Seminars in Oncology RSS feed: Current Issue. Seminars in Oncology brings you current, authoritative, and practical reviews of developments in the diagnosis and management of patients with cancer. Each issue examines a single topic of clinical importance. You're guided through each cancer's biology, epidemiology, and pathophysiology, its clinical presentation and therapeutic options, and appropriate follow-up measures. This journal makes an excellent addition to every oncology practice. 2011 Topics , Volume 38 Molecular and Translational Imaging Carolyn Meltzer and Hyunsuk Shim Personalized Cancer Treatment Richard L. Schilsky MicroRNAs Ramiro Garzon and Carlo M. Croce Advanced Cutaneous Malignancies Vernon Sondak Myelodysplastic Syndrome Guillermo Garcia-Manero Colorectal Cancer Neal Meropol http://www.seminoncol.org/?rss=yesElsevier Inc.en © 2012 Published by Elsevier Inc. All rights reserved. Seminars in Oncology0093-7754391February 2012 © 2012 Published by Elsevier Inc. All rights reserved. healthpermissions@elsevier.comhttp://www.seminoncol.org/article/PIIS0093775411003046/abstract?rss=yesCover10.1053/S0093-7754(11)00304-6Seminars in Oncology 39, 1 (2012)2012-02-01Seminars in Oncology2012-02-01391S0093-7754(11)X0017-9OFCOFChttp://www.seminoncol.org/article/PIIS009377541100306X/abstract?rss=yesMasthead10.1053/S0093-7754(11)00306-XSeminars in Oncology 39, 1 (2012)2012-02-01Seminars in Oncology2012-02-01391S0093-7754(11)X0017-9IFCIFChttp://www.seminoncol.org/article/PIIS0093775411002909/abstract?rss=yes At times we encounter clinical problems for which there are no directly applicable evidence-based solutions, but we are compelled by circumstances to act. When doing so we rely on related evidence, general principles of best medical practice, and our experience. Each ”Current Clinical Practice” feature article in Seminars in Oncology describes such a challenging presentation and offers treatment approaches from selected specialists. We invite readers' comments and questions, which, with your approval, will be published in subsequent issues of the Journal. It is hoped that sharing our views and experiences will better inform our management decisions when we next encounter similar challenging patients. Please send your comments on the articles, your challenging cases, and your treatment successes to me at Dr.gjmorris@gmail.com. I look forward to a lively discussion.A Wealth of New Options: A Case Presentation of the Management of Castration-Recurrent Prostate CancerDouglas F. Beach, Robert A. Somer, Jean Hoffman-Censits, Jianqing Lin, Yu-Ning Wong, Elizabeth Plimeck, Gary Hudes, David Vaughn, Guy T. Bernstein, Gloria J. Morris10.1053/j.seminoncol.2011.11.001Seminars in Oncology 39, 1 (2012)2012-02-01Seminars in Oncology2012-02-01391S0093-7754(11)X0017-9Current Clinical Practice18http://www.seminoncol.org/article/PIIS0093775411003034/abstract?rss=yesIn addition to activating oncogenic mutations, deletions of chromosomal material, hypomorphic/inactivating mutations and aberrant promoter silencing of tumor-suppressor genes (TSG) have been recognized as important pathogenic mechanisms in myeloid malignancies, including acute myelogeneous leukemia (AML), myelodysplastic syndrome (MDS), and myeloproliferative neoplasms (MPN), as well as overlap entities between these diseases (MPN/MDS). Recently, tremendous progress has been made in the molecular investigations of the pathogenesis of these diseases, largely due to broad application of high-throughput molecular technologies, including single-nucleotide polymorphism arrays (SNP-A), comparative genomic hybridization arrays (CGH-A), and especially whole-genome next-generation sequencing (NGS).Introduction: Molecular Pathogenesis of Hematologic MalignanciesJaroslaw P. Maciejewski, Torsten Haferlach10.1053/j.seminoncol.2011.12.002Seminars in Oncology 39, 1 (2012)2012-02-01Seminars in Oncology2012-02-01391S0093-7754(11)X0017-9Jaroslaw P. Maciejewski, MD, PhD, and Torsten Haferlach, MD, Guest Editors912http://www.seminoncol.org/article/PIIS0093775411002995/abstract?rss=yes Single-nucleotide polymorphism array (SNP-A) karyotyping is a new technology that has enabled genome-wide detection of genetic lesions in human cancers, including hematopoietic neoplasms. Taking advantage of very large numbers of allele-specific probes synthesized on microarrays at high density, copy number alterations as well as allelic imbalances can be sensitively detected in a genome-wide manner at unprecedented resolutions. Most importantly, SNP-A karyotyping represents the only platform currently available for genome-scale detection of copy neutral loss of heterozygosity (CN-LOH) or uniparental disomy (UPD), which is widely observed in cancer genomes. Although not applicable to detection of balanced translocations, which are commonly found in hematopoietic malignancies, SNP-A karyotyping technology complements and even outperforms conventional metaphase karyotyping, potentially allowing for more accurate genetic diagnosis of hematopoietic neoplasms in clinical practice. Here, we review the current status of SNP-A karyotyping and its application to hematopoietic neoplasms. Single-Nucleotide Polymorphism Array Karyotyping in Clinical Practice: Where, When, and How?Aiko Sato-Otsubo, Masashi Sanada, Seishi Ogawa10.1053/j.seminoncol.2011.11.010Seminars in Oncology 39, 1 (2012)2012-02-01Seminars in Oncology2012-02-01391S0093-7754(11)X0017-9Jaroslaw P. Maciejewski, MD, PhD, and Torsten Haferlach, MD, Guest Editors1325http://www.seminoncol.org/article/PIIS0093775411002971/abstract?rss=yes Next-generation sequencing (NGS) platforms have evolved to provide an accurate and comprehensive means for the detection of molecular mutations in heterogeneous tumor specimens. Here, we review potential applications of this novel laboratory technology. In particular, we focus on the utility of amplicon deep-sequencing assays in characterizing myeloid neoplasms where the number of molecular markers applied for disease classification, patient stratification, and individualized monitoring of minimal residual disease is constantly increasing. We highlight the potential of this technology by discussing data from a recent study on chronic myelomonocytic leukemia (CMML). Although many facets of this assay need to be taken into account, eg, the preparation of sequencing libraries with molecular barcodes, specific experimental design options when considering sequencing coverage to calculate diagnostic sensitivity, or the use of suitable software and data processing solutions to obtain accurate results, amplicon deep-sequencing has already demonstrated a promising technical performance that warrants the further development towards a routine application of this technology in diagnostic laboratories so that an impact on clinical practice can be achieved. Integration of Next-Generation Sequencing Into Clinical Practice: Are We There Yet?Alexander Kohlmann, Vera Grossmann, Torsten Haferlach10.1053/j.seminoncol.2011.11.008Seminars in Oncology 39, 1 (2012)2012-02-01Seminars in Oncology2012-02-01391S0093-7754(11)X0017-9Jaroslaw P. Maciejewski, MD, PhD, and Torsten Haferlach, MD, Guest Editors2636http://www.seminoncol.org/article/PIIS0093775411002946/abstract?rss=yes Conventional cytogenetic studies have shown that the clinical and biological diversity of acute myeloid leukemia (AML) can be attributed, in part, to distinct chromosome aberrations, several of which are now routinely used for diagnosis, risk stratification, and outcome prediction. Although chromosome banding analysis has recently been complemented by the identification of point mutations in a growing number of hematopoiesis-associated genes, current genetic categories do not fully reflect the heterogeneity of AML. To close the gap between standard karyotyping and molecular analyses at the single–base-pair level and gain additional insight into the genetics underlying myeloid leukemogenesis, AML is increasingly being studied using genome-wide, microarray-based cytogenetic methods. These investigations have revealed that AML genomes commonly harbor acquired submicroscopic copy number alterations, even though the prevalence of most of these cryptic lesions appears to be low, as well as regions of uniparental disomy that are often associated with homozygosity of functionally relevant gene mutations. Current efforts are focusing on the application of this expanded knowledge to improve the classification of AML, develop new tools for prognostication and prediction of response to therapy, and accelerate the discovery of genes that are likely to contribute to AML pathogenesis. Array-Based Cytogenetic Approaches in Acute Myeloid Leukemia: Clinical Impact and Biological InsightsLars Bullinger, Stefan Fröhling10.1053/j.seminoncol.2011.11.005Seminars in Oncology 39, 1 (2012)2012-02-01Seminars in Oncology2012-02-01391S0093-7754(11)X0017-9Jaroslaw P. Maciejewski, MD, PhD, and Torsten Haferlach, MD, Guest Editors3746http://www.seminoncol.org/article/PIIS0093775411002983/abstract?rss=yes Measurement of submicroscopic (minimal) levels of residual disease (MRD) can be used to monitor treatment response much more precisely than morphological screening of bone marrow slides. Several studies have demonstrated that MRD assessment in childhood and adult acute lymphoblastic leukemia (ALL) significantly correlates with clinical outcome. MRD detection is particularly useful for evaluation of early treatment response, but also to monitor disease before and after stem cell transplantation, for early assessment of an impending relapse and in the setting of salvage treatment. Currently, three highly specific and sensitive methodologies for MRD detection are available, namely, real-time quantitative polymerase chain reaction (RQ-PCR) of fusion gene transcripts or breakpoints, RQ-PCR–based detection of clonal immunoglobulin and T-cell receptor (TCR) gene rearrangements, and multiparameter flow cytometric immunophenotyping. Assessment of MRD has gained a prominent position in many ALL treatment studies as a tool for tailoring therapy. Only the results of these studies will answer the question of whether MRD-based treatment intervention is associated with improved outcome. Acute Lymphoblastic Leukemia: Monitoring Minimal Residual Disease as a Therapeutic PrincipleMonika Brüggemann, Nicola Gökbuget, Michael Kneba10.1053/j.seminoncol.2011.11.009Seminars in Oncology 39, 1 (2012)2012-02-01Seminars in Oncology2012-02-01391S0093-7754(11)X0017-9Jaroslaw P. Maciejewski, MD, PhD, and Torsten Haferlach, MD, Guest Editors4757http://www.seminoncol.org/article/PIIS0093775411002910/abstract?rss=yes The introduction of the tyrosine kinase inhibitors (TKIs) imatinib, dasatinib, and nilotinib has dramatically improved the treatment of chronic myeloid leukemia (CML). However, a minority of CML patients in chronic phase (CP) and a substantial proportion of patients in advanced phase are either initially refractory to TKIs or eventually develop resistance. Rates of resistance and relapse directly correlate with disease progression. The most frequently identified mechanism of acquired TKI resistance is BCR-ABL1 kinase domain (KD) mutations that impair TKI binding by disrupting the drug contact sites or causing conformational changes that make the contact sites inaccessible. The underlying mechanisms of disease progression are heterogeneous and only poorly understood. So far the most frequent and best characterized include genomic instability, loss of tumor-suppressor functions, and differentiation arrest. Clinical data indicate that both development of a BCR-ABL1 KD mutation during TKI treatment and/or disease progression are associated with a poorer outcome. Thus, therapeutic strategies are needed for the treatment or prevention of resistance and disease progression. They include, for example, TKI dose escalation, treatment interruption to stop selection of resistant cells, and allogeneic stem cell transplantation in eligible patients, as well as the use of novel TKIs with activity against resistant mutations and/or inhibition of alternative pathways. Chronic Myeloid Leukemia: Clinical Impact of BCR-ABL1 Mutations and Other Lesions Associated With Disease ProgressionThomas Ernst, Andreas Hochhaus10.1053/j.seminoncol.2011.11.002Seminars in Oncology 39, 1 (2012)2012-02-01Seminars in Oncology2012-02-01391S0093-7754(11)X0017-9Jaroslaw P. Maciejewski, MD, PhD, and Torsten Haferlach, MD, Guest Editors5866http://www.seminoncol.org/article/PIIS0093775411002934/abstract?rss=yes Chronic myelomonocytic leukemia (CMML) and atypical chronic myeloid leukemia (aCML) are distinct, yet related, entities of myelodysplastic/myeloproliferative neoplasms (MDS/MPN) characterized by morphologic dysplasia with accumulation of monocytes or neutrophils, respectively. Our understanding of the molecular pathogenesis of CMML and aCML has advanced, mainly due to the application of novel technologies such as array-based karyotyping and next-generation sequencing. In addition to previously known recurrent aberrations, somatic uniparental disomy affecting chromosomes 3, 4, 7, and 11 frequently occurs in CMML. Novel somatic mutations of genes, including those associated with proliferation signaling (CBL, RAS, RUNX1, JAK2 (V617F)) and with modification of epigenetic status (TET2, ASXL1, UTX, EZH2) have been found. Various combinations of mutations suggest a multistep pathogenesis and may account for clinical heterogeneity. Most recently, several spliceosome-associated-gene mutations were reported and SRSF2 mutations are frequently detected in CMML. The prognostic and diagnostic significance of these molecular lesions, in particular their value as biomarkers of response or resistance to specific therapies, while uncertain now is likely to be clarified as large systematic studies come to completion. Chronic Myelomonocytic Leukemia and Atypical Chronic Myeloid Leukemia: Novel Pathogenetic LesionsHideki Muramatsu, Hideki Makishima, Jaroslaw P. Maciejewski10.1053/j.seminoncol.2011.11.004Seminars in Oncology 39, 1 (2012)2012-02-01Seminars in Oncology2012-02-01391S0093-7754(11)X0017-9Jaroslaw P. Maciejewski, MD, PhD, and Torsten Haferlach, MD, Guest Editors6773http://www.seminoncol.org/article/PIIS009377541100296X/abstract?rss=yes Chronic lymphocytic leukemia (CLL) is an indolent B-cell leukemia. While many patients may not require therapy, some patients will suffer a progressive course and die of their disease. This clinical heterogeneity is reflected in the molecular genetic heterogeneity that is becoming apparent through studies of immunoglobulin heavy chain gene mutational status, chromosomal numerical abnormalities, microRNA abnormalities, and genetic abnormalities identified by whole genome sequencing. Indeed, many of these studies are becoming routine in the assessment of patients with CLL or being incorporated into clinical trials to further stratify patients for appropriate therapies. Here, we will review the morphologic, immunophenotypic, and molecular genetic features of CLL and touch upon the concept of monoclonal B-cell lymphocytosis. Pathologic and Molecular Genetic Features of Chronic Lymphocytic LeukemiaEric D. Hsi10.1053/j.seminoncol.2011.11.007Seminars in Oncology 39, 1 (2012)2012-02-01Seminars in Oncology2012-02-01391S0093-7754(11)X0017-9Jaroslaw P. Maciejewski, MD, PhD, and Torsten Haferlach, MD, Guest Editors7479http://www.seminoncol.org/article/PIIS0093775411002958/abstract?rss=yes Until recently, myeloid neoplasms have been attributed to genomic and genetic instability leading to clonal outgrowth. However, it is now increasingly evident that epigenetic abnormalities also play a fundamental role in development of these malignancies. A growing body of evidence has underlined the involvement of epigenetic machinery in the malignant transformation of hematopoietic cells. Epigenetic dysfunction can lead to genetic alterations, including microsatellite instability, nucleotide changes, and chromosomal alterations. Conversely, putative epigenetic instability may be related to mutations of genes involved in epigenetic regulation. Therefore, this review focuses on epigenetic processes, including DNA methylation, post-translational histone modifications, and RNA interference via small noncoding RNAs, which play a critical role in controlling gene expression and are targets of dysregulation in many hematologic malignancies. Further, recent literature identified somatic mutations in several epigenetic regulators with a high frequency in myeloid malignancies. Mutational Determinants of Epigenetic Instablity in Myeloid MalignanciesAnna M. Jankowska, Hadrian Szpurka10.1053/j.seminoncol.2011.11.006Seminars in Oncology 39, 1 (2012)2012-02-01Seminars in Oncology2012-02-01391S0093-7754(11)X0017-9Jaroslaw P. Maciejewski, MD, PhD, and Torsten Haferlach, MD, Guest Editors8096http://www.seminoncol.org/article/PIIS0093775411003009/abstract?rss=yes Cytotoxic chemotherapy for acute myeloid leukemia (AML) usually produces only temporary remissions, at the cost of significant toxicity and risk for death. One fundamental reason for treatment failure is that it is designed to activate apoptosis genes (eg, TP53) that may be unavailable because of mutation or deletion. Unlike deletion of apoptosis genes, genes that mediate cell cycle exit by differentiation are present in myelodysplastic syndrome (MDS) and AML cells but are epigenetically repressed: MDS/AML cells express high levels of key lineage-specifying transcription factors. Mutations in these transcription factors (eg, CEBPA) or their cofactors (eg., RUNX1) affect transactivation function and produce epigenetic repression of late-differentiation genes that antagonize MYC. Importantly, this aberrant epigenetic repression can be redressed clinically by depleting DNA methyltransferase 1 (DNMT1, a central component of the epigenetic network that mediates transcription repression) using the deoxycytidine analogue decitabine at non-cytotoxic concentrations. The DNMT1 depletion is sufficient to trigger upregulation of late-differentiation genes and irreversible cell cycle exit by p53-independent differentiation mechanisms. Fortuitously, the same treatment maintains or increases self-renewal of normal hematopoietic stem cells, which do not express high levels of lineage-specifying transcription factors. The biological rationale for this approach to therapy appears to apply to cancers other than MDS/AML also. Decitabine or 5-azacytidine dose and schedule can be rationalized to emphasize this mechanism of action, as an alternative or complement to conventional apoptosis-based oncotherapy. p53-Independent, Normal Stem Cell Sparing Epigenetic Differentiation Therapy for Myeloid and Other MalignanciesYogen Saunthararajah, Pierre Triozzi, Brian Rini, Arun Singh, Tomas Radivoyevitch, Mikkael Sekeres, Anjali Advani, Ramon Tiu, Frederic Reu, Matt Kalaycio, Ed Copelan, Eric Hsi, Alan Lichtin, Brian Bolwell10.1053/j.seminoncol.2011.11.011Seminars in Oncology 39, 1 (2012)2012-02-01Seminars in Oncology2012-02-01391S0093-7754(11)X0017-9Jaroslaw P. Maciejewski, MD, PhD, and Torsten Haferlach, MD, Guest Editors97108http://www.seminoncol.org/article/PIIS0093775411002922/abstract?rss=yes Aberrant DNA methylation is frequent in the myeloid malignancies, particularly myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). Promoter CpG methylation is correlated with silencing of tumor-suppressor genes (TSGs) in specific pathways that are also targets of mutation or other mechanisms of inactivation, and is thought to contribute to disease progression and poor prognosis. Epigenetic contributions to myeloid pathogenesis are more complex. Examples include TSG inactivation and oncogenic activation associated with formation of altered chromatin separate from CpG methylation. Epigenetic dysregulation occurs at multiple disease stages and at non-CpG island genomic sites, and also includes genomic hypomethylation and small RNA mechanisms of epigenetic regulation. Identification of recurrent mutations in potential epigenetic regulators, including TET2, IDH1, IDH2, DNMT3A, UTX, and ASXL1, were recently described. Accordingly, therapeutics directed towards epigenetic mechanisms including methylation inhibitors and histone deacetylase (HDAC) inhibitors have had some clinical success when applied to MDS and AML. However, identification of the underlying mechanisms associated with clinical responses and drug resistance remain enigmatic. Remarkably, in spite of significant molecular and translational progress, there are currently no epigenetic biomarkers in widespread clinical use. In this review, we explore the potential applications of epigenetic biomarker discovery, including epigenetic profiling for myeloid malignancy pathogenesis understanding, diagnostic classification, and development of effective treatment paradigms for these generally considered poor prognosis disorders. Clinical Applications of Epigenetic Markers and Epigenetic Profiling in Myeloid MalignanciesMichael A. McDevitt10.1053/j.seminoncol.2011.11.003Seminars in Oncology 39, 1 (2012)2012-02-01Seminars in Oncology2012-02-01391S0093-7754(11)X0017-9Jaroslaw P. Maciejewski, MD, PhD, and Torsten Haferlach, MD, Guest Editors109122http://www.seminoncol.org/article/PIIS0093775411003022/abstract?rss=yesIn the Current Clinical Practice column, “Variants of Uncertain Significance in Breast Cancer–Related Genes: Real-World Implications for a Clinical Conundrum. Part One: Clinical Genetics Recommendations,” Seminars in Oncology, August 2011, 38(4):469–80, the name of the second author should be Deborah J. MacDonald.Erratum10.1053/j.seminoncol.2011.12.001Seminars in Oncology 39, 1 (2012)2012-02-01Seminars in Oncology2012-02-01391S0093-7754(11)X0017-9123123http://www.seminoncol.org/article/PIIS0093775411003071/abstract?rss=yesEditorial Board10.1053/S0093-7754(11)00307-1Seminars in Oncology 39, 1 (2012)2012-02-01Seminars in Oncology2012-02-01391S0093-7754(11)X0017-9FrontmatterA1A1http://www.seminoncol.org/article/PIIS0093775411003083/abstract?rss=yesContents10.1053/S0093-7754(11)00308-3Seminars in Oncology 39, 1 (2012)2012-02-01Seminars in Oncology2012-02-01391S0093-7754(11)X0017-9FrontmatterA3A4http://www.seminoncol.org/article/PIIS0093775411003095/abstract?rss=yesFuture and Previous Issues10.1053/S0093-7754(11)00309-5Seminars in Oncology 39, 1 (2012)2012-02-01Seminars in Oncology2012-02-01391S0093-7754(11)X0017-9FrontmatterA5A5