Large-scale Screening Of Patients Research Articles

Progression in Neuroimaging of Normal Pressure Hydrocephalus.

Normal-pressure hydrocephalus is a clinical syndrome that mainly targets the elderly population. It features dementia, impaired walking, and the malfunction of sphincters. The rapid identification and large-scale screening of patients with normal-pressure hydrocephalus (NPH) are of great significance as surgical interventions can greatly improve or even reverse the symptoms. This review aims to summarize the traditional parameters used to diagnose NPH and the emerging progression in neuroimaging of the disease, hoping to provide an up-to-date overall perspective and summarize the possible direction of its future development.

Automatic Measurement of End-Diastolic Arterial Lumen Diameter in ARTSENS

Over past few years, we are developing a system for facilitating large scale screening of patients for cardiovascular risk—arterial stiffness evaluation for noninvasive screening (ARTSENS). ARTSENS is an image-free device that uses a single element ultrasound transducer to obtain noninvasive measurements of arterial stiffness (AS) in a fully automated manner. AS is directly proportional to end-diastolic lumen diameter (Dd). Multilayered structure of the arterial walls and indistinct characteristics of intima-lumen interface (ILI) makes it quite difficult to accurately estimate Dd in A-mode radio-frequency (RF) frames obtained from ARTSENS. In this paper, we propose a few methods based on fitting simple mathematical models to the echoes from arterial walls, followed by a novel method to fuse the information from curve fitting error and distension curve to arrive at an accurate measure of Dd. To bring down the curve fitting time and facilitate processing on low-end processors, a novel approach using the autocorrelation of echoes from opposite walls of the artery has been discussed. The methods were analyzed for their comparative accuracy against reference Dd obtained from 85 human volunteers using Hitachi-Aloka eTRACKING system. Dd from all reported methods show strong and statistically significant positive correlation with eTRACKING and mean error of less than 7% could be achieved. As expected, Dd from all methods show significant positive correlation with age.

Crizotinib and Testing for ALK

Crizotinib was recently approved by the US FDA for the treatment of advanced non-small cell lung cancer (NSCLC) harboring the ALK (anaplastic lymphoma kinase) gene rearrangement. To ensure identification of patients most likely to benefit, the FDA approved crizotinib concurrently with a companion diagnostic test-the Vysis ALK Break Apart FISH Probe Kit. This kit was used in 1 of the 2 pivotal trials leading to the FDA approval of crizotinib and has become the gold standard for detecting ALK rearrangement in NSCLC. Although ALK FISH is clinically validated, the assay can be technically challenging and costly. Therefore, other diagnostic modalities are being explored, including immunohistochemistry (IHC) and reverse transcriptase-polymerase chain reaction. This article provides an overview of the diagnostic assays available for detecting ALK rearrangement. Each assay, including ALK FISH, has its strengths and weaknesses. Recent work with commercially available ALK antibodies suggests that IHC-based tests may represent a reliable and cost-effective screening strategy; however, large multicenter studies comparing IHC with FISH are needed to validate ALK IHC. While ALK FISH remains the current standard for diagnosing ALK positivity, large-scale screening of patients with newly diagnosed advanced NSCLC, as recommended by NCCN, may require development and validation of alternative screening strategies, such as combination IHC and FISH.

Genetic Basis of Prune Belly Syndrome: Screening for HNF1β Gene

Although the cause of prune belly syndrome is unknown, familial evidence suggests a genetic component. Recently 2 nonfamilial cases of prune belly syndrome with chromosome 17q12 deletions encompassing the HNF1β gene have made this a candidate gene for prune belly syndrome. To date, there has been no large-scale screening of patients with prune belly syndrome for HNF1β mutations. We assessed the role of HNF1β in prune belly syndrome by screening for genomic mutations with functional characterization of any detected mutations. We studied patients with prune belly syndrome who were prospectively enrolled in our Pediatric Genitourinary DNA Repository since 2001. DNA from patient samples was amplified by polymerase chain reaction, sequenced for coding and splice regions of the HNF1β gene, and compared to control databases. We performed functional assay testing of the ability of mutant HNF1β to activate a luciferase construct with an HNF1β DNA binding site. From 32 prune belly syndrome probands (30 males, 2 females) HNF1β sequencing detected a missense mutation (V61G) in 1 child with prune belly syndrome. Absent in control databases, V61G was previously reported in 2 patients without prune belly syndrome who had congenital genitourinary anomalies. Functional testing showed similar luciferase activity compared to wild-type HNF1β, suggesting the V61G substitution does not disturb HNF1β function. One genomic HNF1β mutation was detected in 3% of patients with prune belly syndrome but found to be functionally normal. Thus, functionally significant HNF1β mutations are uncommon in prune belly syndrome, despite case reports of HNF1β deletions. Further genetic study is necessary, as identification of the genetic basis of prune belly syndrome may ultimately lead to prevention and improved treatments for this rare but severe syndrome.

Screening for Epidermal Growth Factor Receptor Mutations in Lung Cancer

Activating mutations in the epidermal growth factor receptor gene (EGFR) confer hypersensitivity to the tyrosine kinase inhibitors gefitinib and erlotinib in patients with advanced non-small-cell lung cancer. We evaluated the feasibility of large-scale screening for EGFR mutations in such patients and analyzed the association between the mutations and the outcome of erlotinib treatment. From April 2005 through November 2008, lung cancers from 2105 patients in 129 institutions in Spain were screened for EGFR mutations. The analysis was performed in a central laboratory. Patients with tumors carrying EGFR mutations were eligible for erlotinib treatment. EGFR mutations were found in 350 of 2105 patients (16.6%). Mutations were more frequent in women (69.7%), in patients who had never smoked (66.6%), and in those with adenocarcinomas (80.9%) (P<0.001 for all comparisons). The mutations were deletions in exon 19 (62.2%) and L858R (37.8%). Median progression-free survival and overall survival for 217 patients who received erlotinib were 14 months and 27 months, respectively. The adjusted hazard ratios for the duration of progression-free survival were 2.94 for men (P<0.001); 1.92 for the presence of the L858R mutation, as compared with a deletion in exon 19 (P=0.02); and 1.68 for the presence of the L858R mutation in paired serum DNA, as compared with the absence of the mutation (P=0.02). The most common adverse events were mild rashes and diarrhea; grade 3 cutaneous toxic effects were recorded in 16 patients (7.4%) and grade 3 diarrhea in 8 patients (3.7%). Large-scale screening of patients with lung cancer for EGFR mutations is feasible and can have a role in decisions about treatment.

Detection of RET mutations in multiple endocrine neoplasia type 2a and familial medullary thyroid carcinoma by denaturing gradient gel electrophoresis.

Germline missense mutations within the coding region of the RET proto-oncogene have recently been described in patients with the dominantly inherited cancer syndromes, multiple endocrine neoplasia type 2a (MEN 2a) and familial medullary thyroid carcinoma (FMTC). To date, the sequence variations occur in RET exons 10 and 11 and alter highly conserved cysteine residues in the proposed extracellular domain at codons 609, 611, 618, 620, and 634. To expedite rapid screening of populations at risk of MEN 2a or FMTC, we developed a PCR-based denaturing gradient gel electrophoresis (DGGE) strategy that detects polymorphisms occurring at all five Cys codons in both RET exons using identical gel conditions. In this report, the screening results from DGGE analysis of 15 distinct MEN 2a and FMTC mutations are shown. Each mutation generated a clearly distinguishable and unique homo- and heteroduplex band pattern. Given the highly efficient, reproducible, and sensitive nature of this approach, DGGE is particularly appropriate for rapid, large-scale screening of patients. Since prior knowledge of the RET mutation is unnecessary for analysis, DGGE is potentially valuable for distinguishing germline from seemingly sporadic medullary thyroid cancer as well as identifying novel sequence changes.

Detection of RET mutations in multiple endocrine neoplasia type 2a and familial medullary thyroid carcinoma by denaturing gradient gel electrophoresis

Germline missense mutations within the coding region of the RET proto-oncogene have recently been described in patients with the dominantly inherited cancer syndromes, multiple endocrine neoplasia type 2a (MEN 2a) and familial medullary thyroid carcinoma (FMTC). To date, the sequence variations occur in RET exons 10 and 11 and alter highly conserved cysteine residues in the proposed extracellular domain at codons 609, 611, 618, 620, and 634. To expedite rapid screening of populations at risk of MEN 2a or FMTC, we developed a PCR-based denaturing gradient gel electrophoresis (DGGE) strategy that detects polymorphisms occurring at all five Cys codons in both RET exons using identical gel conditions. In this report, the screening results from DGGE analysis of 15 distinct MEN 2a and FMTC mutations are shown. Each mutation generated a clearly distinguishable and unique homo- and heteroduplex band pattern. Given the highly efficient, reproducible, and sensitive nature of this approach, DGGE is particularly appropriate for rapid, large-scale screening of patients. Since prior knowledge of the RET mutation is unnecessary for analysis, DGGE is potentially valuable for distinguishing germline from seemingly sporadic medullary thyroid cancer as well as identifying novel sequence changes. © 1996 Wiley-Liss, Inc.

Use of bacterially-expressed antigen for detection of antibodies to the EBV-specific deoxyribonuclease in sera from patients with nasopharyngeal carcinoma

A cDNA clone, BG9, corresponding to the open reading frame BGLF5 of Epstein-Barr virus (EBV) DNase was inserted into an E. coli expression vector, pET3a, to generate a recombinant plasmid, pDNase 5. High level of expression of a DNase activity was detected in the E. coli transformed with pDNase 5 following induction with IPTG. The enzyme activity was purified using DEAE-cellulose, phosphocellulose and DNA-cellulose column chromatography. The purified protein appeared to be nearly homogeneous in SDS-PAGE using Coomassie blue staining. The requirement for divalent cations and optimum pH as well as inhibitory concentrations of ionic strength and polyamines for the purified enzyme activity were determined and seemed to be very similar to those of the enzyme activity purified from an EBV producing lymphoblastoid cell line. Using the purified enzyme as an antigen and anti-IgA as the secondary antibody, 82% ( 64 78 ) and 91% ( 71 78 ) of sera from patients with nasopharyngeal carcinoma (NPC) were shown to be positive by dot immunobinding assay and ELISA, respectively. The results suggest that purified E. coli expressed EBV DNase may be useful for preparing specific test for large scale screening of patients with NPC.

Psychotic symptoms in normal‐pressure hydrocephalus

Two patients with a psychiatric history of about 20 years, and clinical and neuroradiological signs of normal-pressure hydrocephalus (NPH) are reported. One had a periodic psychosis subsequent to a tuberculous meningitis, and this overshadowed the slight classical symptoms of NPH. She had received at least 120 treatments with electro-convulsive therapy. The second patient suffered from a paranoid psychosis; other signs of NPH were moderate though progressive. Both patients showed definite improvement of their NPH symptoms after ventriculo-atrial shunting, and psychotic symptoms ceased totally. Follow-up was 5 years for the patient with periodic psychosis. The other patient died from septicaemia 2.5 years after shunting. A large-scale screening of patients with psychiatric symptoms or dementia, particularly when combined with gait disturbance, should be done by using computerized tomography. Patients suspected of having NPH should then be referred for further examination with the aim of selecting patients suitable for shunting. These measures seem well motivated from humanitarian as well as economic points of view.

Parenteral iron in treating surgical patients and the importance of routine evaluation of serum iron-binding capacity: report of three cases.

We have endeavored to show the importance of iron deficiency and to cite a few examples of the systemic effects of such deficiency without anemia. We have shown the need for large-scale screening of patients for iron deficiency and suggest that serum iron and total iron-binding capacity determinations will adequately furnish the vehicle for this purpose. The modes of iron therapy are discussed with the belief that for the surgeon parenteral iron is the best vehicle to replace the deficiency with the least risk.