tbuckley/cabot-search huggingface dataset:
Targeting inflammatory monocytes in human metastatic colorectal cancer.
Authors: Julie G. Grossman, Timothy M. Nywening, Brian Belt, Michael Ahlers, William G. Hawkins, Steven M. Strasberg, Peter S. Goedegebuure, David Linehan, Ryan C. Fields
Journal: Journal of Clinical Oncology (2017)

605 Background: Colorectal cancer (CRC) is the most common gastrointestinal malignancy. 60% of CRC patients are diagnosed with metastatic CRC (mCRC) and the 5-year survival is &lt; 20%. CCR2+ inflammatory monocytes (IM) are recruited from the bone marrow to the tumor microenvironment by the CCL2/CCR2 chemokine axis. At the tumor, they become tumor associated macrophages (TAM) and play a crucial role in promoting tumor progression, metastasis, and chemoresistance. While the importance of IM has been shown in other malignancies, little is known about their role in mCRC. Methods: Flow cytometry was performed on human and murine PBMCs, adjacent normal tissue, and tumors. Qualitative RT-PCR, ELISA, and confocal microscopy were performed for CCL2 expression. T-cell suppression assays were performed using CD14+ IM isolated from patient PBMCs and liver metastasis (LM). A murine model of CRC LM was created by hemispleen injection of luciferase-labelled MC38 CRC cells. Mice were treated with a CCR2 inhibitor and/or FOLFOX. Results: Prior to liver resection, mCRC patients have a higher percentage of IM in the peripheral blood compared to healthy donors (p &lt; 0.0001), and on multivariate analysis elevated monocytes were prognostic of poor survival. We also found higher levels of CCL2 in the serum of mCRC patients (p &lt; 0.01). Additionally, there was increased expression of CCL2 in LM compared to uninvolved tissue (p &lt; 0.01), with the production of CCL2 localized to mCRC cells. FACS analysis showed CCR2+ TAM were elevated in LM compared to adjacent normal liver (p &lt; 0.05) with a paucity of effector T-cells. CD14+ TAMs isolated from mCRC inhibited T-cell proliferation, illustrating the immune suppressive phenotype of these cells. In a murine model of CRC LM, treating mice with a CCR2 inhibitor alone or in combination with FOLFOX chemotherapy resulted in decreased tumor burden. FACS analysis of treated tumors showed increased effector T-cells in mice treated with CCR2 inhibitor. Conclusions: IM are involved in the progression of mCRC. Targeting these immunosuppressive cells with a CCR2 inhibitor decreases tumor burden in a murine model. This represents a potential novel treatment for mCRC.
LCCC 1025: A phase II study evaluating the mTOR inhibitor everolimus with trastuzumab and vinorelbine to treat progressive HER2-positive breast cancer brain metastases.
Authors: Carey K. Anders, Allison Mary Deal, Elizabeth Claire Dees, William Johnson Irvin, Hyman Bernard Muss, Jeanne Noe, Olga Karginova, Barbara Adamo, Aleix Prat, Lisa A. Carey
Journal: Journal of Clinical Oncology (2012)

TPS656 Background: HER2+ breast cancer (BC) is an aggressive subset of BC with high rates of brain metastases (BM) and poor survival. A recent study illustrates activation of the PI3K/mTOR pathway in approximately two-thirds of BCBM across all subtypes. Everolimus, a novel oral derivative of rapamycin that selectively inhibits mTOR, is clinically-active in combination with trastuzumab (with or without chemotherapy) in advanced HER2+ BC. Everolimus penetrates the blood brain barrier. We are evaluating the efficacy and safety of everolimus plus trastuzumab and vinorelbine in patients (pts) with HER2+ BCBM. Methods: Pts with HER2+ BCBM progressing following cranial radiation and measuring &gt; 0.5cm are eligible for enrollment. Treatment with prior vinorelbine or mTOR inhibition is prohibited. Steroid treatment is allowed if stable or decreasing doses ≥7 days prior to study entry. Pts with leptomeningeal disease are excluded. Pts receive everolimus (5mg orally daily), trastuzumab 2mg/kg and vinorelbine 25mg/m 2 (both IV days 1, 8, 15) of a 21 day cycle. Intra- and extracranial disease is assessed every 9 weeks by gadolinium-enhanced brain MRI and CT chest/abdomen/pelvis, respectively. The primary endpoint is intracranial response rate (RR) assessed by modified RECIST. Secondary objectives include extracranial RR (assessed by RECIST 1.1), intra- and extracranial time to progression, progression free survival, overall survival, quality of life, and correlative science endpoints. Statistical considerations: In this two stage design, a sample size of 28 evaluable pts (n=11 in Stage 1) has 80% power to detect a difference between the null (≤5% intracranial RR) and alternative hypothesis (&gt;5%) at a 0.05 significance level. If 1 pt has a CR, PR or SD for ≥ 3 months in the 1st stage, 17 additional pts will be enrolled. Assuming a 20% drop-out rate, 35 total pts will be enrolled. Correlative studies: Archival primary and/or metastatic tissues are required from all pts to evaluate intrinsic BC subtype, protein (p-AKT, pS6, PTEN) and gene expression to identify biomarkers that may be predictive of response or resistance to this novel combination (NCT01305941).
Abstract 229: Follistatin-like 1 Protects Heart From Post-infarction Rupture by Modulating Fibrogenesis
Authors: Sonomi Maruyama, Kazuto Nakamura, Kenneth Walsh
Journal: Circulation Research (2015)

Rationale: Stress injured heart secretes several cardiokines, including Follistatin-like 1 (Fstl1). Fstl1 is a member of SPARC (secreted protein, acidic and rich in cysteine) family. Fstl1 is strongly overexpressed in ischemic lesion and secreted to blood circulation in acute coronary syndrome. However, roles and mechanisms of Fstl1 in acute myocardial infarction have not been elucidated yet. Methods and results: To assess Fstl1 expression after myocardial infarction (MI), C57BL6 WT mice were underwent LAD permanent ligation. Heart and serum Fstl1 protein levels were increased after day 1 and peaked at 7 days after MI. Immunohistochemistry revealed that fibroblasts and myofibroblasts were the major Fstl1 expressing cells in infarcted area and border zone. However, neither cardiomyocytes nor leukocytes (neutrophil, macrophage) produced Fstl1. Fstl1 deleted mice in fibroblasts lineage (Fstl1-CKO mice) were generated by S100a4cre+/- xFstl1flox/flox mice. S100a4cre-/- xFstl1flox/flox mice were used as control. Fstl1 protein overexpression after MI was reduced 50% in Fstl1-CKO mice heart compared to control mice. Mortality rate after MI was significantly higher in Fstl1-CKO mice than control mice (50%;15 of 30 vs 34.8%; 8 of 23, respectively, log-rank test p=0.031). The majority of causes of death were cardiac rupture in acute period. Cardiac function, blood pressure and severity of inflammation were comparable between Fstl1-CKO and control mice. However, amount of myofibroblasts in Fstl1-CKO heart was significantly less than control mice. Overexpression of extracellular matrix proteins (collagen and fibronectin) in infarcted area was also diminished in Fstl1-CKO mice. Autocrine and paracrine functions of Fstl1 for fibroblasts were assessed in vitro study. Endogenous Fstl1 protein in neonatal rat cardiac fibroblasts (NRCFBs) was knocked down by siRNA fstl1. Migratory activity of NRCFBs was attenuated by Fstl1 ablation. Moreover, Fstl1 augmented TGF-β1 activated Smad2/3 signaling pathway in vivo and vitro. Conclusions: Increased Fstl1after MI prevents heart from cardiac rupture. This study revealed a novel function of Fstl1, promotes extracellular matrix generation to repair infarcted lesion.
Phase II trial of adjuvant immunotherapy with autologous tumor-derived Gp96 vaccination in patients with gastric cancer.
Authors: Lin Chen, Kecheng Zhang, Zheng Peng, Bo Wei, Hongqing Xi, Xinxin Wang, Ning Wang, Jianxin Cui
Journal: Journal of Clinical Oncology (2017)

117 Background: Autologous, tumor-derived heat shock protein Gp96 peptides complexes have shown antitumor potential in various cancers. We conducted the first Phase II trial to evaluate the safety and efficacy of Gp96 vaccination in adjuvant settings for patients with gastric cancer. Methods: Consecutive patients from November 2012 to December 2015 were enrolled. Participants were allocated to the experimental group or control group, receiving Gp96 vaccination plus chemotherapy or chemotherapy alone respectively. The primary endpoints were disease-free survival and toxicity. The secondary outcomes were overall survival and tumor-specific immune responses. Results: Thirty-nine and forty patients received Gp96 vaccination plus chemotherapy and chemotherapy alone in the adjuvant settings respectively. Significant increased tumor-specific immune responses were observed after Gp96 vaccination. There were comparable disease-free survival ( p = 0.413; HR: 0.75; 95% CI: 0.37−1.48) and overall survival ( p = 0.485; HR: 0.68; 95% CI: 0.24−1.96) between experimental group and control group. In subgroup of patients with stage II and stage III gastric cancer, patients who have received Gp96 vaccination had improved disease-free survival compared those who have not ( p = 0.044; HR: 0.45; 95% CI: 0.22−0.96). Gp96 vaccination plus chemotherapy was well tolerated and no Gp96-related serious adverse event has been observed. Conclusions: Gp96 vaccination could elicit tumor-specific immune responses and could be safely used in adjuvant settings combined with chemotherapy. Patients with less aggressive diseases might benefit from Gp96 therapy.
The Healing Power of Paint
Authors: Elizabeth Toll, Beth Scanlon Melfi
Journal: JAMA (2017)

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Dynamic contrast enhanced-MRI (DCE-MRI) as a pharmacodynamic biomarker for pazopanib (PZ) in metastatic renal carcinoma (RC).
Authors: Randy F. Sweis, Milica Medved, Shannon Towey, Greg S. Karczmar, Aytekin Oto, Russell Zelig Szmulewitz, Peter H. O'Donnell, Paul A. S. Fishkin, Walter Michael Stadler
Journal: Journal of Clinical Oncology (2015)

e15623 Background: Traditional imaging assessment criteria may not correlate well with clinical benefit from vascular endothelial growth factor pathway directed therapy in RC. DCE-MRI derived Ktrans(Kt) decline is a pharmacodynamic marker for such therapy in RC, and preclinical data suggest that it may rise prior to tumor growth. We thus hypothesized that recovery of Kt is predictive of progression in RC patients (pts) treated with PZ. Methods: Pts with metastatic clear cell RC were enrolled. Baseline MRI with Kt assessment was performed and repeated one week (wk) later, then every 8 wks to a maximum of 5. Kt was calculated for a tumor region-of-interest selected in a blinded manner using the Tofts two-compartment model with a tumor local arterial input function derived using a reference tissue method. The study was designed to accrue 65 pts to detect 48 disease progressions. The primary end point was to determine whether a rise in Kt was predictive of tumor growth. Results: Due to poor enrollment the study was closed after 21 pts were recruited over two years. Seventeen pts underwent at least one post-baseline MRI with a calculable Kt. Median number of prior therapies was one (0–4). Median progression free survival (PFS) was 32.1 wks. Mean Kt log ratios (±SD) compared to baseline after 1, 8, 16, and 24 wks were -0.680 (±0.729), -1.049 (±0.634), -0.998 (±0.757), -0.755 (±0.952), respectively, corresponding to changes of -49%, -65%, -63%, and -53% (p = 0.0012, ANOVA). The recovery of mean Kt at wk 24 compared to the prior time point was not statistically significant (p = 0.40, Wilcoxon). Kaplan-Meier analysis showed a significant difference in PFS in pts grouped dichotomously around median baseline Kt (p = 0.037, log-rank). Baseline Kt did not reach significance in a Cox-proportional hazard model including clinical prognostic index and prior treatments (p = 0.076). Conclusions: DCE-MRI derived Kt is a pharmacodynamic biomarker for PZ therapy in RC with the median nadir occurring 8 wks after initiating therapy. Kt showed a non-significant trend towards recovery by 24 wks. Baseline Kt correlates with PFS. The predictive capacity of Kt recovery on PFS could not be demonstrated due to the small sample size. Clinical trial information: NCT01599832.
Extended cohort study of OPB51602, a novel inhibitor of STAT3/5 activation, in non-small cell lung carcinoma.
Authors: Joline Si Jing Lim, Andrea Li Ann Wong, Ross A. Soo, Soo-Chin Lee, Patrick Marban, Li Ren Kong, Brendan Pang, Richie Chuan Teck Soong, Daniel Shao-Weng Tan, David Shao Peng Tan, Kumi Higuchi, Masaaki Motoyama, Takeshi Tsunoda, Boon C. Goh
Journal: Journal of Clinical Oncology (2014)

8028 Background: STAT3, a signal transduction protein of growth factor receptors including EGFR, is constitutively activated in many solid malignancies, leading to tumor angiogenesis, cell proliferation and immune tolerance. Inhibition of STAT3 in vitro and in vivo induces apoptosis in STAT3-activated tumor cells. OPB51602 is an oral small molecule inhibitor of STAT3 phosphorylation with favorable preclinical profile that has entered clinical development. Methods: We analyzed a subgroup of patients with non-small cell lung cancer (NSCLC) from a phase I study of OPB51602 including an extension cohort at the recommended dose of 4mg daily in NSCLC. Dosing included dosing daily for 2 weeks every 3 weeks, and continuous dosing of 4mg daily. Archival tissue was analyzed for oncogenic mutations and STAT3/5 phosphorylation. Patients were evaluated for treatment response, and pharmacodynamic effects of STAT3 phosphorylation assessed in peripheral blood mononuclear cells by flow cytometry (PBMCs). Results: 25 patients were treated at doses of 2mg, 4mg and 5mg. 23 patients (92%) had adenocarcinoma, and 11 (44%) had tumor EGFR mutations. Two patients treated at doses of 4mg and 5mg had partial response(PR), with progression free survival of 5 and 7 months respectively; both had EGFR mutations that responded and then progressed on EGFR TKIs. Overall disease control rate was 12.5% at 3 months, and duration of disease control was longer in EGFR mutant patients. Patients who achieved PR/stable disease (n=6) had a higher incidence of EGFR mutations compared to those with PD (n=8), (83% vs 50%). 12 patients had repeat FDG PET CT during cycle 1, with metabolic response by EORTC criteria observed in 5 patients(42%). Immunohistochemistry showed pSTAT3(Ser727) overexpression in 44% of patients, and PBMC analysis revealed downregulation of pSTAT3 with treatment (mean decrease 22.1±14.1%), with maximal effect at 4h post-dosing. There was no correlation between extent of downregulation of pSTAT3 and tumor response. Conclusions: OPB51602 demonstrates evidence of clinical activity in treatment refractory NSCLC, particularly for EGFR mutants. Further evaluation of its efficacy and biomarker exploration is warranted in NSCLC.
Tumor infiltrating lymphocytes (TIL) and Ki67 suppression after neoadjuvant therapy for HR+/HER2- breast cancer (BC): Results from two prospective trials.
Authors: Maria Vittoria Dieci, Guido Ficarra, Pier Franco Conte, Valentina Guarneri
Journal: Journal of Clinical Oncology (2015)

562 Background: In BC, TIL predict for pCR after neoadjuvant chemotherapy. Since pCR is a suboptimal surrogate for treatment efficacy for HR+/HER2- patients (pts), we evaluate the association between TIL and molecular response after preoperative endocrine or cytotoxic treatment for HR+/HER2- BC. Methods: Stromal (Str) TIL were evaluated on H&E slides from diagnostic core-biopsies of 140 HR+/HER2- pts included in two prospective randomized trials. The LETLOB trial randomized 92 HR+/HER2- pts to neoadjuvant letrozole +/- lapatinib. The GIOB trial randomized 90 pts (n=48 HR+/HER2-) to primary anthracycline/taxane +/- gefitinib (Guarneri JCO 2012, BCRT 2008). Pre- and post-treatment Ki67 was centrally evaluated. Results: StrTIL were evaluable in 119 cases.Median StrTIL% was 2%. Pts with focal StrTIL or higher (StrTIL>=10%, n=28) were younger (p=0.034), had more frequently BC of ductal histology (p=0.04), high grade (p=0.025) and high Ki67 (p=0.012). After treatment, a significant Ki67 reduction from baseline (Wilcoxon p< 0.01) was observed overall and in each study (mean reduction similar in LETLOB and GIOB, T-test=ns). In the LETLOB trial a significant Ki67 suppression (Wilcoxon p< 0.01) was observed irrespectively of StrTIL, but mean Ki67 reduction was significantly greater in StrTIL>=10% vs < 10% (-13% vs -5%, T-test p=0.012). In the GIOB trial, a significant reduction in Ki67 was observed only for StrTIL< 10% pts (mean reduction -12% vs -0.9%, Wilcoxon p=0.001 and p=0.612 in StrTIL< 10% and >=10%, respectively). There was no difference according to arm in each study. The table reports the association of StrTIL with molecular response (proportional Ki67 reduction from baseline >50%). Test for interaction with treatment (cytotoxic or endocrine) was of borderline significance. Conclusions: The presence of TIL correlates with greater Ki67 suppression after neoadjuvant endocrine therapy but seems to prevent a molecular response after chemotherapy for HR+/HER2- pts. Ki67 reduction < 50% (%) Ki67 reduction > 50% (%) Chi2 Interaction p All StrTIL< 10% 49 60 p=0.3 >=10% 51 40 LETLOB StrTIL< 10% 56 44 p=0.38 p=0.07 >=10% 44 56 GIOB StrTIL< 10% 36 64 p=0.003 >=10% 90 10
HIT antibody positivity as a predictor for early cancer diagnosis.
Authors: Zaid Alirhayim, Herman Dyal, Danielle Heidemann, Cesar Ochoa Perez, Abdulqader Alarhayem, Syed Hassan, Sophia Qureshi, Fatima Khalid, Shehabaldin Alqalyoobi, Waqas Qureshi
Journal: Journal of Clinical Oncology (2013)

e22184 Background: Heparin induced thrombocytopenia (HIT) is known to be caused by the presence of PF 4 antibody. Tumors exert immunomodulatory effects on the host immune response, including development of antibodies. Our aim was to analyze the presence of HIT in cancer patients and determine if HIT Ab is an adverse risk factor in patients with cancer. Methods: Patients with suspected HIT were selected. A case – control study was designed with 1:1 age and gender matched controls. We used chi – square analysis to compare proportions and Cox proportional hazard model to detect various predictors. Time to survival analysis was performed using Kaplan – Meier method. Results: Of 600 patients, 300 (63±15 years, women 48.8%) had a mean 4T pre – probability score of 4 ± 1.6. There were 132 cancers in both groups. 65 of these (49.2%) were in patients with probable HIT. The numbers of carcinomas and sarcomas were not significantly different between the two groups. There were no significant differences between the two groups when comparing the number of cancer diagnoses or the particular types of cancer diagnosed. The mean time to detection of cancer was within 9 ± 23 months for patients with HIT Ab versus 31 ± 54 months in cancer patients without HIT Ab (p &lt;0.0001). In addition, there was a greater number of patients with at least 2 primary cancers among the HIT Ab positive group (p = 0.003). No predictive relationship between the type of cancer and the presence of HIT Ab was found (p &gt;0.05). Patients with advanced cancer (stage 3 or 4) were also more likely to be HIT Ab positive (HR 3.61; 95% CI 1.31 – 10.11, p = 0.013). Cancer patients with HIT Ab were more likely to have venous thromboembolism as compared to cancer patients without HIT Ab (7.7% vs. 4.7, p = 0.0001). Kaplan – Meier’s showed worse mortality for cancer patients with HIT Ab than patients without the HIT Ab (Breslow statistic = 0.04). Conclusions: Among our cohort with suspected HIT, cancer was a common finding. Patients with HIT antibody positivity were more likely to have a new cancer diagnosis within 1 year of a positive result. These patients were also more likely to have thromboembolic complications and worsened mortality. These findings require further study, but perhaps suggest that the presence of HIT Ab should trigger earlier surveillance for cancer.
Albumin-bound paclitaxel plus gemcitabine after first-line FOLFIRINOX therapy in patients with pancreatic cancer.
Authors: Mohamed E. Salem, Angela Tatiana Alistar, Gregory Dyson, Natalja Stanski, Hemchandra Mahaseth, Minsig Choi, Anthony Frank Shields, Philip Agop Philip
Journal: Journal of Clinical Oncology (2014)

e15252 Background: Albumin-bound paclitaxel plus gemcitabine (Gem/nab) and FOLFIRINOX are approved as first-line therapies for metastatic pancreatic cancer (PC). Optimal regimen sequence is unknown. There are limited efficacy and safety data for Gem/nab after first-line FOLFIRINOX. Methods: A retrospective review of patients (pts) with PC treated at Karmanos Cancer Institute and Wake Forest University that progressed on first-line FOLFIRINOX from May 2010 to September 2013 was performed. Survival was estimated with Kaplan-Meier method. Cox regression was used to estimate hazard ratios. Results: A total 44 pts were included (median age, 55 y; 35 white [80%]; 26 men [59%]); 13 pts (29%) had locally advanced and 31 pts (71%) had metastatic disease. At diagnosis, 10 pts (23%) had diabetes mellitus and 27 pts (61%) had liver metastasis. Most (29) tumors were moderately differentiated (66%) and 17 tumors were located at the head of the pancreas (38%); 7 of 24 pts tested (29%) had KRAS wild type tumors. First-line FOLFIRINOX was given for a median 8 cycles (range, 1 to 33). Dose was reduced in 30 pts (71%), mostly due to fatigue (37%), neuropathy (20%), and/or GI toxicities (27%). With FOLFIRINOX first-line therapy, median PFS was 8.6 months (6.4, 11.4) and 42% pts had freedom from treatment failure at 6 months. Most (31) pts (71%) received second-line therapy including 12 pts (28%) who had Gem/nab (median, 2 cycles; range, 1 to 10 cycles) after first-line therapy with median 9 cycles FOLFIRINOX. With second-line GEM/nab, dose was reduced in 45% pts due to fatigue (54%) and/or thrombocytopenia (38%). While on Gem/nab second-line therapy, RECIST-objective response was seen in 1 of the 12 pts (8%); 2 pts (16%) had stable disease, whereas 9 pts (75%) had disease progression. The median PFS was 3.3 months (1.8, NR); 8% pts had freedom from treatment failure at 6 months. In the 12 pts who received Gem/nab second-line after FOLFIRINOX, median OS was 16.2 months (14.3, NR). In multivariate analysis, diabetes was an independent predictor of overall survival (HR, 3.8; 95% CI, 1.0 to 14.3; P≤ .05). Conclusions: Second-line Gem/nab had activity in pts with PC after first-line FOLFIRINOX. Future prospective trials are warranted.