Pipet2Pen
Ajay Malik, Ph.D.
medical writer and cancer biologist
pipet2pen blog- mission tumor
- @pipet2pen
- ajay's CiteULike library
- Storify
Loading,
0
% complete-
Posts
- Sep 13, 12
Reblogged from ScienceRoll: Here is an introduction to Twitter and social media concepts for use in continuing medical education.
- Sep 05, 12
Reblogged from The Scholarly Kitchen: A funny video for Labor Day in the US. The voices are awful, but it still works: Enjoy! (Hat tip to SW for the pointer.) Apple's Patents Ground Starfleet
- Jul 11, 12
If you want someone to tell you what you really care about, plug-in your twitter handle into mirror.me. According to mirror.me, this is what I care about. The results looks very flattering. I liked seeing the buzz words like writer, cancer, editor, health, and so on. But, as I scroll down, mirror.me also tells me [...]
- Jul 07, 12
Companies’ first disclosure of hot clinical trial data often occurs at various conferences in the form of posters or presentations, and also simultaneously as press release summarising top-line data. Sometimes this is the only data on a particular investigational product that will ever be published. Why? Because, in the current biotech environment, many small companies [...]
-
Posts
- May 22, 13Malignant pleural or peritoneal mesothelioma is invariably fatal cancer with options that are largely supportive in nature. The current first-line chemotherapy regimens including pemetrexed with or without cisplatin or carboplatin do not provide long-term survival. This cancer is highly angiogenic and thus preclinical and early data supported the use of anti-angiogenic agent thalidomide.
However, a recent clinical trial published in this month's issue of the journal Lancet Oncology shows that thalidomide when added to chemotherapy does not provide any additional benefit.
Read more » - May 03, 13Latin America and the Caribbean are the next hotspots of cancer-related deaths in the world and countries in this region are woefully ill-prepared to face this growing epidemic. A report by Latin American Cooperative Oncology Group (LACOG) presented at the LACOG Conference 2013 on April 26-27, 2013, at Sao Paulo, Brazil, put these facts in depressing hard numbers: currently 13 people of 22 diagnosed with cancer die in Latin America and the Caribbean in contrast to 13 of 37 in US or 13 of 30 in Europe. This translates to 59% of cancer patients dying of cancer in Latin America and the Caribbean compared to 35% in US or 43% in EU.Read more »
- May 02, 13
Better Preclinical Models. Better Predictions. Better Patient Response.
Tumor Models gives you the tools to develop and utilize the very best preclinical oncology models.This is a meeting for drug developers who are looking for answers to the difficulties faced with preclinical oncology models that are currently being used to test new cancer drugs. This is a forum to learn what you really need to know about the models pharma are using that are superior in predicting efficacy and mimicking tumor activity in patients. It’s also the best way to identify what preclinical questions need to be answered and make the best possible translational decisions. Decisions that will lead to more effective drug performance in the clinic.Read more » - May 19, 13Nearly one-third or 1.3 million women over the past 30 years were overdiagnosed with breast cancer (ie, their tumors would have never led to clinical symptoms in their lifetimes) in the United States, according to the research published in the November 22, 2012 issue of the New England Journal of Medicine.
Read more » - May 03, 13The year 2012 saw conversation on the pricing structure and affordability of oncology drugs taking a center stage with commentaries, such as, "The Truly Staggering Cost Of Inventing New Drugs," by Mathew Herper in Forbes pegging the cost of inventing and developing these drugs at $1-$4 Billion, to news about Sloan-Kettering Cancer Center saying "NO" to Zaltrap (Sanofi's drug for colon cancer, then priced at $11,000 per month) for providing a marginal 1.4 month survival benefit. (Sanofi has since cut the price by 50%.)
What will rein in these Aston Martin-like price tags. At least Herceptin will lose its patent protection soon. Right? And biosimilars will force the price down. Wrong! Those banking on biosimilars to bring the cost down to earth are in for a rude shock.
Read more » - Feb 20, 13An oncolytic virus-based drug JX-594 (also called Pexa-Vec) is highly effective in patients with advanced hepatocellular carcinoma. According to the results of a Phase II clinical trial published online at Nature Medicine journal's website on February 10, 2013, the patients who were given higher (more effective) dose of JX-594 had a median survival of 14.1 months which was twice that seen in the low dose group (6.7 months).
Read more » - Oct 31, 12The path to successful clinical development of oncology drugs starts with using predictive tumor models. This is easier said than done.
The organizers of the Tumor Models meeting in London (January 29-31, 2013) have assembled a roster of speakers from AstraZeneca, Eisai, Roche, MedImmune, Genentech, Sanofi and others to discuss tumor models used at these companies, optimization of traditional models, and explore alternative models and methods to better predict drug efficacy.
Read more » - Apr 15, 13A report released by Tufts Center for the Study of Drug Development concludes that FDA approved more cancer drugs and faster than European regulators during 2000-2011.Read more »
- Jul 09, 12I recently rediscovered an article by Forbes's Mathew Herper, "The Truly Staggering Cost Of Inventing New Drugs." In this article, Mathew pegs the true cost of bringing drugs to market at 4 billion dollars.
Read more » - Jul 07, 12A recent study in the journal Cancer suggests that teenagers and young adults (15-29 years old at diagnosis) who survived cancer often have poor health compared to their peers later in life. Long-term consequences of cancer, treatments and behavior (including approach to life) affect health of body and mind.
Researchers from the Center for Disease Control and Prevention, Atlanta, Georgia, led by Eric Tai, examined data from 4054 adolescent and young adult (AYA) cancer survivors in the registry called Behavioral Risk Factor Surveillance System (BRFSS).
Read more » - Jul 08, 12Sometimes the most obvious and commonplace things are paradoxically equally hard to describe because we often do not think how to define them unless somebody throws a curve ball and asks! "What is cancer?" is one such apparently obvious thing.
Read more » - Jun 29, 12Watching what we eat and how much we eat may be an effective tool to manage the toxicity of chemotherapy drugs says this month's online article in the New England Journal of Medicine.
Read more » - Jun 27, 12Last June, a Romanian start-up Cronian Labs released an iPhone app Skin Scan which claimed that it can help with early diagnosis (or warning signs) of melanoma. The availability of Skin Scan at Apple iTunes Store was widely covered in the media (eg, read here and here). And, it was also the first time I put medical apps on my radar screen.There are now hundreds of medical apps, and it is not unsurprising to find oncologists and cancer researchers using a variety of these as reference tools, calculators and diagnostic aids. Here is a short list:Read more »
- Jun 22, 12In the run up to the Targeting the Tumor Microenvironment meeting, taking place in Boston, this October, there are some great resources available to you to download free of charge from the website resources page.
Read more » - Jun 22, 12"Targeting the Tumor Microenvironment" meeting will take place in Boston in October and will be looking at how to achieve tumor delivery, tackle drug resistance and improve clinical efficacy.
Read more » - Jun 07, 12Sci Transl Med 6 June 2012:Vol. 4, Issue 137, p. 137ra74
Sci. Transl. Med. DOI: 10.1126/scitranslmed.3003649- RESEARCH ARTICLE
Read more » - Jun 05, 12Smoking causes 5-6 million avoidable deaths annually worldwide. One in 5 men and 1 in 20 women who die after age 30 die of smoking-related causes.These distressing numbers should be enough to galvanize the California voters who will decide to accept or reject the California Cancer Research Act, commonly called Proposition 29 (or Prop 29). If Prop 29 passes, the money raised through new taxes on cigarettes will support research into smoking-related diseases.Read more »
- Jun 04, 12EMILIA trial is the first study to evaluate the efficacy of an antibody drug conjugate T-DM1 in metastaic breast cancer (mBC) patients. At ASCO 2012 meeting in Chicago, Dr. Kim Blackwell of Duke University presented the final analysis of the progression-free survival (PFS) results in mBC patients treated with T-DM1. A few days back, this trial was featured in the NBC Nightly News (read here.)
Read more » - Jun 03, 12Phase 3 date on abiraterone trial in asymptomatic or mildly symptomatic patients with metastatic castration-resistant prostate cancer (mCRPC) was profiled in the ASCO daily news. These results have the potential of changing the standard of care in mCRPC.
Read more » - Jun 02, 12Two months ago, Trastuzumab Emtansine (T-DM1) metastatic breast cancer trial (called EMILIA trial) reached a major milestone when patients treated with T-DM1 had longer cancer-free periods, also called progression-free survival or PFS, compared to those patients who were on a combination chemotherapy consisting of lapatinib (Tykerb) and capecitabine (Xeloda). (read here). Today, NBC Nightly News gave a human face to this trial.
Read more » - Jun 01, 12
In a new series on this blog called "Choosing Cancer Charity," I have chosen to present CureSearch National Childhood Cancer Foundation, also called CureSearch for Children's Cancer to the readers this month. There are several reasons that motivates me to pitch this charity for your dollars, and donations of time, expertise and support.
Read more » - May 21, 12
How big is the problem?
25-30% of all cancer patients undergoing chemo suffer form oral mucositis, and almost all of the BMT patients.
Read more » - Apr 11, 12
The tumour microenvironment is an important aspect of cancer biology that contributes to tumour initiation, tumour progression and responses to therapy. Cells and molecules of the immune system are a fundamental component of the tumour microenvironment.
Read more »
- Apr 05, 12
AACR 2012 meeting summary - Breast cancer
Read more »
-
Tweets
- Rampant Plagiarism in "Pharmacologia" and "Insight Biomedical Science" by Science Reuters. via @TheScientistLLC http://t.co/jLSXnem2Ud
- RT @scientre: Get #ASCO13 ready w @MaverickNY post on v popular PD-1 & PDL-1 immunotherapies http://t.co/th1Enge2zN also @genentech http://…
- RT @OncologyTimes: RT @stevenshie: How has Twitter changed medical meetings? #ASCO13 #hcsm #digpharm #Medx http://t.co/Nv1ZaPTo8G
- RT @matthewherper: With 'Cell Death' Drugs, Bristol-Myers May Win No Matter What http://t.co/S6cyd3jKr3 <--#ASCO13, why PD-1/Yervoy news is…
- Antiangiogenic Agent Thalidomide No Good in Mesothelioma http://t.co/GyOUiZaUvX
- Welch: What Angelina Jolie forgot to mention http://t.co/rma4U6tTra
- Transparent pricing becomes marketing tool for Miami hospitals | MedCity News: http://t.co/xEtOYjTzN8 via @medcitynews
- f64ef30fa35ea5b2b45490dd8f15a052.jpg http://t.co/XR0pNC2kfU
- Metamorphosis revealed: time-lapse three-dimensional imaging inside a living chrysalis http://t.co/9GO8rS5mhQ
- BBC News - Blackberry expands BBM chat app to Android and iOS http://t.co/aAS3BTtzqG
- The Scientific Backlash Against the D.S.M. http://t.co/uA9PIdljh0
- FDA OKs pinpoint prostate cancer radiation drug Xofigo from Bayer, Algeta http://t.co/xx41Atk6LV
- Research reveals cancer-suppressing protein 'multitasks' http://t.co/QS0TqVuwhE via @medical_xpress
- A Basic Solution: Effective Science Communication Impacts Research Funding by @sdbn http://t.co/NCVdkgFJh4
- RT @scientre: 2of2 MT @nytimes Cancer will be defined by its genetic fingerprint rather the organ where it originated http://t.co/01RYBgRvl2
- RT @Square: Photo of the Day: The Hummingbird with orange, lemon, strawberry and kumquat served by @SowSF in SF’s Dogpatch. http://t.co/rpd…
- RT @theNCI: What is complementary and alternative medicine (CAM)? http://t.co/MDZMzidOZO
- RT @MaverickNY: Fascinating perspective from a young woman on the state of India http://t.co/0DidrZmDyY
- RT @ShawnUpchurch: "I recommend that the Statue of Liberty be supplemented by a Statue of Responsibility on the west coast." ~ Viktor E. Fr…
- RT @GCPworks: Dartmouth pushes to publish results of clinical trials http://t.co/LAZyDnu4fQ
-
Posts
- May 18, 13Future oncology (London, England), Vol. 8, No. 3. (March 2012), pp. 293-305, doi:10.2217/fon.12.14
Malignant pleural mesothelioma is a rare malignancy with a dismal prognosis. The clinical management of most of the patients with this disease is quite challenging, and, overall, the therapeutic strategy has not yet benefited from the recent advances in molecular biology. Randomized evidence supports the use of cisplatin in combination with pemetrexed or raltitrexed as first-line treatments. In elderly patients with comorbidities cisplatin may be replaced by carboplatin because of a lesser burden of toxicities. The role of second-line chemotherapy is unproven, although pemetrexed can be regarded as the standard option in pemetrexed-naive patients and therapeutic rechallenge with pemetrexed may be considered in selected patients with prolonged disease control after first-line therapy. Targeted therapies failed to demonstrate any substantial activity; however, immunotherapies may complement other treatment strategies. In summary, there is an unmet clinical need and innovative approaches to select new potentially active drugs are highly warranted.
Federica Grosso, Giorgio Vittorio Scagliotti - May 18, 13The New England journal of medicine, Vol. 353, No. 15. (13 October 2005), pp. 1591-1603, doi:10.1056/nejmra050152
Bruce Robinson, Richard Lake - May 18, 13PLoS ONE, Vol. 8, No. 3. (6 March 2013), e57346, doi:10.1371/journal.pone.0057346
Malignant pleural mesothelioma (MPM) is a highly aggressive tumor with poor prognosis. Current treatment is rarely curative, thus novel meaningful therapies are urgently needed. Inhibition of Hedgehog (Hh) signaling at the cell membrane level in several cancers has shown anti-cancer activity in recent clinical studies. Evidence of Hh-independent Gli activation suggests Gli as a more potent therapeutic target. The current study is aimed to evaluate the potential of Gli as a therapeutic target to treat MPM. The expression profiles of Gli factors and other Hh signaling components were characterized in 46 MPM patient tissue samples by RT-PCR and immunohistochemistry. Cultured cell lines were employed to investigate the requirement of Gli activation in tumor cell growth by inhibiting Gli through siRNA or a novel small molecule Gli inhibitor (Gli-I). A xenograft model was used to evaluate Gli-I in vivo. In addition, a side by side comparison between Gli and Smoothened (Smo) inhibition was conducted in vitro using siRNA and small molecule inhibitors. Our study reported aberrant Gli1 and Gli2 activation in a large majority of tissues. Inhibition of Gli by siRNAs or Gli-I suppressed cell growth dramatically both in vitro and in vivo. Inhibition of Gli exhibited better cytotoxicity than that of Smo by siRNA and small molecule inhibitors vismodegib and cyclopamine. Combination of Gli-I and pemetrexed, as well as Gli-I and vismodegib demonstrated synergistic effects in suppression of MPM proliferation in vitro. In summary, Gli activation plays a critical role in MPM. Inhibition of Gli function holds strong potential to become a novel, clinically effective approach to treat MPM.
Hui Li, Natalie Lui, Tiffany Cheng, Hsin-Hui Tseng, Dongsheng Yue, Etienne Giroux-Leprieur, Hanh Do, Qing Sheng, Joy Jin, Thomas Luh, David Jablons, Biao He - May 18, 13The Lancet Oncology, Vol. 14, No. 6. (May 2013), pp. 543-551, doi:10.1016/s1470-2045(13)70125-6
Standard chemotherapy does not lead to long-term survival in patients with malignant pleural mesothelioma. Malignant pleural mesothelioma is strongly dependent on vasculature with high vessel counts and high concentrations of serum vascular growth factors. Thalidomide has shown antiangiogenic activity, and we hypothesised that its use in the maintenance setting could improve outcomes. In this open-label, multicentre, randomised phase 3 study, eligible patients had proven malignant pleural or peritoneal mesothelioma and had received a minimum of four cycles of first-line treatment containing at least pemetrexed, with or without cisplatin or carboplatin, and had not progressed on this treatment. Patients were randomly assigned (in a 1:1 ratio, stratified by previous first-line chemotherapy, histological subtype, and recruiting hospital) to receive thalidomide 200 mg per day (including a 2 week run in of 100 mg per day) plus active supportive care or active supportive care alone until disease progression. Patients were required to be registered and to start treatment with thalidomide within 10 weeks after the end of the first-line chemotherapy. Thalidomide was given for a maximum of 1 year or until unacceptable toxicity. The primary endpoint was time to progression. The primary analyses were by intention to treat. The study is registered, ISRCTN13632914. Between May 11, 2004, and Dec 23, 2009, we randomly assigned 222 patients, 111 in each group (one patient on active supportive care later withdrew consent and was excluded from analyses). At the time of this final analysis, median follow-up was 33·1 months (IQR 22·3–66·8), and physician-reported disease progression had occurred in 104 patients in the thalidomide group and 107 in the active supportive care group; 92 patients in the thalidomide group and 93 in the active supportive care group had died. Median time to progression in the thalidomide group was 3·6 months (95% CI 3·2–4·1) compared with 3·5 months (2·3–4·8) in the active supportive care group (hazard ratio 0·95, 95% CI 0·73–1·20, p=0·72). 43 (39%) grade 3 or 4 adverse events were reported in the thalidomide group and 31 (28%) in the active supportive care group; neurosensory events were reported by two (2%) patients on thalidomide and none on active supportive care, cardiac events by two (2%) patients on thalidomide and three (3%) on active supportive care, and thromboembolic events by three (3%) patients on thalidomide and none on active supportive care. No benefit was noted in time to progression with the addition of thalidomide maintenance to first-line chemotherapy. Different treatment strategies are needed to improve outcomes in patients with malignant mesothelioma. Dutch Cancer Society (KWF), Eli Lilly, NSW Dust Disease Compensation Board, University of Sydney, and Cancer Australia.
Wieneke Buikhuisen, Jacobus Burgers, Andrew Vincent, Catharina Korse, Rob van Klaveren, Franz Schramel, Nick Pavlakis, Anna Nowak, Frank Custers, Hugo Schouwink, Steven Gans, Harry Groen, Wim Strankinga, Paul Baas - May 17, 13Journal of The Royal Society Interface, Vol. 10, No. 84. (6 July 2013), doi:10.1098/rsif.2013.0304
Studies of model insects have greatly increased our understanding of animal development. Yet, they are limited in scope to this small pool of model species: a small number of representatives for a hyperdiverse group with highly varied developmental processes. One factor behind this narrow scope is the challenging nature of traditional methods of study, such as histology and dissection, which can preclude quantitative analysis and do not allow the development of a single individual to be followed. Here, we use high-resolution X-ray computed tomography (CT) to overcome these issues, and three-dimensionally image numerous lepidopteran pupae throughout their development. The resulting models are presented in the electronic supplementary material, as are figures and videos, documenting a single individual throughout development. They provide new insight and details of lepidopteran metamorphosis, and allow the measurement of tracheal and gut volume. Furthermore, this study demonstrates early and rapid development of the tracheae, which become visible in scans just 12 h after pupation. This suggests that there is less remodelling of the tracheal system than previously expected, and is methodologically important because the tracheal system is an often-understudied character system in development. In the future, this form of time-lapse CT-scanning could allow faster and more detailed developmental studies on a wider range of taxa than is presently possible.
Tristan Lowe, Russell Garwood, Thomas Simonsen, Robert Bradley, Philip Withers - May 15, 13Wake Forest School of Medicine (April 2011)
Robert Schwartz - May 15, 13Molecular genetics and metabolism, Vol. 104, No. 3. (November 2011), pp. 295-300, doi:10.1016/j.ymgme.2011.07.019
Spinal cord compression (SCC) is a known complication of mucopolysaccharidosis type VI (MPS VI) secondary to atlantoaxial subluxation, craniovertebral stenosis, posterior longitudinal ligament hypertrophy, or dural thickening. SCC is expected to occur in the natural history of the disease, regardless of enzyme replacement therapy (ERT), as intravenous enzyme does not cross the blood-brain barrier. We describe six MPS VI children with SCC, all diagnosed before 7years of age. Within this group, four of the children were diagnosed with SCC after the introduction of ERT. We hypothesize that these patients may illustrate the previously undetected risk of increased joint mobility caused by ERT which may have contributed to increased cervical instability by loosening the neck joint, thus leading to or unmasking SCC. We reinforce the need for close follow-up of SCC, periodic neurological assessment, spine imaging, and neurophysiology in all MPS VI patients before and during ERT. Neurophysiological abnormalities may precede changes in MRI images (as shown in patients 4 and 5 from this sample) and should, therefore, be accessed in MPS VI patient evaluations, allowing for timely intervention and better prognosis. We recognize the limitations of these data due to the small sample size and recommend further investigation into this patient population. Copyright © 2011 Elsevier Inc. All rights reserved.
Dafne Dain Gandelman Horovitz, Tatiana de Sá Pacheco Carneiro Magalhães, Alessandra Pena e Costa, Luis Eduardo Carelli, Daniel Souza e Silva, Anna Patricia Freitas de Linhares e Riello, Juan Clinton Llerena - May 15, 13Journal of inherited metabolic disease, Vol. 35, No. 5. (10 September 2012), pp. 871-877, doi:10.1007/s10545-011-9436-z
The aim of newborn screening (NBS) programs is to detect a condition in a presymptomatic baby and provide management measures which could significantly improve the natural history of the disease. NBS programs for metabolic diseases were first introduced in North America and Europe and in the 1960s for phenylketonuria, expanded a few years later to include congenital hypothyroidism, and have been growing steadily in terms of number of conditions tested for and number of countries and births covered. Lysosomal storage diseases (LSDs) are a group of around 50 genetic conditions in which a defect in a lysosomal function occurs. LSDs are progressive conditions, being usually asymptomatic at birth, but with clinical features becoming apparent in childhood, with severe manifestations in most instances, high morbidity and shortened life span. Although individually rare, the prevalence of LSDs is significant when the group is considered as a whole (around 1:4,000-1:9,000 live births). Several management techniques, including bone marrow transplantation, enzyme replacement therapy, substrate inhibition therapy, pharmacological chaperones and many other approaches are transforming the LSDs into treatable conditions. However, lack of awareness and lack of access to tests cause a significant delay between onset of symptoms and diagnosis. Several lines of evidence showing that the earlier introduction of therapy may provide a better outcome, are bringing support to the idea of including LSDs in NBS programs. Due to advances in technology, high-throughput multiplex methods are now available for mass screening of several LSDs. Pilot projects were already developed in many countries for some LSDs, with interesting results. Although some NBS in Latin America has been carried out since the 1970s, it has so far been incorporated as a public health program in only a few countries in the region. It will probably take many years before NBS is implemented in most Latin American countries with a comprehensive coverage in terms of number of diseases and number of births. Population medical genetics is the area of medical genetics that aims at the study and medical care of the population, and not of the family, which is the case for clinical or medical genetics itself. It combines different aspects of genetics: clinical genetics; human population genetics, which investigates populations according to micro-evolutionary parameters; epidemiological genetics, traditionally involved in the study of common chronic diseases of polygenic etiology, except for Mendelian diseases; and sanitary or community genetics, which stands at the interface with public health, giving support to preventive health measures. Taking into account that several LSDs were identified in a higher frequency in selected areas and/or populations, the population medical genetics approach could help to introduce the NBS for LSDs in the region, with identification of areas with higher risk for selected diseases and design of customized screening program to address specific needs. As an example of the potential of this approach, a pilot program of NBS for MPS VI was implemented in a community from North East Brazil where 13 cases of MPS VI were identified in an area with 50,000 inhabitants. This program, which will enable not only identification and early treatment of affected newborns but also carrier detection, and which would allow genetic counseling for at-risk couples, could be an alternative model for a customized NBS of LSDs to be carried out in selected regions.
Roberto Giugliani - May 14, 13In Scriver’s Online Metabolic and Molecular Bases of Inherited Disease (2013), pp. 2465-2494, doi:10.1036/ommbid.165
The mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders caused by deficiency of enzymes catalyzing the degradation of glycosaminoglycans (mucopolysaccharides). Depending on the enzyme deficiency, the catabolism of dermatan sulfate, heparan sulfate, keratan sulfate, chondroitin sulfate, or hyaluronan may be blocked, singly or in combination. Lysosomal accumulation of glycosaminoglycan molecules results in cell, tissue, and organ dysfunction. Glycosaminoglycan fragments generated by alternative pathways are excreted in urine. There are 11 known enzyme deficiencies that give rise to 7 distinct MPS. Table 136-1 presents the affected enzymes and glycosaminoglycans, and the corresponding syndromes and subtypes. The stepwise degradation of glycosaminoglycans requires four exoglycosidases, five sulfatases, and one nonhydrolytic transferase. Endoglycosidases also participate in the degradation. The genes and cDNAs encoding most of these enzymes have been cloned, leading to elucidation of their primary structure, to production of recombinant enzymes, and to identification of mutations causing disease. The MPS share many clinical features, although in variable degrees. These include a chronic and progressive course, multisystem involvement, organomegaly, dysostosis multiplex, and abnormal facies. Hearing, vision, airway, cardiovascular function, and joint mobility may be affected. Profound mental retardation is characteristic of MPS IH (Hurler syndrome), the severe form of MPS II (Hunter syndrome), and all subtypes of the MPS III (Sanfilippo syndrome), but normal intellect may be retained in other MPS. The bony lesions of MPS IV (Morquio syndrome) are specific to that disorder. There is clinical similarity between different enzyme deficiencies, and, conversely, a wide spectrum of clinical severity within any one enzyme deficiency. Supportive management—with particular attention to respiratory and cardiovascular complications, loss of hearing and vision, communicating hydrocephalus, and spinal cord compression—can greatly improve the quality of life for patients and their families. The MPS are rare diseases. They are transmitted in an autosomal recessive manner except for MPS II, which is X-linked. Mutations underlying any one MPS are very heterogeneous, but one or a few mutant alleles may predominate in specific populations. Most are point mutations or small changes in the gene, although major DNA rearrangements and large deletions occur in MPS II. Correlation of disease severity with genotype is sometimes possible, but the effect of missense mutations is generally difficult to predict. Enzyme assays are available for diagnosis, including prenatal diagnosis, of all the MPS. Identification of heterozygotes on the basis of enzyme activity is generally difficult or insufficiently accurate. Because of the heterogeneity of mutations, diagnosis and carrier testing by DNA analysis requires knowledge of the mutant alleles in the family under consideration. There are numerous animal models of MPS. In addition to the models derived from mutations that have occurred naturally in dogs, cats, rats, mice, and goats, there are several mouse models created by targeted disruption of the corresponding mouse gene. The biochemical and pathologic features of these animal models is generally quite similar to those of their human counterparts, but the clinical presentations may be milder. The MPS have long been considered potentially amenable to therapy by exogenously supplied enzyme. The success of bone marrow transplantation in altering the course of some MPS demonstrated that enzyme from donor hematopoietic cells could reduce glycosaminoglycan storage in somatic tissues of the recipient. Unfortunately, the variable neurologic benefit and the high risk associated with bone marrow transplantation limit the value of this form of therapy. Enzyme replacement is under active development, while gene therapy is at a much earlier stage. The animal models of MPS are proving extremely useful for developing and testing novel therapies.
Elizabeth Neufeld, Joseph Muenzer - May 13, 13MMWR. Recommendations and reports : Morbidity and mortality weekly report. Recommendations and reports / Centers for Disease Control, Vol. 59, No. RR-9. (10 September 2010), pp. 1-15
In April 2006, the World Health Organization (WHO) released new international growth charts for children aged 0-59 months. Similar to the 2000 CDC growth charts, these charts describe weight for age, length (or stature) for age, weight for length (or stature), and body mass index for age. Whereas the WHO charts are growth standards, describing the growth of healthy children in optimal conditions, the CDC charts are a growth reference, describing how certain children grew in a particular place and time. However, in practice, clinicians use growth charts as standards rather than references. In 2006, CDC, the National Institutes of Health, and the American Academy of Pediatrics convened an expert panel to review scientific evidence and discuss the potential use of the new WHO growth charts in clinical settings in the United States. On the basis of input from this expert panel, CDC recommends that clinicians in the United States use the 2006 WHO international growth charts, rather than the CDC growth charts, for children aged <24 months (available at https://www.cdc.gov/growthcharts). The CDC growth charts should continue to be used for the assessment of growth in persons aged 2--19 years. The recommendation to use the 2006 WHO international growth charts for children aged <24 months is based on several considerations, including the recognition that breastfeeding is the recommended standard for infant feeding. In the WHO charts, the healthy breastfed infant is intended to be the standard against which all other infants are compared; 100% of the reference population of infants were breastfed for 12 months and were predominantly breastfed for at least 4 months. When using the WHO growth charts to screen for possible abnormal or unhealthy growth, use of the 2.3rd and 97.7th percentiles (or ±2 standard deviations) are recommended, rather than the 5th and 95th percentiles. Clinicians should be aware that fewer U.S. children will be identified as underweight using the WHO charts, slower growth among breastfed infants during ages 3-18 months is normal, and gaining weight more rapidly than is indicated on the WHO charts might signal early signs of overweight.
Laurence Grummer-Strawn, Chris Reinold, Nancy Krebs, - May 13, 13Vital Health Stat, No. 246. (May 2002)
http://www.cdc.gov/growthcharts/
Robert Kuczmarski, Cynthia Ogden, Shumei Guo, Laurence Grummer-Strawn, Zuguo Mei, Rong Wei, Lester Curtin, Alex Roche, Clifford Johnson - May 10, 13Archives of disease in childhood, Vol. 93, No. 6. (June 2008), pp. 464-468, doi:10.1136/adc.2007.123653
The 6-minute walk test (6MWT) is an established measure of exercise capacity in adults and children with chronic cardiac or respiratory disease. Despite its widespread use, there are no normal values for healthy children under 12 years of age. We aimed to provide normal values for children between 4 and 11 years. Healthy children were recruited prospectively from two UK primary schools and also children visiting Great Ormond Street Hospital. 328 children (54% male) aged 4 to 11 years were included in the study. Main outcome measures were the distance walked in 6 minutes, and oxygen saturation and heart rate during the 6 minutes and during a 3-minute recovery period. Mean oxygen saturation at baseline and during the 6MWT was 97-99%. Heart rate increased from 102+/-19 bpm at baseline to a maximum of 136+/-12 bpm. Overall, the mean distance walked in 6 minutes was 470+/-59 m. Distance walked correlated with age (r = 0.64, p<0.0001), weight (r = 0.51, p<0.0001) and height (r = 0.65, p<0.0001) with no significant difference between boys and girls. The distance walked increased significantly year on year from 4 to 7 years (4 years 383+/-41 m; 5 years 420+/-39 m, 6 years 463+/-40 m; 7 years 488+/-35 m; p<0.05 between each); further modest increases were observed beyond 7 years of age. Performing a 6MWT is feasible and practical in young children. This study provides data on normal children against which the performance of sick children and the response to therapeutic intervention can be judged.
AE Lammers, AA Hislop, Y Flynn, SG Haworth - May 10, 13Clinical genetics, Vol. 77, No. 5. (May 2010), pp. 492-498, doi:10.1111/j.1399-0004.2009.01324.x
Mucopolysaccharidosis type VI (MPS VI) is a progressive, multisystem disorder caused by a deficiency of the lysosomal enzyme N-acetylgalactosamine-4-sulphatase (ASB). Enzyme replacement therapy (ERT) has been shown to clinically benefit affected individuals greater than 6 years of age. This case control study of affected siblings assessed the safety, efficacy and benefits of ERT in children less than 5 years of age. Siblings, aged 8 weeks and 3.6 years, were treated weekly with 1 mg/kg recombinant human N-acetylgalactosamine-4-sulphatase (rhASB) with an end-point of 3.6 years. Clinical and biochemical parameters were monitored to assess the benefits of ERT. The treatment was well tolerated by both siblings. In the younger sibling, ERT was associated with the absence of the development of scoliosis and preserved joint movement, cardiac valves and facial morphology. The older sibling had a marked improvement in joint mobility and cardiac valve pathology and scoliosis slowed or stabilized. Corneal clouding and progressive skeletal changes were observed despite treatment. This study demonstrated a clear benefit of early initiation of ERT to slow or prevent the development of significant pathological changes of MPS VI. These results indicate that the earlier ERT is started, the greater the response.
JJ McGill, AC Inwood, DJ Coman, ML Lipke, D de Lore, SJ Swiedler, JJ Hopwood - May 08, 13Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 1. (5 January 2010), pp. 222-227, doi:10.1073/pnas.0912937107
Enzyme replacement therapy is currently available for three of the mucopolysaccharidoses (MPSs) but has limited effects on the skeletal lesions. We investigated the involvement of the Toll-like receptor 4 (TLR4) signaling pathway in the pathogenesis of MPS bone and joint disease, and the use of the anti-TNF-alpha drug, Remicade (Centocor, Inc.), for treatment. TLR4 KO (TLR4(lps-/-)) mice were interbred with MPS VII mice to produce double-KO (DKO) animals. The DKO mice had longer and thinner faces and longer femora as revealed by micro-computed tomography analysis compared with MPS VII mice. Histological analyses also revealed more organized and thinner growth plates. The serum levels of TNF-alpha were normalized in the DKO animals, and the levels of phosphorylated STAT1 and STAT3 in articular chondrocytes were corrected. These findings led us to evaluate the effects of Remicade in MPS VI rats. When initiated at 1 month of age, i.v. treatment prevented the elevation of TNF-alpha, receptor activator of NF-kappaB, and other inflammatory molecules not only in the blood but in articular chondrocytes and fibroblast-like synoviocytes (FLSs). Treatment of 6-month-old animals also reduced the levels of these molecules to normal. The number of apoptotic articular chondrocytes in MPS VI rats was similarly reduced, with less infiltration of synovial tissue into the underlying bone. These studies revealed the important role of TLR4 signaling in MPS bone and joint disease and suggest that targeting TNF-alpha may have positive therapeutic effects.
Calogera Simonaro, Yi Ge, Efrat Eliyahu, Xingxuan He, Karl Jepsen, Edward Schuchman - May 07, 13New England Journal of Medicine, Vol. 368, No. 14. (04 April 2013), pp. 1314-1325, doi:10.1056/nejmoa1212299
BACKGROUND: Castration resistance occurs in most patients with metastatic hormone-sensitive prostate cancer who are receiving androgen-deprivation therapy. Replacing androgens before progression of the disease is hypothesized to prolong androgen dependence. METHODS: Men with newly diagnosed, metastatic, hormone-sensitive prostate cancer, a performance status of 0 to 2, and a prostate-specific antigen (PSA) level of 5 ng per milliliter or higher received a luteinizing hormone–releasing hormone analogue and an antiandrogen agent for 7 months. We then randomly assigned patients in whom the PSA level fell to 4 ng per milliliter or lower to continuous or intermittent androgen deprivation, with patients stratified according to prior or no prior hormonal therapy, performance status, and extent of disease (minimal or extensive). The coprimary objectives were to assess whether intermittent therapy was noninferior to continuous therapy with respect to survival, with a one-sided test with an upper boundary of the hazard ratio of 1.20, and whether quality of life differed between the groups 3 months after randomization. RESULTS: A total of 3040 patients were enrolled, of whom 1535 were included in the analysis: 765 randomly assigned to continuous androgen deprivation and 770 assigned to intermittent androgen deprivation. The median follow-up period was 9.8 years. Median survival was 5.8 years in the continuous-therapy groufp and 5.1 years in the intermittent-therapy group (hazard ratio for death with intermittent therapy, 1.10; 90% confidence interval, 0.99 to 1.23). Intermittent therapy was associated with better erectile function and mental health (P<0.001 and P=0.003, respectively) at month 3 but not thereafter. There were no significant differences between the groups in the number of treatment-related high-grade adverse events. CONCLUSIONS: Our findings were statistically inconclusive. In patients with metastatic hormone-sensitive prostate cancer, the confidence interval for survival exceeded the upper boundary for noninferiority, suggesting that we cannot rule out a 20% greater risk of death with intermittent therapy than with continuous therapy, but too few events occurred to rule out significant inferiority of intermittent therapy. Intermittent therapy resulted in small improvements in quality of life. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00002651.)
Maha Hussain, Catherine Tangen, Donna Berry, Celestia Higano, David Crawford, Glenn Liu, George Wilding, Stephen Prescott, Subramanian Kanaga Sundaram, Eric Small, Nancy Dawson, Bryan Donnelly, Peter Venner, Ulka Vaishampayan, Paul Schellhammer, David Quinn, Derek Raghavan, Benjamin Ely, Carol Moinpour, Nicholas Vogelzang, Ian Thompson - May 07, 13Current medical research and opinion, Vol. 25, No. 11. (November 2009), pp. 2723-2727, doi:10.1185/03007990903297782
A number of decisions in the health care field rely heavily on published clinical evidence. A systematic approach to evidence development and publication planning is required to develop a portfolio of evidence that includes at minimum information on efficacy, safety, durability of effect, quality of life, and economic outcomes. The approach requires a critical assessment of available literature, identification of gaps in the literature, and a strategic plan to fill the gaps to ensure the availability of evidence demanded for clinical decisions, coverage/payment decisions and health technology assessments. The purpose of this manuscript is to offer a six-step strategic process leading to a portfolio of evidence that meets the informational needs of providers, payers, and governmental agencies concerning patient access to a therapy.
Michael Wittek, Mary Jo Williams, Angeline Carlson - May 03, 13The Lancet Oncology (April 2013), doi:10.1016/s1470-2045(13)70157-8
Bryan Burmeister, Sandro Porceddu - May 03, 13The lancet oncology (24 April 2013), doi:10.1016/s1470-2045(13)70136-0
BACKGROUND: Definitive chemoradiotherapy (CRT) is an alternative to surgery for the curative treatment of oesophageal carcinoma. The SCOPE1 trial aimed to investigate the addition of cetuximab to cisplatin and fluoropyrimidine-based definitive CRT in patients with localised oesophageal squamous-cell cancer and adenocarcinomas to assess activity, safety, and feasibility of use. METHODS: In this multicentre, randomised, open-label, phase 2/3 trial, we recruited patients aged 18 years and older from UK radiotherapy centres who had non-metastatic, histologically confirmed carcinoma of the oesophagus (adenocarcinoma, squamous-cell, or undifferentiated; WHO status 0-1; stage I-III disease) and been selected to receive definitive CRT. Patients were randomly assigned (1:1) via a central computerised system using stratified minimisation (with an 80:20 random element) to receive CRT alone or CRT with cetuximab (400 mg/m(2) on day 1 followed by 250 mg/m(2) weekly), stratified by recruiting hospital, primary reason for not having surgery, tumour histology, and tumour stage. CRT consisted of cisplatin 60 mg/m(2) (day 1) and capecitabine 625 mg/m(2) twice daily (days 1-21) for four cycles; cycles three and four were given concurrently with 50 Gy in 25 fractions of radiotherapy. The primary endpoint was the proportion of patients who were treatment failure free at week 24 for the phase 2 trial and overall survival for the phase 3 trial, both measured from randomisation. We analysed data by intention to treat. This trial is an International Standard Randomised Controlled Trial, number 47718479. FINDINGS: 258 patients (129 assigned to each treatment group) from 36 UK centres were recruited between Feb 7, 2008, and Feb 22, 2012. Recruitment was stopped without continuation to phase 3 because the trial met criteria for futility, but we continued to follow-up recruited patients until all had reached at least 24-week follow-up (median follow-up of patients who survived was 16·8 months [IQR 11·2-24·5]). Fewer patients were treatment failure free at 24 weeks in the CRT plus cetuximab group (79 of 119 patients [66·4%, 90% CI 58·6-73·6]) than in the CRT only group (93 of 121 patients [76·9%, 69·7-83·0]). The CRT plus cetuximab group also had shorter median overall survival (22·1 months [95% CI 15·1-24·5] vs 25·4 months [20·5-37·9]; adjusted HR 1·53 [95% CI 1·03-2·27]; p=0·035). Patients who received CRT plus cetuximab had more non-haematological grade 3 or 4 toxicities (102 [79%] of 129 patients vs 81 [63%] of 129 patients; p=0·004). The most common grade 3 or 4 toxicities were low white blood cell count (14 [11%] in the CRT plus cetuximab group vs 21 [16%] in the CRT only group), low absolute neutrophil count (15 [12%] vs 24 [19%]), fatigue (26 [20%] vs 25 [19%]), and dysphagia (35 [27%] vs 37 [29%]). INTERPRETATION: The addition of cetuximab to standard chemotherapy and radiotherapy cannot be recommended for patients with oesophageal cancer suitable for definitive CRT. FUNDING: Cancer Research UK. Copyright © 2013 Elsevier Ltd. All rights reserved.
Thomas Crosby, Christopher Hurt, Stephen Falk, Simon Gollins, Somnath Mukherjee, John Staffurth, Ruby Ray, Nadim Bashir, John Bridgewater, Ian Geh, David Cunningham, Jane Blazeby, Rajarshi Roy, Tim Maughan, Gareth Griffiths - May 03, 13The Lancet Oncology, Vol. 14, No. 5. (April 2013), pp. 391-436, doi:10.1016/s1470-2045(13)70048-2
Paul Goss, Brittany Lee, Tanja Badovinac-Crnjevic, Kathrin Strasser-Weippl, Yanin Chavarri-Guerra, Jessica Louis, Cynthia Villarreal-Garza, Karla Unger-Saldaña, Mayra Ferreyra, Márcio Debiasi, Pedro Liedke, Diego Touya, Gustavo Werutsky, Michaela Higgins, Lei Fan, Claudia Vasconcelos, Eduardo Cazap, Carlos Vallejos, Alejandro Mohar, Felicia Knaul, Hector Arreola, Rekha Batura, Silvana Luciani, Richard Sullivan, Dianne Finkelstein, Sergio Simon, Carlos Barrios, Rebecca Kightlinger, Andres Gelrud, Vladimir Bychkovsky, Gilberto Lopes, Stephen Stefani, Marcelo Blaya, Fabiano Souza, Franklin Santos, Alberto Kaemmerer, Evandro de Azambuja, Andres Zorilla, Raul Murillo, Jose Jeronimo, Vivien Tsu, Andre Carvalho, Carlos Gil, Cinthya Sternberg, Alfonso Dueñas-Gonzalez, Dennis Sgroi, Mauricio Cuello, Rodrigo Fresco, Rui Reis, Guiseppe Masera, Raúl Gabús, Raul Ribeiro, Renata Knust, Gustavo Ismael, Eduardo Rosenblatt, Berta Roth, Luisa Villa, Argelia Solares, Marta Leon, Isabel Torres-Vigil, Alfredo Covarrubias-Gomez, Andrés Hernández, Mariela Bertolino, Gilberto Schwartsmann, Sergio Santillana, Francisco Esteva, Luis Fein, Max Mano, Henry Gomez, Marc Hurlbert, Alessandra Durstine, Gustavo Azenha - Apr 26, 13Genetics in medicine (7 March 2013), doi:10.1038/gim.2013.10
Fifty years after the implementation of universal newborn screening programs for phenylketonuria, the first disease identified through newborn screening and considered a success story of newborn screening, a cohort of adults with phenylketonuria treated from birth provides valuable information about effects of long-term treatment for inborn errors of metabolism in general, and phenylketonuria specifically. For phenylketonuria, newborn screening allows early implementation of the phenylalanine-restricted diet, eliminating the severe neurocognitive and neuromotor impairment associated with untreated phenylketonuria. However, executive function impairments and psychiatric problems are frequently reported even for those treated early and continuously with the phenylalanine-restricted diet alone. Moreover, a large percentage of adults with phenylketonuria are reported as lost to follow-up by metabolic clinics. While a group of experts identified by the National Institutes of Health convenes to update treatment guidelines for phenylketonuria, we explore individual patient, social, and economic factors preventing >70% of adult phenylketonuria patients in the United States from accessing treatment. As more conditions are identified through newborn screening, factors affecting access to treatment grow in importance, and we must continue to be vigilant in assessing and addressing factors that affect patient treatment outcomes and not just celebrate amelioration of the most severe manifestations of disease.Genet Med advance online publication 7 March 2013Genetics in Medicine (2013); doi:10.1038/gim.2013.10.
Susan Berry, Christine Brown, Mitzie Grant, Carol Greene, Elaina Jurecki, Jean Koch, Kathryn Moseley, Ruth Suter, Sandra van Calcar, Judy Wiles, Stephen Cederbaum - Apr 25, 13Chest, Vol. 88, No. 2. (August 1985), pp. 201-205, doi:10.1378/chest.88.2.201
Previous studies suggest that pulmonary function of singers and wind-instrument players may be better than normal control subjects due to breath-control training; however, prior studies were poorly controlled or limited in scope. In the present study, we compare 34 singers and 48 wind instrumentalists with a control group of 31 string or percussion instrumentalists using a pulmonary questionnaire, measurements of inspiratory and expiratory pressures, and spirometry. We found no significant difference between groups in maximum voluntary ventilation, forced expiratory volume in one second (FEV1), forced vital capacity (FVC), mean forced expiratory flow during the middle half of the FVC, the FEV1/FVC, peak expiratory pressure, or peak inspiratory pressure, independently or when corrected for age, sex, height, weight, years performing, smoking, presence or absence of cough, or sputum production. Smoking correlated negatively with measurements of pulmonary function in all groups. There was evidence of a heightened awareness of health among singers, who exercised more and smoked less than their colleagues. The differences in health habits may account in part for the myth of improved pulmonary volumes among singers.
B Schorr-Lesnick, AS Teirstein, LK Brown, A Miller - Apr 25, 13British journal of industrial medicine, Vol. 42, No. 1. (January 1985), pp. 55-58, doi:10.1136/oem.42.1.55
In a longitudinal study of a sample of firemen in London 1006 firemen were interviewed and examined in 1976 and 895 were seen a second time 12 months later. On each occasion a Medical Research Council respiratory questionnaire was administered and forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) were measured. The average levels of FEV1, FVC, and FEV1/FVC in both years compared favourably with conventional predicted values. Separate multiple regression analysis for the two years indicated that the FEV1 and FVC fell more rapidly in those aged over 40, and that cigarette smoking had a strong harmful effect on these measures of function. Only among men with over 20 years' service was there possibly any evidence (not statistically significant) of an effect from duration of employment. The comparatively large fall in FEV1 and FVC from 1976 to 1977 was due mainly to instrumental variation. The prevalence of respiratory symptoms was higher in smokers than non-smokers and increased with the number of cigarettes smoked.
DB Douglas, RB Douglas, D Oakes, G Scott - Apr 25, 13Thorax, Vol. 48, No. 8. (August 1993), pp. 803-808
A study was performed to determine reference ranges for whole body plethysmographic gas volumes and single breath gas transfer in healthy prepubertal and pubertal schoolchildren. The study was performed in 772 white London schoolchildren (455 male) who were clinically examined, assessed auxologically and, in 63% of cases, pubertally staged. Regression equations for the calculation of standard deviation scores were derived. Male lung function variables showed a discontinuous pattern of increase with standing height. Linear increases until puberty were followed by a sudden pubertal rise and a further increase with height which was more marked than before puberty. Correction for varying thoracic dimensions eliminated these changes. In females a smoother curvilinear relationship was observed with no correction possible for thoracic size. Male puberty leads to profound changes in pulmonary function mostly related to thoracic size, an effect not observed in females.
M Rosenthal, D Cramer, SH Bain, D Denison, A Bush, JO Warner - Apr 25, 13Pediatric pulmonology, Vol. 36, No. 3. (September 2003), pp. 202-208, doi:10.1002/ppul.10239
The present study evaluates the relationships of pulmonary volumes and flows and the anthropometric variables of standing height, sitting height, and arm span in 100 6-10-year-old children. To be included in the study, all children were required to be healthy and above the 3rd percentile of the curve of Tanner et al. (Arch Dis Child 1966;41:454-471; Arch Dis Child 1966;41:613-635) for height and weight. Standing height, sitting height, and arm span were measured according to standard protocol. The pulmonary function measurements were: tidal volume, minute respiratory volume, respiratory rate, expiratory reserve volume, inspiratory capacity, vital capacity, residual volume (RV), functional residual capacity, total lung capacity (TLC), forced vital capacity (FVC), forced expiratory volume in 1 sec of FVC (FEV(1)), forced expiratory flow measured between 25-75% of FVC, and FEV(1)/FVC and RV/TLC ratios. Simple linear regression best expressed the correlation between pulmonary function and the anthropometric variables. Significant correlations between anthropometric and pulmonary function measurements were observed, with FVC and FEV(1) showing the highest and RV the lowest r(2) values. There was a significant positive correlation between standing height and arm span according to linear regression and Bland-Altman comparison (Bland and Altman, Lancet 1968;8:307-310). Our results suggest that when an accurate determination of standing height cannot be obtained, arm span could be used interchangeably, using the same regression equation. However, for patients with limb deformities, regression equations of pulmonary function measurements in relation to sitting height may be a better choice for estimating pulmonary function. Copyright 2003 Wiley-Liss, Inc.
Lídia Torres, Francisco Martinez, José Manço - Apr 25, 13Acta paediatrica (Oslo, Norway : 1992). Supplement, Vol. 94, No. 447. (March 2005)
Mucopolysaccharidosis VI (Maroteaux-Lamy syndrome) is a lysosomal storage disease caused by a deficiency of the enzyme-N-acetylgalactosamine 4-sulphatase (ASB). Enzyme replacement therapy with recombinant human ASB (rhASB) has been studied in a randomized, double-blind, two-dose (0.2 and 1.0 mg/kg/week) phase I/II study (n = 7) followed by an open-label single dose (1.0 mg/kg/week) extension study. We report the pharmacokinetic profile of rhASB and the impact of antibody development. Pharmacokinetic analysis was performed at weeks 1, 2, 12, 24, 83, 84 and 96. Infusions were administered over 4 hours using a ramp-up protocol. Plasma ASB and rhASB antibody concentrations and urine glycosaminoglycan (GAG) concentrations were determined. The area under the plasma concentration-time curve (AUC(0-t)) for the high-dose group increased from week 1 to week 2, but remained unchanged at weeks 12 and 24. A large difference in mean AUC(0-t) was observed between the low- and high-dose groups. Pharmacokinetic results at weeks 83, 84 and 96 were similar to those at week 24. Six patients developed antibodies to rhASB. One patient developed high antibody levels in combination with a high ASB concentration, while a second patient also developed high antibody levels with undetectable ASB concentrations. Antibodies from the second patient blocked detection of ASB. By week 72, antibody levels had decreased in all patients. The high-dose rhASB produced a more rapid and greater percentage reduction in urinary GAG concentrations than the lower dose (70% versus 55% at 24 weeks). Antibody levels did not appear to influence urinary GAG concentrations. Pharmacokinetic parameters appear to be independent of the duration of treatment and are not linear between the 0.2 and 1.0 mg/kg/week doses. Antibodies to rhASB develop in most patients, but their concentration decreases over time. Antibody formation may influence pharmacokinetic parameters during the early phases of treatment, although it appears to have limited impact on biochemical efficacy.
P Harmatz, WG Kramer, JJ Hopwood, J Simon, E Butensky, SJ Swiedler, - Apr 24, 13CME : Your SA Journal of CPD : Paediatric cardiology, Vol. 29, No. 11. (2011), pp. 452-455
In general, medical practitioners (and paediatricians in particular) are trained to recognise common patterns of abnormalities in order to derive clues to disease diagnosis. This is typical of most clinical settings, especially in history taking and clinical examination, but also for investigations such as X-rays and common routine blood tests. It is therefore curious that even though there are a limited number of typical ECG patterns commonly found in routine paediatric cardiac examination, ECG interpretation is often viewed with trepidation and the common patterns are not readily recognised. Rather, the practitioner (or student) faced with an ECG blindly runs through the mantra of 'rate-rhythm-axis', ignoring (or not recognising) the blatant abnormalities that in clinical context may supply clues to an immediate cardiac diagnosis. A cyanosed newborn with a left axis has tricuspid atresia until proven otherwise; a 6-year-old boy with weakness and large R waves in lead V1 probably has Duchenne muscular dystrophy; a child with Down syndrome and a left axis has an AV canal defect; a child with a history of syncope and unusual T waves may have long QT syndrome. It is not difficult to recognise, within clinical context, a diagnostic ECG pattern. The technicalities of rate, rhythm and axis remain as important as ever, but may play only secondary roles in the diagnostic value of the ECG.
Liesel Andrag, Rik De Decker - Apr 24, 13The American journal of emergency medicine, Vol. 26, No. 2. (February 2008), pp. 221-228, doi:10.1016/j.ajem.2007.08.003
Emergency physicians attending to pediatric patients in acute care settings use electrocardiograms (ECGs) for a variety of reasons, including syncope, chest pain, ingestion, suspected dysrhythmias, and as part of the initial evaluation of suspected congenital heart disease. Thus, it is important for emergency and acute care providers to be familiar with the normal pediatric ECG in addition to common ECG abnormalities seen in the pediatric population. The purpose of this 3-part review will be to review (1) age-related changes in the pediatric ECG, (2) common arrhythmias encountered in the pediatric population, and (3) ECG indicators of structural and congenital heart disease in the pediatric population.
Matthew O'Connor, Nancy McDaniel, William Brady - Apr 24, 13Arthritis and rheumatism, Vol. 37, No. 12. (December 1994), pp. 1761-1769
To develop and validate a self- or parent-administered instrument for measuring functional status in children with juvenile rheumatoid arthritis (JRA). We adapted the Stanford Health Assessment Questionnaire (HAQ) for use in children ages 1-19 years, by adding several new questions, such that for each functional area, there was at least 1 question relevant to children of all ages. The face validity of the instrument was evaluated by a group of 20 health professionals and parents of 22 healthy children. The questionnaire was then administered to parents of 72 JRA patients (mean age 9.1 years, onset type systemic in 16, polyarticular in 21, pauciarticular in 35). The instrument showed excellent internal reliability (Cronbach's alpha = 0.94), with a mean inter-item correlation of 0.6. The convergent validity was demonstrated by strong correlations of the Disability Index (average of scores on all functional areas) with Steinbrocker functional class (Kendall's tau b = 0.77, P < 0.0001), number of involved joints (Kendall's tau b = 0.67, P < 0.0001), and morning stiffness (Kendall's tau b = 0.54, P < 0.0001). Spearman's correlation coefficient between Disability Index scores from questionnaires administered to parents and those from questionnaires administered to older children (> 8 years) was 0.84 (n = 29; P < 0.001), showing that parents can accurately report for their children. The test-retest reliability, studied at a 2-week interval, revealed virtually identical Disability Index scores measured on the 2 occasions (0.96 versus 0.96; P > 0.9 by paired t-test; Spearman's correlation coefficient = 0.8, P < 0.002). The Childhood HAQ, which takes less than 10 minutes to complete, is a valid, reliable, and sensitive instrument for measuring functional status in children with JRA.
G Singh, BH Athreya, JF Fries, DP Goldsmith - Apr 24, 13Arthritis care and research : the official journal of the Arthritis Health Professions Association, Vol. 5, No. 3. (September 1992), pp. 119-129
Over 100 papers describing and utilizing the Stanford Health Assessment Questionnaire (HAQ) have been published since 1980. A brief overview of the HAQ is presented along with a guide to the accumulated literature. The topics covered include: studies using the disability, pain, economic, and drug side effect dimensions of the HAQ; reliability and validity studies; applications to various rheumatic diseases; language adaptations; modifications and derivative scales; studies correlating the HAQ with sociodemographic, health status, laboratory, and physical measures; and randomized controlled trials and observational studies using the HAQ. A few comments regarding future directions for research are also presented.
DR Ramey, JP Raynauld, JF Fries - Apr 24, 13Controlled clinical trials, Vol. 12, No. 4 Suppl. (August 1991), pp. 106S-117S
Health, as defined by the World Health Organization, encompasses the more redundant and cumbersome phrase "health-related quality of life." Valuations by patients naturally separate this entity into the primary dimensions of absence of death, disability, discomfort, drug toxicity, and destitution. These dimensions separate naturally into subdimensions, and the subdimensions into components, thus providing a hierarchy under which assessment of particular aspects of health may be placed. In the clinical trial situation, it is essential that all dimensions always be assessed and reported, because otherwise, misleading conclusions may be drawn. On the other hand, it is much less important which assessment instrument is chosen, or how much detail is assessed for each dimension. The Health Assessment Questionnaire (HAQ) has been developed under a hierarchical conceptual model and widely used; its characteristics are described. A new index for measurement of drug toxicity has been developed for the HAQ, and its crucial role in comparing treatments in a clinical trial discussed. Issues in reliably describing comparative drug toxicity are developed, a toxicity index presented, and some preliminary results and conclusions outlined. With the ability to quantitatively describe drug toxicity, health assessment becomes conceptually more complete.
JF Fries - Apr 24, 13Journal of Electrocardiology, Vol. 40, No. 3. (May 2007), pp. 228-234.e8, doi:10.1016/j.jelectrocard.2006.09.003
Reference ranges for electrocardiogram (ECG) intervals, heart rate, and QRS axis in general use by medical personnel and ECG readers are unrepresentative of true age- and sex-related values in large populations and are not based on modern electrocardiographic and ECG reading technology. The results of ECG interpretation by cardiologists using digital technology for viewing and interpreting ECGs were compiled from single, baseline ECGs of 79,743 individuals included in pharmaceutical company–sponsored clinical trials. Women comprised 48% of the total population. Ages ranged from 3 months to 99 years, and the bulk of the population (56%) was aged 40 to 70 years. Striking differences in numerical ECG values based on age and sex were observed. A subgroup of 46,129 individuals with a very low probability of cardiovascular disease was identified. The following were the reference ranges for this subgroup, determined using the 2nd and 98th percentiles: heart rate, 48 to 98 beats/min; PR interval, 113 to 212 milliseconds; QRS interval, 69 to 109 milliseconds; frontal plane QRS axis, −40° to 91°; QT interval, 325 to 452 milliseconds; QTc-Bazett, 361 to 457 milliseconds; and QTc-Fridericia, 359 to 445 milliseconds. There were marked age- and sex-related variations in the reference ranges of this subgroup, and they differ substantially from previously reported norms. Small differences were observed in ECG values obtained using our digital methods as compared with readings done using paper tracings and values computed by 2 commercial computer algorithms. We observed large differences in electrocardiographic heart rate, interval, and axis reference ranges in this study compared with those reported previously and with reference ranges in general use. We also observed a large influence of age and sex upon normal values. Very large cohorts are required to fully assess age- and sex-related variation of reference ranges. Electrocardiographic reference ranges should be modernized.
Jay Mason, Douglas Ramseth, Dennis Chanter, Thomas Moon, Daniel Goodman, Boaz Mendzelevski - Apr 24, 13In Advanced Nursing Skills: Principles and Practice
- Apr 24, 13South Sudan Medical Journal, Vol. 3, No. 4. (November 2010), pp. 72-75
This is the second in a series of articles that aim to help readers to understand and interpret recordings of the surface ECG. The first article introduced the basic principles of the ECG including the electrophysiology of the heart and the features of a normal ECG (1). This one describes some of the common abnormalities of electrical conduction which can be seen on the ECG.
Dallas Price - Apr 24, 13South Sudan Medical Journal, Vol. 3, No. 4. (May 2010), pp. 26-28
The electrocardiogram (ECG) is one of the simplest and oldest cardiac investigations available, yet it can provide a wealth of useful information and remains an essential part of the assessment of cardiac patients. With modern machines, surface ECGs are quick and easy to obtain at the bedside and are based on relatively simple electrophysiological concepts. However junior doctors often find them difficult to interpret. This is the first in a short series of articles that aim to: (1) Help readers understand and interpret ECG recordings. (2) Reduce some of the anxiety juniors often experience when faced with an ECG.
Dallas Price - Apr 24, 13The Nurse Practitioner, Vol. 33, No. 10. (October 2008), pp. 28-35
Of the many diagnostic tools used to screen for and evaluate cardiac abnormalities, the 12-lead electrocardiogram (ECG) is among the most basic. This inexpensive and noninvasive test provides a vast amount of information that assists in the diagnosis of conditions related to the heart's electrical activity. The ECG can also help evaluate myocardial ischemia and infarction, cardiomyopathy, pericarditis, and electrolyte disturbances. Although there are fundamental methods for interpretation, it is important to recognize that clinical correlation with the patient's signs and symptoms is essential.
Karen Lieberman - Apr 24, 13Eastern Mediterranean health journal = La revue de santé de la Méditerranée orientale = al-Majallah al-ṣiḥḥīyah li-sharq al-mutawassiṭ, Vol. 7, No. 6. (November 2001), pp. 981-991
Cardiac and ocular manifestations were evaluated in 21 patients clinically suspected of mucopolysaccharidosis. After electrophoresis analysis of urinary glycoaminoglycans, 3 patients were excluded because their results did not correlate with any known type of mucopolysaccharidosis. Echocardiography revealed abnormal findings in 11 patients (61.1%). The mitral valve was the most commonly affected valve; 7 patients (38.9%) had thickened mitral valve and 6 had mitral regurge. Corneal opacities were found in 3 patients (16.7%) and progressive increase in intraocular pressure in 1 patient (5.6%), while fundus examination showed early optic atrophy in 1 patient (5.6%) and bilateral papilloedema in 2 patients (11.1%).
RM Shawky, MT Abd el-Monim, AA el-Sebai, SM el-Sayed - Apr 24, 13Circulation, Vol. 52, No. 4. (October 1975), pp. 700-705
The cardiovascular manifestations of the mucopolysaccharidoses (MPS) have not been well characterized. We studied nine children with various forms of MPS, using noninvasive cardiac diagnostic techniques. The echocardiograms of two brothers with Type I H/S MPS showed slow mitral valve early diastolic closure velocities (MVEDC) (18, 29 mm/sec) consistent with mitral stenosis. Each had a soft opening snap, low frequency presystolic murmurs and X-ray evidence of calcific mitral stenosis. Three patients with Type II A MPS had echocardiographic evidence of impaired left ventricular function, suggesting the presence of myocardial damage. One of these had an abnormal electrocardiogram; non had murmurs. No cardiac abnormalities were discovered in two patients with Type III A and IV MPS. One patient with Type VI A MPS had presystolic, holostolic and early diastolic murmurs. A soft opening snap was recorded. The echocardiogram showed a slow MVEDC (18 mm/sec) and a slightly enlarged left atrial dimension (2.2 cm/m2). In summary, noninvasive studies are useful in evaluating patients with MPS. Type I H/S and Type VI A patients may show evidence of valvular deformity, the former associated with mitral valvular calcification and the latter with both aortic and mitral valve involvement. Type II A patients have muscle function abnormalities and Type III A and IV are shown by noninvasive methods to be free of cardiovascular abnormalities.
RM Schieken, RE Kerber, VV Ionasescu, H Zellweger - Apr 24, 13Archives of disease in childhood, Vol. 73, No. 3. (September 1995), pp. 259-260
Echocardiography was performed in 16 children undergoing bone marrow transplantation (BMT) for mucopolysaccharidoses. Cardiac involvement before BMT was detected in seven (44%). One year after BMT (11 patients/five with cardiac involvement), left ventricular restriction resolved in 2/3 patients and hypertrophy in one. In the remainder, at mean follow up of 2.5 years, no progression of preexisting or development of new cardiac involvement was noted. It is concluded that in a significant proportion of patients with mucopolysaccharidoses, cardiac involvement improved after BMT.
MA Gatzoulis, A Vellodi, AN Redington - Apr 24, 13Cardiology in the young, Vol. 19, No. 2. (April 2009), pp. 170-178, doi:10.1017/s1047951109003576
To analyze cardiac involvement and its progression in mucopolysaccharidoses, and to assess the short term impact of new therapeutic strategies. We studied echocardiographically 57 patients with various types of mucopolysaccharidoses, specifically types I, II, III, IV and VI, with a median age at the diagnosis of cardiac involvement of 5 years, following them for a median of 4.6 years, with a range from 0.9 to 21.2 years. We used a scoring system, along with the so-called delta score, to quantify the severity of involvement at baseline and at last examination, and to chart their progression over time. Cases with cardiac involvement increased from 59.6% to 87.3% at the last examination. The scores increased with age, and were significantly different according to the specific type of mucopolysaccharidosis. Involvement of the mitral valve was most common, often associated with an aortic valvar anomaly and/or left ventricular hypertrophy. Patients with the first and second types had more severe involvement than those with the third or fourth types. Patients undergoing transplantation of haematopoietic stem cells seem to stabilize after an initial worsening while, in contrast, we were unable to demonstrate an effect of enzyme replacement therapy on the progression of the cardiac disease, possibly because those receiving such treatment had a higher median age, more severe cardiac disease and shorter follow-up. Cardiac involvement was present early in more than a half of the patients identified as having mucopolysaccharidosis, and generally progressed, being more frequent and severe in the first and second types of the disease. Longer follow-up is needed to demonstrate any significant improvement induced by new therapies.
Vlasta Fesslová, Paola Corti, Giovanna Sersale, Attilio Rovelli, Pierluigi Russo, Savina Mannarino, Gianfranco Butera, Rossella Parini - Apr 24, 13Molecular genetics and metabolism, Vol. 104, No. 4. (December 2011), pp. 695-699, doi:10.1016/j.ymgme.2011.08.024
We present here the first literature description of a predominantly cardiac phenotype in a patient homozygous for missense mutation p.R152W in the N-acetylogalactosamine-4-sulfatase (arylsulfatase B, ARSB) gene. An adult Caucasian woman, who displayed very few symptoms up to her late thirties, was diagnosed with mucopolysaccharidosis type VI (MPS VI) after her hospitalization due to acute heart failure originating mainly from valve disease. In addition to her cardiac phenotype some musculoskeletal involvement without other MPS characteristic features were found. Despite the common pharmacologic treatment and implementation of enzyme replacement therapy with galsulfase the patient died at the age of 38 years because of decompensation of chronic heart failure. Copyright © 2011 Elsevier Inc. All rights reserved.
Agnieszka Jurecka, Adam Golda, Violetta Opoka-Winiarska, Ewa Piotrowska, Anna Tylki-Szymańska - Apr 24, 13European journal of pediatrics, Vol. 157, No. 7. (July 1998), pp. 534-538
Cardiovascular abnormalities were evaluated in 64 children aged between 1 year 9 months and 25 years with mucopolysaccharidoses (MPS) and related disorders. A heart murmur was heard in 18 patients, but in only 6 was it characteristic for specific valvular lesions. Echocardiography was performed in 63 children. In one girl cardiac lesions were diagnosed on autopsy. In 46 patients (72%), valvular lesions and/or different types of cardiomyopathy were detected. There were no characteristic changes for different types of MPS. In the majority of children in whom dermatan sulphate accumulated, cardiac involvement was the most frequent (88%) and severe. The most common lesion, regardless of MPS type, was thickening of the mitral valve (66%), with regurgitation or stenosis in 28 (44%). Aortic valve thickening was detected in 17 patients (27%), asymmetric septal hypertrophy or hypertrophic cardiomyopathy in 18, congestive cardiomyopathy in 1 and endocardial thickening in 13 patients. Cardiac involvement was less frequent in children with Sanfilippo disease. Two or more echocardiographic examinations were performed in 23 patients. In 19 of them (83%) cardiac changes were more severe during the second examination. One 7-year-old boy with Hunter disease underwent successful mitral valve replacement. CONCLUSIONS; Cardiac involvement is present in most patients with MPS although there are few clinical signs and symptoms. The most common and severe changes are in Hurler, Hunter, Maroteaux-Lamy and I-cell disease, rarely in Sanfilippo disease. Mitral valve deformation is most frequent in all patients. The cardiac lesions are progressive.
JH Dangel - Apr 24, 13Acta paediatrica (Oslo, Norway : 1992), Vol. 91, No. 7. (2002), pp. 799-804
The aims of this study were to evaluate cardiac involvement, assess risk factors and mortality, and define the outcome of cardiac abnormalities with age in the different types of mucopolysaccharidoses (MPS). The echocardiograms of 99 patients with MPS, aged 1-24 y (median age 10.3 y) were reviewed between 1978 and 2000. Mitral regurgitation (MR) was detected in 29 patients (29%). MR was more frequent in types IH [n = 11 (38%)], II [n = 10 (24%)] and III [n = 4 (20%)]. Sixteen patients (16%) developed aortic regurgitation (AR), seen mostly in types II [n = 9 (56%)] and IV [n = 4 (24%)]. AR and/or MR was detected in 37 patients and 8 had both abnormalities of borderline significance (odds ratio 2.95, 95% confidence interval 1.0-8.85, p = 0.05). Of 99 patients, 47 had a normal study on their first echocardiogram, whereas only 7 had a normal study on subsequent echocardiograms. Fifty-four (54%) had a single echocardiogram. Of these, 27 (50%) were abnormal and 27 normal. Forty-five patients had more than one echocardiogram, of which 25 (56%) were abnormal and 20 normal. In 13/20 (65%) a cardiac abnormality developed on a subsequent echocardiogram which was statistically significant (p = 0.002). Overall mitral and aortic valve abnormalities showed a positive association with age. Univariate analysis of risk factors showed that increasing age, MPS I and ejection fraction were significant risk factors for death. However, left ventricular hypertrophy, mitral valve abnormalities and type II MPS were not significant risk factors for death, with borderline significance for aortic valve abnormalities. CONCLUSION: This study demonstrates the evaluation of ventricular function, which is a significant risk factor for death, along with increasing age and MPS I, and outlines the borderline significance of aortic valve abnormalities, which has not been mentioned in previous studies. It also shows that mitral valve lesions, commonly seen in MPS, were not a significant risk factor for death. The results emphasize the importance of performing serial echocardiograms in patients with MPS to assess ventricular function and the progression of cardiac abnormalities with age.
UR Mohan, AA Hay, MA Cleary, JE Wraith, RG Patel - Apr 24, 13International journal of cardiology, Vol. 158, No. 1. (28 June 2012), pp. 6-11, doi:10.1016/j.ijcard.2011.06.097
The aim of the article is to gather and summarize the published data about the incidence, course of illness, treatment possibilities and complications of cardiovascular disorders in patients with mucopolysaccharidosis type VI (MPS VI) also known as Maroteaux-Lamy syndrome. MPS VI is a lysosomal storage disorder caused by deficient activity of N-acetylogalactosamine-4-sulfatase leading to progressive intracellular accumulation of glycosaminoglycans. The relatively low birth prevalence ranging from 1 in 43,000 to 1 in 1.5 million births mirrors the limited descriptions of the cardiovascular disorders in the medical literature. Patients with MPS VI can be specifically treated with enzyme replacement therapy. Extra-cardiac features include growth retardation, coarse facial features, stiff joints, skeletal malformations (dysostosis multiplex), respiratory problems, corneal clouding, and hepatosplenomegaly. The clinical presentation varies considerably, however the development of heart disease and cardiac dysfunction is a serious problem in the majority of patients. The most characteristic cardiac presentation is valvular disease, while other MPS VI patients also develop cardiomyopathy, fibroelastosis, pulmonary hypertension, cardiac conduction system disorders and other complications. There are also reports on acute heart failure. Early cardiovascular manifestation may escape detection since joint stiffness or skeletal malformations limit maximal exercise levels and respiratory system involvement may mask the underlining cardiac insufficiency. A correct and timely diagnosis offers the possibility of disease-specific treatment leading to sustained clinical benefits for cardiac and non-cardiac MPS VI manifestations. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
Adam Golda, Agnieszka Jurecka, Anna Tylki-Szymanska - Apr 22, 13Proceedings of the National Academy of Sciences of the United States of America, Vol. 108, No. 33. (16 August 2011), pp. 13618-13623, doi:10.1073/pnas.1105887108
Exposure to erionite, an asbestos-like mineral, causes unprecedented rates of malignant mesothelioma (MM) mortality in some Turkish villages. Erionite deposits are present in at least 12 US states. We investigated whether increased urban development has led to erionite exposure in the United States and after preliminary exploration, focused our studies on Dunn County, North Dakota (ND). In Dunn County, ND, we discovered that over the past three decades, more than 300 miles of roads were surfaced with erionite-containing gravel. To determine potential health implications, we compared erionite from the Turkish villages to that from ND. Our study evaluated airborne point exposure concentrations, examined the physical and chemical properties of erionite, and examined the hallmarks of mesothelial cell transformation in vitro and in vivo. Airborne erionite concentrations measured in ND along roadsides, indoors, and inside vehicles, including school buses, equaled or exceeded concentrations in Boyali, where 6.25% of all deaths are caused by MM. With the exception of outdoor samples along roadsides, ND concentrations were lower than those measured in Turkish villages with MM mortality ranging from 20 to 50%. The physical and chemical properties of erionite from Turkey and ND are very similar and they showed identical biological activities. Considering the known 30- to 60-y latency for MM development, there is reason for concern for increased risk in ND in the future. Our findings indicate that implementation of novel preventive and early detection programs in ND and other erionite-rich areas of the United States, similar to efforts currently being undertaken in Turkey, is warranted.
Michele Carbone, Izzettin Baris, Pietro Bertino, Brian Brass, Sabahattin Comertpay, Umran Dogan, Giovanni Gaudino, Sandro Jube, Shreya Kanodia, Charles Partridge, Harvey Pass, Zeyana Rivera, Ian Steele, Murat Tuncer, Steven Way, Haining Yang, Aubrey Miller - Apr 22, 13Journal of cellular physiology, Vol. 227, No. 1. (January 2012), pp. 44-58, doi:10.1002/jcp.22724
Malignant mesothelioma (MM) is a neoplasm arising from mesothelial cells lining the pleural, peritoneal, and pericardial cavities. Over 20 million people in the US are at risk of developing MM due to asbestos exposure. MM mortality rates are estimated to increase by 5-10% per year in most industrialized countries until about 2020. The incidence of MM in men has continued to rise during the past 50 years, while the incidence in women appears largely unchanged. It is estimated that about 50-80% of pleural MM in men and 20-30% in women developed in individuals whose history indicates asbestos exposure(s) above that expected from most background settings. While rare for women, about 30% of peritoneal mesothelioma in men has been associated with exposure to asbestos. Erionite is a potent carcinogenic mineral fiber capable of causing both pleural and peritoneal MM. Since erionite is considerably less widespread than asbestos, the number of MM cases associated with erionite exposure is smaller. Asbestos induces DNA alterations mostly by inducing mesothelial cells and reactive macrophages to secrete mutagenic oxygen and nitrogen species. In addition, asbestos carcinogenesis is linked to the chronic inflammatory process caused by the deposition of a sufficient number of asbestos fibers and the consequent release of pro-inflammatory molecules, especially HMGB-1, the master switch that starts the inflammatory process, and TNF-alpha by macrophages and mesothelial cells. Genetic predisposition, radiation exposure and viral infection are co-factors that can alone or together with asbestos and erionite cause MM. J. Cell. Physiol. 227: 44-58, 2012. © 2011 Wiley Periodicals, Inc. Copyright © 2011 Wiley Periodicals, Inc.
Michele Carbone, Bevan Ly, Ronald Dodson, Ian Pagano, Paul Morris, Umran Dogan, Adi Gazdar, Harvey Pass, Haining Yang - Apr 22, 13Nature genetics, Vol. 43, No. 10. (28 October 2011), pp. 1022-1025, doi:10.1038/ng.912
Because only a small fraction of asbestos-exposed individuals develop malignant mesothelioma, and because mesothelioma clustering is observed in some families, we searched for genetic predisposing factors. We discovered germline mutations in the gene encoding BRCA1 associated protein-1 (BAP1) in two families with a high incidence of mesothelioma, and we observed somatic alterations affecting BAP1 in familial mesotheliomas, indicating biallelic inactivation. In addition to mesothelioma, some BAP1 mutation carriers developed uveal melanoma. We also found germline BAP1 mutations in 2 of 26 sporadic mesotheliomas; both individuals with mutant BAP1 were previously diagnosed with uveal melanoma. We also observed somatic truncating BAP1 mutations and aberrant BAP1 expression in sporadic mesotheliomas without germline mutations. These results identify a BAP1-related cancer syndrome that is characterized by mesothelioma and uveal melanoma. We hypothesize that other cancers may also be involved and that mesothelioma predominates upon asbestos exposure. These findings will help to identify individuals at high risk of mesothelioma who could be targeted for early intervention.
Joseph Testa, Mitchell Cheung, Jianming Pei, Jennifer Below, Yinfei Tan, Eleonora Sementino, Nancy Cox, Umran Dogan, Harvey Pass, Sandra Trusa, Mary Hesdorffer, Masaki Nasu, Amy Powers, Zeyana Rivera, Sabahattin Comertpay, Mika Tanji, Giovanni Gaudino, Haining Yang, Michele Carbone - Apr 22, 13New Scientist, No. 2913. (20 April 2013), 21
Diagnosing rare illnesses could get easier, thanks to new web-based tools that pool information from a wide variety of sources
Rachel Nuwer - Apr 22, 13New Scientist, No. 2912. (13 April 2013), pp. 34-37, doi:10.1016/S0262-4079(13)60951-3
*** What can explain the mysterious "houses of death" in Turkey? The answer may raise concerns across the world *** WHEN Michele Carbone first visited the Cappadocia region of Turkey, he was struck by the beauty of the volcanic landscape, sculpted by wind and rain into picturesque caverns and rock towers. But the mountains hid a dark secret: some of the villages appeared to be cursed. The inhabitants are plagued by a particularly nasty form of cancer, called mesothelioma. . .
Clare Wilson - Apr 21, 13Nature medicine, Vol. 19, No. 4. (03 April 2013), pp. 465-472, doi:10.1038/nm.3105
To understand why cancer vaccine-induced T cells often do not eradicate tumors, we studied immune responses in mice vaccinated with gp100 melanoma peptide in incomplete Freund's adjuvant (peptide/IFA), which is commonly used in clinical cancer vaccine trials. Peptide/IFA vaccination primed tumor-specific CD8(+) T cells, which accumulated not in tumors but rather at the persisting, antigen-rich vaccination site. Once there, primed T cells became dysfunctional and underwent antigen-driven, interferon-γ (IFN-γ)- and Fas ligand (FasL)-mediated apoptosis, resulting in hyporesponsiveness to subsequent vaccination. Provision of CD40-specific antibody, Toll-like receptor 7 (TLR7) agonist and interleukin-2 (IL-2) reduced T cell apoptosis but did not prevent vaccination-site sequestration. A nonpersisting vaccine formulation shifted T cell localization toward tumors, inducing superior antitumor activity while reducing systemic T cell dysfunction and promoting memory formation. These data show that persisting vaccine depots can induce specific T cell sequestration, dysfunction and deletion at vaccination sites; short-lived formulations may overcome these limitations and result in greater therapeutic efficacy of peptide-based cancer vaccines.
Yared Hailemichael, Zhimin Dai, Nina Jaffarzad, Yang Ye, Miguel Medina, Xue-Fei Huang, Stephanie Dorta-Estremera, Nathaniel Greeley, Giovanni Nitti, Weiyi Peng, Chengwen Liu, Yanyan Lou, Zhiqiang Wang, Wencai Ma, Brian Rabinovich, Kimberly Schluns, Richard Davis, Patrick Hwu, Willem Overwijk
-
Posts
- Jun 05, 12
Storified by Pipet2Pen · Mon, Jun 04 2012 22:15:44
My friend @LanceArmstrong on why he's using his voice to support Prop 29 here in California. http://mariashriver.com/blog/2012/06/my-mission-yes-on-california-prop-29-lance-armstrong
shared a link http://m.guardian.co.uk/business/2012/jun/04/california-prop-29-cigarette-tax?cat=business&type=article
- Jun 04, 12
EMILIA is a phase 3 clinical trial to test a new drug T-DM1 in metastatic breast cancer patients
Storified by Pipet2Pen · Mon, Jun 04 2012 00:43:23
What and Who is EMILIA?EMILIA (LBA1): First Phase 3 trial w/ our investigational antibody-drug conjugate. http://bit.ly/NukPfE #ASCO12
Known for her intelligence and strength (and cynical nature)! @rsm2800: Weiner: Emilia was in Othello; now back to the science #ASCO12
It's happening now!Happening now: Professor Kim Blackwell presents the data from the pIII EMILIA study #ASCO12
Positive data from the EMILIA trial for T-DM1 released at #ASCO12 http://ow.ly/bkjSX #breastcancer
EMILIA Phase III Data on T-DM1 in #BreastCancer (Abstract LBA1) to be reported at today's Plenary Session 1-4pm N Hall B1 #ASCO12
EMILIA study results - #ASCO12 plenary session update from senior PI Dr Sunil Verma - log in to view... http://fb.me/1LFQvblHt
Progression-free survival (PFS) and overall survival (OS) data#ASCO12: EMILIA: T-DM1 offers improvement in PFS over capecitabine, lapatinib http://ow.ly/1Ncuou
Phase III EMILIA study shows T-DM1 significantly improves PFS and OS in HER2-positive metastatic breast cancer #ASCO12
Interim survival EMILIA 23.3 months for lapatinib/capecitabine, not reached for TDM-1. P-value .0005, but needed .0003 #ASCO12
Patient population12% are chemo naive in the metastatic setting #ASCO12 #T-DM1 #EMILIA
Subgroup analysis shows marked improvement in women w visceral disease #ASCO12 #T-DM1 #EMILIA
Study is ongoing but results expected to hold upWe really do get excited when median survival values have not been reached! Nice! #ASCO12 #T-DM1 #EMILIA
Final survival analysis EMILIA study of TDM-1 expected early 2014 #ASCO12
PinkSheetMaryJo: Weiner says future studies unlikely to fail to confirm the benefit of EMILIA. #ASCO12 But didn'... http://bit.ly/LnxDTp
@genentechnews will the patients in the EMILIA trial continue on study without switching until OS is met? #asco12
- Jun 03, 12
Some of the action on Sunday, Jun 3, 2012 in the Windy City by Lake Michigan
Storified by Pipet2Pen · Sun, Jun 03 2012 18:26:33
Abiraterone Delays Progression in Patients with Chemotherapy-Naïve CRPC.From ASCO Daily News: (http://chicago2012.asco.org/ASCODailyNews/LBA4518.aspx)In patients with asymptomatic or mildly symptomatic chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC), abiraterone acetate (AA) plus prednisone produced a statistically significant benefit in radiographic progression-free survival (rPFS) over placebo plus prednisone.Fox discussing FDHT PET for imaging the AR in CRPC #asco12
Fox: one future imaging direction is prostate specific membrane antigen tracers as markers of downstream AR signalling #asco12
Ryan: bone scans used to determine progressive disease in COU-AA-302 trial #asco12
Ryan: many radiologists miss bone flare in mCRPC bone scans #asco12
Cautions, cautions, cautions (about the simplest of technologies). The human factor will not go away.Ryan: brighter bone scan images don't automatically mean PCa progression - need to confirm new lesions #asco12
This is a pilot session for ASCO, a recap of the plenary, then open mike night! #ASCO12 #ProstateBrawl
Prostate Brawl (!) sounds like an English Rugby Match between MDs wearing suits. Just what's needed before people head out to the bar to have a drink.Upcoming: Post-Plenary Discussion on Prostate Cancer: Abstract #4. Expect yelling and interuptions out of room S100a #ASCO12
Less arguing than expected, but crowd really does not seem to buy what they are selling. #ASCO12 #ProstateBrawl
Gleave: Also the issue of post-study interventions is critical. #ASCO12 #ProstateBrawl
Gleave: Retreatment triggers may be an issue when comparing studies. Hussain: No you misunderstand... #ASCO12 #ProstateBrawl
It is so imp in these PC men to individualize against competitive mortality, imaging, CTC's, QOL #ASCO12 #ProstateBrawl
Is the PC result a factor of retreatment triggers? This is very important, in studies it is standardized, in practice individualize #ASCO12
We will forget the past ands repeat all of this with our new toys (MDV and Abiraterone) See concurrent breast cancer/Dickens talk- #ASCO12
The longest survival is not always the best outcome - anonymous speaker #ASCO12 #ProstateBrawl
Why are prostate cancer trials so often muddled, unclear, and thus controversial? #ASCO12 #ProstateBrawl #dobetter
- Jun 03, 12
push to the limits, and beyond the limits
Storified by Pipet2Pen · Sun, Jun 03 2012 01:40:17
"Get born. Find a group. Find a job. Find the one. Have one. Have two. Roast a chicken. Cut bangs. Run. Breathe. Run. Relax. Run a 5K. Run a 10K. Crunch. Listen. Listen. Listen. Be loved. Look lovely. Do good. Give back. We kick asphalt. Power to the She."
Athleta's mantra -- be still, be strong, make mistakes -- will work everytime life pushes you to the wall.This is my favorite -- think and choose what you really want in life and then keep your eyes on that goal no matter what.Yes, if life gives you lemons, then make lemonade. Better still, Mike's hard lemonade.Don't underestimate yourself. People around you (at job or elsewhere) may push you down so they look better. Never let others tell you you are not worthy or smart.This dance will go on till death. So, make it a habit to remain positive.IDEA: Many female-focused brands plead with busy women to take it easy. Not Athleta. The maker of fitness and lifestyle apparel targets women who always want more, out of sports and life.
