tbuckley/cabot-search huggingface dataset:
Impact of deviated balance of regulatory and cytotoxic T cells on release and reseeding of circulating tumor cells in hepatocellular carcinoma.
Authors: Xin-Rong Yang, Yun-Fan Sun, Yang Xu, Zhou Jian, Jia Fan
Journal: Journal of Clinical Oncology (2013)

e22133 Background: Our previous data showed that a preoperative CTC ≥2 was significantly related with relapse of hepatocellular carcinoma (HCC) after surgery. However, how CTCs managed to evade immune surveillance, invade into circulation and reseed in the original organ still remains largely unclear. In this study, we illustrated the pro-tumor effect of Treg infiltration in the context of CTC releasing and reseeding. Methods: Using CellSearch system, 115 HCC patients were tested for CTCs prior to resection. Foxp3 + , CD8 + and Granzyme B-positive (GrB + ) tumor -infiltrating lymphocytes were evaluated by immunohistochemistry (IHC) in tissue microarrays. For IHC markers, the cutoff for stratification subsets was the median value. The pro-invasiveness properties of Tregs were analyzed in both in vitro and vivo assays. Results: Twenty-two patients with high Tregs and low activated CTLs in tumoral tissues had increased number of CTCs compared to 22 patients with low Tregs and high activated CTLs (6.68 vs. 0.91, P&lt;0.001). In 77 patients with detectable CTC, high Tregs and low activated CTLs in peritumoral tissues was significantly associated with an increased incidence of HCC recurrence (80.5% vs. 19.4%, P&lt;0.001), and was an independent prognostic factor for HCC early recurrence (P=0.007). Further in vitro study showed Tregs-derived TGF-β promoted HCC cell migration and invasion; down-regulated E-cadherin and up-regulated N-cadherin, vimentin, fibronectin and snail. The data in human tumor sample also showed that the TGF-β level had positive relationships with Treg count, N-cadherin level and CTC count; and had inverse relationship with E-cadherin (all P values &lt;0.05). In mice, depletion of Tregs by neutralizing antibody abolished intrahepatic colonization and lung metastasis. Conclusions: Local immune contexture in HCC orchestrates with biological behavior of CTCs. High intratumoral Tregs may promote the release of CTCs through inducing tumor cells EMT transition via TGF-β secretion. High peritumoral Tregs created an immune-subversive microenvironment by suppressing CTL to favor colonization of CTCs, which led to recurrence after HCC resection.
Evaluation of tumor marker cancer antigen 72-4 (CA 72-4) in the monitoring of metastatic or recurrent tumors of the gastrointestinal tract, lung, breast, and ovaries.
Authors: Anusiyanthan Isaac Mariampillai, Josephine Pineda Dela Cruz, Jason Suh, Abirami Sivapiragasam, Kyle Nevins, Alexander A. Hindenburg
Journal: Journal of Clinical Oncology (2017)

263 Background: In management of metastatic and recurrent cancers, measuring response is a constant challenge. CA72-4 is a tumor marker (TM) that has been found elevated in a variety of human adenocarcinomas, with reported sensitivities of up 50% and overall specificity of over 95%. Using the DRG TM-CA72-4 assay, we quantified the abnormality rate of TM CA72-4 compared with current FDA-approved TM in various cancers. Methods: We conducted a prospective, single center study by enrolling 96 patients between March 2013 and August 2016 with various de novo or previously diagnosed locally advanced, unresectable and/or metastatic cancers known to express CA72-4. Quantification of CA72-4 was performed according to manufacturer’s instructions using the DRG TM-CA72-4 ELISA kit, which was developed by DRG International (Germany) utilizing the CC-49 monoclonal mouse antibody directed against an epitope on the CA72-4 antigen. Positivity was calculated as greater than A) 0.8 U/mL or B) 4.0 U/mL based on systematic review of prior studies. Results: The positivity rates based on different cut-off points (0.8 U/mL vs 4 U/mL) and their corresponding FDA approved tumor markers are shown in the Table. Conclusions: Positivity rates of CA72-4 varied based on different assay cut-off levels with the highest positivity noted in the pancreatic, ovarian and colorectal carcinomas indicating a potential role for disease monitoring. [Table: see text]
Influence of combined cellular immunotherapy and chemotherapy on clinical outcome in patients with gastric carcinoma.
Authors: Jiuwei Cui, Ling yu Li, Chang Wang, Hao fan Jin, Cheng Yao, Yi zhuo Wang, Dan Li, Hui min Tian, Chao Niu, Guan jun Wang, Wei Han, Jian ting Xu, Jing tao Chen, Wei Li
Journal: Journal of Clinical Oncology (2015)

e15106 Background: Despite the availability of multiple treatment strategies, patients with gastric carcinoma (GC) have a dismal prognosis. Cellular immunotherapy (CIT) with multiple autologous non-MHC restricted immunocytes, such as natural killer cells, AAT cells, and cytokine-induced killer cells, has synergistic antitumor effects with chemotherapy and can also reduce the possibility of immune escape. The aim of this study was to evaluate the efficacy and safety of CIT combined with chemotherapy in patients with GC. Methods: Patients were treated with the combination therapy (chemo/CIT group) or chemotherapy alone (control group). Progression-free survival (PFS), overall survival (OS), quality of life (QOL), and adverse events were investigated. Results: 83 eligible GC patients were enrolled, and only 58 patients with complete clinical data were analyzed, 30 in the chemo/CIT group and 28 in the control group. The median PFS of the chemo/CIT group was significantly longer compared with the control group (p = 0.021). In subgroup analysis, in patients with stage III GC, node-positive metastasis, or poorly differentiated carcinoma, the 2-year PFS rates in chemo/CIT vs. control groups were 62.5% vs. 26.7% (p = 0.022), 50% vs. 27.3% (p = 0.016), 56.3% vs. 28.6% (p = 0.005), respectively. The median OS in either group has not yet been reached, and there was no significant difference in OS between the groups. The QOL improved in the patients treated with chemo/CIT compared with the control group. CIT was well tolerated and not related to any significant adverse events. Conclusions: A combination of CIT and chemotherapy for patients with GC was safe, improved QOL, and might prevent recurrence, especially in GC patients with advanced cancer, poorly differentiated carcinoma, or lymph node metastasis.
CD40 ligand/interferon-γ matured DC immunization with gp100 antigen HLA class I A *0201 restricted peptides in patients with newly diagnosed metastatic melanoma.
Authors: Gerald P. Linette, Michelle Becker-Hapak, Alexander Huang, Amer Alyasiry, Megan Chan, Wen-rong Lie, Lynn Cornelius, Jeffrey F. Moley, Rebecca Aft, Benjamin R. Tan, Kathryn Trinkaus, Beatriz M Carreno
Journal: Journal of Clinical Oncology (2012)

2525 Background: CD40L/IFN-γ matured Dendritic Cells (DCs) produce IL-12 and are potent antigen-presenting cells for naïve resting T cells. We sought to determine the magnitude and kinetics of CD8+ T cell growth in patients receiving autologous CD40L/IFN-γ matured DC and identify biomarkers associated with clinical outcome. Methods: A phase I clinical trial (NCT00683670) incorporating CD40L/IFN-γ for the ex vivo maturation of autologous DCs pulsed with three well characterized gp100 melanoma antigen derived peptides (G154, G209-2M, G280-9V) was initiated with enrollment from 2008-11 at a single center. HLA-A*0201+ individuals with treatment naïve metastatic melanoma were immunized every 3 weeks by intravenous infusion for six doses after a single dose of cyclophosphamide (300 mg/m 2 iv). CT imaging was performed at baseline, week 9 and 18 for clinical assessment using RECIST. Responding patients were eligible for maintenance doses every 2-4 months. PBMC were taken weekly for immune monitoring by tetramer analysis and functional assays. DC preparations were characterized to assess for biomarkers of response. Results: 10 patients were screened. Among the 7 treated patients, there were 3 confirmed responses (independently verified), including one durable CR &gt;3 years and 2 PR. Three patients had rapid disease progression and received only 3 doses. Four patients (1 CR, 2 PR, 1 PD) received 6 or more vaccine doses. No SAEs were noted. There was no correlation between tumor volume and response. Using pre-specified immune response criteria, 6 (86%) treated patients developed CD8+ T cell immunity to all three peptides as assessed by tetramer analysis. The vaccine-induced T cells from all 6 individuals were polyfunctional and killed gp100+, HLA-A2+ human melanoma targets in a standard 51 Cr release assay. IL-12 production by DCs correlated with TTP (p=0.0198, likelihood ratio test) but not OS (p=0.08). Conclusions: Weekly immune monitoring reveals the rapid onset of CD8+ T cell immunity against gp100 among the responder patients. This is the first DC vaccine clinical trial in melanoma to demonstrate a correlation of IL-12 production and TTP.
Bayesian network meta-analysis (NMA) comparison of second-line cytotoxic chemotherapies in advanced or metastatic gastric cancer.
Authors: Norihiro Yamaguchi, Takeo Fujii, Toshihisa Satta, Jaffer A. Ajani, Peter Kozuch
Journal: Journal of Clinical Oncology (2015)

e15055 Background: Many gastric cancers are diagnosed with incurable disease at initial presentation and need systemic chemotherapy. All cases become resistant to the first line treatment and recently second line treatment has been shown to improve survival when compared to best supportive care. We conducted a Bayesian NMA, a validated statistical methodology, which allows direct and indirect comparison among different regimens to identify a regimen with best response and toxicity profile. Methods: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and Google Scholar until January 1st 2015 were searched by two independent authors per standard meta-analysis procedure. We included RCTs assessing second-line regimens for advanced gastric cancer up to January 1st2015. We excluded two RCTs testing ramucirumab due to lack of data required to perform meta-analysis. Our outcome measure was response rate (RR) and Grade 3/4 adverse events (AEs). Bayesian pairwise and network meta-analysis was conducted to estimate pooled Odds Ratio (OR). Results: Five RCTs met our inclusion criteria. irinotecan (Iri) as the reference arm, liposomal irinotecan (PEP02), mFOLFIRI, biweekly irinotecan plus cisplatin (BIRIP), docetaxel, and paclitaxel were evaluated in these RCTs. No regimen can provide significantly better RR compared to Iri. mFOLFIRI trended to have more AEs than Iri. Conclusions: Our study showed that there is no significant difference among second-line regimens for advanced or metastatic gastric cancer with regard to response rate, but combination therapy trends to have more AEs. With individual patient data, we will be able to assess survival rate in the future. Efficacy Pooled OR 95% CI Iri vs BIRIP 0.84 0.22-3.18 Iri vs PEP02 0.72 0.29-1.75 Iri vs Docetaxel 0.66 0.22-2.02 Iri vs Paclitaxel 0.80 0.23-2.78 Iri vs mFOLFIRI 0.92 0.19-4.60 AEs Pooled OR 95% CI Iri vs BIRIP 1.02 0.32-3.28 Iri vs PEP02 1.10 0.42-2.94 Iri vs Docetaxel 1.28 0.59-2.80 Iri vs Paclitaxel 1.45 0.51-4.12 Iri vs mFOLFIRI 0.70 0.16-3.00
Cellular function of the mononuclear phagocyte system (MPS) as a phenotypic probe for pharmacokinetics (PK) and pharmacodynamics (PD) of PEGylated liposomal doxorubicin (PLD) in patients with recurrent ovarian cancer.
Authors: Whitney Paige Caron, John C. Lay, Parag Kumar, Alan M. Fong, Ninh My La-Beck, Suzanne E. Newman, Daniel L. Clarke-Pearson, Wendy R. Brewster, Linda Van Le, Victoria Lin Bae-Jump, Paola A. Gehrig, William Zamboni
Journal: Journal of Clinical Oncology (2012)

2591 Background: A phenotypic probe is a test that can be administered to a patient as a potential indicator of a drug’s PK/PD which can then be used to individualize therapy. Since nanoparticles are cleared via the MPS, including blood monocytes (MO), we hypothesize that circulating MO could potentially play a major role in, and be a surrogate marker of nanoparticle clearance (CL). Furthermore, we postulate that the ability to measure MO functional activity in blood samples can be used to predict CL and subsequently PD endpoints such as progression free survival (PFS) and hand-foot syndrome (HFS), in patients (pt). Methods: PLD 30/40 mg/m 2 IV x 1 with or without carboplatin (AUC = 5 mg/mL/min) was administered to pts (n=10) with recurrent ovarian cancer. Serial PK samples were obtained at time 0 to day 28 post dose. Plasma was processed to measure encapsulated and released doxorubicin using solid phase separation and HPLC. Data was analyzed with WinNonlin to obtain PK parameters. MO and granulocyte phagocytic function (uptake of FITC-labeled opsonized E. Coli) and oxidative burst activity (intracellular oxidation of dihydrorhodamine 123) were assessed via flow cytometry at 0, 48, 96 h, and on day 28. For both assays, changes in mean fluorescence intensity of the gated MO population, following incubation of whole blood with the appropriate substrate, served as an index of activity. Pts were followed from the first dose of PLD until time of disease progression. Results: There was a direct linear relationship between encapsulated doxorubicin CL and both phagocytosis (R 2 = 0.87) and oxidative burst activity (R 2 = 0.64) in blood MO. Similarly, phagocytosis (R 2 = 0.77) and oxidative burst probes correlated with PFS (R 2 = 0.67) in the 4 pts who progressed while on PLD. Oxidative burst also correlated with degree of HFS (R 2 = 0.56). There was no relationship between phagocytosis and oxidative burst in granulocytes and PK/PD of PLD. Conclusions: These findings indicate that probes of MPS function predict PLD CL, HFS and PFS and thus may be useful for individualizing PLD therapy in ovarian cancer and other malignancies.
Genetic testing for hereditary breast cancer: The decision to decline.
Authors: Brook White, Kimberly Showers, Carolyn S. Menendez, Lisa Amacker-North, Kendall W. Carpenter, Stacy Lenarcic, Lindsay McNeely, Claire Harwood, Beth Dellinger, Richard L. White
Journal: Journal of Clinical Oncology (2015)

1552 Background: Genetic testing is an important component of comprehensive cancer care. Testing for hereditary breast and ovarian cancer syndrome is well established, as commercial analysis of the BRCA1/2 genes has been available since 1996. The National Comprehensive Cancer Network (NCCN) guidelines identify those individuals appropriate for BRCA1/2 analysis, and define management recommendations for mutation carriers. Despite recommendations, not all who meet NCCN criteria undergo genetic testing. We assess the frequency that individuals meeting NCCN criteria decline BRCA1/2 analysis, as well as factors that affect the decision making process. Methods: A retrospective chart review was performed from September 2013 through August 2014 of individuals who had genetic counseling at the Levine Cancer Institute (LCI). Results: 1083 individuals identified through the retrospective chart review met NCCN criteria for BRCA1/2 analysis. 268 (24.5%) of the 1083 individuals did not pursue genetic testing. Of those who did not undergo testing, 21.3% (N = 57) did not desire testing and 40.3% (N = 108) were advised to gather additional genetic or medical information prior to genetic analysis. The remaining 38.4% (N = 103) had insurance and desired testing but did not pursue due to expense. The majority of the 103 individuals (N = 88) were responsible for the total cost of the test, although some (N = 15) had a prohibitive co-pay expense. Conclusions: Our analysis reveals that 38% of patients who meet NCCN guidelines for BRCA testing do not undergo testing based on financial barriers. This highlights the need to address public policy initiatives in this high-risk population.
NRF2 in human breast cancer patients as a good prognostic factor.
Authors: Xiao Yu, Hua XUE Jiang
Journal: Journal of Clinical Oncology (2015)

e12570 Background: Nuclear factor erythroid 2-related factor 2 (NRF2 (NFE2L2)) is a positive regulator of cytoprotective gene which involved in the cellular defense mechanisms against oxidative stress. However, recent studies have demonstrated that the High levels of NRF2 protein in several human malignancies might be advantageous for cell growth and chemical resistance, and is finally associated with either good or worse prognosis in these patients. However, the pathological and clinical significance of NRF2 has remained largely unknown in breast cancer patients. Methods: In our study, 72 specimens of breast cancer tissues were immunohistochemically investigated using Nrf2, NQO1, GCLC, BCRP and MRP1 antibodies. Results: NRF2 was detected in the nuclei of the breast carcinoma cells and it was positive in 89% of the cases. NRF2 status was significantly associated with BCRP (Breast Cancer Resistance Protein) and marginally associated with LRP (Lung-resistance-related Protein) immunoreactivity, and the results of multivariate analyses revealed that NRF2 status was an independent good prognostic factor for disease-free survival of the patients. Conclusions: Nuclear Nrf2 is therefore considered a potent prognostic factor in breast cancer patients.
Risk factors for development of second primary malignancies (SPM) after autologous stem cell transplant (ASCT) for multiple myeloma.
Authors: Amrita Y. Krishnan, Matthew Mei, Canlan Sun, Jennifer Berano-Teh, Stephen J. Forman, Myo Htut, Tongjun Kang, Chatchada Karanes, Firoozeh Sahebi, George Somlo, Smita Bhatia
Journal: Journal of Clinical Oncology (2012)

8038 Background: Studies from the CALGB and IFM have suggested an increased incidence of SPM post ASCT in patients on lenalidomide maintenance. Patients with MM as well as patients post ASCT are inherently at higher risk of SPM. Therefore, assessment of risk factors associated with SPM would be useful in therapeutic decisions re preASCT therapy and post ASCTmaintenance. Methods: We conducted a retrospective cohort study of 841 consecutive MM patients who underwent at least one ASCT at City of Hope from 1989 to 2009. Sixty cases with 70 SPMs were identified. A nested case-control study was also conducted to understand the role of therapeutic exposures associated with SPMs. Controls were MM patients post ASCT matched by year of HCT (±5 years). Results: The median length of follow up was 3.3 yrs. (range 0.3-19.9). Median age at ASCT was 56 yrs (range 18-77). 62% had received a single autologous HCT, 27% tandem autologous HCT, 11% had received multiple HCTs (72 had a second allogeneic HCT)). The overall cumulative incidence of any SPM was 7.4% at 5 years and 15.9% at 10 years; the cumulative incidence of SPMs for patients &gt;55 years approached 21.9% at 10 years. The cumulative incidence of MDS/AML was 1.8% and of solid tumors was 13.0%. Factors examined included age, race, sex, number and individual therapeutic exposures ( pre-ASCT, conditioning, and post-ASCT), disease status at ASCT. Multivariate Cox regression analysis revealed non-Hispanic whites (RR=2.4, 95% CI, 1.2-4.6, p=0.01) and older age (&gt;55) at diagnosis of MM (RR=2.3, 95% CI, 1.3-4.1, p=0.004) to be associated with an increased risk of developing SPMs. Only cumulative thalidomide exposure (both pre-ASCT and post-ASCT) demonstrated a trend toward a positive association (OR=3.5, 95% CI, 0.6-19.4, p=0.15). Six patients (3 cases and 3 controls) were exposed to lenalidomide prior to development of SPM (OR=1.0, 95% CI, 0.14-7.10). Conclusions: This single institution analysis identified non-hispanic whites and older age to be associated with increased risk of developing SPM in pts post ASCT for MM. The trend towards increased risk with thalidomide exposure may be suggestive of a class effect from IMIDs that is not restricted to lenalidomide alone.
Impact of pharmacokinetics (PK) of sunitinib (SU) and its metabolite SU12662 on clinical outcome and toxicity in metastatic renal cell cancer (mRCC) patients.
Authors: Nicolas Martin, Delphine Borchiellini, Julien Viotti, Emmanuel Chamorey, Gerard A. Milano, Jean-Marc Ferrero
Journal: Journal of Clinical Oncology (2017)

506 Background: Pharmacological activity of SU is usually attributed to SU and its active metabolite SU12662, known to exhibit similar potency in inhibiting tyrosine kinase activity and cellular proliferation in vitro. However, equivalence is not clearly demonstrated towards clinical endpoints. The objective of this phase 2 study was to determine the impact of SU and SU12662 on clinical outcomes and toxicity in mRCC patients (NCT00943839). Methods: Patients with mRCC, eligible for SU in the first line setting, were prospectively included. SU was given orally at 50 mg qd for 4 weeks on/2 weeks off until progression or unacceptable toxicity. Minimal concentration at steady-state (CSSmin) was evaluated by high-performance liquid chromatography at day 28 of each cycle for both SU and SU12662. Data for tumor response, survival, and toxicity were recorded. Kaplan-Meyer’s curves with log-rank tests and cox regression models were used to identify relationships between PK parameters and survival. Chi2 tests and student t-tests were used to identify relationships with toxicity. Results: 41 patients in 7 French centers were included between 2009 and 2012. 16 patients had favourable prognosis, 13 intermediate prognosis, and 1 poor prognosis according to IMDC risk groups (Heng, J Clin Oncol 2009). Median follow-up was 30.6 months. Median progression-free survival (PFS) was 20.2 months and median overall survival (OS) was 39.5 months. Mean CSSmin for SU and SU12662 were 57.2 and 29.8 ng/ml, respectively. CSSmin of SU12662 was independently correlated to poor PFS and OS (p = 0.01 and 0.003 respectively). Patients with a mean CSSmin of SU12662 higher than 42.5 ng/ml had a worse PFS and OS compared to patients with lower concentrations: 5.7 months and 5.7 months versus 20.6 months and 39.5 months (p = 0.01 and 0.002 respectively). High CSSmin of both SU and SU12662 were associated with increased incidence of asthenia (p&lt;0.001). Conclusions: High exposure to SU12662 was associated with poor outcomes and increased asthenia for patients with mRCC treated with SU in the first line setting. It may be related to a higher metabolism and unequal activity between SU and SU12662 in vivo. Clinical trial information: NCT00943839.