Application of a 5 Marker Panel to the Routine Diagnosis of Peripheral T-Cell Lymphoma With T-Follicular Helper Phenotype.

The 2017 World Health Organization update introduced a new category of nodal peripheral T-cell lymphoma with T-follicular helper phenotype (PTCL-TFH) defined by expression of at least 2 or 3 TFH markers. Our study assesses the utility of an immunohistochemical panel of 5 TFH markers (CD10, BCL6, PD-1, CXCL13, and ICOS) for identification of TFH phenotype in angioimmunoblastic T-cell lymphoma (AITL) and PTCL not otherwise specified (NOS). Immunohistochemical for the 5 markers was performed on 22 cases of AITL and 29 cases of PTCL-NOS. Cases were reviewed for morphologic features characteristic of AITL. All AITL cases showed expression of ≥2 TFH markers. This panel resulted in reclassification of 41% PTCL-NOS cases to PTCL-TFH. Positive percent agreement for the TFH phenotype is 97% for PD1, 94% for ICOS, 44% for CD10 and CXCL13, and 29% for BCL6. Negative percent agreement for TFH phenotype is 100% for CD10, BCL6, and CXCL13, 82% for ICOS and 71% for PD1. AITL cases were more likely than PTCL-TFH cases to contain expanded CD21-positive follicular dendritic cell meshworks, clear cell cytology and polymorphous inflammatory background; however, there was a significant (P<0.005) Kruskal-Wallis trend in all morphologic variables between the 3 groups suggesting a continuum from PTCL-NOS to PTCL-TFH to AITL. The median number of morphologic features of AITL also correlated significantly with number of TFH markers positive (Spearman coefficient ρ=0.759). In summary, the stain panel chosen will have an impact on cases classified as PTCL-TFH. This entity may exist along a spectrum between PTCL-NOS and AITL.

Immunohistochemical Analysis of Endothelial Cells in Vascular Transformation of Lymph Node Sinuses: Vascular or Lymphatic Differentiation?

INTRODUCTION: Vascular transformation of sinuses (VTS) is an uncommon and benign lesion, defined by conversion of lymph node sinuses into complex, anatomizing and endothelial-lined channels. Despite the name of VTS, which implies a change in differentiation from lymphatic to vascular endothelium, very few studies have systematically examined VTS with modern immunohistochemical markers commonly used in clinical laboratories. It is unclear whether endothelial cells in VTS display pure vascular or lymphatic differentiation, or both. DESIGN: A total of 11 cases with a diagnosis of VTS (identified in the tissue archives of the Cleveland Clinic between 1992 and 2015) were reviewed and confirmed. Twenty cases of benign lymph nodes without specific diagnoses were used as control tissues. Immunohistochemical stains were performed on formalin-fixed, paraffin-embedded lymph node tissue using an automated immunohistochemistry platform with antibodies against CD31, CD34, D2-40, and ERG. Positivity in the VTS lesions was defined as distinct expression in the appropriate cell compartment in ≥20% of cells. In control cases, staining was evaluated in both vascular and lymphatic channels-vascular structures were identified by presence of red cells or well-formed vascular walls and lymphatics by anatomic location and absence of vascular features. RESULTS: In the VTS lesions, D2-40 expression was absent in the lesional endothelial cells of 5/11 (45%) cases. In the cases lacking D240 expression, uninvolved lymphatic endothelium maintained expression. CD34 expression was also seen in 6/11 (54%), CD31 was seen in 10/11 (90%), and ERG expression was seen in all cases. In all the control cases, D240 expression was exclusively seen in lymphatic endothelial cells and not seen in vascular endothelial cells (eg, vascular channels in the hilum). CD34 was weakly positive in the lymphatic endothelium of only 7/20 (35%) control cases, but expressed in 20/20 (100%) control cases in the vascular endothelium. 20/20 (100%) of control cases showed expression of CD31 and ERG in both vascular and lymphatic endothelium. CONCLUSION: VTS lesional endothelial cells demonstrate patterns of vascular markers that show mixed blood vascular and lymphatic features. There appears to be a degree of alignment toward endothelial differentiation with decreased expression of D2-40 in some cases.

Design, Validation, and Clinical Implementation of a Gap-Polymerase Chain Reaction Method for α-Thalassemia Genotyping Using Capillary Electrophoresis.

α-Thalassemia (α-thal) is genetically heterogeneous with most cases caused by variably sized deletions of the HBA1 and/or HBA2 loci. In this report, we describe the development, validation, and implementation of a novel gap-polymerase chain reaction (gap-PCR)/capillary electrophoresis (CE). METHOD: This assay utilizes two multiplex reactions and CE to detect the following deletions: -α3.7 (rightward), -α4.2 (leftward), -(α)20.5, - -SEA (Southeast Asian), - -MED, - -FIL and - -THAI. Validation studies using 36 previously characterized patient samples and plasmid controls demonstrated 100.0% accuracy. Following clinical implementation, 423 patients were analyzed over 24 months. Two hundred and twenty-seven cases (46.0%) showed abnormal results including heterozygous -α3.7 (n = 114, 27.0%), homozygous -α3.7 (n = 96, 23.0%), heterozygous - -SEA (n = 9, 2.0%), heterozygous -α 4.2 (n = 5, 1.0%), heterozygous - -MED (n = 1, <1.0%), and compound heterozygous -α3.7/-α4.2 (n = 2, <1.0%) deletions. Correlation with red blood cell (RBC) parameters showed that patients with a deletion of two or more genes were associated with significantly lower mean corpuscular volume (MCV) and mean corpuscular hemoglobin (Hb) (MCH) levels than patients with wild-type results. This novel multiplex gap-PCR protocol reliably detects the seven most common deletions giving rise to α-thal. Use of the fluorescently labeled CE method provides for a high throughput workflow suitable to a clinical diagnostic laboratory serving a multiethnic population.

What Is the Clinical Utility of Repeat SNP Array Testing in the Follow-up of Myeloid Neoplasms?: A Retrospective Analysis of 44 Patients With Serial SNP Arrays.

OBJECTIVES: Single-nucleotide polymorphism (SNP) arrays have been shown to identify cytogenetic abnormalities in myeloid neoplasms that may be missed by metaphase cytogenetics alone at initial diagnosis. This study examines the utility of serial SNP arrays in follow-up testing of myeloid neoplasms. METHODS: We retrospectively reviewed results of SNP array testing in 44 patients with myeloid neoplasms and more than one SNP array study (n = 133 SNP arrays total; median, three per patient; range, two to eight per patient). RESULTS: Baseline abnormalities were identified by SNP array in 35 (79%) of 44 (79%) compared with 18 (50%) of 36 by metaphase karyotype. In follow-up studies, clonal evolution was found by both SNP array and karyotyping in seven (15.9%), by metaphase karyotyping alone in six (13.6%), and SNP arrays alone in two (4.5%). Overall survival was not significantly different between patients with or without clonal evolution detected by SNP array. CONCLUSIONS: This study, the first systematic examination of serial SNP arrays in myeloid neoplasms, confirms the clinical utility of SNP arrays at initial diagnosis but shows that clonal evolution of the karyotype can be detected by metaphase cytogenetics alone in most patients. Follow-up SNP array testing is not required in routine clinical use in most cases.

Novel MIR143-NOTCH fusions in benign and malignant glomus tumors.

Glomus tumors (GT) have been classified among tumors of perivascular smooth muscle differentiation, together with myopericytoma, myofibroma/tosis, and angioleiomyoma, based on their morphologic overlap. However, no molecular studies have been carried out to date to investigate their genetic phenotype and to confirm their shared pathogenesis. RNA sequencing was performed in three index cases (GT1, malignant GT; GT2, benign GT and M1, multifocal myopericytoma), followed by FusionSeq data analysis, a modular computational tool developed to discover gene fusions from paired-end RNA-seq data. A gene fusion involving MIR143 in band 5q32 was identified in both GTs with either NOTCH2 in 1p13 in GT1 or NOTCH1 in 9q34 in GT2, but none in M1. After being validated by FISH and RT-PCR, these abnormalities were screened on 33 GTs, 6 myopericytomas, 9 myofibroma/toses, 18 angioleiomyomas and in a control group of 5 sino-nasal hemangiopericytomas. Overall NOTCH2 gene rearrangements were identified in 52% of GT, including all malignant cases and one NF1-related GT. No additional cases showed NOTCH1 rearrangement. As NOTCH3 shares similar functions with NOTCH2 in regulating vascular smooth muscle development, the study group was also investigated for abnormalities in this gene by FISH. Indeed, NOTCH3 rearrangements were identified in 9% of GTs, all present in benign soft tissue GT, one case being fused to MIR143. Only 1/18 angioleiomyomas showed NOTCH2 gene rearrangement, while all the myopericytomas and myofibroma/toses were negative. In summary, we describe novel NOTCH1-3 rearrangements in benign and malignant, visceral, and soft tissue GTs.

Socio-demographic and consanguinity risk factors associated with low birthweight.

OBJECTIVE: To examine socio-demographic and biological risk factors associated with mothers giving birth to a low birthweight newborn among Arab women in Qatar. METHODS: The case-control study was conducted at two main tertiary hospitals in Qatar in which participants were prospectively identified from January 2010 to April 2011. Data were collected by survey on maternal ethnicity, age, education, socioeconomic status, body mass index, consanguinity and gestational age. A total of 16,500 newborns were screened for low birthweight. A total of 863 mothers of low birthweight cases and an equal number of mothers of normal-weight babies were studied. RESULTS: Qatari mothers were found to be 1.2 times as likely to have a low birthweight (< 2500g) newborn compared to other Arab women (p < 0.057). Mothers with a primary school education were 1.6 times as likely as university educated mothers to have a low birthweight newborn (p < 0.006). Likewise, obese mothers were 1.5 times as likely as their normal-weight counterparts (p < 0.009). Consanguineous couples who were first-degree cousins were 1.9 times as likely as non-related couples to have a low birthweight newborn (p < 0.001). Newborns with a gestational age of < 37 weeks were 19.6 times as likely as those > or = 37 weeks to have a low birthweight (p < 0.001). CONCLUSION: The majority of the risk factors associated with low birthweight were modifiable. Health education campaigns need to target the most vulnerable groups to reduce the rates of low birthweight among Arabs in Qatar.

The impact of the interpregnancy interval on birth weight and other pregnancy outcomes / O impacto do intervalo entre gestações no peso de recém-nascidos e outros desfechos da gravidez

To investigate the relationship between the interpregnancy interval and low birth weight and other pregnancy outcomes. METHODS: this case-control study was carried out in hospitals from January 2010 to April 2011. For cases, mothers of 1216 newborns with birth weight<2500 g were approached and 854 mothers participated (70.2 percent). For controls, mothers of 1158 newborns with >2500 g were approached and 854 mothers participated in this study (73.7 percent). Face-to-face interviews were conducted to complete the questionnaires. RESULTS: of the newborn babies with low birth weight, the risk was higher among mothers with a short interpregnancy interval (40.3 percent), whereas for infants with normal birth weight, the majority of the mothers had a longer interpregnancy interval of 24 months (44.7 percent). A short interpregnancy interval of 612 months was more common among women of <25years (49.4 percent; p<0.001) and those who were illiterate (13.1 percent; p=0.043) with a higher risk of low birth weight compared to the controls. Prenatal care during the 1st trimester was lower in women with low birth weight children (p<0.001). Normal delivery was observed less in women with a short birth interval among cases (58.7 percent) compared to controls (79 percent) (p=0.001). A J-shaped association was observed between low birth weight and the interpregnancy interval. CONCLUSIONS: a short interpregnancy interval is associated with an increased risk of low birth weight, especially in younger and illiterate women...

Investigar a relação entre o intervalo entre gestações e o baixo peso de recém-nascidos e outras conseqüências da gestação. MÉTODOS: este estudo caso-controle foi realizado em hospitais entre janeiro de 2010 e abril de 2011. Dentre as mães dos 1216 recém-nascidos com peso <2500 g, 854 (70,2 por cento) aceitaram participar do estudo de caso. No grupo controle, dentre as mães dos 1158 recém-nascidos com peso > 2500 g, participaram 854(73,7 por cento). Para completar os questionários, foram conduzidas entrevistas face a face. RESULTADOS: dos recém-nascidos com baixo peso, o fator de risco foi mais alto entre as mães com curto intervalo intergestacional (40,3 por cento), enquanto para recém-nascidos com peso normal a maioria das mães tinham uma boa margem de intervalo intergestacional de 24 meses (44,7 por cento). Curtos intervalo intergestacional (6 a 12 meses) foi mais comum entre mulheres de <25 anos (49,4 por cento; p<0,001) e analfabetas (13,1 por cento; p=0,043), com mais alto risco de baixo peso quando comparado aos controle. Cuidados pre-natais durante o primeiro trimestre foi menor nas mulheres com crianças de baixo peso (p<0,001). Menos partos normais foi observado em mulheres com curtos intervalos de nascimento para os casos (58,7 por cento) comparados aos controles (79 por cento) (p=0,001). Uma associação não monotônica tipo função J, foi observada entre o baixo peso e intervalo intergestacional. CONCLUSÕES: um curto intervalo entre gestações é associado a um risco maior de nascerem bebês de baixo peso, principalmente entre mulheres mais jovens e analfabetas...

Endothelial dysfunction in diabetes mellitus: possible involvement of endoplasmic reticulum stress?

The vascular complications of diabetes mellitus impose a huge burden on the management of this disease. The higher incidence of cardiovascular complications and the unfavorable prognosis among diabetic individuals who develop such complications have been correlated to the hyperglycemia-induced oxidative stress and associated endothelial dysfunction. Although antioxidants may be considered as effective therapeutic agents to relieve oxidative stress and protect the endothelium, recent clinical trials involving these agents have shown limited therapeutic efficacy in this regard. In the recent past experimental evidence suggest that endoplasmic reticulum (ER) stress in the endothelial cells might be an important contributor to diabetes-related vascular complications. The current paper contemplates the possibility of the involvement of ER stress in endothelial dysfunction and diabetes-associated vascular complications.

Measuring burden of diseases in a rapidly developing economy: state of Qatar.

BACKGROUND: The Global Burden of Disease (GBD) study has provided a conceptual and methodological framework to quantify and compare the health of populations. AIM: The objective of the study was to assess the national burden of disease in the population of Qatar using the disability-adjusted life year (DALYs) as a measure of disability. METHODS: We adapted the methodology described by the World Health Organization for conducting burden of disease to calculate years of life lost due to premature mortality (YLL), years lived with disability (YLD) and disability adjusted life years (DALYs). The study was conducted during the period from November 2011 to October 2012. RESULTS: The study findings revealed that ischemic heart disease (11.8%) and road traffic accidents (10.3%) were the two leading causes of burden of diseases in Qatar in 2010. The burden of diseases among men (222.04) was found three times more than of women's (71.85). Of the total DALYs, 72.7% was due to non fatal health outcomes and 27.3% was due to premature death. For men, chronic diseases like ischemic heart disease (15.7%) and road traffic accidents (13.7%) accounted great burden and an important source of lost years of healthy life. For women, birth asphyxia and birth trauma (12.6%) and abortion (4.6%) were the two leading causes of disease burden. CONCLUSION: The results of the study have shown that the national health priority areas should cover cardiovascular diseases, road traffic accidents and mental health. The burden of diseases among men was three times of women's.

Do we need to maximise the breast cancer screening awareness? Experience with an endogamous society with high fertility.

BACKGROUND: In the State of Qatar, breast cancer has become the most common form of cancer among women. The aim of this study was to explore knowledge, attitude and practice about breast cancer and to identify potential barriers to screening procedures among women. METHODS: This multistage sampling cross sectional survey in primary health care centers and the outpatient department of the Women's Hospital in the State of Qatar targeted a representative sample of 1,200 Qatari women aged between 30 to 55 years of age during the period from December 2008 to April 2009. A total 1,002 subjects (83.5%) consented to participation. Face to face interviews were conducted with a designed questionnaire covering knowledge about breast cancer, attitudes and practices of breast cancer screening. Socio-demographic variables were included. RESULTS: The majority of Qatari women demonstrated an adequate knowledge about breast cancer, with a significant relation to education status. Almost three quarters were aware that breast cancer is the most common cancer in women. A good proportion knew that nipple retraction (81.2%) and discharge of blood (74.6%) are warning signs. Of the studied Qatari women, 24.9% identified breast self examination, 23.3% clinical breast examination (CBE) and 22.5% mammography as methods for detection of breast cancer. The frequently reported barriers among the Qatari women were asking any doctor/nurse how to perform breast self examination (57.3%), embarrassment about CBE (53.3%) and fear of mammography results (54.9%). Univariate and multivariate logistic regression analysis showed that family history, level of education, living in an urban area and having medical check-ups when healthy were significant predictors for CBE and mammography. CONCLUSION: The study findings revealed that although Qatari women had adequate general knowledge about breast cancer, the screening rates for BSE, CBE and mammography were low, these being performed most frequently by young Qatari women with a higher level of education.

High prevalence of vitamin D deficiency in type 1 diabetes mellitus and healthy children.

Epidemiological studies suggest a link between vitamin D deficiency in early life and the later onset of type 1 diabetes. The aim of this matched case-control study was to find the association between vitamin D and T1DM then to study the difference in the level of vitamin D in T1DM and healthy subjects, and to determine the associated environmental risk factors in young Qatari population. The study was carried out among T1DM children and healthy subjects below 16 years at the pediatric endocrinology outpatient clinics of the Hamad General Hospital and the Primary Health care Clinics (PHCs). The survey was conducted over a period from 6 August to 25 December 2007. The subjects were Qatari nationals male and female aged below 16 years. The study is based on matching by age, gender and ethnicity of 170 cases with those of 170 controls. Face-to-face interviews were based on a questionnaire that included variables such as socio-demographic information, assessment of non-dietary covariates, assessment of dietary intake, vitamin D intake, type of feeding, clinical manifestations and laboratory investigations. Their health status was assessed by medical conditions, family history, BMI, past or present clinical manifestations, 25 (OH)D, Calcium, alkaline phosphatase, phosphorus, HbA1C, PTH, Mg and creatinine analysis. The study revealed that vitamin D deficiency was considerably higher in T1DM children (90.6%) compared to non-diabetic children (85.3%). There was a significant difference found in the mean value of vitamin D between T1DM and non-diabetic children (P = 0.009). There were statistically significant differences between type 1 diabetic and healthy subjects with respect to the occupation of parents (P < 0.001) and consanguinity rate (P < 0.047). Family history of vitamin D deficiency was considerably higher among T1DM children (35.3%) with a significant difference between diabetic and non-diabetic children (22.9) (P < 0.012). Vitamin D supplement with breast milk was very poor in diabetic children (37.4%) compared to non-diabetic children (47.7%). Majority of the studied subjects were breast-fed children (95.1% of diabetic children and 97.2% of healthy children). Multivariate logistic regression analysis revealed that fathers and mothers occupation, family history of DM, physical activity, low duration of time under sun light, breast feeding less than 6 months and low vitamin D level were considered as the main factors associated with the T1DM. In conclusion, the present study revealed that vitamin D deficiency was higher in T1DM children compared to non-diabetic. Moreover, vitamin D deficiency was common in Qatari young population. Vitamin D intake was very poor in children and it shows that supplementing infants with vitamin D might be a safe and effective strategy for reducing the risk of T1DM.

Impact of lifestyle and dietary habits on hypovitaminosis D in type 1 diabetes mellitus and healthy children from Qatar, a sun-rich country.

BACKGROUND: There are no population-based studies that have examined the association between vitamin D and type 1 diabetes mellitus (T1DM) and the role of lifestyle habits and dietary factors in young children in the Arabian Gulf and Middle East region. Little data on the intake of these nutrients in Mediterranean countries exist, and predictors of their suboptimal intake are not well defined. OBJECTIVE: The objective of this study was to determine the association between vitamin D status and T1DM and assess the impact of lifestyle and dietary habits on hypovitaminosis D in the young population of the State of Qatar. A matched case-control study was carried out among T1DM children and healthy subjects <16 years of age at the pediatric endocrinology outpatient clinics of the Hamad General Hospital and the primary health care clinics center. The survey was conducted over a period from 6 August to 25 December 2007. The sample included 170 cases and 170 controls matched by age, gender and ethnicity. METHODS: Face to face interviews were based on a questionnaire that included variables such as sociodemographic information, assessment of non-dietary covariates, assessment of dietary intake including vitamin D, type of feeding, clinical manifestations and laboratory investigations. Their health status was assessed by medical conditions, family history, body mass index, past or present clinical manifestations, serum 25(OH) vitamin D, calcium, alkaline phosphates, phosphorus, hemoglobin A1C, parathyroid hormone, magnesium and creatinine analysis. RESULTS: The study revealed that the incidence of severe vitamin D deficiency was considerably higher in T1DM (28.8%) compared with healthy children (17.1%). Although the mean serum level of vitamin D was significantly lower in T1DM children (15.80+/-9.23 ng/ml), compared with nondiabetic children (18.45+/-9.56 ng/ml), both groups belonged to the mild-moderate vitamin D deficiency category. A family history of vitamin D deficiency (35.3%; p=0.012) and diabetes mellitus (56.5%; p<0.001) was significantly higher in diabetic children. More than half of the diabetic (67.1%) and healthy children (51.2%) had no physical activity in their daily life. Both groups (65.9 vs. 62.9%) had very limited exposure to sunlight. Vitamin D supplement intake was very poor in diabetic children compared with healthy children; 60% of diabetic and 40.6% of healthy children never had any vitamin D supplement. The study revealed that vitamin D serum concentration, phosphorus, hemoglobin A1C, magnesium and creatinine show statistically significant differences between T1DM and healthy control subjects. A significant difference was noted between diabetic and healthy children for fractures (p=0.005), weakness (p=0.001) and gastroenteritis (p=0.025). CONCLUSIONS: The present study revealed that vitamin D deficiency is a common problem in Qatari children, but the incidence of vitamin D deficiency becomes very severe in T1DM children, compared with healthy children. This suggests that there is an association between vitamin D deficiency and T1DM. The data show that vitamin D status is dependent on sunshine exposure and dietary vitamin D intake. The results suggest the necessity of nutrition education to promote healthy eating habits among adolescents and their parents.