Publications by authors named "Silvia Francisci"

66 Publications

The Economic Impact of Rectal Cancer: A Population-Based Study in Italy

Int J Environ Res Public Health 2021 01 8;18(2). Epub 2021 Jan 8.

Registro Tumori Veneto, Azienda Zero, 35132 Padova, Italy.

Costs of cancer care are increasing worldwide, and sustainability of cancer burden is critical. In this study, the economic impact of rectal cancer on the Italian healthcare system, measured as public healthcare expenditure related to investigation and treatment of rectal cancer patients is estimated. A cross-sectional cohort of 9358 rectal cancer patients is linked, on an individual basis, to claims associated to rectal cancer diagnosis and treatments. Costs refer mainly to years 2010-2011 and are estimated by phase of care, as healthcare needs vary along the care pathway: diagnostic procedures are mainly provided in the first year, surveillance procedures are addressed to chronically ill patients, and end-of-life procedures are given in the terminal status. Clinical approaches and corresponding costs are specific by cancer type and vary by phase of care, stage at diagnosis, and age. Surgery is undertaken by the great majority of patients. Thus, hospitalization is the main cost driver. The evidence produced can be used to improve planning and allocation of healthcare resources. In particular, early diagnosis of rectal cancer is a gain in healthcare budget. Policies raising spreading of and adherence to screening plans, above all when addressed to people living in Southern Italy, should be strongly encouraged.
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http://dx.doi.org/10.3390/ijerph18020474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7827442PMC
January 2021

Cancer prevalence by phase of care: an indicator for assessing health service needs.

Tumori 2020 Oct 23:300891620961839. Epub 2020 Oct 23.

Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, MD, USA.

Introduction: Cancer prevalence (people alive on a certain date in a population who previously had a cancer diagnosis) is expected to increase in the United States and Europe due to improvements in survival and population aging. Examination of prevalence by phase of care allows us to identify subgroups of patients according to their care trajectories, thus allowing us to improve health care planning, resource allocation, and calculation of costs.

Methods: A new method to estimate prevalence by phase of care using grouped data is illustrated. Prevalence is divided into 3 mutually exclusive phases: initial, continuing, and end-of-life. An application to US and Italian data is applied to prevalent cases diagnosed with colon-rectum, stomach, lung, or breast cancer.

Results: The distribution of phase of care prevalence estimated by cancer type and sex and results from the two datasets are very similar. Most survivors are in the continuing phase; the end-of-life phase is larger for cancers with worse prognosis. All phases prevalence is generally higher in the Italian than in the US dataset, except for lung cancer in women, where prevalence proportion in the Italian dataset is 30% lower than in the United States.

Discussion: Incidence, survival, and population age structure are the main determinants of prevalence and they can affect differences in all phases of prevalence, as well as in discrete phases. Incidence is the most influential determinant. Ours is the first study that compares prevalence by phase of care between two populations in Italy and the United States. Despite great differences in health care management in the two countries, we found extremely similar distribution of survivors by phase of care for most cancer sites under study.
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http://dx.doi.org/10.1177/0300891620961839DOI Listing
October 2020

Cancer cure for 32 cancer types: results from the EUROCARE-5 study.

Int J Epidemiol 2020 Oct;49(5):1517-1525

National Center for Prevention and Health Promotion, Italian National Institute of Health (ISS), Rome, Italy.

Background: Few studies have estimated the probability of being cured for cancer patients. This study aims to estimate population-based indicators of cancer cure in Europe by type, sex, age and period.

Methods: 7.2 million cancer patients (42 population-based cancer registries in 17 European countries) diagnosed at ages 15-74 years in 1990-2007 with follow-up to 2008 were selected from the EUROCARE-5 dataset. Mixture-cure models were used to estimate: (i) life expectancy of fatal cases (LEF); (ii) cure fraction (CF) as proportion of patients with same death rates as the general population; (iii) time to cure (TTC) as time to reach 5-year conditional relative survival (CRS) >95%.

Results: LEF ranged from 10 years for chronic lymphocytic leukaemia patients to <6 months for those with liver, pancreas, brain, gallbladder and lung cancers. It was 7.7 years for patients with prostate cancer at age 65-74 years and >5 years for women with breast cancer. The CF was 94% for testis, 87% for thyroid cancer in women and 70% in men, 86% for skin melanoma in women and 76% in men, 66% for breast, 63% for prostate and <10% for liver, lung and pancreatic cancers. TTC was <5 years for testis and thyroid cancer patients diagnosed below age 55 years, and <10 years for stomach, colorectal, corpus uteri and melanoma patients of all ages. For breast and prostate cancers, a small excess (CRS < 95%) remained for at least 15 years.

Conclusions: Estimates from this analysis should help to reduce unneeded medicalization and costs. They represent an opportunity to improve patients' quality of life.
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http://dx.doi.org/10.1093/ije/dyaa128DOI Listing
October 2020

Patterns of care and cost profiles of women with breast cancer in Italy: EPICOST study based on real world data.

Eur J Health Econ 2020 Sep 12;21(7):1003-1013. Epub 2020 May 12.

Institute for Research on Population and Social Policies, National Research Council, Rome, Italy.

Objectives: To estimate total direct health care costs associated to diagnosis and treatment of women with breast cancer in Italy, and to investigate their distribution by service type according to the disease pathway and patient characteristics.

Methods: Data on patients provided by population-based Cancer Registries are linked at individual level with data on health-care services and corresponding claims from administrative databases. A combination of cross-sectional approach and a threephase of care decomposition model with initial, continuing and final phases-of-care defined according to time occurred since diagnosis and disease outcome is adopted. Direct estimation of cancer-related costs is obtained.

Results: Study cohort included 49,272 patients, 15.2% were in the initial phase absorbing 42% of resources, 79.7% in the continuing phase absorbing 44% of resources and 5.1% in the final phase absorbing 14% of resources. Hospitalization was the most important cost driver, accounting for over 55% of the total costs.

Conclusions: This paper represents the first attempt in Italy to estimate the economic burden of cancer at population level taking into account the entire disease pathway and using multiple current health care databases. The evidence produced by the study can be used to better plan resources allocation. The model proposed is replicable to countries with individual health care information on services and claims.
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http://dx.doi.org/10.1007/s10198-020-01190-zDOI Listing
September 2020

Prognosis and cure of long-term cancer survivors: A population-based estimation.

Cancer Med 2019 08 17;8(9):4497-4507. Epub 2019 Jun 17.

Department of Oncology and Molecular Medicine, Italian National Institute of Health (ISS), Rome, Italy.

Background: Increasing evidence of cure for some neoplasms has emerged in recent years. The study aimed to estimate population-based indicators of cancer cure.

Methods: Information on more than half a million cancer patients aged 15-74 years collected by population-based Italian cancer registries and mixture cure models were used to estimate the life expectancy of fatal tumors (LEFT), proportions of patients with similar death rates of the general population (cure fraction), and time to reach 5-year conditional relative survival (CRS) >90% or 95% (time to cure).

Results: Between 1990 and 2000, the median LEFT increased >1 year for breast (from 8.1 to 9.4 years) and prostate cancers (from 5.2 to 7.4 years). Median LEFT in 1990 was >5 years for testicular cancers (5.8) and Hodgkin lymphoma (6.3) below 45 years of age. In both sexes, it was ≤0.5 years for pancreatic cancers and NHL in 1990 and in 2000. The cure fraction showed a 10% increase between 1990 and 2000. It was 95% for thyroid cancer in women, 94% for testis, 75% for prostate, 67% for breast cancers, and <20% for liver, lung, and pancreatic cancers. Time to 5-year CRS >95% was <10 years for testis, thyroid, colon cancers, and melanoma. For breast and prostate cancers, the 5-year CRS >90% was reached in <10 years but a small excess remained for >15 years.

Conclusions: The study findings confirmed that several cancer types are curable. Became aware of the possibility of cancer cure has relevant clinical and social impacts.
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http://dx.doi.org/10.1002/cam4.2276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6675712PMC
August 2019

Cancer incidence and mortality trends from 2003 to 2014 in Italy.

Tumori 2019 Apr 28;105(2):121-137. Epub 2019 Mar 28.

5 National Center for Disease Prevention and Health Promotion, National Institute of Health, Rome, Italy.

Objective: To evaluate short-term (2003-2014) cancer incidence and mortality trends in Italy.

Methods: Italian Cancer Registries data, available in the AIRTUM database, from 17 out of 20 regions were used. The number of incident cases and deaths were estimated for those registries and those years with incomplete information. Age-standardized rates, overall and stratified by geographic area, region, sex, cancer site, and major age group, were computed. Time trends were expressed as annual percent change of rates.

Results: In Italy, among males, incidence rates for all cancers showed during 2003-2014, a significant decrease (-0.9%/year), with stronger reductions in the northwest (-1.3%/year) and northeast (-2.0%/year since 2006) than in central (-0.7%/year) and southern (-0.4%/year) areas. Among females, a weak but significant overall reduction was detected (-0.1%/year), with a stronger decrease in the northwest (-0.5%/year). Incidence increased among women in the south (0.3%/year) of Italy. Mortality decreased in both sexes (-1.0%/year among males and -0.5%/year among females), but not in the south, where rates had a stable tendency.

Conclusions: Incidence among males decreased, supported by trends for prostate, lung, colorectal, and urinary bladder cancers; among females the. The overall cancer incidence trend was stable, or even decreasing, in the northern and central areas and increasing in the southern areas, due to lung, thyroid, and melanoma rising trends. Study results provided information on the outcomes, in terms of cancer incidence and mortality, of primary and secondary prevention measures employed by regional health systems.
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http://dx.doi.org/10.1177/0300891619839844DOI Listing
April 2019

Trends of colorectal cancer incidence and mortality rates from 2003 to 2014 in Italy.

Tumori 2019 Oct 27;105(5):417-426. Epub 2019 Mar 27.

Veneto Tumour Registry, Azienda Zero, Padova, Italy.

Objective: To evaluate the trends of colorectal cancer (CRC) incidence and mortality rates from 2003 to 2014 in Italy by age groups and regions.

Methods: We used the data of 48 cancer registries from 17 Italian regions to estimate standardized incidence and mortality rates overall and by sex, age groups (<50, 50-69, 70+ years), and geographic area (northwest, northeast, center, south, and islands). Time trends were expressed as annual percent change in rates (APC) with 95% confidence intervals (95% CI).

Results: Incidence rates decreased from 104.3 (2003) to 89.9 × 100,000 (2014) in men and from 64.3 to 58.4 × 100,000 in women. Among men, incidence decreased during 2007-2010 (APC -4.0, 95% CI -6.0 to -1.9) and 2010-2014 (APC -0.7, 95% CI -1.4 to 0.0), while in women it linearly decreased during the whole period (APC -1.1, 95% CI -1.4 to -0.8). Mortality rates showed a linear reduction both in men (APC -0.7, 95% CI -1.0 to -0.3) and women (APC -0.9, 95% CI -1.2 to -0.6) and decreased respectively from 41.1 to 39.2 × 100,000 and from 24.6 to 23.1 × 100,000. In the 50- to 69-year-old range (screening target age), incidence showed a prescreening increase, followed by a peak after screening started, and a decline thereafter. Incidence and mortality rates significantly decreased in all areas but in the south and islands, where incidence increased and mortality remained stable.

Conclusions: A renewed commitment by all regional health systems to invest in primary (i.e., lifestyle) and secondary (i.e., screening programs) prevention is of utmost importance.
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http://dx.doi.org/10.1177/0300891619838336DOI Listing
October 2019

Gcn5 histone acetyltransferase is present in the mitoplasts.

Biol Open 2019 Feb 18;8(2). Epub 2019 Feb 18.

Department of Biology and Biotechnologies "Charles Darwin", Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.

In the Lysine-acetyltransferase Gcn5 (KAT2) is part of the SAGA complex and is responsible for histone acetylation widely or at specific lysines. In this paper we report that deletion differently affects the growth of two strains. The defective mitochondrial phenotype is related to a marked decrease in mtDNA content, which also involves the deletion of specific regions of the molecule. We also show that in wild-type mitochondria the Gcn5 protein is present in the mitoplasts, suggesting a new mitochondrial function independent from the SAGA complex and possibly a new function for this protein connecting epigenetics and metabolism.
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http://dx.doi.org/10.1242/bio.041244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6398455PMC
February 2019

Ubiquitin protease Ubp8 is necessary for S. cerevisiae respiration.

Biochim Biophys Acta Mol Cell Res 2018 Aug 2. Epub 2018 Aug 2.

Institute of Molecular Biology and Pathology-CNR, Sapienza University of Rome, P.le A. Moro 5, Rome, Italy. Electronic address:

Healthy mitochondria are required in cell metabolism and deregulation of underlying mechanisms is often involved in human diseases and neurological disorders. Post-translational modifications of mitochondrial proteins regulate their function and activity, accordingly, impairment of ubiquitin proteasome system affects mitochondria homeostasis and organelle dynamics. In the present study we have investigated the role of the ubiquitin protease Ubp8 in S. cerevisiae respiration. We show that Ubp8 is necessary for respiration and its expression is upregulated in glycerol respiratory medium. In addition, we show that the respiratory defects in absence of Ubp8 are efficiently rescued by disruption of the E3 Ub-ligase Psh1, suggesting their epistatic link. Interestingly, we found also that Ubp8 is localized into mitochondria as single protein independently of SAGA complex assembly, thus suggesting an independent function from the nuclear one. We also show evidences on the importance of HAT Gcn5 in sustaining Ubp8 expression and affecting the amount of protein in mitochondria. Collectively, our results have investigated the role of Ubp8 in respiratory metabolism and highlight the role of ubiquitin related pathways in the mitochondrial functions of S. cerevisiae.
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http://dx.doi.org/10.1016/j.bbamcr.2018.07.025DOI Listing
August 2018

[Using current data in public health: from a management perspective to an economic evaluation one].

Epidemiol Prev 2018 Mar-Apr;42(2):188-189

Istituto di ricerche sulla popolazione e le politiche sociali, Consiglio nazionale delle ricerche, Roma.

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http://dx.doi.org/10.19191/EP18.2.P188.053DOI Listing
March 2019

Characteristics of people living in Italy after a cancer diagnosis in 2010 and projections to 2020.

BMC Cancer 2018 02 9;18(1):169. Epub 2018 Feb 9.

Cancer Epidemiology Unit, CRO Aviano National Cancer Institute IRCCS, Via Franco Gallini 2, 33081, Aviano, PN, Italy.

Background: Estimates of cancer prevalence are widely based on limited duration, often including patients living after a cancer diagnosis made in the previous 5 years and less frequently on complete prevalence (i.e., including all patients regardless of the time elapsed since diagnosis). This study aims to provide estimates of complete cancer prevalence in Italy by sex, age, and time since diagnosis for all cancers combined, and for selected cancer types. Projections were made up to 2020, overall and by time since diagnosis.

Methods: Data were from 27 Italian population-based cancer registries, covering 32% of the Italian population, able to provide at least 7 years of registration as of December 2009 and follow-up of vital status as of December 2013. The data were used to compute the limited-duration prevalence, in order to estimate the complete prevalence by means of the COMPREV software.

Results: In 2010, 2,637,975 persons were estimated to live in Italy after a cancer diagnosis, 1.2 million men and 1.4 million women, or 4.6% of the Italian population. A quarter of male prevalent cases had prostate cancer (n = 305,044), while 42% of prevalent women had breast cancer (n = 604,841). More than 1.5 million people (2.7% of Italians) were alive since 5 or more years after diagnosis and 20% since ≥15 years. It is projected that, in 2020 in Italy, there will be 3.6 million prevalent cancer cases (+ 37% vs 2010). The largest 10-year increases are foreseen for prostate (+ 85%) and for thyroid cancers (+ 79%), and for long-term survivors diagnosed since 20 or more years (+ 45%). Among the population aged ≥75 years, 22% will have had a previous cancer diagnosis.

Conclusions: The number of persons living after a cancer diagnosis is estimated to rise of approximately 3% per year in Italy. The availability of detailed estimates and projections of the complete prevalence are intended to help the implementation of guidelines aimed to enhance the long-term follow-up of cancer survivors and to contribute their rehabilitation needs.
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http://dx.doi.org/10.1186/s12885-018-4053-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5807846PMC
February 2018

An estimate of the number of people in Italy living after a childhood cancer.

Int J Cancer 2017 06 11;140(11):2444-2450. Epub 2017 Mar 11.

Members of the AIRTUM Working Group: Massimo Rugge (Veneto Tumor Registry), Ettore Bidoli (Friuli Venezia Giulia Cancer Registry), Dania Bucchi (Umbria Cancer Registry), Giovanna Tagliabue (Varese Cancer Registry), Mario Fusco (Naples Cancer Registry), Fabio Falcini (Romagna Cancer Registry), Enza Marani (Genova Cancer Registry), Fabio Pannozzo (Latina Cancer Registry), Giuliano Carrozzi (Modena Cancer Registry), Lucia Mangone (Reggio Emilia Cancer Registry), Ornelia Sechi (Sassari Cancer Registry), Maria Michiara (Parma Cancer Registry), Eugenia Spata (Ragusa Cancer Registry), Stefano Ferretti (Ferrara Cancer Registry), Adriano Giacomin (Biella Cancer Registry), Milena Maule (Childhood Cancer Registry of Piedmont), Gemma Gatta (Fondazione IRCCS Istituto Nazionale dei Tumori, Milan), Riccardo Capocaccia (National Centre for Epidemiology, Surveillance and Health Promotion, Italian National Institute of Health, Rome, Italy.

Cancers diagnosed in children below the age of 15 years represent 1.2% of all cancer cases, and survival after a childhood cancer has greatly improved over the past 40 years in all high income countries. This study aims to estimate the number of people living in Italy after a childhood cancer for all cancers combined and for a selection of cancer types. We computed 15-year prevalence using data from 15 Italian population-based cancer registries (covering 19% of Italian population) and estimated complete prevalence for Italy by using the CHILDPREV method, implemented in the COMPREV software. A total of 44,135 persons were alive at January 1st, 2010 after a cancer diagnosed during childhood. This number corresponds to a proportion of 73 per 100,000 Italians and to about 2% of all prevalent cases. Among them, 54% were males and 64% had survived after being diagnosed before 1995, the start of the observation period. A quarter of all childhood prevalent cases were diagnosed with brain and central nervous system tumors, a quarter with acute lymphoid leukemia, and 7% with Hodgkin lymphoma. Nearly a quarter of prevalent patients were aged 40 years and older. Information about the number of people living after a childhood cancer in Italy by cancer type and their specific health care needs may be helpful to health-care planners and clinicians in the development of guidelines aimed to reduce the burden of late effect of treatments during childhood.
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http://dx.doi.org/10.1002/ijc.30665DOI Listing
June 2017

Novel mutation in mitochondrial Elongation Factor EF-Tu associated to dysplastic leukoencephalopathy and defective mitochondrial DNA translation.

Biochim Biophys Acta Mol Basis Dis 2017 04 26;1863(4):961-967. Epub 2017 Jan 26.

Unit of Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy. Electronic address:

The mitochondrial Elongation Factor Tu (EF-Tu), encoded by the TUFM gene, is a highly conserved GTPase, which is part of the mitochondrial protein translation machinery. In its activated form it delivers the aminoacyl-tRNAs to the A site of the mitochondrial ribosome. We report here on a baby girl with severe infantile macrocystic leukodystrophy with micropolygyria and a combined defect of complexes I and IV in muscle biopsy, caused by a novel mutation identified in TUFM. Using human mutant cells and the yeast model, we demonstrate the pathological role of the novel variant. Moreover, results of a molecular modeling study suggest that the mutant is inactive in mitochondrial polypeptide chain elongation, probably as a consequence of its reduced ability to bind mitochondrial aa-tRNAs. Four patients have so far been described with mutations in TUFM, and, following the first description of the disease in a single patient, we describe similar clinical and neuroradiological features in an additional patient.
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http://dx.doi.org/10.1016/j.bbadis.2017.01.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5335904PMC
April 2017

Mitochondrial diseases: Yeast as a model for the study of suppressors.

Biochim Biophys Acta Mol Cell Res 2017 Apr 12;1864(4):666-673. Epub 2017 Jan 12.

Department of Biology and Biotechnologies "Charles Darwin", Sapienza University of Rome, Piazzale Aldo Moro, 5, 00185 Rome, Italy; Pasteur Institute Italy - Cenci Bolognetti Foundation, Sapienza University of Rome, Viale Regina Elena, 291, 00161 Rome, Italy. Electronic address:

Mitochondrial (mt) tRNA gene mutations are an important cause of human morbidity and are associated with different syndromes. We have previously shown that the mitochondrial protein synthesis elongation factor EF-Tu and isolated sequences from the carboxy-terminal domain of yeast and human mt leucyl-tRNA synthetases (LeuRS), have a wide range of suppression capability among different yeast mt tRNA mutants having defective respiratory phenotype. Here we show that the rescuing capability can be restricted to a specific sequence of six amino acids from the carboxy-terminal domain of mt LeuRS. On the other hand by overexpressing a mutated version of mt EF-Tu in a yeast strain deleted for the endogenous nuclear gene we identified the specific region involved in suppression. Results support the possibility that a small peptide could correct defects associated with many mt tRNA mutations, suggesting a novel therapy for mitochondrial diseases treatment. The involvement of the mt EF-Tu in cellular heat stress response has also been suggested.
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http://dx.doi.org/10.1016/j.bbamcr.2017.01.008DOI Listing
April 2017

SAGA complex and Gcn5 are necessary for respiration in budding yeast.

Biochim Biophys Acta 2016 12 11;1863(12):3160-3168. Epub 2016 Oct 11.

Institute of Molecular Biology and Pathology-CNR, Sapienza University of Rome, P.le A. Moro 5, Rome, Italy. Electronic address:

In budding yeast, growth through fermentation and/or respiration is dependent on the type of carbon source present in the medium. SAGA complex is the main acetylation complex and is required, together with Rtg factors, for nucleus-mitochondria communication and transcriptional activation of specific nuclear genes. Even though acetylation is necessary for mitochondria activity and respiratory pathways the direct role of histone acetyltransferases and SAGA complex has never been investigated directly. In this study we demonstrate, for the first time, that Gcn5 and SAGA are needed for respiratory metabolism and oxygen consumption. According to a central role for acetylation in respiration we find that the Gcn5 inhibitor CPTH2 had higher efficacy on cells grown in glycerol containing media. We also demonstrated that the opposing activities of Gcn5 and Hda1 modify selectively H3-AcK18 and are essential for respiration. Taken together our results suggest a novel paradigm coupling acetyltransferase activity to respiratory metabolism. Correspondingly we propose the selective utilization of KAT inhibitor CPTH2, combined to the modulation of the respiratory metabolism of the cell, as a promising novel tool of intervention in cancer cells.
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http://dx.doi.org/10.1016/j.bbamcr.2016.10.002DOI Listing
December 2016

Mortality in Italian veterans deployed in Bosnia-Herzegovina and Kosovo.

Eur J Public Health 2016 08 3;26(4):712-7. Epub 2015 Dec 3.

1 Cancer Epidemiology Unit, National Center of Epidemiology, Istituto Superiore di Sanità, Rome, Italy.

Background And Aims: The possible increase of cancer risk in military personnel deployed in Balkans during and after the 1992-1999 wars, mainly related to the depleted uranium, was addressed by several studies on European veterans of those war theatres. This article reports on the results of the mortality study on the Italian cohort of Bosnia and Kosovo veterans (Balkan cohort).

Methods: Mortality rates for the Balkan cohort (71 144 persons) were compared with those of the Italian general population as well as to those of a comparable and unselected control cohort of not deployed military personnel (114 269 persons). Ascertainment of vital status during the period 1995-2008 of all the persons in the two cohorts has been carried out through deterministic record linkage with the national death records database, from information provided by the respective Armed Force General Staff, and through the civil registry offices of the veterans' residence or birth municipalities.

Results: The Balkan cohort experienced a mortality rates lower than both the general population (SMR = 0.56; 95% CI 0.51-0.62) and the control group (SMR = 0.88; 95% CI 0.79-0.97). Cancer mortality in the deployed cohort group was half of that from the general population mortality rates (SMR = 0.50; 95% CI 0.40-0.62) and slightly lower if compared with the control group cancer mortality rates (SMR = 0.95; 95% CI 0.77-1.18).

Conclusion: Balkan veteran cohort did not show any increase in general mortality or in cancer mortality.
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http://dx.doi.org/10.1093/eurpub/ckv217DOI Listing
August 2016

Survival patterns in lung and pleural cancer in Europe 1999-2007: Results from the EUROCARE-5 study.

Eur J Cancer 2015 Oct 26;51(15):2242-2253. Epub 2015 Sep 26.

Department of Preventive and Predictive Medicine, Analytical Epidemiology and Health Impact Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Background: Survival of patients diagnosed with lung and pleura cancer is a relevant health care indicator which is related to the availability and access to early diagnosis and treatment facilities. Aim of this paper is to update lung and pleural cancer survival patterns and time trends in Europe using the EUROCARE-5 database.

Methods: Data on adults diagnosed with lung and pleural cancer from 87 European cancer registries in 28 countries were analysed. Relative survival (RS) in 2000-2007 by country/region, age and gender, and over time trends in 1999-2007 were estimated.

Results: Lung cancer survival is poor everywhere in Europe, with a RS of 39% and 13% at 1 and 5years since diagnosis, respectively. A geographical variability is present across European areas with a maximum regional difference of 12 and 5 percentage points in 1-year and 5-year RS respectively. Pleural cancer represents 4% of cases included in the present study with 7% 5-year RS overall in Europe. Most pleural cancers (83%) are microscopically verified mesotheliomas. Survival for both cancers decreases with advancing age at diagnosis for both cancers. Slight increasing trends are described for lung cancer. Survival over time is higher for squamous cell carcinoma and adenocarcinomas than for small and large cell carcinoma; and better among women than men.

Conclusions: Despite the generalised although slight increase, survival of lung and pleural cancer patients still remains poor in European countries. Priority should be given to prevention, with tobacco control policies across Europe for lung cancer and banning asbestos exposure for pleural cancer, and in early diagnosis and better treatment. The management of mesothelioma needs a multidisciplinary team and standardised health care strategies.
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http://dx.doi.org/10.1016/j.ejca.2015.07.033DOI Listing
October 2015

On-going improvement and persistent differences in the survival for patients with colon and rectum cancer across Europe 1999-2007 - Results from the EUROCARE-5 study.

Eur J Cancer 2015 Oct 26;51(15):2158-2168. Epub 2015 Sep 26.

Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), INF 581, 69120 Heidelberg, Germany; Division of Preventive Oncology, German Cancer Research Center (DKFZ), INF 581, 69120 Heidelberg, Germany; German Cancer Consortium (DKTK), German Cancer Research Center, INF 280, 69120 Heidelberg, Germany.

Background: Previous population-based studies revealed major variation in survival for patients with colorectal cancer (CRC) in Europe by age and between different countries and regions, but also a sustained improvement in survival for patients with CRC in recent years. This EUROCARE-5 paper aims to update available knowledge from previous studies and to provide the latest survival estimates for CRC patients from Europe.

Methods: The study analysed data of patients diagnosed with CRC from population-based cancer registries diagnosed in 29 European countries. Estimates of 1-year and 5-year relative survival (RS) were derived for patients diagnosed in 2000-2007 by European region, country and age at diagnosis. Additionally to these cohort estimates, time trends in 5-year RS were obtained for the calendar periods 1999-2001 and 2005-2007, using the period analysis methodology.

Results: European average 5-year RS for patients diagnosed with colon and rectum cancer was 57% and 56%, respectively. The analyses showed persistent differences in cancer survival across Europe with lowest survival for CRC patients observed in Eastern Europe. The analyses further showed a strong gradient in age-specific survival. Even though the study revealed sustained improvement in patient survival between 1999-2001 and 2005-2007 (absolute increase of 4 and 6 percentage points for colon and rectum, respectively), the differences in the survival for CRC patients observed at the beginning of the millennium persisted over time.

Conclusion: Although survival for CRC patients in Europe improved markedly in the study period, significant geographic variations and a strong age gradient still persisted. Enhanced access to effective diagnostic procedures and treatment options might be the keys to reducing the existing disparities in the survival of CRC patients across Europe.
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http://dx.doi.org/10.1016/j.ejca.2015.07.024DOI Listing
October 2015

Age and case mix-standardised survival for all cancer patients in Europe 1999-2007: Results of EUROCARE-5, a population-based study.

Eur J Cancer 2015 Oct 26;51(15):2120-2129. Epub 2015 Sep 26.

National Centre for Epidemiology Surveillance and Health Promotion (CNESPS), National Institute of Health (Istituto Superiore di Sanità), Rome, Italy.

Background: Overall survival after cancer is frequently used when assessing a health care service's performance as a whole. It is mainly used by the public, politicians and the media, and is often dismissed by clinicians because of the heterogeneous mix of different cancers, risk factors and treatment modalities. Here we give survival details for all cancers combined in Europe, correlating it with economic variables to suggest reasons for differences.

Methods: We computed age and cancer site case-mix standardised relative survival for all cancers combined (ACRS) for 29 countries participating in the EUROCARE-5 project with data on more than 7.5million cancer cases from 87 population-based cancer registries, using complete and period approach.

Results: Denmark, United Kingdom (UK) and Eastern European countries had lower survival than neighbouring countries. Five-year ACRS has been increasing throughout Europe, and substantial increases, between 1999-2001 and 2005-2007, have been achieved in countries where survival was lower in the past. Five-year ACRS for men and women are positively correlated with macro-economic variables like the Gross Domestic Product (GDP) and Total National Expenditure on Health (TNEH) (R about 70%). Countries with recent larger increases in GDP and TNEH had greater increases in cancer survival.

Conclusions: ACRS serves to compare all cancer survival in Europe taking account of the geographical variability in case-mixes. The EUROCARE-5 data on ACRS confirm previous EUROCARE findings. Survival appears to correlate with macro-economic determinants, particularly with investments in the health care system.
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http://dx.doi.org/10.1016/j.ejca.2015.07.025DOI Listing
October 2015

Cancer survival in Europe, 1999-2007: Doing better, feeling worse?

Eur J Cancer 2015 Oct 26;51(15):2101-2103. Epub 2015 Sep 26.

Centro Nazionale di Epidemiologia, Sorveglianza e Promozione della Salute, Istituto Superiore di Sanità, Rome, Italy.

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http://dx.doi.org/10.1016/j.ejca.2015.08.019DOI Listing
October 2015

Increased circulating levels of vitamin D binding protein in MS patients.

Toxins (Basel) 2015 Jan 13;7(1):129-37. Epub 2015 Jan 13.

Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome 00161, Italy.

Vitamin D (vitD) low status is currently considered a main environmental factor in multiple sclerosis (MS) etiology and pathogenesis. VitD and its metabolites are highly hydrophobic and circulate mostly bound to the vitamin D binding protein (DBP) and with lower affinity to albumin, while less than 1% are in a free form. The aim of this study was to investigate whether the circulating levels of either of the two vitD plasma carriers and/or their relationship are altered in MS. We measured DBP and albumin plasma levels in 28 MS patients and 24 healthy controls. MS patients were found to have higher DBP levels than healthy subjects. Concomitant interferon beta therapy did not influence DBP concentration, and the difference with the control group was significant in both females and males. No significant correlation between DBP and albumin levels was observed either in healthy controls or in patients. These observations suggest the involvement of DBP in the patho-physiology of MS.
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http://dx.doi.org/10.3390/toxins7010129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4303818PMC
January 2015

Estimate of the penetrance of BRCA mutation and the COS software for the assessment of BRCA mutation probability.

Fam Cancer 2015 Mar;14(1):117-28

Department of Preventive and Predictive Medicine, Fondazione IRCSS Istituto Nazionale dei Tumori, Via Venezian 1, 20133, Milan, Italy.

We have designed the user-friendly COS software with the intent to improve estimation of the probability of a family carrying a deleterious BRCA gene mutation. The COS software is similar to the widely-used Bayesian-based BRCAPRO software, but it incorporates improved assumptions on cancer incidence in women with and without a deleterious mutation, takes into account relatives up to the fourth degree and allows researchers to consider an hypothetical third gene or a polygenic model of inheritance. Since breast cancer incidence and penetrance increase over generations, we estimated birth-cohort-specific incidence and penetrance curves. We estimated breast and ovarian cancer penetrance in 384 BRCA1 and 229 BRCA2 mutated families. We tested the COS performance in 436 Italian breast/ovarian cancer families including 79 with BRCA1 and 27 with BRCA2 mutations. The area under receiver operator curve (AUROC) was 84.4 %. The best probability threshold for offering the test was 22.9 %, with sensitivity 80.2 % and specificity 80.3 %. Notwithstanding very different assumptions, COS results were similar to BRCAPRO v6.0.
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http://dx.doi.org/10.1007/s10689-014-9766-8DOI Listing
March 2015

The yeast model suggests the use of short peptides derived from mt LeuRS for the therapy of diseases due to mutations in several mt tRNAs.

Biochim Biophys Acta 2014 Dec 28;1843(12):3065-74. Epub 2014 Sep 28.

Department of Biology and Biotechnologies "C. Darwin", Sapienza University of Rome, Piazzale A. Moro 5, 00185 Rome, Italy. Electronic address:

We have previously established a yeast model of mitochondrial (mt) diseases. We showed that defective respiratory phenotypes due to point-mutations in mt tRNA(Leu(UUR)), tRNA(Ile) and tRNA(Val) could be relieved by overexpression of both cognate and non-cognate nuclearly encoded mt aminoacyl-tRNA synthetases (aaRS) LeuRS, IleRS and ValRS. More recently, we showed that the isolated carboxy-terminal domain (Cterm) of yeast mt LeuRS, and even short peptides derived from the human Cterm, have the same suppressing abilities as the whole enzymes. In this work, we extend these results by investigating the activity of a number of mt aaRS from either class I or II towards a panel of mt tRNAs. The Cterm of both human and yeast mt LeuRS has the same spectrum of activity as mt aaRS belonging to class I and subclass a, which is the most extensive among the whole enzymes. Yeast Cterm is demonstrated to be endowed with mt targeting activity. Importantly, peptide fragments β30_31 and β32_33, derived from the human Cterm, have even higher efficiency as well as wider spectrum of activity, thus opening new avenues for therapeutic intervention. Bind-shifting experiments show that the β30_31 peptide directly interacts with human mt tRNA(Leu(UUR)) and tRNA(Ile), suggesting that the rescuing activity of isolated peptide fragments is mediated by a chaperone-like mechanism. Wide-range suppression appears to be idiosyncratic of LeuRS and its fragments, since it is not shared by Cterminal regions derived from human mt IleRS or ValRS, which are expected to have very different structures and interactions with tRNAs.
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http://dx.doi.org/10.1016/j.bbamcr.2014.09.011DOI Listing
December 2014

Strain-specific nuclear genetic background differentially affects mitochondria-related phenotypes in Saccharomyces cerevisiae.

Microbiologyopen 2014 Jun 2;3(3):288-98. Epub 2014 Apr 2.

Department of Biology and Biotechnologies "C. Darwin", Sapienza University of Rome, Piazzale A. Moro 5, Rome, 00185, Italy; Pasteur Institute-Cenci Bolognetti Foundation, Sapienza University of Rome, Piazzale A. Moro 5, Rome, 00185, Italy.

In the course of our studies on mitochondrial defects, we have observed important phenotypic variations in Saccharomyces cerevisiae strains suggesting that a better characterization of the genetic variability will be essential to define the relationship between the mitochondrial efficiency and the presence of different nuclear backgrounds. In this manuscript, we have extended the study of such relations by comparing phenotypic assays related to mitochondrial functions of three wild-type laboratory strains. In addition to the phenotypic variability among the wild-type strains, important differences have been observed among strains bearing identical mitochondrial tRNA mutations that could be related only to the different nuclear background of the cells. Results showed that strains exhibited an intrinsic variability in the severity of the effects of the mitochondrial mutations and that specific strains might be used preferentially to evaluate the phenotypic effect of mitochondrial mutations on carbon metabolism, stress responses, and mitochondrial DNA stability. In particular, while W303-1B and MCC123 strains should be used to study the effect of severe mitochondrial tRNA mutations, D273-10B/A1 strain is rather suitable for studying the effects of milder mutations.
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http://dx.doi.org/10.1002/mbo3.167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4082703PMC
June 2014

The isolated carboxy-terminal domain of human mitochondrial leucyl-tRNA synthetase rescues the pathological phenotype of mitochondrial tRNA mutations in human cells.

EMBO Mol Med 2014 02 10;6(2):169-82. Epub 2014 Jan 10.

Department of Radiology, Oncology and Pathology, Sapienza University of Rome, Rome, Italy.

Mitochondrial (mt) diseases are multisystem disorders due to mutations in nuclear or mtDNA genes. Among the latter, more than 50% are located in transfer RNA (tRNA) genes and are responsible for a wide range of syndromes, for which no effective treatment is available at present. We show that three human mt aminoacyl-tRNA syntethases, namely leucyl-, valyl-, and isoleucyl-tRNA synthetase are able to improve both viability and bioenergetic proficiency of human transmitochondrial cybrid cells carrying pathogenic mutations in the mt-tRNA(Ile) gene. Importantly, we further demonstrate that the carboxy-terminal domain of human mt leucyl-tRNA synthetase is both necessary and sufficient to improve the pathologic phenotype associated either with these "mild" mutations or with the "severe" m.3243A>G mutation in the mt-tRNA(L)(eu(UUR)) gene. Furthermore, we provide evidence that this small, non-catalytic domain is able to directly and specifically interact in vitro with human mt-tRNA(Leu(UUR)) with high affinity and stability and, with lower affinity, with mt-tRNA(Ile). Taken together, our results sustain the hypothesis that the carboxy-terminal domain of human mt leucyl-tRNA synthetase can be used to correct mt dysfunctions caused by mt-tRNA mutations.
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http://dx.doi.org/10.1002/emmm.201303198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3927953PMC
February 2014

Human mitochondrial leucyl tRNA synthetase can suppress non cognate pathogenic mt-tRNA mutations.

EMBO Mol Med 2014 02 10;6(2):183-93. Epub 2014 Jan 10.

The Wellcome Trust Centre for Mitochondrial Research Institute for Ageing and Health The Medical School, Newcastle University, Newcastle upon Tyne, UK.

Disorders of the mitochondrial genome cause a wide spectrum of disease, these present mainly as neurological and/or muscle related pathologies. Due to the intractability of the human mitochondrial genome there are currently no effective treatments for these disorders. The majority of the pathogenic mutations lie in the genes encoding mitochondrial tRNAs. Consequently, the biochemical deficiency is due to mitochondrial protein synthesis defects, which manifest as aberrant cellular respiration and ATP synthesis. It has previously been reported that overexpression of mitochondrial aminoacyl tRNA synthetases has been effective, in cell lines, at partially suppressing the defects resulting from mutations in their cognate mt-tRNAs. We now show that leucyl tRNA synthetase is able to partially rescue defects caused by mutations in non-cognate mt-tRNAs. Further, a C terminal peptide alone can enter mitochondria and interact with the same spectrum of mt-tRNAs as the entire synthetase, in intact cells. These data support the possibility that a small peptide could correct at least the biochemical defect associated with many mt-tRNA mutations, inferring a novel therapy for these disorders.
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http://dx.doi.org/10.1002/emmm.201303202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3927954PMC
February 2014

Cancer survival in Europe 1999-2007 by country and age: results of EUROCARE--5-a population-based study.

Lancet Oncol 2014 Jan 5;15(1):23-34. Epub 2013 Dec 5.

Centro Nazionale di Epidemiologia, Sorveglianza e Promozione della Salute, Istituto Superiore di Sanità, Rome, Italy.

Background: Cancer survival is a key measure of the effectiveness of health-care systems. EUROCARE-the largest cooperative study of population-based cancer survival in Europe-has shown persistent differences between countries for cancer survival, although in general, cancer survival is improving. Major changes in cancer diagnosis, treatment, and rehabilitation occurred in the early 2000s. EUROCARE-5 assesses their effect on cancer survival in 29 European countries.

Methods: In this retrospective observational study, we analysed data from 107 cancer registries for more than 10 million patients with cancer diagnosed up to 2007 and followed up to 2008. Uniform quality control procedures were applied to all datasets. For patients diagnosed 2000-07, we calculated 5-year relative survival for 46 cancers weighted by age and country. We also calculated country-specific and age-specific survival for ten common cancers, together with survival differences between time periods (for 1999-2001, 2002-04, and 2005-07).

Findings: 5-year relative survival generally increased steadily over time for all European regions. The largest increases from 1999-2001 to 2005-07 were for prostate cancer (73.4% [95% CI 72.9-73.9] vs 81.7% [81.3-82.1]), non-Hodgkin lymphoma (53.8% [53.3-54.4] vs 60.4% [60.0-60.9]), and rectal cancer (52.1% [51.6-52.6] vs 57.6% [57.1-58.1]). Survival in eastern Europe was generally low and below the European mean, particularly for cancers with good or intermediate prognosis. Survival was highest for northern, central, and southern Europe. Survival in the UK and Ireland was intermediate for rectal cancer, breast cancer, prostate cancer, skin melanoma, and non-Hodgkin lymphoma, but low for kidney, stomach, ovarian, colon, and lung cancers. Survival for lung cancer in the UK and Ireland was much lower than for other regions for all periods, although results for lung cancer in some regions (central and eastern Europe) might be affected by overestimation. Survival usually decreased with age, although to different degrees depending on region and cancer type.

Interpretation: The major advances in cancer management that occurred up to 2007 seem to have resulted in improved survival in Europe. Likely explanations of differences in survival between countries include: differences in stage at diagnosis and accessibility to good care, different diagnostic intensity and screening approaches, and differences in cancer biology. Variations in socioeconomic, lifestyle, and general health between populations might also have a role. Further studies are needed to fully interpret these findings and how to remedy disparities.

Funding: Italian Ministry of Health, European Commission, Compagnia di San Paolo Foundation, Cariplo Foundation.
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http://dx.doi.org/10.1016/S1470-2045(13)70546-1DOI Listing
January 2014

Cancer estimates up to 2015 in Friuli Venezia Giulia.

Tumori 2013 May-Jun;99(3):318-26

Aims And Background: This analysis intended to estimate the incidence, mortality and prevalence time trends for the major cancer sites up to 2015 in the Friuli Venezia Giulia region, northeastern Italy, where a population-based cancer registry has been covering the whole area since 1995.

Methods: The MIAMOD method, a statistical back-calculation approach, was applied to estimate incidence, mortality and prevalence figures, in the period 1970-2015, using mortality data from the Italian National Institute of Statistics and relative survival data from Italian cancer registries.

Results: We estimated that the cancer sites with the highest incidence rates in the forthcoming years will be breast in women (with an age-standardized incidence rate of 130 per 100,000 in 2015), prostate in men (97 per 100,000) and colon-rectum in both sexes (85 and 42 per 100,000 in men and women, respectively). The incidence rates for lung cancer will continue to decrease only in men (down to 43 per 100,000 in 2015). Although the decline in the mortality rates of lung, breast and colorectal cancers is likely to persist, these tumors will remain the big killers in the near future. The number of people living in Friuli Venezia Giulia after a cancer diagnosis is expected to continue to rise in particular for breast cancer (with a crude prevalence of 3,000 per 100,000 women in 2015), prostate cancer (1,700 per 100,000 men) and colorectal cancer (1,100 and 800 per 100,000 in men and women, respectively).

Conclusion: These estimates confirmed the epidemiological patterns in time trends of major cancer sites recorded in Friuli Venezia Giulia. They highlighted in particular the increasing number of people living after a cancer diagnosis as a result of population aging, earlier diagnosis and better prognosis, which warrants adequate public health policies.
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http://dx.doi.org/10.1700/1334.14795DOI Listing
December 2013

Initial treatment for newly diagnosed elderly colorectal cancer patients: patterns of care in Italy and the United States.

J Natl Cancer Inst Monogr 2013 ;2013(46):88-98

Istituto di Ricerche sulla Popolazione e le Politiche Sociali, Consiglio Nazionale delle Ricerche, Via Palestro 32-00185 Roma, Italy.

Cancer is a major component of health-care expenditures in most developed countries. The costs of cancer care are expected to increase due to rising incidence (as the population ages) and increasing use of targeted anticancer therapies. However, epidemiological analysis of patterns of care may be required prior to empirically well-grounded cost analyses. Additionally, comparisons of care between health-care delivery systems and countries can identify opportunities to improve practice. They can also increase understanding of patient outcomes and economic consequences of differences in policies related to cancer screening, treatment, and programs of care. In this study, we compared patterns of colorectal cancer treatment during the first year following diagnosis in two cohorts of elderly patients from some areas of Italy and the United States using cancer registry linked to administrative data. We evaluated hospital use, initial treatments (surgery, chemotherapy, and radiation), and timeliness of surgery and adjuvant therapy, taking into account patient characteristics and clinical features, such as stage at diagnosis and the cancer subsite. We observed greater use of adjuvant chemotherapy in stage III and IV colon cancer patients and adjuvant therapy in all stages of rectal cancer patients in the US cohort. We found a higher rate of open surgeries in the Italian cohort, a similar rate of hospitalization, but a higher number of hospital days in the Italian cohort. However, in spite of structural differences between the United States and Italy in health-care organization and delivery as well as in data collection, patterns of care and the timing of care in the year after diagnosis are generally similar among patients within stage of disease at diagnosis. Comparative studies of the costs associated with patterns of cancer care will be important for future research.
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http://dx.doi.org/10.1093/jncimonographs/lgt006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3888186PMC
February 2014