Discrepant Cases Research Articles

On the notion of visual illusions

The usual definitions of illusions, as incorrect perceptions or cases of discrepancies between reality and our perception of reality, have been criticized as inadequate. The reason is that it is not clear how to apply this notion in a number of interesting cases. This paper is an attempt to provide an adequate definition of illusions, appropriate for many classical phenomena usually referred to as illusions.

Assessment of germline and somatic alterations in main candidate genes among patients with multiple primary melanoma

Background A series of patients with multiple primary melanoma (MPM) has been studied for assessing frequency and distribution of alterations in candidate genes involved in susceptibility (CDKN2A) and pathogenesis (BRAF, cKIT, CyclinD1) of such a disease. Methods Two hundred and twenty-seven genomic DNA samples from paired synchronous and/or asynchronous tumour tissues of 106 MPM patients (92 cases with two, 13 with three, and 1 with four primary melanomas) were screened for somatic mutations in BRAF gene and FISHbased amplifications in cKIT and CyclynD1 genes. For 87 (84%) MPM patients from our series, peripheral blood was available and germline DNAs was analyzed for mutations in p16CDKN2A and p14CDKN2A genes. All mutation analyses we performed by direct automated DNA sequencing. Family history for melanoma was defined according to standardized criteria. Results At somatic level, BRAF mutations were identified in 108/ 227 (48%) primary melanoma tissues, whereas amplification of cKIT and CyclinD1 genes was observed in 8/208 (4%) and 28/204 (14%) analyzed tissue samples, respectively. Considering all types of genetic events, paired samples presented a poorly consistent distribution of somatic alterations in same patients [55/106 (52%) discrepant cases). Among them, 35/106 (33%) patients presented discrepant MPM lesions according to the BRAF mutation status. Among the 87 MPM patients whose germline DNA was available, 8 (9%) of them showed different CDKN2A germline mutations: 7 in p16CDKN2A and 1 in p14CDKN2A. Assessment of family history for melanoma revealed that 13/87 (15%) patients presented at least one additional family member affected; a total of ≥ 3 melanomas in family was observed in 20/87 (23%) cases of our series. The CDKN2A germline mutations were found significantly more frequent in patients with familial history of melanoma (7/13; 54%) compared with patients without (1/74; 1.4%) (P<0.001); analogously, CDKN2A mutations were observed in 1/67 (1.5%) and 7/20 (35%) patients with 2 and 3 or more melanomas in family, respectively (P<0.001). Conclusions The low consistency in mutation patterns at somatic level among MPM lesions from the same patients provide further evidence that melanomagenesis is heterogeneous and molecularly different cell types may participate to the development of multiple melanomas. Our findings on germline DNA indicate that occurrence of at least 3 melanomas (in patients or families) or familial recurrence of melanoma may represent strong indicators to address patients to CDKN2A mutation screening.

Comparative Study Using Intramedullary K-wire Fixation Over Titanium Elastic Nail in Paediatric Shaft Femur Fractures.

Fracture shaft femur is common paediatric trauma leading to significant morbidity. Conservative treatments available are associated with prolonged periods of immobilization. Use of flexible intramedullary implant allows early rehabilitation in diaphyseal fractures of femur in children. The aim of the present study is to compare fixation of diaphyseal femur fracture by titanium elastic nail and intramedullary K-wires in children. Prospective randomized study in a tertiary care hospital. Fifty-two children between 6 years and 14 years of age with femoral shaft fracture were assigned either in Group I or Group II based on computer generated random numbers. In Group I closed percutaneous intramedullary K- wire fixation and in Group II closed percutaneous intramedullary titanium elastic nail was used to fix the fractures. Partial weight bearing was allowed after 6 weeks of surgery and full weight bearing at clinico-radiological union. Average time of radiological union was 6 to 10 weeks in both groups. In both the groups two cases had entry site irritation which resolved with early implant removal. One case in both the groups had unacceptable mal-alignment. Both the groups had few cases of limb-length discrepancy, which was in acceptable limit, except two cases of TENS. There was no statistically significant difference between the results of both the groups. But, using K-wires significantly reduced the cost of treatment. Most of such fractures in our society are neglected because of high cost of treatment. Providing a cheaper alternative in form of K-wires may be beneficial for the patients from low socio-economic status.

Three dimensional finite element analysis of the stress distribution around the mandibular posterior implant during non-working movement according to the amount of cantilever.

PURPOSEIn case of large horizontal discrepancy of alveolar ridge due to severe resorption, cantilevered crown is usually an unavoidable treatment modality. The purpose of this study was to evaluate the clinical criteria for the placement of the aforementioned implant crown.MATERIALS AND METHODSThe mandible model with 2 mm thick cortical bone and cancellous bone was fabricated from CT cross-section image. An external connection type implant was installed and cantilevered crowns with increasing offset of 3, 4, 5, 6, and 7 mm were connected. Vertical load and 30° oblique load of 300 N was applied and stress around bone and implant component was analyzed. A total of 14 cases were modeled and finite element analysis was performed using COSMOS Works (Solid works Inc, USA).RESULTSAs for the location of the vertical load, the maximum stress generated on the lingual side of the implant became larger according to the increase of offset distance. When the oblique load was applied at 30°, the maximum stress was generated on the buccal side and its magnitude gradually decreased as the distance of the offset load increased to 5 mm. After that point, the magnitude of implant component's stress increased gradually.CONCLUSIONThe results of this study suggest that for the patient with atrophied alveolar ridge following the loss of molar teeth, von-Mises stress on implant components was the lowest under the 30° oblique load at the 5 mm offset point. Further studies for the various crown height and numbers of occusal points are needed to generalize the conclusion of present study.

Comments on Point of Care D-Dimer Testing in the Emergency Department: A Bioequivalence Study

Dear Editor We read with interest the article Point of Care D-Dimer Testing in the Emergency Department: A Bioequivalence Study by Perveen et al. published in Ann Lab Med 2013;33:34-38 [1]. In this article, the authors compared the performance of the D-dimer assays on the AQT90 FLEX analyzer (Radiometer Medical Aps, Akandevej, Denmark) and the VIDAS analyzer (bioMerieux SA, RCS Lyon, France). The study had 2 objectives: To determine any significant difference between the 2 assays in the time from sample draw until result. To quantify the agreement between the results obtained by the 2 assays when performed on samples from the same sample draw. A pilot study determined that a minimum sample size of 100 patients was required for the first objective. The main study included 104 patients and revealed a significant difference between the 2 assays in the time from sample draw until result. For the second objective, determining the agreement between the results obtained by the 2 assays, the pilot study did not determine a minimum sample size; however, the data from the 104 patients were used in this regard. Additionally, imaging results were available for 40 patients in the study sample. Among these, 7 patients had positive imaging and 33 patients had negative imaging results. Only these 40 imaging results were used to calculate the sensitivity and the specificity for the 2 assays. Therefore, we agree with the authors when they state that the sample size was not large enough to compare the clinical performance of both assays with respect to venous thromboembolism. Discordant results between the 2 assays were found in 8 patients. In all of these 8 cases, a positive result was found with the VIDAS assay and a negative result with the AQT90 FLEX assay. All of these 8 patients had negative imaging results. The authors have presented the results for these 8 patients in a table. Then, the authors measured the ratios between the AQT90 FLEX and VIDAS results. The range is presented as 0.34-2.13. However, this must be a typographical error since the results for sample 7 in Table 2, using the 2 analyzers, is 318 ng/mL and 1,300 ng/mL. Thus, we assume the true range to be 0.24-2.13. This means that there is a 9-fold difference between the highest and the lowest ratio. The authors concluded that the average ratio is 0.85. The authors claim that the average ratio of 0.85 is the reason behind the 8 discrepant results and that this difference between the assays raises the question of whether it is acceptable to use the AQT90 FLEX assay in the emergency department. We disagree with that statement since the imaging results yielded negative findings in the 8 cases. There is no consensus on the standardization of D-dimer assays. Goodacre et al. [2] found in their meta-analysis, which included 97 study reports on 198 D-dimer assays in 99 different patient groups, a substantial heterogeneity, particularly with regard to specificity. Even though linear regression analysis may show a good correlation between the 2 D-dimer assays, the correlations are often not good across the measuring range [3]. The variation, which can be seen especially near the cutoff, is clearly shown by Sukhu et al. [4]. Although 12% of their samples showed discordant values, the 2 assays (Stalia and VIDAS) did not differ significantly in clinical performance. A useful comparison of the D-dimer assay performance is the one made against a gold standard or truth. For D-Dimer assays, that gold standard is imaging. Since the imaging results, were in agreement with the AQT90 FLEX D-Dimer results in the discrepant cases (VIDAS vs. AQT90 FLEX), we believe that the data from Perveen et al. support the findings by Sidelmann et al. [5] who compared the AQT90 FLEX assay to several other assays including the VIDAS. Sidelmann et al. [5] concluded that the AQT90 FLEX D-dimer assay demonstrated excellent performance and that it was comparable to routine D-dimer assays.

HER2 In Situ Hybridization in Gastric and Gastroesophageal Adenocarcinoma

Patients with gastric and gastroesophageal junction (GEJ) adenocarcinomas that are HER2 positive by immunohistochemistry (IHC) or in situ hybridization show a significant survival benefit with trastuzumab therapy. In situ hybridization is traditionally done by fluorescence in situ hybridization (FISH), despite some limitations. An alternative is the dual in situ hybridization (Dual ISH) technique that is fully automated and uses differentially labeled CEP17 and HER2 probes that can be read by light microscopy on 1 slide. The aim of this study was to assess the utility of Dual ISH in gastric/GEJ cancer and to compare the results with those obtained by IHC and FISH. Cases of gastric/GEJ adenocarcinoma were analyzed by IHC, FISH, and Dual ISH and the correlation between methods calculated. Results for 50 patients were available. There was a 98% (49/50) concordance rate between Dual ISH and FISH. One discrepant case was nonamplified by FISH but showed focal amplification by Dual ISH. Discrepancy was attributed to tumor heterogeneity, which was a frequent finding (78% of HER2-positive cases). There was excellent correlation between Dual ISH and FISH for assessment of HER2 amplification. Dual ISH was rapid, easy to interpret, and maintained cell morphology, which was valuable in identifying tumor heterogeneity.

Performance of the Roche cobas 4800 high‐risk human papillomavirus test in cytologic preparations of squamous cell carcinoma of the head and neck

Determining high-risk human papillomavirus (HR-HPV) status of head and neck squamous cell carcinoma (HNSCC) defines a tumor subset with important clinical implications. Cytologic sampling often provides the sentinel or sole diagnostic specimen. The authors assessed the performance characteristics for the Roche cobas 4800 HPV real-time polymerase chain reaction (PCR)-based system (cobas) on cytologic specimens of HNSCC compared with standard methods of in situ hybridization (ISH) for HR-HPV and immunohistochemistry (IHC) for p16 on formalin-fixed, paraffin-embedded (FFPE) tissue. Samples of HNSCC were collected by fine-needle aspiration and from surgical biopsies or resections, fixed, and processed with the cobas system. Available corresponding FFPE samples were synchronously evaluated for HR-HPV using ISH and IHC. Discrepant cases underwent additional PCR studies for adjudication. Thirty-six samples from 33 patients were analyzed. Forty-two percent (n = 15) of tumors were positive for HR-HPV according to cobas. Corresponding histology with ISH (n = 30) was concordant in 91% of samples. Compared with the adjudication PCR standard, there were 3 false-positive cases according to cobas. Ninety-two percent (n = 12) of cases were the HPV16 subtype. The overall sensitivity for the cobas system was 100%, and the specificity was 86%. Concordance in HNSCC HR-HPV status between cobas and ISH/IHC was > 90%, and cobas demonstrated a sensitivity of 100% and a specificity of 86%, broadening options for HR-HPV testing of fine-needle aspiration samples. Advantages for this system include subtyping of HR-HPV and the ability to discern HR-HPV status earlier in a patient's treatment course.

Comparison of Oncotype DX and Mammostrat risk estimations and correlations with histologic tumor features in low-grade, estrogen receptor-positive invasive breast carcinomas

Several molecular tests have been developed to estimate risk of distant recurrence and help clinical decision-making regarding adjuvant chemotherapy in patients with early stage breast carcinoma. Both Oncotype DX, a 21-gene expression profile, and Mammostrat, an immunohistochemistry-based assay, are validated to stratify patients into groups with low, intermediate and high risk of distant recurrence. However, they have not been compared head-to-head and little data are available regarding their correlation with clinicopathologic tumor features. In this study, we compared the clinicopathologic tumor features with risk estimations by Oncotype DX and Mammostrat in 106 low-grade estrogen receptor (ER)-positive breast carcinomas. Double immunohistochemical stain for pancytokeratin and Ki-67 was performed to assess cell proliferation in cancer vs stromal/inflammatory cells. Tumors showing intermediate/high risk by Oncotype DX, but not by Mammostrat, showed increased stromal cellularity, presence of inflammatory cells and increased proliferation in stromal/inflammatory cells. Discrepant cases showing intermediate/high risk by Oncotype DX but low risk by Mammostrat were associated with increased stromal cellularity, presence of inflammatory cells and increased proliferation in stromal/inflammatory cells, compared with concordant cases showing low risk by both assays. Our results suggest that low-grade ER-positive breast carcinomas with increased stromal/inflammatory cell proliferation may show an apparent increased risk of distant recurrence as assessed by Oncotype DX, which uses RNA extracted from a mixture of tumor and stromal/inflammatory cells in the assay. Mammostrat, which examines cancer cells only, may provide a better estimation of likely tumor behavior in a subgroup of low-grade breast carcinomas.

Suppression of severe achondroplasia with developmental delay and acanthosis nigricans by the p.Thr651Pro mutation

Severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN) is an extremely rare severe skeletal dysplasia characterized by significant developmental delay, brain structural abnormalities, hearing loss, and acanthosis nigricans. The disorder is the result of a single missense mutation at codon 650 (p.Lys650Met) in the fibroblast growth factor receptor 3 gene (FGFR3). We describe a child who initially presented with a mild achondroplasia or hypochondroplasia like phenotype. Molecular analysis of the FGFR3 gene showed the common SADDAN mutation and a second novel mutation at codon 651 (p.Thr651Pro). Both mutations were shown to occur on the same allele (cis) and de novo. Transient transfection studies with FGFR3 double mutant constructs show that the p.Thr651Pro mutation causes a dramatic decrease in constitutive receptor kinase activity than that observed by the p.Lys650Met mutation. Our data suggest that the molecular effect by the p.Thr651Pro is to elicit a conformational change that decreases the FGFR3 tyrosine kinase activity, which is constitutively activated by the SADDAN mutation. Due to the inheritance of both a gain-of-function and a loss-of-function mutation, we conclude that a reduction of constitutive activation caused the milder skeletal phenotype. Although the occurrence of double mutations are expected to be rare, the presence of other FGFR3 modifiers may be responsible for some of the clinically discrepant skeletal dysplasia cases.

Detecting EGFR alterations in clinical specimens—pitfalls and necessities

We investigated the epidermal growth factor receptor (EGFR) status in early stage lung cancer in Southern Sweden, a population for which there are no previous reports on the EGFR mutation frequency. Three hundred fifty small cell lung cancers, adenocarcinomas (AC), squamous cell carcinomas (SqCC), and large cell carcinomas were analyzed using a combination of techniques for the analysis of protein expression, gene copy numbers, and mutations. Immunohistochemical (IHC) staining with antibodies for the EGFR mutations L858R and del E746-A750 revealed intratumoral heterogeneity and several discrepant cases when compared to mutation-specific polymerase chain reaction (PCR)-based analysis. The frequencies of these two mutations, when considering IHC staining with mutation-specific antibodies in a cohort of 298 cases and subsequent confirmation by PCR, were 10 % in AC and <2 % in SqCC. Furthermore, screening by sequencing of EGFR in a cohort of 52 lung AC and squamous carcinomas demonstrated a more diverse mutation spectrum, not covered by the mutation-specific antibodies. High expression of total EGFR protein was correlated to high gene copy numbers but did not reflect the mutational status of the tumors. We believe that the mutation spectra in a Southern Swedish population is too diverse to be covered by the mutation-specific antibodies, and we also raise some other issues regarding the use of the mutation-specific antibodies, for example concerning heterogeneous expression of the mutated protein, optimal antibody dilution, and discrepancies between staining results and PCR.

Poorly differentiated thyroid carcinomas: application of the Turin proposal provides prognostic results similar to those from the assessment of high‐grade features

To investigate the performance of two proposed methods for assessing the prognosis of poorly differentiated thyroid carcinomas (PDTC): the Turin proposal and Hiltzik's histological grade (HHG). This was done using a series of 82 thyroid carcinomas of follicular origin. The two methods were able to classify patients accurately into two different prognosis groups. Although the Turin proposal and HHG displayed discrepant cases, they provided similar prognostic information. The Turin proposal gave accurate numbers and thresholds of PTDC criteria (loss of follicular architecture and mitoses, necrosis or convoluted nuclei). One Turin criterion, convoluted nuclei, failed to provide any prognostic value. Hiltzik's histological grade was also a simple and reliable method, allowing detection of tumours with high-grade features (mitosis and/or tumour necrosis), notably some papillary carcinomas that displayed an intermediate prognosis. We show that Ki67 labelling (≥ 4%) was an independent factor and predictor of cause-specific survival. With similar performances in predicting prognosis, the Turin proposal and HHG provided complementary results in identifying a larger group of 'intermediate prognosis' thyroid carcinomas, which require adequate treatment and follow-up.

Evaluación longitudinal con FP-CIT en pacientes con parkinsonismo

ObjectiveTo assess a group of patients with parkinsonism using serial studies with FP-CIT, basically the initial false negative results. MethodsRestrospective study of 92 patients (55 men and 37 women) who had undergone 2 different FP-CIT studies because of discrepancies between study results and clinical progression. The mean elapsed time between the studies was 26 months (SD: 6). We performed a semi-quantitative study using the patient's clinical history and the available literature to analyse discrepant cases with a normal initial study and subsequent pathological findings. ResultsA total of 184 studies were completed for 92 patients; 11 of those 92 showed discrepancies between initial and subsequent studies. Among the 11 discrepant cases, 7 showed a normal initial study and pathological findings at a later date. Analysis of the predominant clinical features that might explain this behaviour revealed that 4 of these 7 subjects presented tremor-dominant parkinsonism. Regarding the rest, 1 presented early stage parkinsonism and was treated with antidopaminergic agents; 1 was classified as probable multisystem atrophy type C, and the third showed clinical signs of atypical parkinsonism without any causes of those signs being identified. ConclusionsSerial FP-CIT studies are unnecessary in the large majority of cases, but they may be justifiable in certain clinical situations.

Use of Web-based training for quality improvement between a field immunohistochemistry laboratory in Nigeria and its United States–based partner institution

The importance of hormone receptor status in assigning treatment and the potential use of human epidermal growth factor receptor 2 (HER2)-targeted therapy have made it beneficial for laboratories to improve detection techniques. Because interlaboratory variability in immunohistochemistry (IHC) tests may also affect studies of breast cancer subtypes in different countries, we undertook a Web-based quality improvement training and a comparative study of accuracy of immunohistochemical tests of breast cancer biomarkers between a well-established laboratory in the United States (University of Chicago) and a field laboratory in Ibadan, Nigeria. Two hundred and thirty-two breast tumor blocks were evaluated for estrogen receptors (ERs), progesterone receptors (PRs), and HER2 status at both laboratories using tissue microarray technique. Initially, concordance analysis revealed κ scores of 0.42 (moderate agreement) for ER, 0.41 (moderate agreement) for PR, and 0.39 (fair agreement) for HER2 between the 2 laboratories. Antigen retrieval techniques and scoring methods were identified as important reasons for discrepancy. Web-based conferences using Web conferencing tools such as Skype and WebEx were then held periodically to discuss IHC staining protocols and standard scoring systems and to resolve discrepant cases. After quality assurance and training, the agreement improved to 0.64 (substantial agreement) for ER, 0.60 (moderate agreement) for PR, and 0.75 (substantial agreement) for HER2. We found Web-based conferences and digital microscopy useful and cost-effective tools for quality assurance of IHC, consultation, and collaboration between distant laboratories. Quality improvement exercises in testing of tumor biomarkers will reduce misclassification in epidemiologic studies of breast cancer subtypes and provide much needed capacity building in resource-poor countries.

La pratique de l’IRM mammaire au centre hospitalier de Chambéry

ObjectiveTo determine indications, technique and results of breast MRI performed at Chambery hospital (CH). Patients and methodsAnalytical retrospective study of 12 months, conducted at CH. It involved the analyzing of 100 breast MRI examinations performed in 84 patients using a brand device Siemens Magneton Area®. ResultsThe mean age of patients was 56.2 years. The indications for breast MRI were the assessment of local and regional extension of breast cancer (28%), the results of monitoring of neoadjuvant chemotherapy (22%), the research of local recurrence after conservative treatment (14%) and cases of diagnostic discrepancies (13%). The most commonly used sequences were axial T1 ES (91%), axial T2 STIR (91%) and axial T1 with gadolinium injection (97%). The assessment of locoregional extension revealed multifocal invasion in 14 cases, pectoral in 3 cases, lymph node in 7 cases and skin in 4 cases. Concerning the monitoring of neoadjuvant chemotherapy, tumor involution was found in 10 patients and stability in 3 others. The distinction between tumor recurrence and postoperative scar showed 10 negative cases and 4 cases of tumor recurrence. ConclusionBreast MRI is an excellent non-invasive method for studying fully and satisfactorily within. It is mainly practiced in the CH to the extension of cancer and monitoring neoadjuvant chemotherapy balance.

Validation and workflow optimization of human epidermal growth factor receptor 2 testing using INFORM HER2 dual-color in situ hybridization

Human epidermal growth factor receptor 2 (HER2) status is useful for predicting response to trastuzumab. Fluorescence in situ hybridization (FISH) for HER2 gene amplification is accurate but limited because of cost, the need for fluorescence microscopy, the limited assessment of histology, and the fading of its signal over time. Dual-color in situ hybridization (Dual ISH) is fully automated, is viewable by bright-field microscopy, has a stable signal, and has separate colors for HER2 and chromosome 17 signals. HER2 immunohistochemistry (IHC), FISH, and Dual ISH were performed on 101 breast cancer cases. Sixteen of 17 cases with 3+ HER2 by IHC showed gene amplification by FISH, and 15 showed amplification by Dual ISH. Three of the 2+ IHC cases were either amplified or equivocal by Dual ISH. None of the IHC-negative cases were amplified by either FISH or Dual ISH. Dual ISH agreed with FISH in 93% of cases. Among the 6 discrepancies, 4 were for an equivocal result for 1 test compared with either a positive or a negative result for the other test. The average differences in readings between Dual ISH and FISH in the discrepant cases were only 0.02, with a range of -1.37 to 1.85. Turnaround time for FISH as a send-out test from test ordering to reporting averaged 8.27 workdays, whereas the turnaround time for Dual ISH performed in-house averaged 4.94 workdays (P < .0000001). Our results indicated that automated Dual ISH is a useful method for evaluating HER2 status in a clinical setting.

Cytologic Features of Metastatic Micropapillary Urothelial Carcinoma on Fine Needle Aspiration and Effusion Cytology

s S9 Materials and Methods: SLN evaluation using IC of BC patients from January to December 2011 were identified using Moffitt Cancer Center's Anatomic Pathology cytology-histology correlation database. IC slides (airdried and Diff-Quik stained) were classified as negative, positive or deferred (atypical and suspicious). The corresponding SLN histologic samples were evaluated with one Hematoxylin and eosin section and immunohistochemistry (AE1/3). The final diagnosis was classified into negative or positive for macrometastasis. After reviewing the IC smears of discrepant cases, errors were classified as: sampling, screening or interpretation. Results: 915 IC of SLNs were performed. The average number of SLN per case was 2.1. Eighty-two SLN were positive on final diagnosis, and 33 of these were accurately diagnosed as positive on IC (40%). Twelve SLN were deferred (9 atypical, 3 suspicious) (15%). There were 37 false negative (FN) SLN (45%) due to sampling (17, 46%), screening (14, 38%) and interpretative (6, 16%) errors. Screening errors occurred with less than 3 groups or isolated malignant cells only. Interpretation errors occurred when the malignant cells were not recognized and/or interpreted as macrophages. The sensitivity of IC was 69%, specificity 100%, positive predictive value 100%, and negative predictive value 96%. Conclusions: Our results are comparable with the previously reported sensitivity of IC (33 to 96%) and support the usefulness of this technique. We had no false positives. The majority of FN were due to sampling error, in which the malignant cells were not sampled by the IC. Improvement of SLN sampling technique by IC could improve sensitivity. Figure 1 Diagram displaying histologic type and reason for discrepancy in false negative SLN (37). Table FNA of Breast Masses in Pregnant and Lactating Women LAd CA AS Other Inadequate Cytology 19 2 0* 4 (abscess, cyst) 3 (including 1 AS*) Histopathology 17 2 1 1 Abbreviations: LAd: Lactating adenoma; CA: Invasive carcinoma; AS: Angiosar-

Value of immunohistochemistry in the detection of BRAFV600E mutations in fine‐needle aspiration biopsies of papillary thyroid carcinoma

Fine-needle aspiration biopsy (FNAB) is important in the diagnostic establishment of suspicious thyroid nodules. In thyroid neoplasms, mutation of the BRAF gene occurs rather exclusively in papillary thyroid carcinoma (PTC) and results in>98% of the cases in V600E amino acid substitution. In the current study, the authors investigated the diagnostic value of a recently described monoclonal antibody that detects this specific mutation on FNAB specimens from patients with PTC. BRAF(V600E) status of FNAB cell blocks from 55 patients with PTC was analyzed by immunohistochemistry (IHC) with the new BRAF(V600E) antibody (clone VE1) and by Sanger sequencing (SaS). In discrepant cases, ultra-deep sequencing was also performed. Available corresponding histological specimens were investigated by IHC and, in selected cases, with SaS as well. All cases yielded evaluable IHC staining results of the cell block sections with good interobserver agreement (kappa value, 0.650). Ten tumors (18.2%) demonstrated no staining, 10 tumors (18.2%) demonstrated equivocal staining, 25 tumors (45.4%) demonstrated moderate staining, and 10 tumors (18.2%) demonstrated strong staining. SaS was able to be performed in 48 cases. Nineteen cases demonstrated wild-type BRAF and 29 cases were found to have the BRAF(V600E) mutation. After performing ultra-deep sequencing 1 false-positive and 2 false-negative VE1 IHC cases remained, resulting in a sensitivity of 93.8% and a specificity of 93.8%. BRAF(V600E) mutations in FNAB specimens from patients with PTC can be reliably detected in most cases by IHC with a new mutation-specific antibody. Interpretation of VE1 IHC staining results on cell block slides of PTC can be difficult in some cases.

Postmortem lung volume/body weight standards for term and preterm infants

Assessment of lung growth is a critical component of the perinatal autopsy. Increased lung liquid content may lead to overestimation of lung growth based on (wet) lung weight. In contrast, lung volume is not influenced by intraalveolar lung liquid. Our aim was to establish age-specific reference values for postmortem lung volume/BW in preterm and term infants. We performed a retrospective analysis of fetuses/infants (16-41 weeks' gestation) without (N = 134) or with (N = 79) risk factors for pulmonary hypoplasia. Lungs were inflated at standardized pressure and volumes determined by water immersion method. Lung volume increased 11-fold between 16 and 41 weeks' gestation, concomitant with a 16-fold increase in BW. Mean lung volume/BW remained constant at 33-34 ml/kg between 16 and 31 weeks' gestation and decreased to 23.4 ml/kg at term. Lung volume/BW of infants with severe risk factors (renal anomalies, diaphragmatic hernia) was significantly lower than age-matched standards. In this group, all fetuses/infants diagnosed as having lung hypoplasia by lung volume/BW also had lung hypoplasia LW/BW standards. However, in infants with "softer" risk factors (rupture of membranes, chromosomal anomalies), 5/26 cases diagnosed with lung hypoplasia based on lung volume/BW had normal LW/BW ratios. In these discrepant cases, lung sections showed significant inflammation and edema, likely accounting for increased wet lung weight. In conclusion, we determined age-specific lung volume/BW reference values for preterm and term infants. In selected situations assessment of lung volume/BW may represent a useful complementary tool to LW/BW for postmortem evaluation of lung size.

Correlação entre diagnóstico clínico e patológico das lesões brancas da cavidade oral

ObjectivesTo evaluate the discrepancy indexes (DI) between clinical and histopathological diagnoses in patients with oral white lesions. Methods: The histological reports of 64 white lesions subject to biopsy between 2000 and 2010, in the Faculty of Dental Medicine of Oporto, were reviewed in the Faculty archives. The DI for each pathology was expressed by the percent ratio between the number of discrepant cases and all cases. ResultsOf the 26 lichens there were two leukoplakias (DI=7.7%), while in the 14 leukoplakias two lichens occurred (DI=14.4%). Within the five traumatic white lesions, the laboratory recorded one lichen, one inflammatory hyperplasia and one Fordyce disease (DI=60%). Of two erytroleukoplakias one was a carcinoma (50%). Among the 14 papillomas there was a DI of 21% due to one inflammatory hyperplasia, one leukoplakia and one carcinoma. A DI of 50% occurred within the 2 carcinomas since one was a leukoplakia. The sole candidose was in fact a lichen (100% ID). The overall DI for the 64 cases amounted to 25%. ConclusionThe considerable DI's recorded recommend histopathological examination in all doubtful oral white lesions.

Assessing the reliability of an automated dose-rounding algorithm

ObjectivePediatric dose rounding is a unique and complex process whose complexity is rarely supported by e-prescribing systems, though amenable to automation and deployment from a central service provider. The goal of this project was to validate an automated dose-rounding algorithm for pediatric dose rounding. MethodsWe developed a dose-rounding algorithm, STEPSTools, based on expert consensus about the rounding process and knowledge about the therapeutic/toxic window for each medication. We then used a 60% subsample of electronically-generated prescriptions from one academic medical center to further refine the web services. Once all issues were resolved, we used the remaining 40% of the prescriptions as a test sample and assessed the degree of concordance between automatically calculated optimal doses and the doses in the test sample. Cases with discrepant doses were compiled in a survey and assessed by pediatricians from two academic centers. The response rate for the survey was 25%. ResultsSeventy-nine test cases were tested for concordance. For 20 cases, STEPSTools was unable to provide a recommended dose. The dose recommendation provided by STEPSTools was identical to that of the test prescription for 31 cases. For 14 out of the 24 discrepant cases included in the survey, respondents significantly preferred STEPSTools recommendations (p<0.05, binomial test). Overall, when combined with the data from all test cases, STEPSTools either matched or exceeded the performance of the test cases in 45/59 (76%) of the cases. The majority of other cases were challenged by the need to provide an extremely small dose. We estimated that with the addition of two dose-selection rules, STEPSTools would achieve an overall performance of 82% or higher. ConclusionsResults of this pilot study suggest that automated dose rounding is a feasible mechanism for providing guidance to e-prescribing systems. These results also demonstrate the need for validating decision-support systems to support targeted and iterative improvement in performance.