bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.
Biologic Agents in the Treatment of Colorectal Cancer: The Last Decade; the Lost Decade?
Authors: Venook Alan P. , Saltz Leonard B. 
Published: February 2020

KEY POINTS After almost 40 years of minimal progress, the period from 1996 to 2003 saw a flurry of new drugs become available. Progress since 2003 has been minimal. Most new agents with activity in the metastatic setting (irinotecan, bevacizumab, cetuximab) do not have activity in the adjuvant setting and so have not increased the cure rate. Combinations of biologics have been disappointing. Progress to date is less than we would have expected. Therapy individualized according to molecular characterization of each tumor appears to be the way forward.