tbuckley/cabot-search huggingface dataset:
Phase I study of LErafAON-ETU, an easy-to-use formulation of liiposome entrapped c-raf antisense oligonucleotide, in advanced cancer patients
Authors: J. L. Steinberg, D. S. Mendelson, H. Block, S. B. Green, V. S. Shu, K. Parker, P. Cullinan, J. L. Dul, D. D. von Hoff, M. S. Gordon
Journal: Journal of Clinical Oncology (2005)

3214 Background: Raf kinases play key roles in integrating the K-Ras and mitogen-activated protein kinase (MAPK) intracellular signaling cascades, which are important regulators of tumor cell proliferation. LErafAON-ETU is an easy-to-use, liquid, liposomal formulation of an antisense oligonucleotide complementary to the c-raf mRNA sequence. The lipid component consists of a novel, positively charged, synthetic cardiolipin (PCL-2). Formulation with liposomes eliminates the need for extensive phosphorothioate modification; thus, only the 3'- and 5'- termini of the LErafAON-ETU oligonucleotide are modified. Methods: This Phase I dose-escalation study is designed to determine the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD) of LErafAON-ETU in patients with advanced cancer. LErafAON-ETU is administered as a 60 minute intravenous infusion once weekly for 3 consecutive weeks (a treatment cycle). Patients are eligible to receive repeated treatment cycles until disease progression or unacceptable toxicity occurs. Dose levels of 7.5, 15, 30, 60, 120, 240, and 480 mg/m2 or more are planned, depending on the tolerability of LErafAON-ETU. An accelerated dosing strategy will be implemented after the safety and tolerability of the initial dose level has been established in 3 patients. In this design, a single patient will be treated at each subsequent dose level until an adverse event of Grade ≥2, a pre-infusion platelet count of <75,000/mm3, or an increase in the serum creatinine level to ≥1.5 x the upper limit of normal occurs. At such time this cohort will be expanded, and a standard dose-escalation scheme will be employed with 3–6 patients in each cohort dependent upon the occurrence of DLTs. Results: Patient enrollment has begun. Three patients have completed infusion at the initial dose of 7.5 mg/m2. Conclusions: This accelerated dose-escalation scheme should reach potentially therapeutic doses more rapidly than would a standard design. This study represents the initial clinical dosing and proof of concept for a novel, liquid, PCL-2 based liposomal formulation of an antisense oligonucleotide with minimal phosphorothioation. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration NeoPharm NeoPharm
Visualization of a neurotropic flavivirus infection in mouse reveals unique viscerotropism controlled by host type I interferon signaling
Authors: Xiao-Feng Li, Xiao-Dan Li, Cheng-Lin Deng, Hao-Long Dong, Qiu-Yan Zhang, Qing Ye, Han-Qing Ye, Xing-Yao Huang, Yong-Qiang Deng, Bo Zhang, Cheng-Feng Qin
Journal: Theranostics (2017)

Flavivirus includes a large group of human pathogens with medical importance.Especially, neurotropic flaviviruses capable of invading central and peripheral nervous system, e.g.Japanese encephalitis virus (JEV) and Zika virus (ZIKV), are highly pathogenic to human and constitute major global health problems.However, the dynamic dissemination and pathogenesis of neurotropic flavivirus infections remain largely unknown.Here, using JEV as a model, we rationally designed and constructed a recombinant reporter virus that stably expressed Renilla luciferase (Rluc).The resulting JEV reporter virus (named Rluc-JEV) and parental JEV exhibited similar replication and infection characteristics, and the magnitude of Rluc activity correlated well with progeny viral production in vitro and in vivo.By using in vivo bioluminescence imaging (BLI) technology, we dissected the replication and dissemination dynamics of JEV infection in mice upon different inoculation routes.Interestingly, besides replicating in mouse brain, Rluc-JEV predominantly invaded the abdominal organs in mice with typical viscerotropism.Further tests in mice deficient in type I interferon (IFN) receptors demonstrated robust and prolonged viral replication in the intestine, spleen, liver, kidney and other abdominal organs.Combined with histopathological and immunohistochemical results, the host type I IFN signaling was evidenced as the major barrier to the viscerotropism and pathogenicity of this neurotropic flavivirus.Additionally, the Rluc-JEV platform was readily adapted for efficacy assay of known antiviral compounds and a live JE vaccine.Collectively, our study revealed abdominal organs as important targets of JEV infection in mice and profiled the unique viscerotropism trait controlled by the host type I IFN signaling.This in vivo visualization technology described here provides a powerful tool for testing antiviral agents and vaccine candidates for flaviviral infection.
Bone remodeling markers in breast and prostate cancer patients undergoing endocrine and bisphosponate therapy
Authors: F. K. Wenz, G. Welzel, A. Keller, P. Findeisen, M. Neumaier, B. Hermann
Journal: Journal of Clinical Oncology (2008)

9602 Background: Bone metastases are frequent and often the first manifestation of disseminated tumor spread in patients with breast and prostate cancer. In this regard the bone resorption marker peptide-bound collagen type I cross-links C-telopeptides (ICTP) and bone formation marker N-terminal propeptide of type I collagen (NTX) might be of diagnostic relevance. The serum levels correlate with the presence of bone metastases, however little is known about the influence of endocrine and bisphosphonate therapy. Methods: We prospectively investigated 208 patients (63.4 ± 10.8 yrs) with either breast (n = 95) or prostate cancer (n = 77) without (n = 172) and with (n = 18 breast, n = 18 prostate) bone metastases in this longitudinal follow-up study. ICTP and NTX were measured in serum samples. Patients were treated according to clinical guidelines using endocrine therapy, bisphosphonates and/or radiotherapy if required. Results: At baseline, serum bone marker levels were higher in patients with bone metastases compared to patients without bone metastases (ICTP: 5.44 ± 0.38 vs 4.72 ± 0.17 ug/l, p = .029, NTX 48.3 ± 5.7 vs 41.9 ± 2.2 ug/l p = ns). Bisphosphonate therapy reduced ICTP and NTX values on average by about 0.6 - 0.7 ug/l and 10 - 20 ug/l respectively. Endocrine therapy with Tamoxifen (TAM) reduced ICTP and NTX values whereas aromatase inhibitors (AIs) lead to a reduction of ICTP and an increase of NTX. The serum levels of NTX were significantly higher in patients on AIs as compared to TAM (55.5 ± 9.2 ug/l vs 32.1 ± 2.7 ug/l, p = .016). Conclusions: Bone remodeling markes may be useful for the diagnosis and follow-up of patients with breast and prostate cancer with bone metastases, as well as patients at high risk of developing skeletal metastases. Early detection of bone metastases would otherwise require the repeated use of expensive imaging studies. Sensitive and specific serological markers of bone turnover would be of high clinical value during follow-up of these patients. However, the present data show that the typical comedications given to patients with breast and prostate cancer influence the serum levels of bone remodeling markers. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis Novartis
Frequency and factors associated with placebo response in cancer-related fatigue treatment trials.
Authors: Sriram Yennu, Kyu-Hyoung Lim, Janet L. Williams, Zhanni Lu, Eduardo Bruera
Journal: Journal of Clinical Oncology (2016)

210 Background: There is limited literature on specific patient characteristics associated with response to placebo. The aim of this study was to identify frequency, and predictors of response to placebo. Methods: We conducted pooled analysis of the placebo arm in six randomized, double-blind, placebo-controlled clinical trials for cancer related fatigue. Baseline patient characteristics, symptoms (FACIT-F, and ESAS), Global Symptom Evaluation (GSE, rated as better, same and worse). Response was defined as an increase (D FACIT-F score) ≥ 3.5 points from baseline or change in ESAS of ≤ 1. Baseline patient characteristics and symptoms (as assessed by ESAS) were analyzed to determine their association with response to placebo using logistic regression analysis. ROC was calculated for GSE “better” of “4” or more (i.e., moderately better to very great deal better) and FACIT-F change. Results: Total of 306 patients with advanced cancer received placebo. The median age was 59, 54% were female, 76% were white, 51% were had college education or higher, the most common cancer type was genitourinary 24%. 55% had Zubrod performance ≤ 2. Median FACIF-F subscale score was 21. Placebo response was 176/306 (58%) with FACIT-F subscale ≥ 3.5 points and 185 (60%) with ESAS fatigue ≤ 1. Mean change in fatigue using FACIT- F subscale score was 7.18 (11.68) and ESAS was -2.21 (2.82). Change in FACIT-F and ESAS were significantly correlated (r = 0.56, P ≤ 0.001). 99/306 (32%) reported that their fatigue was “better” by GSE. Female gender (OR 2.72, P = 0.04), and anxiety (OR 1.39, P = 0.046) were significantly associated with placebo response. ROC with cut-off of GSE ≥ 4 and change in FACIT-F score was 11.5 and placebo response rate based on cut-off of 7.5 was 84/306 (27%). Conclusions: Our results confirm that placebo response is substantial in fatigue treatment trials in palliative patients. Placebo response rate varies based on the methods used to estimate response (from 27% to 60%). Female patients and higher anxiety at baseline were significantly associated with placebo response. More research is needed to accurately benchmark placebo response.
Effect of a multidisciplinary cancer conference for thoracic malignancies on patient care management.
Authors: Henner M. Schmidt, John M. Roberts, Artur M. Bodnar, Steven H. Kirtland, Sonia H. Kunz, Sheraz Markar, Donald E. Low
Journal: Journal of Clinical Oncology (2014)

112 Background: Treatment of thoracic cancers frequently involve multiple subspecialties thus treatment decisions are typically best facilitated in multidisciplinary tumor boards (MTB). This approach should facilitate and improve treatment decision making, standardize staging and therapeutic decisions and improve outcomes. In this study we analyze the evolution in staging and treatment decision making associated with presentation at MTB. Methods: Retrospective review of all patients with lung or esophageal cancer presented at our weekly MTB from June 1, 2010 to September 30, 2012. All providers submitting patients to tumor board recorded their current treatment plan prior to presentation. The physician’s plan was then compared to the tumor board’s final recommendation. Changes made were graded according to degree of magnitude as minor, moderate or major change. Minor changes included changes in diagnostic imaging. Moderate changes involved modifications in the type of invasive staging or biopsy procedures. Major changes were defined as changes to final therapeutic plans such as surgery, chemotherapy, or radiation therapy. Results: 435 patients with esophageal or lung cancer were discussed in the MTB. 86 patients having no prior treatment plan available were excluded. In the remaining 347 patients there were 163 patients with esophageal cancer (47%) and 184 patients with lung cancer (53%). In the esophageal cancer patients a change to the physician’s prior treatment plan was recommended in 33 cases (21%). For lung cancer patients a change in the treatment plan was recommended in 50 cases (27%). Overall a recommendation for change in treatment occurred in 83 cases (24 %). Changes were major 13%, moderate 6% and minor 5%. Follow-up in 249 patients confirmed that MTB recommendations were followed in 97% of cases. Conclusions: MTB recommendations frequently differs from the physician’s primary treatment plan. MTB reviews have previously been documented to improve patient’s outcome. The study demonstrates that in one quarter of patients MTB recommendation will be different from the primary treatment plan. Complex cancer patients should be considered for presentation at MTB whenever feasible.
External beam radiotherapy for small cell carcinoma of the urinary bladder: The Memorial Sloan-Kettering experience.
Authors: Marisa Kollmeier, Chu-Cheng Kan, Bernard Bochner, Guido Dalbagni, Dean F. Bajorin, Michael J. Zelefsky
Journal: Journal of Clinical Oncology (2012)

290 Background: To report our experience using definitive external beam radiotherapy for small cell carcinoma of the urinary bladder. Methods: We reviewed records of 17 patients (14 male, 3 female) with small cell carcinoma of the urinary bladder treated at our institution with external beam radiation therapy (median dose 64.8Gy) for small cell carcinoma of the bladder between January 1994 and June 2011. Median age was 69 years. Sixteen (94.1%) patients received neoadjuvant and/or concurrent platinum-based chemotherapy. All patients underwent pretreatment maximal transurethral resection (visibly complete (n=7); incomplete (n=10). Seven patients had radiographic or pathologic evidence of nodal spread. Patients were followed with cystoscopy and radiographic imaging post-RT. Median followup was 7 months (range, 2-161 mos). Acute (&lt;90days) and late (≥90days) toxicity was recorded using CTCAE v 3.0. Kaplan Meier method was used for survival analysis. Results: The 2-year overall survival was 62%. Of 17 patients, 3 patients developed local recurrence (LR) with a median time to local recurrence of 19 months. Two of three patients had noninvasive LR managed with transurethral resection and had no evidence of disease at last followup. One patient with invasive LR had both LR and distant metastasis identified &lt;3 months after RT. Four patients developed distant metastases at a median time to progression of 2.5mos in bone (n=2), lung (n=1), and retroperitoneal lymph nodes (n=1). All but one patient with distant metastases had node-positive disease at diagnosis. The 2y distant metastasis-free survival for node (-) and node (+)patients was 90% and 30% (p=0.03). Of 12 patients currently without evidence of disease, 5 have followup ≥30mos. The incidence of grade ≥2 acute and late GU/GI toxicity was 53% and 6% respectively. Conclusions: Bladder preservation therapy for small cell carcinoma is feasible with encouraging early results. Nodal disease portends a poor prognosis. Brain metastases are uncommon suggesting a limited role for prophylactic cranial irradiation. Radiation therapy with concurrent platinum-based chemotherapy was associated with a low risk of late GU/GI toxicity in our cohort.
The association between sarcopenia and treatment outcomes in patients with pancreatic cancer undergoing chemoradiation.
Authors: Kajal Patel, Talha Shaikh, Lora S Wang, John Parker Hoffman, Steven J. Cohen, Joshua E. Meyer
Journal: Journal of Clinical Oncology (2016)

415 Background: Sarcopenia (Sp) or severe loss of muscle mass is a prognostic factor in cancer patients. We assessed the association between Sp and outcomes in borderline resectable or locally advanced/unresectable pancreatic cancer patients undergoing chemoradiation (CRT). Methods: We reviewed all patients who underwent CRT at an NCI-designated cancer center between 2007-2012. Patients with available pre-treatment imaging were included in the analysis. Sp was defined as a lumbar skeletal muscle area/height of &lt; 55.4 cm 2 /m 2 for males and &lt; 38.9 cm 2 /m 2 for females. Sp was correlated to treatment toxicity, cause specific survival (CSS), and overall survival (OS). Analysis was performed using chi-square test for categorical variables and Mann-Whitney U test for continuous variables. Kaplan-Meier method and Cox regression was used for survival analysis. Results: A total of 86 patients met the inclusion criteria with 32 (37%) patients being sarcopenic. The median age was 70 (range 46-91) with a median follow-up of 14 months (3-68). The majority of patients were male (57%), had T3 disease (47%), or were borderline resectable (63%). Twenty nine (33.7%) patients underwent surgery. Sarcopenic patients were less likely to undergo surgery (p = 0.024) versus non-sarcopenic patients. Otherwise there was no difference in clinical or treatment factors. The 12-month actuarial OS for patients with and without Sp was 47.9% and 70.7%, respectively (p = 0.047). The 12-month actuarial CSS for patients with and without Sp was 48% and 76%, respectively (p = 0.007). On multivariable analysis, after controlling for T-stage, N-stage, resectability, gender, pre-treatment CA 19-9, and surgery, Sp was no longer associated with CSS (HR 0.284 95% CI 0.774-2.398) or OS (HR 1.077 95% CI 0.626-1.853). Surgery remained associated with CSS (HR 0.205 95% CI = 0.102-0.412) and OS (HR 0.187 95% CI 0.096-0.363). T-stage also remained associated with both CSS (HR 0.616 95% CI 0.410-0.925) and OS (HR 0.649 95% CI 0.440-0.957). Conclusions: The presence of Sp decreases the likelihood of undergoing curative surgery for pancreatic cancer. This may be another useful tool to identify poor prognosis patients.
Therapeutic Strategy for Elderly Patients with ACUTE Myeloid Leukemia (AML) Carrying the DNMT3A Mutation
Authors: Elena Rossetti, Monica Crugnola, Cecilia Caramatti, Luisa Craviotto, Elena Masselli, Lucia Prezioso, Alessandro Monti, Benedetta Cambò, Chiara Lambertini, Claudio Pietropaolo, Anna Minardi, Gabriella Sammarelli, Sabrina Bonomini, Rodanthi Fioretzaki, Franco Aversa
Journal: Blood (2014)
The role of microRNA-9 in hepatocellular oncogenesis.
Authors: Alexandra Drakaki, Maria Hatziapostolou, Christos Polytarchou, Dimitrios Iliopoulos
Journal: Journal of Clinical Oncology (2013)

168 Background: Hepatocellular carcinoma (HCC) is the main type of liver cancer. MicroRNAs are non-coding RNAs that have been involved in the pathogenesis of different cancer types. Our aim was to identify microRNAs that have functional and clinical significance in liver oncogenesis and understand how manipulation of their levels could have a therapeutic potential. Methods: MicroRNA expression analysis was performed in 38 HCC tissues and 25 normal liver tissues. A microRNA library (318 microRNAs) was transfected in SNU-449 liver cancer cells and invasiveness was measured 24 h later by a matrigel invasion assay. Cell growth and matrigel invasion assays were performed in SNU-449 cells that were transfected with miR-9 or antisense-miR-9 (20nM). TargetScan algorithm was used to identify miR-9 direct downstream target genes. The mRNA levels of PPARalpha, and E-cadherin were assessed by real-time PCR 48h after miR-9 overexpression and down-regulation in SNU-449 cells. Results: MicroRNA expression analysis in 38 HCCs and 25 normal liver tissues identified a 25-microRNA signature of HCC. Integration of the library screen and patient data revealed that miR-9 has clinical and functional relevance for liver cancer. Specifically, we found that miR-9 increases 2.7-fold the invasiveness and the growth of SNU-449 cells, 48h post transfection. Bioinformatic analysis revealed that miR-9 has a binding site in the 3’UTR of PPARalpha gene. MiR-9 overexpression inhibited 35% PPARalpha 3’UTR luciferase activity and 60% mRNA levels, while miR-9 down-regulation led to 75% increased PPARalpha mRNA levels. These data suggest that miR-9 targets directly the 3'UTR of PPARalpha and regulates its expression levels in liver cancer cells. In addition, miR-9 overexpression led to 95% suppression of E-cadherin mRNA levels in SNU-449 cells, thus increasing their metastatic potential. Conclusions: We found that miR-9 is highly overexpressed in liver cancer patients and its up-regulation increases the growth and metastatic potential of liver cancer cells. Overall these data suggest that miR-9 is a novel oncogene involved in liver oncogenesis and its suppression could have therapeutic potential in liver cancer patients.
IL-6/STAT3 signaling impaired induction of cancer-antigen specific T cells via down-regulation of dendritic cells in tumor microenvironment.
Authors: Yosuke Ohno, Hidemitsu Kitamura, Junya Ohtake, Shun Kaneumi, Kentaro Sumida, Shigenori Homma, Hideki Kawamura, Norihiko Takahashi, Akinobu Taketomi
Journal: Journal of Clinical Oncology (2015)

590 Background: Immunosuppression in tumor microenvironments is a critical issue for cancer immunotherapy. Recently, the effectiveness of immuno-check point therapy has been reported on various types of solid tumors. But, the effectiveness in colorectal cancer was poor compared to other cancers, such as melanoma and renal cell carcinoma. Correct regulation of dendritic cell (DC) function in tumors is important for inducing anti-tumor immunity. We have been demonstrated that IL-6 inhibits antigen presentation by DCs through STAT3 activation in tumor-bearing mice. In this study, we focused on the role of the IL-6/STAT3 signaling cascade in human DCs. Methods: Both IL-6 and pSTAT3 expressions in tumor sites of colorectal cancers was verified by immunohistostaining. CD11b + CD11c + DCs in cancer tissues and PBMCs were isolated by fluorescence-activated cell sorting system and investigated about the surface molecules such as HLA-DR, T cell stimulating ability, and effector gene expression levels. Moreover, we investigated influence of IL-6/STAT3 signaling in human DCs in vitro. Results: The results of IHC revealed that IL-6 was preferentially produced by cancer-associated fibroblasts and immune cells in the tissues of colorectal cancers. In addition, it was confirmed that STAT3 was activated in tumor-infiltrating immune cells. Tumor infiltrating CD11b + CD11c + DCs highly induced IL-6 gene, down-regulated surface expression of HLA-DR, and attenuated T cell stimulating ability. In vitro experiments showed that IL-6-mediated STAT3 activation reduced surface expression of HLA-DR. COX2, cathepsin L (CTSL), and arginase activity were are involved in the IL-6-mediated down-regulation of surface expression levels of HLA-DR expression levels on DCs. Gene expressions of CTSL, ARG1 as well as IL6 in tumor infiltrating CD11b + CD11c + DCs were much higher than those of PBMCs. Conclusions: IL-6-mediated STAT3 activation inhibits functional maturation of DCs, causing suppression of anti-tumor immunity in colorectal cancer. Therefore, inhibition of the IL-6/STAT3 signaling pathway could be a promising strategy for improving immunotherapies for colorectal cancer patients.