Updated World Health Organization Research Articles

Collecting and using reliable vaccination coverage survey estimates: Summary and recommendations from the “Meeting to share lessons learnt from the roll-out of the updated WHO Vaccination Coverage Cluster Survey Reference Manual and to set an operational research agenda around vaccination coverage surveys”, Geneva, 18–21 April 2017

Household surveys are frequently used as means of vaccination coverage measurement, but obtaining accurate survey estimates present several challenges. In 2015, the World Health Organization (WHO) released a working draft of its updated Vaccination Coverage Survey Reference Manual that moved well beyond the traditional Expanded Program on Immunization (EPI) survey design. In April 2017, WHO convened a four-day meeting, to review lessons learned using the updated manual and to define an agenda for operational research about vaccination coverage surveys. About 70 stakeholders, including EPI managers and participants from 10 countries that have used the updated Survey Manual, survey experts, statisticians, partners, representatives from WHO regional offices and headquarters, and providers of technical assistance discussed methodological issues from sampling to accurately ascertaining a person’s vaccination status, optimizing data collection and data management and conducting appropriate analyses. Participants also discussed data sharing and how to best survey data for immunization decision-making. The lessons learned from the use of the updated WHO Survey Manual related mainly to operational issues to implement better quality vaccination coverage surveys. It resulted in a list of 23 recommendations for WHO, donors and partners, immunization programs, and household surveys that collect immunization data. Similarly, 14 research topics, categorized in six themes (overall survey conduction, sampling, vaccination ascertainment, data collection, data analysis and use, and inclusion of questions on knowledge, attitudes and practices) were prioritized. Top areas of further work included improving our understanding of the accuracy of caregiver recall when documented evidence of vaccination is not available, improving engagement and coordination between immunization programs and entities conducting multi-purpose household surveys such as Demographic and Health Survey and Multiple Cluster Indicator Survey, improving mechanisms for sharing vaccination survey datasets and documentation, and making better use of survey results to translate data into knowledge for decision-making. This manuscript summarizes the meeting proceedings and provides an update of actions taken by WHO since this meeting.

Diffuse Gliomas for Nonneuropathologists: The New Integrated Molecular Diagnostics.

Diffuse gliomas comprise the bulk of "brain cancer" in adults. The recent update to the 4th edition of the World Health Organization's classification of tumors of the central nervous system reflects an unprecedented change in the landscape of the diagnosis and management of diffuse gliomas that will affect all those involved in the management and care of patients. Of the recently discovered gene alterations, mutations in the Krebs cycle enzymes isocitrate dehydrogenases (IDHs) 1 and 2 have fundamentally changed the way the gliomas are understood and classified. Incorporating information on a few genetic parameters (IDH, ATRX and/or p53, and chromosome 1p19q codeletion), a relatively straightforward diagnostic algorithm has been generated with robust and reproducible results that correlate with patients' survival far better than relying on conventional histology alone. Evidence also supports the conclusion that the vast majority of diffuse gliomas without IDH mutations (IDH-wild-type astrocytomas) behave like IDH-wild-type glioblastomas ("molecular GBM"). Together, these changes reflect a big shift in the practice of diagnostic neuropathology in which tumor risk stratification aligns better with molecular information than histology/grading. The purpose of this review is to provide the readers with a brief synopsis of the changes in the 2016 World Health Organization update with an emphasis on diffuse gliomas and to summarize key gene abnormalities on which these classifications are based. Practical points involved in day-to-day diagnostic workup are also discussed, along with a comparison of the various diagnostic tests, including immunohistochemistry, with an emphasis on targeted next-generation sequencing panel technology as a future universal approach.

The 2017 WHO update on mature T- and natural killer (NK) cell neoplasms.

Over the last decade, there has been a significant body of information regarding the biology of the lymphoid neoplasms. This clearly supports the need for updating the 2008 WHO (World Health Organization) classification of haematopoietic and lymphoid tumours. The 2017 WHO classification is not a new edition but an update and revision of the 4th edition. New provisional entities but not new definitive entities are included, and novel molecular data in most of the entities and changes in the nomenclature in few of them have been incorporated. In the context of the mature T- and NK-cell neoplasms, the most relevant updates concern to: 1-dysregulation of the JAK/STAT pathway due to gene mutations which are common to various aggressive and indolent neoplasms; 2-incorporation of new molecular players that are relevant to the pathogenesis of these neoplasms and/or have prognostic implications; 3-inclusion of new provisional entities within the subgroups of anaplastic, primarily intestinal and cutaneous lymphomas such as breast implant-associated anaplastic large cell lymphoma, indolent T-cell lymphoproliferative disorder of the gastrointestinal tract and primary cutaneous acral CD8+ T-cell lymphoma; 4-identification of poor prognostic subtypes of peripheral T-cell lymphomas not otherwise specified (PTCL, NOS) characterized by overexpression of certain genes and of a subgroup PTCL, NOS with a T follicular phenotype that now is included together with angioimmunoblastic T-cell lymphoma under the umbrella of lymphomas with a T follicular helper phenotype; and 5-refinement on the designation and definition of already established entities. A review of the major changes will be outlined.

Data Set for the Reporting of Carcinomas of the Cervix: Recommendations From the International Collaboration on Cancer Reporting (ICCR).

A comprehensive pathologic report is essential for optimal patient management, cancer staging and prognostication. In many countries, proforma reports are used but the content of these is variable. The International Collaboration on Cancer Reporting is an alliance formed by the Royal Colleges of Pathologists of Australasia and the United Kingdom, the College of American Pathologists, the Canadian Partnership Against Cancer and the European Society of Pathology, for the purpose of developing standardized, evidence-based reporting data sets for each cancer site. This will reduce the global burden of cancer data set development and reduplication of effort by different international institutions that commission, publish and maintain standardized cancer-reporting data sets. The resultant standardization of cancer-reporting benefits not only those countries directly involved in the collaboration but also others not in a position to develop their own data sets. We describe the development of an evidence-based cancer data set by the International Collaboration on Cancer Reporting expert panel for the reporting of primary cervical carcinomas and present the "required" and "recommended" elements to be included in the pathology report as well as an explanatory commentary. This data set encompasses the International Federation of Obstetricians and Gynaecologists and Union for International Cancer Control staging systems for cervical neoplasms and the updated World Health Organization classification of gynecologic tumors. The data set also addresses controversial issues such as tumor grading and measurement, including measurement of multifocal carcinomas. The widespread implementation of this data set will facilitate consistent and accurate data collection, comparison of epidemiological and pathologic parameters between different populations, facilitate research, and hopefully result in improved patient management.

Pathology and Genetics of Gliomas.

Current World Health Organization (WHO) classification of the neuroepithelial tumors is cell lineage-oriented and based on a presumed developmental tree of the central nervous system (CNS). It defines three main groups of gliomas, namely astrocytomas, oligodendrogliomas, and ependymomas, and additionally presumes their 4-tiered histopathological grading (WHO grades I to IV). Nevertheless, the impact of tumor pathology on clinically related parameters may be frequently much better predicted by genetics, than by histological appearance of the lesion. Recent studies have revealed several major molecular alterations typical for different types of neoplasms, such as IDH1/IDH2 mutations in diffusely infiltrating gliomas, mutations of TP53 and ATRX in astrocytomas, 1p/19q co-deletion in oligodendrogliomas, mutations of TERT promoter in oligodendrogliomas and IDH wild-type glioblastomas, and mutations or fusions of BRAF in circumscribed astrocytomas, particularly in children. Identification of those and several other genetic abnormalities in the tumor is clinically important and may help clinicians to determine proper treatment strategy and to predict prognosis. Therefore, the updated WHO classification of CNS tumors (2016) considers not only phenotype, but also some genetic characteristics of gliomas.

PROTOCOL: Mass deworming for improving health and cognition of children in endemic helminth areas: a systematic review and individual participant data network meta-analysis.

PROTOCOL: Mass deworming for improving health and cognition of children in endemic helminth areas: a systematic review and individual participant data network meta-analysis.

Histological approach to neuronal and mixed neuronal-glial tumors of the central nervous system

The 2016 updated World Health Organization Classification of Tumors of the Central Nervous System shows an increasing number of entities under the classification of neuronal and mixed neuronal-glial tumors. Despite being a biogenetically heterogeneous group of tumors, the members frequently display some overlapping histological and clinical features, leading to diagnostic dilemmas among neuropathologists, especially when the aid of advanced molecular and immunohistochemical tools is not available. Nonetheless, meticulous assessment of the morphological features with careful interpretation of the immunophenotypes can be rewarding often without the investment of an expensive molecular investigation. We propose a method of approaching the neuronal-glial tumors based on pattern recognition. We briefly discuss the key histological features that are helpful in narrowing down the differentials, with the aid of immunohistochemistry or available molecular information, directing the pathologist toward the correct diagnosis.

Results of Fertility-Sparing Surgery for Expansile and Infiltrative Mucinous Ovarian Cancers.

No series had been reported focusing on the results of fertility-sparing surgery in stage I mucinous ovarian cancers according to histotype (infiltrative vs. expansile). Investigating such outcomes was the aim of the present study. The present study was a retrospective analysis of patients treated conservatively with preservation of the uterus and contralateral ovary from 1976 to 2016. The pathology of the tumors was reviewed by two expert pathologists according to the 2014 World Health Organization (WHO) classification criteria. Oncologic and fertility results were analyzed. Twenty-one patients fulfilled the inclusion criteria, twelve with expansile and nine with infiltrative cancer. All patients had a unilateral tumor and underwent unilateral salpingo-oophorectomy in one-step (n = 6) or two-step (n = 15) surgeries. All but one had complete peritoneal staging surgery based on cytology, omentectomy, and random peritoneal biopsies. Ten had nodal staging surgery. The International Federation of Gynecology and Obstetrics stages were IA (n = 9), IC1 (n = 6), and IC2 (n = 6); the nuclear grades were grade 1 (n = 9), grade 2 (n = 5), and grade 3 (n = 1). Two patients recurred (one expansile and one infiltrative type) 19 and 160 months after surgery, respectively. One stage IA, nuclear grade 2 expansile tumor recurred on the spared ovary; the patient remains alive. The other stage IA infiltrative tumor recurred as peritoneal spread; the patient is alive with disease. Six patients became pregnant; four with expansile tumors and two with infiltrative tumors. The type of mucinous cancer has no impact on the oncologic outcome in this series of patients treated conservatively. Fertility-sparing surgery should be considered for early-stage infiltrative-type tumors. According to the most recently updated World Health Organization classification guidelines, mucinous cancers should be classified as either expansile or infiltrative. The infiltrative type has a poorer prognosis, but there are no data about the safety of fertility-sparing surgery (FSS) in this context. A collection of 21 cases reviewed by two expert pathologists this study is the first devoted to the conservative treatment of mucinous tumors according to both subtypes. The key result was that the type of mucinous cancer has no impact on the oncologic outcome; thus, FSS may be considered in both subtypes.

The Updated World Health Organization Glioma Classification: Cellular and Molecular Origins of Adult Infiltrating Gliomas.

- In the recently updated World Health Organization (WHO) classification of central nervous system tumors, our concept of infiltrating gliomas as a molecular dichotomy between oligodendroglial and astrocytic tumors has been codified. Advances in animal models of glioma and a wealth of sophisticated molecular analyses of human glioma tissue have led to a greater understanding of some of the biologic underpinnings of gliomagenesis. - To review our understanding of gliomagenesis in the setting of the recently updated WHO classification of central nervous system tumors. Topics addressed include a summary of an updated diagnostic schema for infiltrating gliomas, the crucial importance of isocitrate dehydrogenase mutations, candidate cells of origin for gliomas, environmental and other posited contributing factors to gliomagenesis, and the possible role of chromatin topology in setting the stage for gliomagenesis. - We conducted a primary literature search using PubMed. - With multidimensional molecular data sets spanning increasingly larger numbers of patients with infiltrating gliomas, our understanding of the disease at the point of surgical resection has improved dramatically and this understanding is reflected in the updated WHO classification. Animal models have demonstrated a diversity of candidates for glioma cells of origin, but crucial questions remain, including the role of neural stem cells, more differentiated progenitor cells, and glioma stem cells. At this stage the increase in data generated from human samples will hopefully inform the creation of newer animal models that will recapitulate more accurately the diversity of gliomas and provide novel insights into the biologic mechanisms underlying tumor initiation and progression.

Assessment of World Health Organization Collaborating Centres in the Eastern Mediterranean Region.

Following in-house training, there was a need for assessing perceived performance of World Health Organization (WHO) collaborating centres in the Eastern Mediterranean Region, with special relevance to WHO's programme of work. Thus, a questionnaire was shared with responsible officers covering: selection process, frequency of communication, monitoring mechanisms, key delivered activities, and identified gaps during implementation. These included: tendency to implement regular activities, weak technical capacity and communication, and discrepancies between planned activities and actual implementation. Recommendations for centres included: establishing communication plan/modalities, selecting activities of global/regional nature, and mobilizing resources for work plan implementation. Recommendations for responsible officers included: carefully explaining updated WHO rules and regulations; ensuring that specific terms of reference are set as per WHO's global/regional mandates; setting up regular communication mechanisms; agreeing on regular monitoring and coordination modalities; and ensuring that redesignation planning takes place during the 4th year of prior designation period.

Update to CDC's U.S. Medical Eligibility Criteria for Contraceptive Use, 2016: Revised Recommendations for the Use of Hormonal Contraception Among Women at High Risk for HIV Infection.

CDC's U.S. Medical Eligibility Criteria for Contraceptive Use (U.S. MEC) (first published in 2010 and updated in 2016) provides evidence-based guidance for the safe use of contraceptive methods among U.S. women with certain characteristics or medical conditions (1), and is adapted from global guidance from the World Health Organization (WHO) and kept up to date based on continual review of published literature (2).* CDC recently evaluated the evidence and the updated WHO guidance on the risk for human immunodeficiency virus (HIV) acquisition among women using hormonal contraception.† After careful review, CDC adopted the updated WHO guidance for inclusion in the U.S. MEC guidance; this guidance states that the advantages of progestin-only injectable contraceptive use (including depot medroxyprogesterone acetate [DMPA]) by women at high risk for HIV infection outweigh the theoretical or proven risks (U.S. MEC category 2). The guidance also includes an accompanying updated clarification, which states that "there continues to be evidence of a possible increased risk of acquiring HIV among progestin-only injectable users. Uncertainty exists about whether this is due to methodological issues with the evidence or a real biological effect. In many settings, unintended pregnancies and/or pregnancy-related morbidity and mortality are common, and progestin-only injectables are among the few types of methods widely available. Women should not be denied the use of progestin-only injectables because of concerns about the possible increased risk. Women considering progestin-only injectables should be advised about these concerns, about the uncertainty over whether there is a causal relationship, and about how to minimize their risk of acquiring HIV." Recommendations for other hormonal contraceptive methods (including combined hormonal methods, implants, and progestin-only pills) remain the same; there is no restriction for their use among women at high risk for HIV infection (U.S. MEC category 1).

Multinodular and Vacuolating Neuronal Tumor of the Cerebrum: A New "Leave Me Alone" Lesion with a Characteristic Imaging Pattern.

Multinodular and vacuolating neuronal tumor of the cerebrum is a recently reported benign, mixed glial neuronal lesion that is included in the 2016 updated World Health Organization classification of brain neoplasms as a unique cytoarchitectural pattern of gangliocytoma. We report 33 cases of presumed multinodular and vacuolating neuronal tumor of the cerebrum that exhibit a remarkably similar pattern of imaging findings consisting of a subcortical cluster of nodular lesions located on the inner surface of an otherwise normal-appearing cortex, principally within the deep cortical ribbon and superficial subcortical white matter, which is hyperintense on FLAIR. Only 4 of our cases are biopsy-proven because most were asymptomatic and incidentally discovered. The remaining were followed for a minimum of 24 months (mean, 3 years) without interval change. We demonstrate that these are benign, nonaggressive lesions that do not require biopsy in asymptomatic patients and behave more like a malformative process than a true neoplasm.

Japanese Encephalitis Surveillance and Immunization - Asia and Western Pacific Regions, 2016.

Japanese encephalitis (JE) virus is the most important vaccine-preventable cause of encephalitis in the Asia-Pacific region. The World Health Organization (WHO) recommends integration of JE vaccination into national immunization schedules in all areas where the disease is a public health priority (1). This report updates a previous summary of JE surveillance and immunization programs in Asia and the Western Pacific in 2012 (2). Since 2012, funding for JE immunization has become available through the GAVI Alliance, three JE vaccines have been WHO-prequalified,* and an updated WHO JE vaccine position paper providing guidance on JE vaccines and vaccination strategies has been published (1). Data for this report were obtained from a survey of JE surveillance and immunization practices administered to health officials in countries with JE virus transmission risk, the 2015 WHO/United Nations Children's Fund Joint Reporting Form on Immunization, notes and reports from JE meetings held during 2014-2016, published literature, and websites. In 2016, 22 (92%) of 24 countries with JE virus transmission risk conducted JE surveillance, an increase from 18 (75%) countries in 2012, and 12 (50%) countries had a JE immunization program, compared with 11 (46%) countries in 2012. Strengthened JE surveillance, continued commitment, and adequate resources for JE vaccination should help maintain progress toward prevention and control of JE.

Pathology and classification of aggressive mature B-cell lymphomas.

Pathology and classification of aggressive mature B-cell lymphomas.

Molecular classification of adult diffuse gliomas: conflicting IDH1/IDH2, ATRX, and 1p/19q results

Until recently, the diagnosis of brain tumors was primarily based on microscopic examination of hematoxylin and eosin-stained tissue sections. The updated World Health Organization (WHO) Classification of Tumours of the Central Nervous System incorporates genetic alterations into the classification system, with the goal of creating more homogenous disease categories with greater prognostic value. Hence, under the new classification system, the diagnosis of diffuse gliomas incorporates the evaluation of mutations in the IDH1 and IDH2 genes and simultaneous deletion of chromosomes 1p and 19q. For example, although under the 2007 WHO classification system, oligodendrogliomas could be diagnosed based solely on the presence of characteristic histologic features, the newly molecularly defined entity of "oligodendroglioma, IDH-mutant and 1p/19q codeleted" requires the presence of both an IDH1 or IDH2 mutation and 1p/19q codeletion. Given that diagnosis requires evaluation of critical genetic alterations, molecular diagnostics is becoming an increasingly important aspect of clinical oncologic neuropathology practice. As molecular testing is applied more frequently to the diagnosis of brain tumors, inconsistent or conflicting molecular information will create diagnostic challenges. Here we present 6 cases of diffuse glioma that presented a diagnostic challenge due to conflicting molecular testing results. These cases exemplify some of the potential complications that arise when introducing the new 2016 central nervous system WHO classification system diagnostic criteria into routine clinical practice. We aim to alert the general practice pathology community to these potential conflicts to help mitigate the risk of potential misdiagnosis.

Prognostic significance of morphotypes in canine lymphomas: A systematic review of literature.

Correlation between morphotypes and prognosis of canine lymphomas presented discordant results in literature, leading to some dilemma for application in clinical practice. The aim of this study was to present a systematic review of literature on the prognostic significance of morphotypes in canine lymphomas. Standardized Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria were applied. Retrospective and prospective studies were included. Level of evidence was determined for each study. Some acceptable evidence suggested a significant prognostic impact of morphotypes in canine lymphomas. However, the evidence is not sufficiently robust to determine with precision the most appropriate classification scheme. Updated Kiel and World Health Organization (WHO) classifications seem to remain the most appropriate classification systems with regards to the number of available studies and their levels of evidence. Limitations included lack of randomized control trial, and relative lack of prospective studies available. Current recommended classification of canine lymphoma is the systematic determination of morphotype in each new case. The Updated Kiel and the WHO classifications adapted to dog both remain the schemes with the most valuable interest. Prospective studies in larger population, and international consensus to define precisely each morphotype, are warranted, with application of standardized staging method and treatment.

Exploration of Involved Key Genes and Signaling Diversity in Brain Tumors.

Brain tumors are becoming a major cause of death. The classification of brain tumors has gone through restructuring with regard to some criteria such as the presence or absence of a specific genetic alteration in the 2016 central nervous system World Health Organization update. Two categories of genes with a leading role in tumorigenesis and cancer induction include tumor suppressor genes and oncogenes; tumor suppressor genes are inactivated through a variety of mechanisms that result in their loss of function. As for the oncogenes, overexpression and amplification are the most common mechanisms of alteration. Important cell cycle genes such as p53, ATM, cyclin D2, and Rb have shown altered expression patterns in different brain tumors such as meningioma and astrocytoma. Some genes in signaling pathways have a role in brain tumorigenesis. These pathways include hedgehog, EGFR, Notch, hippo, MAPK, PI3K/Akt, and WNT signaling. It has been shown that telomere length in some brain tumor samples is shortened compared to that in normal cells. As the shortening of telomere length triggers chromosome instability early in brain tumors, it could lead to initiation of cancer. On the other hand, telomerase activity was positive in some brain tumors. It is suggestive that telomere length and telomerase activity are important diagnostic markers in brain tumors. This review focuses on brain tumors with regard to the status of oncogenes, tumor suppressors, cell cycle genes, and genes in signaling pathways as well as the role of telomere length and telomerase in brain tumors.

Rapid progression to glioblastoma in a subset of IDH-mutated astrocytomas: a genome-wide analysis.

According to the recently updated World Health Organization (WHO) classification (2016), grade II-III astrocytomas are divided into IDH-wildtype and IDH-mutant groups, the latter being significantly less aggressive in terms of both progression-free and total survival. We identified a small cohort of WHO grade II-III astrocytomas that harbored the IDH1 R132H mutation, as confirmed by both immunohistochemistry and molecular sequence analysis, which nonetheless had unexpectedly rapid recurrence and subsequent progression to glioblastoma. Among these four cases, the mean time to recurrence as glioblastoma was only 16months and the mean total survival among the three patients who have died during the follow-up was only 31months. We hypothesized that these tumors had other, unfavorable genetic or epigenetic alterations that negated the favorable effect of the IDH mutation. We applied genome-wide profiling with a methylation array (Illumina Infinium Human Methylation 450k) to screen for genetic and epigenetic alterations in these tumors. As expected, the methylation profiles of all four tumors were found to match most closely with IDH-mutant astrocytomas. Compared with a control group of four indolent, age-similar WHO grade II-III astrocytomas, the tumors showed markedly increased levels of overall copy number changes, but no consistent specific genetic alterations were seen across all of the tumors. While most IDH-mutant WHO grade II-III astrocytomas are relatively indolent, a subset may rapidly recur and progress to glioblastoma. The precise underlying cause of the increased aggressiveness in these gliomas remains unknown, although it may be associated with increased genomic instability.

Klasyfikacja WHO 2016 chłoniaków z komórek B — ważne zmiany

W zaktualizowanej klasyfikacji Światowej Organizacji Zdrowia (WHO) 2016 chłoniaków z ko­mórek B uwzględniono najnowsze dane dotyczące objawów klinicznych, biologii, patomorfologii, kryteriów diagnostycznych i bardzo intensywnie rozwijających się badań genetycznych, głównie w zakresie już istniejących jednostek histoklinicznych. Zwrócono szczególną uwagę na wczesne sta­dia limfoidalnej neoplazji, grupę wysoce agresywnych chłoniaków z komórek B oraz na znaczenie nowych badań genetycznych/molekularnych, szczególnie w kontekście potencjalnego zastosowania w terapiach celowanych. Pojawiło się kilka nowych jednostek „tymczasowych”. Podobnie jak w poprzednich wydaniach zaktualizowana klasyfikacja WHO 2016 chłoniaków z komórek B jest platformą do kodyfikacji zmieniających się danych, stanowiąc wyraz porozumienia między hema­topatologami, genetykami i klinicystami w zakresie potencjalnie kontrowersyjnych zagadnień. Jest również podstawą do wytycznych praktycznego postępowania klinicznego.

Pure erythroid leukemia.

The category of acute erythroid leukemia was significantly revised in the recently published 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms. In the previous 2008 WHO classification, acute erythroid leukemia was categorized into two subtypes: erythroleukemia and pure erythroid leukemia (PEL), whereas in the 2016 WHO update, erythroleukemia was merged into myelodysplastic syndrome, and PEL becomes the only type of acute erythroid leukemia. PEL is a rare and aggressive form of acute leukemia whose biology remains poorly characterized. In this review, we discuss the clinicopathologic features, diagnosis, putative pathogenesis, and molecular biology of PEL, with an overview of novel concepts and future directions in this area.