tbuckley/cabot-search huggingface dataset:
Phase II study of dose-adjusted EPOCH-R in untreated de novo CD20+ diffuse large B-cell lymphoma (DLBCL)-CALGB 50103
Authors: W. H. Wilson, P. Porcu, D. Hurd, S. E. Martin, M. Czuczman, D. Niedzwiecki, J. D. Saint Louis, J. L. Johnson, B. Cheson, G. P. Canellos, A. D. Zelenetz
Journal: Journal of Clinical Oncology (2005)

6530 Background: DA-EPOCH-R is a rationally designed regimen based on schedule optimization and pharmacodynamic dosing. Studies suggest it overcomes adverse effects of tumor proliferation and bcl-2 in de novo DLBCL and adjusts for differences in patient drug clearance. An NCI study in 83 untreated de novo DLBCL patients shows a PFS and OS of 82% at 32 months median follow-up and no relapses beyond 2 years. PFS is 94% for low (0–2) and 57% for high (3–5) IPI at 3 years. Hence, CALGB undertook a confirmatory phase II study. Methods: Eligibility: untreated de novo CD20+ DLBCL; ≥ 18 years; stage II-IV; ECOG PS 0–2; and adequate organ function unless due to disease. Patients received DA-EPOCH-R + filgrastim for 6–8 cycles, based on response, and no patients received radiation. Endpoints were PFS, OS and toxicity. Study design is a cooperative group prospective phase II. Results: Of 78 patients, 5 were ineligible. Patient characteristics are median age (range) 58 (23–80) years, and IPI of low (0–2) in 60% and high (3–5) in 40% of patients. Treatment was administered in 18 centers and toxicity assessed in 72 patients. The pharmacodynamic endpoint of grade 4 neutropenia occurred in 96% of patients. Febrile neutropenia occurred in 33% of patients. Grade 4 anemia and thrombocytopenia occurred in 11% and 15% of patients, respectively. Gastrointestinal, thrombosis or neurological toxicities were rare at grade 4 (0–3%) and infrequent at grade 3 (0–14%). No patients had cardiac failure and there was one treatment associated death from CNS hemorrhage. Ninety percent of patients completed at least 6 cycles and 20% received 8 cycles. ORR was 100% with 68% CR and 32% PR. With a median (range) follow-up of 11 (2.4–22.8) months, 10 patients progressed (8 in the first year) with similar rates in CR’s (6/49) and PR’s (4/23). At 18 months, PFS is 80% overall, and 93% and 46%, respectively, in low (0–2) and high (3–5) IPI. Survival is 88% at 18 months. Conclusions: DA-EPOCH-R can be administered in a cooperative group with acceptable toxicity. Preliminary survival results are encouraging and consistent with the NCI study. A CALGB randomized phase III study of DA-EPOCH-R versus R-CHOP with microarray tumor analysis will begin early next year. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb, Genentech Genentech Genentech
Differentiation between the EGFR antibodies necitumumab, cetuximab, and panitumumab: In vitro biological and binding activities.
Authors: B. Saxena, S. T. Sundaram, W. Walton, I. Patel, P. Kuo, S. Khan, A. Matathia, A. Purohit, R. Crowley, Q. Zhou
Journal: Journal of Clinical Oncology (2011)

e13030 Background: The monoclonal antibodies cetuximab (chimeric IgG1), necitumumab (human IgG1), and panitumumab (human IgG2) competitively inhibit ligand binding to epidermal growth factor receptor (EGFR) in domain 3. These antibodies block ligand induced EGFR activation and downstream molecular signaling. Beyond protein backbone differences, further differentiation of these EGFR antibodies is an important area of investigation. Methods: The effect on the in vitro proliferation of DiFi human colorectal cancer cells was assessed by ATP luminescence. The binding of the antibodies to the soluble extracellular domain of EGFR was evaluated by ELISA and surface plasmon resonance (SPR). Inhibition of ligand induced EGFR activation and downstream signaling was evaluated utilizing electrochemiluminescence method. Finally, binding kinetics was analyzed by SPR using a capture method. Results: The necitumumab concentration producing a half-maximal anti proliferative response (IC50) in DIFI cells was comparable to that of cetuximab. In contrast, a 1.6 fold greater concentration of panitumumab was required to produce the similar level of anti- proliferative response. This observation is supported by in vitro binding assays, which indicated that cetuximab and necitumumab binds to EGFR more effectively than panitumumab. Furthermore, the IC50 of nectitumab for the inhibition of EGFR phosphorylation was at least two fold greater than that of panitumumab. When EGFR binding kinetics were analyzed by SPR, panitumumab showed a much higher affinity (Kd) to EGFR than necitumumab and cetuximab, with a lower binding rate (kon) and a much slower dissociation rate (koff). Given the results in functional assays and the SPR data indicates that the high binding affinity (Kd) of panitumumab does not correlate with improved ability to block EGFR activation, downstream pathway activation and tumor cell proliferation. Conclusions: Although, as published, panitumumab has a higher affinity (Kd) than cetuximab and necitumumab, in vitro functional assays indicate that necitumumab and cetuximab have equal or greater ability to impact EGFR signaling and effect downstream activation of EGFR.
Elevated expression of VEGFR-2 and VEGFA in desmoplastic small round cell tumor (DSRCT) and activity of bevacizumab and irinotecan in a xenograft model of DSRCT
Authors: H. D. Magnan, T. Chou, M. P. LaQuaglia, W. Gerald, M. Ladanyi, M. S. Merchant
Journal: Journal of Clinical Oncology (2009)

10016 Background: Desmoplastic small round cell tumor (DSRCT) is an aggressive tumor with poor response to multimodality therapies. Given the vascular nature of many DSRCT, we sought to determine if VEGF targeting could be effective in a preclinical model of DSRCT. Methods: RNA was extracted from frozen tumor samples (DSRCT, alveolar soft part sarcoma, alveolar rhabdomyosarcoma, synovial sarcoma, and Ewing sarcoma) and a human DSRCT cell line, JN-DSRCT. Microarray profiling utilized Affymetrix U133A/B or Affymetrix U133 Plus 2.0 chips. DSRCT xenografts were established by intramuscular injection of 20 million JN-DSRCT cells into the lower extremity of SCID/bg mice. A primary tumor developed within 8 - 12 weeks with concomitant development of abdominal metastases. Mice were treated during primary tumor growth with bevacizumab (5ug/kg IP weekly), irinotecan (2.5mg/kg IP ×10 days q3 weeks), or a combination of both. Results: Microarray data demonstrated an average of 4.5 times higher RNA expression of VEGFR-2 (KDR) in DSRCT tumor samples as compared to the other translocation-associated sarcomas (p = 3.6 E-12). VEGFR-2 was highly expressed in the JN-DSRCT line as compared to other sarcoma lines. VEGFA was also highly overexpressed in the DSRCT line and tumor samples when compared to the other translocation-associated sarcomas (2.5 times, p = 1.1E-10). Xenografts treated with bevacizumab had slowed growth over 100 days compared to control groups (volume of 0.52 mm3 vs 1.52, p = 0.002). Marked long term regressions were evident following treatment with the combination of irinotecan plus bevacizumab compared with irinotecan alone (0.12mm3 vs 0.44 at 100 days, p &lt; 0.0001). Conclusions: VEGFR-2 and VEGFA are overexpressed in DSRCT. DSRCT xenografts were highly responsive to bevacizumab or bevacizumab plus irinotecan. Taken together, the expression data and the sustained response of DSRCT xenografts to bevacizumab suggest that VEGF-dependent angiogenesis is important for DSRCT tumor biology and represents an attractive target for therapy. These studies suggest that irinotecan and bevacizumab should be considered for inclusion in clinical trials for the treatment of DSRCT. No significant financial relationships to disclose.
Back to square one
Authors: S. J Evans
Journal: BMJ (2009)

It is tragic that we now have a respected body, the Medicines and Healthcare products Regulatory Agency (MHRA), granting a licence for a product for which there is not only no evidence of efficacy but good evidence against any efficacy.1I have some sympathy with the MHRA in the face of a European Directive which has to be obeyed but which is almost totally irrational.However, I think that because "efficacy" appears in the directive and there is evidence against efficacy, it could have resisted granting a licence.This fiasco takes us back to the days before drug regulation was introduced, partly to prevent the hazards of snake oiltype remedies.While this product may have no benefit, it probably has no direct harm either.But it may have major indirect harms-not only in individual patients who may not benefit from other effective remedies but also in a general sense by undermining the rational basis for medicine.
Electron Microscopic Studies of &lt;italic&gt;Mycoplasma&lt;/italic&gt; (PPLO strain 880) in Artificial Medium and in Tissue Culture
Authors: Douglas R. Anderson, Robert A. Manaker
Journal: JNCI Journal of the National Cancer Institute (1966)

Mycoplasma [pleuropneumonia-like organisms (PPLO)] strain 880 was studied in broth cultures and in several cell culture lines. This strain exhibited considerable pleomorphism in size, internal structure, and shape, including forms with filamentous projections. The most common form observed was 0.5 to 1 µ in diameter and had a nuclear area of fibrillar strands, probably DNA. The cytoplasm of the organisms contained ribosome-like granules and a RaHened vacuole which indented the nuclear area. There were various other forms, including “elementary bodies” 100 mµ. in diameter that were very electron-dense. In the tissue culture lines in which the cells grew as a monolayer, the Mycoplasma were closely associated with the cell surface and were occasionally seen in membrane-lined cytoplasmic vacuoles. In cell lines that did not aHach to the glass, the Mycoplasma were fewer and not attached to the cell surface. Although the ultrastructure of this strain is similar to that of previously described strains, there are differences in details of structure which may be related either to the growth conditions used or to characteristics of the strain. The various forms of the organism are consistent with the suggestion that Mycoplasma may have several mechanisms of reproduction (growth). The intracellular Mycoplasma may be protected from antibiotics. This would partly explain the difficulty of eradicating Mycoplasma from infected cell cultures.
Late relapses in Hodgkin's disease: Outcome of patients relapsing more than twelve months after primary chemotherapy
Authors: L. Salvagno, M. Sorarù, S.M.L. Aversa, A. Bianco, V. Chiarion Sileni, G.L. Pappagallo, M.V. Fiorentino
Journal: Annals of Oncology (1993)
Abstract 12688: Augmenting Mitofusin-2 in Females With Pulmonary Arterial Hypertension Increases Mitochondrial Fusion, Reduces Smooth Muscle Cell Hyperproliferation and Regresses Experimental Disease
Authors: John J Ryan, Glenn Marsboom, Yong Hu Fang, Peter T Toth, Erik Marrow, Nancy Luo, Lin Piao, Zhigang Hong, Hannah Zhang, Chad Haney, Chin-Tu Chen, Willard Sharp, Stephen Archer
Journal: Circulation (2012)

John J Ryan, 2012 Finalist and Presenting Author
Phase II trial of nemorubicin hydrocloride (nemorubicin) in combination with cisplatin (cDDP) in patients (pts) with hepatocellular carcinoma (HCC): First step results
Authors: F. Izzo, A. M. Catino, T. J. Vogl, M. Middleton, J. W. Valle, F. Fiore, C. D. Gadaleta, R. M. Pirotta, M. Martignoni, B. Laffranchi
Journal: Journal of Clinical Oncology (2009)

4593 Background: Nemorubicin is a novel DNA-intercalator, mainly metabolized in liver by CYP3A4 enzyme and showing synergic antitumor activity with cDDP. The objective of this study was to evaluate the efficacy and adverse effects of nemorubicin administered by intra-hepatic artery in combination with cDDP to unresectable HCC pts. Methods: The study was in two HCC pt populations: intermediate risk (IRP) (CLIP 0–1, bilirubin &lt; 1.5 x upper normal limit, no portal vein thrombosis [PVT]) and advanced risk (ARP) (CLIP 2, bilirubin &lt; 2.5 mg/dL, PVT admitted). Treatment was repeated every 4–6 weeks for a maximum of six courses, if no toxicity and disease progression occurred. A single-arm, Simon's minimax two-stage design was adopted to evaluate the primary endpoint of tumour response (WHO criteria). In the first step &gt;5/18 responses (IRP) and &gt;2/10 responses (ARP) are needed to proceed with the second step. Results: Twenty-three IRP pts (13 evaluable) and 13 ARP pts (10 evaluable) were enrolled. The median number of treatments was 3 (range 1–6) in IRP (dose 600 mcg/m 2 nemorubicin and 60 mg/m 2 cDDP) and 4 (range 1–4) in ARP (dose 400 mcg/m 2 nemorubicin and 60 mg/m 2 cDDP). In IRP, so far 1 pt (8%) achieved complete response, 3 pts (23%) had partial response (PR), 5 pts (38%) had minor response (MR)/disease stabilization (SD) &gt;3 months. In ARP, 2 pts (20%) had PR, satisfying the first step efficacy criteria. Also, 2 ARP pts (20%) had MR/SD. Overall, the main grade 3 and 4 hematological toxicities were thrombocytopenia (47%), leukopenia (42%), anemia (12%) and neutropenia (6%). Grade 3 and 4 biochemical alterations were aspartate aminotranferase (29%) alanine transferase (24%) and bilirubin increase (12%). The most frequent adverse events were fatigue (35%), vomiting (29%), diarrhoea (24%) and nausea (18%). Conclusions: Hepatic arterial infusion of nemorubicin with cisplatin showed promising activity in the first step of the study and it was a well tolerated regimen. These encouraging results warrant further development in HCC pts. No significant financial relationships to disclose.
Retraction of biased journal articles
Authors: Ymkje Anna de Vries, Erick H Turner, Annelieke M Roest
Journal: BMJ (2015)

We hope that Le Noury and colleagues’ re-analysis of Study 329 will lead to the long overdue retraction of the 2001 paper.1

Study 329 may be the most infamous example of biased reporting within psychiatry, but this practice is widespread. We examined the reporting of antidepressant trials submitted to the …
Immunogenetic Aspects of Nasopharyngeal Carcinoma. IV. Increased Risk in Chinese of Nasopharyngeal Carcinoma Associated With a Chinese-Related HLA Profile (A2, Singapore 2)2
Authors: M. J. Simons, G. B. Wee, E. H. Goh, S. H. Chan, K. Shanmugaratnam, N. E. Day, G. de-Thé
Journal: JNCI Journal of the National Cancer Institute (1976)

The results of this study of 110 Singapore Chinese with nasopharyngeal carcinoma (NPC) and 91 controls confirmed the association between the occurrence of HLA antigen Singapore 2 (Sin 2) and NPC in the Chinese population, and indicated that their increased risk for NPC was confined to the joint occurrence of Sin 2 and A2 antigens. These findings suggested that the genotype of importance in susceptibility to NPC is the A2-Sin 2 haplotype.
Murine Stromal Cells Counteract the Loss of Long-Term Culture-Initiating Cell Potential Induced by Cytokines in CD34+CD38low/neg Human Bone Marrow Cells
Authors: Annelise Bennaceur-Griscelli, Cristina Tourino, Brigitte Izac, William Vainchenker, Laure Coulombel
Journal: Blood (1999)
TMOD-03MOTILITY CONTROLS GROWTH AND PROGRESSION PATTERNS OF GLIOBLASTOMA MULTIFORME
Authors: Hassan Fathallah-Shaykh, Elizabeth Scribner, Olivier Saut, Thierry Colin
Journal: Neuro-Oncology (2015)

PURPOSE: Glioblastoma multiforme (GBM) is a malignant brain tumor with poor prognosis and high morbidity due to its invasiveness.Hypoxia-driven motility (HM) and concentration-driven motility (CM) are two mechanisms of GBM invasion in the brain.The use of anti-angiogenic drugs has uncovered new progression patterns of GBM associated with significant differences in overall survival times.Here, we test the hypotheses that the types and rates of GBM motility predict its progression pattern and the patients' survival times.METHODS: We applied a mathematical model of GBM growth and invasion in humans to simulate a clinical trial and study the effects of the rate and mechanism of motility on the patterns of progression and on survival times.RESULTS: The motility phenotype appears to determine the progression pattern as well as the survival time of a patient treated by anti-angiogenesis.Highly-dispersive tumors are associated with the longest survival times (p , 0.001) and with progression by Expanding FLAIR.Moderately-Dispersive tumors are associated with short survival times and with progression by Expanding FLAIR + Necrosis.Tumors with HM are associated with the shortest survival times and with progression by Expanding Necrosis.The survival times of the latter are similar to non-responders.This investigation also uncovered the HM-CM principle: the aggressive HM-dependent phenotype surfaces only when therate of CM is low in both untreated and bevacizumab-treated GBM.CONCLUSIONS: Finding that the motility phenotype is a fundamental property that controls progression and survival times, has biological, clinical and therapeutic implications.
Abstract 13329: MRI-Assessed Carotid Plaque Inflammation Decreases With Lipid Lowering Therapy
Authors: Kevin D O’Brien, Suzanne Peck, Huijin Chen, Moni Neradilek, Gador Canton, Daniel Isquith, Nayak Polissar, Chris Geohas, David A Hinchman, Xue-Qiao Zhao, Jeffrey L Probstfield, William S Kerwin
Journal: Circulation (2013)

Background:  K trans   is a dynamic contrast-enhanced magnetic resonance (DCE-MRI) pharmacokinetic variable that has been correlated with plaque inflammation. We determined whether carotid plaque  K trans   decreases with intensive lipid intervention in an ancillary study to the AIM-HIGH Trial.   Methods:  Ancillary study participants had carotid artery DCE-MRI scanning at Baseline and at on-trial Years 1 and/or 2; 102 participants had scans at ≥2 time-points. LDL-C was treated to a target of 40-80 mg/dL. Changes in  K trans   between baseline and later time points were assessed using the paired t-test.   Results:  Participants were (mean±SD) age 62±9 years, 16% female, 23% with diabetes, and 80% with metabolic syndrome. All but 4 (4%) were on statins prior to study entry, and 72 (73%) had been on statins for >1 year. Baseline LDL-C decreased from 77±26 to 70± 19 mg/dL at Year 1 (-9.1%). Though  K trans  change (mean± SE) did not reach significance from Baseline to Year 1 (-4.2± 2.6 x 10 -3  min -1 , N=72, p=0.11),  K trans  change from Baseline to Year 2 was significant (-8.1± 3.4 x 10 -3  min -1 , N=59, p=0.02). Also, the annualized rate of decrease in  K trans  was significant in a combined analysis of all subjects with scans from at least 2 time points (N=102, p=0.04).   Conclusions:  In CAD patients with well-treated lipids at baseline, further decrease in LDL was associated with a decrease in plaque inflammation, as detected by DCE-MRI. These results demonstrate the potential utility of DCE-MRI for serial monitoring, and suggest that aggressive lipid intervention continues to decrease plaque inflammation.
Spatial Modeling of Drug Delivery Routes for Treatment of Disseminated Ovarian Cancer
Authors: Kimberly R. Kanigel Winner, Mara P. Steinkamp, Rebecca J. Lee, Maciej Swat, Carolyn Y. Muller, Melanie E. Moses, Yi Jiang, Bridget S. Wilson
Journal: Cancer Research (2016)

In ovarian cancer, metastasis is typically confined to the peritoneum. Surgical removal of the primary tumor and macroscopic secondary tumors is a common practice, but more effective strategies are needed to target microscopic spheroids persisting in the peritoneal fluid after debulking surgery. To treat this residual disease, therapeutic agents can be administered by either intravenous or intraperitoneal infusion. Here, we describe the use of a cellular Potts model to compare tumor penetration of two classes of drugs (cisplatin and pertuzumab) when delivered by these two alternative routes. The model considers the primary route when the drug is administered either intravenously or intraperitoneally, as well as the subsequent exchange into the other delivery volume as a secondary route. By accounting for these dynamics, the model revealed that intraperitoneal infusion is the markedly superior route for delivery of both small-molecule and antibody therapies into microscopic, avascular tumors typical of patients with ascites. Small tumors attached to peritoneal organs, with vascularity ranging from 2% to 10%, also show enhanced drug delivery via the intraperitoneal route, even though tumor vessels can act as sinks during the dissemination of small molecules. Furthermore, we assessed the ability of the antibody to enter the tumor by in silico and in vivo methods and suggest that optimization of antibody delivery is an important criterion underlying the efficacy of these and other biologics. The use of both delivery routes may provide the best total coverage of tumors, depending on their size and vascularity.
The effect of five different administration intervals on the pharmacokinetics (pk) of paclitaxel (PTX) and pegylated liposomal doxorubicin (PLD) association regimen
Authors: M. Airoldi, L. Cattel, R. Passera, P. Milla, E. Cerutti, F. Pedani, C. Zanon, A. Crova
Journal: Journal of Clinical Oncology (2007)

13012 Background: The PTX-PLD association is a promising schedule for recurrent head/neck cancer. Their pk behavior could be dependent not only on PTX excipient (polyethoxylated castor oil) interference, but even on different i.v. administration intervals between the two drugs. This study evaluated any possible administration interval-dependent pk interaction, when PLD infusion started 0, 1, 3, 12 or 24 h after PTX infusion end. Methods: 25 patients, affected by recurrent cisplatin pre-treated squamous cell head/neck cancer, were randomized to receive PTX 80 mg/m 2 q1w and PLD 12.5 mg/m 2 q2w at administration intervals of 0, 1, 3, 12 or 24 h. Pk parameters were evaluated during the first course by non-compartmental analysis, while statistical analysis was performed by non-parametric Kruskal Wallis test. Results: Median PK parameters are reported in the table . PTX pk profile is strongly affected by PLD administration. PTX total exposure is highly reduced, with a consequent increase in Cl tot ; this alteration is totally due to K el modifications. On the other side, no statistically significant interactions affected PLD pk parameters. Some in vitro experiments indicate that PLD is able to partially absorb PTX, driving to PTX plasmatic concentration reduction, when PLD is administered at 0–1 h intervals. Conclusions: PLD liposomal components seem to be able to entrap PTX, therefore reducing PTX plasmatic concentrations; so, it is very important to choose the ideal administration interval. In order to avoid pk interaction, the i.v. administration interval between PTX and PLD had to be 3 h at least. For shorter intervals, patients could be underexposed to PTX, with lesser clinical efficacy. [Table: see text] No significant financial relationships to disclose.