Routine Diagnostic Work-up Research Articles

Immunological findings in psychotic syndromes: a tertiary care hospital's CSF sample of 180 patients

Immunological mechanisms and therapy approaches in psychotic syndromes were recently supported by the discovery of autoantibody-associated limbic and non-limbic encephalitis. However, how clinical diagnostic procedures in psychiatry should be adapted to these new insights is still unclear. In this study, we analyzed the cerebrospinal fluid (CSF) and neuroimmunological alterations and their association with cerebral MRI (cMRI) and electroencephalographic (EEG) findings. From 2006 to 2013, we acquired 180 CSF samples from psychotic patients. Between 2006 and 2009, CSF examinations were only performed in cases in which organic brain disease was suspected. Since then, this procedure has been integrated into our routine diagnostic workup. CSF basic diagnostics were supplemented by measuring antineuronal antibodies against intracellular synaptic antigens, antibodies against intracellular onconeural antigens, antibodies against neuronal cell surface antigens and thyroid antibodies. In addition, cMRIs and EEGs were conducted. We found white cell counts elevated in 3.4% of the cases, albumin quotient elevated in 21.8%, and protein concentration elevated in 42.2%. Evidence of intrathecal immunoglobulin synthesis was found in 7.2% of the cases. Antibodies measured against neuronal cell surface antigens were positive in 3.2%. Reactivity on antibodies against intracellular onconeural antigens were detected in 3.5%. Serum thyroid antibodies were elevated in 24.7%. Abnormalities were found in 39.5% of cMRIs and in 34.3% of EEGs. The main finding of our study was the high prevalence of CSF and autoantibody abnormalities in 54.4% of psychotic patients. In combination with cMRIs and EEGs, 75.6% showed abnormal findings. Our results are discussed with regard to the concept of immunological encephalopathy. Future studies should analyze the efficacy of immunomodulatory therapies.

Italian Survey on Prevalence and Disease Management of Chronic Heart Failure and Chronic Obstructive Pulmonary Disease comorbidity in ambulatory patients. SUSPIRIUM study rationale and design.

Chronic heart failure (CHF) and chronic obstructive pulmonary disease (COPD) are leading causes of morbidity and mortality worldwide. Through shared risk factors and pathophysiological mechanisms, CHF and COPD frequently coexist. The concurrent disease has important therapeutic implications and independently predicts worsened mortality, impaired functional status, and health service use. However, assessment of the comorbidity varies widely according to the population studied, diagnostic criteria and measurement tools applied. Both syndromes have been studied extensively but largely separately, mostly in the domain of the pulmonologist for COPD and in the domain of the cardiologist for CHF. The aim of the study is to evaluate in an Italian outpatients setting (10 cardiology and 10 pulmonology centers from the same institution) the prevalence, clinical profile and the routine diagnostic, functional and therapeutic work-up applied by cardiologists and pulmonologists in the presence/suspicion of concurrent disease in patients in a stable phase of their disease. For this purpose, CHF and COPU outpatients will be enrolled in a multicenter, nationwide, prospective observational study. Risk estimation of comorbidity will be based on suspected, documented or patient-reported diagnosis of COPD/CHF. In the absence of documented concurrent diagnosis, each specialist will describe the diagnostic, functional and therapeutic work-up applied. The design of the study focused on the diagnostic validation of the CHF-COPD comorbidity aims to provide relevant new information on the assessment of the coexistent condition in the cardiac and pulmonary outpatients setting and on specialty-related different diagnostic and therapeutic strategies of comorbidity utilized in real life clinical practice. The symptomatic and prognostic benefits resulting from a combined approach to CHF/COPD could outweigh those attainable by treating either condition alone.

Flow cytometric analysis of T cell/monocyte ratio in clinically isolated syndrome identifies patients at risk of rapid disease progression

Background: Multiple sclerosis is a chronic inflammatory central nervous system disease diagnosed by clinical presentation and characteristic magnetic resonance imaging findings. The role of cerebrospinal fluid (CSF) analysis has been emphasized in particular in the context of differential diagnosis in patients with a first episode suggestive of multiple sclerosis. Objective: We investigated here the potential additional value of analysis of CSF cellularity by fluorescence activated cell sorting (FACS) in the setting of a routine diagnostic work-up in our inpatient clinic. Methods: CSF cells from back-up samples from patients with suspected chronic inflammatory central nervous system disorder were analyzed by FACS and correlated with clinical data, magnetic resonance imaging findings and oligoclonal band status. Results: We found distinct changes of T cell/monocyte (CD4/CD14) and B cell/monocyte (CD20/CD14) ratios between clinically isolated syndrome (CIS)/multiple sclerosis and other neurologic diseases or other inflammatory neurologic diseases. In particular, patients with a rapid transition from CIS to multiple sclerosis had an elevated CD4/CD14 ratio. A subgroup analysis showed diagnostic value of CD4/CD8 ratio in the differential diagnosis of CIS/multiple sclerosis to neurosarcoidosis. Conclusion: The diagnostic and prognostic accuracy of autoimmune neuroinflammatory diseases can be improved by FACS analysis of CSF cells.

Tu1386 Systematic Genomic Characterization of Normal Mucosa, Adenomatous Polyps, and Cancer in Patients With Familial Adenomatous Polyposis

Introduction: Serum tryptase measurement is part of the routine diagnostic work-up of anaphylaxis or suspected mastocytosis. Levels >20 ng/ml would be consistent with recent anaphylaxis and are associated with an elevated risk for mastocytosis. The clinical relevance of a basal elevated tryptase between 11.5 and 20 remains unclear, and autosomal dominant inheritance of such elevations has recently been reported. In this study, families with inherited basal elevations in serum tryptase levels were evaluated at the NIH. The patients (pts) shared similar features, such as atopic symptoms, connective tissue abnormalities, autonomic dysfunctions, neuropsychiatric disorders, and chronic gastrointestinal (GI) symptoms. Here we describe the GI findings from this unique cohort of pts. Methods: Pts were referred to the NIH for evaluation, and the index pts's family was also invited to undergo evaluation. Pts were evaluated by a gastroenterologist and/or completed the Bowel Disease Questionnaire (BDQ). The pts's basic demographic information was noted as well as their GI clinical symptoms, and diagnostic and treatment histories. Laboratory data, including tryptase level, were taken, and endoscopic procedures were performed when clinically indicated. Results: A total of 28 pts with confirmed elevated tryptase levels were seen and evaluated at the NIH. 13 pts were evaluated by a gastroenterologist and completed the BDQ, 9 pts completed the BDQ only, and 6 pts were evaluated by a gastroenterologist only. These pts represented 16 different families. There were 15 males and 13 females, and the median age was 39.1 years. The average BMI was 25.6 and the median tryptase level was 17.9. Of the pts who completed the questionnaire, 13 complained of abdominal pain while 9 did not. Of the pts who had abdominal pain, 11 fulfilled Rome III criteria for irritable bowel syndrome (IBS). 6 had IBS-Mixed, 2 had IBS-Constipation, and 3 had IBS-Diarrhea. Of the pts without abdominal pain, 6 fulfilled Rome III criteria for chronic constipation (CC). Evaluation of upper tract symptoms revealed that 23 of the 28 pts had gastroesophageal reflux disease (GERD) based on history and/or BDQ, and GERD was common in pts with and without abdominal pain (14/16, 9/12, respectively). Conclusions: In this cohort of families with basal elevated tryptase levels, functional GI disorders such as IBS and CC, as well as GERD, were more frequently seen in this cohort than in the general population. An autosomal dominant pattern of inheritance has been discovered. The percentage of functional GI pts with this genetic variation remains unknown, however eliciting personal and familial histories of the comorbid symptoms seen in these families, and, potentially, serum tryptase levels, may be warranted in the workup of patients with functional GI disease.

The Ratio Between Cor a 1- and Hazelnut-Specific IgE Predicts Negative Challenge Outcome in Children

Background: Hazelnut represents one of the most important food allergens. Yet, sensitization to hazelnut is often randomly detected during routine diagnostic workup without a clear-cut history of allergy. The aim of this study was to assess the diagnostic usefulness of recombinant hazelnut components and whole hazelnut extract for the prediction of clinical reactivity in sensitized children. Methods: Fifty-three consecutive children were investigated who underwent oral food challenge (OFC) due to positive in vitro test results and/or cutaneous reactions after hazelnut ingestion. Determination of specific immunoglobulin E (sIgE) against allergen extracts and recombinant hazelnut components had been performed in all patients prior to OFC. Results: OFC revealed hazelnut allergy in 19 children (36%). At a mean total IgE of 518 kU/L, sIgE to hazelnut extract was significantly higher in allergic than in tolerant children (38 vs. 13 kU/L). In contrast, no significant difference in sIgE levels against allergen components was detected. A ratio of rCor a 1 to hazelnut extract sIgE levels >1 predicted hazelnut tolerance with a sensitivity and a negative predictive value of 100%. The corresponding specificity (47%) and positive predictive value (51%) were low. Conclusions: In the present study, a ratio of rCor a 1 to hazelnut extract sIgE >1 predicted hazelnut tolerance during OFC in children with suspected hazelnut allergy. However, further investigations in larger populations are warranted to investigate the transferability of these results to other patient populations. Until then, OFC remain the diagnostic gold standard for the definitive diagnostic workup of suspected food allergy.

FNA needle rinses preserved in Cytolyt are acceptable specimen type for mutation testing of thyroid nodules

This study investigated the application of molecular testing to residual thyroid fine-needle aspiration material from needle rinses collected in Cytolyt. Two thyroid needle rinses from 135 patients were collected in Cytolyt during routine diagnostic workup in our institution. Molecular testing was performed to detect 14 genetic alterations in BRAF, K-, H-, N-RAS genes as well as RET/PTC1, RET/PTC3, and PAX8/PPARγ and verified by next generation sequencing and correlated with cytologic diagnoses. Molecular testing revealed a total of 17 mutations across specimens with benign nodule (n = 5; HRAS, NRAS), Hürthle cell neoplasm (n = 2; BRAF, HRAS) and Papillary thyroid carcinoma (n = 10, 9BRAF, 1 KRAS) cytology. No RNA gene rearrangements were detected. Mutations and translocations associated with thyroid cancer can be detected in thyroid fine-needle aspiration needle rinses preserved in Cytolyt specimens collected during routine patient management, which are typically discarded when a diagnosis is attained.

High-Throughput Sequencing to Identify Cytogenetic and Molecular Genetic Aberrations in 24 AML Exomes

Introduction: In acute myeloid leukemia (AML), the karyotype and the molecular mutation profile are the strongest parameters for classification and prognostication. Yet, diagnostic analyses rely on chromosome analysis and sequencing of a constantly growing number of genes.Aim: To evaluate whether whole exome sequencing (WES) can reliably identify copy number states and molecular mutations in a single-step procedure.Patients and Methods: The cohort included 24 AML with an aberrant karyotype at initial diagnosis (ID) who achieved cytogenetic remission (CR) after chemotherapy. Patients showed complex karyotype (n=6), 11q23/MLL-rearrangement (n=4), t(15;17)(q24;q21) (n=4), inv(16)(p13q22) (n=4), t(8;21)(q22;q22) (n=3), and 3q26/EVI1-rearrangement (n=3).For WES DNA was extracted from bone marrow and treated with the TruSeq Exome enrichment kit targeting 201,071 exons. 2x100 bp paired-end sequencing was performed on an Illumina HiSeq machine (Illumina, San Diego, CA) at Fasteris (Geneva, Switzerland). After mapping the sequenced reads with Burrows-Wheeler Aligner [Li&Durbin, Bioinformatics, 2009], variants where called with GATK [McKenna et al., Genome Res., 2010] and copy number variations (CNV) were detected by Excavator [Magi et al., 2013, Genome Biol.]. For validation of the detected variants, 21 leukemia related genes were screened by amplicon sequencing (Illumina MiSeq, or Roche 454, Branford, CT). Array-based comparative genomic hybridization (aCGH) using 12x270K microarrays (Roche NimbleGen, Madison, WI) or 4 x 180K microarray slides (Agilent Technologies, Santa Clara, CA) was performed on all samples. We called CNV using default settings as well as fixed thresholds on the probe medians (0.3 for gains and -0.5 for losses on probe medians and at least 10 probes per segment).Results: The targeted regions were covered by 86 reads on average, while 90% of the bases were covered by at least 15 reads. By comparing ID and CR we detected an average of 15 somatic single nucleotide variants and short indels per patient (range 4-25), affecting 303 genes in total, including genes involved in leukemogenesis. After excluding polymorphisms we screened the mutated genes for recurrence among all cases. Four genes were mutated in at least 3 samples: WT1 (n=5), TP53 (n=4), NRAS (n=3) and TNS1 (n=3). Fourteen genes were mutated in 2 samples: ASXL2, DSCAM, GATA2, IDH2, KIT, OR4C5, POU4F1, LOC93432, RPTOR, SMC1A, SYNE2, TET2, TTN and USP9X. Mutations in OR4C5, LOC93432, SYNE2, TTN and USP9X have not been associated with AML yet. They were rated as damaging according to the SIFT algorithm [Ng and Henikoff, Genome Res., 2003]. In a prior diagnostic work-up 21 different genes had been screened and revealed 16 mutations affecting 7 genes. WES identified 14 mutations correctly (the 2 remaining mutations were covered by reads only insufficiently) and did not call any mutation in genes classified as negative in the routine diagnostic work-up.We further compared CNV derived from WES and aCGH in all 24 patients. Gains and losses detected by aCGH involved 2.65 and 1.40 billion bp, respectively. 96% of bp involved in these CNV were also detected by WES. Of the regions in which WES could not reproduce CNV calls, 15% did not contain exons. WES called gains and losses covering in total 2.56 and 1.47 billion bp, respectively. With aCGH we detected 98% of the gains and 86% of the losses. Regions missed by aCGH did show concordant signal that did not pass the fixed thresholds. However, while relaxing the thresholds to default settings, aCGH reproduces 99% of the WES results. Thus, an excellent concordance was observed (R = 0.99, p < 2.2e-16).We further analysed 19 cytogenetically balanced rearrangements that caused 42 breakpoints in affected chromosomes in 17 patients. As most breakpoints occur in non-coding regions, WES in general is limited in detecting these balanced rearrangements. However, short CNV were detected by WES in 10 cases and confirmed by aCGH.Conclusion: WES was capable of delineating molecular mutation profiles and of robustly detecting copy number states in AML at diagnosis. We suggest that WES in combination with multiplex RT-PCR-based techniques for the detection of recurrent fusion transcripts is a promising approach for a future diagnostic work-up for AML classification and prognostication.This project has been funded by the Seventh Framework Programme (FP7/2007-2013) under grant agreement n. 306242. DisclosuresAlthammer:MLL Munich Leukemia Laboratory: Employment; Seventh Framework Programme (FP7/2007-2013): Research Funding. de Albuquerque:MLL Munich Leukemia Laboratory: Employment; Seventh Framework Programme (FP7/2007-2013): Research Funding. Nadarajah:MLL Munich Leukemia Laboratory: Employment; Seventh Framework Programme (FP7/2007-2013): Research Funding. Meggendorfer:MLL Munich Leukemia Laboratory: Employment; Seventh Framework Programme (FP7/2007-2013): Research Funding. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership; Seventh Framework Programme (FP7/2007-2013): Research Funding. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership; Seventh Framework Programme (FP7/2007-2013): Research Funding. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership; Seventh Framework Programme (FP7/2007-2013): Research Funding. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership; Seventh Framework Programme (FP7/2007-2013): Research Funding.

BCR-ABL1-like Acute Lymphoblastic Leukemia Is Associated with IKZF1 and JAK2 Alterations and inferior Outcome in Adults

Background: BCR-ABL1-like (Ph-like) B-precursor acute lymphoblastic leukemia (ALL) displays a gene expression profile closely related to B-precursor ALL with t(9;22)(q34;q11). In addition, Ph-like ALL patients (pts) are characterized by distinct genetic alterations and inferior prognosis in pediatric trials. The purpose of this study was the genetic and clinical characterization of Ph-like ALL in adults.Methods: Affymetrix gene expression profiles (GEP) generated from diagnostic bone marrow samples of 306 adult B-precursor and T-ALL pts (median age 41 years, range 16-84 years) were classified as Ph-like ALL according to published algorithms (Roberts et al., Cancer Cell 2012) and separated from BCR-ABL1-positive and B-other ALL pts (BCR-ABL1-negative; non Ph-like). The incidence and genetic characteristics of the Ph-like subset were analyzed in the overall cohort, whereas clinical and outcome analysis were restricted to B-precursor ALL pts treated within GMALL trials 06/99 and 07/03 (n=107). The median age of this population was 30 (16-64) years. The routine diagnostic work-up included immunophenotyping, fluorescent in situ hybridization (FISH) for BCR-ABL1 and KMT2A (MLL) rearrangements, cytogenetics and molecular analyses of BCR-ABL1 translocations and MLL rearrangements. A subgroup of pts with B-precursor ALL was analyzed for CRLF2 alterations by FISH (n=88) and by RT-PCR for the P2RY8-CRLF2 translocation (n=117). Multiplex ligation-dependent probe amplification (MLPA) for common copy number variations (SALSA MLPA probemix P335-B1) and targeted amplicon sequencing of 131 genes recurrently mutated in ALL were performed in BCR-ABL1 positive (n=30), Ph-like (n=16) and B-other ALL pts (n=23).Results: Of the 306 pts, we classified 26 pts (9%) as Ph-like ALL based on their GEP and the absence of the BCR-ABL1 translocation, corresponding to an incidence of 13% (26/207) in B-precursor ALL and 24% (26/110) among BCR-ABL1-negative B-precursor ALL.Nineteen of 107 B-precursor ALL pts treated within the GMALL trials displayed a Ph-like phenotype. There were no significant differences in baseline characteristics like age, sex, white-cell count, hemoglobin or platelet count and risk group in comparison to the B-other subgroup (n=51). All 19 Ph-like pts showed no MLL rearrangement and 58% belonged to the standard risk group. The complete remission rate after induction was similar for Ph-like and B-other pts (96% vs 100%; p>0.05). At 5 years, the Ph-like ALL subgroup had a lower probability of continuous complete remission (RD: 24% vs 63%; p=0.004) and overall survival (OS: 22% vs 56%; p=0.05) compared to B-other ALL pts. After exclusion of pts with MLL rearrangement from the B-other group (n=11), these differences remained significant (RD: 24% vs 62%; p<0.001; OS: 22% vs 64%; p=0.006).MLPA and amplicon sequencing revealed specific genetic alterations associated with the Ph-like ALL subgroup (Figure 1). All pts with IGH-CRLF2 (n=6) were identified in the Ph-like subgroup, whereas all pts with P2RY8-CRLF2 (n=2) were found in the B-other group (p<0.001 and p>0.05, respectively). Additionally, most pts with high CRLF2 expression clustered in the Ph-like ALL subgroup (13/26, 50% vs 8/79, 10% of B-other; p<0.001). Deletions of IKZF1 were significantly more common in Ph-like ALL (13/16, 81%; p=0.003) and in BCR-ABL1 positive ALL (21/30, 70%; p=0.005) in contrast to B-other ALL (7/21, 30%). Mutations in JAK2 were exclusively found in the Ph-like subgroup (0/53, 0% vs 7/16, 44%; p<0.001). In our data set, FISH for IGH-CRLF2 and sequencing of JAK2 was sufficient to identify Ph-like cases with a sensitivity and specificity of 59% and 100%, respectively.Conclusion: Ph-like ALL in adults is associated with inferior survival in a homogenously treated group of pts. Additionally, molecular analysis revealed distinct genetic alterations identifying this specific ALL subtype. Since gene expression analysis could be difficult to be implemented in routine diagnostics our data suggest, that testing for JAK2 mutations and the IGH-CRLF2 translocation could be options for the diagnosis of the Ph-like subtype. Future treatment strategies should be explored to improve the dismal prognosis for these high risk pts. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Incremental value of cardiac magnetic resonance imaging in the diagnostic work-up of patients with apparently idiopathic ventricular arrhythmias of left ventricular origin

Routine diagnostic work-up of patients with ventricular arrhythmias (VAs) commonly includes 12-lead electrocardiogram (ECG), transthoracic echocardiography, exercise stress test and, in selected cases, invasive coronary angiography [1]. According to these investigations, structural heart disease (SHD), such as ischemic heart disease and non-ischemic cardiomyopathies, is frequently diagnosed among patients with VAs originating from the left ventricle (LV) [2]. Less frequently, structural myocardial abnormalities are not identified; in these patients, VAs are considered as idiopathic or of unknown etiology [1,2].

Role of CT in assessing pleural malignancy prior to thoracoscopy

The definitive diagnosis of pleural malignancy depends upon histological confirmation by pleural biopsy. CT is reported to have a high sensitivity and specificity for the diagnosis of malignant pleural disease,...

Pain therapy in irritable bowel syndrome

Irritable bowel syndrome (IBS) is one of the most common gastrointestinal diseases. It is characterized by chronic abdominal pain, typically associated with altered bowel habits that cannot be explained by structural abnormalities in routine diagnostic workup. Based on the predominant symptom, IBS can be divided into different subtypes: IBS with predominant constipation, diarrhea, bloating, or pain. Knowledge about the complex and multifactorial IBS pathophysiology has increased tremendously in recent years, e.g., IBS may be related to alterations in gastrointestinal motility, visceral sensitivity, and the mucosal immune system. It is important, both for the patient and the physician, that IBS diagnosis is made quickly and thoroughly based on the typical symptom complex and exclusion of relevant differential diagnoses and to reassure the patient that IBS is a chronic, but benign disease. These components are the fundamental basis for a good patient-physician relationship and for a successful long-term management of this potentially very compromising disorder. IBS therapy is based on general measures as well as symptom-oriented medical therapy, where improvement of abdominal pain is one of the main goals in treating IBS patients. Several pain treatment options are available, which may be used long-term or on demand and which may be combined with other therapies. General medical approaches include antispasmodics, improvement of bowel function, phytotherapy, and probiotics. Especially in patients with psychological comorbidities, antidepressants may be used. Modern drug treatments include the GC-C agonist linaclotide in IBS with predominant constipation, the locally acting antibiotic rifaximin in IBS with bloating, and 5-HT3 antagonists in IBS with predominant diarrhea. Psychotherapy should be included in an interdisciplinary approach in refractory cases or in psychological comorbidity.

Cardiac MRI Improves Identification of Etiology of Acute Ischemic Stroke

Background: An accurate subtype classification of acute ischemic stroke is important in clinical practice as it can greatly influence patient care in terms of acute management and devising secondary stroke prevention strategies. Approximately, one third of ischemic strokes are cryptogenic despite a comprehensive workup. Diagnostic workup for detecting cardioaortic sources of cerebral embolism commonly includes transthoracic echocardiography (TTE). However, TTE has a limited diagnostic power to detect some of the cardioaortic abnormalities and additional imaging modalities are often needed to accurately assess such abnormalities. Purpose: We evaluated the feasibility of cardiovascular magnetic resonance (CMR) imaging to detect the cardioaortic sources of ischemic stroke. Methods: A total of 106 patients were included, of which 85 had an ischemic stroke and 21 had a transient ischemic attack (TIA). Routine diagnostic workup (RDW) included brain diffusion-weighted image MRI, telemetry, magnetic resonance angiography/CT angiography of head and neck, carotid duplex ultrasonography, laboratory studies and TTE. Patients additionally underwent CMR. Subtype assignment was performed in accordance with the Stop Stroke Study of the Trial of Org 10172 in Acute Stroke Treatment classification system by a stroke neurologist after reviewing the admission notes and diagnostic test results. A second subtype classification was assigned with an additional criterion defined based on delayed enhancement (DE)-CMR findings. Additionally, the presence of non-coronary artery disease (CAD) scarring was assessed in ischemic stroke patients and compared with the TIA patients as the control group. Results: RDW detected cardioaortic embolism (CAE) stroke in 32 (37.6%) patients and cryptogenic stroke in 23 patients (27.1%). Addition of CMR resulted in a 26.1% reduction in the rate of cryptogenic strokes (6 patients). Furthermore, DE-CMR findings allowed for reclassification of three additional cryptogenic subtypes, resulting in a 39.1% reduction of cryptogenic stroke rate. Non-CAD scarring was detected in 13 (15.3%) stroke patients as opposed to only 1 (4.8%) TIA patient. Conclusions: CMR is a valuable tool for the detection of CAE sources in patients with cryptogenic ischemic stroke and provides clinicians with a unique set of information that may substantially change the long-term management of these patients. DE-CMR also detects non-CAD scarring, which may indicate a predisposition to ischemic stroke. Further studies with larger samples and long-term follow-up are needed to further evaluate the clinical significance of our findings.

Primary central nervous system lymphoma and atypical glioblastoma: multiparametric differentiation by using diffusion-, perfusion-, and susceptibility-weighted MR imaging.

To compare multiparametric diagnostic performance with diffusion-weighted, dynamic susceptibility-weighted contrast material-enhanced perfusion-weighted, and susceptibility-weighted magnetic resonance (MR) imaging for differentiating primary central nervous system lymphoma (PCNSL) and atypical glioblastoma. This retrospective study was institutional review board-approved and informed consent was waived. Pretreatment MR imaging was performed in 314 patients with glioblastoma, and a subset of 28 patients with glioblastoma of atypical appearance (solid enhancement with no visible necrosis) was selected. Parameters of diffusion-weighted (apparent diffusion coefficient [ADC]), susceptibility-weighted (intratumoral susceptibility signals [ITSS]), and dynamic susceptibility-weighted contrast-enhanced perfusion-weighted (relative cerebral blood volume [rCBV]) imaging were evaluated in these 28 patients with glioblastoma and 19 immunocompetent patients with PCNSL. A two-sample t test and χ(2) test were used to compare parameters.The diagnostic performance for differentiating PCNSL from glioblastoma was evaluated by using logistic regression analyses with leave-one-out cross validation. Minimum, maximum, and mean ADCs and maximum and mean rCBVs were significantly lower in patients with PCNSL than in those with glioblastoma (P < .01, respectively), whereas mean ADCs and mean rCBVs allowed the best diagnostic performance. Presence of ITSS was significantly lower in patients with PCNSL (32% [six of 19]) than in those with glioblastoma (82% [23 of 28]) (P < .01). Multiparametric assessment of mean ADC, mean rCBV, and presence of ITSS significantly increased the probability for differentiating PCNSL and atypical glioblastoma compared with the evaluation of one or two imaging parameters (P < .01), thereby correctly predicting histologic results in 95% (18 of 19) of patients with PCNSL and 96% (27 of 28) of patients with atypical glioblastoma. Combined evaluation of mean ADC, mean rCBV, and presence of ITSS allowed reliable differentiation of PCNSL and atypical glioblastoma in most patients, and these results support an integration of advanced MR imaging techniques for the routine diagnostic workup of patients with these tumors.

Excellent interrater agreement for the differentiation of fasciculations and artefacts – A dynamic myosonography study

ObjectiveThe aim of the study was to confirm the diagnostic performance of dynamic myosonography with regard to its reliability to correctly identify fasciculations and to distinguish them from artefacts. Furthermore, interrater agreement regarding the identification of different muscle movements was investigated. MethodsA total of 11 observers analysed 25 muscle ultrasound videos acquired using a standardized protocol. The video files illustrated fasciculations and artefacts (voluntary probe movements, voluntary contractions or swallowing and pulsating vessels) in different muscle groups. ResultsFasciculations could be distinguished from artefacts with a sensitivity of 90.9% and specificity of 98.5%. Interrater agreement regarding the presence or absence of fasciculations showed an overall median of 100% (interquartile range, IQR: 96–100%). In every investigated muscle group, the median of the interpreter agreement was found to be 100% (correct ratings of all observers: submental muscles: 43 of 44; biceps muscles: 22 of 22; forearm flexors: 31 of 33; rectus abdominis muscles: 33 of 33; quadriceps muscles: 19 of 22; tibialis anterior muscles: 51 of 55; undefinable muscles: 65 of 66). ConclusionDynamic myosonography is an extremely reliable tool with excellent interrater agreement to correctly identify fasciculations and to distinguish them from artefacts. SignificanceMyosonography should be further incorporated in clinical routine diagnostic work-up.

Immunohistochemistry and other ancillary techniques in the diagnosis of gestational trophoblastic diseases.

Gestational trophoblastic disease (GTD) encompasses entities ranging from ubiquitous hydatidiform moles to rare neoplastic gestational trophoblastic tumors. In practice, the histological diagnosis of GTD continues to have significant diagnostic inaccuracy with marked inter- and intra-observer variability, even among expert pathologists. Studies in correlation with genotypic evidence have confirmed a lack of accuracy in diagnosis of hydatidiform moles using histology alone. Applications of new immunohistochemical markers and molecular techniques have significantly enhanced the diagnostic precision of various GTDs in recent years. p57 Immunohistochemistry is a highly useful marker in confirming complete hydatidiform mole. PCR-based DNA genotyping has emerged as a powerful diagnostic measure to precisely classify both complete and partial hydatidiform moles. With acquisition of molecular diagnostic capabilities at most medical centers, these ancillary techniques have been increasingly integrated into the routine diagnostic workup of GTD. We propose an algorithmic approach combining histology and these ancillary tests to provide the best diagnostic practice possible. Under this algorithm, all cases with histological suspicion for complete mole are subject to p57 immunohistochemical confirmation, and all cases with histological suspicion for partial mole undergo DNA genotyping workup. Beyond hydatidiform mole, recognition of gestational trophoblastic tumors requires a high index of suspicion and application of immunohistochemical markers of trophoblast is helpful to accurately diagnose these rare tumors.

Routine vaginoscopic office hysteroscopy in modern infertility work-up: a randomized controlled trial

This study aims to estimate the safety, efficacy, and patient acceptability of adding vaginoscopic office hysteroscopy (VOH) to the routine infertility diagnostic work-up for evaluation of the endometrial cavity. This study is a prospective comparative diagnostic trial. This study was conducted in a tertiary care referral facility and university hospital. This study comprised a total of 156 infertile patients scheduled for laparoscopy. Seventy-eight patients had VOH on one stop bases in addition to the usual infertility work-up and were assigned as group B while a similar number was examined by the usual diagnostic work-up and assigned as group A. The main outcome measure is the diagnostic accuracy of VOH alone in comparison to hysterosalpingography (HSG) and diagnostic laparoscopy (DL) and assessment of combined VOH and HSG in diagnosing intrauterine abnormalities. There was insignificant difference between both groups regarding socio-demographic and HSG data. Abnormal DL findings were more significant in group A. VOH detected 50 % abnormal endometrial cavity in group B with a significant superiority over HSG. There was a high percentage of agreement in the diagnosis of uterine abnormalities between HSG and VOH (96 %). Generally, VOH was an acceptable procedure with mild pain and feasible in most cases. Adding VOH to the routine diagnostic work-up of infertile couples prior to laparoscopy seems to be a feasible, safe, simple, tolerable, and quick outpatient procedure. It can diagnose intrauterine abnormalities in about a quarter of infertile women with normal HSG. VOH has an additional value to HSG and DL in diagnosing uterine. Nevertheless, whether its use would increase pregnancy rate among infertile women requires a further longitudinal comparative study.

Tumor Vascularity and Glucose Metabolism Correlated in Adenocarcinoma, but Not in Squamous Cell Carcinoma of the Lung

Background/ObjectivesTo prospectively examine the relation between tumor vascularity and glucose metabolism in adenocarcinoma (AC) and squamous cell carcinoma(SCC) of the lung by using positron emission tomography/computed tomography (PET/CT) and dynamic contrast enhanced magnetic resonance imaging (DCE-MRI).Materials and MethodsForty-one consecutive patients with histologically confirmed untreated NSCLC underwent routine diagnostic work-up, including DCE-MRI and PET/CT. PET/CT images were used to derive glucose metabolism (SUVmax and SUVmean), and DCE-MRI images were used to derive tumor vascularity (Ktrans, Kep, Ve and iAUC). Any differences in the DCE-MRI and PET/CT estimations between the NSCLC subtypes were determined by the Wilcoxon rank sum test. Spearman’s rank correlation coefficients were calculated between the DCE-MRI parameter values and the SUV.ResultsSUVmean and SUVmax in AC were significantly lower than in SCC, but Ktrans and Ve in AC were significantly higher than in SCC. Significant correlations between SUV and DCE-MRI parameters were observed for SUVmax and Ve (ρ = −0.357, P = 0.022), SUVmean and Ktrans (ρ = −0.341, P = 0.029), and SUVmean and iAUC (ρ = −0.374, P = 0.016 ) in total; for SUVmax and iAUC (ρ = −0.420, P = 0.037), SUVmean and Ktrans (ρ = −0.411, P = 0.041), SUVmean and Kep (ρ = −0.045, P = 0.026), and SUVmean and iAUC (ρ = −0.512, P = 0.009) in AC; However, for neither in SCC.ConclusionAC and SCC showed different patterns in both tumor vascularity and glucose metabolism. Tumor vascularity and glucose metabolism negatively correlated in AC, but not in SCC. These differences may underlie the heterogeneity in clinical aspect of NSCLC subtypes and have implications for their imaging profiling and monitor the treatment response.

Liver Transplant in Budd-Chiari Syndrome: A Single-center Experience in Saudi Arabia

If they do not respond to other treatments, patients with Budd-Chiari syndrome are potential candidates for a liver transplant. Timing for transplant is controversial; however, before other systems deteriorate, early intervention in relatively stable patient may improve the outcome and survival of these patients. Six patients (2 women and 4 men) had Budd-Chiari syndrome (1.2%) among 475 patients who had undergone a liver transplant at our center between 2001 and 2012. Imaging modalities including duplex ultrasound, abdominal computed tomography angiography, and hematologic evaluation were part of our routine diagnostic work-up. Although we perform mostly living-donor liver transplants, these patients received a liver transplant from a deceased donor, because there was not enough evidence to justify a living-donor liver transplant. We thought that not replacing the caval vein might negatively influence the outcome. Postoperatively, these recipients were started on a heparin infusion and triple therapy immunosuppression; only then was warfarin introduced as long-term anticoagulant. Two patients died, 1 from uncontrollable bleeding and disseminated intravascular coagulopathy, and the other died in the intensive care unit after 5 months because of multiorgan failure and sepsis. One patient had portal vein thrombosis 9 months after the liver transplant; the other patient needed a liver retransplant after 5 years owing to liver failure, secondary to chronic rejection. Graft survival rate was 75%, and patient survival rate was 66.6%. This is the first article from Saudi Arabia to describe the outcome of a liver transplant in this subgroup of patients with Budd-Chiari syndrome. Treatment of Budd-Chiari syndrome follows a therapeutic algorithm that should start with anticoagulation and may end up with liver transplant; however, it should be considered early if other treatments fail.

Diagnostic performance of different pleural fluid biomarkers in tuberculous pleurisy.

Due to the paucibacillary nature of tuberculous pleural effusion the diagnosis of pleural tuberculosis is challenging. This prospective study was undertaken to evaluate the diagnostic performance of ten different pleural fluid biomarkers in the differentiation between tuberculous and non-tuberculous pleural effusions. Two hundred and three patients with pleural effusion (117 men and 86 women, median age 65 years) were enrolled. Routine diagnostic work-up, including thoracentesis and pleural fluid analysis, was performed to determine the cause of pleural effusion. The following biomarkers were measured in pleural fluid: adenosine deaminase (ADA), interferon gamma (IFN-γ), interleukin 2 soluble receptor (IL-2sRα), sub-unit p40 of interleukin 12b (IL-12p40), interleukin 18 (IL-18), interleukin 23 (IL-23), IFN-γ induced protein 10 kDa (IP-10), Fas-ligand, human macrophage-derived chemokine (MDC) and tumor necrosis factor alfa (TNF-α). There were 44 (21.7%) patients with tuberculous pleural effusion, 88 (43.3%) patients with malignant pleural effusion, 35 (17.2%) with parapneumonic effusion/pleural empyema, 30 (14.8%) with pleural transudates, and 6 (3%) with miscellaneous underlying diseases. Pleural fluid IFN-γ was found the most accurate marker differentiating tuberculous from non-tuberculous pleural effusion, with sensitivity, specificity, PPV, NPV, and AUC 97%, 98%, 95.5%, 99.4%, and 0.99, respectively. Two other biomarkers (IP-10 and Fas ligand) also showed very high diagnostic accuracy with AUC≥0.95. AUC for ADA was 0.92. We conclude that IFN-γ, IP-10, and Fas-ligand in pleural fluid are highly accurate biomarkers differentiating tuberculous from non-tuberculous pleural effusion.

Role of Nucleic Acid Amplification Tests (NAATs) in Tuberculous Pleural Effusion: Where It Fits In Routine Diagnostic Workup?

Background: Commonest cause of pleural effusion in India is tuberculosis (TB) and poses a diagnostic difficulty because of the low sensitivity of culture technique. Methods: Prospective study conducted during Jan 2012 to Sept. 2013 with an objective to find role of Nucleic acid amplification tests (NAATs) in tuberculous pleural effusion. We also observed comparison of NAATs i.e. MTB DNA PCR with other conventional diagnostic techniques like pleural fluid biochemistry, ADA (adenosine deaminase level), cytology and culture for mycobacterium tuberculosis, included 100 cases with signs, symptoms, history and radiological features suggestive of tuberculous pleural effusion. All the cases were subjected to pleural fluid analysis, smear for AFB, ADA, cytology, AFB culture on LJ media & MTB DNA PCR. Statistical analysis was done by using t-test and chi-test. Results: Out of total 100 cases with pleural effusion, 09% cases were sputum positive for AFB, 3% pleural fluid samples positive for AFB, 28% were culture positive, 74% were DNA PCR positive, and 85% cases had ADA >40 units/liter, 87% cases had a LN Ratio greater than 0.75. Sensitivity, specificity, PPV & NPV of PCR for MTB was observed 92.86%, 33.33%, 35.13% & 92.30% respectively (p 0.4). In PCR negative cases; there was statistically significant association between ADA levels in pleural fluid culture for MTB positive and negative results. (P 40 units/liter, DNA PCR and LN ratio >0.75 gave a positive diagnostic yield in 98% of cases, 2% with diagnostic dilemma were diagnosed by pleural biopsy. ATT response was observed in 78% cases in 2 weeks, 98% cases in 4 weeks and 100% cases at the end of 6 weeks. Conclusion: In cases with exudative pleural effusion with Lymphocyte in pleural fluid >50% and L/N ratio>0.75 with ADA <40 units, MTB DNA PCR (NAATs) will be very useful in confirming tuberculosis as a cause for pleural effusion. Results of NAATs in this situation are very useful, sensitive, less time consuming and comparable to pleural fluid culture. Hence we recommend MTB DNA PCR in these cases.