tbuckley/cabot-search huggingface dataset:
A phase I evaluation of intravenous (IV) <sup>131</sup>I-chlorotoxin delivery to solid peripheral and intracranial tumors
Authors: T. E. Gribbin, N. Senzer, J. J. Raizer, S. Shen, L. B. Nabors, M. Wiranowska, J. B. Fiveash
Journal: Journal of Clinical Oncology (2009)

e14507 Background: Pre-clinical studies demonstrate TM601 binding to glioblastoma, melanoma, and other tumor types in vitro and in vivo (human xenograft tumors in mice). Here we report imaging and safety data from a Phase I clinical trial in patients with recurrent metastatic somatic and/or cerebral solid tumors that received IV 131 I-TM601. Methods: Patients received an IV imaging test dose of 10 mCi/0.2mg 131 I-TM601. Subjects not showing tumor localization, received a second imaging test dose of 20 mC/0.4mg 131 I-TM601. Subjects without localization at either dose were dropped from study; patients showing tumor localization without toxicity then received a 30 mCi/0.6mg 131 I-TM601 IV injection. The primary objectives were to: 1) determine whole body localization and dosimetry, 2) estimate the maximum tolerated dose based on normal tissue dosimetry and 3) determine the acute toxicity of IV 131 I-TM601. Results: A total of 44 evaluable patients received IV doses of 131 I-TM601 without dose-limiting toxicity. 31/44 (70%) showed tumor specific uptake on follow-up gamma camera or SPECT imaging. Tumor-specific uptake was observed in patients with malignant glioma (7/8), metastatic melanoma (7/7), non-small cell lung cancer (3/4), colon cancer (6/7), pancreatic cancer (2/3), prostate cancer (2/2), breast cancer (1/4) and in one evaluable patient each with transitional cell carcinoma, pleomorphic xanthoastrocytoma and metastatic paraganglioma. Notably, all patients with metastatic cerebral disease showed tumor-specific uptake of systemically injected 131 I-TM601. No uptake was seen in CNS lymphoma (n=1), ovarian (n=2), small cell lung (n=2), or medulllary thyroid cancers (n=1). Conclusions: Tumor-specific uptake of IV 131 I-TM601 in primary and metastatic (including brain) solid tumors suggests that further dose escalation is warranted. Notably, IV injected 131 I-TM601 crossed the blood brain barrier. Based on normal tissue dosimetry from this study, future clinical trials will evaluate safety and therapeutic efficacy in patients with recurrent glioma and metastatic melanoma at doses up to 100 mCi 131 I-TM601 (maximum single dose). [Table: see text]
Effect of adoptive T-cell therapy and intratumoral heat-killed bacteria on large tumors.
Authors: David C. Binder, Frank Wen, Ainhoa Arina, Tony Tu, Ming Zhao, Robert M. Hoffman, Hans Schreiber
Journal: Journal of Clinical Oncology (2014)

11112 Background: Preventing tumor relapse as antigen-loss variants remains a challenge in T cell therapy. T cells eradicate tumors by secreting cytokines that mediate bystander killing of tumor stromal cells and antigen-negative cancer cells. However, when tumors express a lower
Gemcitabine and docetaxel for metastatic breast cancer—Further data
Authors: L. R. Laufman, C. H. Spiridonidis, T. Parker, P. Boury, V. Maggard, S. Miller
Journal: Journal of Clinical Oncology (2006)

10704 Background: A previous study with weekly gemcitabine and monthly docetaxel at 100 mg/m 2 yielded a 79% response rate and a median survival of 24 months. (Laufman, Ann Oncology 2001; 12:1–6). This study was designed to see if the efficacy to toxicity ratio could be improved by decreasing the docetaxel dose to 75 mg/m 2 . Methods: Gemcitabine and docetaxel were given to 25 patients, all of whom had received prior chemotherapy. Nine had had taxanes, more than 12 months before entry. A maximum of 6 cycles of gemcitabine 800 mg/m 2 on days 1, 8 and 15 and docetaxel 75 mg/m 2 on day 1 were given every 28 days. Prophylactic antibiotics were given during neutropenia. Growth factors were used for anemia, neutropenia, or for secondary neutropenic prophylaxis. Maintenance therapy consisting of gemcitabine 800 mg/m 2 on days 1, 8 and 15 every 28 days was given to 12 patients, 2 of whom also received consolidation radiation. Results: A total of 122 cycles of induction therapy were given, with 14 patients receiving all 6. Dose delivery was 91.9% for docetaxel and 70.2% for gemcitabine. A total of 43 maintenance cycles were given, ranging from 1 to 12 cycles per patient. Dose delivery was 70.6%. Toxicity consisted of myelosuppression and fatigue. Grade 4 neutropenia occurred in 20 patients but was complicated by infection or fever in only 3. Five patients had grade 3 anemia and 4 had grade 3 thrombocytopenia. Other grade 3 toxicities consisted of fatigue in 8 patients, myalgia/arthralgias in 4, mucositis in 1, pneumonia in 1 and diarrhea in 1. Responses defined by RECIST criteria occurred in 12 patients (48%), including 8 of 16 taxane-naïve and 4 of 9 taxane-exposed patients. Conclusion: This regimen is active, and the most common toxicity is asymptomatic neutropenia. Sponsored by Eli Lilly and Aventis. No significant financial relationships to disclose.
Phase 1/2 trial of the indoleamine 2,3-dioxygenase pathway (IDO) inhibitor indoximod plus ipilimumab for the treatment of unresectable stage 3 or 4 melanoma.
Authors: Eugene Kennedy, Gabriela R. Rossi, Nicholas N. Vahanian, Charles J. Link
Journal: Journal of Clinical Oncology (2014)

TPS9117 Background: IDO is an enzyme that catalyzes the initial and rate limiting step in the conversion of tryptophan to kynurenine. Tryptophan depletion enhances the number and function of the Treg (suppressive) arm of the immune system and inhibits the effector T cell (stimulatory) arm. In addition, it has been shown that kynurenine metabolites may augment the suppressive effects on inflammation and immune responses. The main function of IDO is the regulation of acquired local and peripheral immune tolerance in normal and pathological conditions. In cancer, IDO can either be expressed directly by the tumor cells themselves, or induced indirectly in host antigen presenting cells by the presence of tumor. In these settings, IDO mediates an acquired immune tolerance towards tumors, allowing tumors to thwart an immune response by the host. Therefore, IDO is an attractive target. Ipilimumab is a monoclonal antibody that blocks the immunosuppressive receptor CTLA-4 on T cells, thus enhancing immune responses against tumors. Tumor models have shown synergistic effects with anti-CTLA-4 treatment in combination with indoximod providing a rationale for combination therapy for the treatment of melanoma. Methods: This is a Phase 1/2 study of indoximod dose escalation in combination with ipilimumab (3mg/kg q3 weeks x 4 doses) in a standard 3+3 design during the Phase 1 portion. Eligible patients will have unresectable Stage 3 or 4 melanoma. Up to 12 patients will be enrolled in the Phase 1 portion. Indoximod will be administered concurrently with ipilimumab as a twice daily oral dose, continuously for each 21 day cycle. Treatment with indoximod will continue beyond treatment with ipilimumab (halted either due to reaching 4 doses or toxicity) until disease progression or toxicity. The Phase 2 portion will enroll up to 80 patients in a non-randomized study. Patients will receive ipilimumab at the standard dose with concurrent indoximod at the dose determined in Phase 1. Primary endpoints for the Phase 1 portion include safety, toxicity, and determination of a Phase 2 dose. Primary endpoints for the Phase 2 portion will be to evaluate safety and efficacy. Clinical trial information: NCT02073123.
What does evolutionary theory add to stereotype theory in the explanation of attractiveness bias?
Authors: Kirby Q Maguire, Timothy P Racine
Journal: Behavioral and Brain Sciences (2017)

Maestripieri et al. seem to put forth an argument in which they become vulnerable to some of the same criticisms that they level against stereotype theory As a result, the explanatory utility of their account of attractiveness bias comes into question, and it is unclear whether it offers anything superior to stereotype theory in conceptual soundness.
Optimizing Cardiac Delivery of Modified mRNA
Authors: Nishat Sultana, Ajit Magadum, Yoav Hadas, Jason Kondrat, Neha Singh, Elias Youssef, Damelys Calderon, Elena Chepurko, Nicole Dubois, Roger J. Hajjar, Lior Zangi
Journal: Molecular Therapy (2017)

Modified mRNA (modRNA) is a new technology in the field of somatic gene transfer that has been used for the delivery of genes into different tissues, including the heart. Our group and others have shown that modRNAs injected into the heart are robustly translated into the encoded protein and can potentially improve outcome in heart injury models. However, the optimal compositions of the modRNA and the reagents necessary to achieve optimal expression in the heart have not been characterized yet. In this study, our aim was to elucidate those parameters by testing different nucleotide modifications, modRNA doses, and transfection reagents both in vitro and in vivo in cardiac cells and tissue. Our results indicate that optimal cardiac delivery of modRNA is with N1-Methylpseudouridine-5'-Triphosphate nucleotide modification and achieved using 0.013 μg modRNA/mm2/500 cardiomyocytes (CMs) transfected with positively charged transfection reagent in vitro and 100 μg/mouse heart (1.6 μg modRNA/μL in 60 μL total) sucrose-citrate buffer in vivo. We have optimized the conditions for cardiac delivery of modRNA in vitro and in vivo. Using the described methods and conditions may allow for successful gene delivery using modRNA in various models of cardiovascular disease.
Neurocognitive outcomes of head and neck chemoradiotherapy: A pilot study
Authors: H. K. Gan, L. J. Bernstein, J. Brown, J. Ringash, M. Vakilha, L. Wang, B. O'Sullivan, J. Waldron, E. X. Chen, L. L. Siu
Journal: Journal of Clinical Oncology (2009)

6068 Background: Evidence suggests cancer-related treatments affect cognition. To our knowledge, no studies have systematically investigated cognitive impairment in head and neck cancer (HNC) patients (pts). We assessed ten relapse-free HNC pts after curative-intent radiotherapy (RT), half of whom received cisplatin (Cp). Methods: Pts completed a 2-hr battery of tests/questionnaires assessing objective cognitive function (CF), subjective CF, quality of life and affect. Objective measures of CF were transformed to Z-scores (mean=0, standard deviation=1) using age normative data. A negative value for the Difference Score (DS=Z-score minus IQ score) in each tested domain indicates cognitive deterioration as IQ is a pre-morbid estimate of pts’ CF. A Global Deficit Score (GDS) was obtained by averaging the DS of all tested CF domains. Results: Pt demographics were: M:F=8:2; mean age=58 yrs(range 47–66); mean smoking pack yrs=15(0–45); mean drinks/week=7(0–25); mean IQ Z-score=+1.2(-1.0 to +2.0), mean school yrs=15 (6–18) and mean time post treatment=20 mo(9–41). All pts completed the battery within 2 hr. Nine participants appeared to have impaired CF based on negative DS and GDS scores ( Table 1 ). Exploratory univariate analyses showed trends that higher RT dose and Cp use were associated with increased impairment but cytokines, anemia, hormonal status and affective state were not. Conclusions: This feasibility study suggests cancer-related treatment affects cognition in HNC survivors. A longitudinal study is underway. [Table: see text] No significant financial relationships to disclose.
A combination docetaxel-capecitabine in patients (pts) with hormone refractory advanced prostate cancer
Authors: J. Ferrero, J. F. Berdah, E. Chamorey, S. Oudard, S. Dides, G. Lesbats, G. Cavaglione, P. Nouyrigat, C. Foa, P. Guillet, R. Kaphan
Journal: Journal of Clinical Oncology (2004)

4624 Background: Docetaxel monotherapy is active in hormone refractory metastatic prostate cancer. Pre-clinical models indicate a synergistic cytotoxicity between capecitabine and docetaxel. Recently, this association has proven survival benefits in advanced breast cancer. This multicenter phase II study reports on preliminary efficacy and safety data of docetaxel-capecitabine combination in hormone-refractory prostate cancer with metastases (HRPC). Methods: Eligible pts had histologically and biologically confirmed HRPC. Other requirements included a Karnofsky index of more than 50% and no prior chemotherapy except estramustine. Treatment consisted of 4 cycles of docetaxel 35mg/m2 on day 1, day 8, day 15 and capecitabine 1250mg/m2/day in 2 divided doses from day 5 to day 18 of each 28 days cycle. A minimum of 2 treatment cycles were required for response assessment. Biological efficacy was defined as a decline of >50% from baseline PSA levels. Clinical response was evaluated using RECIST criteria. Results: 23/50 planned pts were enrolled between June to November 2003. Patient baseline characteristics were: median age 69.5 years (range 51.4–81.3), median Gleason score: 8 (range 6–9), median PSA 73.2 ng/ml (range 0.93–2010.9). Sixty-height percent had prior radiation and 52.3% had prior surgical treatment. Disease related pain was present in 82.3% of pts. Pts received a median of 2 courses of treatment (range 1–4). A total of 54 cycles of treatment were administered. The most common grade (G) 3–4 toxicities included 1 G-3 anemia, 4 G-3 digestive toxicities and 1 G-3 stomatitis. Biological response was observed in 17 pts after the 2nd cycle and in 7 pts after the 4th cycle. Seven pts (41.2%) exhibited a PSA decrease of >50% after the 2nd cycle and 5 pts (71.4%) after the 4th cycle. Conclusions: This combination appears to be a very promising regimen with a favorable toxicity profile. These early encouraging data have to be confirmed with the analysis of the next 27 planned patients and final results will be presented at the meeting. No significant financial relationships to disclose.
Prognostic implication of monosomal karyotype in patients with acute myeloid leukemia who received allogeneic hematopoietic cell transplantation.
Authors: Yunsuk Choi, Sung-Doo Kim, Young-Hun Park, Jae Seok Lee, Dae-Young Kim, Jung-Hee Lee, Kyoo-Hyung Lee, Miee Seol, Young-Shin Lee, Young-Ah Kang, Mijin Jeon, Ah Rang Jung, Je-Hwan Lee
Journal: Journal of Clinical Oncology (2012)

6564 Background: Monosomal karyotype (MK), defined as at least two autosomal monosomies or one single autosomal monosomy with one or more structural cytogenetic abnormalities, has been associated with worse outcomes in acute myeloid leukemia (AML). We evaluated the prognostic impact of MK on outcomes after allogeneic hematopoietic cell transplantation (allo-HCT) in AML. Methods: We retrospectively analyzed 169 adult patients with AML, who received allo-HCT in the first complete remission (CR) between 2000 and 2009. All patients had cytogenetic results at the diagnosis of AML. Patients were classified as having good, intermediate, or poor risk cytogenetics according to the NCCN guideline, and MK status was also determined. Results: MK was observed in 12 patients (7.1%); of whom, 11 patients also had complex karyotype (CK). Compared to patients without MK, those with MK had significantly lower overall survival (OS) (62.2% vs. 0%) and event free survival (EFS) (58.9% vs. 0%), and higher relapse probability (RP) (22.9% vs. 66.7%) at 5 years (all, p&lt;0.001). 22 patients with CK also showed inferior outcomes, but CK with MK was associated with more inferior outcomes than CK without MK. Multivariate analysis showed that MK had a significantly adverse impact on OS (hazard ratio [HR], 5.192; p&lt;0.001), EFS (HR, 4.531; p&lt;0.001), and RP (HR, 6.558; p&lt;0.001) after allo-HCT (Table). Conclusions: MK is a major prognostic factor predicting extremely worse outcomes in AML patients who underwent allo-HCT in the first CR. [Table: see text]
IMPACT OF AN ULTRA-MARATHON OF 330 KM ON PLASMA LEVELS OF CARDIAC BIOMARKERS
Authors: Caroline Le Goff, Jean-François Kaux, Laurent Gergelé, Grégoire P Millet, Guido Giardini, Magalie Viallon, Pierre Croisille, Etienne Cavalier
Journal: British Journal of Sports Medicine (2017)

Background While a moderate exercise benefits on the cardiovascular system, consequences of a supraphysiological effort are not yet clear. Objective The aim of our study was to evaluate the consequences of an ultra-marathon on cardiac and muscles markers (CK, myoglobin, hsTnT, NT-proBNP, copeptin, H-FABP) but also markers of inflammation CRP DFO, GB) and of renal function (urinary NGAL and plasma and urinary creatinine). This project also studied the evolution of new cardiac fibrosis biomarkers: ST2 and Gal-3. Design Longitudinal, cohort study. Setting The Tor des Geants (TdG), a 330 km long ultra distance trail running, with +24,000 m elevation changes in the Valley of Aosta (Italy), is considered as one of the most difficult mountain marathon race in the world. The maximum time allowed to complete the race is 150 h. Patients (or Participants) 51 participants attending the TdG have been followed and the study was conducted on 33 subjects having reached at least half of the race (148.7 km). Interventions (or Assessment of Risk Factors) Repeated blood and urine samples collection were carried out at four key time points: before, during (mid-point) and after the race (less than 1 h) and 3 days after the end of the race. Main Outcome Measurements Biological samples were collected at these four different times. Several biomarkers were assayed on different analyzers such COBAS®, KRYPTOR®, VIDAS® and ETIMAX®, meanwhile, the ST2 and Gal-3 were measured manually. Results During the TdG, the plasma levels of cardiac markers, muscle and inflammation have increased significantly to halfway. Meanwhile, the markers of renal function have only slightly varied, excepting plasma creatinine. Conclusions The study suggests that there is no permanent structural damage at the myocardium level. However, the low pace adopted by the tired runners caused an inflammatory response as well as muscle damage less important than a shorter race.
Use of radiation therapy in locally advanced pancreatic cancer to improve outcomes: A SEER review.
Authors: Monique Z. Sajjad, Sachin Batra, Gregory M. Springett, Aaron Cleveland Denson, Sarah E. Hoffe, Amit Mahipal
Journal: Journal of Clinical Oncology (2015)

e15233 Background: Pancreatic cancer survival rates remain poor despite treatment. Although radiotherapy in addition to chemotherapy is frequently employed, the role of radiation therapy (XRT) in the treatment of locally advanced pancreatic cancer (LAPC) remains controversial. The majority of the data evaluating the efficacy of radiotherapy is derived from small, dated, randomized trials which have provided conflicting results. Methods: We queried the SEER database from 2004-2011 to identify patients with locally advanced pancreatic adenocarcinoma. Pts with survival <2 months, surgery prior to XRT, unknown radiation status, and those who received post-operative radiation were excluded. Multivariate analysis of prognostic factors related to survival was performed using a Cox proportional hazard regression model. Results: We identified 4,460 patients that met the inclusion criteria; 59% of pts received radiation and 41% did not. The two groups were similar with respect to gender and tumor differentiation. Pts in the radiation group were younger (ages<65: 49% vs. 38%), had smaller tumor size (largest dimension <4.5 cm: 80% vs. 75%), lesser lymph node involvement (33% vs. 36%) and lower rate of surgical resection (4% vs. 9%). Radiation treatment, age, tumor grade and surgical resection showed improved survival on univariate analysis. Patients who received radiation therapy had improved survival (HR: 0.773; 95% CI 0.687-0.782). On multivariate analysis, radiation was independently associated with improved outcomes. Conclusions: Radiation therapy was associated with improved survival in patients with LAPC in this population-based registry in both univariate and multivariate analysis. This is the largest and most recent review of the SEER database to date. Larger randomized trials are needed to confirm these findings. The optimal schedule and type of radiation remains unknown. Multivariate analysis. Variable HR (95% CI) P-Value Radiation, yes vs no 0.74 [0.69-0.79] <0.001 Age, ≥ 65 vs < 65 years 1.26 [1.18-1.34] <0.001 Surgery 0.55 [0.44-0.67] <0.001 Lymph Node, positive vs. negative 1.10 [1.03-1.18] 0.006 Tumor Grade (reference Grade 1) Grade II 0.91 [0.85-0.98] 0.013 Grade III/IV 1.06 [0.86-1.31] 0.569
Limited Added Value of Circulating Inflammatory Biomarkers in Chronic Heart Failure
Authors: Ståle H. Nymo, Pål Aukrust, John Kjekshus, John J.V. McMurray, John G.F. Cleland, John Wikstrand, Pieter Muntendam, Ursula Wienhues-Thelen, Roberto Latini, Erik Tandberg Askevold, Jørgen Gravning, Christen P. Dahl, Kaspar Broch, Arne Yndestad, Lars Gullestad, Thor Ueland
Journal: JACC Heart Failure (2017)
Dual specific antibody, scds-D2C7-PE38KDEL, for GBM therapy
Authors: Vidyalakshmi Chandramohan, Charles Pegram, Scott Szafranski, Darell Bigner, Chien-Tsun Kuan
Journal: Cancer Research (2008)

4053  Glioblastoma multiforme (GBM) is the most malignant and most frequently occurring brain tumor in the adult and pediatric populations. The epidermal growth factor receptor (EGFR) is expressed by normal epithelial cells in most tissues but overexpressed in 60%-90% of all GBMs. In addition, 58%-61% of all GBMs also express the EGFR variant III mutant (EGFRvIII), which is not found in normal tissues. Monoclonal antibodies (MAbs) targeting either the wild-type EGFR (wt) or EGFRvIII have been developed, and one of them, D2C7, a murine IgG1κ, recognizes both the wt and tumor-specific EGFRvIII receptors. In the present study, we have demonstrated cloning of a novel recombinant single chain variable region antibody fragment (scFv) from the D2C7 hybridoma and engineered a disulfide-stabilized linkage between variable heavy (VH) and light (VL) domains to generate scds-D2C7. The scds-D2C7 is connected to a truncated form of Pseudomonas exotoxin (PE38KDEL). The binding affinity (KA) of scds-D2C7-PE38KDEL by surface plasmon resonance, against the wt and against the EGFRvIII extracellular domain (ecd) was 6.3 x 108 (mol/L)-1 and 7.8 x 108 (mol/L)-1, respectively. Flow cytometry against wt transfected (NR6W), EGFRvIII transfected (NR6M) and parental NR6 cells, a mouse 3T3 fibroblast cell line that naturally lacks EGFR expression, further confirmed the dual specificity of scds-D2C7-PE38KDEL. The immunotoxin was highly cytotoxic, with an IC50 of 1 ng/ml and 3 ng/ml respectively, on cells expressing the wt (NR6W) and EGFRvIII (NR6M) receptors. There was no cytotoxic activity at 1000 ng/ml on the parental NR6 cells. Further investigations of the scds-D2C7-PE38KDEL are in progress to assess its in vivo therapeutic potential as a targeting agent for wt and EGFRvIII expressing malignant gliomas.