Creighton University

OBJECTIVE: The objective was to provide guidelines to clinicians for the evaluation, treatment, and prevention of vitamin D deficiency with an emphasis on the care of patients who are at risk for deficiency. PARTICIPANTS: The Task Force was composed of a Chair, six additional experts, and a methodologist. The Task Force received no corporate funding or remuneration. CONSENSUS PROCESS: Consensus was guided by systematic reviews of evidence and discussions during several conference calls and e-mail communications. The draft prepared by the Task Force was reviewed successively by The Endocrine Society's Clinical Guidelines Subcommittee, Clinical Affairs Core Committee, and cosponsoring associations, and it was posted on The Endocrine Society web site for member review. At each stage of review, the Task Force received written comments and incorporated needed changes. CONCLUSIONS: Considering that vitamin D deficiency is very common in all age groups and that few foods contain vitamin D, the Task Force recommended supplementation at suggested daily intake and tolerable upper limit levels, depending on age and clinical circumstances. The Task Force also suggested the measurement of serum 25-hydroxyvitamin D level by a reliable assay as the initial diagnostic test in patients at risk for deficiency. Treatment with either vitamin D(2) or vitamin D(3) was recommended for deficient patients. At the present time, there is not sufficient evidence to recommend screening individuals who are not at risk for deficiency or to prescribe vitamin D to attain the noncalcemic benefit for cardiovascular protection.

Journal of Bone and Mineral ResearchVolume 2, Issue 6 p. 595-610 Article Bone histomorphometry: Standardization of nomenclature, symbols, and units: Report of the asbmr histomorphometry nomenclature committee A. Michael Parfitt M.D., Corresponding Author A. Michael Parfitt M.D. Chairman Bone and Mineral Research Laboratory, Department of Medicine, Henry Ford Hospital, Detroit, MIBone and Mineral Research Laboratory Henry Ford Hospital 2799 West Grand Boulevard Detroit, MI 48202Search for more papers by this authorMarc K. Drezner, Marc K. Drezner Bone and Mineral Metabolism Section, Division of Metabolism, Endocrinology and Genetics, Department of Medicine, Duke University Medical Center, Durham, NCSearch for more papers by this authorFrancis H. Glorieux, Francis H. Glorieux Genetics Unit, Shriners Hospital for Crippled Children, Montreal, Quebec, CanadaSearch for more papers by this authorJohn A. Kanis, John A. Kanis Department of Human Metabolism and Clinical Biochemistry, University of Sheffield, Sheffield, UKSearch for more papers by this authorHartmut Malluche, Hartmut Malluche Department of Medicine, Division of Nephrology, Bone and Mineral Metabolism, University of Kentucky College of Medicine, Lexington, KTSearch for more papers by this authorPierre J. Meunier, Pierre J. Meunier INSERM Unit 234, Faculte Alexis Carrel, Lyon, FranceSearch for more papers by this authorSusan M. Ott, Susan M. Ott Department of Medicine, Harborview Medical Center, University of Washington, Seattle, WASearch for more papers by this authorRobert R. Recker, Robert R. Recker Metabolic Research Unit, Department of Internal Medicine, Creighton University School of Medicine, Omaha, NBSearch for more papers by this author A. Michael Parfitt M.D., Corresponding Author A. Michael Parfitt M.D. Chairman Bone and Mineral Research Laboratory, Department of Medicine, Henry Ford Hospital, Detroit, MIBone and Mineral Research Laboratory Henry Ford Hospital 2799 West Grand Boulevard Detroit, MI 48202Search for more papers by this authorMarc K. Drezner, Marc K. Drezner Bone and Mineral Metabolism Section, Division of Metabolism, Endocrinology and Genetics, Department of Medicine, Duke University Medical Center, Durham, NCSearch for more papers by this authorFrancis H. Glorieux, Francis H. Glorieux Genetics Unit, Shriners Hospital for Crippled Children, Montreal, Quebec, CanadaSearch for more papers by this authorJohn A. Kanis, John A. Kanis Department of Human Metabolism and Clinical Biochemistry, University of Sheffield, Sheffield, UKSearch for more papers by this authorHartmut Malluche, Hartmut Malluche Department of Medicine, Division of Nephrology, Bone and Mineral Metabolism, University of Kentucky College of Medicine, Lexington, KTSearch for more papers by this authorPierre J. Meunier, Pierre J. Meunier INSERM Unit 234, Faculte Alexis Carrel, Lyon, FranceSearch for more papers by this authorSusan M. Ott, Susan M. Ott Department of Medicine, Harborview Medical Center, University of Washington, Seattle, WASearch for more papers by this authorRobert R. Recker, Robert R. Recker Metabolic Research Unit, Department of Internal Medicine, Creighton University School of Medicine, Omaha, NBSearch for more papers by this author First published: December 1987 https://doi.org/10.1002/jbmr.5650020617Citations: 4,046AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume2, Issue6December 1987Pages 595-610 RelatedInformation

BACKGROUND: In 2002 the American Thoracic Society/European Respiratory Society (ATS/ERS) classification of idiopathic interstitial pneumonias (IIPs) defined seven specific entities, and provided standardized terminology and diagnostic criteria. In addition, the historical "gold standard" of histologic diagnosis was replaced by a multidisciplinary approach. Since 2002 many publications have provided new information about IIPs. PURPOSE: The objective of this statement is to update the 2002 ATS/ERS classification of IIPs. METHODS: An international multidisciplinary panel was formed and developed key questions that were addressed through a review of the literature published between 2000 and 2011. RESULTS: Substantial progress has been made in IIPs since the previous classification. Nonspecific interstitial pneumonia is now better defined. Respiratory bronchiolitis-interstitial lung disease is now commonly diagnosed without surgical biopsy. The clinical course of idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia is recognized to be heterogeneous. Acute exacerbation of IIPs is now well defined. A substantial percentage of patients with IIP are difficult to classify, often due to mixed patterns of lung injury. A classification based on observed disease behavior is proposed for patients who are difficult to classify or for entities with heterogeneity in clinical course. A group of rare entities, including pleuroparenchymal fibroelastosis and rare histologic patterns, is introduced. The rapidly evolving field of molecular markers is reviewed with the intent of promoting additional investigations that may help in determining diagnosis, and potentially prognosis and treatment. CONCLUSIONS: This update is a supplement to the previous 2002 IIP classification document. It outlines advances in the past decade and potential areas for future investigation.

This article summarizes the new 2011 report on dietary requirements for calcium and vitamin D from the Institute of Medicine (IOM). An IOM Committee charged with determining the population needs for these nutrients in North America conducted a comprehensive review of the evidence for both skeletal and extraskeletal outcomes. The Committee concluded that available scientific evidence supports a key role of calcium and vitamin D in skeletal health, consistent with a cause-and-effect relationship and providing a sound basis for determination of intake requirements. For extraskeletal outcomes, including cancer, cardiovascular disease, diabetes, and autoimmune disorders, the evidence was inconsistent, inconclusive as to causality, and insufficient to inform nutritional requirements. Randomized clinical trial evidence for extraskeletal outcomes was limited and generally uninformative. Based on bone health, Recommended Dietary Allowances (RDAs; covering requirements of ≥97.5% of the population) for calcium range from 700 to 1300 mg/d for life-stage groups at least 1 yr of age. For vitamin D, RDAs of 600 IU/d for ages 1-70 yr and 800 IU/d for ages 71 yr and older, corresponding to a serum 25-hydroxyvitamin D level of at least 20 ng/ml (50 nmol/liter), meet the requirements of at least 97.5% of the population. RDAs for vitamin D were derived based on conditions of minimal sun exposure due to wide variability in vitamin D synthesis from ultraviolet light and the risks of skin cancer. Higher values were not consistently associated with greater benefit, and for some outcomes U-shaped associations were observed, with risks at both low and high levels. The Committee concluded that the prevalence of vitamin D inadequacy in North America has been overestimated. Urgent research and clinical priorities were identified, including reassessment of laboratory ranges for 25-hydroxyvitamin D, to avoid problems of both undertreatment and overtreatment.

This study describes comprehensive polling of transcription start and termination sites and analysis of previously unidentified full-length complementary DNAs derived from the mouse genome. We identify the 5' and 3' boundaries of 181,047 transcripts with extensive variation in transcripts arising from alternative promoter usage, splicing, and polyadenylation. There are 16,247 new mouse protein-coding transcripts, including 5154 encoding previously unidentified proteins. Genomic mapping of the transcriptome reveals transcriptional forests, with overlapping transcription on both strands, separated by deserts in which few transcripts are observed. The data provide a comprehensive platform for the comparative analysis of mammalian transcriptional regulation in differentiation and development.

Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is a common autosomal dominant syndrome characterized by early age at onset, neoplastic lesions, and microsatellite instability (MSI). Because cancers with MSI account for approximately 15% of all colorectal cancers and because of the need for a better understanding of the clinical and histologic manifestations of HNPCC, the National Cancer Institute hosted an international workshop on HNPCC in 1996, which led to the development of the Bethesda Guidelines for the identification of individuals with HNPCC who should be tested for MSI. To consider revision and improvement of the Bethesda Guidelines, another HNPCC workshop was held at the National Cancer Institute in Bethesda, MD, in 2002. In this commentary, we summarize the Workshop presentations on HNPCC and MSI testing; present the issues relating to the performance, sensitivity, and specificity of the Bethesda Guidelines; outline the revised Bethesda Guidelines for identifying individuals at risk for HNPCC; and recommend criteria for MSI testing.

Before publication of the original version of this report in 1987, practitioners of bone histomorphometry communicated with each other in a variety of arcane languages, which in general were unintelligible to those outside the field. The need for standardization of nomenclature had been recognized for many years,1 during which there had been much talk but no action. To satisfy this need, B Lawrence Riggs (ASBMR President, 1985 to 1986) asked A Michael Parfitt to convene an ASBMR committee to develop a new and unified system of terminology, suitable for adoption by the Journal of Bone and Mineral Research (JBMR) as part of its Instructions to Authors. The resulting recommendations were published in 19872 and were quickly adopted not only by JBMR but also by all respected journals in the bone field. The recommendations improved markedly the ability of histomorphometrists to communicate with each other and with nonhistomorphometrists, leading to a broader understanding and appreciation of histomorphometric data. In 2012, 25 years after the development of the standardized nomenclature system, Thomas L Clemens (Editor in Chief of JBMR) felt that it was time to revise and update the recommendations. The original committee was reconvened by David W Dempster, who appointed one new member, Juliet E Compston. The original document was circulated to the committee members and was extensively revised according to their current recommendations. The key revisions include omission of terminology used before 1987, recommendations regarding the parameters and technical information that should be included in all histomorphometry articles, recommendations on how to handle dynamic parameters of bone formation in settings of low bone turnover, and updating of references. It is generally agreed that a bone is an individual organ of the skeletal system, but the term “bone” has at least three meanings. The first is mineralized bone matrix excluding osteoid; this usage conforms rigorously to the definition of bone as a hard tissue. Osteoid is bone matrix that will be (but is not yet) mineralized, and is sometimes referred to as pre-bone. The second meaning of “bone,” and the one we have adopted, is bone matrix, whether mineralized or not, ie, including both mineralized bone and osteoid. The third meaning of “bone” is a tissue including bone marrow and other soft tissue, as well as bone as just defined. We refer to the combination of bone and associated soft tissue or marrow as “bone tissue.” “Tissue” is defined3 as “an aggregation of similarly specialized cells united in the performance of a particular function.” In this sense, bone, bone marrow, and the contents of osteonal canals are certainly not the same tissue, but in a more general sense, most textbooks of histology recognize only four fundamental tissues—epithelium, nerve, muscle, and connective tissue4—of which the last-named includes bone and all its accompanying nonmineralized tissue. In current clinical and radiologic parlance, “trabecular” and “cortical” refer to contrasting structural types of bone. But “trabecular” does not appear in any standard textbook of anatomy or histology as a name for a type of bone; rather, “spongy” or “cancellous” is used. “Spongiosa” (primary or secondary) is best restricted to the stages of endochondral ossification; “cancellous” is most commonly used in textbooks4, 5 and is the term we have chosen. We retain the noun “trabecula” and its associated adjective “trabecular” to refer to an individual structural element of cancellous bone, in accordance with current practice in histology,4 pathology,6 and biomechanics.7 Etymologically, a trabecula is a beam or rod, and in young people plates rather than rods are the predominant structural elements, both in the spine8 and in the ilium,9 but no convenient alternative is available. The size, shape, and orientation of trabeculae (as just defined) vary considerably between different types of cancellous bone.9, 10 “Density” is a frequent source of confusion in discussions about bone. We propose that the term should be restricted as far as possible to its primary meaning in physics of mass per unit volume,11, 12 with a subsidiary meaning analogous to population density, which is applied mainly to cells. This precludes the use of “density” in its stereologic sense, as will be to the the to which mass is referred be of mineralized bone, bone, bone tissue or or a bone. bone is than bone density, which the of and This is and generally be but is to Bone the of osteoid; bone matrix excluding and has been referred to as bone Bone tissue the of soft tissue, or bone density, referred to as bone density, the of bone tissue, cancellous bone tissue, and marrow a bone, the organ of which is by is in the clinical and In most bone are or formation and all cells on the are or but in the most bone are with to bone We refer to the cells that bone as cells and the term to cells that are bone matrix or with only rather than including all cells that are not cells are of and are to have The term is restricted to cells and are have only one or no for of and whether or should be or A of types of primary be on of a or between or between and histomorphometrists report all only in the for to three be to and the of the or the of an are not this is a but bone be in In other of that as an the is to by the of which is the We that this also should be the of bone are for between between and between different types of bone, for element of bone for of and for many of bone as the of and the of individual But as a it is to on adoption of a stereologic that be and a only in bone the is to the bone its before In the the use of a in the was a convenient of of but this for at an the of the of to most stereologic also that the be meaning that a to any element of has an of in any in not for all cancellous bone, in the there is only and stereologic be used with 25 But it is more to the of a is which is with the use of a but there is no other of canals generally not the by more than stereologic in bone are but of the stereologic to bone has not been we that histomorphometric should one of all and in the and or (as by the only the the and with the an is for each type of of how it was the primary as A of and should not be used in the same The only is the type of primary for which there is no convenient of to three the of the of in three is possible the same be in of and but this has not been applied to bone. as also be The original committee not to the terminology of the of as was at the on Bone use the term “density” in a general to any referred to that is and per unit is the of terminology is in the the of “density” in different the all to at the of bone histomorphometry will need to be with the of many to bone are published in the Journal of which is the of the of of and are of the of tissue and be between only to a which will be or the and in have no and in three but it is convenient to refer to as and to as the is the of and of individual have meaning in and are the only type that not a different and to different that use of is and it is to between used include tissue bone bone and and their or of the the use of as a term The of the is not commonly used as a at but is for with of bone for the of and cancellous bone of or for the of different types of bone and different to as of and of and for in the between and of bone of the as a the possible an to the in of to bone as an be as of the the of the to the mainly on the of the bone at the of be with a the but the of and cancellous tissue in the bone be with type of the be by the of and cancellous bone tissue in the The same be applied to and to bone by the by the as the The individual are in in of their or general are in a the is to be rather than the use of is mainly to time or there is a more for as for other their use in other but confusion is with that be with is not to or the use of and but to that the same are used by To this we have the to and the of new with different meanings. We have included in bone their and commonly used in and as well as for all the structural of bone and of and for of bone with are and in to their one the and in of only is it is and used and a suitable The most commonly used are a have an in many to the second or and the second of the by the are used for that are in to for the primary of and and for in its used in should be by a in the of each is to be as an individual In this any combination of be to which are included in the Bone histomorphometry be applied to many types of but the most are of of bone and of we first the terminology for to the the between and is it is to the of the bone at the for the the term is more is and cancellous for on the their are but it is possible to of their and In this the are generally by their of the and that one be in by or at the time of the but this is The generally has more and tissue than the The other of the is referred to as only the of the have the same as the the more term is the of the is to the of the its are It is convenient to as and of for and cancellous for are by the between and in the to of bone different on on by and with of of of on on cancellous to cancellous the and not and their is used for for the the by the and are the be used to and the of bone bone is similarly and cancellous for or marrow for The between and bone and cancellous or marrow on the of the be at in to the in both and bone it is for to recognize a between and cancellous bone tissue and in and This is not in or of its are not A has been used to this in This be to bone but this has not been all all in with bone marrow are referred to as and are cancellous bone and the is the of the between is to in accordance with and will also on whether the is not in with bone marrow are generally referred to as with as the also be referred to as the or osteonal of the of a bone; is on the and is on the the cancellous bone of the is not bone cancellous marrow The standard and for all should be that the of to as well as to the and are used only as and are used only as to the on which the was whether this was a particular or a particular type of tissue. of the commonly used have been many are by the are restricted to of a as the of a or the of cancellous the same be but the should be in the of on the the source is as it will not be to the source each time a particular is referred only one source is used in an it need only be are their be used as for of in or and in most will need to be only are that confusion between is as only one source is possible and its is The three and the are the key to one to is to in stereologic terminology, and and are to in stereologic are the and by which is for or by which has been for cancellous The with that the be and and to in stereologic terminology and are with the and a of the bone is as a and are to and it be to to the mineralized as an alternative to the more bone and of bone formation be to the or to the of as well as to or bone it be to use the between mineralized bone and or bone as a for the of or of the is are In many as only one is used for each the need only be and not each time the is more than one is with the same be to are with in both and in have been but need is used for of mineralized bone and is by Osteoid need to be as or as the in the between which to a and which to a for all are with the is a general term to all tissue that is not and includes marrow in cancellous bone and and canals in bone. both types of tissue, with on individual as cells or The be as an of tissue, by use of the is the of all referred to the of tissue and in The also be as individual by of a is the of individual confusion is the term be as or in be to in the are in be used to but it is to this as Osteoid not that should be for of We the formation and the of current be and for the same we the is with or and the and the individual also be as or cells and are for and the cells on the or cells. is with or the term that will at The of connective tissue the cells on should not be referred to as It is possible that by cells should be as rather than as In all be in by at or by of and The is more and a and a standard as well as a but that be The is and to The is used for between and and and the is used for and are used for and The is for the the between individual at particular and at particular during the The by in an individual be the in a of is the the to the between bone and It is used in and in different types of and different stages of in the should be to the between and is on an individual it has been used in the for of the of and in as an of in is the between on of a as for the is an of bone the but is of the of bone to the most of the but that are the of be restricted to the of the of are but to and need for a be In most the will be an or but of also be per is the of per to bone in cancellous bone tissue, a that with as and as are are and are in a that has been to of its The of to in a is an of be structural or of the are on that are but not rigorously and individual to use or of the that we have is with and time are L and but have other in the according to the as which is to of for cancellous the alternative is with by To between the alternative this is to the with It should be that there is in the term which has been a different by the ASBMR with with the it as the between rather than between is according to the as or as This by is an of the marrow to the and a is by but be in any to the of the marrow as the between is by and also be The of in at a particular time is by the of the resulting at that The of the of is to the of the first and second the of the of are available. of the term or a between the of the the second it is in time to the the only one was in of the or after the the and of the and of the of are the of the and should be be in to a variety of is to the of during which It should be that of individual on the Parfitt and that were than of the in which were This should be in the of and and it is to a is used to in bone formation in a Mineral is the between the or between the of by the time between the of the the of for and the of the vary with the of the which be and We the and to confusion between and and are used in to refer to the bone formation is no convenient of between the and by different that the is it is that the be used is as and the or the bone formation the It is analogous to the and is with formation and “bone formation but of alternative is The is in a and in the of the is the best a of the of the of formation of mineralized bone and of bone matrix, the including of and are their are of and the term be used. We refer to and as rather than as formation to the that an has meaning at a on the a formation has meaning only in to of tissue, or in the of a of but a formation is by the of and on the of as well as on their The rather than the is as the unit the of the on the of its members as well as on their individual Mineral formation is the of mineralized bone per unit as the of and as this term be as to the of the more term mineralized bone formation be used. In a and in the of the formation is with the bone formation and the is the and more term should be used. is a bone formation to each possible for and Bone formation the is to the as bone formation per unit of bone most on bone Bone formation per unit of bone is to the bone which bone and of Bone formation per unit of tissue most of bone the tissue is and its to the The of the was Bone be by histomorphometry but be as the bone formation or by an or of of bone that all are in to the same or of bone a be by and and osteonal with in but it be that bone formation at the current the time which the of bone of the of bone turnover, most the that and formation are is than the of but it is more to that mineralized in to or of bone alternative is to use to the in bone which is for a of but to in a it is be in to a variety of different including time is the time between and of any of matrix, the of the and is by The is in the understanding of and the of it be that to the and of individual of has been as for and be time which is the time between the of matrix and the of at each The name that the of the matrix, as In the and are but in is and than be as and has also been referred to as rather than but it is more to by the of than but it be more convenient for use it is in that be applied to as and information about the of which be with and dynamic of bone is the time to a new bone structural unit or the to the bone at a and is by It includes or or other to the between and that be to and be as by or by or of a that to a between and is the of during the of bone formation is low to of or of of to its has also been referred to as is the key for of all other of the In a of are to of that is any other than including and but will the in are and their of their current and in the by be used to The of the and formation is the which is the of a of bone at any on a bone is a of or than the of bone that a of the for a the bone or the many are much than a including both and and the of many is much than the of a or a not commonly it is this that is the for of a new after any or it is used and in key an for this is an alternative that the and use of The of the and the is the which is the time between the of at the same on the The of is the which is the that a new of will at any on the by the of also be in the more as the of of or and in to the in the is that current does not of the in cancellous bone. It be that which is be as the of bone per were first for of parameters of bone of low were in bone in with the and use of are in which are low that there are no or only in cancellous for of is that the was not or This sometimes be by the of in in the or on the The that a of a low be by low for parameters of bone as or a for the and of the and a In there are no in an we that be as a and that the of in a be in the of the In this it is to a of for and to include in the of for In only or are to be and in the be as a or one has the of a to have been or on the for in the first or the in the The for in the the is also be used. are in of the the the for in that be used or one use the for for the to which the In any of is in three the should be applied The of a to only are is that a of be used to for and parameters as with the that for and the parameters be of will have the The key is that all the of in a with the with only and the and the of with is to the both have applied to for the this a to be on the of in a that have it does not the and the be to the information are low or in an it is that will be low or in the of the The or of and should be for and cancellous The recommendations for and also in the in which only one is primary of and and primary of and should be with the on and the of the most information in of rather than after the are for and and for the between in different and we rather than in this the be used to the and unit of are not used for the be by the type of only We as their with to three 10 also not to the and it more to that the is should be in all primary and in or and all in should be in with as an alternative for should be as and formation with as and should be in or years as most and in We recognize that many who bone histomorphometry or its will on most need to use only a of the we a of its most but this is not to on its to the of the We also a of parameters that should be included in all histomorphometry are in only the most are The term “bone” to bone matrix whether mineralized or not and “bone to bone as with its associated marrow or other soft tissue. Bone tissue is or the between which is the of the is referred to as A trabecula is an individual structural element of cancellous bone tissue, whether or in The term to bone matrix that in the of will mineralized, and does not include the of connective tissue that bone cells on all The between and mineralized bone is referred to as the “bone more The term is restricted to cells that are to be bone and does not refer to all cells with The and are not are that as and are the and are used. 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BACKGROUND: Niraparib is an oral poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) 1/2 inhibitor that has shown clinical activity in patients with ovarian cancer. We sought to evaluate the efficacy of niraparib versus placebo as maintenance treatment for patients with platinum-sensitive, recurrent ovarian cancer. METHODS: In this randomized, double-blind, phase 3 trial, patients were categorized according to the presence or absence of a germline BRCA mutation (gBRCA cohort and non-gBRCA cohort) and the type of non-gBRCA mutation and were randomly assigned in a 2:1 ratio to receive niraparib (300 mg) or placebo once daily. The primary end point was progression-free survival. RESULTS: Of 553 enrolled patients, 203 were in the gBRCA cohort (with 138 assigned to niraparib and 65 to placebo), and 350 patients were in the non-gBRCA cohort (with 234 assigned to niraparib and 116 to placebo). Patients in the niraparib group had a significantly longer median duration of progression-free survival than did those in the placebo group, including 21.0 vs. 5.5 months in the gBRCA cohort (hazard ratio, 0.27; 95% confidence interval [CI], 0.17 to 0.41), as compared with 12.9 months vs. 3.8 months in the non-gBRCA cohort for patients who had tumors with homologous recombination deficiency (HRD) (hazard ratio, 0.38; 95% CI, 0.24 to 0.59) and 9.3 months vs. 3.9 months in the overall non-gBRCA cohort (hazard ratio, 0.45; 95% CI, 0.34 to 0.61; P<0.001 for all three comparisons). The most common grade 3 or 4 adverse events that were reported in the niraparib group were thrombocytopenia (in 33.8%), anemia (in 25.3%), and neutropenia (in 19.6%), which were managed with dose modifications. CONCLUSIONS: Among patients with platinum-sensitive, recurrent ovarian cancer, the median duration of progression-free survival was significantly longer among those receiving niraparib than among those receiving placebo, regardless of the presence or absence of gBRCA mutations or HRD status, with moderate bone marrow toxicity. (Funded by Tesaro; ClinicalTrials.gov number, NCT01847274 .).

BACKGROUND: Vascular endothelial growth factor is a key promoter of angiogenesis and disease progression in epithelial ovarian cancer. Bevacizumab, a humanized anti-vascular endothelial growth factor monoclonal antibody, has shown single-agent activity in women with recurrent tumors. Thus, we aimed to evaluate the addition of bevacizumab to standard front-line therapy. METHODS: In our double-blind, placebo-controlled, phase 3 trial, we randomly assigned eligible patients with newly diagnosed stage III (incompletely resectable) or stage IV epithelial ovarian cancer who had undergone debulking surgery to receive one of three treatments. All three included chemotherapy consisting of intravenous paclitaxel at a dose of 175 mg per square meter of body-surface area, plus carboplatin at an area under the curve of 6, for cycles 1 through 6, plus a study treatment for cycles 2 through 22, each cycle of 3 weeks' duration. The control treatment was chemotherapy with placebo added in cycles 2 through 22; bevacizumab-initiation treatment was chemotherapy with bevacizumab (15 mg per kilogram of body weight) added in cycles 2 through 6 and placebo added in cycles 7 through 22. Bevacizumab-throughout treatment was chemotherapy with bevacizumab added in cycles 2 through 22. The primary end point was progression-free survival. RESULTS: Overall, 1873 women were enrolled. The median progression-free survival was 10.3 months in the control group, 11.2 in the bevacizumab-initiation group, and 14.1 in the bevacizumab-throughout group. Relative to control treatment, the hazard ratio for progression or death was 0.908 (95% confidence interval [CI], 0.795 to 1.040; P=0.16) with bevacizumab initiation and 0.717 (95% CI, 0.625 to 0.824; P<0.001) with bevacizumab throughout. At the time of analysis, 76.3% of patients were alive, with no significant differences in overall survival among the three groups. The rate of hypertension requiring medical therapy was higher in the bevacizumab-initiation group (16.5%) and the bevacizumab-throughout group (22.9%) than in the control group (7.2%). Gastrointestinal-wall disruption requiring medical intervention occurred in 1.2%, 2.8%, and 2.6% of patients in the control group, the bevacizumab-initiation group, and the bevacizumab-throughout group, respectively. CONCLUSIONS: The use of bevacizumab during and up to 10 months after carboplatin and paclitaxel chemotherapy prolongs the median progression-free survival by about 4 months in patients with advanced epithelial ovarian cancer. (Funded by the National Cancer Institute and Genentech; ClinicalTrials.gov number, NCT00262847.).

BACKGROUND: mutations. The efficacy of niraparib in patients with newly diagnosed advanced ovarian cancer after a response to first-line platinum-based chemotherapy is unknown. METHODS: In this randomized, double-blind, phase 3 trial, we randomly assigned patients with newly diagnosed advanced ovarian cancer in a 2:1 ratio to receive niraparib or placebo once daily after a response to platinum-based chemotherapy. The primary end point was progression-free survival in patients who had tumors with homologous-recombination deficiency and in those in the overall population, as determined on hierarchical testing. A prespecified interim analysis for overall survival was conducted at the time of the primary analysis of progression-free survival. RESULTS: Of the 733 patients who underwent randomization, 373 (50.9%) had tumors with homologous-recombination deficiency. Among the patients in this category, the median progression-free survival was significantly longer in the niraparib group than in the placebo group (21.9 months vs. 10.4 months; hazard ratio for disease progression or death, 0.43; 95% confidence interval [CI], 0.31 to 0.59; P<0.001). In the overall population, the corresponding progression-free survival was 13.8 months and 8.2 months (hazard ratio, 0.62; 95% CI, 0.50 to 0.76; P<0.001). At the 24-month interim analysis, the rate of overall survival was 84% in the niraparib group and 77% in the placebo group (hazard ratio, 0.70; 95% CI, 0.44 to 1.11). The most common adverse events of grade 3 or higher were anemia (in 31.0% of the patients), thrombocytopenia (in 28.7%), and neutropenia (in 12.8%). No treatment-related deaths occurred. CONCLUSIONS: Among patients with newly diagnosed advanced ovarian cancer who had a response to platinum-based chemotherapy, those who received niraparib had significantly longer progression-free survival than those who received placebo, regardless of the presence or absence of homologous-recombination deficiency. (Funded by GlaxoSmithKline; PRIMA/ENGOT-OV26/GOG-3012 ClinicalTrials.gov number, NCT02655016.).

The question, "Is cancer hereditary?" has been answered beyond any doubt through the discovery of germ-line cancer-causing mutations in a subset of colorectal cancers (CRCs). Clearly, this authentication of the role of genetics was not solely dependent on molecular genetic studies, since hereditary cancer syndromes such as familial adenomatous polyposis (FAP) had been known for at least 100 years, but molecular advances are clarifying and refining clinical impressions. Have clinicians acted on the importance of hereditary factors in cancer so that this knowledge might be translated into patient benefit? Data showing that 59% of patients with FAP still die of metastatic CRC suggest that the answer is no.

Research in autophagy continues to accelerate,(1) and as a result many new scientists are entering the field. Accordingly, it is important to establish a standard set of criteria for monitoring macroautophagy in different organisms. Recent reviews have described the range of assays that have been used for this purpose.(2,3) There are many useful and convenient methods that can be used to monitor macroautophagy in yeast, but relatively few in other model systems, and there is much confusion regarding acceptable methods to measure macroautophagy in higher eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers of autophagosomes versus those that measure flux through the autophagy pathway; thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from fully functional autophagy that includes delivery to, and degradation within, lysosomes (in most higher eukaryotes) or the vacuole (in plants and fungi). Here, we present a set of guidelines for the selection and interpretation of the methods that can be used by investigators who are attempting to examine macroautophagy and related processes, as well as by reviewers who need to provide realistic and reasonable critiques of papers that investigate these processes. This set of guidelines is not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to verify an autophagic response.

BACKGROUND: Radiation therapy as an adjunct to surgery for rectal cancer has been shown to reduce local recurrence but has not improved survival. In a previous study, combined radiation and chemotherapy improved survival significantly as compared with surgery alone, but not as compared with adjuvant radiation, which many regard as standard therapy. We designed a combination regimen to optimize the contribution of chemotherapy, decrease recurrence, and improve survival as compared with adjuvant radiation alone. METHODS: Two hundred four patients with rectal carcinoma that was either deeply invasive or metastatic to regional lymph nodes were randomly assigned to postoperative radiation alone (4500 to 5040 cGy) or to radiation plus fluorouracil, which was both preceded and followed by a cycle of systemic therapy with fluorouracil plus semustine (methyl-CCNU). RESULTS: After a median follow-up of more than seven years, the combined therapy had reduced the recurrence of rectal cancer by 34 percent (P = 0.0016; 95 percent confidence interval, 12 to 50 percent). Initial local recurrence was reduced by 46 percent (P = 0.036; 95 percent confidence interval, 2 to 70 percent), and distant metastasis by 37 percent (P = 0.011; 95 percent confidence interval, 9 to 57 percent). In addition, combined therapy reduced the rate of cancer-related deaths by 36 percent (P = 0.0071; 95 percent confidence interval, 14 to 53 percent) and the overall death rate by 29 percent (P = 0.025; 95 percent confidence interval, 7 to 45 percent). Its acute toxic effects included nausea, vomiting, diarrhea, leukopenia, and thrombocytopenia. These effects were seldom severe. Severe, delayed treatment-related reactions, usually small-bowel obstruction requiring surgery, occurred in 6.7 percent of all patients receiving radiation, and the frequencies of these complications were comparable in both treatment groups. CONCLUSIONS: The combination of postoperative local therapy with radiation plus fluorouracil and systemic therapy with a fluorouracil-based regimen significantly and substantively improves the results of therapy for rectal carcinoma with a poor prognosis, as compared with postoperative radiation alone.

A small proportion of breast cancer, in particular those cases arising at a young age, is due to the inheritance of dominant susceptibility genes conferring a high risk of the disease. A genomic linkage search was performed with 15 high-risk breast cancer families that were unlinked to the BRCA1 locus on chromosome 17q21. This analysis localized a second breast cancer susceptibility locus, BRCA2, to a 6-centimorgan interval on chromosome 13q12-13. Preliminary evidence suggests that BRCA2 confers a high risk of breast cancer but, unlike BRCA1, does not confer a substantially elevated risk of ovarian cancer.

Some cases of hereditary nonpolyposis colorectal cancer (HNPCC) are due to alterations in a mutS-related mismatch repair gene. A search of a large database of expressed sequence tags derived from random complementary DNA clones revealed three additional human mismatch repair genes, all related to the bacterial mutL gene. One of these genes (hMLH1) resides on chromosome 3p21, within 1 centimorgan of markers previously linked to cancer susceptibility in HNPCC kindreds. Mutations of hMLH1 that would disrupt the gene product were identified in such kindreds, demonstrating that this gene is responsible for the disease. These results suggest that defects in any of several mismatch repair genes can cause HNPCC.

In the United States, colorectal cancer (CRC) is the third most common cancer diagnosed among men and women and the second leading cause of death from cancer. CRC largely can be prevented by the detection and removal of adenomatous polyps, and survival is significantly better when CRC is diagnosed while still localized. In 2006 to 2007, the American Cancer Society, the US Multi Society Task Force on Colorectal Cancer, and the American College of Radiology came together to develop consensus guidelines for the detection of adenomatous polyps and CRC in asymptomatic average-risk adults. In this update of each organization's guidelines, screening tests are grouped into those that primarily detect cancer early and those that can detect cancer early and also can detect adenomatous polyps, thus providing a greater potential for prevention through polypectomy. When possible, clinicians should make patients aware of the full range of screening options, but at a minimum they should be prepared to offer patients a choice between a screening test that is effective at both early cancer detection and cancer prevention through the detection and removal of polyps and a screening test that primarily is effective at early cancer detection. It is the strong opinion of these 3 organizations that colon cancer prevention should be the primary goal of screening.

Treatment of infectious diseases becomes more challenging with each passing year. This is especially true for infections caused by the opportunistic pathogen Pseudomonas aeruginosa, with its ability to rapidly develop resistance to multiple classes of antibiotics. Although the import of resistance mechanisms on mobile genetic elements is always a concern, the most difficult challenge we face with P. aeruginosa is its ability to rapidly develop resistance during the course of treating an infection. The chromosomally encoded AmpC cephalosporinase, the outer membrane porin OprD, and the multidrug efflux pumps are particularly relevant to this therapeutic challenge. The discussion presented in this review highlights the clinical significance of these chromosomally encoded resistance mechanisms, as well as the complex mechanisms/pathways by which P. aeruginosa regulates their expression. Although a great deal of knowledge has been gained toward understanding the regulation of AmpC, OprD, and efflux pumps in P. aeruginosa, it is clear that we have much to learn about how this resourceful pathogen coregulates different resistance mechanisms to overcome the antibacterial challenges it faces.

ALICE (A Large Ion Collider Experiment) is a general-purpose, heavy-ion detector at the CERN LHC which focuses on QCD, the strong-interaction sector of the Standard Model. It is designed to address the physics of strongly interacting matter and the quark-gluon plasma at extreme values of energy density and temperature in nucleus-nucleus collisions. Besides running with Pb ions, the physics programme includes collisions with lighter ions, lower energy running and dedicated proton-nucleus runs. ALICE will also take data with proton beams at the top LHC energy to collect reference data for the heavy-ion programme and to address several QCD topics for which ALICE is complementary to the other LHC detectors. The ALICE detector has been built by a collaboration including currently over 1000 physicists and engineers from 105 Institutes in 30 countries, Its overall dimensions are 16 x 16 x 26 m(3) with a total weight of approximately 10 000 t. The experiment consists of 18 different detector systems each with its own specific technology choice and design constraints, driven both by the physics requirements and the experimental conditions expected at LHC. The most stringent design constraint is to cope with the extreme particle multiplicity anticipated in central Pb-Pb collisions. The different subsystems were optimized to provide high-momentum resolution as well as excellent Particle Identification (PID) over a broad range in momentum, up to the highest multiplicities predicted for LHC. This will allow for comprehensive studies of hadrons, electrons, muons, and photons produced in the collision of heavy nuclei. Most detector systems are scheduled to be installed and ready for data taking by mid-2008 when the LHC is scheduled to start operation, with the exception of parts of the Photon Spectrometer (PHOS), Transition Radiation Detector (TRD) and Electro Magnetic Calorimeter (EMCal). These detectors will be completed for the high-luminosity ion run expected in 2010. This paper describes in detail the detector components as installed for the first data taking in the summer of 2008.

Answer questions and earn CME/CNE The recently released eighth edition of the American Joint Committee on Cancer (AJCC) Staging Manual, Head and Neck Section, introduces significant modifications from the prior seventh edition. This article details several of the most significant modifications, and the rationale for the revisions, to alert the reader to evolution of the field. The most significant update creates a separate staging algorithm for high-risk human papillomavirus-associated cancer of the oropharynx, distinguishing it from oropharyngeal cancer with other causes. Other modifications include: the reorganizing of skin cancer (other than melanoma and Merkel cell carcinoma) from a general chapter for the entire body to a head and neck-specific cutaneous malignancies chapter; division of cancer of the pharynx into 3 separate chapters; changes to the tumor (T) categories for oral cavity, skin, and nasopharynx; and the addition of extranodal cancer extension to lymph node category (N) in all but the viral-related cancers and mucosal melanoma. The Head and Neck Task Force worked with colleagues around the world to derive a staging system that reflects ongoing changes in head and neck oncology; it remains user friendly and consistent with the traditional tumor, lymph node, metastasis (TNM) staging paradigm. CA Cancer J Clin 2017;67:122-137. © 2017 American Cancer Society.

Cancer immune evasion is a major stumbling block in designing effective anticancer therapeutic strategies. Although considerable progress has been made in understanding how cancers evade destructive immunity, measures to counteract tumor escape have not kept pace. There are a number of factors that contribute to tumor persistence despite having a normal host immune system. Immune editing is one of the key aspects why tumors evade surveillance causing the tumors to lie dormant in patients for years through "equilibrium" and "senescence" before re-emerging. In addition, tumors exploit several immunological processes such as targeting the regulatory T cell function or their secretions, antigen presentation, modifying the production of immune suppressive mediators, tolerance and immune deviation. Besides these, tumor heterogeneity and metastasis also play a critical role in tumor growth. A number of potential targets like promoting Th1, NK cell, γδ T cell responses, inhibiting Treg functionality, induction of IL-12, use of drugs including phytochemicals have been designed to counter tumor progression with much success. Some natural agents and phytochemicals merit further study. For example, use of certain key polysaccharide components from mushrooms and plants have shown to possess therapeutic impact on tumor-imposed genetic instability, anti-growth signaling, replicative immortality, dysregulated metabolism etc. In this review, we will discuss the advances made toward understanding the basis of cancer immune evasion and summarize the efficacy of various therapeutic measures and targets that have been developed or are being investigated to enhance tumor rejection.