Current World Health Organization Criteria Research Articles

Frequent nuclear β-catenin expression in pulmonary enteric-type adenocarcinoma according to the current World Health Organization criteria.

Based on the current World Health Organization classification criteria, five of 3895 consecutive cases of surgically resected primary lung carcinomas (0.13%) categorized as enteric-type were analyzed. Three cases completely comprised tumor cells that resemble colorectal adenocarcinoma, while the other two cases exhibited features of conventional adenocarcinomas admixed with enteric components. Immunohistochemically, all patients expressed at least three of the five intestinal markers: CDX2, CK20, HNF4α, MUC2, and SATB2. None of the patients expressed TTF-1 and NKX3.1. Three cases showed nuclear accumulation of β-catenin, indicating activation of the Wnt/β-catenin signaling pathway; APC mutations were detected in one of these cases. TP53 mutations were detected in three cases. Mutated EGFR or ALK fusions were not detected. Our study demonstrates that pulmonary enteric-type adenocarcinomas share immunohistochemical features and genetic alterations with colorectal adenocarcinomas, which are characterized by frequent activation of the Wnt/β-catenin signaling pathway and a lack of actionable mutations.

Proposal for a Novel Histological Scoring System as a Potential Grading Approach for Muscle-invasive Urothelial Bladder Cancer Correlating with Disease Aggressiveness and Patient Outcomes

BackgroundGrading of muscle-invasive bladder cancer (MIBC) according to the current World Health Organization (WHO) criteria is controversial due to its limited prognostic value. All MIBC cases except a tiny minority are of high grade. ObjectiveTo develop a prognostic histological scoring system for MIBC integrating histomorphological phenotype, stromal tumor-infiltrating lymphocytes (sTILs), tumor budding, and growth and spreading patterns. Design, setting, and participantsTissue specimens and clinical data of 484 patients receiving cystectomy and lymphadenectomy with curative intent with or without adjuvant chemotherapy. Histomorphological phenotypes, sTILs, tumor budding, and growth and spreading patterns were evaluated and categorized into four grade groups (GGs). GGs were correlated with molecular subtypes, immune infiltration, immune checkpoint expression, extracellular matrix (ECM) remodeling, and epithelial-mesenchymal transition (EMT) activity. Outcome measurements and statistical analysisGGs were associated with overall (OS), disease-specific (DSS), and progression-free (PFS) survival in univariable and multivariable analyses. Association with biological features was analyzed with descriptive statistics. Results and limitationsIntegration of two histomorphological tumor groups, three sTILs groups, three tumor budding groups, and four growth/spread patterns yielded four novel GGs that had high significance in the univariable survival analysis (OS, DSS, and PFS). GGs were confirmed as independent prognostic predictors with the greatest effect in the multivariable Cox regression analysis. Correlation with molecular data showed a gradual transition from basal to luminal subtypes from GG1 to GG4; a gradual decrease in survival, immune infiltration, and immune checkpoint activity; and a gradual increase in ECM remodeling and EMT activity. ConclusionsWe propose a novel, prognostically relevant, and biologically based scoring system for MIBC in cystectomies applicable to routine pathological sections. Patient summaryWe developed a novel approach to assess the aggressiveness of advanced bladder cancer, which allows improved risk stratification compared with the method currently proposed by the World Health Organization.

Neutrophil-to-Lymphocyte Ratio Is More Accurate Than Erythropoietin Level for the Polycythemia Vera Diagnosis

Background Polycythemia vera (PV) is a myeloproliferative neoplasm (MPN). The MPNs are cancers in which the malignant clone triggers inflammatory cytokines, which sustain the inflammatory drive in a self-perpetuating vicious cycle. The current World Health Organization (WHO) criteria for PV diagnosis are gender-specific elevated hemoglobin or hematocrit levels, tri-lineage bone marrow hypercellularity, the presence of JAK2 V617F or JAK2 exon 12 mutation, and low serum erythropoietin (EPO) concentration. Below normal EPO continues to remain the only minor criterion for the PV diagnosis, although controversy exists regarding its predictive validity. The neutrophil-to-lymphocyte ratio (NLR) is a fast and simple method for assessing inflammatory status. While it is being studied as a useful predictive marker in many disease categories, not much research has been done on NLR in MPNs. In a previous study, we confirmed that the NLR was higher in MPN patients than in the normal population. Herein, we analyzed NLR in patients with PV and secondary polycythemia and studied whether it can be a marker to help diagnose PV. Furthermore, we compared the diagnostic capacity of NLR with that of the erythropoietin level. Methods This retrospective case-control study included patients with erythrocytosis who have been tested for JAK2 between June 2007 and April 2022 at Soonchunhyang University Seoul and Bucheon hospitals. Diagnosis of PV was definitively ascertained by 2016 WHO criteria. NLR and EPO levels in patients with PV were compared to those in patients with secondary polycythemia at the time of diagnosis. The discriminatory power was calculated by area under the receiver operating characteristic curve analysis Results Of 240 patients, 70 patients had a diagnosis of PV and 170 patients had a diagnosis of secondary polycythemia. The median NLR was significantly higher in PV group than in secondary polycythemia group (6.04 vs 1.77, p < 0.001). For diagnosing PV, the AUC value of NLR was better than that of EPO (0.921 vs 0.827, respectively). The model approximated by NLR with EPO had an AUC of 0.962 (95% CI, 0.936-0.988) for differentiating PV from secondary polycythemia, which was higher than individual components of the model used alone. Conclusions We found that NLR is more accurate than EPO level for the PV diagnosis. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The association between elevated body mass index and wide blood chemistry panel results in apparently healthy individuals

BackgroundBlood chemistry panel and body mass index (BMI) are common ways to evaluate individual health. The study aimed to compare a wide range of blood chemistry tests between obese, overweight, and normal weight populations that are otherwise apparently healthy. MethodsWe conducted a cross-sectional study of all adults (20-65 years) with BMI ≥18.5 kg/m2 who underwent routine annual health check-ups. Participants who had any known morbidity or taking medication were excluded. BMI was categorized using the current World Health Organization criteria. After fasting, glucose, renal and liver functions, albumin and total protein levels, lipid profile, electrolytes levels and inflammatory marker were observed and compared between BMI categories. ResultsThe study included 10,211 adults (median BMI 25.1 kg/m2, 48.8% normal weight, 39.7% overweight, 11.5% obese). The mean age was 40.78 years (SD 9.69) and 35.4% were female. Triglyceride level was 23.5% in overweight and 50.6% higher in obese participants (p < 0.001). Liver enzymes were higher in overweight (5.6-18.7%, p < 0.001) and obese participants (13.4-48.3%, p < 0.001). C-reactive protein level was 134% higher in overweight and 430% higher in obese participants (p < 0.001). Differences were also documented in other blood tests. ConclusionsOverweight and obesity were found to be associated with significant abnormalities in blood tests. A periodic wide panel of blood tests, especially for overweight and obese populations, is essential to identify and intervene as secondary prevention before the onset of symptoms.

Validation of the Who-Defined 20% Circulating Blasts Threshold for Diagnosis of Acute Leukemia in Myelofibrosis: A Single Center Study of 144 Patients with Blast or Chronic Phase Disease with Excess Blasts

Background:The World Health Organization (WHO)-defined criteria for acute myeloid leukemia (AML), including blast phase myeloproliferative neoplasms (MPN-BP), includes the presence of ≥20% blasts in the peripheral blood (PB), regardless of blast content in the bone marrow (BM) (Blood 2016;127:2391) . It is currently unclear if this 20% threshold is valid for primary myelofibrosis (PMF), in terms of distinguishing PB-defined MPN-BP from either chronic phase disease with excess blasts (PMF-EB; defined by the presence of 5-19% circulating blasts) or BM-defined MPN-BP.Methods:Diagnoses of MPN, including PMF and MPN-BP, were according to WHO criteria (Blood 2016;127:2391). The study population included chronic phase PMF patients with 5-19% circulating blasts (PMF-EB) and MPN patients with blast phase disease (MPN-BP), defined by the presence of ≥20% blasts in PB only (PB-defined MPN-BP) or BM (BM-defined MPN-BP). Statistical analyses for PMF-EB considered clinical and laboratory data collected at the time of documented PB blast count of ≥5% and for MPN-BP, date of leukemic transformation. Phenotypic and prognostic comparisons considered four distinct categories: i) chronic phase disease with 5-9% circulating blasts (PMF-EB-1), ii) chronic phase disease with 10-19% circulating blasts (PMF-EB-2), iii) MPN-BP defined by ≥20% BM blasts (BM-defined) and iv) MPN-BP defined by ≥20% blasts in PB only (PB-defined).Results:The total number of study patients was144 and included 41 patients with PMF-EB and 103 with MPN-BP; the 41 patients with PMF-EB included 28 with PMF-EB-1 (median age 69 years; 61% males) and 13 with PMF-EB-2 (median age 64 years; 54% males); the 103 patients with MPN-BP included 71 BM-defined (median age 68 years; 69% males) and 32 PB-defined (median age 66 years; 72% males) MPN-BP (p=0.6 for age and 0.6 for gender distribution). The four operational groups were also similar in their need for red cell transfusions (p=0.4), hemoglobin level (p=0.9), leukocyte count (p=0.9) and driver mutational status (p=0.3), including incidence of type 1/like CALR mutations (11% for PMF-EB-1 vs 15% for PMF-EB-2 vs 17% for PB-defined MPN-BP vs 19% for BM-defined MPN-BP). Significant differences were noted for platelet count (lower for both PB and BM defined MPN-BP; p=0.004) and incidence of abnormal karyotype (p=0.02) and unfavorable karyotype (22% for PMF-EB-1, 62% PMF-EB-2, 61% PB-defined MPN-BP and 49% BM-defined MPN-BP; p=0.03). Survival data showed significant difference in favor of PMF-EB, compared to both BM- and PB-defined MPN-BP, while they were similar for PMF-EB-1 vs PMF-EB-2 and for PB- vs BM-defined MPN-BP (Figure 1).Conclusions:The observations from the current study support the prognostic validity of current WHO criteria in distinguishing chronic phase PMF with excess blasts (PMF-EB) from PB-defined MPN-BP. The current study also confirms the validity of using circulating blast percentage to define MPN-BP, regardless of BM blast percentage. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Isolated Myeloperoxidase Expression in Pediatric B/Myeloid Mixed Phenotype Acute Leukemia Is Associated with Improved Survival Using ALL-Only Regimens

Background: Mixed phenotype acute leukemia (MPAL) represents a heterogeneous group of leukemias accounting for 2-5% of all newly diagnosed acute leukemias. Diagnostic criteria for mixed phenotype MPAL have evolved over time, with the World Health Organization (WHO) 2016 criteria now being recognized as the more definitive standard. According to WHO classification, isolated expression of myeloperoxidase (MPO) allows for myeloid lineage assignment in patients with an otherwise typical B-acute lymphoblastic leukemia (B-ALL) phenotype, thus meeting criteria for MPAL B/myeloid. Our goal was to determine if there were differences in treatment and survival between this group of patients, classified as MPAL B/myeloid isoMPO, and other MPAL patients.Methods: Data was obtained through a retrospective chart review of pediatric MPAL patients treated between 2001 and 2016 at Children's Healthcare of Atlanta. Cases were identified through our institutional tumor registry and pathology department flow cytometry database. Cases were eligible if the patients were between ages of 1 and 21 years at diagnosis and the leukemia met the WHO 2016 MPAL criteria. We excluded therapy related cases, non-myeloid cases (rare B/T subtype), and cases with a t(9;22) translocation. Data were extracted from clinical records for patient, disease and treatment related variables. All flow cytometry reports were reviewed by study hematopathologists. Cases were divided into two groups - MPAL B/Myeloid isoMPO and other MPAL cases. MPAL B/myeloid cases were classified as MPAL B/Myeloid isoMPO if there was a single B-lineage blast population expressing MPO as the only WHO MPAL myeloid marker. An event was defined as treatment failure requiring therapy change prior to end of induction (EOI), induction failure, induction death, remission death, or relapse. Event-free survival (EFS) and overall survival (OS) were calculated using Kaplan-Meier survival curves. Groups were compared using the log rank test. Chi-squared test was used for sampling distribution analyses.Results: Of the 35 MPAL cases included in our study, 21 (60%) met criteria for MPAL B/myeloid isoMPO. 20 of these patients were treated with ALL chemotherapy alone. One patient underwent bone marrow transplantation (BMT) due to a low DNA index. None of these patients were switched to myeloid therapy during their treatment course. The other 14 MPAL cases consisted of 5 MPAL B/myeloid (non-isolated MPO), 7 MPAL T/myeloid and 2 MPAL patients with t(v;11q23); MLL rearranged. Of these 14 cases, 10 were treated at least in part with myeloid chemotherapy and 7 proceeded to BMT. 6 of 10 patients in this group who started with ALL induction were switched over to AML therapy, with 3 being changed prior to EOI due to treatment failure. Despite these treatment differences, those with MPAL B/myeloid isoMPO had better outcomes. 3-year EFS was significantly higher at 84% for the MPAL B/myeloid isoMPO group compared to 57% in the other MPAL group (p=0.027 log rank test, Fig 1A). 3-year overall survival was 100% and 68%, respectively (p=0.083 log rank test, Fig 1B).Conclusion: There continues to be no consensus as to how to treat MPAL and the changing definition of MPAL has contributed to the difficulty in treating this rare and heterogeneous disease. While the WHO 2016 criteria have simplified the definition of MPAL, it has created a group of patients as shown here, that may be falsely categorized as MPAL. Our results suggest that MPAL B/myeloid isoMPO patients behave clinically like typical B-ALL patients, and should be treated as such. Consideration should be given to redefining the current MPAL WHO criteria to explicitly exclude these cases. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Clinicopathological characteristics of Epstein-Barr virus and microsatellite instability subtypes of early gastric neoplasms classified by the Japanese and the World Health Organization criteria.

Gastric cancer is a heterogenous disease with different phenotypes, genotypes, and clinical outcomes, including sensitivity to treatments and prognoses. Recent medical advances have enabled the classification of this heterogenous disease into several groups and the consequent analysis of their clinicopathological characteristics. Gastric cancer associated with Epstein–Barr virus (EBV) and microsatellite‐unstable tumors are considered to be the two major subtypes as they are clearly defined by well‐established methodologies, such as in situ hybridization and polymerase chain reaction‐based analyses, respectively. However, discrepancies in the histological diagnosis of gastric neoplasms remain problematic, and international harmonization should be performed to improve our understanding of gastric carcinogenesis. We re‐evaluated Japanese cases of early gastric cancer according to the current World Health Organization (WHO) criteria and classified them into genomic subtypes based on microsatellite instability (MSI) and EBV positivity to determine the initial genetic events in gastric carcinogenesis. A total of 113 Japanese early gastric cancers (including low‐ and high‐grade dysplasias) treated with endoscopic resection over 5 years were archived in our hospital. A histological re‐evaluation according to the WHO criteria revealed 54 adenocarcinomas, which were divided into 6 EBV‐positive (11.1%), 7 MSI‐high (MSI‐H, 13.0%), and 41 microsatellite stable cases (75.9%). MSI‐H adenocarcinoma was confirmed by an immunohistochemistry assay of mismatch repair proteins. Programmed death‐ligand 1 immunostaining with two antibodies (E1L3N and SP263) was positive in tumor cells of one MSI‐H adenocarcinoma case (1/7, 14.3%). The proportion of stained cells was higher with clone SP263 than with E1L3N. Histologically, EBV‐positive carcinomas were poorly differentiated (83.8%), and MSI‐H cancers were frequent in well to moderately differentiated adenocarcinoma (85.7%), indicating that the EBV‐positive subtype presented with high‐grade morphology even when an early lesion. Our study indicates that the WHO criteria are useful for subdividing Japanese early gastric cancers, and this subdivision may be useful for comparative analysis of precursor lesions and early carcinoma.

Primary Mediastinal (Thymic) Large B-Cell Lymphoma: Fidelity of Diagnosis Using WHO Criteria

PurposeDiagnosing primary mediastinal (thymic) large B-cell lymphoma (PMBCL) is challenging because it is a clinicopathologic entity that shares characteristics with other lymphomas and lacks pathognomonic features. We sought to investigate the fidelity between a working diagnosis of PMBCL at our institution and the clinicopathologic criteria established within the 2017 World Health Organization (WHO) classification. Patients and MethodsMedical records and archived tissue of patients treated for stage I-II PMBCL from 1998 to 2018 were retrospectively reviewed for clinical and pathologic conformity with current WHO criteria. Disease was characterized as definitely PMBCL if all of the following were present: anterior mediastinal mass with or without lymph node involvement, no extranodal disease, B-cell antigen expression, Epstein-Barr virus negativity, and at least one supportive feature: female gender under age 40, bulky primary tumor, CD30 weakly positive, compartmentalizing alveolar fibrosis, lack of surface immunoglobulin expression, and MUM1 or CD23 positivity. Disease without supportive features or other pathologic findings more suggestive of other entities was characterized as equivocal for PMBCL. Lack of an anterior mediastinal mass, presence of distant lymph node involvement or extranodal disease, lack of B-cell antigen expression, or Epstein-Barr virus positivity were characterized as definitely not PMBCL. Clinical management and outcomes were also assessed. ResultsOf 63 patients treated for presumed stage I-II PMBCL, 58 (92%) met the criteria for PMBCL. The most common reason for a discordant diagnosis was lack of an anterior mediastinal mass (n = 3). Two additional patients were characterized as having disease equivocal for PMBCL. In retrospect, one patient most likely had a mediastinal gray zone lymphoma due to CD15 positivity and another diffuse large B cell, not otherwise specified, at pathologic review. Five-year progression-free and overall survival were 67% (95% confidence interval, 54-77) and 81% (95% confidence interval, 68-89), respectively, for all patients. ConclusionDespite the complexity of the clinicopathologic criteria of PMBCL, most patients (92%) who were treated for stage I-II PMBCL at our institution appear to have been accurately diagnosed.

From Mixed Hyperplastic/Adenomatous Polyp to Sessile Serrated Lesion: A Long and Winding Road for Long and Winding Crypts.

During the past 3 decades, numerous articles in the literature have offered terminology, diagnostic criteria, and consensus recommendations regarding the entity currently referred to by the World Health Organization as sessile serrated lesion. Given the many names and various, variably reproducible diagnostic criteria ascribed to sessile serrated lesion, confusion persists for many pathologists and gastroenterologists regarding the diagnosis. This distinction is important, as sessile serrated lesion can progress to malignancy, unlike its main differential diagnosis, hyperplastic polyp. Research studies have shed light on the characteristic architecture and morphology, immunohistochemical patterns, and molecular alterations of sessile serrated lesion, and multiple consensus meetings around the globe have developed their criteria and nomenclature, often clashing or mixing terms. To provide a narrative review from the entity's early description to our current understanding. The existing scientific and clinical literature, published texts, medical society recommendations, and specialty consensus guidelines. The current World Health Organization criteria are a distillation of this scientific process, but terminology is still a point of contention worldwide.

Hyperplastic polyp or sessile serrated lesion? The contribution of serial sections to reclassification

BackgroundThe histological discrimination of hyperplastic polyps from sessile serrated lesions can be difficult. Sessile serrated lesions and hyperplastic polyps are types of serrated polyps which confer different malignancy risks, and surveillance intervals, and are sometimes difficult to discriminate. Our aim was to reclassify previously diagnosed hyperplastic polyps as sessile serrated lesions or confirmed hyperplastic polyps, using additional serial sections.MethodsClinicopathological data for all colorectal hyperplastic polyps diagnosed in 2016 and 2017 was collected. The slides were reviewed and classified as hyperplastic polyps, sessile serrated lesion, or other, using current World Health Organization criteria. Eight additional serial sections were performed for the confirmed hyperplastic polyp group and reviewed.ResultsOf an initial 147 hyperplastic polyps from 93 patients, 9 (6.1%) were classified as sessile serrated lesions, 103 as hyperplastic polyps, and 35 as other. Of the 103 confirmed hyperplastic polyps, 7 (6.8%) were proximal, and 8 (7.8%) had a largest fragment size of ≥5 mm and < 10 mm. After 8 additional serial sections, 11 (10.7%) were reclassified as sessile serrated lesions. They were all less than 5 mm and represented 14.3% of proximal polyps and 10.4% of distal polyps. An average of 3.6 serial sections were required for a change in diagnosis.ConclusionHistopathological distinction between hyperplastic polyps and sessile serrated lesions remains a challenge. This study has uncovered a potential role for the use of additional serial sections in the morphological reappraisal of small hyperplastic polyps, especially when proximally located.

GLANDULAR ODONTOGENIC CYST: A SERIES OF 17 NEW CASES

Objective Our aim is to report a series of 17 new cases of glandular odontogenic cyst (GOC) diagnosed in a Brazilian laboratory of oral pathology in the last 7 years. Study Design All clinical and radiographic features were retrieved from patients’ charts and the diagnosis of GOC was confirmed after microscopic evaluation following the current World Health Organization (WHO) criteria. Results There were 13 women and 4 men, with a mean age of 46 years. Eleven cases involved the mandible and 6 cases involved the maxilla, particularly the anterior region (10 cases), as extensive well-defined unilocular radiolucencies with limited expansion of bone cortices. The most common histologic criteria observed were eosinophilic cuboidal cells, epithelial detachment, variable thickness, and mucous cells. Most cases were treated by surgical enucleation, with 1 case showing recurrence. Conclusions GOC is an uncommon developmental cyst with features resembling glandular differentiation that may show large size with limited bone expansion.

MON-628 Noninvasive Encapsulated Papillary RAS-Like Thyroid Tumor (NEPRAS) as a Possible Novel Subtype of Borderline Tumor

Background: A subset of thyroid tumors was classified into borderline/precursor tumors in the latest World Health Organization (WHO) classification. However, these tumors were defined only in terms of follicular structure, including hyalinizing trabecular tumor (HTT), noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), and uncertain malignant potential (UMP). As papillary microcarcinoma was proposed to be renamed to papillary microtumor (PMiT), there would be no reasons for restricting borderline/precursor tumors to the follicular growth pattern. Clinical Case: A 26-year-old man was incidentally found to have a 23 mm nodule in his thyroid. After undergoing left lobectomy, histological findings revealed extremely delicate nuclear changes in a noninvasive encapsulated papillary growth-patterned tumor. Tumor cells showed nuclear enlargement, irregularity, elongation, and overlapping as well as a few nuclear grooves. Nuclear pseudoinclusions were absent and chromatin characteristics were insufficient (nuclear score 2 according to Nikiforov et al. (1)). The patient was diagnosed with an encapsulated conventional papillary thyroid carcinoma by a local pathologist; however, a second-opinion consultation endorsed a follicular adenoma with papillary hyperplasia. In a third-opinion consultation, immunohistochemical analyses revealed a low MIB-1 labeling index and negative staining for cytokeratin 19 and BRAFV600E, which supported the expected indolent clinical behavior. Remarkably, mutational analysis identified a heterozygous point mutation of the KRAS gene but not the BRAF genes. Eventually, we speculated that this tumor could be a possible example of a novel borderline tumor with a papillary architecture, which does not qualify as NIFTP or UMP under the current WHO criteria. The patient refused additional surgery (complete thyroidectomy), and developed no recurrence or distant metastasis for 24 months. Conclusion: We reported a significant observer variation in a noninvasive encapsulated papillary growth-patterned tumor with delicate nuclear changes and a KRAS mutation. We speculated that our case could be an example of a novel borderline tumor with a papillary structure. Further studies using a larger number of patients are needed to elucidate this disease entity, because the possible introduction of terminology such as “noninvasive encapsulated papillary RAS-like thyroid tumor (NEPRAS)” without the word “cancer” could relieve psychological burdens of the patients similar to NIFTP. Reference: (1) Nikiforov YE, et al. Nomenclature Revision for Encapsulated Follicular Variant of Papillary Thyroid Carcinoma: A Paradigm Shift to Reduce Overtreatment of Indolent Tumors. JAMA Oncol. 2016;2:1023-9.

A community-level investigation following a yellow fever virus outbreak in South Omo Zone, South-West Ethiopia.

BackgroundDespite the availability of a highly effective vaccine, yellow fever virus (YFV) remains an important public health problem across Africa and South America due to its high case-fatality rate. This study investigated the historical epidemiology and contemporary entomological and social determinants of a YFV outbreak in South Omo Zone (SOZ), Ethiopia.MethodsA YFV outbreak occurred in SOZ, Ethiopia in 2012–2014. Historical epidemiological data were retrieved from the SOZ Health Department and analyzed. Entomological sampling was undertaken in 2017, including mosquito species identification and molecular screening for arboviruses to understand mosquito habitat distribution, and finally current knowledge, attitudes and preventative practices within the affected communities were assessed.ResultsFrom October 2012 to March 2014, 165 suspected cases and 62 deaths were reported, principally in rural areas of South Ari region (83.6%). The majority of patients were 15–44 years old (75.8%) and most case deaths were males (76%). Between June and August 2017, 688 containers were sampled across 180 households to identify key breeding sites for Aedes mosquitoes. Ensete ventricosum (“false banana”) and clay pots outside the home were the most productive natural and artificial breeding sites, respectively. Entomological risk indices classified most sites as “high risk” for future outbreaks under current World Health Organization criteria. Adult mosquitoes in houses were identified as members of the Aedes simpsoni complex but no YFV or other arboviruses were detected by PCR. The majority of community members had heard of YFV, however few activities were undertaken to actively reduce mosquito breeding sites.DiscussionStudy results highlight the potential role vector control could play in mitigating local disease transmission and emphasize the urgent need to strengthen disease surveillance systems and in-country laboratory capacity to facilitate more rapid responses to future YFV outbreaks.

Effect of varicocele repair on sperm DNA fragmentation: a review.

Varicocele, the leading cause of male infertility, can impair sperm quality and fertility via various oxidative stress mechanisms. An imbalance between excessive reactive oxygen species production and antioxidant protection causes alterations in nuclear and mitochondrial sperm DNA, thus rendering a subset of varicocele men less fertile. In particular, sperm DNA fragmentation is usually elevated in men with clinical varicocele in both abnormal and normal semen parameters by the current World Health Organization criteria. In this review, we discuss the evidence concerning the association between varicocele, oxidative stress, and SDF, and the possible mechanisms involved in infertility. Furthermore, we summarize the role of varicocele repair as a means of alleviating SDF and improving fertility. Lastly, we critically appraise the evidence-based algorithm recently issued by the Society for Translational Medicine aimed at guiding urologists on the use of SDF testing in men with varicocele seeking fertility. Current evidence based on careful review of published studies confirms the effectiveness of varicocelectomy as a means of both reducing oxidatively induced sperm DNA damage and potentially improving fertility. Varicocele repair should be offered as part of treatment option for male partners of infertile couples presenting with palpable varicoceles.

Myeloid neoplasms with features intermediate between primary myelofibrosis and chronic myelomonocytic leukemia

Monocytosis can develop during disease course in primary myelofibrosis simulating that seen in chronic myelomonocytic leukemia, and should not lead to disease reclassification. In contrast, at presentation, rare cases have clinical, morphologic, and molecular genetic features truly intermediate between primary myelofibrosis and chronic myelomonocytic leukemia. The taxonomy and natural history of these diseases are unclear. We identified cases which either: (1) fulfilled the 2008 World Health Organization criteria for primary myelofibrosis but had absolute monocytosis and, when available, chronic myelomonocytic leukemia-related mutations (ASXL1, SRSF2, TET2) or (2) fulfilled criteria of chronic myelomonocytic leukemia but had megakaryocytic proliferation and atypia, marrow fibrosis, and myeloproliferative-type driver mutations (JAK2, MPL, CALR). Patients with established primary myelofibrosis who developed monocytosis and those with chronic myelomonocytic leukemia with marrow fibrosis were excluded. By combining the pathology databases of two large institutions, six eligible cases were identified. Patients were predominantly male and elderly with monocytosis at diagnosis (average 17.5%/2.3 × 103/μl), organomegaly, primary myelofibrosis-like atypical megakaryocytes admixed with a variable number of chronic myelomonocytic leukemia-like hypolobated forms, variable myelodysplasia, marrow fibrosis and osteosclerosis. All had a normal karyotype and no myelodysplasia-associated cytogenetic abnormalities. Five of the patients in whom a more extensive molecular characterization was performed showed co-mutations involving JAK2 or MPL and ASXL1, SRSF2, TET2, NRAS, and/or KRAS. Disease progression has occurred in all and two have died. Rare patients present with features that overlap between primary myelofibrosis and chronic myelomonocytic leukemia and are thus difficult to classify based on current World Health Organization criteria. Biologically, these cases likely represent primary myelofibrosis with monocytosis, dysplasia, and secondary (non-driver) mutations at presentation. Alternatively, they may represent a true gray zone of neoplasms. Their clinical behavior appears aggressive and innovative therapeutic approaches may be beneficial in this particular subset.

Clinicopathological analysis of Large Cell Lung Carcinomas definitely diagnosed according to the New World Health Organization Criteria

ObjectiveThe definition of large cell lung carcinoma (LCC) has undergone an extensive modification in the World Health Organization (WHO) Classification (2015). Present study aimed to investigate the clinicopathological characteristics of patients diagnosed as LCC according to current WHO criteria. MethodsLCCs diagnosed based on the previous WHO classification were reevaluated, and 17 cases of LCC were finally identified at Peking Union Medical College Hospital and Beijing Chest Hospital between 2009 and 2015. The clinicopathologic features were examined and EGFR and KRAS mutations were tested. Survival of the patients was analyzed by Kaplan-Meier method. ResultsThe median age of the patients was 64 years (range: 40–78). Most patients were male (64.7%) and about half of the patients were at TNM stage III (47.1%). Morphologically, most cases (70.6%) were classic LCC. All patients were treated by lobectomy plus lymph node dissection, 2 with bi-lobectomy and 1 with complex lobectomy, and the other 2 patients were further treated by partial pericardiotomy. Ten patients received postoperative chemotherapy, while only 3 patients were treated with radiotherapy after surgery. Molecular analysis showed two cases of EGFR mutation (L858R) but without non-overlapping KRAS mutation. The 3-year overall survival rate was 48.4 ± 15.1%. Chemotherapy was the only predictive factor that is associated with the prognosis of the patients (P = 0.003). ConclusionThe clinicopathological characteristics of 17 cases of stringently diagnosed LCC were retrospectively analyzed. LCC in our study showed aggressive behavior with high recurrence and metastasis and poor prognosis. Chemotherapy was only predictive factor that is significantly associated with the prognosis of the patients. Future studies based on a larger series and long term follow-up are still needed to characterize it further.

Editor's Choice- Diagnosis of type 2 diabetes and prediabetes among patients with acute coronary syndromes.

Previously undetected dysglycaemia is common among patients with acute coronary syndromes (ACSs). The aim of this study was to identify the most reliable method of diagnosing type 2 diabetes mellitus (T2DM) and prediabetes in ACS patients. Patients admitted to the coronary care unit with ACSs and no previous history of T2DM were consecutively included in the study. Glucose metabolism was measured by glycated haemoglobin (HbA1c), fasting plasma glucose (FPG) and 2-hour plasma glucose (2hPG) with a standard oral glucose tolerance test during hospital admission, and this process was repeated 3 months later. In this study, the diagnosis of T2DM required at least two measurements above the diabetes cut-off point according to current American Diabetes Association and World Health Organization criteria. A total of 250 patients were included in the study. T2DM was diagnosed in 7.2%. The sensitivities for detecting T2DM were 33.3%, 61.1% and 77.8% during admission and 27.8%, 61.1% and 72.2% at follow-up for HbA1c, FPG and 2hPG, respectively. The positive predictive values (PPVs) for diagnosing T2DM were 100%, 91.7% and 51.9% during admission and 71.4%, 91.7% and 65.0% at follow-up for HbA1c, FPG and 2hPG, respectively. The specificities and negative predictive values were high for all methods. By combining all measurements, the sensitivity was 100% and the PPV was 44.2%, while the combination of all HbA1c and FPG measurements provided 88.9% sensitivity and 80.0% PPV. Diagnosis of T2DM can be reliably carried out by repeated measurements of FPG and HbA1c in ACS patients, with limited added value of an oral glucose tolerance test.

Optimal therapy for polycythemia vera and essential thrombocythemia: Preferred use of interferon therapy based on phase 2 trials

Objectives: To determine the value of recombinant interferon-alfa (rIFNα) in the treatment of polycythemia vera (PV) and essential thrombocythemia (ET) based on its biological activities and phase 2 clinical studies, pending completion of phase 3 trials; to determine importance of the Internet in patient decision-making in treatment selection.Results: The value of rIFNα in PV and ET is based upon its biological effects on PV stem cells and megakaryocyte proliferation. Single-arm trials are useful for life-threatening diseases when there are relatively few patients to evaluate endpoints, such as rIFNα treatment of PV and ET. Proper diagnostic criteria are mandatory; for PV, the current World Health Organization criteria emphasizing increased hemoglobin values exclude approximately one-third of eligible patients.Importance of these data: Single-arm studies in diseases exemplified by rIFNα in PV require updated diagnostic criteria for research and for clinical practice. The influence of the Internet on patient decisions for treatment is noteworthy.Conclusion: The biologic basis for selecting therapy is exemplified by rIFNα in treating PV and ET. Current single-arm studies of rIFNα in PV and ET are relevant and acceptable. The importance of the Internet in patient decision-making is important.

Patterns and Significance of PIM Kinases in Urothelial Carcinoma.

The Provirus integrating site Moloney murine leukemia virus (Pim) family are proteins with serine/threonine kinase activity. Studies have demonstrated overexpression of Pims in cancer. To our knowledge, only a single study has examined Pim-1 in urothelial carcinoma. The aim of this investigation was to evaluate Pim-1, Pim-2, and Pim-3 in urothelial carcinoma and assess for expression that may contribute to disease progression and serve as a site for targeted therapy. This retrospective study included 137 cases taken from specimens from the University of Utah, Department of Pathology (2008 to 2011). Tissue was stained with antibodies against Pim-1, Pim-2, and Pim-3. Cases were classified into 3 groups, based upon current World Health Organization criteria (invasive high-grade urothelial carcinoma [IHG] [n=84], noninvasive high-grade urothelial carcinoma/carcinoma in situ [n=32], and noninvasive low-grade urothelial carcinoma [NILG] [n=21]). Cases were scored and recorded as positive or negative on the basis of the percentage of cells with cytoplasmic and/or nuclear staining. NILG showed higher expression of Pim-1 (relative expression rate [RER]=2.28; 95% confidence interval [CI], 0.183-0.764) and Pim-3 (RER=3.06; 95% CI, 0.423-0.816) compared with other lesions. IHG had lower expression of Pim-1 (RER=0.31; 95% CI, 0.401-0.844) and Pim-3 (RER=0.354; 95% CI, 0.322-0.816) and noninvasive high-grade urothelial carcinoma (NIHG) demonstrated increased expression of Pim-1 and (RER=2.09; 95% CI, 0.124-0.739) and Pim-2 (RER=1.70; 95% CI, 0.151-0.591). At least 1 Pim kinase protein was expressed at the following rates: 49% in IHG, 66% in NIHG, and 76% in NILG. A high percentage of urothelial carcinomas express Pim kinases. Pim expression differs in NILG, NIHG, and IHG lesions.

TMIC-13MUTANTIDH1/2SUPPRESSES LOCAL AND SYSTEMIC THROMBOSIS IN GLIOMA PATIENTS

Mutations in isocitrate dehydrogenase 1 and 2 (mutIDH1/2) are common in gliomas, resulting in enzymes that produce D-2-hydroxyglutarate (D-2-HG). The effects of mutIDH1/2 on the microenvironment, including thrombosis, are not known. In discovery and validation cohorts of World Health Organization (WHO) grade II-IV gliomas from two institutions (total N = 317), microthrombi were present in 85-90% of wild-type gliomas but in only 2-6% of mutant gliomas (P < 0.0001), and their absence was an independent predictor of mutIDH1/2. Systemic hypercoagulation occurred in 25-30% of patients with wild-type IDH1/2 gliomas, but in 0% of patients with mutIDH1/2 gliomas (P < 0.0001). The prognostic strength of microthrombi was comparable to necrosis and microvascular proliferation, the current WHO criteria for a diagnosis of glioblastoma. In silico analysis of 428 gliomas from The Cancer Genome Atlas (TCGA) revealed that, in the coagulome, the mRNA with the strongest inverse relationship to mutIDH1/2 was F3, encoding tissue factor procoagulant (P = 1.06E-52). MutIDH1/2 gliomas in the TCGA also had significantly elevated F3 promoter methylation (P < 0.0001). In a separate tissue microarray containing 95 gliomas, mutIDH1/2 tumors showed dramatically reduced tissue factor protein expression (P < 0.0001). Additionally, D-2-HG inhibited human platelet aggregation by blocking intracellular calcium accumulation. In human in vitro and mouse in vivo models, mutIDH1 and D-2-HG lowered free serum calcium by up to 40% and markedly impaired coagulation (P < 0.0001). In sum, mutIDH1/2 enzymes have potent antithrombotic activity within gliomas and systemically. These findings have profound implications for the pathologic evaluation of gliomas, the effect of altered isocitrate metabolism on tumor microenvironment and calcium homeostasis, and the pre-and postoperative management of these patients.