bluuebunny/crossref_metadata_2025 huggingface dataset:
Theoretical analysis of non‐Gaussian heterogeneity effects on subsurface flow and transport
Authors: Riva Monica , Guadagnini Alberto , Neuman Shlomo P.
Published: March 2017

Much of the stochastic groundwater literature is devoted to the analysis of flow and transport in Gaussian or multi‐Gaussian log hydraulic conductivity (or transmissivity) fields,
(x being a position vector), characterized by one or (less frequently) a multiplicity of spatial correlation scales. Yet Y and many other variables and their (spatial or temporal) increments, ΔY, are known to be generally non‐Gaussian. One common manifestation of non‐Gaussianity is that whereas frequency distributions of Y often exhibit mild peaks and light tails, those of increments
are generally symmetric with peaks that grow sharper, and tails that become heavier, as separation scale or lag between pairs of Y values decreases. A statistical model that captures these disparate, scale‐dependent distributions of Y and
in a unified and consistent manner has been recently proposed by us. This new “generalized sub‐Gaussian (GSG)” model has the form
where
is (generally, but not necessarily) a multiscale Gaussian random field and
is a nonnegative subordinator independent of G. The purpose of this paper is to explore analytically, in an elementary manner, lead‐order effects that non‐Gaussian heterogeneity described by the GSG model have on the stochastic description of flow and transport. Recognizing that perturbation expansion of hydraulic conductivity
diverges when Y is sub‐Gaussian, we render the expansion convergent by truncating Y's domain of definition. We then demonstrate theoretically and illustrate by way of numerical examples that, as the domain of truncation expands, (a) the variance of truncated Y (denoted by Yt) approaches that of Y and (b) the pdf (and thereby moments) of Yt increments approach those of Y increments and, as a consequence, the variogram of
approaches that of
. This in turn guarantees that perturbing
to second order in
(the standard deviation of Yt) yields results which approach those we obtain upon perturbing
to second order in
even as the corresponding series diverges. Our analysis is rendered mathematically tractable by considering mean‐uniform steady state flow in an unbounded, two‐dimensional domain of mildly heterogeneous Y with a single‐scale function G having an isotropic exponential covariance. Results consist of expressions for (a) lead‐order autocovariance and cross‐covariance functions of hydraulic head, velocity, and advective particle displacement and (b) analogues of preasymptotic as well as asymptotic Fickian dispersion coefficients. We compare these theoretically and graphically with corresponding expressions developed in the literature for Gaussian Y. We find the former to differ from the latter by a factor k = 
(
denoting ensemble expectation) and the GSG covariance of longitudinal velocity to contain an additional nugget term depending on this same factor. In the limit as Y becomes Gaussian, k reduces to one and the nugget term drops out.
PeaksOverThreshold (POT): A methodology for automatic threshold estimation using goodness of fitp‐value
Authors: Solari Sebastián , Egüen Marta , Polo María José , Losada Miguel A.
Published: March 2017

Threshold estimation in the Peaks Over Threshold (POT) method and the impact of the estimation method on the calculation of high return period quantiles and their uncertainty (or confidence intervals) are issues that are still unresolved. In the past, methods based on goodness of fit tests and EDF‐statistics have yielded satisfactory results, but their use has not yet been systematized. This paper proposes a methodology for automatic threshold estimation, based on the Anderson‐Darling EDF‐statistic and goodness of fit test. When combined with bootstrapping techniques, this methodology can be used to quantify both the uncertainty of threshold estimation and its impact on the uncertainty of high return period quantiles. This methodology was applied to several simulated series and to four precipitation/river flow data series. The results obtained confirmed its robustness. For the measured series, the estimated thresholds corresponded to those obtained by nonautomatic methods. Moreover, even though the uncertainty of the threshold estimation was high, this did not have a significant effect on the width of the confidence intervals of high return period quantiles.
Multiscale temporal variability and regional patterns in 555 years of conterminous U.S. streamflow
Authors: Ho Michelle , Lall Upmanu , Sun Xun , Cook Edward R.
Published: March 2017

The development of paleoclimate streamflow reconstructions in the conterminous United States (CONUS) has provided water resource managers with improved insights into multidecadal and centennial scale variability that cannot be reliably detected using shorter instrumental records. Paleoclimate streamflow reconstructions have largely focused on individual catchments limiting the ability to quantify variability across the CONUS. The Living Blended Drought Atlas (LBDA), a spatially and temporally complete 555 year long paleoclimate record of summer drought across the CONUS, provides an opportunity to reconstruct and characterize streamflow variability at a continental scale. We explore the validity of the first paleoreconstructions of streamflow that span the CONUS informed by the LBDA targeting a set of U.S. Geological Survey streamflow sites. The reconstructions are skillful under cross validation across most of the country, but the variance explained is generally low. Spatial and temporal structures of streamflow variability are analyzed using hierarchical clustering, principal component analysis, and wavelet analyses. Nine spatially coherent clusters are identified. The reconstructions show signals of contemporary droughts such as the Dust Bowl (1930s) and 1950s droughts. Decadal‐scale variability was detected in the late 1900s in the western U.S., however, similar modes of temporal variability were rarely present prior to the 1950s. The twentieth century featured longer wet spells and shorter dry spells compared with the preceding 450 years. Streamflows in the Pacific Northwest and Northeast are negatively correlated with the central U.S. suggesting the potential to mitigate some drought impacts by balancing economic activities and insurance pools across these regions during major droughts.
Biofuel as an Integrated Farm Drainage Management crop: A bioeconomic analysis
Authors: Levers L. R. , Schwabe K. A.
Published: March 2017

Irrigated agricultural lands in arid regions often suffer from soil salinization and lack of drainage, which affect environmental quality and productivity. Integrated Farm Drainage Management (IFDM) systems, where drainage water generated from higher‐valued crops grown on high quality soils are used to irrigate salt‐tolerant crops grown on marginal soils, is one possible strategy for managing salinity and drainage problems. If the IFDM crop were a biofuel crop, both environmental and private benefits may be generated; however, little is known about this possibility. As such, we develop a bioeconomic programming model of irrigated agricultural production to examine the role salt‐tolerant biofuel crops might play within an IFDM system. Our results, generated by optimizing profits over land, water, and crop choice decisions subject to resource constraints, suggest that based on the private profits alone, biofuel crops can be a competitive alternative to the common practices of land retirement and nonbiofuel crop production under both low to high drainage water salinity. Yet IFDM biofuel crop production generates 30–35% fewer GHG emissions than the other strategies. The private market competitiveness coupled with the public good benefits may justify policy changes encouraging the growth of IFDM biofuel crops in arid agricultural areas globally.
Hyphenated hydrology: Interdisciplinary evolution of water resource science
Authors: McCurley Kathryn L. , Jawitz James W.
Published: March 2017

Hydrology has advanced considerably as a scientific discipline since its recognized inception in the mid‐twentieth century. Modern water resource related questions have forced adaptation from exclusively physical or engineering science viewpoints toward a deliberate interdisciplinary context. Over the past few decades, many of the eventual manifestations of this evolution were foreseen by prominent expert hydrologists. However, their narrative descriptions have lacked substantial quantification. This study addressed that gap by measuring the prevalence of and analyzing the relationships between the terms most frequently used by hydrologists to define and describe their research. We analyzed 16,591 journal article titles from 1965–2015 in Water Resources Research, through which the scientific dialogue and its time‐sensitive progression emerged. Our word frequency and term cooccurrence network results revealed the dynamic timing of the lateral movement of hydrology across multiple disciplines as well as the deepening of scientific discourse with respect to traditional hydrologic questions. The conversation among water resource scientists surrounding the hydrologic subdisciplines of catchment‐hydrology, hydro‐meteorology, socio‐hydrology, hydro‐climatology, and eco‐hydrology gained statistically significant momentum in the analyzed time period, while that of hydro‐geology and contaminant‐hydrology experienced periods of increase followed by significant decline. This study concludes that formerly exotic disciplines can potentially modify hydrology, prompting new insights and inspiring unconventional perspectives on old questions that may have otherwise become obsolete.
Chorus whistler wave source scales as determined from multipoint Van Allen Probe measurements
Authors: Agapitov O. , Blum L. W. , Mozer F. S. , Bonnell J. W. , Wygant J.
Published: March 2017

Whistler mode chorus waves are particularly important in outer radiation belt dynamics due to their key role in controlling the acceleration and scattering of electrons over a very wide energy range. The key parameters for both nonlinear and quasi‐linear treatment of wave‐particle interactions are the temporal and spatial scales of the wave source region and coherence of the wave field perturbations. Neither the source scale nor the coherence scale is well established experimentally, mostly because of a lack of multipoint VLF waveform measurements. We present an unprecedentedly long interval of coordinated VLF waveform measurements (sampled at 16384 s−1) aboard the two Van Allen Probes spacecraft—9 h (0800–1200 UT and 1700–2200 UT) during two consecutive apogees on 15 July 2014. The spacecraft separations varied from about 100 to 5000 km (mostly radially); measurements covered an L shell range from 3 to 6; magnetic local time 0430–0900, and magnetic latitudes were ~15 and ~5° during the two orbits. Using time‐domain correlation techniques, the single chorus source spatial extent transverse to the background magnetic field has been determined to be about 550–650 km for upper band chorus waves with amplitudes less than 100 pT and up to 800 km for larger amplitude, lower band chorus waves. The ratio between wave amplitudes measured on the two spacecraft is also examined to reveal that the wave amplitude distribution within a single chorus element generation area can be well approximated by a Gaussian exp(−0.5 · r2/r02), with the characteristic scale r0 around 300 km. Waves detected by the two spacecraft were found to be coherent in phase at distances up to 400 km.
The global distribution of Earth's critical zone and its controlling factors
Authors: Xu Xianli , Liu Wen
Published: March 2017

The near‐surface layer of Earth which provides essential elements for supporting life is now recognized as the critical zone (CZ). This study provides the first global assessment of the CZ thickness (CZT) and its controlling factors by combining data sets of climate, vegetation height (VH), water table depth (WTD), groundwater thickness (GWT), topography, and lithologic data. The analysis shows that CZT ranges from 0.7 to 223.5 m with an average value of 36.8 m across continental areas; CZT is thickest in midlatitudes (subtropical to temperate zones). The proportion of aboveground part (VH) to CZT is 19.9 ± 16.7% (mean ±one standard deviation), while it is 80.1 ± 16.7% for the underground part (WTD + GWT). A generalized linear model shows that compound topographic index (ln(a/tan(b)), where a is the upslope contributing area and b is the slope degree of the landscape) and potential evapotranspiration are the first two major controlling factors on the variations in CZT. This study opens opportunities for further advancing CZ science by providing one of its most important properties—its thickness.
The Hfq regulon of Neisseria meningitidis
Authors: Huis in ‘t Veld Robert A. G. , Kramer Gertjan , van der Ende Arie , Speijer Dave , Pannekoek Yvonne
Published: March 2017

The conserved RNA‐binding protein, Hfq, has multiple regulatory roles within the prokaryotic cell, including promoting stable duplex formation between small RNAs and mRNAs, and thus hfq deletion mutants have pleiotropic phenotypes. Previous proteome and transcriptome studies of Neisseria meningitidis have generated limited insight into differential gene expression due to Hfq loss. In this study, reversed‐phase liquid chromatography combined with data‐independent alternate scanning mass spectrometry (LC‐MSE) was utilized for rapid high‐resolution quantitative proteomic analysis to further elucidate the differentially expressed proteome of a meningococcal hfq deletion mutant. Whole‐cell lysates of N. meningitidis serogroup B H44/76 wild‐type (wt) and H44/76Δhfq (Δhfq) grown in liquid growth medium were subjected to tryptic digestion. The resulting peptide mixtures were separated by liquid chromatography (LC) prior to analysis by mass spectrometry (MSE). Differential expression was analyzed by Student's t‐test with control for false discovery rate (FDR). Reliable quantitation of relative expression comparing wt and Δhfq was achieved with 506 proteins (20%). Upon FDR control at q ≤ 0.05, 48 up‐ and 59 downregulated proteins were identified. From these, 81 were identified as novel Hfq‐regulated candidates, while 15 proteins were previously found by SDS/PAGE/MS and 24 with microarray analyses. Thus, using LC‐MSE we have expanded the repertoire of Hfq‐regulated proteins. In conjunction with previous studies, a comprehensive network of Hfq‐regulated proteins was constructed and differentially expressed proteins were found to be involved in a large variety of cellular processes. The results and comparisons with other gram‐negative model systems, suggest still unidentified sRNA analogs in N. meningitidis.
The neuronal and astrocytic proteinSLC38A10 transports glutamine, glutamate, and aspartate, suggesting a role in neurotransmission
Authors: Hellsten Sofie V. , Hägglund Maria G. , Eriksson Mikaela M. , Fredriksson Robert
Published: March 2017

In brain cells, glutamine transporters are vital to monitor and control the levels of glutamate andGABA. There are 11 members of theSLC38 family of amino acid transporters of which eight have been functionally characterized. Here, we report the first histological and functional characterization of the previously orphan member,SLC38A10. We used pairwise global sequence alignments to determine the sequence identity between theSLC38 family members.SLC38A10 was found to share 20–25% transmembrane sequence identity with several family members, and was predicted to have 11 transmembrane helices.SLC38A10 immunostaining was abundant in mouse brain using a custom‐made anti‐SLC38A10 antibody and colocalization ofSLC38A10 immunoreactivity with markers for neurons and astrocytes was detected. UsingXenopus laevisoocytes overexpressingSLC38A10, we show thatSLC38A10 mediates bidirectional transport ofl‐glutamine,l‐alanine,l‐glutamate, andd‐aspartate, and efflux ofl‐serine. This profile mostly resembles system A members of theSLC38 family. In conclusion, the bidirectional transport of glutamine, glutamate, and aspartate bySLC38A10, and the immunostaining detected in neurons and astrocytes, suggest thatSLC38A10 plays a role in pathways involved in neurotransmission.
Cancer Genomics and Evolution
Authors: Hendricks William P. D. , Sekulic Aleksandar , Bryce Alan H. , Murtaza Muhammed , Ramos Pilar , Trent Jeffrey M.
Published: March 2017

Overview

Over 100 years ago, the Nobel Prize in Physiology or Medicine was given to Paul Ehrlich for postulating that “magic bullets” could specifically target and kill cells such as cancer cells based on their unique molecular features. The completed Human Genome Project and the cancer genomics revolution have now mapped the specific genetic changes underlying unique features of many common malignancies. However, although cancer has long been recognized to be heterogeneous in its clinical presentation, course, and pathology, we now recognize that it is far more molecularly heterogeneous than anticipated and that such variability will require an individualized approach to patient care. Rather than a single magic bullet, we will need an arsenal and this arsenal will require precise delivery. While inter‐ and intratumoral genomic heterogeneity present significant challenges to cancer management and drug discovery, a number of developments foster hope for accelerated progress in the war on cancer. First, our catalog of genomic targets underlying diverse cancers is rapidly growing. Second, we are beginning to understand how diverse mutations converge on a small number of druggable pathways. Third, we continue to develop drugs and biologic agents (e.g., immune checkpoint inhibitors) that target an increasingly wide array of genomic subtypes of cancer. Finally, advances in next‐generation sequencing technologies now enable far earlier detection of disease recurrence than ever before. This chapter will focus on these developments and how their integration is aiding in the precise delivery of “magic bullets.”
MicroRNA
Expression in Cancer
Authors: Nana‐Sinkam Serge Patrick , Acunzo Mario , Croce Carlo M.
Published: March 2017

Overview

In the last two decades, researchers have identified a novel group of noncoding RNAs (ncRNAs) classified according to their function and size. The best studied of these ncRNAs termed microRNAs (miRNAs) are short noncoding RNAs that are approximately 22 nucleotides in length and play a key role in the regulation of a large number of biological processes and diseases, including cancer. Since the initial description of an association between miRNA and cancer in 2002, miRNAs have emerged as central regulators of processes fundamental to the initiation and progression of cancer. More recently, miRNAs have been detected in bodily fluids including blood, sputum, and urine, thus making them potential noninvasive diagnostic and prognostic biomarkers of disease. The application of miRNAs in human cancer therapy has become a fascinating field of study, representing one of the newest frontiers for cancer treatment. However, our knowledge for these small molecules and their application to human cancers is still growing. In this chapter, we provide an overview of the connection between miRNAs and cancer with a focus on translation to human application.
Cancer Cell Immortality: Targeting Telomerase
Authors: Mender Ilgen , Gunnur Dikmen Zeliha , Wright Woodring E. , Shay Jerry W.
Published: March 2017

Overview

Finding specific targeted agents for cancer therapy remains a challenge. One of the hallmarks of cancer is the limitless proliferation (immortalization) of cancer cells, which correlates with the activation of the ribonucleoprotein enzyme complex called telomerase. As 85–90% of primary human cancers express telomerase activity, while most normal cells do not, telomerase is a unique and almost universal therapeutic target for cancer. Although there have been several approaches developed for telomerase‐targeted therapies, there is still no agent that has been approved. This chapter focuses on the pros and cons of the different approaches to target telomerase and summarizes preclinical and clinical results. We will also review novel telomerase‐mediated telomere uncapping approaches that target telomerase‐expressing cancer cells, but not normal cells.
Systems Biology and Genomics
Authors: Hassan Saima , Heiser Laura M. , Gray Joe W.
Published: March 2017

Overview

Cancers are complex, adaptive systems comprised of cancer cells, the proximal and distal cells, and soluble and insoluble proteins that influence the behavior of the cancer cells. Features pertaining to the cancer are referred to as intrinsic to the cancer and those comprising the proximal and distal microenvironments are referred to as extrinsic to the cancer. Genomics studies seek to develop comprehensive cellular and molecular profiles of cancers and cancer systems biology studies seek to develop the experimental and theoretical methods needed to understand how the components work together to determine cancer function. The overall goal of these efforts is to develop the ability to predict the behavior of cancers—including progression and response to therapy—from measurements of the intrinsic and extrinsic molecular and cellular components of the cancers. Here, we review recent progress in international efforts to measure the genomic, epigenomic, and proteomic features (aka omic features) of major tumor types. We summarize work on establishing associations between omic features and cancer behavior. Finally, we summarize the computational and experimental models that are currently being used to understand and manipulate the behavior of complex cancer systems.
Clinical Informatics
Authors: Ambinder Edward P.
Published: March 2017

Overview

Informatics is the integration of information technology into health care. For oncology, the need to understand informatics is critical because of the need to keep up with the rapidly changing basic, translational and clinical cancer research findings, therapeutic interventions using panomic data required for precision medicine, latest practice guidelines, shifting reimbursement practices, and the dominating and at times frustrating electronic health record (EHR) that is the repository of our health data and window into the health care system. All of this must take place in a value‐enhanced practice environment that constantly measures our quality of care in a well‐coordinated system for our engaged patients who are digitally connected to multiple practices, their hospital, their smartphones and medical devices, their personal health record and multiple EHRs. Oncologists will soon have a well‐defined “Oncology Digital Health Information Technology System” that will redefine cancer research by capturing meaningful and actionable patient data in every cancer patient. They will continue to participate in the mobile computing revolution that is just beginning to have a transformative effect on all of medicine where computers will do our work, apps work with other apps and EHRs to educate us and our patients and use real electronically shareable and reusable medical data. Today, the majority of patients have their cancer care documented in EHRs. As rapid learning systems (RLSs) such as ASCO's CancerLinQ capture all this data and use Big Data analytic tools for capturing and comparing similar cancer patients as to the best treatments and outcomes, we will have real precision medicine. The evolving “Internet of Things” where medical devices and health care platforms will give us the unprecedented ability to measure in real time the health and wellness of our cancer patients undergoing chemotherapy treatments on a 24‐h basis will provide huge monetary savings for the health system, improved quality of care, and innovative medical research as cancer care develops into a RLS.
Ultraviolet Radiation Carcinogenesis
Authors: Cleaver James E. , Ortiz‐Urda Susana , Gulhar Radhika , T. Arron Sarah , Brookes Lionel , Mitchell David L.
Published: March 2017

Overview

Skin carcinogenesis from solar ultraviolet (UV) exposure is initiated by UV photoproducts formed in the DNA of precursor cells that give rise to squamous cell carcinomas, basal cell carcinomas, and melanomas. These photoproducts consist of dimers between adjacent pyrimidines that are repaired by nucleotide excision repair (NER). Two branches of NER differ in mechanisms of damage recognition: in global genome repair (GGR), damage is recognized in nontranscribed DNA by the DDB2 and XPC proteins; in transcription‐coupled repair (TCR), damage is recognized by arrest of the transcribing RNA polymerase at damaged sites. The T = C photoproduct is the predominant mutagenic product which, if unrepaired, gives rise to C to T or CC to TT mutations through replication by the low‐fidelity polymerase Pol H. TCR reduces the mutation frequency in regions of transcription, in comparison to the rest of the genome subject to GGR. Deficiencies in GGR in the human disease xeroderma pigmentosum cause earlier onset and increased rates of skin cancer, which often contain UV‐type mutations in genes that are rarely mutated in the general population. Deficiencies in TCR in the human disease Cockayne syndrome are associated with photosensitivity, developmental, and neurological disorders, but no cancer has been reported.
Parasites
Authors: El Azzouni Mervat Z. , Diab Radwa G.
Published: March 2017

Overview

Many parasites were studied for a possible role in oncogenesis.Schistosoma haematobiumwas proved to play an important role in developing urinary bladder cancer. OtherSchistosomaspecies,Schistosoma japonicumis classified as a colorectal carcinogen especially in the Far East. Other helminthsClonorchisandOpisthorchisare proved to induce hepatobiliary cancer. In Africa, a strong correlation between Ebstein–Barr virus infection and Burkitt lymphoma is present, with an evident enhancing role forPlasmodium falciparum. Chronic inflammation was incriminated to be the most accepted mechanism for parasite‐induced cancer; however, the roles of certain carcinogens, oncogenes, DNA mutations, and others were all approved as mechanisms enhancing carcinogenesis in parasitic infections. Strikingly, despite the above‐mentioned data, it seemed that certain parasites can modulate the host immune response in a manner that could lead to cancer regression or prevention. This is in the prospect of revaluation of the clinical importance of infectious agents; an issue that requires future concern.
Chemoprevention of Cancer
Authors: William William N. , Hong Waun Ki , Lippman Scott M.
Published: March 2017

Overview

The field of cancer chemoprevention is underpinned by two phenomena of neoplasia: field carcinogenesis and multistep carcinogenesis. Accurate cancer risk models are critical to chemoprevention and may accelerate drug development in this setting. The Food and Drug Administration has approved several chemoprevention strategies. This chapter describes completed chemoprevention clinical trials focused on the four major cancer sites in the Western world (lung, colon and rectum, prostate, and breast), as well as site‐agnostic chemoprevention studies. The contributions of vaccines to cancer prevention are also discussed.
Principles of Medical Oncology
Authors: Hait William N. , Holland James F. , Frei Emil , Kufe Donald W. , Bast Robert C. , Hong Waun Ki
Published: March 2017

Overview

The practice of medical oncology is evolving more rapidly than any field in medicine. The uncovering of the molecular basis of the numerous malignancies and their subtypes created a seemingly bewildering collection of new information that confronts the practicing physician. Since the principles that underlie the practice of this subspecialty, by definition, should remain constant, they can provide the scaffolding on which new information can be attached. To that end, this chapter attempts to define those immutable areas that apply to the care of the oncology patient, and through their understanding the massive amount of new information presented in this text can be organized.
Principles of Psycho‐Oncology
Authors: Holland Jimmie C. , Wiesel Talia W.
Published: March 2017

Overview

This chapter provides oncologists with the present state of the art in psycho‐oncology, a subspecialty that has evolved over the past 30 years. The basic treatment, particularly pharmacologic, is outlined for anxiety, depression, and delirium, as well as the psychotherapeutic interventions which are based on evidence. The field has come of age since it received the Institute of Medicine blessing in 2008 stating that quality cancer care must integrate the psychosocial domain in routine care. This was given a strong boost from the American College of Surgeons Commission on Cancer which made screening for distress a quality standard for accreditation in 2015, requiring that all cancer centers have in place—or in development—an on‐site program to identify and triage patients who are distressed. This has resulted in a strong effort to develop routine screening of all new patients to assure that they are recognized early and treated appropriately. Implementation of programs is in progress across the country with assistance available from the American Psychosocial Oncology Society (APOS) which has organized training, consultation, and ongoing mentoring for cancer staff. Indeed, thanks to these changes in national policy related to cancer, it is a different experience for patients today to cope with cancer. Attention has turned to providing patient‐centered care which encompasses care of the whole person.
Preclinical and Early Clinical Development of Chemotherapeutic Drugs, Mechanism‐Based Agents and Biologics
Authors: Hanauske Axel‐R. , Von Hoff Daniel D.
Published: March 2017

Overview

Over the past 10 years, the approach to drug development has changed considerably. Owing to the enormous increase in insights into the molecular biology of cancer cells, a largely empirical approach has been mostly abandoned and replaced with a biology‐driven, hypothesis‐based, and translational approach. Notwithstanding this dramatic development, the hierarchical sequence of clinical drug‐development trials basically remained unchanged and is divided into three phases. This chapter provides an overview of the various steps of early clinical development with milestones of the drug‐development process, the role of the National Cancer Institute, and the switch to mechanism‐based drug development. It outlines challenges in the clinical development of these new agents and provides a fundamental understanding of the complexity involved in early clinical drug development.
Cytokines, Interferons, and Hematopoietic Growth Factors
Authors: Ekmekcioglu Suhendan , Grimm Elizabeth A.
Published: March 2017

Overview

Cytokines are important mediators of immune responses and produced by almost every cell in the body. Growth stimulatory or inhibitory cytokines could be subclassified as interleukins (ILs), lymphokines, monokines, chemokines, and hematopoietic growth factors. In cancer, certain cytokines act directly on the growth, differentiation, or survival of endothelial cells, whereas others act by attracting inflammatory cell types affecting angiogenesis or by inducing secondary cytokines or other mediators regulating angiogenesis. Proinflammatory and chemotactic cytokines influence the tumor environment and control the quantity and nature of infiltrating hematopoietic effector cells, with inhibiting or enhancing effects on tumor growth. The important role of cytokines in regulating immune responses may permit an effective immune response against the tumors or suppress the function of antigen‐presenting cells (APC).

The understanding of cytokines has now emerged as complex picture of interacting stimulatory and inhibitory factors. Many of the molecules that govern this process have been cloned and have entered clinical trials. It is now clear that regulatory cytokines are characteristically pleiotropic and, at the same time, exhibit significant functional redundancy.

The biologic characterization of the known clinically relevant ILs, interferons and selected growth factors, the rationale for their use in therapy for patients with cancer, and the accumulated clinical experience represent the subjects of this chapter.
Cancer Gene Therapy
Authors: Tashiro Haruko , Brenner Malcolm
Published: March 2017

Overview

Gene therapy of cancer has shown increasingly encouraging results and now is ready to enter mainstream oncological practice. Gene transfer can modify the cellular phenotype and behavior of malignant cells or host immune cells in order to modulate tumor responses. In this chapter, we discuss both of the above approaches and describe the vector systems that are able to produce the intended genetic modifications. We describe current clinical successes of gene therapy and outline the challenges it has yet to overcome. The success of either approach depends on efficient, safe gene transfer with vectors that can either integrate (e.g., retroviral, lentiviral, or adeno‐associated viral, or transposons) or not integrate (e.g., adenoviral, herpesviral, or nonviral) into the human genome. To date, reversing the phenotype of all stem cells within a cancer has not proven feasible, and infectious cytolytic viral therapy has not yet had a significant impact in the clinic. Enhancement of active cancer immunotherapy with forced expression of antigens and cytokines or the enhancement of adoptive immunotherapy by engineering T lymphocytes with specific T‐cell receptors and chimeric antigen receptors shows greater immediate promise, although ultimately a combination of multiple approaches will prove optimal.
Principles of Pediatric Oncology
Authors: Bhatla Teena , Carroll William L.
Published: March 2017

Overview

Pediatric malignancies differ from those that occur in adults in their relative incidence, pathological type, clinical presentation, and prognosis. The last several decades of the twentieth century have been a period of enormous accomplishment in the field of pediatric cancer research and outcomes have steadily improved largely due to results from large well‐controlled clinical trials conducted by various cooperative groups at the national and international level. This chapter seeks to provide a broad overview of pediatric oncology, outlining the several common cancer types that are unique to the pediatric age group.
Cancer and Aging
Authors: Hurria Arti , Muss Hyman B. , Cohen Harvey J.
Published: March 2017

Overview

Cancer is a disease of aging. Approximately sixty percent of all cancers and seventy percent of cancer mortality occurs in people >/= age 65. The number of older adults with cancer is on the rise as the US population is aging. However, there is great heterogeneity in the health status of older adults which may impact cancer treatment decisions and outcomes. This chapter will review the principles of geriatric assessment and frailty, the biology of cancer and aging, as well as the unique issues and considerations in caring for older patients with cancer during treatment and into the survivorship years.
Disparities in Cancer Care
Authors: Brawley Otis W.
Published: March 2017

Overview

Differences in healthcare outcome have become increasingly apparent over the past 50 years. It is especially apparent in cancer, a discipline that has had tremendous advancement. Ironically, the more progress that is made, the greater the disparities become. There are populations that do not enjoy the progress usually because of socioeconomic differences. The field of health disparities has grown into its own discipline within epidemiology. It involves population categorization by race, area of geographic origin, socioecomic status, and so on. The discipline looks at differences in risk of cancer, risk of death, survival, and the survival experience.

A number of well‐designed studies show that equal treatment yields equal outcome among equal patients whether one categorizes population by race, socioeconomics, or other major factors. If people with the same genetic markers are compared, race for example is not a factor in outcome unless it is allowed to be. Numerous patterns of care studies demonstrate that there is not equal treatment by race in the United States. The discipline of health disparities has progressed to include assessment of interventions to reduce disparities.

The advent of precision medicine and tailored therapy will make categorization using genes and polymorphisms more important. The crude categories of race and ethnicity and even socioeconomic status will only be important in terms of social issues such as access to care and equality of treatment.

Social interventions to overcome disparities and bring about equity include efforts to (1) increase cultural competence and understanding of the patient among healthcare providers; (2) increase access to care; and (3) improve communications and educate those needing service.
Primary and Metastatic Neoplasms of the Brain in Adults
Authors: DeAngelis Lisa M.
Published: March 2017

Overview

Primary brain tumors are uncommon but aggressive neoplasms even when histology is low grade. Secondary, or metastatic, tumors are at least 3 times more common than all primary tumors combined. Diagnosis is easily established by magnetic resonance imaging (MRI), and surgical resection provides histologic confirmation and decompression; surgery alone may suffice for low‐grade tumors and most extra‐axial tumors such as meningiomas. Treatment of parenchymal brain tumors, primary or metastatic, often requires a combination of radiotherapy and chemotherapy, which may improve patient function and control disease but rarely achieves cure.
Cancer of the Lung
Authors: Lu Charles , Morgensztern Daniel , Chiang Anne , Onn Amir , Sepesi Boris , Vaporciyan Ara A. , Chang Joe Y. , Komaki Ritsuko K. , Wistuba Ignacio I. , Herbst Roy S.
Published: March 2017

Overview

Worldwide, lung cancer is responsible for the largest number of cancer‐related deaths, and reducing tobacco consumption is the most effective way to reduce lung cancer mortality. Standard therapy options continue to include surgery, radiotherapy, and/or chemotherapy. As lung cancer is a heterogeneous disease, it is hoped that translational proteomic and genomic research will advance our understanding of driver molecular pathways and allow development of more effective, less toxic, targeted therapies. Recent developments in immunotherapy have generated significant excitement and represent a novel therapeutic strategy, which has already impacted current standard of care.
Malignant Pleural Mesothelioma
Authors: Gomez Daniel R. , Tsao Anne S. , Yang Haining , Pass Harvey I.
Published: March 2017

Overview

Malignant pleural mesothelioma is an aggressive malignancy with an incidence that may be peaking worldwide in the next 5–10 years. While the majority of patients do ultimately die of this disease, there have been substantial treatment and diagnostic shifts over the past decade that may improve long‐term outcomes. These changes include worldwide interest in defining early detection biomarkers for the disease, a debate as to the optimal surgical approach (extrapleural pneumonectomy vs lung‐sparing methods such as pleurectomy/decortication), further refinement of radiation techniques that allow for conformal treatment fields and the delivery of radiation with the involved lung intact, and the emergence of systemic therapies that are targeted in nature and allow for the increased individualization of care. Indeed, prospective clinical trials assessing the safety and efficacy of novel treatment approaches will be essential to the standardization of paradigms that improve the outcomes. It is hoped that the maturation of these efforts will lead to an optimal approach in which earlier‐stage patients will benefit from multiple modalities that will provide synergistic control while limiting toxicity, thereby increasing the number of long‐term survivors over the next one to two decades.
Neoplasms of the Prostate
Authors: Logothetis Christopher J. , Kim Jeri , Davis John W. , Chapin Brian F. , Kuban Deborah , Efstathiou Eleni , Aparicio Ana
Published: March 2017

Overview

Cancer of the prostate is the most commonly diagnosed nonskin neoplasm and the second leading cause of cancer‐related mortality in men in the United States. Considerable advances have been made in screening, diagnosis, and therapy options, particularly in advanced disease, but controversies about the diagnosis and management of prostate cancer, especially in the areas of screening and choice of therapy, continue to evolve. Controversies in advanced disease states have shifted from prognostication to prediction, and current treatment considerations are focused on optimization of sequence or combinations of therapy, determining the role of local control and bone targeting. It is anticipated that addressing these knowledge gaps will lead to an integrated and more effective treatment strategies. Further advances in therapy can be achieved by development of new agents with unique mechanisms of action and rational integration into combination therapies.

Prostate cancer awareness, clinical application of improved biopsy schemes, and advances in imaging combined with the widespread use of prostate‐specific antigen (PSA) have resulted in increased detection of prostate cancer. The evolving use of the serum PSA concentration and its change over time have not been paralleled by studies that tested the relevance of those findings until the results of the European Randomized Study of Screening for Prostate Cancer (ERSPC) and the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial were first published in 2009. Though many of the apparent discrepancies between these trials can be accounted for by trial design and patient cross‐contamination, they brought to the forefront the dilemma of overdiagnosis and overtreatment and the urgent need to improve the accuracy of clinically significant prostate cancer. It is hoped that replacement of the current morphologic and anatomic classification of prostate cancer with one based on improved understanding of biology will lead to molecular classification and bring closer a personalized management of this complex disease.

Salient features that distinguish prostate cancer from other malignancies and that frame the dilemmas surrounding it are its striking age‐dependent incidence, with progressively increasing frequency with increasing age; the variable lethality of morphologically identified cancers; the central role of androgen signaling; and the preponderance of bone‐forming metastases on its lethal progression. The important advances made in each of these areas will, in the near future, modify the approaches currently used to prevent, prognosticate, and treat prostate cancer.
Tumors of the Penis and the Urethra
Authors: Holland James F. , Lance Raymond S. , Lynch Donald F.
Published: March 2017

Overview

Carcinoma of the penis, predominantly squamous, some related to human papilloma virus, is rare in the developed world and among circumcised men, but of major importance elsewhere. Surgery early can be curative. Other modalities are less robust. Voluntary adult circumcision to diminish susceptibility to human immunodeficiency virus infection is being observed as possibly preventive. Urethral cancer, rare, usually of transitional epithelium, is often detected too late for cure.
Nonepithelial Ovarian Malignancies
Authors: Berek Jonathan S. , Friedlander Michael L. , Bast Robert C.
Published: March 2017

Overview

Compared with epithelial ovarian cancers, nonepithelial ovarian tumors are uncommon, constituting <10% of all ovarian malignancies. They include germ cell malignancies, sex‐cord–stromal tumors, carcinomas metastatic to the ovary, and a variety of extremely rare ovarian cancers, including sarcomas and lipoid cell tumors. Although there are many similarities in the presentation, evaluation, and management of patients, these tumors also have unique features that require special approaches to management. Germ cell malignancies are derived from primordial germ cells of the ovary and can be distinguished by histotype and expression of the biomarkers alpha‐fetoprotein (AFP) and/or human chorionic gonadotropin (hCG). They include dysgerminomas (AFP−hCG−), embryonal carcinomas (AFP+hCG+), immature teratomas (AFP−hCG−), endodermal sinus (yolk sac) tumors (AFP+hCG−), and ovarian choriocarcinomas (AFP−hCG+). Germ cell tumors occur in premenarchal girls and young women, grow rapidly, and can present with a symptomatic pelvic mass. As preservation of fertility is often an important priority, unilateral salpingo‐oophorectomy can often be performed followed by adjuvant platinum‐based therapy. Among the germ cell tumors, dysgerminomas can be bilateral in 10–15% of cases and are associated with gonadal dysgenesis in 5% of cases. Metastatic germ cell cancers can be quite sensitive to chemotherapy and the long‐term survival rate is high, even in advanced stages. At some institutions, young patients with stage IA germ cell tumors are followed carefully after resection and chemotherapy given only if there is recurrence with excellent outcomes. Sex‐Cord‐Stromal tumors include Granulosa‐Stromal tumors, Juvenile Granulosa tumors, and Sertoli–Leydig cell tumors. Granulosa‐Stromal tumors can occur at all ages and produce estrogen resulting in pseudoprecocious puberty in a small fraction of girls, amenorrhea in pre‐menopausal women, and endometrial hyperplasia in postmenopausal adults. Granulosa‐Stromal tumors are indolent and often confined to one ovary where surgery can cure stage I disease in more than 75% of cases. Adjuvant chemotherapy is generally not given after complete resection. Late recurrence has, however, been observed. Persistent or recurrent disease has responded to platinum based and hormonal therapy, including progestational agents, luteinizing hormone‐releasing hormone agonists, and aromatase inhibitors. Inhibin B has been a useful biomarker. Sertoli–Leydig cell tumors generally present in the third or fourth decade, produce androgens, and induce virilization in more than 70% of patients. As many Sertoli–Leydig cell tumors are in early stage and rarely bilateral, unilateral salpingo‐oophorectomy is often performed with 70–90% 5‐year survival.
Molar Pregnancy and Gestational Trophoblastic Neoplasia
Authors: Goldstein Donald P. , Berkowitz Ross S. , Horowitz Neil S.
Published: March 2017

Overview

Gestational trophoblastic neoplasia (GTN) is among the rare human malignancies that can be cured in the presence of widespread metastases. GTN includes a spectrum of interrelated tumors, including hydatidiform mole, invasive mole, choriocarcinoma, placental‐site trophoblastic tumor (PSTT), and epithelioid trophoblastic tumor (ETT), which has varying propensities for local invasion and metastasis. With the exception of PSTT and ETT, all GTNs arise from the cytotrophoblast and syncytial cells of the villous trophoblast and produce abundant amounts of human chorionic gonadotropin (hCG). Measurement of hCG levels serves as a reliable tumor marker for diagnosis, monitoring of treatment response, and follow‐up to detect recurrence. PSTT and ETT originate from the intermediate cells of extravillous trophoblast and produce hCG sparsely, making its use as a tumor marker that is less reliable. Although GTN most commonly follows a molar pregnancy, it may follow any gestational event, including therapeutic or spontaneous abortion and ectopic or term pregnancy. Before the development of effective chemotherapy in 1956, the majority of patients with GTN localized to the uterus were cured with hysterectomy, but metastatic disease was almost always fatal. Most women can now be cured and their reproductive function preserved if treated early and according to well‐established guidelines. GTN patients are categorized using a prognostic scoring system into low‐ and high‐risk disease based on response to single‐agent chemotherapy. Low‐risk GTN generally responds to monotherapy while high‐risk disease requires multiagent regimens to achieve remission. Despite chemotherapy, subsequent pregnancy outcomes are similar to the general population.