bluuebunny/crossref_metadata_2025 huggingface dataset:
Three of 7 Hemoglobin A1c Point-of-Care Instruments Do Not Meet Generally Accepted Analytical Performance Criteria
Authors: Lenters-Westra Erna , Slingerland Robbert J
Published: May 2014

BACKGROUND

In 2009, we investigated the conformance of 8 hemoglobin A1c (Hb A1c) point-of-care (POC) instruments. Since then, instruments have improved and new devices are available on the market. In this second study, we evaluated the performance of DCA Vantage, Afinion, InnovaStar, Quo-Lab, Quo-Test, Cobas B101, and B-analyst Hb A1c POC instruments.

METHODS

Clinical and Laboratory Standards Institute protocols EP-5 and EP-9 were applied to investigate imprecision, accuracy, and bias. We assessed bias using the mean of 3 certified secondary reference measurement procedures (SRMPs). Assay conformance with the National Glycohemoglobin Standardization Program (NGSP) certification criteria was also evaluated. Interference of common Hb variants was investigated for methods that could work with hemolysed material.

RESULTS

The total CVs for all instruments, except for the DCA Vantage at a high Hb A1c value, were ≤3.1% in SI units and ≤2.1% in Diabetes Control and Complications Trial (DCCT) units. Afinion, DCA Vantage, B-analyst, and Cobas B101 instruments passed the NGSP criteria with 2 different reagent lot numbers. Quo-Test, Quo-Lab, and InnovaStar instruments had a negative bias compared to the mean of the 3 SRMPs and failed NGSP criteria. Most of the common Hb variants did not interfere with the investigated instruments, except Hb AE for the Cobas B101.

CONCLUSIONS

Afinion, DCA Vantage, Cobas B101, and B-analyst instruments met the generally accepted performance criteria for Hb A1c. Quo-Test, Quo-Lab, and InnovaStar met the criteria for precision but not for bias. Proficiency testing should be mandated for users of Hb A1c POC assays to ensure quality.
Liver-Directed Therapies: Surgical Approaches, Alone and in Combination with Other Interventions
Authors: Spolverato Gaya , Pawlik Timothy M.
Published: May 2014

When feasible, surgical resection is typically the preferred therapeutic option in patients with both primary and secondary hepatic malignancies. Improved patient selection, preoperative management, and advances in perioperative care have had a considerable effect on short-term and long-term outcomes following hepatic resection. Parenchymal transection of the liver can be performed using many different techniques such as digitoclasia, clamp crushing, vessel sealing system, harmonic scalpel, water-jet, Cavitron Ultrasonic Surgical Aspirator, or radiofrequency dissecting sealer. At the time of surgery, one of the main factors that influences postoperative morbidity and mortality is blood loss. Different techniques are used to decrease blood loss, such as the Pringle maneuver, selective ligation of the right, left, or smaller branches of the portal system; extrahepatic dissection; isolation; and transection of the hepatic artery and portal vein and the total vascular exclusion. Liver resection is on occasion accompanied by a concomitant procedure. Given that colorectal liver metastasis is a common indication for liver resection, colon resection is one of the more common concurrent procedures, but also surgical management of other disease in the lung or pancreas may sometimes be indicated. A subset of patients with primary or secondary liver malignancies may also require the addition of an ablative therapy to treat the extent of disease in the liver. Moreover, occasionally, hepatic resection takes place following intra-arterial therapy administration to the liver. Although many of these patients may benefit from surgical therapy, a multidisciplinary team approach remains critical.
Ampullary Cancer: An Overview
Authors: Ahn Daniel H. , Bekaii-Saab Tanios
Published: May 2014

Ampullary cancers are rare, accounting for only 0.2% of gastrointestinal cancers and approximately 7% of all periampullary cancers.1They arise from the ampullary complex, distal to the confluence of the common bile and pancreatic duct ( Fig. 1 ). In contrast to other periampullary malignancies, true ampullary cancers present earlier in their disease course with symptoms that result from biliary obstruction. It is often difficult to distinguish primary ampullary cancers from other periampullary cancers preoperatively. In early stages, ampullary cancers are surgically treated, similar to pancreatic cancers, and typically with a pancreatico-duodenoectomy (or Whipple procedure). Because of their earlier presentation, resection rates for all patients are much higher than other periampullary carcinomas. Moreover, their prognosis tends to be better than those with other periampullary- and pancreatic-originating cancers. In patients with true ampullary cancer, there is very limited data to guide physicians on the choice of therapy, largely because of the rarity of the disease and the paucity of related research. Herein, we provide an overview of the biology, histology, current therapeutic strategies, and potential future therapies for carcinomas arising from the ampulla of Vater.
50 Years of Progress in the Systemic Therapy of Non–Small Cell Lung Cancer
Authors: Wakelee Heather , Kelly Karen , Edelman Martin J.
Published: May 2014

Non-small cell lung cancer constitutes 85% to 90% of lung cancer and is the most common cause of cancer death. Over the past 50 years, substantial progress has been made in all aspects of lung cancer including screening, diagnostic evaluation, surgery, radiation therapy, and chemotherapy. This review focuses on the advances in systemic therapy during this half century.
Where We Were, Where We Are, Where We Are Going: Progress in Multiple Myeloma
Authors: Bergsagel P. Leif
Published: May 2014

The celebration of the 50th anniversary of the founding of the American Society of Clinical Oncology provides the occasion to review the progress that has been made in the biology and treatment of multiple myeloma. With the advent of melphalan and cyclophosphamide in the early 1960s the median survival of patients with multiple myeloma more than doubled from 10 months to approximately 24 months. Throughout multiple clinical trials in the 1970s and 1980s, melphalan and prednisone remained the gold standard, with a 3-year survival of 42%. The use of high-dose melphalan with autologous hematopoietic stem cell support provided an incremental advance in the 1990s. The outlook for patients was dramatically improved in the 2000s with the introduction of thalidomide analogs and proteasome inhibitors, so that the 3-year survival of patients treated in 2008 with melphalan and prednisone had increased to 66%. The 2010s are dominated by studying the optimal combination, sequence, and duration of therapies. These clinical advances have occurred along with our evolving understanding of the molecular pathogenesis of myeloma. Myeloma can be divided into two main groups: hyperdiploid, with multiple trisomies of odd-numbered chromosomes, and nonhyperdiploid, with recurrent immunoglobulin heavy chain gene translocations. Disease progression is associated with rearrangements of MYC, the most common mutation in myeloma, present in nearly half of patients. Genomic studies have highlighted marked subclonal heterogeneity that poses one of the main challenges to successful control of the disease. This problem will be addressed in future studies in the 2020s, which will include a focus on immunologic approaches such as monoclonal antibodies, checkpoint inhibitors, engineered T-cells, and novel immunomodulators.
Radiotherapy for Soft Tissue Sarcoma: 50 Years of Change and Improvement
Authors: Wang Dian , Abrams Ross A.
Published: May 2014

Radiotherapy for soft tissue sarcoma (STS) has advanced significantly over the past 50 years. This review focuses briefly on the period from 1964 to 1999 and more substantially on the changes of the past 15 years, such as IMRT and image-guided radiotherapy (IG-RT), especially when brought together (IG-IMRT) in the same planning and delivery process to treat localized STS. In particular, the introduction of IG-RT, target volume definitions for IG-RT, and review of recent clinical trials using IG-RT to treat localized STS in extremity will be reviewed. Finally, potential investigational agents combined with IG-RT to improve outcomes in patients with localized STS are discussed.
Surgical Advances in Bone and Soft Tissue Sarcoma: 50 Years of Progress
Authors: Henshaw Robert M.
Published: May 2014

As the American Society of Clinical Oncology celebrates its 50th anniversary, physicians can appreciate the significant advances made in the treatment of patients with sarcoma. Historically, these rare tumors have garnered great interest in the medical profession, due to their ability to reach extraordinary size, resulting in substantial deformities and disabilities. Fortunately, advances in surgical management, which have occurred concurrently with advances in imaging, diagnostic techniques, and both local and systemic adjuvant treatments, offer patients diagnosed with sarcoma significant hope for successful treatment and the expectation of a meaningful quality of life.
Cancer Log-Kill Revisited
Authors: Norton Larry
Published: May 2014

INTRODUCTION

At the root of science lie basic rules, if we can discover or deduce them. This is not an abstract project but practical; if we can understand the why then perhaps we can rationally intervene. One of the unifying unsolved problems in physics is the hypothetical “Theory of Everything.” In a similar vein, we can ask whether our own field contains such hidden fundamental truths and, if so, how we can use them to develop better therapies and outcomes for our patients. Modern oncology has developed as drugs and translational science have matured over the 50 years since ASCO's founding, but almost from that beginning tumor modeling has been a key tool. Through this general approach Norton and Simon changed our understanding of cancer biology and response to therapy when they described the fit of Gompertzian curves to both clinical and animal observations of tumor growth. The practical relevance of these insights has only grown with the development of DNA sequencing promising a raft of new targets (and drugs). In that regard, Larry Norton's contribution to this year's Educational Book reminds us to always think creatively about the fundamental problems of tumor growth and metastases as well as therapeutic response. Demonstrating the creativity and thoughtfulness that have marked his remarkable career, he now incorporates a newer concept of self-seeding to further explain why Gompertzian growth occurs and, in the process, provides a novel potential therapeutic target. As you read his elegantly presented discussion, consider how this understanding, wisely applied to the modern era of targeted therapies, might speed the availability of better treatments. But even more instructive is his personal model—not only the Norton-Simon Hypothesis—of how to live and approach science, biology, patients and their families, as well as the broader community. He shows that with energy, enthusiasm, optimism, intellect, and hard work we can make the world better.

Clifford A. Hudis, MD, FACP, 2013–2014 ASCO President
Precision Cancer Medicine: The Future Is Now, Only Better
Authors: Tsimberidou Apostolia M. , Eggermont Alexander M. M. , Schilsky Richard L.
Published: May 2014

The promise of precision medicine for cancer is already being realized with the recent introduction of many targeted therapies, some with companion diagnostic tests that identify patients most likely to benefit from treatment. The utility of molecular profiling of cancer to identify actionable aberrations has been suggested by several small clinical trials conducted in patients with advanced cancer and by many anecdotes but is yet to be proven in well-designed, prospective, randomized trials. Several trials that will definitively test this strategy are now underway or soon to be launched. Melanoma, a disease once largely untreatable when metastatic, may be a paradigm for understanding how the molecular drivers of a disease can lead to highly effective targeted therapies, as well as for realizing the enormous therapeutic potential of unleashing the immune system against cancer to produce long-term disease control. Looking to the future, advanced omics technologies and computational techniques will enable assessment of not only genomic variants, as performed today, but also of pathway and network aberrations that will greatly facilitate selection of drug combinations likely to benefit specific patients. As our deepening understanding of tumor biology converges with rapid advances in measurement science and technology and computational analysis, we have an enormous opportunity to create a future for precision medicine in oncology that provides for highly specific, minimally toxic, and dramatically effective treatment for each patient.
Social Media in Clinical Trials
Authors: Thompson Michael A.
Published: May 2014

Social media has potential in clinical trials for pointing out trial issues, addressing barriers, educating, and engaging multiple groups involved in cancer clinical research. Social media is being used in clinical trials to highlight issues such as poor accrual and barriers; educate potential participants and physicians about clinical trial options; and is a potential indirect or direct method to improve accrual. We are moving from a passive “push” of information to patients to a “pull” of patients requesting information. Patients and advocates are often driving an otherwise reluctant health care system into communication. Online patient communities are creating new information repositories. Potential clinical trial participants are using the Twittersphere and other sources to learn about potential clinical trial options. We are seeing more organized patient-centric and patient-engaged forums with the potential to crowd source to improve clinical trial accrual and design. This is an evolving process that will meet many individual, institutional, and regulatory obstacles as we move forward in a changed research landscape.
Early Phase Trial Designs and Endpoints for Targeted Therapies in Rare Genotype Subsets
Authors: Mandrekar Sumithra J.
Published: May 2014

The primary goal of phase I dose-finding trials has been historically to understand the safety profile of a new treatment/regimen and establish the maximum tolerated dose (MTD) for further investigation in a specific tumor type. These designs hinged on the assumption that the highest safe dose is also likely to be the most efficacious dose. In the current era of stratified medicine and targeted therapies, these assumptions and designs are quickly becoming obsolete. Newer approaches to dose-finding designs are emerging with a focus on not just safety, but also an efficacy (clinical- or biomarker-based) measure to guide the determination of the “optimal” dose (not necessarily the MTD) model, as opposed to rule-based designs. These designs allow for flexibility in trial conduct, with improved precision in estimating the dose to take forward for further testing, patient selection/enrichment strategies to maximize the chance of therapeutic effect, and expansion cohorts to further understand the safety/efficacy of the agent and patient subsets most likely to benefit from the agent under investigation. Although advances in technology have enabled the possibility of using these newer approaches, the acceptance and integration of these approaches in practice can only be accelerated if it is developed in concert with a clinical paradigm.
ASCO's Community Research Forum: Addressing Challenges of Community-Based Research from the Grass Roots
Authors: Robert Nicholas , Lilenbaum Rogerio , Hurley Patricia
Published: May 2014

ASCO's Community Research Forum is a solution-oriented venue for community research sites to overcome barriers to conducting clinical trials. The key objectives of the Forum are to (1) convene community-based researchers to identify challenges to conducting research that ASCO can address, (2) develop solution-oriented projects to address these challenges to facilitate clinical trial participation in community research settings, and (3) shape ASCO programs and policies to support members engaged in community research. The Community Research Forum holds an annual in-person meeting that convenes physician investigators, research administrators, research nurses, and clinical research associates from community-based research programs and practices. To meet identified needs, the Community Research Forum has developed the ASCO Clinical Trial Workload Assessment Tool and the ASCO Research Program Quality Assessment Tool. Both of these tools will be available to the public in 2014. The Forum is currently exploring the concept and potential metrics of a research certification program to formally assess community-based research programs, and to identify gaps and areas to improve the program in order to meet quality standards. The Community Research Forum's website aims to serve as a go-to resource for community-based physician investigators and research staff. The Community Research Forum will continue to provide a forum for community-based researchers to network, share challenges, and develop initiatives that provide solutions and facilitate the conduct of clinical trials.
Alpha-Emitter Radium-223 in the Management of Solid Tumors: Current Status and Future Directions
Authors: Nilsson Sten
Published: May 2014

Bone metastases, which are commonly seen in patients with advanced cancers, are a major cause of skeletal events, disability, and death. Radium-223 dichloride (radium-223; Xofigo, formerly Alpharadin), a first-in-class, alpha-emitting radiopharmaceutical that selectively targets bone metastases with high-energy short-range alpha-particles, has been approved for the treatment of patients with castration-resistant prostate cancer (CRPC) with symptomatic bone metastases and no known visceral metastases. Approval is based on results of the randomized phase III trial Alpharadin in Symptomatic Prostate Cancer (ALSYMPCA), in which radium-223 prolonged overall survival and time to first symptomatic skeletal event versus placebo among patients with CRPC with symptomatic bone metastases and was generally well tolerated, with low myelosuppression rates and manageable gastrointestinal adverse events. Long-term follow-up of the ALSYMPCA safety population showed that the incidence of myelosuppression remained low among patients treated with radium-223, with no additional safety issues of acute myelogenous leukemia, myelodysplastic syndrome, aplastic anemia, or primary bone cancer within approximately 1.5 years after treatment. The radium-223 overall survival benefit and low toxicity make it an effective, well-tolerated, and novel treatment option for CRPC and symptomatic bone metastases and opens the possibility of exploring radium-223 in the treatment of bone metastases from other cancers. A phase I clinical trial of patients with breast and prostate cancer with skeletal metastases demonstrated that radium-223 was safe and well tolerated at all therapeutically relevant dosages. Moreover, a phase IIa trial of patients with advanced breast cancer and progressive bone-dominant disease demonstrated that radium-223 targeted areas of increased bone metabolism and showed biologic activity.
Radiation Oncology Approaches in Liver Malignancies
Authors: Kennedy Andrew S.
Published: May 2014

Radiation therapy plays an increasingly important role in the treatment of hepatic malignancies. There is convincing evidence of safety and efficacy employing brachytherapy (yttrium-90), three-dimensional conformal radiotherapy, intensity-modulated radiotherapy, stereotactic body radiotherapy (SBRT), and proton beam therapy (PBT) in all stages of primary and metastatic involvement in the liver. Technologic advances in tumor imaging, real-time tracking of moving targets during radiotherapy delivery, and superb radiation dose deposition control have enabled treatment of previously unapproachable lesions. Recently completed and ongoing clinical trials are refining optimal dose fractionation schedules for SBRT as monotherapy. Radioembolization as part of first-line therapy in metastatic colorectal tumors is being tested in large international trials combined with FOLFOX6 and bevacizumab, as well as in hepatocellular carcinoma with sorafenib. PBT is becoming more available as new facilities open in many countries providing particle beam therapy, which delivers unparalleled control of radiation dose close to critical structures. A major point of research is understanding how best to safely destroy tumors in the background of often fragile hepatic function from cirrhosis or heavily pretreated chemotherapy liver parenchyma. Fortunately, serious complications from radiotherapy are rare, acute toxicities are typically Common Terminology Criteria for Adverse Events v4.0 grade 1–2, with consistent response rates of 50% to 97% in the modern era.
Current Controversies in the Stage-Specific Multidisciplinary Management of Pancreatic Cancer
Authors: Katz Matthew H. G. , Landry Jerome , Kindler Hedy Lee
Published: May 2014

Encouraging therapeutic approaches and treatment regimens for patients with both localized and metastatic pancreatic cancer have emerged over the last 5 years. However, these new strategies have brought important challenges and controversy. Clinical staging criteria are constantly evolving. No system has been uniformly adopted, limiting our understanding of the role of both pancreatectomy and neoadjuvant therapies for localized disease. The role of radiation therapy for the treatment of both resectable and unresectable pancreatic cancer remains unclear despite multiple prospective studies. Although two new systemic chemotherapy regimens have essentially transformed the care of many patients with metastatic cancer, criteria to guide their use in the general population have yet to be clearly established. Herein we provide an overview of these important controversies in the context of a broad update on the stage-specific management of patients with newly diagnosed pancreatic cancer.
A Review of Recent Data in the Treatment of Gallbladder Cancer: What We Know, What We Do, and What Should Be Done
Authors: Müller Bettina G. , De Aretxabala Xabier , González Domingo Manuel
Published: May 2014

Gallbladder cancer is now considered a distinct clinical entity, allowing for a separate analysis from that of other malignancies of the biliary tree. Symptoms related to a malignant tumor of the gallbladder include jaundice and abdominal pain, or a palpable abdominal mass that occurs in a late stage of the disease. The majority of patients with operable gallbladder cancer are diagnosed by cholecystectomy performed for presumed benign disease, mostly cholelithiasis, a clinical entity known as incidental gallbladder cancer. Given the poor prognosis if tumor invasion beyond the muscular layer and/or nodal metastasis is found, adjuvant treatments have been implemented, but few data are available to guide treatment decisions in this setting. For advanced disease, a multidisciplinary treatment approach including biliary drainage procedures and palliative support is needed in the management of this aggressive disease. Palliative chemotherapy with a combination of gemcitabine and cisplatin or oxaliplatin is the standard treatment based on the findings of two phase III trials that showed improved overall survival compared to single-agent chemotherapy and best supportive care. Several phase II studies have been reported investigating the role of targeted agents against EGFR, VEGF, HER2, and MEK. International collaboration to enhance our knowledge of gallbladder cancer should be encouraged.
Building on Prostate Cancer Working Group 2 to Change the Paradigm from Palliation to Cure
Authors: Scher Howard I.
Published: May 2014

Developing systemic therapies for advanced prostate cancer has significant challenges, including the difficulty of assessing baseline disease status, disease heterogeneity, and the lack of standards for assessing treatment effects that reliably reflect clinical benefit. To address these issues, the Prostate Cancer Working Group (PCWG2) took three actions. First, the Group incorporated a prostate cancer clinical states model framework for patient management and drug development. Second was establishing a two-objective paradigm in which trials are designed to evaluate a drug's ability to either (a) control, relieve, or eliminate present disease manifestations or (b) prevent or delay future disease manifestations. Third was the development of consensus criteria for eligibility, outcomes, and reporting in prostate cancer clinical trials. Now that the molecular interrogation of prostate cancer has led to a more complex understanding of disease biology, drug development has transitioned from evaluating cytotoxic agents with activity in multiple tumor types to the rational development of therapies targeting different aspects of the malignant process. In addition, the current availability of multiple therapies for advanced prostate cancer that prolong life brings a new mandate: that we define, validate, and qualify predictive biomarkers of sensitivity to guide treatment selection and establish endpoints short of survival that can lead to drug approval. Optimization of outcomes in future trials will require revised guidance on how to align clinically relevant objectives and eligibility with an evolving disease framework.
Endocrine Therapy Toxicity: Management Options
Authors: Henry N. Lynn
Published: May 2014

Treatment with adjuvant endocrine therapy, including tamoxifen and the aromatase inhibitors, has resulted in notable improvements in disease-free and overall survival for patients with hormone receptor-positive breast cancer. Despite their proven benefit, however, adherence to and persistence with the medications is poor in part because of bothersome side effects that can negatively affect quality of life. Retrospective analyses have identified possible predictors of development of toxicity. Reports have also suggested that development of toxicity may be a biomarker of better response to therapy. In addition, there has been considerable research investment into the management of these side effects, which may lead to improved adherence and persistence with therapy. However, although notable advances have been made, much more remains to be done to provide patients with truly personalized therapy for hormone receptor-positive breast cancer.
Can We Maximize Both Value and Quality in Gynecologic Cancer Care? A Work in Progress
Authors: Havrilesky Laura J. , Fountain Cynthia
Published: May 2014

Value is defined as desirable health outcomes achieved per monetary unit spent. Comparative effectiveness research and cost-effectiveness research are methods that have been developed to quantify effectiveness and value to inform management decisions. In this article we review the comparative and cost-effectiveness literature in the field of ovarian cancer treatment. Studies have shown that improved ovarian cancer survival is associated with complete primary surgical cytoreduction, with treatment at high volume facilities by subspecialist providers (gynecologic oncologists) and with National Comprehensive Cancer Network (NCCN) guideline-adherent care in both surgical staging and chemotherapy regimens. Intraperitoneal/intravenous chemotherapy (compared with intravenous alone) has been associated with improved survival and cost-effectiveness. Bevacizumab for primary and maintenance therapy has been found to not be cost-effective (even in selective subsets) despite a small progression-free survival (PFS) advantage. For platinum-sensitive recurrent ovarian cancer, secondary cytoreduction and platinum-based combinations are associated with improved overall survival (OS); several platinum-based combinations have also been found cost-effective. For platinum-resistant recurrence, single agent therapy and supportive care are cost-effective compared with combination therapies. Although little prospective clinical research has been done around end-of-life care, one study reported that for platinum-resistant ovarian cancer, palliative intervention would potentially reduce costs and increase quality adjusted life years compared with usual care (based on improvement in quality of life [QOL]). Overall, cost comparisons of individual chemotherapy regimens are highly dependent on market prices of novel therapeutic agents.
Novel Treatments for Chronic Lymphocytic Leukemia and Moving Forward
Authors: Brown Jennifer R. , Porter David L. , O'Brien Susan M.
Published: May 2014

The last several years have seen an explosion of novel therapies for chronic lymphocytic leukemia (CLL). These include the antibody obintutuzumab (GA-101), as well as small-molecule inhibitors of key pathways involved in the pathogenesis of CLL, specifically the B-cell receptor (BCR) pathway (especially Bruton's tyrosine kinase [BTK] and P13K), and the antiapoptotic pathway (especially BCL-2). We will consider each in turn, focusing on the molecules most advanced in clinical development. There has also been extensive development in rewiring the patient's own immune system to treat CLL. This has been done through modifying autologous T cells to express a chimeric antigen receptor (CAR). Thus far all CAR-T preparations have targeted the CD19 antigen. This is a good rational for B-cell malignancies as CD19 expression is limited to B-cell malignancies and normal B cells. The in vivo amplification of the transduced T cells relies on signaling and co-signaling domains and provides significant killing of CLL cells. As exciting as these novel agents and approaches are, they obviously beg the question, will chemotherapy as a treatment for CLL soon be obsolete? Although chemotherapy is associated with known short-term toxicities, it has the advantage of being completed in a short period of time and being relatively inexpensive in comparison to novel therapies. In addition, long-term follow-up of results with chemoimmunotherapy have now identified a group of patients whose remissions are maintained for more than 10 years. An important question that will arise going forward is how to incorporate novel agents without eliminating the long term benefits possible with chemoimmunotherapy in a subset of patients with CLL.
Indications for Allogeneic Hematopoietic Cell Transplantation for Acute Myeloid Leukemia in the Genomic Era
Authors: Appelbaum Frederick R.
Published: May 2014

Few choices in medical oncology are as stark as the decision of whether or not to proceed with allogeneic hematopoietic cell transplantation (HCT) in the treatment of acute myeloid leukemia (AML). Recent advances provide more information to inform the decision, including molecular studies of leukemia that predict tumor responsiveness, assays of minimal residual disease that measure early treatment outcome, and comorbidity indices that predict nonrelapse mortality. Although large prospective studies incorporating all of these factors are lacking, literature reviews and consensus statements exist that can help the clinician in this difficult choice. Allogeneic HCT should be considered for all patients younger than age 65, with an available donor, an acceptable comorbidity index, and whose had initial induction therapy has failed. Similarly, allogeneic HCT is appropriate therapy for all patients with AML in second remission younger than age 75, with an appropriate donor, and a comorbidity index of 5 or less. For patients younger than age 60 with AML in first complete remission (CR), there is little evidence that HCT benefits those with favorable-risk disease who achieve CR with one cycle of induction and have no evidence of minimal residual disease. Allogeneic HCT is indicated for essentially all other categories of patients. For those age 60 and older, few prospective studies are available on which to base recommendations, but, as in younger patients, the benefit of allogeneic HCT is questionable for patients with favorable-risk AML. For patients with higher-risk disease, allogeneic HCT is a reasonable option with the caution that the risk of HCT increases dramatically in those with a comorbidity index of 3 or higher.
New Molecular Abnormalities and Clonal Architecture in AML: From Reciprocal Translocations to Whole-Genome Sequencing
Authors: Graubert Timothy A. , Brunner Andrew M. , Fathi Amir T.
Published: May 2014

Acute myeloid leukemia (AML) is characterized by recurrent genetic alterations, including amplifications, deletions, rearrangements, and point mutations. Clinically, these lesions can be used to stratify patients into categories of risk, which directs further clinical management and prognostication. Patient risk categories were first described based on recurrent karyotypic abnormalities; most patients with AML, however, fall into intermediate cytogenetic risk, the majority harboring a normal karyotype. Subsequently, identification of recurrently mutated genes, including FLT3, NPM1, and CEBPA, allowed further stratification of patients with a normal karyotype. More extensive genomic and epigenomic analysis of AML samples has expanded the number of known molecular alterations present in this disease. The further understanding of this mutational landscape has shed light into the pathogenesis of AML. AML arises in a founding clone that often gives rise to subclones. Clonal evolution is a feature of the natural history of the disease but may also be influenced by the selective pressure of chemotherapy. The complex network of genetic and epigenetic alterations in this disease has yielded numerous new targets for intervention. In the future, further understanding of this mutational framework, along with the development of novel therapeutic targets, may lead to improved outcomes for patients with AML.
Optimizing Chemotherapy in Triple-Negative Breast Cancer: The Role of Platinum
Authors: Telli Melinda
Published: May 2014

Although characterization of triple-negative breast cancer (TNBC) using mRNA gene expression profiling has certainly provided important insights, the concept of targeting DNA repair defects with DNA damaging therapeutics such as platinum in TNBC has been advanced from studies focusing on both germline and somatic genetic alterations associated with this breast cancer subtype. A growing body of preclinical and clinical data suggests that platinum chemotherapy has a potential role to play in the treatment of both early-stage and advanced TNBC, though results are not yet definitive. Randomized clinical trials that incorporate biomarkers of response, including germline BRCA1 and BRCA2 mutation status as well as tumor-based measures of genomic “scarring” resulting from the accumulation of DNA damage in tumors with deficient repair capacity, will help to clarify the optimal use and activity of platinum in TNBC.
Community Oncology in an Era of Payment Reform
Authors: Cox John V. , Ward Jeffery C. , Hornberger John C. , Temel Jennifer S. , McAneny Barbara L.
Published: May 2014

Patients and payers (government and private) are frustrated with the fee-for-service system (FFS) of payment for outpatient health services. FFS rewards volume and highly valued services, including expensive diagnostics and therapeutics, over lesser valued cognitive services. Proposed payment schemes would incent collaboration and coordination of care among providers and reward quality. In oncology, new payment schemes must address the high costs of all services, particularly drugs, while preserving the robust distribution of sites of service available to patients in the United States. Information technology and personalized cancer care are changing the practice of oncology. Twenty-first century oncology will require increasing cognitive work and shared decision making, both of which are not well regarded in the FFS model. A high proportion of health care dollars are consumed in the final months of life. Effective delivery of palliative and end-of-life care must be addressed by practice and by new models of payment. Value-based reimbursement schemes will require oncology practices to change how they are structured. Lessons drawn from the principles of primary care's Patient Centered Medical Home (PCMH) will help oncology practice to prepare for new schemes. PCMH principles place a premium on proactively addressing toxicities of therapies, coordinating care with other providers, and engaging patients in shared decision making, supporting the ideal of value defined in the triple aim—to measurably improve patient experience and quality of care at less cost. Payment reform will be disruptive to all. Oncology must be engaged in policy discussions and guide rational shifts in priorities defined by new payment models.
Taking on Challenging Targets: Making MYC Druggable
Authors: Horiuchi Dai , Anderton Brittany , Goga Andrei
Published: May 2014

The transcription factor proto-oncogene c-MYC (hereafter MYC) was first identified more than 3 decades ago and has since been found deregulated in a wide variety of the most aggressive human malignancies. As a pleiotropic transcription factor, MYC directly or indirectly controls expression of hundreds of coding and noncoding genes, which affect cell cycle entry, proliferation, differentiation, metabolism, and death/survival decisions of normal and cancer cells. Tumors with elevated MYC expression often exhibit highly proliferative, aggressive phenotypes, and elevated MYC expression has been correlated with diminished disease-free survival for a variety of human cancers. The use of MYC overexpression or MYC-dependent transcriptional gene signatures as clinical biomarkers is currently being investigated. Furthermore, preclinical animal and cell-based model systems have been extensively utilized in an effort to uncover the mechanisms of MYC-dependent tumorigenesis and tumor maintenance. Despite our ever-growing understanding of MYC biology, currently no targeted therapeutic strategy is clinically available to treat tumors that have acquired elevated MYC expression. This article summarizes the progresses being made to discover and implement new therapies to kill MYC over-expressing tumors—a target that was once deemed undruggable.
The Horizon of Precision Medicine in Breast Cancer: Fragmentation, Alliance, or Reunification?
Authors: Andre Fabrice , Vicier Cecile , Delaloge Suzette
Published: May 2014

Genomic studies have shown that breast cancer includes a large number of targetable genomic alterations. Most of these genomic alterations are rare and can evolve during the natural history of the disease. Three paths are being followed to develop precision medicine in metastatic breast cancer. First, the conventional path will consist of fragmenting the disease and developing drugs in each rare genomic segment. This will require screening large numbers of patients for genomic alterations to run the therapeutic trials, especially the registration trials. The second path will consist in clustering rare genomic alterations in more frequent segments defined by an altered pathway. Finally, one possible path for precision medicine will be to test genomic algorithms for the whole patient population with metastatic breast cancer. This latter scenario would reunify breast cancer into a single entity and test whether the use of genomics would improve outcomes in this population of patients. Challenges and perspective in the field of precision medicine will include the prediction of resistance, the integration of immunology, and DNA repair in the genomic algorithms and the transfer of concepts to early-stage breast cancers.
Hype versus Hope: Metformin and Vitamin D as Anticancer Agents
Authors: Lohmann Ana Elisa , Goodwin Pamela J.
Published: May 2014

There has been increasing interest in the use of metformin and vitamin D to reduce cancer risk and improve outcomes. Metformin, an oral antidiabetic drug, improves insulin resistance and has been associated with reduced cancer incidence and cancer mortality. Low levels of vitamin D have also been associated with increased cancer risk, mainly in retrospective studies, and it has been suggested that vitamin D supplementation might play a role in cancer prevention. Preclinical data provide a biologic rationale for these associations; however, the human data arise predominantly from observational studies and caution is needed in their translation into clinical practice. This is because of the recognized limitations of observational studies, such as time-related survival biases, selection and referral biases, short follow-up, and the presence of confounding factors that can lead to spurious or inaccurate findings. Combined examination of associations with cancer risk and outcome (occurring when exposure in a population that does not yet have cancer is analyzed in relation to cancer death) may yield results that are difficult to interpret. Finally, associations across all cancers may differ from those in specific cancer types. These shortcomings can be overcome in properly designed and adequately powered prospective randomized trials; however, such trials are both expensive and time consuming. We review the literature examining the associations of metformin and vitamin D with cancer, discussing weakness and strengths and making recommendations for further research and clinical practice.
Shedding Light on Adult Medulloblastoma: Current Management and Opportunities for Advances
Authors: Brandes Alba A. , Franceschi Enrico
Published: May 2014

Few evidence-based guidelines are available for the treatment of adult medulloblastoma, an extremely rare disease. Therapeutic regimens, typically modeled following pediatric protocols, consist of surgical resection followed by radiotherapy with or without adjuvant chemotherapy. Because of the rarity of this disease in adults, any treatment undertaken is based mainly on small and retrospective studies. Unlike pediatric patients, adults with medulloblastoma have been treated according to risk-adapted therapeutic strategies in only a few prospective studies. Overall, approximately 30% of patients experience recurrence and die of disease-related causes. Although the patients could respond to second-line treatments, the prognosis of patients with recurrence remains dismal. An important challenge for the future will be the biologic characterization of medulloblastoma in adults, with the identification of specific genetic patterns of patients with different prognosis and different response to targeted treatments.
For the Next Trick: New Discoveries in Radiobiology Applied to Glioblastoma
Authors: Debus Juergen , Abdollahi Amir
Published: May 2014

Glioblastoma (GBM) is the most common malignant brain tumor. Radiotherapy post surgical resection remained the mainstay of the management of GBM for decades until the addition of temozolomide was shown to prolong the median overall survival (OS) by 2.5 months to 14.6 months in 2005. Infiltrative growth to surrounding normal brain tissue and cooption of vascular niches, peripheral microvasuclar hyperplasia, and central hypoxic regions with pseudopalisading necrosis are characteristics of GBM and are causally linked to their exceptional radio- and chemo-resistant phenotype. An intratumoral hierarchy is postulated consisting of tumor stem cells in the apex with high DNA-repair proficiency resisting radiotherapy. It is conceivable that the stem cell property is more dynamic than originally anticipated. Niche effects such as exposure to hypoxia and intercellular communication in proximities to endothelial or bone marrow–derived cells (BMDC), for example, may activate such “stem cell” programs. GBM are exceptionally stroma-rich tumors and may consist of more than 70% stroma components, such as microglia and BMDC. It becomes increasingly apparent that treatment of GBM needs to integrate therapies targeting all above-mentioned distinct pathophysiological features. Accordingly, recent approaches in GBM therapy include inhibition of invasion (e.g., integrin, EGFR, CD95, and mTOR inhibition), antiangiogenesis and stroma modulators ( TGFbeta, VEGF, angiopoetin, cMET inhibitors) and activation of immune response (vaccination and blockage of negative co-stimulatory signals). In addition, high LET-radiotherapy, for example with carbon ions, is postulated to ablate tumor stem cell and hypoxic cells more efficiently as compared with conventional low-LET photon irradiation. We discuss current key concepts, their limitations, and potentials to improve the outcome in this rapidly progressive and devastating disease.
Spinoza über Tiere
Authors: Perler Dominik
Published: May 2014

According to Spinoza, there is no categorical distinction between human and non-human animals: they all belong to the same nature and all consist of bodies with corresponding ideas. This thesis gives rise to two problems. How is it possible to distinguish different types of animals, in particular nonrational and rational ones, if all of them have the same metaphysical structure? And why does Spinoza nevertheless claim that human beings have a privileged status that gives them the right to use non-rational animals? This paper examines these two problems, arguing that the solution to both of them lies in Spinoza’s all-embracing naturalism.
Petrinetzmodell für die Formalisierung von
GRAFCET-Spezifikationen
Authors: Schumacher Frank , Fay Alexander
Published: May 2014

GRAFCET ist ein ausdrucksstarkes grafisches Beschreibungsmittel zur
Spezifikation von Steuerungsabläufen. Eine
implementierungsunabhängige rechnergestützte Handhabung ist bisher
allerdings nicht möglich. Der nachfolgende Beitrag
stellt einen Ansatz vor, wie
GRAFCET-Spezifikationen systematisch formalisiert
werden können. Somit wird eine automatische
Generierung von SPS-Code aus GRAFCET
möglich.
Verfahren zur Lösung von hybriden Optimalsteuerungsproblemen und deren Anwendung auf den Betrieb von Hybridfahrzeugen
Authors: Schori Markus , Böhme Thomas J. , Becker Uwe , Schultalbers Matthias
Published: May 2014

In diesem Beitrag werden Algorithmen zur Approximation einer Lösung
von Optimalsteuerungsproblemen (OSP) für hybride Systeme
vorgeschlagen. Die Algorithmen eignen sich dabei für hybride OSPs
unterschiedlicher Komplexität. Ein Beispiel für ein solches hybrides
System stellen parallele Hybridfahrzeuge dar, die sowohl
kontinuierliche Freiheitsgrade, als auch diskrete Freiheitsgrade
aufweisen. Der kraftstoffoptimale Betrieb eines Hybridfahrzeuges kann
daher als hybrides OSP formuliert werden. Die Anwendbarkeit der
vorgeschlagenen Algorithmen wird anhand dieses Beispiels demonstriert.
Für eine neue Geschichtsphilosophie
Authors: Rohbeck Johannes
Published: May 2014

The central idea of this paper is that our contemporary historical awareness which is increasingly turning towards the future is accessible to philosophical reflection. This raises the question whether we need a new Philosophy of History which refers less to the past, but rather aims primarily at present and future problems. If thereby a moral responsibility for future generations is addressed, Philosophy of History then goes hand in hand with Future Ethics. By means of this programme I expressly follow the Philosophy of History since the European Enlightenment. This entails an ethical perspective since progress in history is not simply predicted, but is more or less explicitly declared as desirable tendency.
A Tutorial on Interaction
Authors: VanderWeele Tyler J. , Knol Mirjam J.
Published: May 2014

In this tutorial, we provide a broad introduction to the topic of interaction between the effects of exposures. We discuss interaction on both additive and multiplicative scales using risks, and we discuss their relation to statistical models (e.g. linear, log-linear, and logistic models). We discuss and evaluate arguments that have been made for using additive or multiplicative scales to assess interaction. We further discuss approaches to presenting interaction analyses, different mechanistic forms of interaction, when interaction is robust to unmeasured confounding, interaction for continuous outcomes, qualitative or “crossover” interactions, methods for attributing effects to interactions, case-only estimators of interaction, and power and sample size calculations for additive and multiplicative interaction.