tbuckley/cabot-search huggingface dataset:
HSV amplicon mediated augmentation of antitumor effects induced by tumor-specific T cells in the lymphopenic host
Authors: D. Morgensztern, J. D. Rosenblatt, D. G. Pham, K. Yi, S. Shah, K. A. Tolba, H. Nechushtan
Journal: Journal of Clinical Oncology (2004)

2559 Background: Adoptive transfer of T cells has been used in combination with chemotherapy or radiation in order to decrease tumor growth. The specific role of lymphopenia on adoptively transferred T cells in the setting of established tumors is not known. We studied the adoptive transfer of transgenic ovalbumin-specific OT-I T cells into irradiated immunocompetent mice or RAG-1 mice bearing LLC tumor expressing ovalbumin (LLC-ova). In addition, we evaluated the antitumor effects induced by intratumoral injection of HSV amplicons encoding beta-galactosidase (HSV-LacZ), or the combination of HSV-SLC and HSV-CD40L (HSV-S/C). Methods: C57BL/6 mice were injected with LLC-ova cells in the right flank and treated with 550 cGy when the tumor size reached approximately 5mm in diameter. Tumor implants were protected from direct irradiation by a 5 half-value layer lead shield. One day after irradiation, mice were injected intratumorally with PBS, HSV-LacZ, or HSV-S/C every 2 days times 4. RAG-1 mice were injected in both flanks with LLC-ova and right-sided tumors received intratumoral injection of PBS or HSV-LacZ. OT-I T cells were adoptively transferred one day after the first intratumoral injection in both experiments. Results: On day 21, mean tumor size for mice treated with radiation, OT-I T cells, and HSV-LacZ was significantly smaller than for mice treated with radiation, OT-I T cells, and PBS (40 mm2 vs 190 mm2 respectively, p < 0.01). Injection of HSV-S/C did not result in additional improvement compared to HSV-LacZ (77 mm2 versus 40 mm2, p = 0.51). Tumor response in mice treated with HSV-LacZ required the presence of OT-I T cells (178 mm2 vs 40 mm2, p < 0.01). In the RAG-1 model, bilateral tumor responses were observed in mice injected with HSV-LacZ. Conclusions: In the lymphopenic environment, adoptively transferred OT-I T cells require an additional stimulus for optimal antitumor effect. Contralateral tumor response in the RAG-1 experiment indicates a systemic effect. These results suggest a major role for the innate immune system in activating adoptively transferred T cells. Supported by ASCO 2003 YIA. No significant financial relationships to disclose.
Annals Graphic Medicine - Code Blue
Authors: Michael Natter
Journal: Annals of Internal Medicine (2017)

Web Exclusives4 April 2017Annals Graphic Medicine - Code BlueFREEMichael Natter, BAMichael Natter, BASearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/G16-0029 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Download figure Download PowerPoint Download figure Download PowerPoint Download figure Download PowerPoint Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: Disclosures: The author has disclosed no conflicts of interest. The form can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=G16-0029.Author/Illustrator Information: Michael Natter is currently in his final year at Sidney Kimmel Medical College of Thomas Jefferson University in Philadelphia. His artwork is inspired by his medical studies, anatomy, and the human condition. Mr. Natter has highlighted his medical journey on Instagram. (www.instagram.com/mike.natter; e-mail, [email protected]edu.)Author Contributions: Conception and design: M. Natter.Drafting of the article: M. Natter.Critical revision of the article for important intellectual content: M. Natter.Final approval of the article: M. Natter.Provision of study materials or patients: M. Natter.Administrative, technical, or logistic support: M. Natter. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 4 April 2017Volume 166, Issue 7Page: W7-W10KeywordsConflicts of interestDisclosureHealth care ePublished: 4 April 2017 Issue Published: 4 April 2017 Copyright & PermissionsCopyright © 2017 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
MGCD265, a multitargeted oral tyrosine kinase receptor inhibitor of Met and VEGFR, in combination with erlotinib in patients with advanced solid tumors.
Authors: Peter J. O'Dwyer, Kyriakos P. Papadopoulos, Anthony W. Tolcher, Ursina R. Teitelbaum, Kathleen Harlacker, Lon S. Smith, Davendra Sohal, Drew Warren Rasco, Muralidhar Beeram, Mariam Mehran, Manal Tawashi, Michel A. Drouin, James Wang, Marielle Fournel, Christiane R. Maroun, Andre Karam, Jeffrey M. Besterman, Amita Patnaik
Journal: Journal of Clinical Oncology (2012)

e13602 Background: MGCD265 is a multi-target oral tyrosine kinase receptor inhibitor that targets Met (wild type and clinically-relevant Met mutants), VEGFRs 1, 2, 3, Tie and Ron. Combining Met and EGFR inhibitors has been shown to be synergistic and can overcome resistance to EGFR inhibitors. MGCD265 in combination with erlotinib is being evaluated clinically for safety and efficacy. Methods: This is a phase I dose escalation trial of patients (pts) with advanced solid tumors, using the classic 3+3 design. MGCD265 and erlotinib were administered every day over a 21-day cycle. Safety evaluation included determination of dose limiting toxicities (DLTs) and the maximum tolerated dose of the combination. The pharmacokinetic (PK), pharmacodynamic (PD) profiles as well as anti-tumor activity, using RECIST 1.1, were also evaluated. Results: As ofJanuary 11, 2012, 45 pts were enrolled (median age: 58 years old; M/F: 27/18; ECOG 0/1: 20/25). MGCD265 was dose escalated from 96 mg/m 2 QD to 162 mg/m 2 BID, in combination with erlotinib (initially at 100 mg then at 150 mg QD). Diarrhea (n=6) was the only treatment-related ≥ grade 3 adverse event observed in ≥ 2 pts. The observed DLTs (all grade 3) were (n=1): diarrhea (96 mg/m 2 QD MGCD265+100 mg erlotinib), rash and fatigue (144 mg/m 2 QD MGCD265+150 mg erlotinib) and rhabdomyolysis (162 mg/m 2 BID MGCD265+150 mg erlotinib). One out of 3 pts with NSCLC, who was positive for activating EGFR mutation, experienced a partial response (duration of response of 8 cycles). Seven pts with a variety of tumors experienced stable disease for 6 cycles or more. Three out of 8 pts with gastroesophageal cancer remained on study for ~12-26 cycles. The PD profile indicated a decrease in the plasma level of HGF at Cycle 1 Day 8 compared to baseline in some patients. Conclusions: MGCD265, at the doses tested, was well tolerated in combination with full-dose erlotinib. The activity of MGCD265 combined with erlotinib supports phase II development of the combination.
Tuberculous Disease in Children: Its Pathology and Bacteriology.
Journal: JAMA (1933)

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Phase II trial of chemoradiotherapy concurrent with S-1 plus cisplatin in patients with unresectable, locally advanced squamous cell carcinoma of the head and neck (SCCHN): Results of the Japan Clinical Oncology Group study, JCOG 0706.
Authors: Makoto Tahara, Naomi Kiyota, Junki Mizusawa, Kenichi Nakamura, Ryuichi Hayashi, Tetsuo Akimoto, Yasuhisa Hasegawa, Shigemichi Iwae, Nobuya Monden, Kazuto Matsuura, Hirofumi Fujii, Yusuke Onozawa, Akihiro Homma, Akira Kubota, Haruhiko Fukuda, Masato Fujii
Journal: Journal of Clinical Oncology (2012)

5542 Background: To evaluate the efficacy and safety of chemoradiotherapy (CRT) concurrent with S-1 plus cisplatin in patients with unresectable locally advanced SCCHN. Methods: Eligibility criteria included histologically proven SCCHN with unresectable locally advanced lesions, PS 0-1, aged 20 to 75 years old, adequate organ function, and no prior treatment. Chemotherapy consisted of administration of S-1 twice daily on days 1-14 at 60 mg/m 2 /day, and cisplatin at 20 mg/m 2 /day on days 8-11, repeated twice at a 5-week interval. Single daily radiation of 70 Gy in 35 fractions was given concurrently startingon day 1. For patients achieving an objective response after CRT, two additional cycles of chemotherapy wereadministered. The primary endpoint was clinical complete response rate (%CR), which was the proportion of complete response (CR) and good partial response (good PR). Good PR was defined as remaining tissue with tumor shrinkage, which was not regarded as residual tumor but rather as scar material.The planned sample size was 45 patients, which was calculated by SWOG's two-stage attained design based on an expected %CR of 60% and a threshold of 45%, with a one-sided alpha of 0.1 and a power of 0.9. Results: From July 2008 to July 2010, 45 eligible subjects were accrued, including 43 males, with median age 63 years, ECOG PS 0/1 (36/9), oropharynx/ hypopharynx/larynx (26/15/4), T1/T2/T3/T4a/T4b (1/11/7/17/9) and N0/N2a/N2b/N2c/N3 (2/3/10/24/6). %CR was 64.4% (8 CR, 21 good PR) on central review. After a median follow-up of 1.56 years, 1-year local progression-free survival was 77.8%, with 1-year progression-free survival of 70.9%, 1-year overall survival of 93.3% and 1-year time to treatment failure of 57.6%. Grade 3 or 4 toxicity included mucositis (46.7%), dysphagia (46.7%), anorexia (42.2%), radiation dermatitis (26.7%), neutropenia (26.7%) and febrile neutropenia (4.4%). No treatment-related deaths were observed. Conclusions: This combination showed promising efficacy with acceptable toxicities. Further investigation in a phase III trial is planned.
From Pregnancy to Preeclampsia: A Key Role for Estrogens
Authors: Nadia Berkane, Philippe Liere, Jean-Paul Oudinet, Alexandre Hertig, Guillaume Lefèvre, Nicola Pluchino, Michael Schumacher, Nathalie Chabbert-Buffet
Journal: Endocrine Reviews (2017)

Preeclampsia (PE) results in placental dysfunction and is one of the primary causes of maternal and fetal mortality and morbidity. During pregnancy, estrogen is produced primarily in the placenta by conversion of androgen precursors originating from maternal and fetal adrenal glands. These processes lead to increased plasma estrogen concentrations compared with levels in nonpregnant women. Aberrant production of estrogens could play a key role in PE symptoms because they are exclusively produced by the placenta and they promote angiogenesis and vasodilation. Previous assessments of estrogen synthesis during PE yielded conflicting results, possibly because of the lack of specificity of the assays. However, with the introduction of reliable analytical protocols using liquid chromatography/mass spectrometry or gas chromatography/mass spectrometry, more recent studies suggest a marked decrease in estradiol levels in PE. The aim of this review is to summarize current knowledge of estrogen synthesis, regulation in the placenta, and biological effects during pregnancy and PE. Moreover, this review highlights the links among the occurrence of PE, estrogen biosynthesis, angiogenic factors, and cardiovascular risk factors. A close link between estrogen dysregulation and PE occurrence might validate estrogen levels as a biomarker but could also reveal a potential approach for prevention or cure of PE.
Clinical phenotypes and endophenotypes of atopic dermatitis: Where are we, and where should we go?
Authors: Thomas Bieber, Angelo M. D'Erme, Cezmi A. Akdis, Claudia Traidl-Hoffmann, Roger Lauener, Georg Schäppi, Peter Schmid-Grendelmeier
Journal: Journal of Allergy and Clinical Immunology (2017)
Irinotecan and docetaxel as first-line chemotherapy in patients with stage IIIB/IV non-small cell lung cancer
Authors: L. E. Raez, M. Rosado, E. S. Santos, K. Hamilton, I. Reis
Journal: Journal of Clinical Oncology (2004)

7246 Background: Cisplatin-based chemotherapy is considered the standard first line for patients (pts) with non-small cell lung cancer (NSCLC). Non-platinum combinations have been developing with the goal to decrease toxicity and obtain similar or better results. Irinotecan has demonstrated activity in NSCLC as single agent and in combination. Docetaxel is active in NSCLC. Methods: We designed a Phase II trial to examine the activity and toxicity of this combination as first line chemotherapy for patients with stage IIIB/IV NSCLC. The doses and schedule were based on a phase I trial done by Masuda (J Clin Oncol 2000,18:2996–3003); and included: docetaxel 50mg/m2 on day 2, and irinotecan 50mg/m2on days 1,8,and 15 of a 28-day cycle. We planned to enroll 41 pts, but the trial was closed after evaluation of the first 14 due to the low response rate. Results: We enrolled 10 males and 4 females, with a median age of 59 years (range, 42–71). Twelve patients (86%) with stage IV and two with stage IIIB.Four patients (29%) had an ECOG performance status of 0, and the remaining ten (72%) had an ECOG performance status of 1. A total of 44 cycles of chemotherapy were delivered. The analysis of the first 14 patients showed only 1 partial response (7%) and no complete responses. However, five patients experienced stable disease (36%) for a clinical benefit of 43%. The median survival time was 11 months and the 1-year survival was 43%. This combination was well tolerated with only few grade 3/4 toxicities: 3 cases of neutropenia (21%), 1 case of anemia (7%), and no cases of diarrhea. Maybe the chemotherapy schedule that we choose was not the most appropriate, however the ORR reported by Masuda was 37% with the same schedule. Other phase I studies done by Adjei or Murren (Oncol 1999 and 2001) have recommended different schedules. A phase II trial of docetaxel plus cisplatin or irinotecan in advanced NSCLC showed that response rates and survival were not statistically different. (Satouchi, ASCO 2001). Conclusions: This chemotherapy combination has a favorable toxicity profile, however the schedule and the doses delivered may not be the most appropriate for the first line therapy of NSCLC. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Aventis
Long-term results of imatinib mesylate therapy in philadelphia chromosome (Ph) positive chronic phase chronic myelogenous leukemia (CML) post interferon-a (IFN) failure M.D. Anderson experience in 261 patients
Authors: H. M. Kantarjian, J. Cortes, S. O'Brien, F. Giles, S. Verstovsek, S. Faderl, M. B. Rios, J. Shan, M. Talpaz
Journal: Journal of Clinical Oncology (2004)

6622 Background: The initial results of imatinib in Ph-positive CML in chronic phase post IFN failure were positive with a median follow up times of 17 months. The major cytogenetic (CG) response rate (Ph 5% (p<0.05) or prior hematologic resistance to IFN (p=0.01). Achieving any CG response at 3 months was associated with a 4-year survival rate of 95% (versus 78% for others; p=0.0001); the 4-year FFP rates were 94% versus 64%, respectively (p<0.0001). Achieving a major CG response at 6 months was associated with a 4-year survival rate of 95% (versus 81% for others; p=0.001); the 4-yr FFP rates were 94% versus 68% (p<0.0001). Among 167 patients achieving CG CR, 152 pts had quantitative PCR (QPCR) studies: 82 pts (49%; 31% total) had a major molecular response (QPCR= BCR-ABL/ABL <0.05%) and 38 pts (15%) had a complete molecular response (BCR-ABL undetectable). The 3-yr cumulative major molecular response rate was 55%, and complete molecular response rate 22%. Compared with a historical group of 131 similar patients in CML chronic phase post IFN failure treated with non-imatinib therapies, imatinib was associated with better 4-year survival rates (88%, versus 35% p<0.0001); this survival advantage for imatinib was confirmed by multivariate analysis (p<0.0001). Conclusions: The results with imatinib in CML chronic phase post IFN failure are improving and durable. Major and complete responses are now noted in a substantial proportion of patients with longer follow-up time. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis; Supergen
Survivin as a novel radiation/CIS platinum/tumor specific promoter for conditional oncolytic viral therapy
Authors: W. O. Arafat, D. Rein, D. Buchsbaum, D. Curiel, Z. Zhu
Journal: Journal of Clinical Oncology (2004)

1535 Background: Conditional oncolytic viral therapy (CRVT) is a novel approach in treatment of cancer. It implies using viral genetic modification to exploit the powerful oncolytic potency of competent virus strictly in tumor. Using recombinant adenovirus (Ad) with tissue specific promoter (TSP) as a vector, different clinical trial has utilized CRVT concept. Although most of these trials employed CRVT in combination with radio or chemotherapy, none of the vector delivered was originally designed for combination treatment. We hypothesize that; radiotherapy (RT)and/or chemotherapy may enhance the selectivity and level of induction of TSP leading to a powerful CRVT system Methods: We have constructing eligible radiation or cis platinum inducible promoter in context of Ad. including Survivin. Glioma cell lines, cervical cancer as well as prostate cancer cell lines were infected with different MOI of the TSP Ad or CMV Ad then cells were exposed to a RTor to cis platinum. FACS analysis and Luc assay was used to detect level of gene expression. Quantitative RTPCR to the corresponding genes was done from RNA isolated from RT or platinum treated cells. A replicative Ad driven by survivin promoter were constructed and tested in glioma cell lines. Results: Ad driven Survivin was made and shows specificity to glioma cell lines, prostate cell lines and cervical cell lines. RT increase the expression of gene expression by Cells treated with RT and Ad Luc driven by Survivin promoter up to 5-fold increase in expression after 2 Gy of RT in compare to non-irradiated cells. RNA analysis was done and has shown increase copy 30 fold for survivin. Cis-platinum treatment shown similar trend in primary cancer cervix cell. Replicative Ad driven by survivin promoter showed a significant enhancing oncolytic effect after treatment with RT in glioma cell lines. Conclusions: Replicative Ad vector employing survivin promoter is a promising tool that could lead to the enhancement of selectivity and specificity of CRVT in radiogenetic and chemotherapy context No significant financial relationships to disclose.
Development of a patient question prompt list to improve communication and clinical trial enrollment in a diverse patient population.
Authors: Lauren M. Hamel, Louis Penner, Elisabeth I. Heath, Dina Lansey, Michael Anthony Carducci, Terrance Lynn Albrecht, Ellen Barton, Mark A. Manning, Mark Wojda, Susan Eggly
Journal: Journal of Clinical Oncology (2017)

143 Background: Few patients, especially racial/ethnic minorities, enroll in clinical trials (CT), in part due to patient-oncologist communication. Question prompt lists (QPLs) improve communication, but have not been tested in CT discussions in a diverse patient population. We describe the development and acceptability of a theory-based QPL to improve communication and enrollment of White and Black men in prostate cancer CTs. Methods: Two existing QPLs were adapted by a team of communication scientists, psychologists, clinicians and patients. Guiding theories were the common ingroup identity model, which suggests people from different social groups can better achieve goals when they are on the same team, and patient-centered communication, which suggests that patient active participation improves clinical communication. The revised QPL included text to encourage patients to see themselves and their oncologist as a team, and 33 questions about CTs to encourage patients to participate actively in clinical interactions that include a CT discussion. To test acceptability, we recruited 15 Black or White men currently enrolled in a prostate cancer CT at an urban comprehensive cancer center. We asked patients to provide feedback on the QPL, to endorse which questions were most important, and for suggested improvements. Results: Patients participated anonymously. All patients said the QPL would be useful. Four patients reported liking the graphics/layout. Six patients reported liking the team text, but one commented that it was unnecessary. Three patients liked that the QPL included many questions, several of which they had not thought to ask when they discussed a CT with their oncologist. Ten patients endorsed the questions they thought were important to ask (M = 24 questions, SD = 9). The most frequently endorsed questions were what is already known about this treatment and how serious are the side effects? Conclusions: Patients found the QPL to be acceptable and useful. The QPL was revised according to patient feedback. We are testing the revised QPL's influence on patient-oncologist communication about CTs, patient understanding of CTs offered, and patient decisions to enroll in a CT.