WHO Working Group Research Articles

Profile of long COVID symptoms needing rehabilitation: a cross-sectional household survey of 12,925 SARS-CoV-2 cases between July and December 2021 in Bangladesh

Background and aims: It is important to determine the profile of long COVID (LC) symptoms within the scope of rehabilitation in Bangladesh. This study’s objective was to estimate the newly experienced long COVID symptoms needing rehabilitation by determining the prevalence and spectrum of impairments due to LC in Bangladesh.MethodsA Cross-sectional household survey of 12,925 COVID-19 patients confirmed by RT-PCR from 24 testing facilities in Bangladesh. LC was diagnosed according to WHO working group definition. COVID-19 Yorkshire Rehabilitation Scale (C19-YRS) was used to determine the symptom responses, symptom severity, new long COVID symptoms, and scope of rehabilitation.ResultsThe population proportion of LC symptoms requiring rehabilitation interventions are 0.22 [95% CI, 0.20–0.24] in Bangladeshi people diagnosed with SARS-CoV-2. Among them, 0.08 [95% CI, 0.07–0.09] had mild, 0.07 [95% CI, 0.06–0.09] had moderate, and 0.05 [95% CI, 0.04–0.06] had severe long COVID symptoms (LCS). There was a significant positive correlation between LCS and functional disabilities (r = 0.889, p < 0.001), while a negative correlation was observed between the severity of symptoms and overall health (r=-0.658, p < 0.001). In comparison to the pre-COVID status, 17 new LCS were observed and the increase in the scope of rehabilitation intervention among LCS ranged between 0.01 [95% CI, 0.001–0.01] and 0.21 [95% CI, 0.19–0.22]. In Bangladesh, 59% (n = 334) of the LC cases are out of reach for any rehabilitation interventions.ConclusionNearly one-fourth of Bangladeshi Post-COVID-19 have long COVID (LC). Seventeen symptoms (LCS) were observed and more than half of the populations having long COVID are out of reach of any rehabilitation facilities.

Оптимизация физической активности детей и подростков в рамках кампании по прекращению детского ожирения

В статье приведен обзор текущих регламентирующих документов международных организаций, посвященный организационным вопросам оптимизации физической активности детей. Показано, что, по данным Всемирной организации здравоохранения (ВОЗ; 2015), основной причиной смертности населения являются кардиоваскулярные заболевания и их осложнения, формирование которых в наибольшей степени связано с ожирением, имеющим корни в детском возрасте. Приведены глобальные рекомендации ВОЗ относительно физической активности для укрепления здоровья (2010) и рекомендации Американской кардиологической ассоциации относительно организации физической активности детей (2014). Представлены критерии выбора типа физической активности для детей и подростков по данным Centers for Disease Control and Prevention (2011). Проанализированы результаты работы рабочей группы ВОЗ по прекращению детского ожирения (2015). Сделаны акценты на необходимости проведения мультисекторальных государственных, образовательных и социальных мероприятий.

Pituitary neuroendocrine tumors: a model for neuroendocrine tumor classification.

The classification of adenohypophysial neoplasms as "pituitary neuroendocrine tumors" (PitNETs) was proposed in 2017 to reflect their characteristics as epithelial neuroendocrine neoplasms with a spectrum of clinical behaviors ranging from small indolent lesions to large, locally invasive, unresectable tumors. Tumor growth and hormone hypersecretion cause significant morbidity and mortality in a subset of patients. The proposal was endorsed by a WHO working group that sought to provide a unified approach to neuroendocrine neoplasia in all body sites. We review the features that are characteristic of neuroendocrine cells, the epidemiology and prognosis of these tumors, as well as further refinements in terms used for other pituitary tumors to ensure consistency with the WHO framework. The intense study of PitNETs has provided information about the importance of cellular differentiation in tumor prognosis as a model for neuroendocrine tumors in different locations.

Key criteria for the ethical acceptability of COVID-19 human challenge studies: Report of a WHO Working Group

This report of the WHO Working Group for Guidance on Human Challenge Studies in COVID-19 outlines ethical standards for COVID-19 challenge studies. It includes eight Key Criteria related to scientific justification, risk-benefit assessment, consultation and engagement, co-ordination of research, site selection, participant selection, expert review, and informed consent. The document aims to provide comprehensive guidance to scientists, research ethics committees, funders, policymakers, and regulators in deliberations regarding SARS-CoV-2 challenge studies by outlining criteria that would need to be satisfied in order for such studies to be ethically acceptable.

Editorial introductions

Current Opinion in Infectious Diseases was launched in 1988. It is part of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of infectious diseases is divided into 11 sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Section Editors for this issue. SECTION EDITORS Christina M. CoyleChristina M. CoyleChristina M. Coyle, MD, MS is a Professor of Medicine at Albert Einstein College of Medicine, USA. Dr Coyle received her medical degree from SUNY Downstate in Brooklyn, USA, and completed her residency training at Albert Einstein College of Medicine and an Infectious Disease Fellowship at Montefiore Medical Center in the Bronx, USA. She runs an active Tropical Medicine Clinic and has a clinical expertise in tropical medicine with a focus on larval tapeworms including, neurocysticercosis and echinococcus. Dr Coyle has been a surveillance site director since 2001 for Geosentinel, which is a worldwide communication and data collection network for the surveillance of travel related morbidity that was initiated in 1995 by the International Society of Travel Medicine (ISTM) and the US Centers for Disease Control (CDC). As an active member of the American Society of Tropical Medicine & Hygiene (ASMTH), she co-directs the two-day Pre-Meeting Course prior to the annual ASTMH meeting and provides an intensive update in tropical medicine to academic clinicians and other practitioners who are already experts in their fields. She is a much sought-after educator and teaches parasitology in two medical schools in New York City. Her students and peers at Albert Einstein College of Medicine have recognized her with every teaching award available to faculty. She also serves on the Infectious Disease Boards Exam Committee, lectures both nationally and internationally, and is a known expert in the clinical management of neurocysticercosis. Dr Coyle is the Assistant Dean for Faculty Development at the Albert Einstein College of Medicine and a PI on the CDC award, “Reducing the Burden of Neglected Parasitic Infections (NPIs) in the United States through Evidence-Based Research, (NU2GGHOO2180)”. James Platts-MillsJames Platts-MillsDr Platts-Mills is an Associate Professor of Medicine in the Division of Infectious Diseases and International Health at the University of Virginia, USA. His research focuses on the application of molecular diagnostics to the epidemiology of enteric diseases in children in developing countries. This work has helped define the etiology and burden of diarrheal disease and the long-term impact of early enteric infections on child growth and development, with a particular focus on Campylobacter and Shigella. He serves as a diarrheal disease expert for the Global Burden of Disease Study, sits on a WHO working group on enteric diseases burden estimation, and with colleagues at the CDC and WHO, co-founded the Global Pediatric Diarrhea Surveillance network.

Immunization stress-related response – Redefining immunization anxiety-related reaction as an adverse event following immunization

The Council for the International Organizations of Medical Sciences (CIOMS) and WHO working group on pharmacovigilance defines five cause specific AEFI which includes an immunization anxiety-related reaction. Historically this term has been used to describe a range of symptoms and signs that may arise after immunization that are related to “anxiety” about the immunization. However, the term “anxiety” does not adequately capture all the elements of this cause specific AEFI. In 2015, the Global Advisory Committee for Vaccine Safety convened an expert working group with the purpose of redefining, preventing and managing this particular AEFI. The term “Immunization Stress-Related Response” is proposed to replace the former terminology. We present a manual that redefines this AEFI and present a framework for prevention, diagnosis and management in both an individual and also when such events occur as clusters and affect multiple individuals. Since such mass events can result in cessation of immunization programmes and/or a loss of public confidence, a communication response is essential.

Abstract P3-08-03: Dissecting the heterogeneity of metaplastic breast cancer: A morphological, immunohistochemical and genomic analysis of a large cohort

Abstract Although rare, Metaplastic Breast Carcinomas (MBC) account for significant global breast cancer mortality. This subgroup is extremely heterogeneous and by definition exhibits metaplastic change to squamous and/or mesenchymal elements, including but not limited to spindle, squamous, chondroid, osseous and rhabdomyoid elements. The WHO working group recognizes that the current classification is inadequate and in the interim, has suggested a purely descriptive classification. The mixed epithelial-mesenchymal morphology has led to speculation that MBC represent 'stem cell tumours'; in support of this, MBC have been shown to have a CD44+/CD24-/low phenotype. Clinically, patients present with tumours that are larger (higher stage), have increased likelihood of distant metastases at presentation and overall, have a reduced 5-year survival rate compared to Invasive Carcinoma-NST. Hence, this is a unique subtype with poor outcome but without a robust classification or understanding of the biology to aid clinical management. We present a detailed morphological, immunohistochemical and genomic analysis of a large series of MBC (n=347), as amassed through the Asia-Pacific MBC consortium. We consider our morphological dissection using the WHO subtyping guidelines and show that an increasing number of phenotypes in a mixed MBC (classified as WHO_1) significantly associates with a poor prognosis. Immunohistochemical analysis showed that a pure spindle (WHO_5) is significantly less likely to express vimentin, CK5/6, CK14, and CK19 than a mixed WHO_1 with spindle features. Similarly, a WHO_1 with chondroid features is less likely to express EGFR than WHO_1 with chondroid features and rhabdoid or osseous differentiation. Across the cohort, positivity for the AE1/3 antibody and a lack of EGFR expression both significantly associate with a better outcome. We report no significant association between patient age at diagnosis and breast cancer specific survival, nor between age and specific WHO MBC subtypes. We report a significant association between WHO_1 types and increasing tumour grade, and also between tumour size and grade, with tumour size being a highly significant prognostic indicator in this cohort. Our exome sequencing confirms a significant enrichment for TP53 and PTEN mutations in MBC, and intriguingly for concurrent mutations of TP53, PTEN and PIK3CA. A novel enrichment for NF1 mutations is also presented. In summary, we provide a thorough assessment of a large cohort of MBC, including morphology, survival, IHC and exome sequencing, and present our analysis contextualized by the WHO guidelines, extending the existing knowledge base of this rare tumour type. Citation Format: McCart Reed AE, Kalaw E, Nones K, Bettington M, Lim M, Bennett J, Johnstone K, Kutasovic JR, Kazakoff S, Xu QC, Saunus JM, Reid LE, Black D, Niland C, Ferguson K, Gresshoff I, Raghavendra A, Liu JC, Kalinowski L, Reid AS, Davidson M, Pearson JV, Yamaguchi R, Harris G, Tse G, Papadimos D, Pathmanathan R, Pathmanathan N, Tan PH, Fox S, O'Toole S, Waddell N, Simpson PT, Lakhani SR. Dissecting the heterogeneity of metaplastic breast cancer: A morphological, immunohistochemical and genomic analysis of a large cohort [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-08-03.

The 2016 World Health Organization classification of tumours of the central nervous system

The 2016 WHO classification of tumours of the central nervous system represents the new paradigm among the specialists in the brain tumours and proposes a new approach combining histopathological and molecular features into diagnosis named 'integrated diagnosis'. The aim of this challenge is to overstep the interobserver variability of diagnosis based on previous classifications in order to ensure homogenous biological entities with a more accurate clinical significance. Over the last two decades, several molecular aberrations into gliomagenesis were highlighted and then confirmed as emerging biomarkers through prognostic stratification. In particular, IDH1/IDH2 genes mutations, 1p/19q codeletion and mutations in genes encoding histone H3 variants drastically changed the knowledge about diffuse gliomas inducing the WHO working group to consider the phenotype-genotype approach. In the present review, the historical development of the diagnosis of brain tumours from the 3D spatial configuration to the integration of multidisciplinary data up to recent molecular alterations is discussed. At the national level, the RENOCLIP network (supported by the National Cancer Institute) contributes to improve the standardization of histological diagnosis and the facilitation of access to molecular biology platforms for the detection of genetic aberrations necessary for integrated diagnosis. Importantly, the French POLA cohort allowed to test the clinical impact of the new criteria introduced by 2016 WHO classification of CNS tumours confirming the high accuracy in predicting clinical behaviour for diffuse gliomas.

New proposals of the WHO working group (2016) for the diagnosis of myelodysplastic syndromes (MDS): Characteristics of refined MDS types

Based on centrally diagnosed 3528 patients in the Düsseldorf registry, we validated the new proposals for the classification of the MDS by the WHO working group: 256 patients were diagnosed as MDSSLD (7,3%), 978 MDSMLD (27,7%), 227 MDS RS SLD (6,4%); 321 MDS RS MLD (9,1%), 159 MDS del(5q) (4,5%), 481 MDSEB 1 (13,6%), 620 MDSEB 2 (17,6%), and 148 MDS-U (4,2%). 352 patients (16,9% of the non blastic types) changed the category, mainly moving from RCMD to MDS RS MLD, RCUD and RCMD to MDS del(5q). Median survival times of the refined groups differed from more than 60 months in the MDSSLD (RS) groups, 37 months in the MDSMLD (RS) groups, 79 months of the MDS del(5q) group and 21 and 11 months in the MDSEB 1 and 2 groups, respectively. The difference between the groups with regard to the risk of AML evolution was also impressing. No major changes were made with regard to the MDS-U categories. In summary, the proposals of the WHO group for the classification of MDS are thoughtful, taking into account biologic parameters of the diseases, a more precise wording, to some extend pragmatic and feasible.

Use of dual-energy X-ray absorptiometry (DXA) for diagnosis and fracture risk assessment; WHO-criteria, T- and Z-score, and reference databases

Dual-energy X-ray absorptiometry (DXA) is a two-dimensional imaging technology developed to assess bone mineral density (BMD) of the entire human skeleton and also specifically of skeletal sites known to be most vulnerable to fracture. In order to simplify interpretation of BMD measurement results and allow comparability among different DXA-devices, the T-score concept was introduced. This concept involves an individual's BMD which is then compared with the mean value of a young healthy reference population, with the difference expressed as a standard deviation (SD). Since the early nineties of the past century, the diagnostic categories “normal, osteopenia, and osteoporosis”, as recommended by a WHO working Group, are based on this concept. Thus, DXA is still the globally accepted “gold-standard” method for the noninvasive diagnosis of osteoporosis. Another score obtained from DXA measurement, termed Z-score, describes the number of SDs by which the BMD in an individual differs from the mean value expected for age and sex. Although not intended for diagnosis of osteoporosis in adults, it nevertheless provides information about an individual's fracture risk compared to peers. DXA measurement can either be used as a “stand-alone” means in the assessment of an individual's fracture risk, or incorporated into one of the available fracture risk assessment tools such as FRAX® or Garvan, thus improving the predictive power of such tools. The issue which reference databases should be used by DXA-device manufacturers for T-score reference standards has been recently addressed by an expert group, who recommended use National Health and Nutrition Examination Survey III (NHANES III) databases for the hip reference standard but own databases for the lumbar spine. Furthermore, in men it is recommended use female reference databases for calculation of the T-score and use male reference databases for calculation of Z-score.

Editorial introductions

Editorial introductions

Dredging Method-A Conservative Approach for the Treatment of Keratocystic Odontogenic Tumor -

Keratocystic odontogenic tumor (KCOT) was previously designated as odontogenic keratocyst, which stresses the benign behavior of this lesion. In 2005, WHO Working Group recommends the term KCOT as it better reflects its neoplastic nature.

Protecting health from climate change in the WHO European Region.

“How far are we in the WHO European Region in implementing action to counter the health impacts of climate change?” This was the question posed to representatives of Member States in the WHO European Region of in the WHO working group on health in climate change (HIC). Twenty-two Member States provided answers to a comprehensive 2012 questionnaire that focused on eight thematic areas (governance; vulnerability, impact and adaptation (health) assessments (VIA); adaptation strategies and action plans; climate change mitigation; strengthening health systems; raising awareness and building capacity; greening health services; and sharing best practices). Strong development has been in climate change vulnerability and impact assessments, as well as strengthening health systems and awareness raising. Areas where implementation would benefit from further action are the development of national health adaptation plans, greening health systems, sharing best practices and reducing greenhouse gas (GHG) emissions in other sectors. At the Fifth Ministerial Conference on Environment and Health in Parma, Itatly in 2010, the European Commitment to Act on climate change and health and the European Regional Framework for Action to protect health from climate change were endorsed by the fifty-three European Member States. The results of this questionnaire present the most comprehensive assessment so far of progress made by European Member States to protect public health from climate change since the Parma Conference agreements.

Drug susceptibility surveillance of influenza viruses circulating in the United States in 2011‐2012: application of the WHO antiviral working group criteria

BackgroundAssessing susceptibility of influenza viruses to neuraminidase (NA) inhibitors (NAIs) is primarily done in NA inhibition (NI) assays, supplemented by NA sequence analysis. However, two factors present challenges for NI assay data interpretation: lack of established IC50 values indicative of clinically relevant resistance and insufficient harmonization of NI testing methodologies among surveillance laboratories. In 2012, the WHO working group on influenza antiviral susceptibility (WHO-AVWG) developed criteria to facilitate consistent interpretation and reporting of NI assay data.MethodsThe WHO-AVWG classification criteria were applied in interpreting NI assay data for two FDA-licensed NAIs, oseltamivir and zanamivir, for viruses collected in the United States during the 2011–2012 winter season.ResultsAll A (H1N1)pdm09 viruses (n = 449) exhibited normal inhibition by oseltamivir and zanamivir, with the exception of eight viruses (1·8%) with highly reduced inhibition by oseltamivir, which carried the H275Y marker of oseltamivir resistance. A (H3N2) viruses (n = 978) exhibited normal inhibition by both NAIs, except for one virus with highly reduced inhibition by zanamivir due to the cell culture-selected NA change, Q136K. Type B viruses (n = 343) exhibited normal inhibition by both drugs, except for an isolate with reduced inhibition by both NAIs that had the cell culture-selected A200T substitution.ConclusionsWHO-AVWG classification criteria allowed the detection of viruses carrying the established oseltamivir resistance marker, as well as viruses whose susceptibility was altered during propagation. These criteria were consistent with statistical-based criteria for detecting outliers and will be useful in harmonizing NI assay data among surveillance laboratories worldwide and in establishing laboratory correlates of clinically relevant resistance.

PB.26: Significance of flat epithelial atypia at image guided breast biopsy

The term flat epithelial atypia (FEA) was introduced in 2003 by the WHO working group on the Pathology & Genetics committee of tumours of the breast. Previously known as columnar cell change with atypia, these lesions usually present as microcalcification and although there is some evidence to suggest that FEA represents a precursor lesion in the spectrum of low-grade breast neoplasia, there are limited data concerning the ultimate clinical impact and optimum management strategy. The aim of this study was to determine the radiological characteristics of FEA and final histology following surgical excision at our centre.

Central liponeurocytoma: Case report and review of literature

Abstract Cerebellar liponeurocytoma consists of well-differentiated neurons with the cytology of neurocytes in addition to a population of lipidized cells. Hence it is biphasic in appearance and has been included in the category of glioneuronal tumors of the central nervous system by the WHO working group on the Classification of Tumors of the Nervous System. However, liponeurocytoma is not exclusive to the cerebellar or fourth ventricular location. Since its inclusion in the central nervous system tumor classification, nine cases with similar histological and immunohistochemical features have also been described in the lateral ventricles. We describe here such a lateral ventricular tumour in a 30-year-old woman, characteristically showing divergent glio-neuronal differentiation and lipidized neoplastic cells. Therefore, we suggest that future WHO tumor classification should consider that liponeurocytomas are not entirely restricted to the cerebellum and henceforth change of nomenclature might be considered, as also pointed out by other authors.

Toxicology and risk assessment of acrolein in food

Acrolein is an α,β-unsaturated aldehyde formed by thermal treatment of animal and vegetable fats, carbohydrates and amino acids. In addition it is generated endogenously. As an electrophile, acrolein forms adducts with gluthathione and other cellular components and is therefore cytotoxic. Mutagenicity was shown in some in vitro tests. Acrolein forms different DNA adducts in vivo, but mutagenic and cancerogenous effects have not been demonstrated for oral exposure. In subchronic oral studies, local lesions were detected in the stomach of rats. Systemic effects have not been reported from basic studies. A WHO working group established a tolerable oral acrolein intake of 7.5 μg/kg body weight/day. Acrolein exposure via food cannot be assessed due to analytical difficulties and the lack of reliable content measurements. Human biomonitoring of an acrolein urinary metabolite allows rough estimates of acrolein exposure in the range of a few μg/kg body weight/day. High exposure could be ten times higher after the consumption of certain foods. Although the estimation of the dietary acrolein exposure is associated with uncertainties, it is concluded that a health risk seems to be unlikely.

Report from a WHO Working Group: standard method for detecting upper respiratory carriage of Streptococcus pneumoniae: ERRATUM

Report from a WHO Working Group: standard method for detecting upper respiratory carriage of Streptococcus pneumoniae: ERRATUM

Beyond detuning: 10 years of progress and new challenges in the development and application of assays for HIV incidence estimation

Beyond detuning: 10 years of progress and new challenges in the development and application of assays for HIV incidence estimation

RAD001, An Inhibitor of mTOR, Shows Clinical Activity in a Phase I/II Study in Patients with Primary Myelofibrosis (PMF) and Post Polycythemia Vera/Essential Thrombocythemia Myelofibrosis (PPV/PET MF).

Abstract 307Constitutive and enhanced activation of JAK/STAT pathway is found in patients (pts) with myeloproliferative neoplasms (MPN), particularly but not exclusively in those with mutation in the Janus tyrosine kinase 2 gene (JAK2V617F) or the MPL gene (MPLW515L/K/A). Activation of the Erk and PI3K/Akt pathways have also been described in cells harboring the JAK2V617F mutation. In in-vitro studies performed in our laboratory (AM Vannucchi et al, ASH 2009, abstract submitted) we observed that RAD001, a specific inhibitor of the serine/threonine kinase mTOR (mammalian target of rapamycin) that is a downstream target of PI3K, remarkably inhibited proliferation of JAK2V617F mutant cell lines and reduced the clonogenic activity of CD34+ cells from MPN pts. The PI3K/Akt/mTOR pathway has become an important focus for cancer therapy, and mTOR inhibitors have demonstrated activity against solid tumors and lymphomas. A phase I/II trial of RAD001 is being conducted in pts with PMF and PPV/PET MF, including JAK2V617F or MPL mutated as well as wild-type pts with intermediate/high risk score according to Lille criteria. Diagnosis of PMF and of PPV/PET-MF was made following the WHO and International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) criteria, respectively. Phase I is a dose escalation of RAD001 involving 3 sequential cohorts of 3 pts each at 5.0, 7.5, and 10 mg daily, orally, for 3 months, to define maximum tolerated dose (MTD). Phase II involves the use of MTD for 4 months, according to a two-stage Simon design, aimed at assessing efficacy of the drug. Responses are evaluated using the EUMNET criteria for treatment response in myelofibrosis (Barosi G et al, Blood 2005). At the time of writing, 8 of 9 pts included in the Phase I have completed the 3-month study period without dose-limiting toxicities or other significant adverse events; the ninth pt at 10 mg is completing the last month of treatment. There were seven pts with PMF and 2 with PPV-MF. Main toxicities were represented by grade 2 mouth ulcers in 3 pts and transient grade 1/2 hypertrigliceridemia in 5 pts, that occurred irrespective of the dose. One pt at 10 mg presented transient muscular weakness and arthralgia. The initial dose of 5.0 mg resulted in a reduction in spleen size consistent with a complete response (CR) in one pt (from 4 to 0 cm below the left costal margin) and partial responses (PR) in two pts (from 10 and 13 cm to 1 and 9 cm, respectively). In the 7.5 mg cohort, there were one CR (from 4 to 0 cm) and one PR (from 16 to 8 cm) in splenomegaly; none of the 2 pts at 10 mg had a response in splenomegaly. In 1 pt CR in splenomegaly was maintained at +4 mo after suspension of drug while in the other responding pts there was a progressive re-enlargment of the spleen to baseline level. A complete resolution of systemic symptoms was achieved in 2 of 3 pts while aquagenic pruritus disappeared in all the 5 pts who complained of it. Overall, there were 2 major and 3 moderate responses, while 3 pts did not show a measurable response. At the end of therapy, the absolute count of circulating CD34+ cells had decreased in all but one pt of a median value of 39% from baseline (range 16% to 72%). There was no significant decrease in the burden of granulocyte V617F allele at the end of treatment in the 8 mutated pts. Single-colony JAK2V617F genotyping was performed in 4 pts, 2 each from the 5.0 and 7.5 mg cohort. In one patient receiving 7.5 mg the percentage of homozygous BFU-E and CFU-GM decreased from 14% and 45%, respectively, at baseline to 0 and 18% at the end of therapy; in the other 3 pts changes were minimal. In conclusion, initial results showed rapid reduction of splenomegaly and symptomatic improvement, without relevant toxicity, in pts with myelofibrosis receiving RAD001. The drug also reduced the circulating CD34+ cell count and V617F-homozygous progenitor cells appeared to be decreasing at least in some patients, although the allelic burden measured in granulocytes did not modify. Updated results on current patients and future patients enrolled in Phase II will be presented at the meeting. Disclosures:No relevant conflicts of interest to declare.