bonferroni's method, fixed sequence method, Hochberg's step up method, Holm's step-down method, alpha fall back method, and flexible alpha spending method(by Alosh and Huque) as well as their variations by taking the correlation between the two populations into consideration. Comparisons were made in terms of the power of rejecting the null hypothesis in all comers, subgroup, or either group under different parameter settings. The optimal alpha sharing strategy under different scenarios was then explored. Results: A function in R was developed for the comparison of six methods. Hochberg's method consistently outperforms Bonferroni's and Holm's method in all scenarios. By taking consideration of the correlation between subgroup and all comers, the performance of Bonferroni's, Hochberg's and Holm's methods are all improved. The choice of an optimal method strongly depends on the strategic context of each trial. But among the six methods including the variations discussed in this work, flexible alpha spending method by Alosh and Huque seems to outperform other methods when alpha is appropriately allocated between the subgroup and all comers. Conclusions: Our work provided a practical tool for users to compare the pros-and-cons and make trade offs between different alpha-spending methods under possible scenarios.
Cost-utility analysis of panitumumab use compared with cetuximab and bevacizumab for the first-line therapy of <i>wild-type</i> <i>RAS</i> metastatic colorectal cancer in the Peruvian health system.
Authors: Valderrama Milton, Moises Apolaya-Segura, Paola Catherine Montenegro
Journal: Journal of Clinical Oncology (2017)

e15171 Background: To estimate the cost-utility of Panitumumab compared to Cetuximab (Erbitux®) and Bevacizumab (Avastin®) for the first-line therapy of metastatic colorectal cancer in the Peruvian health system Methods: A cost-utility analysis was performed using a Markov's model based in epidemiological parameters, metastatic colorectal cancer (mCRC) associated costs, and the efficacy of therapy using specific monoclonal antibodies against wild-type RAS mCRC. The costs of biological agents were estimated from the payers' viewpoint, using a 3.5% discount rate. The model includes the transition between five health states (mCRC, surgery, remission, progression, and death), and each cycle lasts for one month in a 3-year temporal horizon Results: The results of the model indicate that Bevacizumab and Panitumumab were cost–effective compared with Cetuximab. Therapy using Bevacizumab for a three-year period cost PEN 178,950.96 less than Panitumumab, but generated 0.91 less QALYs. The incremental cost-effectiveness ratio (ICER) showed that Cetuximab had extended dominance when compared to Panitumumab and Bevacizumab. This means that Panitumumab is more expensive, but it leads to a greater clinical benefit. Conclusions: Using the best published data available, these results suggest that the clinical effectiveness of Panitumumab and Bevacizumab translates into a favorable cost-utility ratio; and it particularly generates savings. The use of Panitumumab is associated to a longer survival, more QALYs gained and more months in remission.
Correlation between PD-L1 expression level and clinical benefit in 204 patients across malignancies at a single institution.
Authors: Kenneth Byrd, Panduka Nagahawatte, Michael Gary Martin, Matthew K Stein, Kruti Patel, Lee Steven Schwartzberg, Ari M. Vanderwalde
Journal: Journal of Clinical Oncology (2017)

e14573 Background: The utility of PD-L1 expression levels in predicting response to anti-PD-1 agents in many malignancies is uncertain. In this study, we describe outcomes of patients treated with anti-PD-1 agents by PD-L1 expression level. Methods: Molecular profiling of tumors in patients with newly diagnosed metastatic cancer was performed at West Cancer Center starting late 2014. Most profiling was performed by Caris, which in addition to NGS also reports PD-L1 expression (IHC, reported as percent expressed). Patients were included in this retrospective analysis if they were treated with an anti-PD-1 antibody and had available results from PD-L1 testing between 11/2014 and 11/2016. Time to treatment failure (TTF) was defined as time from first dose to documented progression, intolerance or death. Those without treatment failure were censored at the date of last contact. Pending formal retrospective RECIST review, clinical benefit rate (CBR) is reported. Results: 204 patients with reported PD-L1 expression started treatment with anti-PD-1 agents. Of these, 125 had non-small cell lung cancer, 31 had melanoma, 12 had renal cell carcinoma, and the remainder had other malignancies. 110 patients (54%) had PD-L1 expression level of 0%, 22 patients (11%) between 1-4%, 37 patients (18%) between 5-49%, and 35 patients (17%) &gt;50%. Median TTF and CBR by PD-L1 overall and by malignancy are shown in the table below. Conclusions: Higher PD-L1 expression does appear to be associated with increased clinical benefit rate and time to treatment failure, though the highest levels of PD-L1 did not follow this pattern. Based on these surrogate endpoints, there appears to be substantial benefit with PD-1 inhibitor treatment even with 0% PD-L1 expression. Objective response rate will be presented. [Table: see text]
Long-term renal function after treatment for Wilms tumor: A report from the St. Jude Lifetime Cohort (SJLIFE) study.
Authors: Daniel M. Green, Mingjuan Wang, Matthew J. Krasin, Andrew M. Davidoff, Deo Kumar Srivastava, Dennis W. Jay, Kirsten K. Ness, Barry L. Shulkin, Jennifer Q. Lanctot, Kyla C. Shelton, Rachel Christine Brennan, Matthew J. Ehrhardt, Todd M. Gibson, Beth A. Kurt, Leslie L. Robison, Melissa M. Hudson, Sheri L. Spunt
Journal: Journal of Clinical Oncology (2018)

10566 Background: The impact of specific treatment modalities on long-term renal function among adult survivors of Wilms tumor (WT) has not been well-documented. Methods: We clinically evaluated 40 WT survivors and 35 non-cancer controls (NCC) with creatinine and cystatin C, estimated the glomerular filtration rate (eGFR) using the Chronic Kidney Disease – Epidemiology (CKD-EPI) equations with and without cystatin C, and, among survivors only, measured 99mTc diethylenetriamine pentaacetic acid (DTPA) plasma clearance. WT survivors consisted of 20 treated with unilateral nephrectomy (UN), non-nephrotoxic chemotherapy (NNC) and whole abdomen radiation therapy (WART) (mean – 20.2 Gy; standard deviation (SD) – 9.12 Gy), and 20 treated with UN, no radiation therapy, and NNC. Pairwise comparisons between WT survivors treated with and without WART, and of each group to NCC were performed using two-sample t-test. Results: WT survivors were female (n = 26), non-Hispanic white (n = 33). Results are shown in the Table. Conclusions: Among WT survivors who have undergone UN, long-term renal function is normal in those without WART, and only mildly impaired in some with WART. These data can guide development of future surgical recommendations for patients with WT. WART No WART Controls WART vs. No WART No WART vs Controls WART vs Controls Mean (SD) Mean (SD) Mean (SD) p-value p-value p-value Age at diagnosis (years) 4.0 (2.5 ) 2.3 (1.6) - 0.013 Age at evaluation (years) 33.7 (5.2 ) 28.8 (4.0) 31.5 (5.6) 0.002 0.069 0.152 Elapsed time from diagnosis (years) 30.1 (5.0) 26.9 (4.5) - 0.040 Creatinine (mg/dL) 0.9 (0.2) 0.9 (0.2) 0.8 (0.1) 0.754 0.190 0.078 Cystatin C (mg/L) 1.0 (0.2) 0.9 (0.2) 0.9 (0.1) 0.494 0.139 0.024 24-hour urine protein (mg/24 hours) 59.5 (35.7) 146.3 (312.2) 18.5 (80.3) 0.231 0.087 0.013 eGFR (CKD-EPI) (creatinine only) (ml/min/1.73m2) 88.7 (17.0) 96.9 (22.7) 99.9 (19.2) 0.204 0.606 0.035 eGFR (CKD-EPI) (creatinine and cystatin C) (ml/min/1.73m2) 90.3 (15.3) 87.4 (14.8) 102.9 (13.8) 0.147 0.173 0.003 99mTc DTPA plasma clearance (ml/min/1.73m2) 75.6 (12.1) 91.2 (17.9) - 0.004
Novel In Situ Gelling Hydrogels Loaded with Recombinant Collagen Peptide Microspheres as a Slow‐Release System Induce Ectopic Bone Formation
Authors: Shorouk Fahmy‐Garcia, Didem Mumcuoglu, Laura de Miguel, Veerle Dieleman, Janneke Witte‐Bouma, Bram C. J. van der Eerden, Marjolein van Driel, David Eglin, Jan A. N. Verhaar, Sebastiaan G. J. M. Kluijtmans, Gerjo J. V. M. van Osch, Eric Farrell
Journal: Advanced Healthcare Materials (2018)

Abstract New solutions for large bone defect repair are needed. Here, in situ gelling slow release systems for bone induction are assessed. Collagen‐I based Recombinant Peptide (RCP) microspheres (MSs) are produced and used as a carrier for bone morphogenetic protein 2 (BMP‐2). The RCP‐MSs are dispersed in three hydrogels: high mannuronate (SLM) alginate, high guluronate (SLG) alginate, and thermoresponsive hyaluronan derivative (HApN). HApN+RCP‐MS forms a gel structure at 32 ºC or above, while SLM+RCP‐MS and SLG+RCP‐MS respond to shear stress displaying thixotropic behavior. Alginate formulations show sustained release of BMP‐2, while there is minimal release from HApN. These formulations are injected subcutaneously in rats. SLM+RCP‐MS and SLG+RCP‐MS loaded with BMP‐2 induce ectopic bone formation as revealed by X‐ray tomography and histology, whereas HApN+RCP‐MS do not. Vascularization occurs within all the formulations studied and is significantly higher in SLG+MS and HApN+RCP‐MS than in SLM+RCP‐MS. Inflammation (based on macrophage subset staining) decreases over time in both alginate groups, but increases in the HApN+RCP‐MS condition. It is shown that a balance between inflammatory cell infiltration, BMP‐2 release, and vascularization, achieved in the SLG+RCP‐MS alginate condition, is optimal for the induction of de novo bone formation.
Abstract 15179: Photoplethysmography Using a Smartphone Application for Assessment of Ulnar Patency Prior to Transradial Angiography
Authors: Pietro Di Santo, David T Harnett, Trevor Simard, F. D Ramirez, Ali Pourdjabbar, Altayyeb Yousef, Robert Moreland, Jordan Bernick, George Wells, Alexander Dick, Michel R Le May, Marino Labinaz, Derek Y So, Aun-Yeong Chong, Benjamin Hibbert
Journal: Circulation (2016)

Introduction: The transradial approach for coronary angiography and percutaneous intervention is increasingly used due to a lower incidence of vascular complications, patient preference and a poten...
Neurocognitive functions and psychological distress in young adults with cancer (YAC): A prospective, longitudinal study.
Authors: Kim Edelstein, Norma Mammone D'Agostino, Gregory Russell Pond, Petr Kavan, Abha A. Gupta, Sylvie Aubin, Andrew Matthew, Kate Wahl, Michael Crump, David C. Hodgson, Philippe L. Bedard, Thierry Muanza, Gerald Batist, Lori J. Bernstein
Journal: Journal of Clinical Oncology (2017)

10064 Background: Non-CNS cancer and treatments are associated with neurocognitive sequelae in older adults; whether YAC (age 18-39 yrs) are protected from these effects is unknown. In YAC, cancer interferes with education and occupational attainment and is associated with psychological distress. This prospective, inception-cohort study characterizes neurocognitive functions and psychological distress in YAC. Methods: YAC completed a 2-hr battery of standardized neurocognitive tests and questionnaires 1.7 ± 1 months after diagnosis prior to chemotherapy (mean ± SD, T1) and 8.2 ± 1.2 (T2) and 14.2 ± 1.6 (T3) months later. Healthy YA with no cancer history (HYA) were tested at similar time points. Tests were scored using published norms, transformed to T-scores, and grouped into neurocognitive domains. Results: YAC (n = 108; lymphoma, breast, gyne, GI, GU, sarcoma) were grouped according to whether they required chemotherapy (n = 70) or not (n = 38), and compared to 63 HYA. At baseline, there were no group differences in neurocognitive performance, number of impaired tests, or neurocognitive complaints (Kruskal Wallis, all p-values &gt; .4). About 70% of each group completed assessments at T2 and T3. Mean performance improved over time (random effects models, all p-values &lt; .01), but there were no group differences or interactions between group and time. There were also no differences in proportions of participants in each group whose test scores improved ( &gt; 10 points) or declined ( &lt; 10 points) from T1 to T2 or T3. Adjusting for psychological distress, fatigue, or neurocognitive complaints did not change these results, despite higher symptoms of somatic distress, anxiety and fatigue in YAC compared to healthy YA over time (all p-values &lt; .03). Conclusions: Before chemotherapy and up to about 14 months later, YAC have elevated distress and fatigue, but do not demonstrate the cognitive decline reported in older cancer patients. Our findings are consistent with research suggesting that aging brains are more vulnerable to neurotoxic insult. Whether the effects of cancer treatment emerge later in YAC, placing them at risk for accelerated aging as reported in older patients, remains to be examined.
Second-line prescribing preferences of U.S. hematology-oncology physicians for patients (pts) with recurrent multiple myeloma (MM): Impact of novel agents.
Authors: Robert Z. Orlowski, Joanne P. Willey, Maria L. Lankford, Arden Buettner, Stewart Kaufman, Susan Lynne Britton, Mitchell Scharf, Brynn Tiscione, Doug B. Neely, Joel H. Schwartz
Journal: Journal of Clinical Oncology (2016)

8061 Background: In July 2015, the combination of carfilzomib (K), lenalidomide (R) and dexamethasone (d) was approved for pts with recurrent MM after 1-3 prior lines of therapy (Rx). In 2015 we studied PPrefs of 360 U.S.-based hematology-oncology physicians for 2nd line Rx across a range of scenarios. Methods: PPrefs were assessed through a validated, case-based market research tool. Assessment dates in 2015 were 3/21; 5/2 (PRE-) and 8/8; 11/7 (POST-approval). Data were acquired using blinded, audience-response technology. A core scenario (CS) with 2 variant scenarios (V1, V2) was utilized. CS: 59-year-old (42% plasma cells in BM, no cytogenetic abnormalities, CrCl 65 ml/min, B2M 5.8, PS 1) treated with induction therapy of choice achieves a CR. V1: Pt has stem cell transplant (SCT), followed by maintenance (maint) R 10 mg. The same query was posed in each of 3 settings: Recurrence while on maint R at 24 months (mos), or at 11 mos or at 6 mos. V2: All equal to CS except SCT deferred; maint R x 18 mos; stopped per pt. Recurred 10 mos after stopping maint. Results: PPrefs by scenario in table below. Conclusions: Following the approval of the KRd triplet, overall PPrefs for triplet therapy increased across all 2nd line scenarios, with a 2.5 – 5 fold increase in the use of KRd and a nearly 2 fold increase in the use of KPd, despite the lack of approved indication for the latter combination. Time to Recurrence V1 24 mos V1 11 mos V1 6 mos V2 28 mos PPref PRE N = 171 POST N = 189 p PRE N = 172 POST N = 191 p PRE N = 169 POST N = 189 p PRE N = 172 POST N = 183 p Doublet Rx† 60% 50% 63% 40%* < 0.0001 52% 23%* < 0.0001 60% 47%* 0.0146 Triplet Rx 39% 50%* 0.0368 36% 60%* < 0.0001 48% 77%* < 0.0001 34% 50%* 0.0025 R+bortezomib (V)+d 12% 4% 5% 1% 4% 0 13% 7% KRd 11% 28%* 0.0001 10% 29%* < 0.0001 5% 25%* < 0.0001 9% 27%* < 0.0001 KPd 6% 13%* 0.0255 13% 25%* 0.0048 25% 46%* 0.0001 6% 13%* 0.0259 Pomalidomide(P)+V+d 6% 3% 6% 3% 9% 4% 3% 2% Panobinostat + V + d 4% 2% 2% 2% 4% 2% 3% 1% Other 1% 0 1% 0 1% 0 6% 3% *Significant change from pre-approval period; p-values shown only for Triplet, Doublet, KRd and KPd regimens when P < 0.05 †Doublet Rx includes Rd, Vd, Kd, Pd
Genomic amplification of CDK4 in dedifferentiated liposarcomas as a predictive biomarker for microtubule disrupting agents.
Authors: Bryce Demoret, Andrew Rogers, Nathan David Seligson, Esko Antero Kautto, John L. Hays, James Lin Chen
Journal: Journal of Clinical Oncology (2018)

11581 Background: Dedifferentiated liposarcoma (DDLPS) represents a common but morbid subtype of sarcoma. Microtubule disrupting agents (MDA), including eribulin and taxanes, disrupt the cell cycle and have modest clinical activity in patients with DDLPS. Unfortunately, no clinically validated biomarkers exist to predict MDA response in this population. DDLPS is characterized by amplification of cyclin-dependent kinase 4 (CDK4), which regulates the cell cycle. We hypothesized that CDK4 amplification may predict response to MDAs. Methods: 25 DDLPS trial patients (NCT01574716) who received docetaxel as part of their therapy and for whom tissue was available were profiled using DNA next generation sequencing (NGS) to quantify CDK4 copy number alteration. Patients were divided into CDK4-high and -low cohorts based on median amplification level. Progression-free survival (PFS) was calculated using Kaplan-Meier analysis. Patient derived DDLPS cell lines (LPS246, LPS815, LPS863) were analyzed for CDK4 amplification level via NGS. Sensitivity to MDA (eribulin and docetaxel) was quantified using cell viability assays. CDK4 activity was attenuated using palbociclib and drug synergy was ascertained via Chou-Talalay algorithm. Results: DDLPS patients treated with MDA revealed patients’ CDK4 levels greater than median had improved median PFS compared to patients with CDK4 levels lower than median (19.7 vs 11.1 m, p = 0.03). This suggested improved biologic activity of MDAs in CDK4-high tumors, and was further investigated using in vitro models. DDLPS cell lines were characterized for sensitivity to eribulin and docetaxel. LPS246 had the highest CDK4 gene copy number vs. LPS815 and LPS863 (1373, 533, 563 transcripts per cell, respectively) and showed a greater sensitivity to both docetaxel and eribulin compared to LPS815 and LPS863 in cell viability assays. Pharmacologic inhibition of CDK4 demonstrated drug antagonism (avg. CI > 1.3). Conclusions: These data suggest that MDA sensitivity in DDLPS may be associated with levels of CDK4. Prospective clinical trials are needed to confirm whether CDK4 expression levels may predict response to eribulin and other microtubule disrupting agents.
NKILA lncRNA promotes tumor immune evasion by sensitizing T cells to activation-induced cell death
Authors: Di Huang, Jianing Chen, Linbin Yang, Qian Ouyang, Jiaqian Li, Liyan Lao, Jinghua Zhao, Jiang Liu, Yiwen Lu, Yue Xing, Fei Chen, Fengxi Su, Herui Yao, Qiang Liu, Shicheng Su, Erwei Song
Journal: Nature Immunology (2018)