tbuckley/cabot-search huggingface dataset:
Anti-tumor effect of a series of engineered peptides in N-MYC amplified Neuroblastoma.
Authors: Don Wilson Coulter, Xiaoyu Chen, Timothy R. McGuire, J. Graham Sharp, Erin McIntyre, Guangshun Wang, Xiuqing Wang
Journal: Journal of Clinical Oncology (2015)

e21013 Background: Neuroblastoma (NB) is a pediatric tumor of neural crest origin. Patients who have N-MYC amplified tumors that respond sub optimally to initial therapies have poor outcomes with 30-40% long-term survival. These tumors may have higher content of therapy resistant cancer stem cells (CSC) and prognosis is related in part to the extent of N-MYC amplification. We evaluated a novel series of engineered polypeptides for activity in highly N-MYC amplified (BE-2) and intermediately N-MYC amplified (IMR-32) NB cells. Methods: This in-vitro evaluation was completed using a combination of cellular monolayers in a MTT assay to measure cell viability, and neurospheres that have been considered structures enriched for CSC. MTT screening assays were performed on a 96 well platform with absorption measured at 550nm on a microplate reader. Neurospheres form on low adherence plates in media supplemented with bFGF, EGF and N-2 supplement. To assess treatment effect, spheres were counted and photographs taken before and after treatment. LDH cytotoxicity assays supplemented sphere counts and changes in morphology and color of the spheres. Toxicity was assessed using a RBC lysis assay which identifies membrane toxic agents and a CFU-GM assay using human bone marrow which assesses bone marrow toxicity. Results: MTT assay demonstrated a concentration dependent cytotoxicity associated with 3 of 8 polypeptides that were screened (D128A, D74, and D233B). The most active of the agents was D128A with complete cytotoxicity at a concentration of 25 and 50 μM in IMR-32 cells and at 50 μM in BE-2 cells. Toxicity of D128A on RBCs occurred at concentrations 10X higher than concentrations which were active in the neurosphere assay suggesting an advantageous therapeutic index. Conclusions: A new class of antitumor polypeptides shows interesting activity in two cell lines which model high-risk NB. The cytotoxicity was concentration dependent with complete cell kill occurring at the highest concentrations tested. The toxicity profile was advantageous with effective concentrations occurring at levels much lower then toxicity. Currently the most active of the screened compounds are being tested for anti-tumor activity against NB growing in NSG mice.
Inhibition of soft-tissue sarcoma lung metastasis by tumor-targeting <i>Salmonella typhimurium </i>A1-R.
Authors: Shinji Miwa, Yong Zhang, Michael Bouvet, Hiroyuki Tsuchiya, Robert M. Hoffman, Ming Zhao
Journal: Journal of Clinical Oncology (2015)

e13515 Background: Prognosis of patients with lung metastases of soft-tissue sarcoma is still poor, therefore, more effective therapeutics are needed. Methods: In the present study, tumor-targeting therapy with a genetically-modified auxotrophic strain of Salmonella typhimurium, termed A1-R, was evaluated on mouse models of primary soft tissue sarcoma where spontaneous lung metastasis occurred after orthotopic intra-muscular injection of HT1080-RFP human fibrosarcoma cells. S. typhimurium A1-R was administered from day 14, once a week for two weeks. On day 28, lung samples were excised and observed with a fluorescence imaging system. A mouse model of experimental lung metastasis was obtained by tail vein injection of HT1080-RFP cells. The mice were treated with S. typhimurium A1-R (i.v.) on day 7, once a week for three weeks. Results: The number of spontaneous lung metastasis was 8.8 ± 3.4 in the untreated group and 0.8 ± 0.8 in the S. typhimurium A1-R treated group (P = 0.024). S. typhimurium A1-R also significantly reduced experimental lung metastases and improved overall survival (P = 0.004). Conclusions: S. typhimurium A1-R bacterial therapy has clinical potential for treating advanced soft tissue sarcoma in the adjuvant setting.
Systematic meta-analysis on percutaneous ethanol injection and percutaneous acid injection for the treatment of early HCC: A Cochrane analysis
Authors: K. Schoppmeyer, S. Weis, J. Mossner, W. E. Fleig
Journal: Journal of Clinical Oncology (2009)

e15657 Background: Hepatocellular carcinoma (HCC) is the fifth most common global cancer with high geographical variability. When HCC is detected early, percutaneous approaches such as percutaneous ethanol injection (PEI), percutaneous acetic acid injection (PAI), and radiofrequency thermal ablation (RFTA) have curative potential and represent low invasive alternatives to surgery. The role of percutaneous ethanol or acetic acid injection and other percutaneous interventions except RFTA has not been addressed in a systematic metaanalysis. The objective was to evaluate the effects of PEI and PAI for early HCC. Methods: A systematic search was performed in EMBASE, Cochrane Central, The Cochrane Hepato-Biliary Group Controlled Trials Register, Medline and Scopus as well as a handsearch of meeting abstracts. Only randomised controlled trials were included. RFTA studies were not considered. Primary endpoint was overall survival, secondary endpoints were cancer free survival, number and type of adverse events, duration of hospital stay, and quality of life. Results: 3 studies covering 261 patients were identified. Two studies compared PEI with PAI. 91 and 94 patients with one to three HCC-nodules ≤ 3cm underwent PEI and PAI, respectively. Overall survival (HR 1.47; 95% CI 0.68 to 3.19) and cancer free survival (HR 1.42; 95% CI 0.68 to 2.94) were not significantly different after treatment by PEI versus PAI. Both treatments were safe with no serious adverse events reported and modest pain being the most frequent adverse event. Data on the duration of hospital stay were inconclusive and data on quality of life not available. One study compared PEI with surgery. 38 patients were allocated to each treatment arm. There was no significant difference in survival (HR 1.57; 95% CI 0.53 to 4.61) and cancer free survival (HR 1.35; 95% CI 0.69 to 2.63). No serious adverse events were reported in the PEI group but 3 postoperative deaths occurred in the surgery arm. Conclusions: PEI and PAI are similarly effective and safe in patients with one to three small (≤ 3 cm) HCC nodules. Although the evidence is weaker, the beneficial effect of PEI is comparable to that of segmental liver resection and thus should be used preferentially due to its low morbidity and mortality. No significant financial relationships to disclose.
Patient-specific biomathematical model to predict benefit of resection in human gliomas.
Authors: Anne Baldock, Russell Rockne, Sunyoung Ahn, Maxwell Neal, David Corwin, Kamala Clark-Swanson, Greg Sterin, Andrew Daniel Trister, Hani Malone, Adam Sonabend, Maciej M. Mrugala, Jason K. Rockhill, Daniel L. Silbergeld, Albert Lai, Timothy Francis Cloughesy, Guy McKhann, Jeffrey N. Bruce, Robert Rostomily, Peter Canoll, Kristin Swanson
Journal: Journal of Clinical Oncology (2013)

e13017 Background: Gliomas are incurable, primary brain tumors noted for their invasion of brain parenchyma. Our goal was to apply a biomathematical model to estimate the overall tumor invasiveness on an individual basis and determine whether the estimated number of residual glioma cells after resection of any extent is predictive of survival. Methods: Estimates of net rates of proliferation (ρ) and diffusion (D) of glioma cells, based on a biomathematical model of cell density, yield a ratio describing relative invasiveness (ρ/D). This metric was derived for 185 contrast enhancing gliomas from pretreatment MRIs. The residual MRI-detectable volume was combined with the ρ/D tuned to each patient's tumor to allow estimation of the number of glioma cells remaining post-resection. The patients were split into three cohorts by ρ/D values. Within each cohort, all possible cut-off values were considered as a possible threshold between low and high residual patient groups. Log-rank tests were performed for each possible threshold to determine if the Kaplan-Meyer curves were significantly different. Results: We demonstrate that for low ρ/D tumors there was no threshold of residual tumor cell population observed that could yield a significant survival benefit. Both the mid ρ/D and high ρ/D had robust thresholds of residual tumor cell population, below which patients saw significantly higher survival than patients with similar invasiveness and more residual tumor. Conclusions: These results suggest that our patient-specific biomathematical model-based estimates of tumor invasiveness and residual tumor cells have clinical utility in driving neurosurgical decision making. Given the physicians understanding of patient-specific risk factors such as tumor location, age, and physical health, an understanding of the differential surgical benefit allows for more informed cost-benefit analysis and improved quality of life. This metric enables physicians to identify a subset of patients who do not see a survival benefit from resection, making the operation potentially not worth the risks.
Prognostic significance of preoperative plasma fibrinogen and Albumin Score in esophageal cancer patients.
Authors: Yusuke Maeda, Hiroya Takeuchi, Hirofumi Kawakubo, Koichi Suda, Rieko Nakamura, Norihito Wada, Yuko Kitagawa
Journal: Journal of Clinical Oncology (2017)

36 Background: The clinical outcome of esophageal cancer has recently improved. However, the relapse rate in any stages is still high. Prognostic classification in patients with esophageal cancer has not yet established. If the patients with poor prognosis could be extracted before surgery, we can add more intensive preoperative treatment, which might lead more favorable prognosis. We have previously reported clinical utility of fibrinogen (FNG) and Albumin (Alb) Score (FA score) in esophageal cancer. The purpose of this study was to analyze the utility of FA score comparing at each stage as a prognostic factor in esophageal cancer. Methods: Patient characteristics, clinicopathological factors, and preoperative biochemical markers (FNG, Alb, and CRP) were investigated in esophageal cancer patients who underwent transthoracic esophagectomy between January 2004 and November 2013. Correlation between preoperative FNG, CRP, Alb, clnicopathological factors and survival were investigated. We evaluated between recurrence-free survival (RFS), overall survival (OS) and FA score comparing at each stage. The cut-off value was defined according to previous reports; fibrinogen 350mg/dl, albumin 3.8mg/dl. Results: 252 patients were recorded. High FA score were correlated to worse OS and RFS (p &lt; 0.001). Especially in cStageI, high FA score showed remarkably worse 5-year RFS (score0/ score1/ score2, 5-year RFS 84%/ 64%/ 33%; p = 0.038). Conclusions: FA score was significantly associated with postoperative survival in esophageal cancer patients. If the patients with poor prognosis in cStageI could be extracted before surgery, we can add more intensive preoperative treatment, which might lead more favorable prognosis.
A phase 3 study of trabectedin (T) plus pegylated liposomal doxorubicin (PLD) versus PLD for treatment of advanced-relapsed epithelial ovarian, primary peritoneal, or fallopian tube cancer.
Authors: Robert L. Coleman, Bradley J. Monk, Marcela G. del Carmen, Roland Elmar Knoblauch, Trilok V. Parekh, Fitzroy W. Dawkins, Raymond Scott Maul, Youn Choi Park, Thomas J. Herzog
Journal: Journal of Clinical Oncology (2014)

TPS5612 Background: Ovarian cancer (OVC) is the eighth most common cancer among women globally, with approximately 60%–70% of cases being diagnosed at an advanced stage (III or IV). Five-year survival rate for stage IV is <20%. In a previous pivotal trial, patients with OVC who relapsed after first-line platinum-based chemotherapy (PCT) demonstrated superior progression free survival (PFS) when treated with the T+PLD combination vs. PLD monotherapy (7.3 vs. 5.8 months; HR=0.79; p=0.019). In a subgroup analysis by platinum free interval (PFI), T+PLD showed an improved overall survival (OS) for patients with PFI of 6–12 months (HR=0.64). Given this demonstrated efficacy, we are conducting a global phase 3 registration trial to investigate the OS of T+PLD vs. PLD in patients with platinum sensitive epithelial OVC, peritoneal or fallopian tube cancer, in the third-line setting. Methods: In this open-label, active-controlled trial, approximately 670 women who have received 2 prior lines of PCT will be enrolled at approximately 135 sites in 9 countries. Key inclusion criteria: all women must be platinum sensitive defined as no evidence of disease progression for ≥6 months after the last dose of first-line PCT, and have known BRCA mutation status prior to randomization. Key exclusion criteria: OVC with mucinous histology and >2 prior lines of chemotherapy. Patients will be stratified by PFI (6–12 months vs. >12–24 months vs. >24 months), ECOG performance status (0 vs. 1), BRCA 1 or 2 mutation status (yes vs. no), and prior PLD therapy (yes vs. no). Stratified patients will be randomized (1:1) to receive PLD (30 mg/m2, 1.5 h, i.v.) followed by T (1.1 mg/m2, 3 h, i.v.) every 3 weeks or PLD alone (50 mg/m2, 1.5 h, i.v.) every 4 weeks. Primary endpoint is OS. Secondary endpoints include PFS, overall response rate (ORR), safety, and pharmacokinetics of T. Planned study duration is 64 months. An interim OS analysis is planned after 308 deaths. Final OS analysis will be done after ≥514 deaths have been observed. As of 29 January 2014, 11 patients have been randomized. Clinical trial information: NCT01846611.
Mercaptopurine Ingestion Habits, Red Cell Thioguanine Nucleotide Levels, and Relapse Risk in Children With Acute Lymphoblastic Leukemia: A Report From the Children’s Oncology Group Study AALL03N1
Authors: Wendy Landier, Lindsey Hageman, Yanjun Chen, Nancy Kornegay, William E. Evans, Bruce C. Bostrom, Jacqueline Casillas, David S. Dickens, Anne L. Angiolillo, Glen Lew, Kelly W. Maloney, Leo Mascarenhas, A. Kim Ritchey, Amanda M. Termuhlen, William L. Carroll, Mary V. Relling, F. Lennie Wong, Smita Bhatia
Journal: Journal of Clinical Oncology (2017)

Purpose Children with acute lymphoblastic leukemia (ALL) are generally instructed to take mercaptopurine (6-MP) in the evening and without food or dairy products. This study examines the association between 6-MP ingestion habits and 6-MP adherence, red cell thioguanine nucleotide (TGN) levels, and risk of relapse in children with TMPT wild-type genotype. Methods Participants included 441 children with ALL receiving oral 6-MP for maintenance. Adherence was monitored over 48,086 patient-days using the Medication Event Monitoring System; nonadherence was defined as adherence rate &lt; 95%. 6-MP ingestion habits examined included: takes 6-MP with versus never with food, takes 6-MP with versus never with dairy, and takes 6-MP in the evening versus morning versus varying times. Results Median age at study was 6 years (range, 2 to 20 years); 43.8% were nonadherent. Certain 6-MP ingestion habits were associated with nonadherence (taking 6-MP with dairy [odds ratio (OR), 1.9; 95% CI, 1.3 to 2.9; P = .003] and at varying times [OR, 3.4; 95% CI, 1.8 to 6.3; P = .0001]). After adjusting for adherence and other prognosticators, there was no association between 6-MP ingestion habits and relapse risk (6-MP with food: hazard ratio [HR], 0.7; 95% CI, 0.3 to 1.9; P = .5; with dairy: HR, 0.3; 95% CI, 0.07 to 1.5; P = .2; taken in evening/night: HR, 1.1; 95% CI, 0.2 to 7.8; P = .9; at varying times: HR, 0.3; 95% CI, 0.04 to 2.7; P = .3). Among adherent patients, there was no association between red cell TGN levels and taking 6-MP with food versus without (206.1 ± 107.1 v 220.6 ± 121.6; P = .5), with dairy versus without (220.1 ± 87.8 v 216.3 ± 121.3; P =.7), or in the evening/night versus morning/midday versus varying times (218.8 ± 119.7 v 195.5 ± 82.3 v 174.8 ± 93.4; P = .6). Conclusion Commonly practiced restrictions surrounding 6-MP ingestion might not influence outcome but may hinder adherence. Future recommendations regarding 6-MP intake during maintenance therapy for childhood ALL should aim to simplify administration.
Outcomes of high, t(11;14), and standard cytogenetic risk multiple myeloma following early high dose therapy and autologous hematopoietic cell transplantation (SCT).
Authors: Gregory Peter Kaufman, Morie A. Gertz, Angela Dispenzieri, Martha Lacy, Francis Buadi, David Dingli, Suzanne R. Hayman, Prashant Kapoor, S. Vincent Rajkumar, Shaji Kumar
Journal: Journal of Clinical Oncology (2015)

8583 Background: Current cytogenetic risk stratification in newly diagnosed multiple myeloma (NDMM) is not derived from recent patients (pts) treated with novel agents. High dose melphalan and SCT is a preferred management strategy for transplant eligible NDMM pts following novel agent induction. We investigated outcomes of high cytogenetic risk (HR), t(11;14), and standard cytogenetic risk (SR) NDMM treated with early SCT. Methods: Following Mayo Clinic IRB approval and in accordance with the Declaration of Helsinki, all pts treated at Mayo Clinic Rochester with SCT for NDMM between 2003 and 2012 were identified (n = 941). We excluded pts without FISH cytogenetics from diagnosis (dx) and those who did not undergo SCT within 12 months of dx. HR was defined as a composite of mSMART high and intermediate risk abnormalities including del(17p), t(4;14), t(14;20) or t(14;16). Response and progression were defined per IMWG criteria. Overall survival (OS) and progression free survival (PFS) were calculated from dx. Results: The study cohort had 409 pts [SR = 244, t(11;14) = 69, HR = 96], with a median estimated follow up of 43 months from dx. Novel agents (IMiDs or proteasome inhibitors) were used in 95% of pts prior to SCT, and 80% of pts achieved partial response. Median PFS for HR, t(11;14), and SR pts was 24.9 (23,30), 28.1 (21,31), and 30.4 (28-34) months respectively (p = 0.034). Median OS for HR, t(11;14), and SR pts was 60.5 (46,71), 73.4 (54,89), and 103 (98,113) months respectively (log rank < 0.0001). When only pts who received post-transplant maintenance therapy were evaluated (IMiDs or proteasome inhibitors), there was no difference in OS at 5 years from diagnosis between HR and SR pts treated with early SCT (p = 0.19). Conclusions: Following novel agent induction and early SCT, pts with t(11;14) NDMM have inferior OS compared to a SR cohort of similarly treated pts. This is contrary to the current classification scheme. HR pts have similar OS at 5 years from diagnosis compared to SR pts with the use of early SCT and maintenance therapy.
Contents, Vol. 51, 1989
Authors: K. O'Connor, C. Chambers, R. Hinchcliffe, C. van Heeringen, M. van Moffaert, G. de Cuypere, Myriam van Moffaert, Carol C. Nadelson, R.W. Trijsburg, J.A. Bal, W.P. Parsowa, R.A.M. Erdman, H.J. Duivenvoorden, Andres M. Kanner, Rachel G. Klein, Boris Rubinstein, Armond Mascia, Liisa Keltikangas-Järvinen, Katri Räikkönen, Nechama Weizer, Abraham Weizman, Zaki Shapira, Alexander Yussim, Hanan Munitz
Journal: Psychotherapy and Psychosomatics (1989)
Prevention of Hypoglycemia With Predictive Low Glucose Insulin Suspension in Children With Type 1 Diabetes: A Randomized Controlled Trial
Authors: Tadej Battelino, Revital Nimri, Klemen Dovc, Moshe Phillip, Natasa Bratina
Journal: Diabetes Care (2017)

OBJECTIVE To investigate whether predictive low glucose management (PLGM) of the MiniMed 640G system significantly reduces the rate of hypoglycemia compared with the sensor-augmented insulin pump in children with type 1 diabetes. RESEARCH DESIGN AND METHODS This randomized, two-arm, parallel, controlled, two-center open-label study included 100 children and adolescents with type 1 diabetes and glycated hemoglobin A1c ≤10% (≤86 mmol/mol) and using continuous subcutaneous insulin infusion. Patients were randomly assigned to either an intervention group with PLGM features enabled (PLGM ON) or a control group (PLGM OFF), in a 1:1 ratio, all using the same type of sensor-augmented insulin pump. The primary end point was the number of hypoglycemic events below 65 mg/dL (3.6 mmol/L), based on sensor glucose readings, during a 14-day study treatment. The analysis was performed by intention to treat for all randomized patients. RESULTS The number of hypoglycemic events below 65 mg/dL (3.6 mmol/L) was significantly smaller in the PLGM ON compared with the PLGM OFF group (mean ± SD 4.4 ± 4.5 and 7.4 ± 6.3, respectively; P = 0.008). This was also true when calculated separately for night (P = 0.025) and day (P = 0.022). No severe hypoglycemic events occurred; however, there was a significant increase in time spent above 140 mg/dL (7.8 mmol/L) in the PLGM ON group (P = 0.0165). CONCLUSIONS The PLGM insulin suspension was associated with a significantly reduced number of hypoglycemic events. Although this was achieved at the expense of increased time in moderate hyperglycemia, there were no serious adverse effects in young patients with type 1 diabetes.
Pharmacokinetics of MEDI4736, a fully human anti-PDL1 monoclonal antibody, in patients with advanced solid tumors.
Authors: David Fairman, Rajesh Narwal, Meina Liang, Paul B. Robbins, Amy Schneider, Carlos Chavez, Hong Lu, Min Pak, Andy Blake-Haskins, Jim Vasselli, Ramy A. Ibrahim, Aiman M. Shalabi, Lorin Roskos
Journal: Journal of Clinical Oncology (2014)

2602 Background: MEDI4736 is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody directed against human programmed death ligand 1 (PD-L1). MEDI4736 blocks inhibitory interaction of PD-L1 with the PD-1 (CD279) and B7-1 (CD80) molecules, and enhances T-cell activation. The primary objectives of this analysis were to assess the pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of MEDI4736 in patients with advanced solid tumors. Methods: Data were collected from a Phase 1 study (NCT01693562) designed to evaluate safety, tolerability and PK following 0.1, 0.3, 1.0, 3.0, and 10 mg/kg every 2 weeks (Q2W) and 15 mg/kg every 3 weeks (Q3W) intravenous (IV) doses of MEDI4736. A total of 32 patients provided evaluable data. PK, ADA and soluble PD-L1 (sPD-L1) as PD were measured using validated electrochemiluminescence assays in human serum. Data analysis was performed using Phoenix Winnonlin and NONMEM software. Results: Area under the curve (AUC) increased more than dose-proportionally over the dose range of 0.1 to 10 mg/kg Q2W and approached linearity at ≥3 mg/kg Q2W. Soluble PD-L1 was fully suppressed over the entire dosing interval with doses ≥ 0.3 mg/kg Q2W. MEDI4736 PK profiles were best described using a 2-compartment model with both linear and nonlinear (target mediated) clearances. The linear clearance, volume of distribution and concentration at half maximal elimination (KM) were 240 mL/day, 3.6 L and 0.4 μg/mL, respectively. The half-life was ~23 days at doses ≥ 3 mg/kg Q2W. Greater than 99% target saturation (soluble and membrane bound) is expected at ≥40 μg/mL of MEDI4736. PK simulations indicate that following 10 mg/kg Q2W, >90% patients are expected to maintain PK exposure ≥40 μg/mL throughout the dosing interval. Three of 31 patients were ADA positive with an impact on PK and PD in 1 subject. Based on preclinical/clinical PK, PD, and safety data, a dose of 10 mg/kg Q2W was selected for the ongoing expansion phase. Conclusions: MEDI4736 exhibited non-linear (dose-dependent) PK and yielded dose-dependent sPD-L1 suppression. Evidence of ADA impacted exposure in 1 (3%) patient. A monotherapy dose of 10 mg/kg Q2W is currently being evaluated in multiple tumor types in the expansion phase.