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Showing 1 - 200 of 368 Journals sorted alphabetically
Acta Biochimica et Biophysica Sinica     Hybrid Journal   (Followers: 6, SJR: 0.881, h-index: 38)
Adaptation     Hybrid Journal   (Followers: 8, SJR: 0.111, h-index: 4)
Aesthetic Surgery J.     Hybrid Journal   (Followers: 6, SJR: 1.538, h-index: 35)
African Affairs     Hybrid Journal   (Followers: 57, SJR: 1.512, h-index: 46)
Age and Ageing     Hybrid Journal   (Followers: 76, SJR: 1.611, h-index: 107)
Alcohol and Alcoholism     Hybrid Journal   (Followers: 14, SJR: 0.935, h-index: 80)
American Entomologist     Full-text available via subscription   (Followers: 5)
American Historical Review     Hybrid Journal   (Followers: 120, SJR: 0.652, h-index: 43)
American J. of Agricultural Economics     Hybrid Journal   (Followers: 41, SJR: 1.441, h-index: 77)
American J. of Epidemiology     Hybrid Journal   (Followers: 147, SJR: 3.047, h-index: 201)
American J. of Hypertension     Hybrid Journal   (Followers: 19, SJR: 1.397, h-index: 111)
American J. of Jurisprudence     Hybrid Journal   (Followers: 15)
American journal of legal history     Full-text available via subscription   (Followers: 4, SJR: 0.151, h-index: 7)
American Law and Economics Review     Hybrid Journal   (Followers: 26, SJR: 0.824, h-index: 23)
American Literary History     Hybrid Journal   (Followers: 12, SJR: 0.185, h-index: 22)
Analysis     Hybrid Journal   (Followers: 23)
Annals of Botany     Hybrid Journal   (Followers: 33, SJR: 1.912, h-index: 124)
Annals of Occupational Hygiene     Hybrid Journal   (Followers: 24, SJR: 0.837, h-index: 57)
Annals of Oncology     Hybrid Journal   (Followers: 49, SJR: 4.362, h-index: 173)
Annals of the Entomological Society of America     Full-text available via subscription   (Followers: 9, SJR: 0.642, h-index: 53)
Annals of Work Exposures and Health     Hybrid Journal  
AoB Plants     Open Access   (Followers: 4, SJR: 0.78, h-index: 10)
Applied Economic Perspectives and Policy     Hybrid Journal   (Followers: 18, SJR: 0.884, h-index: 31)
Applied Linguistics     Hybrid Journal   (Followers: 51, SJR: 1.749, h-index: 63)
Applied Mathematics Research eXpress     Hybrid Journal   (Followers: 1, SJR: 0.779, h-index: 11)
Arbitration Intl.     Full-text available via subscription   (Followers: 19)
Arbitration Law Reports and Review     Hybrid Journal   (Followers: 12)
Archives of Clinical Neuropsychology     Hybrid Journal   (Followers: 25, SJR: 0.96, h-index: 71)
Aristotelian Society Supplementary Volume     Hybrid Journal   (Followers: 2, SJR: 0.102, h-index: 20)
Arthropod Management Tests     Hybrid Journal   (Followers: 2)
Astronomy & Geophysics     Hybrid Journal   (Followers: 46, SJR: 0.144, h-index: 15)
Behavioral Ecology     Hybrid Journal   (Followers: 47, SJR: 1.698, h-index: 92)
Bioinformatics     Hybrid Journal   (Followers: 221, SJR: 4.643, h-index: 271)
Biology Methods and Protocols     Hybrid Journal  
Biometrika     Hybrid Journal   (Followers: 18, SJR: 2.801, h-index: 90)
BioScience     Hybrid Journal   (Followers: 28, SJR: 2.374, h-index: 154)
Bioscience Horizons : The National Undergraduate Research J.     Open Access   (Followers: 1, SJR: 0.213, h-index: 9)
Biostatistics     Hybrid Journal   (Followers: 15, SJR: 1.955, h-index: 55)
BJA : British J. of Anaesthesia     Hybrid Journal   (Followers: 132, SJR: 2.314, h-index: 133)
BJA Education     Hybrid Journal   (Followers: 65, SJR: 0.272, h-index: 20)
Brain     Hybrid Journal   (Followers: 61, SJR: 6.097, h-index: 264)
Briefings in Bioinformatics     Hybrid Journal   (Followers: 43, SJR: 4.086, h-index: 73)
Briefings in Functional Genomics     Hybrid Journal   (Followers: 4, SJR: 1.771, h-index: 50)
British J. for the Philosophy of Science     Hybrid Journal   (Followers: 32, SJR: 1.267, h-index: 38)
British J. of Aesthetics     Hybrid Journal   (Followers: 24, SJR: 0.217, h-index: 18)
British J. of Criminology     Hybrid Journal   (Followers: 488, SJR: 1.373, h-index: 62)
British J. of Social Work     Hybrid Journal   (Followers: 77, SJR: 0.771, h-index: 53)
British Medical Bulletin     Hybrid Journal   (Followers: 7, SJR: 1.391, h-index: 84)
British Yearbook of Intl. Law     Hybrid Journal   (Followers: 25)
Bulletin of the London Mathematical Society     Hybrid Journal   (Followers: 3, SJR: 1.474, h-index: 31)
Cambridge J. of Economics     Hybrid Journal   (Followers: 55, SJR: 0.957, h-index: 59)
Cambridge J. of Regions, Economy and Society     Hybrid Journal   (Followers: 9, SJR: 1.067, h-index: 22)
Cambridge Quarterly     Hybrid Journal   (Followers: 10, SJR: 0.1, h-index: 7)
Capital Markets Law J.     Hybrid Journal  
Carcinogenesis     Hybrid Journal   (Followers: 2, SJR: 2.439, h-index: 167)
Cardiovascular Research     Hybrid Journal   (Followers: 11, SJR: 2.897, h-index: 175)
Cerebral Cortex     Hybrid Journal   (Followers: 37, SJR: 4.827, h-index: 192)
CESifo Economic Studies     Hybrid Journal   (Followers: 15, SJR: 0.501, h-index: 19)
Chemical Senses     Hybrid Journal   (Followers: 1, SJR: 1.436, h-index: 76)
Children and Schools     Hybrid Journal   (Followers: 5, SJR: 0.211, h-index: 18)
Chinese J. of Comparative Law     Hybrid Journal   (Followers: 3)
Chinese J. of Intl. Law     Hybrid Journal   (Followers: 18, SJR: 0.737, h-index: 11)
Chinese J. of Intl. Politics     Hybrid Journal   (Followers: 8, SJR: 1.238, h-index: 15)
Christian Bioethics: Non-Ecumenical Studies in Medical Morality     Hybrid Journal   (Followers: 11, SJR: 0.191, h-index: 8)
Classical Receptions J.     Hybrid Journal   (Followers: 17, SJR: 0.1, h-index: 3)
Clinical Infectious Diseases     Hybrid Journal   (Followers: 58, SJR: 4.742, h-index: 261)
Clinical Kidney J.     Open Access   (Followers: 4, SJR: 0.338, h-index: 19)
Community Development J.     Hybrid Journal   (Followers: 23, SJR: 0.47, h-index: 28)
Computer J.     Hybrid Journal   (Followers: 8, SJR: 0.371, h-index: 47)
Conservation Physiology     Open Access   (Followers: 1)
Contemporary Women's Writing     Hybrid Journal   (Followers: 11, SJR: 0.111, h-index: 3)
Contributions to Political Economy     Hybrid Journal   (Followers: 6, SJR: 0.313, h-index: 10)
Critical Values     Full-text available via subscription  
Current Legal Problems     Hybrid Journal   (Followers: 25)
Current Zoology     Full-text available via subscription   (SJR: 0.999, h-index: 20)
Database : The J. of Biological Databases and Curation     Open Access   (Followers: 11, SJR: 1.068, h-index: 24)
Digital Scholarship in the Humanities     Hybrid Journal   (Followers: 12)
Diplomatic History     Hybrid Journal   (Followers: 18, SJR: 0.296, h-index: 22)
DNA Research     Open Access   (Followers: 4, SJR: 2.42, h-index: 77)
Dynamics and Statistics of the Climate System     Open Access   (Followers: 2)
Early Music     Hybrid Journal   (Followers: 13, SJR: 0.124, h-index: 11)
Economic Policy     Hybrid Journal   (Followers: 46, SJR: 2.052, h-index: 52)
ELT J.     Hybrid Journal   (Followers: 25, SJR: 1.26, h-index: 23)
English Historical Review     Hybrid Journal   (Followers: 45, SJR: 0.311, h-index: 10)
English: J. of the English Association     Hybrid Journal   (Followers: 12, SJR: 0.144, h-index: 3)
Environmental Entomology     Full-text available via subscription   (Followers: 11, SJR: 0.791, h-index: 66)
Environmental Epigenetics     Open Access   (Followers: 1)
Environmental History     Hybrid Journal   (Followers: 25, SJR: 0.197, h-index: 25)
EP-Europace     Hybrid Journal   (Followers: 1, SJR: 2.201, h-index: 71)
Epidemiologic Reviews     Hybrid Journal   (Followers: 10, SJR: 3.917, h-index: 81)
ESHRE Monographs     Hybrid Journal  
Essays in Criticism     Hybrid Journal   (Followers: 15, SJR: 0.1, h-index: 6)
European Heart J.     Hybrid Journal   (Followers: 46, SJR: 6.997, h-index: 227)
European Heart J. - Cardiovascular Imaging     Hybrid Journal   (Followers: 9, SJR: 2.044, h-index: 58)
European Heart J. - Cardiovascular Pharmacotherapy     Full-text available via subscription   (Followers: 1)
European Heart J. - Quality of Care and Clinical Outcomes     Hybrid Journal  
European Heart J. Supplements     Hybrid Journal   (Followers: 8, SJR: 0.152, h-index: 31)
European J. of Cardio-Thoracic Surgery     Hybrid Journal   (Followers: 7, SJR: 1.568, h-index: 104)
European J. of Intl. Law     Hybrid Journal   (Followers: 140, SJR: 0.722, h-index: 38)
European J. of Orthodontics     Hybrid Journal   (Followers: 4, SJR: 1.09, h-index: 60)
European J. of Public Health     Hybrid Journal   (Followers: 23, SJR: 1.284, h-index: 64)
European Review of Agricultural Economics     Hybrid Journal   (Followers: 12, SJR: 1.549, h-index: 42)
European Review of Economic History     Hybrid Journal   (Followers: 25, SJR: 0.628, h-index: 24)
European Sociological Review     Hybrid Journal   (Followers: 37, SJR: 2.061, h-index: 53)
Evolution, Medicine, and Public Health     Open Access   (Followers: 11)
Family Practice     Hybrid Journal   (Followers: 12, SJR: 1.048, h-index: 77)
Fems Microbiology Ecology     Hybrid Journal   (Followers: 8, SJR: 1.687, h-index: 115)
Fems Microbiology Letters     Hybrid Journal   (Followers: 19, SJR: 1.126, h-index: 118)
Fems Microbiology Reviews     Hybrid Journal   (Followers: 24, SJR: 7.587, h-index: 150)
Fems Yeast Research     Hybrid Journal   (Followers: 13, SJR: 1.213, h-index: 66)
Foreign Policy Analysis     Hybrid Journal   (Followers: 22, SJR: 0.859, h-index: 10)
Forestry: An Intl. J. of Forest Research     Hybrid Journal   (Followers: 17, SJR: 0.903, h-index: 44)
Forum for Modern Language Studies     Hybrid Journal   (Followers: 6, SJR: 0.108, h-index: 6)
French History     Hybrid Journal   (Followers: 29, SJR: 0.123, h-index: 10)
French Studies     Hybrid Journal   (Followers: 19, SJR: 0.119, h-index: 7)
French Studies Bulletin     Hybrid Journal   (Followers: 10, SJR: 0.102, h-index: 3)
Gastroenterology Report     Open Access   (Followers: 2)
Genome Biology and Evolution     Open Access   (Followers: 10, SJR: 3.22, h-index: 39)
Geophysical J. Intl.     Hybrid Journal   (Followers: 31, SJR: 1.839, h-index: 119)
German History     Hybrid Journal   (Followers: 24, SJR: 0.437, h-index: 13)
GigaScience     Open Access   (Followers: 3)
Global Summitry     Hybrid Journal  
Glycobiology     Hybrid Journal   (Followers: 14, SJR: 1.692, h-index: 101)
Health and Social Work     Hybrid Journal   (Followers: 46, SJR: 0.505, h-index: 40)
Health Education Research     Hybrid Journal   (Followers: 12, SJR: 0.814, h-index: 80)
Health Policy and Planning     Hybrid Journal   (Followers: 21, SJR: 1.628, h-index: 66)
Health Promotion Intl.     Hybrid Journal   (Followers: 19, SJR: 0.664, h-index: 60)
History Workshop J.     Hybrid Journal   (Followers: 25, SJR: 0.313, h-index: 20)
Holocaust and Genocide Studies     Hybrid Journal   (Followers: 22, SJR: 0.115, h-index: 13)
Human Molecular Genetics     Hybrid Journal   (Followers: 10, SJR: 4.288, h-index: 233)
Human Reproduction     Hybrid Journal   (Followers: 73, SJR: 2.271, h-index: 179)
Human Reproduction Update     Hybrid Journal   (Followers: 15, SJR: 4.678, h-index: 128)
Human Rights Law Review     Hybrid Journal   (Followers: 60, SJR: 0.7, h-index: 21)
ICES J. of Marine Science: J. du Conseil     Hybrid Journal   (Followers: 53, SJR: 1.233, h-index: 88)
ICSID Review     Hybrid Journal   (Followers: 8)
ILAR J.     Hybrid Journal   (Followers: 1, SJR: 1.099, h-index: 51)
IMA J. of Applied Mathematics     Hybrid Journal   (SJR: 0.329, h-index: 26)
IMA J. of Management Mathematics     Hybrid Journal   (Followers: 2, SJR: 0.351, h-index: 20)
IMA J. of Mathematical Control and Information     Hybrid Journal   (Followers: 2, SJR: 0.661, h-index: 28)
IMA J. of Numerical Analysis - advance access     Hybrid Journal   (SJR: 2.032, h-index: 44)
Industrial and Corporate Change     Hybrid Journal   (Followers: 8, SJR: 1.37, h-index: 81)
Industrial Law J.     Hybrid Journal   (Followers: 29, SJR: 0.184, h-index: 15)
Information and Inference     Free  
Integrative and Comparative Biology     Hybrid Journal   (Followers: 7, SJR: 1.911, h-index: 90)
Interacting with Computers     Hybrid Journal   (Followers: 10, SJR: 0.529, h-index: 59)
Interactive CardioVascular and Thoracic Surgery     Hybrid Journal   (Followers: 4, SJR: 0.743, h-index: 35)
Intl. Data Privacy Law     Hybrid Journal   (Followers: 27)
Intl. Health     Hybrid Journal   (Followers: 4, SJR: 0.835, h-index: 15)
Intl. Immunology     Hybrid Journal   (Followers: 4, SJR: 1.613, h-index: 111)
Intl. J. for Quality in Health Care     Hybrid Journal   (Followers: 32, SJR: 1.593, h-index: 69)
Intl. J. of Constitutional Law     Hybrid Journal   (Followers: 50, SJR: 0.613, h-index: 19)
Intl. J. of Epidemiology     Hybrid Journal   (Followers: 114, SJR: 4.381, h-index: 145)
Intl. J. of Law and Information Technology     Hybrid Journal   (Followers: 3, SJR: 0.247, h-index: 8)
Intl. J. of Law, Policy and the Family     Hybrid Journal   (Followers: 18, SJR: 0.307, h-index: 15)
Intl. J. of Lexicography     Hybrid Journal   (Followers: 8, SJR: 0.404, h-index: 18)
Intl. J. of Low-Carbon Technologies     Open Access   (Followers: 1, SJR: 0.457, h-index: 12)
Intl. J. of Neuropsychopharmacology     Open Access   (Followers: 4, SJR: 1.69, h-index: 79)
Intl. J. of Public Opinion Research     Hybrid Journal   (Followers: 8, SJR: 0.906, h-index: 33)
Intl. J. of Refugee Law     Hybrid Journal   (Followers: 33, SJR: 0.231, h-index: 21)
Intl. J. of Transitional Justice     Hybrid Journal   (Followers: 12, SJR: 0.833, h-index: 12)
Intl. Mathematics Research Notices     Hybrid Journal   (Followers: 1, SJR: 2.052, h-index: 42)
Intl. Mathematics Research Surveys - advance access     Hybrid Journal  
Intl. Political Sociology     Hybrid Journal   (Followers: 24, SJR: 1.339, h-index: 19)
Intl. Relations of the Asia-Pacific     Hybrid Journal   (Followers: 17, SJR: 0.539, h-index: 17)
Intl. Studies Perspectives     Hybrid Journal   (Followers: 7, SJR: 0.998, h-index: 28)
Intl. Studies Quarterly     Hybrid Journal   (Followers: 33, SJR: 2.184, h-index: 68)
Intl. Studies Review     Hybrid Journal   (Followers: 17, SJR: 0.783, h-index: 38)
ISLE: Interdisciplinary Studies in Literature and Environment     Hybrid Journal   (Followers: 1, SJR: 0.155, h-index: 4)
ITNOW     Hybrid Journal   (Followers: 2, SJR: 0.102, h-index: 4)
J. of African Economies     Hybrid Journal   (Followers: 15, SJR: 0.647, h-index: 30)
J. of American History     Hybrid Journal   (Followers: 38, SJR: 0.286, h-index: 34)
J. of Analytical Toxicology     Hybrid Journal   (Followers: 13, SJR: 1.038, h-index: 60)
J. of Antimicrobial Chemotherapy     Hybrid Journal   (Followers: 20, SJR: 2.157, h-index: 149)
J. of Antitrust Enforcement     Hybrid Journal   (Followers: 1)
J. of Applied Poultry Research     Hybrid Journal   (Followers: 3, SJR: 0.563, h-index: 43)
J. of Biochemistry     Hybrid Journal   (Followers: 43, SJR: 1.341, h-index: 96)
J. of Chromatographic Science     Hybrid Journal   (Followers: 18, SJR: 0.448, h-index: 42)
J. of Church and State     Hybrid Journal   (Followers: 11, SJR: 0.167, h-index: 11)
J. of Competition Law and Economics     Hybrid Journal   (Followers: 34, SJR: 0.442, h-index: 16)
J. of Complex Networks     Hybrid Journal   (Followers: 1, SJR: 1.165, h-index: 5)
J. of Conflict and Security Law     Hybrid Journal   (Followers: 11, SJR: 0.196, h-index: 15)
J. of Consumer Research     Full-text available via subscription   (Followers: 38, SJR: 4.896, h-index: 121)
J. of Crohn's and Colitis     Hybrid Journal   (Followers: 9, SJR: 1.543, h-index: 37)
J. of Cybersecurity     Hybrid Journal   (Followers: 2)
J. of Deaf Studies and Deaf Education     Hybrid Journal   (Followers: 8, SJR: 0.69, h-index: 36)
J. of Design History     Hybrid Journal   (Followers: 15, SJR: 0.166, h-index: 14)
J. of Economic Entomology     Full-text available via subscription   (Followers: 6, SJR: 0.894, h-index: 76)
J. of Economic Geography     Hybrid Journal   (Followers: 31, SJR: 2.909, h-index: 69)
J. of Environmental Law     Hybrid Journal   (Followers: 25, SJR: 0.457, h-index: 20)
J. of European Competition Law & Practice     Hybrid Journal   (Followers: 19)
J. of Experimental Botany     Hybrid Journal   (Followers: 13, SJR: 2.798, h-index: 163)
J. of Financial Econometrics     Hybrid Journal   (Followers: 21, SJR: 1.314, h-index: 27)
J. of Global Security Studies     Hybrid Journal   (Followers: 1)
J. of Heredity     Hybrid Journal   (Followers: 3, SJR: 1.024, h-index: 76)
J. of Hindu Studies     Hybrid Journal   (Followers: 7, SJR: 0.186, h-index: 3)
J. of Hip Preservation Surgery     Open Access  
J. of Human Rights Practice     Hybrid Journal   (Followers: 21, SJR: 0.399, h-index: 10)
J. of Infectious Diseases     Hybrid Journal   (Followers: 39, SJR: 4, h-index: 209)
J. of Insect Science     Open Access   (Followers: 9, SJR: 0.388, h-index: 31)
J. of Integrated Pest Management     Open Access   (Followers: 1)

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Journal Cover Annals of Oncology
  [SJR: 4.362]   [H-I: 173]   [49 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0923-7534 - ISSN (Online) 1569-8041
   Published by Oxford University Press Homepage  [368 journals]
  • Cabozantinib in hepatocellular carcinoma: results of a phase 2
           placebo-controlled randomized discontinuation study
    • Authors: Kelley RK; Verslype CC, Cohn AL, et al.
      Abstract: BackgroundCabozantinib, an orally bioavailable inhibitor of tyrosine kinases including MET, AXL, and VEGF receptors, was assessed in patients with hepatocellular carcinoma (HCC) as part of a phase 2 randomized discontinuation trial with nine tumor-type cohorts.Patients and methodsEligible patients had Child-Pugh A liver function and ≤1 prior systemic anticancer regimen, completed ≥4 weeks before study entry. The cabozantinib starting dose was 100 mg daily. After an initial 12-week cabozantinib treatment period, patients with stable disease (SD) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 were randomized to cabozantinib or placebo. The primary endpoint of the lead-in stage was objective response rate (ORR) at week 12, and the primary endpoint of the randomized stage was progression-free survival (PFS).ResultsAmong the 41 HCC patients enrolled, the week 12 ORR was 5%, with 2 patients achieving a confirmed partial response (PR). The week 12 disease control rate (PR or SD) was 66% (Asian subgroup: 73%). Of patients with ≥1 post-baseline scan, 78% had tumor regression, with no apparent relationship to prior sorafenib therapy. Alpha-fetoprotein (AFP) response (>50% reduction from baseline) occurred in 9 of the 26 (35%) patients with elevated baseline AFP and ≥1 post-baseline measurement. Twenty-two patients with SD at week 12 were randomized. Median PFS after randomization was 2.5 months with cabozantinib and 1.4 months with placebo, although this difference was not statistically significant. Median PFS and overall survival from Day 1 in all patients were 5.2 and 11.5 months, respectively. The most common grade 3/4 adverse events, regardless of attribution, were diarrhea (20%), hand-foot syndrome (15%), and thrombocytopenia (15%). Dose reductions were utilized in 59% of patients.ConclusionsCabozantinib has clinical activity in HCC patients, including objective tumor responses, disease stabilization, and reductions in AFP. Adverse events were managed with dose reductions.Trial registration numberNCT00940225.
      PubDate: 2017-02-28
  • Efficacy of androgen deprivation therapy and the role of oxidative stress
    • Authors: Price DK.
      Abstract: Androgen deprivation therapy (ADT) is the reduction in the production and/or action of androgens by either surgical or medical castration, and is the current first-line treatment of metastatic prostate cancer. This is accomplished with anti-androgens or luteinizing hormone-releasing hormone agonists or antagonists. While initially successful, most patients will experience a biochemical recurrence within 2–5 years, with the tumors proliferating even though the patient remains at castrate levels of androgens (Figure 1). This growing population of patients with castration-resistant prostate cancer (CRPC) is faced with a drug-resistant, lethal form of prostate cancer. Although confronted with this dire situation, the hopeful news is that patients with CRPC have become the focus of recent clinical trials leading to six FDA approved agents that are available for therapeutic use. These agents include docetaxel (microtubule inhibitor, 2004) [1], sipuleucel-T (dendritic cell immunotherapy, 2010) [2], cabazitaxel (microtubule inhibitor, 2010) [3], abiraterone acetate (CYP-17 inhibitor, 2012) [4], enzalutamide (androgen receptor inhibitor, 2012) [5], and radium-223 (alpha particle radionuclide, 2013) [6]. Despite these recent advances, the biology and subsequent understanding of prostate cancer metastasis and progression is still ongoing, and there is always room for more cellular targets, reliable biomarkers, therapeutic agents, and clinical options. Figure 1.Continuum of prostate cancer. *Androgen receptor (AR) activity roughly follows tumor volume.
      PubDate: 2017-02-27
  • Phase II study of cabazitaxel with or without abiraterone acetate and
           prednisone in patients with metastatic castrate resistant prostate cancer
           after prior docetaxel and abiraterone acetate
    • Authors: Kessler ER; Gao DD, Flaig TW, et al.
      Abstract: Traditionally, agents for the treatment of metastatic castrate-resistant prostate cancer (mCRPC) have been used sequentially rather than in combination. The combination of abiraterone acetate, prednisone, and cabazitaxel is an intriguing approach to concurrent use of both hormone-directed therapy and a cytotoxic approach. We congratulate Dr Massard and his colleagues on the recent publication of results of a phase I/II trial of cabazitaxel plus abiraterone acetate and prednisone in 37 patients with mCRPC after prior docetaxel and abiraterone acetate [1]. They found that the combination was well tolerated at the approved doses for both drugs, with a toxicity profile that is consistent with the established safety profiles of cabazitaxel and abiraterone acetate/prednisone separately. The primary endpoint was PSA response rate (PSA response defined as >/= 50% reduction in PSA). Even though an absolute difference of 25% increase in PSA response rate (RR) was not observed (null hypothesis of 25% PSA RR; alternative hypothesis of 50% PSA RR), the combination of cabazitaxel and abiraterone showed a PSA RR of 46%, RECIST radiographic objective response rate (ORR) of 21%, and median progression-free survival (mPFS) of 6.9 months. For comparison, in the TROPIC study [2], cabazitaxel monotherapy showed a PSA RR of 39%, ORR 14.4%, and mPFS of 2.8 months. In the COU-AA-301 study of abiraterone acetate post docetaxel [3], PSA RR was 29%, ORR was 14%, and mPFS was 5.6 months.
      PubDate: 2017-02-14
  • A phase II study of a human anti-PDGFRα monoclonal antibody (olaratumab,
           IMC-3G3) in previously treated patients with metastatic gastrointestinal
           stromal tumors
    • Authors: Wagner AJ; Kindler HH, Gelderblom HH, et al.
      Abstract: BackgroundThis study evaluated tumor response to olaratumab (an anti-PDGFRα monoclonal antibody) in previously treated patients with metastatic gastrointestinal stromal tumor (GIST) with or without PDGFRα mutations (cohorts 1 and 2, respectively).Patients and methodsPatients received olaratumab 20 mg/kg intravenously every 14 days until disease progression, death, or intolerable toxicity occurred. Outcome measures were 12-week tumor response, progression-free survival (PFS), overall survival (OS), and safety.ResultsOf 30 patients enrolled, 21 patients received ≥1 dose of olaratumab. In the evaluable population (cohort 1, n = 6; cohort 2, n = 14), no complete response (CR) or partial response (PR) was observed. Stable disease (SD) was observed in 3 patients (50.0%) in cohort 1 and 2 patients (14.3%) in cohort 2. Progressive disease (PD) was observed in 3 patients (50.0%) in cohort 1 and 12 patients (85.7%) in cohort 2. The 12-week clinical benefit rate (CR + PR + SD) (90% CI) was 50.0% (15.3–84.7%) in cohort 1 and 14.3% (2.6–38.5%) in cohort 2. SD lasted beyond 12 weeks in 5 patients (cohort 1, n = 3; cohort 2, n = 2). Median PFS (90% CI) was 32.1 (5.0–35.9) weeks in cohort 1 and 6.1 (5.7–6.3) weeks in cohort 2. Median OS was not reached in cohort 1 and was 24.9 (14.4–49.1) weeks in cohort 2. All patients in cohort 1 and 9 (64.3%) in cohort 2 experienced an olaratumab-related adverse event (AE), most commonly fatigue (38.1%), nausea (19.0%), and peripheral edema (14.3%). Two grade ≥3 olaratumab-related events were reported (cohort 1, syncope; cohort 2, hypertension).ConclusionsOlaratumab had an acceptable AE profile in patients with GIST. While there was no apparent effect on PFS in patients without PDGFRα mutations, patients with PDGFRα-mutant GIST (all with D842V mutations) treated with olaratumab had longer disease control compared with historical data for this IdentifierNCT01316263.
      PubDate: 2017-02-14
  • Dual HER2 inhibition and pathological complete response in early breast
           cancer: increasing success of treatment by improving patient selection
    • Authors: Curigliano GG; Goldhirsch AA.
      Abstract: HER2 positive breast cancer is a family of biologically distinct diseases including hormone receptor positive (HR+) and HR negative (HR−) phenotypes. These biological features have clear implications for patient selection and for the optimization of drug choices. Trials in the adjuvant setting are large, take many years to complete, and often result in a modest improvement in treatment outcome. Neoadjuvant treatments are evaluated for efficacy in a much shorter time period, having the degree of pathological response, assessed at definitive surgery, as the ultimate outcome measure of treatment success. The number of neoadjuvant randomized clinical trials has increased greatly and in 2013, the US Food and Drug Administration (FDA) awarded accelerated approval to pertuzumab on the basis of data from neoadjuvant trials [1]. The design of trials in the neoadjuvant setting, having pathological complete response (pCR) as the primary endpoint, allows new regimens to be tested in much smaller trials and for results to be obtained far more rapidly than in adjuvant studies.
      PubDate: 2017-02-07
  • Cabozantinib: targeted therapy back to the future'
    • Authors: Abou-Alfa GG.
      Abstract: Thanks to Kelley et al. the interest in c-met inhibition in hepatocellular carcinoma (HCC) remains alive and well. In this well-designed randomized phase II study, reported in this issue of Annals of Oncology, of cabozantinib in patients with advanced HCC whose disease had progressed on prior therapies [1], there are clear indications of meaningful activity. Although a low response rate of 5% was observed, which is expected for this class of drug [2], improvements in PFS and OS of 5.2 and 11.5 months, respectively, suggest that within the context of this phase II study a potential role for c-met inhibition in the treatment of advanced HCC exists. It justifies and supports the current ongoing phase III clinical trial of cabozantinib versus placebo in patients with advanced HCC whose disease progressed on or was intolerant to prior sorafenib ( NCT01908426).
      PubDate: 2017-01-30
  • PARP inhibitor and chemotherapy combination trials for the treatment of
           advanced malignancies: does a development pathway forward exist'
    • Authors: Matulonis UA; Monk BJ.
      Abstract: Poly (ADP ribose) polymerase (PARP) inhibitor combinations are currently being developed as a treatment strategy for advanced cancers with partial, potential, or no known DNA repair deficits in order to augment the anti-cancer potential of both the PARP inhibitor and the chemotherapy partner. The phase III development of PARP inhibitors in ovarian cancer has focused on single agents. As such, PARP inhibitors have demonstrated their greatest efficacy in cancers with underlying DNA repair deficits, such as deleterious mutations in BRCA1 or BRCA2, or when used in clinical situations when homologous recombination deficiency (HRD) is operative, such as recently described results for niraparib in platinum-sensitive high-grade serous ovarian cancer [1–4]. Single-agent PARP inhibitors have less activity in BRCA wildtype, especially platinum resistant, or HR proficient cancers [5].
      PubDate: 2017-01-05
  • Biomarker-directed molecularly targeted therapy: the importance of
           prospective evaluation
    • Authors: Stinchcombe TE.
      Abstract: The SHIVA trial was a randomized phase 2 trial that compared the outcomes of patients assigned to a matched molecularly targeted therapy (investigational arm) to those assigned to treatment based on physician choice (standard arm) [1]. Patients with an alteration in one of three molecular pathways (hormone receptors, PI3k/AKT/mTOR, and RAF/MEK) were assigned to 1 of the 10 targeted therapy regimens using a defined algorithm. The molecularly targeted agents were drugs approved for clinical use in France but were being studied outside their indications. The primary end-point was progression-free survival (PFS), and PFS in the molecularly targeted therapy and standard arms were similar (hazard ratio of 0.88, 95% CI, 0.65–1.19, P = 0.41; median PFS 2.3 and 2.0 months, respectively). In the safety analysis, 43% of patients assigned to the molecularly targeted therapy and 35% of patients treated with cytotoxic chemotherapy had grade 3 and 4 adverse events (P = 0.30). Thus, the study did not suggest an efficacy or safety advantage to the molecularly targeted therapy based on the assigned pathways.
      PubDate: 2017-01-05
  • Cardiotoxicity of aromatase inhibitors and tamoxifen in postmenopausal
           women with breast cancer: a systematic review and meta-analysis of
           randomized controlled trials
    • Authors: Khosrow-Khavar FF; Filion KB, Al-Qurashi SS, et al.
      Abstract: BackgroundAromatase inhibitors (AIs) have been associated with cardiovascular disease in adjuvant randomized controlled trials (RCTs) comparing these drugs to tamoxifen. However, it is unclear whether this risk is real or due to cardioprotective effects of tamoxifen. To address this question, we conducted a systematic review and meta-analysis of all RCTs of AIs and tamoxifen in adjuvant and extended adjuvant setting.Patients and methodsWe searched PubMed, Embase (OVID), Cochrane CENTRAL, WHO International Clinical Trials Registry Platform, and from inception to June 2016 for all RCTs comparing cardiovascular and cerebrovascular safety of AIs to tamoxifen, AIs to placebo or no-treatment, or tamoxifen to placebo or no-treatment in the adjuvant or extended adjuvant setting. Relative risks (RRs) were pooled using DerSimonian and Laird random-effects models with analyses stratified by RCT design.ResultsA total of 19 RCTs were included in the meta-analysis (n  =  62 345). In the adjuvant setting, AIs were associated with a 19% (RR: 1.19, 95% confidence interval [CI]: 1.07–1.34) increased risk of cardiovascular events compared with tamoxifen. AIs were not associated with an increased risk compared with placebo in the extended-adjuvant setting (RR: 1.01, 95% CI: 0.85–1.20). In the adjuvant setting, tamoxifen was associated with a 33% (RR: 0.67, 95% CI: 0.45–0.98) decreased risk compared with placebo or no-treatment. The results from extended adjuvant RCTs comparing tamoxifen to placebo were inconclusive but suggestive of a small protective effect (RR: 0.91, 95% CI: 0.77–1.07).ConclusionsThe increased risk of cardiovascular events with AIs relative to tamoxifen is likely the result of cardioprotective effects of the latter. This new evidence should be considered when assessing the benefits and risks of AIs in the treatment of breast cancer.
      PubDate: 2016-12-27
  • Phase I dose escalation study of the PI3kinase pathway inhibitor BKM120
           and the oral poly (ADP ribose) polymerase (PARP) inhibitor olaparib for
           the treatment of high-grade serous ovarian and breast cancer
    • Authors: Matulonis UA; Wulf GM, Barry WT, et al.
      Abstract: BackgroundBased upon preclinical synergy in murine models, we carried out a phase I trial to determine the maximum tolerated dose (MTD), toxicities, pharmacokinetics, and biomarkers of response for the combination of BKM120, a PI3K inhibitor, and olaparib, a PARP inhibitor.Patients and methodsOlaparib was administered twice daily (tablet formulation) and BKM120 daily on a 28-day cycle, both orally. A 3 + 3 dose-escalation design was employed with the primary objective of defining the combination MTD, and secondary objectives were to define toxicities, activity, and pharmacokinetic profiles. Eligibility included recurrent breast (BC) or ovarian cancer (OC); dose-expansion cohorts at the MTD were enrolled for each cancer.ResultsIn total, 69 of 70 patients enrolled received study treatment; one patient never received study treatment because of ineligibility. Twenty-four patients had BC; 46 patients had OC. Thirty-five patients had a germline BRCA mutation (gBRCAm). Two DLTs (grade 3 transaminitis and hyperglycemia) were observed at DL0 (BKM120 60 mg/olaparib and 100 mg b.i.d.). The MTD was determined to be BKM120 50 mg q.d. and olaparib 300 mg b.i.d. (DL8). Additional DLTs included grade 3 depression and transaminitis, occurring early in cycle 2 (DL7). Anticancer activity was observed in BC and OC and in gBRCAm and gBRCA wild-type (gBRCAwt) patients.ConclusionsBKM120 and olaparib can be co-administered, but the combination requires attenuation of the BKM120 dose. Clinical benefit was observed in both gBRCAm and gBRCAwt pts. Randomized phase II studies will be needed to further define the efficacy of PI3K/PARP-inhibitor combinations as compared with a PARP inhibitor alone.
      PubDate: 2016-12-27
  • Rapamycin-insensitive companion of mTOR ( RICTOR ) amplification defines a
           subset of advanced gastric cancer and is sensitive to AZD2014-mediated
           mTORC1/2 inhibition
    • Authors: Kim ST; Kim SY, Klempner SJ, et al.
      Abstract: BackgroundTargeting oncogenic genomic aberrations is an established therapeutic strategy in multiple tumor types. Molecular classification has uncovered a number of novel targets, and rapamycin-insensitive companion of mTOR (RICTOR) amplification has been identified in lung cancer. Further investigation assessing the therapeutic potential of RICTOR amplification as a novel target across advanced cancers is needed.Patients and methodsTumor samples from 640 patients with metastatic solid tumors, primarily gastrointestinal and lung cancers were prospectively subjected to a next-generation sequencing (NGS) assay to identify molecular targets. Samples with NGS-detected RICTOR amplification were confirmed with FISH. A RICTOR-amplified patient-derived cell (PDC) line was generated and used to investigate the effectiveness of selective AKT, mTORC1, and mTORC1/2 inhibition.ResultsNGS identified 13 (2%) of 640 patients with RICTOR-amplified tumors (6 gastric, 3 NSCLC, 1 SCLC, 1 CRC, 1 sarcoma, 1 MUO). Of the 13 patients, seven patients had RICTOR protein overexpression by IHC. The prevalence of RICTOR amplification in gastric cancer by NGS was 3.8% (6/160). FISH testing confirmed amplification (RICTOR/control >2) in 5/13 (38%) of samples, including four gastric cancers and one lung cancer. Treatment of a RICTOR amplified PDC with a selective AKT (AZD5363), selective mTORC1 (everolimus), dual mTORC1/2 (AZD2014), and the multi-target kinase inhibitor pazopanib demonstrated preferential sensitivity to the mTORC1/2 inhibitor (AZD2014). Knockdown of RICTOR reversed PDC sensitivity to AZD2014, validating the importance of RICTOR amplification to the PDC line.ConclusionsRICTOR amplification is a rare but therapeutically relevant genomic alteration across solid tumors. Our results support further pre-clinical and clinical investigation with AZD2014 in RICTOR amplified gastric cancer and highlights the importance of genomic profiling.
      PubDate: 2016-12-27
  • Interventions for preventing cardiomyopathy due to anthracyclines: a
           Bayesian network meta-analysis
    • Authors: Abdel-Qadir HH; Ong GG, Fazelzad RR, et al.
      Abstract: BackgroundThe relative efficacy of interventions for primary prevention of anthracycline-associated cardiotoxicity is unknown.MethodsWe conducted a systematic review of randomized controlled trials for primary prevention of anthracycline-associated cardiotoxicity in adult cancer patients. We used hierarchal outcome definitions in the following order of priority: (1) composite of heart failure or decline in left ventricular ejection fraction, (2) decline in ejection fraction, or (3) heart failure. Data were analyzed using a Bayesian network meta-analysis with random effects.ResultsA total of 16 trials reported cardiotoxicity as a dichotomous outcome among 1918 patients, evaluating dexrazoxane, angiotensin antagonists, beta-blockers, combination angiotensin antagonists and beta-blockers, statins, Co-enzyme Q-10, prenylamine, and N-acetylcysteine. Compared with control, dexrazoxane reduced cardiotoxicity with a pooled odds ratio (OR) of 0.26 (95% credible interval [CrI] 0.11–0.74) and had the highest probability (33%) of being most effective. No other agent was demonstrably better than placebo. Angiotensin antagonists had an 84% probability of being most effective in a sensitivity analysis excluding one outlying study (OR 0.06 [95% CrI 0.01– 0.24]). When the outcome was restricted to heart failure, dexrazoxane was associated with an OR of 0.12 (95% CrI 0.06–0.23) relative to control and had 58% probability of being most effective, while angiotensin antagonists had an OR of 0.18 (95% CrI 0.05–0.55). Available data suggested that dexrazoxane and angiotensin antagonists did not affect malignancy response rate or risk of death.ConclusionModerate quality data suggest that dexrazoxane, and low quality data suggest angiotensin antagonists, are likely to be effective for cardiotoxicity prevention.
      PubDate: 2016-12-27
  • Circulating tumor markers: harmonizing the yin and yang of CTCs and ctDNA
           for precision medicine
    • Authors: Batth IS; Mitra AA, Manier SS, et al.
      Abstract: Current trajectory of clinical care is heading in the direction of personalized medicine. In an ideal scenario, clinicians can obtain extensive diagnostic and prognostic information via minimally-invasive assays. Information available in the peripheral blood has the potential to bring us closer to this goal. In this review we highlight the contributions of circulating tumor cells and circulating tumor DNA and RNA (ctDNA/ctRNA) towards cancer therapeutic field. We discuss clinical relevance, summarize available and upcoming technologies, and hypothesize how future care could be impacted by a combined study.
      PubDate: 2016-12-20
  • Does severe toxicity affect global quality of life in patients with
           metastatic colorectal cancer during palliative systemic treatment' A
           systematic review
    • Authors: Schuurhuizen CW; Braamse AJ, Konings IM, et al.
      Abstract: Background New palliative systemic treatment regimens in patients with metastatic colorectal cancer (mCRC) have significantly improved overall survival and prognosis. These treatment regimens are often accompanied by increased toxicity, which may impair patients’ quality of life (QOL). We systematically reviewed whether severe toxicity affects global QOL in patients with mCRC receiving palliative systemic treatment in recent published randomized controlled trials (RCTs).Materials and methodsPhase III RCTs evaluating palliative systemic treatments in patients with mCRC and published between 2004 and 2016 were considered. Studies were evaluated on the basis of global QOL scores, toxicity during treatment (assessed by scoring relevant adverse events) and primary outcomes (POs).ResultsA total of 30 studies were identified in which 19863 patients were included. In 25 out of these 30 trials (83%), no difference in global QOL between treatment arms was observed. In contrast, 22 out of 30 trials (73%) showed increased toxicity during treatment in the experimental arm as compared with the control arm. In 19 out of 22 trials with higher toxicity (86%) global QOL outcomes remained unaffected or improved. In ten out of eleven studies with a better PO, no improvement in global QOL was seen.ConclusionGlobal QOL of patients with mCRC included in phase III RCTs evaluating palliative systemic treatment did not differ across treatment arms despite consistently higher toxicity during treatment of the experimental compared with the standard treatment arms. Based on these findings we conclude that the use of global QOL for comparing treatment arms in RCTs for patients with mCRC does not provide information of clinical relevance. Further consideration of how to better assess the net effect of new agents on patients’ QOL is urgently needed.
      PubDate: 2016-12-20
  • A phase I trial of paclitaxel, cisplatin, and veliparib in the treatment
           of persistent or recurrent carcinoma of the cervix: an NRG Oncology Study
    • Authors: Thaker PH; Salani RR, Brady WE, et al.
      Abstract: BackgroundPreclinical studies demonstrate poly(ADP-ribose) polymerase (PARP) inhibition augments apoptotic response and sensitizes cervical cancer cells to the effects of cisplatin. Given the use of cisplatin and paclitaxel as first-line treatment for persistent or recurrent cervical cancer, we aimed to estimate the maximum tolerated dose (MTD) of the PARP inhibitor veliparib when added to chemotherapy.Patients and methodsWomen with persistent or recurrent cervical carcinoma not amenable to curative therapy were enrolled. Patients had to have received concurrent chemotherapy and radiation as well as possible consolidation chemotherapy; have adequate organ function. The trial utilized a standard 3 + 3 phase I dose escalation with patients receiving paclitaxel 175 mg/m2 on day 1, cisplatin 50 mg/m2 on day 2, and escalating doses of veliparib ranging from 50 to 400 mg orally two times daily on days 1–7. Cycles occurred every 21 days until progression. Dose-limiting toxicities (DLTs) were assessed at first cycle. Fanconi anemia complementation group D2 (FANCD2) foci was evaluated in tissue specimens as a biomarker of response.ResultsThirty-four patients received treatment. DLTs (n = 1) were a grade 4 dyspnea, a grade 3 neutropenia lasting ≥3 weeks, and febrile neutropenia. At 400 mg dose level (DL), one of the six patients had a DLT, so the MTD was not reached. Across DLs, the objective response rate (RR) for 29 patients with measurable disease was 34% [95% confidence interval (CI), 20%–53%]; at 400 mg DL, the RR was 60% (n = 3/5; 95% CI, 23%–88%). Median progression-free survival was 6.2 months (95% CI, 2.9–10.1), and overall survival was 14.5 months (95% CI, 8.2–19.4). FANCD2 foci was negative or heterogeneous in 31% of patients and present in 69%. Objective RR were not associated with FANCD2 foci (P = 0.53).ConclusionsCombining veliparib with paclitaxel and cisplatin as first-line treatment for persistent or recurrent cervical cancer patients is safe and feasible.Clinical trial informationNCT01281852.
      PubDate: 2016-12-20
  • Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in
           patients with non-small-cell lung cancer
    • Authors: Osorio JC; Ni AA, Chaft JE, et al.
      Abstract: BackgroundProgrammed cell death protein-1 (PD-1) blockade therapies have demonstrated durable responses and prolonged survival in a variety of malignancies. Treatment is generally well tolerated although immune-related adverse events (irAEs) can occur. Autoimmune thyroid dysfunction is among the most common irAE, but an assessment of the clinical, mechanistic, and immunologic features has not been previously described.Patient and methodsPatients with advanced non-small-cell lung cancer (NSCLC) treated with pembrolizumab at Memorial Sloan Kettering Cancer Center (n = 51) as part of KEYNOTE-001 (NCT01295827) were included. Thyroid function test and anti-thyroid antibodies were assessed prospectively at each study visit, beginning before the first treatment. Frequency of development of thyroid dysfunction, association with anti-thyroid antibodies, clinical course, and relationship with progression-free survival and overall survival to treatment with pembrolizumab was evaluated.ResultsOf 51 patients treated, 3 were hypothyroid and 48 were not at baseline. Ten of 48 [21%, 95% confidence interval (CI) 10% to 35%] patients developed thyroid dysfunction requiring thyroid replacement. Anti-thyroid antibodies were present in 8 of 10 patients who developed thyroid dysfunction, compared with 3 of 38 who did not (80% versus 8%, P 
      PubDate: 2016-12-20
  • What is the optimal neoadjuvant treatment for locally advanced oesophageal
    • Authors: Mariette CC.
      Abstract: Although surgery is the primary treatment modality, the prognosis of locally advanced oesophageal and junctional adenocarcinoma (OJA) after surgery alone remains unsatisfactory, with reported 5-year survival rates between 23% and 34% [1]. Such reports have led many investigators to evaluate the combination of surgery with chemo(radio)therapy. The neoadjuvant setting has been shown to be more efficient than the adjuvant setting alone in Western nations, with an additional 5-year survival rate compared with that of surgery alone reported from 6% to 14% with neoadjuvant or perioperative chemotherapy (NCS) [2–4] and 14% with neoadjuvant chemoradiotherapy (NCRS) [5]. These findings have led to the recommendation of both neoadjuvant strategies in the recent European Society of Medical Oncology guidelines [6]. Whereas NCRS seems to have a greater downstaging effect, a higher rate of pathological response and a lower risk of incomplete resection compared to NCS in underpowered randomised trials (Table 1) [7–9], an increased postoperative mortality rate has been reported by some authors [7, 9, 10] in association with NCRS, and the 5-year survival benefit over NCS remains to be proven. Direct comparison of NCRS versus NCS is an intense area of research, including a notable ongoing randomised European phase III trial investigating the benefit of NCRS with a focus on the paclitaxel-carboplatin radiotherapy CROSS regimen compared with NCS according to the ECF/ECX MAGIC regimen in OJA (NCT01726452). With the expectation of a 3-year increase in survival in 10% of the NCRS group, the Neo-AEGIS trial needs to enrol 594 patients. Results are expected in 2021. Another German phase III trial, the ESOPEC trial, has the same study design but is testing the FLOT regimen instead of the ECF/ECX MAGIC regimen, with 438 patients needing to be enrolled (NCT02509286). Prior to the completion of these landmark trials, in the last issue of the Annals of Oncology [11], Markar and colleagues’ retrospective study is the largest and most adequately powered cohort study reported to date comparing survival in association with NCRS versus NCS for the treatment of stage II and III OJA. In that study, 608 consecutive patients from 10 European centres, a sample size that is similar to the one in the Neo-AEGIS trial, were recruited. Propensity score matching and Cox regression analyses were used to compensate for differences in baseline characteristics. The authors confirmed that NCRS increases the rates of ypT0, ypN0 and complete (R0) resection compared to NCS but highlighted the increased risk of anastomotic leakage (23.1% versus 6.8%, P 
      PubDate: 2016-12-19
  • 3D waterfall plots: a better graphical representation of tumor response in
    • Authors: Castanon Alvarez EE; Aspeslagh SS, Soria JC.
      Abstract: In order to visualize a tumor response, a variety of representation methods can be used. To add more information, the classical waterfall plots were complemented by swimmer plots [1] and more recently by spider plots [2] popularized since the advent of immune checkpoint blockade (ICB).
      PubDate: 2016-12-19
  • Different efficacy of ramucirumab in patients with metastatic gastric and
           gastroesophageal junction cancer according to ECOG performance status
    • Authors: Roviello GG; Pacifico CC, Polom KK, et al.
      Abstract: Yoon et al. [1] reported the first randomized, phase II trial of ramucirumab, an anti-vascular endothelial growth factor receptor-2 monoclonal antibody, as front-line therapy in patients with advanced adenocarcinoma of the esophagus or gastric/gastroesophageal junction. Unfortunately, the addition of ramucirumab to front-line mFOLFOX6 did not improve progression-free survival (PFS) in these patients. We noted from the subgroup analysis of PFS in Figure 3A Yoon et al. [1] that, although not statistically significant, ramucirumab shows improved efficacy in patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS)=1 compared with ECOG PS 0 (hazard ratio 0.88 and 1, respectively). Based on these findings, we extended this subgroup analysis to all ramucirumab data available from literature. The studies were identified according to the following inclusion criteria: (i) ramucirumab-based experimental arm; (ii) the presence of a control arm for comparison (placebo or not); (iii) the presence of data on PFS according to ECOG PS. The following exclusion criteria were used: (i) insufficient data available to estimate the outcomes; (ii) animal studies; (iii) 
      PubDate: 2016-12-19
  • Moving beyond sorafenib alone in advanced hepatocellular carcinoma: is
           hepatic arterial infusion chemotherapy the best option'
    • Authors: Fornaro LL; Vivaldi CC, Lorenzoni GG, et al.
      Abstract: Ikeda et al. recently published the results of an interesting randomized phase II trial comparing sorafenib alone with sorafenib plus hepatic arterial infusion chemotherapy (HAIC) with cisplatin in advanced hepatocellular carcinoma (HCC) [1]. The investigators reported an overall survival (OS) benefit for HAIC added to sorafenib, even though no significant advantage was reported in terms of time to progression (TTP) and response rate (RR). This combination strategy certainly represents an interesting approach in such a difficult setting and the findings justify further investigation in larger patient populations; however, some points deserve discussion in order to rationally design future clinical trials.
      PubDate: 2016-12-19
  • High incidence of interstitial lung disease following practical use of
           osimertinib in patients who had undergone immediate prior nivolumab
    • Authors: Kotake MM; Murakami HH, Kenmotsu HH, et al.
      Abstract: Osimertinib is an irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that is effective in patients with EGFR-TKI sensitizing and T790M resistant mutation-positive advanced non-small cell lung cancer (NSCLC) [1, 2]. Although interstitial lung disease (ILD) is a serious adverse drug reaction of EGFR-TKIs [3], the prevalence of and risk factors for ILD following the practical use of osimertinib remain unknown. Here we report the incidence of ILD related to osimertinib use at the Shizuoka Cancer Center.
      PubDate: 2016-12-19
  • Integrating communication as a core skill in the global curriculum for
           medical oncology
    • Authors: Horlait MM; Leys MM, De Grève JJ, et al.
      Abstract: A recent editorial paid attention to the third edition (2016) of the joint European Society for Medical Oncology and American Society of Clinical Oncology (ESMO/ASCO) recommendations for a global curriculum in medical Oncology (GC) [1]. The new version answers to the need for updated recommendations in a continuously changing field of oncology where a broad range of competences need to be acquired for delivering qualitative and comprehensive oncological care. Future medical oncologists, who are at the centre of cancer care, need to be supported in developing adequate competences. Moreover, recommendations are of utmost importance to pursue equal chances of receiving state-of-the-art treatment from well-trained physicians for every patient worldwide.
      PubDate: 2016-12-19
  • Nivolumab-induced cholangitic liver disease: a novel form of serious liver
    • Authors: Gelsomino FF; Vitale GG, D’Errico AA, et al.
      Abstract: In recent years, immunotherapy has become a landmark for the development of new anticancer agents. Nivolumab, a fully human IgG4 monoclonal antibody, binds to the PD-1 (programmed cell death-1) receptor, blocking the interaction with its ligands (PD-L1 and PD-L2) and restoring immune competence against tumor cells [1].
      PubDate: 2016-12-19
  • Pembrolizumab induced bulbar myopathy and respiratory failure with
           necrotizing myositis of the diaphragm
    • Authors: Haddox CL; Shenoy NN, Shah KK, et al.
      Abstract: Pembrolizumab, an anti-PD 1 antibody, has been approved for the treatment of metastatic melanoma [1, 2], non-small cell lung carcinoma [3, 4], and head and neck cancers [5]; and is being investigated in other cancers. We describe a case of Pembrolizumab induced severe bulbar myopathy and respiratory failure with necrotizing myositis of the diaphragm.
      PubDate: 2016-12-19
  • Incidence of second tumors after treatment with or without radiation for
           rectal cancer
    • Authors: Rombouts AM; Hugen NN, Elferink MG, et al.
      Abstract: BackgroundThe aim of this study was to analyze the association between radiation therapy (RT) for rectal cancer and the development of second tumors.Patients and methods Data on all surgically treated non-metastatic primary rectal cancer patients diagnosed between 1989 and 2007 were retrieved from the Netherlands population-based cancer registry. Fine and Gray’s competing risk model was used for estimation of the cumulative incidence of second tumors. Multivariable analysis was conducted using Cox regression.Results The cohort consisted of 29 027 patients of which 15 467 patients had undergone RT. Median follow-up was 7.7 years (range 0–27). Among all 4398 patients who were diagnosed with a second primary tumor, 1030 had one or more pelvic tumors. The standardized incidence risk for any second tumor was 1.16 (95% confidence interval [CI] 1.12–1.19), resulting in 27.7/10 000 excess cancer cases per year in patients treated for rectal cancer compared with the general population. RT reduced the cumulative incidence of second pelvic tumors compared with patients who did not receive RT (subhazard ratio [SHR] 0.77, CI 0.68–0.88). Second prostate tumors were less common in patients who received RT (SHR 0.54, CI 0.46–0.64), gynecological tumors were more frequently observed in patients who received RT (SHR 1.49, CI 1.11–2.00).ConclusionsPatients with previous rectal cancer had a marginally increased risk of a second tumor compared with the general population. Gynecological tumors occurred more often in females who received RT, but this did not result in an overall increased risk for a second cancer. RT even seemed to have a protective effect on the development of other second pelvic tumors, pre-dominantly for prostate cancer. These findings are highly important and can contribute to improved patient counseling.
      PubDate: 2016-12-19
  • Investigating the poor outcomes of BRAF -mutant advanced colorectal
           cancer: analysis from 2530 patients in randomised clinical trials
    • Authors: Seligmann JF; Fisher DD, Smith CG, et al.
      Abstract: BackgroundTo improve strategies for the treatment of BRAF-mutant advanced colorectal cancer (aCRC) patients, we examined individual data from patients treated with chemotherapy alone in three randomised trials to identify points on the treatment pathway where outcomes differ from BRAF wild-types.Patients and methods2530 aCRC patients were assessed from three randomised trials. End-points were progression-free survival, response rate, disease control rate, post-progression survival (P-PS) and overall survival. Treatments included first-line oxaliplatin/fluorouracil (OxFU) and second-line irinotecan. Clinicians were unaware of BRAF-status.Results231 patients (9.1%) had BRAF-mutant tumours. BRAF-mutation conferred significantly worse survival independent of associated clinicopathological factors known to be prognostic. Compared with wild-type, BRAF-mutant patients treated with first-line OxFU had similar DCR (59.2% versus 72%; adjusted OR = 0.76, P = 0.24) and PFS (5.7 versus 6.3 months; adjusted HR = 1.14, P = 0.26). Following progression on first-line chemotherapy, BRAF-mutant patients had a markedly shorter P-PS (4.2 versus 9.2 months, adjusted HR = 1.69, P 
      PubDate: 2016-12-19
  • Gene polymorphisms in antioxidant enzymes correlate with the efficacy of
           androgen-deprivation therapy for prostate cancer with implications of
           oxidative stress
    • Authors: Shiota MM; Fujimoto NN, Itsumi MM, et al.
      Abstract: BackgroundOxidative stress mitigated by antioxidant enzymes is thought to be involved in the progression to castration-resistant prostate cancer (CRPC) during androgen-deprivation therapy (ADT). This study investigated the association between genetic variations in antioxidant enzymes and the efficacy of ADT as well as its biological background.Patients and methodsThe non-synonymous or promoter-locating polymorphisms of antioxidant enzymes were examined as well as the time to CRPC progression and overall survival in 104 and 92 patients treated with ADT for metastatic and non-metastatic prostate cancer, respectively. In addition, intracellular reactive oxygen species and expression levels of antioxidant enzymes were examined in castration-resistant and enzalutamide-resistant cells.ResultsIn metastatic prostate cancer, the AG/GG allele in GSTM3 rs7483 and CT/TT allele in CAT rs564250 were associated with a significantly lower risk of progression to CRPC and all-cause death compared with homozygotes of the major AA allele (hazard ratio [HR]; [95% confidence interval (CI)], 0.55 [0.34–0.86], P = 0.0086) and CC allele (HR; [95% CI], 0.48 [0.24–0.88], P = 0.016), respectively. On multivariate analyses, only GSTM3 rs7483 was associated with significant progression risk (AG/GG versus AA; HR; [95% CI], 0.45 [0.25–0.79], P = 0.0047) even after Bonferroni adjustment. In non-metastatic prostate cancer, the AG/GG allele in GSTM3 rs7483 was associated with a significantly lower risk of progression to CRPC (HR; [95% CI], 0.35 [0.10–0.93], P = 0.034) and all-cause death (HR; [95% CI], 0.26 [0.041–0.96], P = 0.043) compared with the AA allele. Intracellular reactive oxygen species levels were increased, accompanied with augmented GSTM3 expression in both castration-resistant and enzalutamide-resistant cells.ConclusionsDifferential activity of antioxidant enzymes caused by the polymorphism in GSTM3 may contribute to resistance to hormonal therapy through oxidative stress. The GSTM3 rs7483 polymorphism may be a promising biomarker for prostate cancer patients treated with ADT.
      PubDate: 2016-12-19
  • Impact of primary metastatic bone disease in germ cell tumors: results of
           an International Global Germ Cell Tumor Collaborative Group G3 Registry
    • Authors: Oing CC; Oechsle KK, Necchi AA, et al.
      Abstract: BackgroundBone metastases (BM) are rare in germ cell tumor (GCT) patients. Systematic data on risk factors, treatment and outcome are largely lacking.Patients and methodsA database created by an international consortium including 123 GCT patients with BM at primary diagnosis was retrospectively analysed. Survival estimates were calculated by the method of Kaplan–Meier and compared by log-rank testing. Cox regression analysis was applied for risk factor analyses.ResultsIn our cohort of patients, BM at primary diagnosis more often affected multiple sites (61%) and BM as the only metastatic site were scarce (9%). Histology was non-seminoma in 77% and seminoma in 23% of patients. After a median follow-up of 18 months (range, 0–228), estimated median PFS and OS were 21 (range, 0–225) and 98 months (95%CI, 36–160), respective 2-year PFS and OS rates were 34% and 45%. Negative prognosticators in univariate analysis were a mediastinal primary (PFS; HR 1.92; 95%CI, 1.05–3.50; OS; HR 2.16; 95%CI, 1.14–4.09) and the presence of liver and/or brain metastases (PFS; HR 1.89; 95%CI, 1.13–3.17; OS; HR 1.91; 95%CI, 0.024) Seminomatous histology was the strongest predictor for favorable PFS (multivariate Cox regression; HR, 0.32; P=0.011) with respective 2-year PFS and OS rates of 68% and 75% compared with 24% and 36% for non-seminoma patients.ConclusionsOutcome of GCT patients with primary metastatic bone disease is particularly poor in non-seminoma patients, even worse than the expected outcomes of the general IGCCCG ‘poor prognosis’ group. This series does not indicate that mutlimodal treatment improves the prognosis over stage-adapted chemotherapy alone, however, the statistical power of these results is limited due to low patient numbers in each specific subgroup.
      PubDate: 2016-12-19
  • Randomized phase II trial comparing molecularly targeted therapy based on
           tumor molecular profiling versus conventional therapy in patients with
           refractory cancer: cross-over analysis from the SHIVA trial
    • Authors: Belin LL; Kamal MM, Mauborgne CC, et al.
      Abstract: BackgroundSeveral studies used the ratio of progression-free survival (PFS) on genotype-matched treatment to PFS on genotype-unmatched treatment to assess the efficacy of therapy guided by patients’ tumor molecular profiling. We evaluated the PFS ratio from patients who cross-over in the SHIVA trial.Patients and methodsThe primary end point of the SHIVA trial was to compare PFS on molecularly targeted agents (MTAs) based on tumor molecular profiling and treatment at physician’s choice (TPC) in patients with any kind of cancer who had failed standard-of-care therapy. The experimental treatment included only marketed MTAs given outside their indications according to a pre-specified treatment algorithm. Patients were allowed to cross-over at disease progression in both arms. Response was evaluated according to RECIST 1.1 at randomization and at cross-over. We evaluated the ratio of PFS on MTA (PFSMTA) to PFS on TPC (PFSTPC) in patients who crossed-over.ResultsAmong 741 patients enrolled in the SHIVA trial, 197 were randomized, and 95 crossed-over, including 70 patients from the TPC to the MTA arm and 25 patients from the MTA to the TPC arm. Two patients crossed-over in the TPC arm without disease progression. The PFSMTA/PFSTPC ratio exceeded 1.3 in 37% of patients who crossed-over from the TPC to the MTA arm. The PFSMTA/PFSTPC ratio exceeded 1.3 in 61% of patients who crossed-over from the MTA arm to the TPC arm.ConclusionsThe cross-over analysis of the SHIVA trial identified 37% of patients who crossed-over from TPC to MTA with a PFSMTA/PFSTPC ratio exceeding 1.3.
      PubDate: 2016-12-19
  • Drug-sensitive FGFR3 mutations in lung adenocarcinoma
    • Authors: Chandrani PP; Prabhash KK, Prasad RR, et al.
      Abstract: BackgroundLung cancer is the leading cause of cancer-related deaths across the world. In this study, we present therapeutically relevant genetic alterations in lung adenocarcinoma of Indian origin.Materials and methodsForty-five primary lung adenocarcinoma tumors were sequenced for 676 amplicons using RainDance cancer panel at an average coverage of 1500 × (reads per million mapped reads). To validate the findings, 49 mutations across 23 genes were genotyped in an additional set of 363 primary lung adenocarcinoma tumors using mass spectrometry. NIH/3T3 cells over expressing mutant and wild-type FGFR3 constructs were characterized for anchorage independent growth, constitutive activation, tumor formation and sensitivity to FGFR inhibitors using in vitro and xenograft mouse models.ResultsWe present the first spectrum of actionable alterations in lung adenocarcinoma tumors of Indian origin, and shows that mutations of FGFR3 are present in 20 of 363 (5.5%) patients. These FGFR3 mutations are constitutively active and oncogenic when ectopically expressed in NIH/3T3 cells and using a xenograft model in NOD/SCID mice. Inhibition of FGFR3 kinase activity inhibits transformation of NIH/3T3 overexpressing FGFR3 constructs and growth of tumors driven by FGFR3 in the xenograft models. The reduction in tumor size in the mouse is paralleled by a reduction in the amounts of phospho-ERK, validating the in vitro findings. Interestingly, the FGFR3 mutations are significantly higher in a proportion of younger patients and show a trend toward better overall survival, compared with patients lacking actionable alterations or those harboring KRAS mutations.ConclusionWe present the first actionable mutation spectrum in Indian lung cancer genome. These findings implicate FGFR3 as a novel therapeutic in lung adenocarcinoma.
      PubDate: 2016-12-19
  • Differential gene expression profiling of matched primary renal cell
           carcinoma and metastases reveals upregulation of extracellular matrix
    • Authors: Ho TH; Serie DJ, Parasramka MM, et al.
      Abstract: BackgroundThe majority of renal cell carcinoma (RCC) studies analyze primary tumors, and the corresponding results are extrapolated to metastatic RCC tumors. However, it is unknown if gene expression profiles from primary RCC tumors differs from patient-matched metastatic tumors. Thus, we sought to identify differentially expressed genes between patient-matched primary and metastatic RCC tumors in order to understand the molecular mechanisms underlying the development of RCC metastases.Patients and methodsWe compared gene expression profiles between patient-matched primary and metastatic RCC tumors using a two-stage design. First, we used Affymetrix microarrays on 15 pairs of primary RCC [14 clear cell RCC (ccRCC), 1 papillary] tumors and patient-matched pulmonary metastases. Second, we used a custom NanoString panel to validate seven candidate genes in an independent cohort of 114 ccRCC patients. Differential gene expression was evaluated using a mixed effect linear model; a random effect denoting patient was included to account for the paired data. Third, The Cancer Genome Atlas (TCGA) data were used to evaluate associations with metastasis-free and overall survival in primary ccRCC tumors.ResultsWe identified and validated up regulation of seven genes functionally involved in the formation of the extracellular matrix (ECM): DCN, SLIT2, LUM, LAMA2, ADAMTS12, CEACAM6 and LMO3. In primary ccRCC, CEACAM6 and LUM were significantly associated with metastasis-free and overall survival (P 
      PubDate: 2016-12-19
  • Network-guided modeling allows tumor-type independent prediction of
           sensitivity to all- trans -retinoic acid
    • Authors: Bolis MM; Garattini EE, Paroni GG, et al.
      Abstract: BackgroundAll-trans-retinoic acid (ATRA) is a differentiating agent used in the treatment of acute-promyelocytic-leukemia (APL) and it is under-exploited in other malignancies despite its low systemic toxicity. A rational/personalized use of ATRA requires the development of predictive tools allowing identification of sensitive cancer types and responsive individuals.Materials and methodsRNA-sequencing data for 10 080 patients and 33 different tumor types were derived from the TCGA and Leucegene datasets and completely re-processed. The study was carried out using machine learning methods and network analysis.ResultsWe profiled a large panel of breast-cancer cell-lines for in vitro sensitivity to ATRA and exploited the associated basal gene-expression data to initially generate a model predicting ATRA-sensitivity in this disease. Starting from these results and using a network-guided approach, we developed a generalized model (ATRA-21) whose validity extends to tumor types other than breast cancer. ATRA-21 predictions correlate with experimentally determined sensitivity in a large panel of cell-lines representative of numerous tumor types. In patients, ATRA-21 correctly identifies APL as the most sensitive acute-myelogenous-leukemia subtype and indicates that uveal-melanoma and low-grade glioma are top-ranking diseases as for average predicted responsiveness to ATRA. There is a consistent number of tumor types for which higher ATRA-21 predictions are associated with better outcomes.ConclusionsIn summary, we generated a tumor-type independent ATRA-sensitivity predictor which consists of a restricted number of genes and has the potential to be applied in the clinics. Identification of the tumor types that are likely to be generally sensitive to the action of ATRA paves the way to the design of clinical studies in the context of these diseases. In addition, ATRA-21 may represent an important diagnostic tool for the selection of individual patients who may benefit from ATRA-based therapeutic strategies also in tumors characterized by lower average sensitivity.
      PubDate: 2016-12-19
  • Treatment outcomes for older patients with relapsed/refractory aggressive
           lymphoma receiving salvage chemotherapy and autologous stem cell
           transplantation are similar to younger patients: a subgroup analysis from
           the phase III CCTG LY.12 trial
    • Authors: Davison KK; Chen BE, Kukreti VV, et al.
      Abstract: BackgroundHigh-dose therapy and autologous stem cell transplantation (ASCT) is often considered for older patients (age >60 years) with relapsed/refractory aggressive lymphomas. Although registry data support the safety and potential efficacy of this approach, there are no prospective trials evaluating outcomes of ASCT in older patients. We evaluated the result of second-line chemotherapy and ASCT in older versus younger patients in the CCTG randomized LY.12 trial.Patients and methodsFrom August 2003 to November 2011, 619 patients with relapsed/refractory aggressive lymphoma were randomized to gemcitabine, dexamethasone, cisplatin (GDP) or dexamethasone, cytarabine, cisplatin (DHAP); 177 patients (28.6%) enrolled were >60.0 years of age (range, 60–74) and 442 were ≤60.0 years of age. After two to three cycles, responding patients proceeded to ASCT. Intention-to-treat analysis was used to compare response rate, transplantation rate, event-free survival (EFS) and overall survival (OS) between patients aged ≤60.0 and >60.0 years.ResultsPatient characteristics were comparable between the two cohorts, except a larger proportion of older patients had high International Prognostic Index risk scores. Response to salvage therapy was 48.6% for patients aged  >60.0 versus 43.0% for those aged  ≤60.0 (P = 0.21). Transplantation rates were also similar: 50.3% versus 49.8% (P = 0.87) for older versus younger patients. Rates of febrile neutropenia and adverse events requiring hospitalization were comparable for older and younger patients (30.5% versus 22.9% and 37.9% versus 32.1%, respectively). With a median follow-up of 53 months, there was no difference in 4-year OS (36% and 40% for patients aged >60.0 and ≤60.0 years, P = 0.42), or 4-year EFS (20% versus 28%, P = 0.43). Mortality from salvage therapy was 8/174 (4.60%) and 5/436 (1.15%), and 100-day mortality post-ASCT was 7/88 (8.06%) and 4/219 (1.85%).ConclusionThis subgroup analysis suggests that older patients derive similar benefit from salvage therapy and ASCT to younger patients, with acceptable IdentifierNCT00078949.
      PubDate: 2016-12-19
  • Vemurafenib in metastatic melanoma patients with brain metastases: an
           open-label, single-arm, phase 2, multicentre study
    • Authors: McArthur GA; Maio MM, Arance AA, et al.
      Abstract: BackgroundVemurafenib has shown activity in patients with BRAFV600 mutated melanoma with brain metastases (BM). This phase 2 study evaluated vemurafenib in patients with/without prior treatment for BM.MethodsPatients with BRAFV600 mutated melanoma with BM were enrolled into cohort 1 (previously untreated BM) and cohort 2 (previously treated BM) and received vemurafenib (960 mg BID) until disease progression (PD) or intolerance. Primary endpoint was best overall response rate (BORR) in the brain in cohort 1 that was evaluated using modified RECIST 1.1 criteria using lesions ≥0.5 cm to assess response.Results146 patients were treated (cohort 1 n = 90; cohort 2 n = 56), 62% of whom were male. Median (range) time since diagnosis of BM: 1.0 (0–9) month in cohort 1 and 4.2 (1–68) months in cohort 2. Median duration of treatment was 4.1 months (range 0.3–34.5) in cohort 1 and 4.1 months (range 0.2–27.6) in cohort 2. Intracranial BORR in cohort 1 by an independent review committee (IRC) was 18% (2 CRs, 14 PRs). Extracranial BORR by IRC was 33% in cohort 1 and 23% in cohort 2. Median PFS (brain only, investigator-assessed) was 3.7 months (range 0.03–33.4; IQR 1.9–5.6) in cohort 1 and 4.0 months (range 0.3–27.4; IQR 2.2–7.4) in cohort 2. Median OS was 8.9 months (range 0.6–34.5; IQR 4.9–17.0) in cohort 1 and 9.6 months (range 0.7–34.3; IQR 4.5–18.4) in cohort 2. Adverse events (AEs) were similar in type, grade and frequency to other studies of single-agent vemurafenib. Grade 3/4 AEs occurred in 59 (66%) patients in cohort 1 and 36 (64%) in cohort 2. Overall, 84% of patients died during the study (86% in cohort 1 and 80% in cohort 2), mainly due to disease progression.ConclusionsThe study demonstrates clinically meaningful response rates of melanoma BM to vemurafenib, which was well tolerated and without significant CNS toxicity.
      PubDate: 2016-12-19
  • Multiplex KRAS G12/G13 mutation testing of unamplified cell-free DNA from
           the plasma of patients with advanced cancers using droplet digital
           polymerase chain reaction
    • Authors: Janku FF; Huang HJ, Fujii TT, et al.
      Abstract: BackgroundCell-free DNA (cfDNA) from plasma offers easily obtainable material for KRAS mutation analysis. Novel, multiplex, and accurate diagnostic systems using small amounts of DNA are needed to further the use of plasma cfDNA testing in personalized therapy.Patients and methodsSamples of 16 ng of unamplified plasma cfDNA from 121 patients with diverse progressing advanced cancers were tested with a KRASG12/G13 multiplex assay to detect the seven most common mutations in the hotspot of exon 2 using droplet digital polymerase chain reaction (ddPCR). The results were retrospectively compared to mutation analysis of archival primary or metastatic tumor tissue obtained at different points of clinical care.ResultsEighty-eight patients (73%) had KRASG12/G13 mutations in archival tumor specimens collected on average 18.5 months before plasma analysis, and 78 patients (64%) had KRASG12/G13 mutations in plasma cfDNA samples. The two methods had initial overall agreement in 103 (85%) patients (kappa, 0.66; ddPCR sensitivity, 84%; ddPCR specificity, 88%). Of the 18 discordant cases, 12 (67%) were resolved by increasing the amount of cfDNA, using mutation-specific probes, or re-testing the tumor tissue, yielding overall agreement in 115 patients (95%; kappa 0.87; ddPCR sensitivity, 96%; ddPCR specificity, 94%). The presence of ≥ 6.2% of KRASG12/G13 cfDNA in the wild-type background was associated with shorter survival (P = 0.001).Conclusion(s)Multiplex detection of KRASG12/G13 mutations in a small amount of unamplified plasma cfDNA using ddPCR has good sensitivity and specificity and good concordance with conventional clinical mutation testing of archival specimens. A higher percentage of mutant KRASG12/G13 in cfDNA corresponded with shorter survival.
      PubDate: 2016-12-19
  • Resistance to anticancer immunity in cancer patients: potential strategies
           to reverse resistance
    • Authors: Bonavida BB; Chouaib SS.
      Abstract: In the 1990s, the application of immunotherapy approaches to target cancer cells resulted in significant clinical responses in patients with advanced malignancies who were refractory to conventional therapies. While early immunotherapeutics were focused on T cell-mediated cytotoxic activity, subsequent efforts were centered on targeted antibody-mediated anticancer therapy. The initial success with antibody therapy encouraged further studies and, consequently, there are now more than 25 FDA-approved antibodies directed against a range of targets. Although both T cell and antibody therapies continue to result in significant clinical responses with minimal toxicity, a significant subset of patients does not respond to immunotherapy and another subset develops resistance following an initial response. This review is focused on describing examples showing that cancer resistance to immunotherapies indeed occurs. In addition, it reviews the mechanisms being used to overcome the resistance to immunotherapies by targeting the tumor cell directly and/or the tumor microenvironment.
      PubDate: 2016-11-17
  • Estimating 12-week death probability in patients with refractory
           metastatic colorectal cancer: the Colon Life nomogram
    • Authors: Pietrantonio FF; Miceli RR, Rimassa LL, et al.
      Abstract: BackgroundRegorafenib and TAS-102 have recently demonstrated statistically significant survival gains in patients with refractory metastatic colorectal cancer (mCRC). Life expectancy ≥12 weeks was an inclusion criterion in registrative trials, and the identification of proper clinical selection tools for the daily use of these drugs in heavily pre-treated patients is needed to improve the cost-benefit ratio. We aimed at building a nomogram able to predict death probability within 12 weeks from the date of assessment of refractory mCRC.Patients and methodsFour hundred eleven refractory mCRC patients with ECOG performance status (PS) ≤2 receiving regorafenib, TAS-102 or other treatments were used as developing set. Putative prognostic variables were selected using a random forest model and included in a binary logistic model from which the nomogram was developed. The nomogram was externally validated and its performance was evaluated by examining calibration (how close predictions were to the actual outcome) and discriminative ability (Harrell C index) both on developing (internal validation) and validating (external validation) sets.ResultsFour variables were selected and included in the nomogram: PS (P 
      PubDate: 2016-11-17
  • Neoadjuvant chemotherapy (NACT) increases immune infiltration and
           programmed death-ligand 1 (PD-L1) expression in epithelial ovarian cancer
    • Authors: Mesnage SL; Auguste AA, Genestie CC, et al.
      Abstract: BackgroundLymphocytic infiltration at diagnosis is prognostic in EOC, however, the impact of NACT on tumour infiltrating lymphocytes (TILs) or PD-L1 expression remains poorly described.Patients and methodsPatients with EOC and sequential samples (pre-NACT, post-NACT or relapse) were retrospectively identified. TILs were evaluated on whole sections; stromal TILs (sTILs) scored as percentage of stromal area with high sTILs defined as ≥50%; intra-epithelial TILs (ieTILs) scored semi-quantitatively (0–3) with high ieTILs ≥2. A smaller number were available for PD-L1 evaluation, cut-off for positivity was ≥5% staining.ResultssTILs were detected in all tumours at diagnosis (range 2–90%, median 20%), with 22% (25/113) showing high sTILs. Among evaluable paired pre/post-NACT samples (N = 83), an overall increase in median sTILs from 20% to 30% was seen following NACT (P = 0.0005); individually the impact of NACT varied with sTILs increasing in 51% (42/83), decreasing in 25%, and stable in 24%. Post-NACT sTILs were predictive of platinum-free interval (PFI), patients with PFI ≥6 months had significantly higher post-NACT sTILs (sTILs 28% versus 18% for PFI 
      PubDate: 2016-11-17
  • Should rectal cancer located 10–15 cm from the anal verge be
           defined as colon cancer
    • Authors: Swets MM; Breugom AJ, Gelderblom HH, et al.
      Abstract: Because colon and rectal tumours biologically differ, a clear separation of colon and rectal cancer for scientific research and treatment strategies is needed. However, the definition of the rectum is inconsistent across countries regarding location of the peritoneal reflection and distance from the anal verge. A recently published meta-analysis on individual patient data demonstrated that adjuvant chemotherapy after preoperative (chemo)radiotherapy and TME surgery did not improve overall survival, disease-free survival (DFS) and distant recurrence rates in patients with pathological stage II-III rectal cancer [1, 2]. In the meta-analysis, it was suggested that a subgroup of patients with rectal tumours 10–15 cm from the anal verge might benefit from adjuvant chemotherapy in terms of DFS and distant recurrences [2]. Consequently, it could be debated whether tumours located 10–15 cm from the anal verge should be defined as colon tumours rather than rectal tumours, since patients with stage III and high-risk stage II colon cancer do benefit from adjuvant chemotherapy [3]. Further investigation for patients with rectal tumours 10-15cm from the anal verge is essential, although a randomized trial is not feasible. Therefore, we report on the results of the PROCTOR/SCRIPT trial after a median follow-up of 5.5 years, with a focus on rectal tumours 10–15 cm from the anal verge. In this study, a multicenter randomized phase III trial, patients were randomly assigned to adjuvant chemotherapy or observation in patients with (y)pTNM stage II–III rectal cancer treated with preoperative (chemo)radiotherapy and TME surgery. Study design, patient characteristics, definitions of endpoints and exclusion criteria were described elsewhere [1]. In agreement with the previous reported results with a median follow-up of 5 years, no beneficial effect of adjuvant treatment was observed in the total study cohort (N = 437). However, a significant benefit in DFS (HR 0.59, 95% CI: 0.36-0.98, P = 0.04) was observed in patients randomized to adjuvant chemotherapy for (y)pTNM stage II–III rectal cancer located 10–15 cm of the anal verge treated with preoperative (chemo)radiotherapy and TME surgery (Figure 1). This beneficial effect has not been observed in patients with tumours located 
      PubDate: 2016-11-10
  • Dual HER2-blockade with pertuzumab and trastuzumab in HER2-positive early
           breast cancer: a subanalysis of data from the randomized phase III
           GeparSepto trial
    • Authors: Loibl SS; Jackisch CC, Schneeweiss AA, et al.
      Abstract: BackgroundThe neoadjuvant phase III GeparSepto study showed that substituting nab-paclitaxel for standard solvent-based paclitaxel significantly improved the pathologic complete response (pCR) rate achieved with a sequential neoadjuvant chemotherapy regimen of paclitaxel, epirubicin, and cyclophosphamide for high-risk primary breast cancer. Recent trials demonstrated that in HER2+ breast cancer pCR can be increased by using pertuzumab in addition to trastuzumab and chemotherapy. The present analysis focuses on efficacy and safety data from the subset of patients with HER2+ tumors from the GeparSepto trial (n = 396) in comparison to the HER2- cohort.Patients and methodsPatients with histologically confirmed breast cancer (n = 1206) received four cycles of weekly paclitaxel [either solvent-based (Pac) or nab-paclitaxel (nab-Pac), according to randomization] followed by 4 cycles of epirubicin 90 mg/m2 plus cyclophosphamide 600 mg/m2 q3w, with concurrent trastuzumab and pertuzumab q3w for those with HER2+ tumors. The primary endpoint was pCR defined as ypT0 ypN0.ResultsHigher rates of pCR were achieved in HER2+ than in HER2- tumors (57.8% versus 22.0%, P 
      PubDate: 2016-11-10
  • Industry corner: perspectives and controversies - The challenges of
           patient access to new medicines
    • Authors: Gann CN; Morsli NN, Kaiser RR.
      Abstract: In this Industry Corner article, we describe the experience with nintedanib in combination with docetaxel, which was first approved in the European Union in 2014 for the treatment of patients with non-small cell lung cancer (NSCLC) of adenocarcinoma histology after first-line chemotherapy. In therapeutic indications such as NSCLC, where there is a clear unmet medical need, delayed patient access to new therapies following regulatory approval is a significant challenge. Although nintedanib in combination with docetaxel has satisfied the obligation of meeting a medical need, as noted by successfully receiving European Medicines Agency approval and passing several HTA evaluations, including the National Institute for Health and Care Excellence, and by demand for patient access to nintedanib via the CUP/NPP, patients across Europe are not gaining equal access to this new therapy due to varying reimbursement procedures.
      PubDate: 2016-11-09
  • Multimodality treatment for esophageal adenocarcinoma: multi-center
           propensity-score matched study
    • Authors: Markar SR; Noordman BJ, Mackenzie HH, et al.
      Abstract: BackgroundThe primary aim of this study was to compare survival from neoadjuvant chemoradiotherapy plus surgery (NCRS) versus neoadjuvant chemotherapy plus surgery (NCS) for the treatment of esophageal or junctional adenocarcinoma. The secondary aims were to compare pathological effects, short-term mortality and morbidity, and to evaluate the effect of lymph node harvest upon survival in both treatment groups.MethodsData were collected from 10 European centers from 2001 to 2012. Six hundred and eight patients with stage II or III oesophageal or oesophago-gastric junctional adenocarcinoma were included; 301 in the NCRS group and 307 in the NCS group. Propensity score matching and Cox regression analyses were used to compensate for differences in baseline characteristics.ResultsNCRS resulted in significant pathological benefits with more ypT0 (26.7% versus 5%; P 
      PubDate: 2016-10-25
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