bluuebunny/crossref_metadata_2025 huggingface dataset:
PRE-REPAIR DIAGNOSIS OF THE FINGER METAL OF THE DRAW CHAIN BY ULTRASOUND
Authors: Berezin E. K. , Rodushkin V. M.
Published: February 2020

The work presents a technique of diagnostics of fingers of a draw chain with the help of ultrasound, based on control of metal damage. The procedure of detection of fingers with maximum damaged metal is described. It is proposed to introduce in the practice of pre-repair diagnostics a non-burdensome procedure of sound attenuation control.
Mechanisms of Resistance to Targeted Therapies in Acute Myeloid Leukemia and Chronic Myeloid Leukemia
Authors: Smith Catherine C. , Shah Neil P.
Published: February 2020

Overview:

Small molecule kinase inhibitors of BCR-ABL in chronic myeloid leukemia (CML) and of FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) in acute myeloid leukemia (AML) have been successful at achieving remissions in these diseases as monotherapy, but these leukemias do not initially respond in a subset of patients (primary resistance) and they progress in an additional group of patients after an initial response (secondary resistance). Resistance to these agents can be divided into mechanisms that allow reactivation kinase activity and those that bypass reliance on oncogenic signaling mediated by the target kinase. Elucidation of clinical resistance mechanisms to targeted therapies for patients can provide important insights into disease pathogenesis and signaling.
Targeting the Insulin-Like Growth Factor (IGF) System Is Not as Simple as Just Targeting the Type 1 IGF Receptor
Authors: Scotlandi Katia , Belfiore Antonino
Published: February 2020

Overview:

Increased signaling of the insulin-like growth factor (IGF) system via alterations in expression levels of its components has been demonstrated in various tumor types. Numerous experimental studies have supported the involvement of the IGF system signaling axis in tumor initiation and progression. These studies, combined with data that link alterations in the levels of circulating IGFs with cancer risk and prognosis, have focused on the IGF-1 receptor (IGF-1R) as a therapeutic target for patients with cancer. As a consequence, most therapeutic strategies have been designed to specifically inhibit IGF-1R but have for the most part ignored the insulin receptor (IR), based on concerns that targeting IR would lead to unacceptable toxicity both because of its role in physiologic metabolism and because we frequently try to oversimplify biologic complexity whenever we are urged to find practical, friendly solutions for clinical practice. Although this is an understandable and necessary starting point in the complex and long-lasting processes that leads to translational biology, the crude reality of the results obtained from phase I and II studies suggest a need for researchers to be humble and go back to the drawing board. Cancer research has substantially neglected the role of IR, and it remains unclear whether and to what extent avoiding the inhibition of IR has compromised the efficacy of anti–IGF-1R therapy. Clarifying its role might also help us take advantage of older drugs that could offer new perspectives in cancer care.
Chemoprevention for Breast Cancer: Overcoming Barriers to Treatment
Authors: Brewster Abenaa M. , Davidson Nancy E. , McCaskill-Stevens Worta
Published: February 2020

Overview:

Evidence from placebo-controlled, randomized clinical trials supports the use of chemoprevention in women at high risk for developing breast cancer, and two agents—tamoxifen and raloxifene—are U.S. Food and Drug Administration (FDA)-approved for the indication. Despite clinical guidelines that recommend physicians counsel high-risk women about the use of chemoprevention and the estimated 2.4 million women in the United States who meet eligibility criteria for net benefit, the uptake of breast cancer chemoprevention has been exceedingly low. Assessments of the risks and benefits of chemoprevention are aided by the availability of models that can be used to estimate of the risk–benefit ratio. However, many physicians remain unaware of these resources to determine patient eligibility for chemoprevention and lack the time to provide informed counseling to their patients. The barriers for patients' acceptance of chemoprevention treatment include fear of side effects and the perception that chemoprevention will not substantially lower their risk of developing breast cancer. Despite these challenges, there are substantial opportunities to increase the utilization of chemoprevention. These strategies include education, dissemination of user-friendly risk–benefit models, and the support of research efforts focused on identifying biomarkers that can more accurately select women most likely to develop breast cancer and predict responsiveness of treatment.
Communication and Decision Support for Children with Advanced Cancer and Their Families
Authors: Mack Jennifer W. , Feudtner Chris , Hinds Pamela S.
Published: February 2020

Overview:

Clinician communication related to treatment decision making is a fundamentally important health care intervention and is often reported by parents of seriously ill children to be the most valued of clinician skills. Since different children and families have different communication styles and expectations, and since these may change over the course of the illness experience, one of the early and recurring tasks is to clarify and work with these diverse styles and expectations. Adopting a stance of compassionate desire to know more about patients and families, in addition to imparting information, is vital, and can be facilitated by following a general strategy of “ask, tell, ask.” In addition to the exchange of information, communication between clinician and patient and family also involves the signaling and exchange of emotions, in which the pace, verbal inflection, and body language of the conversation are fundamental. Discussions about prognosis and goals of care, while needing to be handled in a gentle manner, should start early in the illness experience and be revised whenever there is a relapse or major complication. Children often want to participate in these conversations to a degree of their own choosing, which they themselves can clarify. Effective and empathetic clinician communication can greatly facilitate decision making and care for children with advanced cancer and their families, and provide a substantial source of comfort.
Development and Refinement of Augmented Treatment Regimens for Pediatric High-Risk Acute Lymphoblastic Leukemia
Authors: Hunger Stephen P.
Published: February 2020

Overview:

The 5-year survival rate for children and adolescents with acute lymphoblastic leukemia (ALL) is now at least 90%. However, clinical features (age and initial white blood cell count [WBC]), early treatment response, and the presence/absence of specific sentinel genomic lesions can identify subsets of high-risk (HR) ALL patients with a much higher risk of treatment failure. Chemotherapy regimens used to treat HR ALL have been refined over the past 3 decades through randomized clinical trials conducted by the Children's Oncology Group (COG) in North America and the Berlin-Frankfurt-Muenster (BFM) group in Western Europe. Contemporary COG HR ALL treatment regimens were developed from the BFM-76 regimen, with subsequent changes that led to development and refinement of a so-called augmented BFM (ABFM) regimen used today. Although contemporary COG and BFM treatment regimens are not identical, there are many more similarities than differences. With improvements in survival, it has become clear that although the outcome of some patients with HR ALL can be improved by optimizing use of standard cytotoxic chemotherapy agents, this approach has had only limited success for other patient subsets. In contrast, introduction of the tyrosine kinase inhibitor imatinib has led to dramatic outcome improvements for children and adolescents with Philadelphia chromosome–positive ALL. Genomic studies are identifying new sentinel genomic lesions that can serve as potential therapeutic targets, which will likely lead to the testing of novel and/or targeted therapies in more children with HR ALL. Such studies will require increased collaboration between Western European and North American cooperative groups.
New Options and New Questions: How to Select and Sequence Therapies for Patients with Metastatic Melanoma
Authors: Flaherty Keith T. , Sosman Jeff A. , Atkins Michael B.
Published: February 2020

Overview:

Recent advances in the understanding of the melanoma biology and tumor immunology have yielded new treatment strategies for patients with advanced melanoma. Within the past year, the selective BRAF inhibitor vemurafenib and immune checkpoint inhibitor ipilimumab have been added to the treatment armamentarium. In addition, other molecularly targeted agents and immunotherapies are showing considerable promise. The availability of multiple, effective treatment options for patients with melanoma, although long sought, has complicated treatment decisions. This article will review the advances in our understanding of melanoma biology and tumor immunology, the current status of immunotherapy, the advances in molecularly targeted therapy for patients with BRAF mutant melanomas, the possible approaches to patients with BRAF wild-type (WT) tumors, and the current considerations for treatment selection of individual patients.
Screening for Prostate Cancer with Prostate-Specific Antigen: What's the Evidence?
Authors: Marcus Pamela M. , Kramer Barnett S.
Published: February 2020

Overview:

In October 2011, the U.S. Preventive Services Task Force (USPSTF, or “Task Force”) released draft recommendations on prostate cancer screening with prostate-specific antigen (PSA), concluding that “PSA-based screening results in small or no reduction in prostate cancer–specific mortality and is associated with harms related to subsequent evaluation and treatments, some of which may be unnecessary.” This statement was accompanied by a grade “D” recommendation, which indicates that in the Task Force's judgment there “is moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits.” The Task Force, an independent panel of nonfederal (U.S.) experts in prevention and evidence-based medicine, conducts systematic evidence reviews of preventive health care services and makes recommendations about preventive services in primary care. Task Force recommendations do not set U.S. federal policy but can and do influence reimbursement and clinical practice. In this article, we will present evidence the Task Force considered when making its decision, including two highly influential randomized controlled trials (RCTs) of prostate cancer screening, the European Randomized Study of Prostate Cancer (ERSPC) and the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO). The two trials arrived at different conclusions about the efficacy of routine prostate cancer screening, but similar conclusions about the accompaniment of clinically relevant harms with prostate cancer screening, including overdiagnosis (screen detection of cancers that never would be diagnosed in the absence of screening). We also will present other available evidence on benefits and harms of PSA-based screening and consider that evidence and the findings of ERSPC and PLCO in conjunction with one another.
Onclogists' Difficulties in Facing and Disclosing Medical Errors: Suggestions for the Clinic
Authors: Surbone Antonella
Published: February 2020

Overview:

Along with improved safety measures and changes in the culture of medicine, communication is key to reducing the effect of medical errors and to easing the medical, psychologic, and existential burdens they impose on all parties. Disclosure demonstrates respect for patients' autonomy and promotes patient's involvement in informed decision making about ways to correct or alleviate the effects of the error. It also enhances oncologists' integrity and helps restore trust in the patient-doctor relationship. Because of the complexity of cancer treatments and the uncertainty regarding outcomes in oncology, oncologists may rationalize nondisclosure as a way to avoid adding to the physical and existential suffering of their patients. Although there is broad agreement among professional and regulatory bodies, as well as medical ethicists, that physicians should disclose errors to patients—and physicians largely support disclosure of error to patients—studies show discrepancy between physicians' responses to hypothetical clinical scenarios of truth telling about medical errors and actual practices of withholding or tempering the truth. Among common reasons for avoiding disclosure are risk of malpractice lawsuits, fear of being exposed as incompetent, and feeling shame before patients and colleagues. Proper disclosure, however, including a sincere apology, should be part of the management of errors and of their long-term aftermaths. In disclosing medical errors, it is essential for oncologists to pay equal attention to the medical and the emotional aspects of the information they are giving and the reaction that it elicits in patients and families. Specific communication skills regarding disclosure of medical errors can be learned.
Systemic Therapeutic Approaches to Advanced Thyroid Cancers
Authors: Menefee Michael E. , Smallridge Robert C. , Bible Keith C. ,   the Mayo Clinic Endocrine Malignancies Disease-Oriented Group
Published: February 2020

Overview:

Until only recently, few effective systemic therapies were available to treat patients with metastatic thyroid cancers. Recent advances in better understanding the pathogenesis and altered signaling pathways—especially in medullary and differentiated thyroid cancers (MTCs and DTCs)—have begun to change this situation substantially. Vandetanib, an orally bioavailable inhibitor of the RET kinase that is constitutively activated in MTC, has now been approved by the U.S. Food and Drug Administration (FDA) for use in progressive and symptomatic metastatic MTC; it has been shown to delay time to progression relative to placebo in a randomized phase III trial. Further, vascular endothelial growth factor receptor (VEGF-R) inhibitory agents including sorafenib, sunitinib, pazopanib, and axitinib that are already approved in the United States for use in advanced renal cell carcinoma have shown high response rates in treating advanced DTCs in multiple phase II trials, and have become commonly used in progressive radioiodine-refractory metastatic DTC. Yet additional agents are now in development, with several including XL184 (cabozantinib) also showing promise in DTC and MTC. In anaplastic thyroid cancer (ATC), progress has been slower, with the greatest apparent gains resulting more from the application of systemic therapies earlier in the disease course, especially when used in conjunction with initial surgical and radiation therapies. Despite recent progress, additional effective systemic therapeutic approaches remain sorely needed for treating metastatic MTC, DTC, and ATC.
Lung Cancer Screening: Promise and Pitfalls
Authors: Berg Christine D. , Aberle Denise R. , Wood Douglas E.
Published: February 2020

OVERVIEW:

The results of the National Lung Screening Trial (NLST) have provided the medical community and American public with considerable optimism about the potential to reduce lung cancer mortality with imaging-based screening. Designed as a randomized trial, the NLST has provided the first evidence of screening benefit by showing a 20% reduction in lung cancer mortality and a 6.7% reduction in all-cause mortality with low dose helical computed tomography (LDCT) screening relative to chest X-ray. The major harms of LDCT screening include the potential for radiation-induced carcinogenesis; high false-positivity rates in individuals without lung cancer, and overdiagnosis. Following the results of the NLST, the National Comprehensive Cancer Network (NCCN) published the first of multiple lung cancer screening guidelines under development by major medical organizations. These recommendations amalgamated screening cohorts, practices, interpretations, and diagnostic follow-up based on the NLST and other published studies to provide guidance for the implementation of LDCT screening. There are major areas of opportunity to optimize implementation. These include standardizing practices in the screening setting, optimizing risk profiles for screening and for managing diagnostic evaluation in individuals with indeterminate nodules, developing interdisciplinary screening programs in conjunction with smoking cessation, and approaching all stakeholders systematically to ensure the broadest education and dissemination of screening benefits relative to risks. The incorporation of validated biomarkers of risk and preclinical lung cancer can substantially enhance the effectiveness screening programs.
Hedgehog Pathway in Pediatric Cancers: They're Not Just for Brain Tumors Anymore
Authors: MacDonald Tobey J.
Published: February 2020

Overview:

The Hedgehog (HH) pathway regulates fundamental processes in embryonic development, including stem cell maintenance, cell differentiation, tissue polarity, and cell proliferation. In the vertebrate pathway, Sonic hedgehog (SHH) binds to Patched1 (PTCH1), which relieves its inhibition of Smoothened (SMO), allowing the GLI family of transcription factors to translocate to the nucleus and activate HH target genes such as GLI1, GLI2, PTCH1, CYCLIN D1, BCL-2, and MYCN. The HH pathway is also an active participant in tumorigenesis. In 1996, loss-of-function mutation in PTCH1 was discovered to be the cause of nevoid basal cell carcinoma syndrome (NBCCS, or Gorlin syndrome), an autosomal dominant disease associated with increased rates of basal cell carcinoma (BCC), medulloblastoma (MB), and rarely, rhabdomyosarcoma. It is now estimated that 100% of sporadic BCC and up to 20% to 30% of MB also harbor activating HH pathway mutations. Together, these discoveries firmly established the linkage between HH pathway activation and cancer development. Intense research has since been focused on further defining the role of the HH pathway in BCC and MB and potential therapeutic strategies to inhibit HH signaling. Early clinical trials of SMO inhibitors have shown promising results in the treatment of adult BCC and SHH-driven MB. More recently, a number of other pediatric cancers have been reported to show HH activity, making these tumors potential candidates for HH inhibitor therapy. To date however, no HH pathway mutations have been identified in other pediatric cancers. This review will describe the HH pathway signaling in development and cancer with a focus on recent evidence for HH pathway activation in central nervous system (CNS) and non-CNS pediatric cancers.
Management of Tyrosine Kinase Inhibitor–Resistant Gastrointestinal Stromal Tumors
Authors: Barnett Christine M. , Heinrich Michael C.
Published: February 2020

Overview:

The treatment of gastrointestinal stromal tumors (GISTs) has been a model for targeted cancer therapy. The discovery of driver somatic mutations in the KIT and PDGFRA receptor tyrosine kinases led to a shift of therapy from conventional cytotoxic chemotherapy to inhibitors of these receptors. Targeted molecular therapy of GIST has markedly increased the overall survival of patients with advanced disease. However, the ability of kinase therapy to control metastatic disease is ultimately limited by the ability of these agents to overcome intrinsic or acquired resistance mechanisms. Ongoing basic and clinical research is focusing on identifying new agents to inhibit KIT/PDGFRA kinase activity and/or other novel molecular targets in GIST.
Adjuvant Therapy for Older Women with Early-Stage Breast Cancer: Treatment Selection in a Complex Population
Authors: Owusu Cynthia , Hurria Arti , Muss Hyman
Published: February 2020

Overview:

Breast cancer is a disease of aging. However, older women with breast cancer are less likely to participate in clinical trials or to receive recommended treatment. This undertreatment has contributed to a lag in breast cancer survival outcomes for older women compared with that for their younger counterparts. The principles that govern recommendations for adjuvant treatment of breast cancer are the same for younger and older women. Systemic adjuvant treatment recommendations should be offered on the basis of tumor characteristics that divide patients into three distinct subgroups. These include (1) older women with hormone receptor (HR)-positive and human epidermal growth factor 2 (HER2)-negative breast cancer who should be offered endocrine therapy; (2) older women with HR-negative and HER2-negative breast cancer who should be offered adjuvant chemotherapy; and (3) older women with HER2-positive disease who should be offered chemotherapy with trastuzumab. Exceptions to these guidelines may be made for older women with small node-negative tumors or frail older women with limited life expectancy, where close surveillance may be a reasonable alternative. Addressing the current age-related disparities in breast cancer survival will require that older women are offered the same state-of-the-art-treatment as their younger counterparts, with a careful weighing of the risks and benefits of each treatment in the context of the individual's preferences. In addition, older women should be encouraged to participate in breast cancer clinical trials to generate additional chemotherapy efficacy, toxicity, and quality of life data.
Translating PI3K-Delta Inhibitors to the Clinic in Chronic Lymphocytic Leukemia: The Story of CAL-101 (GS1101)
Authors: Byrd John C. , Woyach Jennifer A. , Johnson Amy J.
Published: February 2020

Overview:

Targeted therapy with imatinib has transformed the treatment of chronic myeloid leukemia (CML). Unlike CML, chronic lymphocytic leukemia (CLL) lacks a common genetic aberration but does demonstrate constitutive activation of PI3-kinase (PI3K) as compared to normal B cells. This constitutively active PI3K in CLL likely relates to tonic B-cell receptor signaling that is present across a wide variety of B-cell malignancies. Although PI3K is quite proximal and represents an ideal target to pharmacologically modulate, the complexity of this pathway on which many normal functions are dependent had for many years been problematic. The p110 delta isoform of PI3K is relatively specific to hematopoietic cells, and elegant mouse studies where p110 delta was genetically inactivated demonstrated only a selective B-cell defect. Subsequent development of a potent, selective p110 delta inhibitor prompted translation into the clinic for the treatment of CLL and low-grade non-Hodgkin lymphoma (NHL). From the first patient treated where a dramatic early nodal response was noted, considerable excitement has developed for this class of drugs in CLL and NHL. We will summarize the development process of CAL-101 (now GS1101) in the treatment of chronic lymphoid malignancies such as CLL.
Identification, Management, and Evaluation of Children with Cancer-Predisposition Syndromes
Authors: Knapke Sara , Zelley Kristin , Nichols Kim E. , Kohlmann Wendy , Schiffman Joshua D.
Published: February 2020

Overview:

A substantial proportion of childhood cancers are attributable to an underlying genetic syndrome or inherited susceptibility. Recognition of affected children allows for appropriate cancer risk assessment, genetic counseling, and testing. Identification of individuals who are at increased risk to develop cancers during childhood can guide cancer surveillance and clinical management, which may improve outcomes for both the patient and other at-risk relatives. The information provided through this article will focus on the current complexities involved in the evaluation and management of children with cancer-predisposing genetic conditions and highlight remaining questions for discussion.
Strategies to Overcome Clinical, Regulatory, and Financial Challenges in the Implementation of Personalized Medicine
Authors: Tsimberidou Apostolia M. , Ringborg Ulrik , Schilsky Richard L.
Published: February 2020

This article highlights major developments over the last decade in personalized medicine in cancer. Emerging data from clinical studies demonstrate that the use of targeted agents in patients with targetable molecular aberrations improves clinical outcomes. Despite a surge of studies, however, significant gaps in knowledge remain, especially in identifying driver molecular aberrations in patients with multiple aberrations, understanding molecular networks that control carcinogenesis and metastasis, and most importantly, discovering effective targeted agents. Implementation of personalized medicine requires continued scientific and technological breakthroughs; standardization of tumor tissue acquisition and molecular testing; changes in oncology practice and regulatory standards for drug and device access and approval; modification of reimbursement policies by health care payers; and innovative ways to collect and analyze electronic patient information that are linked to prospective clinical registries and rapid learning systems. Informatics systems that integrate clinical, laboratory, radiologic, molecular, and economic data will improve clinical care and will provide infrastructure to enable clinical research. The initiative of the EurocanPlatform aims to overcome the challenges of implementing personalized medicine in Europe by sharing patients, biologic materials, and technological resources across borders. The EurocanPlatform establishes a complete translational cancer research program covering the drug development process and strengthening collaborations among academic centers, pharmaceutical companies, regulatory authorities, health technology assessment organizations, and health care systems. The CancerLinQ rapid learning system being developed by ASCO has the potential to revolutionize how all stakeholders in the cancer community assemble and use information obtained from patients treated in real-world settings to guide clinical practice, regulatory decisions, and health care payment policy.
Molecular Profiling and the Reclassification of Cancer: Divide and Conquer
Authors: Munoz Javier , Swanton Charles , Kurzrock Razelle
Published: February 2020

Cancer is one of the leading causes of mortality in the world. Choosing the best treatment is dependent on making the right diagnosis. The diagnostic process has been based on light microscopy and the identification of the organ of tumor origin. Yet we now know that cancer is driven by molecular processes, and that these do not necessarily segregate by organ of origin. Fortunately, revolutionary changes in technology have enabled rapid genomic profiling. It is now apparent that neoplasms classified uniformly (e.g., non-small cell lung cancer) are actually comprised of up to 100 different molecular entities. For instance, tumors bearing ALK alterations make up about 4% of non-small cell lung cancers, and tumors bearing epidermal growth factor receptor (EGFR) mutations, approximately 5% to 10%. Importantly, matching patients to therapies targeted against their driver molecular aberrations has resulted in remarkable response rates. There is now a wealth of evidence supporting a divide-and-conquer strategy. Herein, we provide a concise primer on the current state-of-the-art of molecular profiling in the cancer clinic.
The Ethics of Health Information Technology in Oncology: Emerging Isssues from Both Local and Global Perspectives
Authors: LeBlanc Thomas W. , Shulman Lawrence N. , Yu Peter P. , Hirsch Bradford R. , Abernethy Amy P.
Published: February 2020

Health information technology (HIT) is ever-increasing in complexity and has incrementally become a fundamental part of our everyday clinical lives. As HIT becomes more complex and commonplace, so do the questions it raises about stewardship and usage of data, along with the ethics of these applications. With the development of rapid-learning systems, such as ASCO's CancerLinQ, careful thought about the ethics and applications of these technologies is necessary. This article uses the principles-based framework of modern bioethics to examine evolving ethical issues that arise in the context of HIT and also discusses HIT's application in reducing cancer care disparities in the developing world. We recognize that this topic is quite broad, so here we provide an overview of the issues, rather than any definitive conclusions about a particular “correct path.” Our hope is to stimulate discussion about this important topic, which will increasingly need to be addressed in the oncology community.
Early Integration of Palliative and Supportive Care in the Cancer Continuum: Challenges and Opportunities
Authors: Davis Mellar P. , Bruera Eduardo , Morganstern Daniel
Published: February 2020

Palliative care has become synonymously associated with hospice care in the minds of patients and physicians. Supportive care is a more acceptable term and leads to earlier referral. Miscommunication and a “collusion of hope” centered on cancer treatment is detrimental to care at the end of life and results in complicated bereavement. Patients, despite being told prognosis, may not comprehend the news even if delivered in an empathetic manner. There are resource and policy barriers to palliative care. However, integration of palliative care early in the management of advanced cancer has demonstrated multiple benefits without reducing survival.
Cancer of Unknown Primary Site: Improved Patient Management with Molecular and Immunohistochemical Diagnosis
Authors: Greco F. Anthony
Published: February 2020

Cancer of unknown primary site (CUP) is a common heterogeneous clinicopathologic syndrome, but investigations and publications regarding these patients are rare. For the last 20 years, empiric “broad-spectrum” chemotherapy has been the standard therapy for the majority of these patients. More recently, improved immunocytochemistry and advent of gene-expression profiling have provided the diagnostic tools necessary to accurately define the tissue of origin in most patients. Molecular profiling assays complement standard pathologic diagnosis, and a recently reported large prospective study demonstrated an improvement in outcome for patients treated with site-specific therapy directed by the molecular assay diagnoses compared with empiric chemotherapy. Survival in molecularly diagnosed patients was as expected for those particular tumor types. The evaluation of patients has become more standardized. The empiric-chemotherapy era is ending and customized therapies based on accurate tissue of origin diagnoses have arrived. Eventually the recognition of the molecular aberrations responsible for the growth and metastasis of solid tumors, regardless of the tissue of origin, will lead to more precise and effective therapy for patients with advanced cancers.
Targeting Molecular Aberrations in Urothelial Carcinoma: Are We Almost There?
Authors: Apolo Andrea B. , Kwiatkowski David J.
Published: February 2020

Advances in tumor biology and cancer genetics have led to the development of effective targeted therapies in oncology over the past decade. However, targeted drug development for urothelial carcinoma has been slower than for some other malignancies. The path forward in drug development is through a better understanding of the aberrant pathways driving urothelial tumor development. Steady progress has been made in the characterization of genomic alterations in urothelial carcinoma. The Cancer Genome Atlas (TCGA) project is well underway in the analysis of a large set of urothelial cancer specimens using multiple approaches and technologies. In addition, there are already many well-established mutations and genetic alterations in urothelial carcinoma that likely contribute in an important way to tumor development. In addition, urothelial cancer genome-wide association studies have identified common variants associated with urothelial cancer risk and protein expression that can potentially be therapeutically targeted. Furthermore, the MET pathway has emerged as an exciting target in multiple tumors, including urothelial carcinoma. Our knowledge of how to clinically target many emerging molecular aberrations in urothelial cancer is still in the early stages of development. However, there is much promise in the ongoing research being conducted in urothelial cancer molecular pathogenesis.
A Multidisciplinary Approach in Muscle-Invasive Disease: Novel Chemotherapy Combinations and Targets in Chemoradiation
Authors: James Nicholas D. , Hussain Syed A.
Published: February 2020

The basic management of bladder cancer has changed depressingly little in the last 20 years, with a largely unquestioning acceptance of the role of surgery as the standard of care despite a rising mean age at diagnosis, now well into the mid-70s, meaning many patients will be high risk for a major surgical procedure. Overall survival rates for those diagnosed with bladder cancer have not improved for many years. There is a growing body of studies demonstrating the safety and efficacy of bladder preservation with combined chemo-radiation with good long-term function after such treatment. Two recent studies from the United Kingdom compared radiation alone with sensitized radiotherapy using distinct strategies, one (BCON) focusing on trying to improve tumor oxygenation, one (BC2001) using the combination of 5FU and mitomycin C. Importantly, both studies collected data on late toxicity and showed both good function and low rates of serious side effects with no increase with radio-sensitization. Furthermore, there is good evidence that survival after salvage cystectomy is similar to that seen after primary surgery, suggesting a strategy of primary chemo-radiation with salvage surgery (as used, for example, in anal cancer) may be both rational and safe. This article reviews the evidence on outcomes with chemo-radiation and calls for a rethink in our approaches to this major cancer killer.
Molecular Pathways in Head and Neck Cancer: EGFR, PI3K, and More
Authors: Psyrri Amanda , Seiwert Tanguy Y. , Jimeno Antonio
Published: February 2020

The treatment of head and neck squamous cell carcinoma (HNSCC) is set to undergo rapid changes, as novel treatment targets informed by genomic profiling and novel molecularly targeted therapies continue to make strides. In this review we provide an overview of the latest developments regarding (1) EGFR targeting for HNSCC, (2) PI3K as a novel treatment target, and (3) newly described key genetic events in HNSCC such as NOTCH1 mutations and emerging candidate targets including ALK1 and hedgehog. The first molecular targeting strategy to demonstrate a survival advantage for patients with HNSCC has emerged in the context of EGFR biology. Cetuximab remains the only U.S. Food and Drug Administration (FDA)-approved targeted therapy available for HNSCC, but EGFR as a target has not been individualized in this disease. The PI3K-AKT pathway is downstream of EGFR and is emerging as potentially one of the most important pathways in HNSCC. PIK3CA is the most frequently mutated oncogene for HNSCC (approximately 20%) and may play a role for both HPV-negative and HPV-positive tumors. Multiple therapeutic strategies targeting PI3K are being explored, and multiple agents either alone or in combination are in development. NOTCH1 is a key tumor suppressor gene and its genetic alterations lead to abnormal pathway activation. ALK1 is a novel target involved in angiogenesis, and efficacy in patients with HNSCC was documented in an early inhibitor trial. The hedgehog pathway modulates EGFR dependence and epithelial to mesenchymal transition (EMT), a key invasion and drug-resistance mechanism in HNSCC.
Understanding Variation in the Quality of the Surgical Treatment of Prostate Cancer
Authors: Schroeck Florian R. , Jacobs Bruce L. , Hollenbeck Brent K.
Published: February 2020

More than 80% of men with prostate cancer undergo active treatment, which can be associated with significant morbidity. Outcomes of surgical treatment vary widely depending on who treated the patient and where the patient was treated, implying that there is room for improvement. Factors influencing outcomes include patient characteristics as well as some measure of procedure volume. Although relationships between volume and outcomes for prostatectomy can most likely be explained by differences between surgeons (e.g., experience, technical skill), the hospital environment (e.g., team communication, safety culture) has the potential to either amplify or dampen the effects. Although most patient factors are immutable, these other aspects of surgical care and the delivery environment provide opportunities for quality improvement. Collaborative quality improvement initiatives may prove to be an important vehicle for achieving better prostate cancer care. These grass roots organizations, driven largely by urologists dedicated to providing prostate cancer care, have had initial successes in improving some aspects of quality in prostate cancer care, including reducing unwarranted use of imaging and perioperative morbidity. However, much of the variation in functional outcomes after prostate cancer surgery arises from differences in technical skill. Evaluating and improving intraoperative surgeon performance will inevitably be challenging, as they require acquisition and interpretation of data collected in the operating room. To this end, several methods have been described to objectively assess what happens in the operating room.
The Role of Chemotherapy in the Management of Stage IIIA Non-Small Cell Lung Cancer
Authors: Baik Christina S. , Vallières Eric , Martins Renato G.
Published: February 2020

Patients with confirmed stage IIIA non-small cell lung cancer (NSCLC) represent a very heterogeneous group which includes those with limited microscopic ipsilateral mediastinal lymph node involvement discovered after a surgical resection, as well as those who have radiologically evident bulky subcarinal lymph node involvement at presentation. Different therapeutic options in stage IIIA disease include neoadjuvant chemo- or chemoradiotherapy followed by surgery, primary surgery followed by adjuvant chemotherapy with or without sequential adjuvant radiation therapy or definitive chemoradiation without surgery. The roles of surgery and radiation in stage IIIA disease are controversial, and there is inadequate data from randomized trials to inform the optimal therapeutic strategy. In contrast, chemotherapy has a clear indication in the curative setting. Data from randomized trials indicates that cisplatin-based chemotherapy should be given in either adjuvant or neoadjuvant settings to patients who are undergoing curative surgical resection and who are candidates for cisplatin therapy. In definitive chemoradiotherapy, cisplatin-based therapy is recommended although a carboplatin-based regimen may be given if patients cannot receive cisplatin. Finally, all patients with stage IIIA NSCLC should be evaluated early in a multidisciplinary setting that includes medical and radiation oncologists and thoracic surgeons with experience in lung cancer therapy.
Europe Does It Better: Molecular Testing across a National Health Care System—The French Example
Authors: Nowak Frédérique , Calvo Fabien , Soria Jean-Charles
Published: February 2020

Drug approvals for molecularly stratified tumor subgroups make molecular testing mandatory and require that molecular diagnostics be performed nationwide. To this end, the French National Cancer Institute (INCa) and the French Ministry of Health have set up a national network of 28 regional molecular genetics centers. Selective molecular tests are performed in these facilities. They are free of charge for all patients in their region, irrespective of the type of establishment in which they are receiving treatment. A specific program has also been implemented to anticipate the launch of new targeted therapies and to accelerate the time-to-access to new drugs and experimental therapies. The initiative has been operational for 5 years and has been successful in meeting its initial aims of uniform nationwide test provision and fast implementation of molecular tests for new tumor biomarkers.
Genomic Landscape of Squamous Cell Carcinoma of the Lung
Authors: Morgensztern Daniel , Devarakonda Siddhartha , Govindan Ramaswamy
Published: February 2020

Outcomes with standard therapy for patients with advanced squamous cell carcinoma (SQCC) of the lung have not improved significantly over the past decade using a predominantly empiric approach. Recent advances in pulmonary adenocarcinomas (ACs) have allowed the subdivision according to molecular subsets and the identification of specific molecular alterations that predict significant benefit from specific targeted therapies. Genomic alterations reported by The Cancer Genome Atlas (TCGA) Project identified a number of molecular targets that need to be studied systematically to improve the overall survival of patients with SQCC of the lung.
Limited-Stage Hodgkin Lymphoma: Optimal Chemotherapy and the Role of Radiotherapy
Authors: Bartlett Nancy L.
Published: February 2020

Approximately 90% of patients with early-stage Hodgkin lymphoma (HL) will be cured with first-line therapy. Chemotherapy alone or combined-modality therapy are both acceptable standard treatment options for nonbulky early-stage HL. Combined-modality therapy is associated with more serious late effects and, in at least one study, showed inferior survival rates compared with chemotherapy alone. Modern radiotherapy fields and doses are likely to result in fewer complications, but given the common involvement of the mediastinum in HL, complete avoidance of the heart, lungs, and breasts in the radiotherapy field is unlikely. In patients receiving chemotherapy alone, four to six cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD), with fewer cycles being given to those with an early complete remission, is recommended. Three cycles of ABVD may be adequate in those with an early negative PET, but these results have been published only in abstract form. Current standards for combined-modality therapy include two cycles of ABVD and 20 Gy of involved field radiotherapy in those with a favorable risk profile and four cycles of ABVD plus 30 Gy for unfavorable HL in early-stage patients. Standard of care for bulky early-stage HL remains combined-modality therapy. Whether an interim PET will allow selection of patients with nonbulky HL who will benefit most from consolidative radiotherapy is still under investigation.
Risk Stratification of Rhabdomyosarcoma: A Moving Target
Authors: Arndt Carola A. S.
Published: February 2020

Known prognostic factors for rhabdomyosarcoma include primary site, stage, group (amount of tumor remaining after initial surgery before chemotherapy), lymph node involvement, age, and histology. These factors are taken into account when determining risk stratification for treatment allocation, with some differences between the European and U.S. approaches. The relationship of fusion status for PAX-3 of PAX-7 FOXO1 to outcome has been analyzed by a number of groups, but many of the studies are troubled by problems inherent in the use of convenience cohorts and the fact that patients in the analyzed groups are not always treated in a uniform fashion. One recent study analyzed outcome of patients treated in a similar fashion on the same protocol and found that patients with alveolar histology who were fusion negative had an outcome similar to those with embryonal histology. This article reviews many of the studies surrounding fusion status and outcome, risk stratification issues, and outcome of risk groups. The time is rapidly approaching in which fusion status will be used to allocate therapy for rhabdomyosarcoma.
The Power of Words: Discussing Decision Making and Prognosis
Authors: Dizon Don S. , Politi Mary C. , Back Anthony L.
Published: February 2020

One of the most important skills in medicine is communication. It lies at the heart of the doctor-patient relationship, and is particularly important when one has been diagnosed with a potentially life-threatening condition. Words are powerful and too often can be interpreted in ways not intended. In our session at the 2013 ASCO Annual Meeting, we discuss the communication of cancer and ways we might want to consider discussions regarding treatment options and prognosis. We recognize that all patients are different and that approaches should be individualized, to reflect each person's needs (what they want to know) while respecting their limits (how much they want to know). We discuss the concept of shared decision making, and how it can be used when there is uncertainty in what treatments may (or may not) accomplish. Finally, we discuss the skills that constitute a toolkit for communication, which we hope can be tailored to meet the variable needs of those we are caring for and by doing so, can be of help to clinicians in their own practices. In the era of personalized medicine, treatments may become more complex, and more options may be available. We hope to encourage providers to welcome patients as active participants in their care by sharing information, requesting their input, and by engaging them in important processes such as advance care planning—to ensure their needs and wishes are respected in the present and for whatever may come in the future.
Women in Oncology: Progress, Challenges, and Keys to Success
Authors: Reeder-Hayes Katherine , Felip Enriqueta , Patt Debra , Jaffee Elizabeth
Published: February 2020

Women have an increasingly significant presence in the oncology physician workforce but remain underrepresented in leadership positions and at the senior levels of academic medicine. Initiatives to close these gaps are underway both in the United States and Europe. However, many areas for improvement remain on an organizational level and in the trenches of career development and mentorship for individual female oncologists in both community and academic settings. Solutions to advance women in the oncology workforce will involve policy initiatives by professional and funding organizations, individual initiatives by universities and practices to recognize and develop female leaders, an increased focus on teamwork and novel practice arrangements, and high-quality mentorship of young women entering the oncology field.
An Unappreciated Challenge to Oncology Drug Discovery: Pitfalls in Preclinical Research
Authors: Begley C. Glenn
Published: February 2020

Unfortunately, preclinical research studies frequently suffer from a lack of rigor and robustness that precludes their use as a foundation for a drug-development program. Too often they lack the characteristics that typically are expected in high-quality clinical studies, yet despite that, they are published in top-tier scientific journals. The key attributes that are missing include lack of blinding of investigators, failure to repeat experiments, lack of positive and negative controls, use of nonvalidated reagents, inappropriate use of statistical tests, and data selection (ignoring results that do not fit the hypothesis). Physicians and scientists should view preclinical findings that lack these characteristics with skepticism and should proceed very cautiously in applying such findings to the clinic.