tbuckley/cabot-search huggingface dataset:
Locoregional treatment of ‘immune escape' metastatic melanoma in the setting of immune checkpoint inhibition for widespread disease.
Authors: Maria Frances Coakley, David Cormican, Cynthia Heffron, Richard Martin Bambury, Deirdre O'Mahony, Seamus O'Reilly, Henry Paul Redmond, Derek Gerard Power
Journal: Journal of Clinical Oncology (2016)

e14544 Background: Metastectomy confers a survival advantage in advanced melanoma in appropriately selected patients. Combining local therapies, e.g. surgery and electrochemotherapy (ECT) with immune checkpoint inhibitors is largely unexplored. No histopathology analysis has been previously reported on resected specimens from patients receiving pembrolizumab. Methods: In a cancer center in Ireland we collected data on patients with metastatic melanoma (MM) who received sequenced or combined surgery, ECT and pembrolizumab. Histolopathological analysis of the resected surgical specimens was performed. Results: Case1: A 36-year-old female with BRAF wild type(wt) widespread MM, following ipilimumab, was commenced on pembrolizumab due to progressive disease. Following 19 cycles of pembrolizumab, two growing FDG-avid lesions were resected in sequence from both lungs. Three months later, she continues pembrolizumab with stable metastatic disease. Case 2: A 65-year-old male with BRAF wt MM, after progression of disease on ipilimumab was commenced on pembrolizumab. Following 12 cycles of pembrolizumab, intracranial metastatic disease was found on neuroimaging. These areas were resected and whole brain RT was preformed. He recovered well, and continues pembrolizumab therapy. Case 3: A 33-year-old male with BRAFV600 mutated MM, after progression of disease on ipilimumab was commenced on pembrolizumab. During treatment, he received ECT to growing neck disease, and 2 growing lesions were resected from his back. He remains clinically well after 17 cycles of pembrolizumab. On histopathologic analysis, four resected specimens showed a non-brisk lymphocyte infiltration (from 3 patients). Conclusions: We found combining pembrolizumab and local measures to be safe and effective in highly selected MM patients. Histopathologic analysis showed a limited lymphocyte infiltration in specimens suggesting these deposits were sanctuary sites with mechanisms of immune escape and resistance to PD1 directed therapy, supporting the rationale for resection of the lesions. Further research and a longer follow up time is required to further evaluate this practice.
P04.12 The preclinical efficacy study using mesenchymal stem cells expressing TRAIL & CD for glioblastoma.
Authors: S Ahn, S Jeun
Journal: Neuro-Oncology (2018)

Our previous study using mesenchymal stem cells (MSCs) as delivery vehicles for tumor necrosis factor-related apoptosis inducing ligand (TRAIL) showed an anti-tumor effect in vitro and in vivo for glioblastoma. However, because most malignant glioma cells exhibit TRAIL resistance, we need to find new strategies to overcome it. We developed MSCs expressing both TRAIL and cytosine deaminase (CD) which convert the prodrug 5-fluorocytosine (5-FC) to the cytotoxic agent 5-fluorouracil (5-FU). We also immortalized these MSCs and introduced a doxycycline-dependent gene-inducible system to maintain the quality control. Lastly, we enhanced tumor tropism by overexpression of CCR2 and CXCR4. In this study, we investigated the anti-tumor efficacy of our novel MSCs (BM-03) with a 5-FC in vitro and in vivo orthotopic xenograft glioblastoma model. Human bone marrow-derived MSCs were isolated and cultured as described previously after approval by our institutional review board. The multiple genes mentioned above were transfected into the MSCs using a lentivirus vector system. Using a U87 human glioma cell line and male athymic nude mice, we developed an orthotopic glioblastoma xenograft model. We injected BM-03 in a dose-dependent manner (control; low dose, 2.0X104 cells; intermediate dose, 1.0X105 cells, and high dose, 5.0X105 cells) intratumorally with the intraperitoneal injection of 5-FC (500 mg/kg). Additionally, with in vivo bioluminescence imaging, we assessed the tumor volume. First, we confirmed the doxycycline-dependent inducible gene expression system of BM-03 and showed the high expression of TRAIL, CCR2, and CXCR4 using FACS analysis. The synergistic anti-tumor efficacy of BM-03 with 5-FC was shown compared with BM-03 alone, in vitro. Moreover, we revealed the enhanced tumor tropism of BM-03 using in vivo bioluminescence imaging. After BM-03 injection of the contralateral side of the tumor, we could see that our MSCs moved toward the inoculated tumor lesion located on the contralateral side. Finally, when treated with BM-03 and 5-FC, we showed an increased antitumor efficacy in terms of both the median survival rate (control, 44 days; low dose, 46 days; intermediate, 57 days, and high dose, 69 days) and the tumor volume in a dose-dependent manner compared with the control and BM-03 only in the orthotopic xenograft glioblastoma mouse model. Our novel immortalized and inducible MSCs expressing TRAIL and CD showed an enhanced antitumor efficacy in an orthotopic xenograft glioblastoma model. This successful preclinical result will serve as a foundation for IND approval and a phase I clinical trial using our novel MSCs (BM-03).
Do pancreas cancer stem cells play crucial role in survival outcome?
Authors: Gokce Askan, Ibrahim Halil Sahin, Marinela Capanu, Mesruh Turkekul, Kenneth H. Yu, Maeve Aine Lowery, Olca Basturk, Christine Iacobuzio-Donahue, Eileen Mary O'Reilly
Journal: Journal of Clinical Oncology (2017)

e15721 Background: Recent studies indicate that pancreatic cancer stem cells (CSC) may predict disease behavior and survival outcomes of pancreatic ductal adenocarcinomas (PDACs) patients (pts). Several CSC markers have been reported in PDAC (Fitzgerald, TL, 2014). We herein evaluated the impact of CSC markers including CD44 and Epithelial Specific Antigen (ESA) on survival outcome of PDAC pts who had liver or lung metastasis after initial surgical resection (IR). Methods: Clinicopathologic features and survival of 59 PDACs were analyzed. Pts with IRB approval, and whom had available primary tumor tissue, were included. All neoplasms were immuno labeled with CD44 and ESA. Staining intensity was scored as weak (1), moderate (2), strong (3), while the staining pattern was scored as: few (1), patchy (2), and diffuse (3). The expression for CD44 and ESA was accepted positive if total score ≥4. Time from relapse to death (TRD) was estimated using the Kaplan-Meier method censoring patients that were alive at the last follow up. Survival curves were compared using the log-rank test Results: Of 59 pts, 42 (71 %) had liver, 10 (17%) had lung and 7 (12%) had both liver and lung metastasis. M/F = 34/25; mean age = 64.2 (range, 34-90). Patients were subcategorized as follows; thirteen cases were CD44 (+)/ESA (-) (group1) and 13 were CD44 (-)/ESA (+) (group 2). Eight (61.5%) of group 1 tumors and 2 (15.3%) of group 2 were poorly differentiated. At last follow-up, except one with 63 months survival, all pts died of disease with 23.3 months (range, 3-67) median OS. No significant difference in TRD was observed between group 1 (6.9 months) and 2 (13.8 months) (p = 0.62). However, we observed group 1 tumors had worse OS (12 months) compared to group 2 (36 months). Conclusions:A worse outcome trend was observed for pts with CD44 (+)/ESA (-), albeit not statistically significant and likely limited by small numbers. Further studies are warranted to evaluate the robustness of this observation.
Optimized economic evaluation for the United States (US) of nab-paclitaxel plus gemcitabine (NAB-P+GEM), FOLFIRINOX (FFX), and gemcitabine (GEM) as first-line treatment for metastatic pancreatic cancer (mPDA).
Authors: Mahdi Gharaibeh, Ali McBride, J. Lyle Bootman, Hitendra Patel, Ivo Abraham
Journal: Journal of Clinical Oncology (2016)

4113 Background: Per conference feedback we optimized our 2015 ASCO reported independent economic evaluation of GEM, NAB-P+GEM, and FFX in mPDA by improving survival curve fitting (exponential v. Weibull distributions) and modifying disease monitoring. Methods: We used published direct efficacy estimates of GEM v. FFX or NAB-P+GEM, complemented by FFX v. NAB-P+GEM efficacy estimated with Bucher’s indirect comparison method. Kaplan Meier curve fit was tested for exponential and Weibull parametric distributions. A state transition model with full time horizon was used to estimate the life years (LY) and quality-adjusted life years (QALY) gained and incremental cost-effectiveness (ICER) and cost-utility ratios (ICUR) (payer perspective; 3%/year discount rate; 2015 US$). We did not benchmark to categorical thresholds as pharmacoeconomic analysis is to inform, not determine, policy or clinical practice. Results: Per Bucher method, HR for NAB-P+GEM vs. FFX was 1.47 (95%CI = 1.10-1.96) for PFS and 1.26 (95%CI = 0.95-1.67, p = ns) for OS indicating superiority in PFS for FFX but no superiority in OS for either regimen.In direct comparison, differentials for FFX over GEM were +0.372 LY and +0.257 QALY gained for ICER of $252,474/LY and ICUR of $365,530/QALY at incremental cost of $93,941; for NAB-P+GEM over GEM +0.182 LY and +0.130 QALY for ICER of $136,202/LY and ICUR of $190,349/QALY at incremental cost of $24,751. In indirect comparison, differentials for FFX over NAB-P+GEM were +0.19 LY and +0.127 QALY gained for ICER of $363,470/LY and ICUR of $544,803/QALY at an incremental total cost of $69,190. Conclusions: In the absence of a statistically significant (indirectly estimated) OS benefit of either NAB-P+GEM or FFX, the economic benefits in terms of cost-savings and incremental cost-effectiveness and cost-utility favor NAB-P+GEM over FOLFIRINOX therapy in mPDA.
Correlation of microRNA expression profile and prognosis of penile cancer: A prospective study using microarray data analysis.
Authors: Claudio Bovolenta Murta, Jose Pontes Jr, Tatiane Katsue Furuya, Miyuki Uno, Alexis Carrasco, Laura Sichero, Luisa Lina Villa, Mauricio Cordeiro, Giuliano Guglielmetti, Rafael Coelho, Katia Ramos Moreira Leite, Miguel Srougi, Roger Chammas, William Carlos Nahas
Journal: Journal of Clinical Oncology (2018)

e16590 Background: Penile cancer (PeC) is a rare disease that has high morbidity and mortality rates. Although a few biomarkers related to prognosis have been previously described, to date none of them was adopted in clinical practice. Our aim was to identify a molecular signature based on miRNA expression that could identify those patients with high risk for metastatic PeC. Methods: We prospectively collected fresh samples of primary tumors from 11 patients with squamous cell PeC who were treated between July/15 and June/17. Five patients had localized disease (non-metastatic group) and 6 had lymph node metastases (metastatic group). RNA microarray analysis was performed using miRNA 4.0 Genechip (Affymetrix). We identified differentially expressed miRNAs (DEmiRs) comparing metastatic to non-metastatic groups using TAC Software (Affymetrix), fold change (FC) > 1.5 and p < 0.05. RT-qPCR were used to validate the findings. Their validated/predicted targets were investigated using miRTarBase 7.0, mirWalk 2.0 and MetaCore 6.32 softwares. Results: Twenty two DEmiRs (17 up- and 5 downregulated) were identified. Hierarchical clustering analysis showed a set of 5 DEmiRs (miR-181c-5p, 744-5p, 196b-5p, 421, 149-5p) which clustered samples according to prognosis. Results of technical validations using RT-qPCR were presented in Table 1. Network interaction analyses identified the transcriptional factors (NANOG, Oct-3/4, SOX2 and c-Jun) that commonly regulate those DEmiRs. Moreover, TGFB, CMYC, RICTOR, ADAM-17 and PTEN are common targets of those DEmiRs and are more likely to be deregulated. Conclusions: We found 5 DEmiRs correlated with prognosis and capable of discriminate metastatic from non-metastatic tumors. In addition, their targets are enriched in cancer pathways and could be potential biomarkers in prognosis in PeC. Table 1. DEmiRs able to cluster accordingly with metastatic status and their fold changes (FC) in the microarray assay and after validation with qRT-PCR. DEmiR Microarray qRT-PCR FC p value FC p value miR-421 2.89 0.0005 2.03 0.068 miR-149-5p 6.30 0.0022 4.37 0.068 miR-744-5p 1.65 0.0010 1.85 0.028 miR-196b-5p 1.66 0.0245 1.72 0.082 miR-181c-5p 0.63 0.0314 0.70 0.018
The role of exosomes in promoting acquired resistance to gemcitabine and nanoparticle albumin-bound (NAB) paclitaxel in pancreatic ductal adenocarcinoma cells.
Authors: Moh'd M. Khushman, Girijesh K. Patel, Arun Bhardwaj, Sanjeev K. Srivastava, Mohammad Aslam Khan, Seema Singh, Benjamin Brandt, William R. Taylor, Ajay Singh
Journal: Journal of Clinical Oncology (2016)

e23253 Background: Acquired resistance to available chemotherapy is a major cause of treatment failure and poor prognosis in pancreatic ductal adenocarcinoma (PDAC). Exosomes, small (50-150 nm) secreted membrane-enclosed vesicles containing functional biomolecules, are important mediator of intercellular communication and play pivotal role in various physiological and pathological functions. However, the role of exosomes in chemoresistance has not fully explored. Here, we explored the role of exosomes in promoting acquired resistance to Gemcitabine and Nab-paclitaxel in PDAC. Methods: Conditioned media from vehicle-treated (V-CM), gemcitabine-treated (Gem-CM), nab-paclitaxel-treated (P-CM) and gem/nab-paclitaxel-treated (G/P-CM) PDAC (MiaPaCa and Colo-357) cells was collected and fractionated into soluble (Sol) and vesicular (EV) fractions. PDAC cells were pre-treated with Sol and EV fractions followed by treatment with various doses (0-80 μM) of gemcitabine, (0-100 nM) of nab-paclitaxel or both for different time intervals (48 and 72 h). EVs were separated by differential ultracentrifugation, size was determined using Dynamic Light Scattering (DLS) and assessed for their chemoresistance conferring activity in PDAC cells. Immunoblotting was performed to examine the specific markers associated with EVs. Results: Both Gem-CM and Gem-EV provided significant protection to gemcitabine-treated cells, while Gem-Sol had only negligible effect. DLS based-size distribution analysis identified EVs of three different size viz. large ( > 1500 nm), medium (500-1500 nm) and small (100-300 nm). Treatment of large and medium sized Gem-EVs did not show any chemoprotective effect in PDAC cells, while smaller Gem-EVs provided remarkable survival benefits to PDAC cells against gemcitabine treatment. Immunoblot data revealed that these active EVs are enriched with CD9 and CD63, specific markers of exosomes. Conclusions: Gemcitabine induces secretion of exosomes in PDAC cells and promoted acquired resistance. Studies are ongoing for Nab-paclitaxel-treated (P-CM) and Gem/Nab-paclitaxel-treated (G/P-CM) and will be reported in the meeting.
Type I and type IR PPB: An update from the International PPB Registry.
Authors: Gretchen M. Williams, Yoav H. Messinger, Douglas R Stewart, Louis P Dehner, Amanda Field, Anne Harris, D Ashley Hill, Kris Ann Pinekenstein Schultz
Journal: Journal of Clinical Oncology (2016)

10517 Background: Pleuropulmonary blastoma (PPB) is a rare lung neoplasm of early childhood. Purely cystic PPB, Type I, and the regressed form, Type Ir, are generally associated with a good prognosis. When Type I or Type Ir progress to cystic solid/completely solid high grade sarcoma (Type II and Type III), the outcome is much worse. This report provides an update on the outcome of a large group of patients with Type I and Type Ir PPB. Additionally, interim results from a small cohort of infants with prospectively identified DICER1mutations are reported. Methods: Central pathology reviewof 437 International PPB Registry cases collected since 1987 confirmed 115 individuals with Type I PPB and 40 with Type Ir PPB. The treating physician decided whether to use chemotherapy after surgery. Additionally 9 infants with DICER1 mutations underwent prospective surveillance imaging. Results: Type I PPB patients were young (median: 7 months; only one diagnosed after 65 months).Fifty-eight patients underwent surgery alone. Surgery was followed by chemotherapy in 43 patients. Therapy was unknown for 16 individuals. Type Ir PPB was diagnosed throughout childhood and adulthood (median: 41 months; range 3 months – 46 years). All Type Ir in this report underwent surgery; one also received chemotherapy. Overall 16/155 (10%) individuals with Type I or Type Ir PPB demonstrated progression, all by 53 months of age. Of those who received surgery plus chemotherapy, 3/45 (7%) progressed compared with 13/54 (24%) who underwent surgery alone. At last follow-up 109/115 (94.8%) of those with Type I PPB and 100% with Type Ir were alive. Nine individuals with prospectively identified DICER1mutations had surveillance lung imaging during infancy. Of these, 3 developed cysts that were removed. Two had Type Ir; one Type I. None of these children have received chemotherapy and all are without evidence of disease 4 to 19 months following surgery. Conclusions: Young children with Type I or Type Ir PPB may experience progression. Surveillance CT may detect cystic PPB before progression to Types II or III PPB. Risk of progression of asymptomatic cysts remains unknown. Type I PPB & Type Ir Progression No Progression Total Surgery + Chemotherapy 4 43 47 Surgery only 15 77 92 Unknown 0 16 16 Total 19 136 155
Clinical applicability of comprehensive genomic profiling (CGP) and assessment of tumor mutation burden (TMB): An Indian experience.
Authors: Amit Verma, Pramod Kumar Julka, Nitesh Rohatgi, Jatinder Kaur
Journal: Journal of Clinical Oncology (2018)

e24210 Background: Comprehensive genomic profiling (CGP) in tumors is used extensively globally since it provides insight into clinically relevant genomic alterations (GA), revealing new therapeutic options and guiding clinical decision making. Since limited experience is reported from India, we sought to evaluate the actionable targets and challenges. Methods: CGP was done on 120 advanced/refractory invasive cancer patients using the hybrid capture-based NGS that included calculation of TMB and MSI (FoundationOne, 106 cases; FoundationOne Heme, 14 cases). It detects all relevant classes of GA: base substitutions, small indels, rearrangements and copy number changes. TMB status was reported as low (≤5 Muts/Mb), intermediate (6-19 Muts/Mb) or high (≥20 Muts/Mb). The cohort consisted of 29 NSCLC, 14 breast, 6 Colon, 14 sarcoma, 13 unknown primary and other tumor types (44, 37%). Results: 183 genes were altered having 650 GA, of which 44 genes were actionable; affecting major pathways: apoptosis/cell cycle (34%), PI3K/AKT (23%), chromatin modification (12%), RAS/MAPK (9%), transcription regulation (7%) and others (15%). 95 (79%) patients had actionable mutations, of which 40 had > 1 actionable mutation. FDA approved therapy in patient tumor type was recommended for 42 and in another tumor type for 53 patients. Unfortunately in 43 (45%) patients corresponding target therapies (TT) were not approved in India. Similarly, of 1212 clinical trials recommended for all patients, none had India as a recruitment site and further not all patients meet the eligibility criteria. Immunotherapy (IT) was recommended in 5% (6/120) patients only: TMB was available for 103/120 patients, only 3 had high TMB that correlated with high MSI (p < 0.001); PDL1/PDL2 gene amplification was found in 3 patients. Conclusions: This is the first largest real world data from India demonstrating that CGP can identify mutations that could improve clinical decision making in routine cancer care, however, it is restricted because of the challenges viz. multiple actionable targets, lack of access to therapies and clinical trials, and low prevalence of high TMB status.
Variation in use of palliative care services in advanced colorectal cancers.
Authors: Mark Andrew Healy, Robert Wallace Krell, Vahagn A Nikolian, Christine Marie Veenstra, Scott E. Regenbogen, Samantha K. Hendren, Arden M. Morris, Sandra L. Wong, Pasithorn Amy Suwanabol
Journal: Journal of Clinical Oncology (2016)

e15016 Background: Palliative care services have been shown to have many benefits in patients with advanced colorectal cancers. However, it is unclear what factors drive variation in use of palliative care in these patients. We sought to determine factors associated with utilization of these services. Methods: Using the National Cancer Data Base (NCDB) Participant User File, we identified 144,290 patients diagnosed with Stage IV colorectal cancers. Using multilevel mixed-effects logistic regression, we examined odds of utilization of palliative care services with fixed effects from patient factors and random effects from hospital and regional factors in a hierarchical variance components model. Results: At the patient level, use of any palliative service was independently associated with increased age (OR: 1.01; 95% CI: 1.00 – 1.01; P < 0.001), black race (OR: 1.22; 95% CI: 1.14 – 1.31; P < 0.001), rectosigmoid primary tumor site (OR: 1.14; 95% CI: 1.05 – 1.24), and rectal primary tumor site (OR: 1.68; 95% CI: 1.59-1.77). Factors independently associated with not receiving palliative services included Charlson-Deyo comorbidity index ≥ 2 (OR: 0.10; 95% CI: 0.09 – 0.11; P < 0.001) and female sex (OR: 0.95; 95% CI: 0.91 – 0.99). Controlling for these patient-level factors, inter-hospital variation was responsible for 28.3% of the observed variance (95% CI: 25.9% – 31.0%), and inter-regional variation was responsible for 1.2% of additional observed variance (95% CI: 0.3% – 5.1%). Conclusions: In advanced colorectal cancers, patient and tumor factors appear to have a strong influence on use of palliative care services. Beyond this, hospital practice patterns appear to contribute substantially, accounting for over one quarter of observed variation in use of palliative care services. This suggests that hospitals are an appropriate target for interventions to increase availability of these services. Alternatively, high use hospitals may not have the institutional resources necessary to provide potentially curative treatments that are available at other hospitals. Further study is needed to better understand these observed differences.