Medico-legal assessment of disability in narcolepsy: an interobserver reliability study

Impairment because of narcolepsy strongly limits job performance, but there are no standard criteria to assess disability in people with narcolepsy and a scale of disease severity is still lacking. We explored: (1) the interobserver reliability among Italian Medical Commissions making disability and handicap benefit decisions for people with narcolepsy, searching for correlations between the recognized disability degree and patients' features; (2) the willingness to report patients to the driving licence authority and (3) possible sources of variance in judgement. Fifteen narcoleptic patients were examined by four Medical Commissions in simulated sessions. Raw agreement and interobserver reliability among Commissions were calculated for disability and handicap benefit decisions and for driving licence decisions. Levels of judgement differed on percentage of disability (P < 0.001), severity of handicap (P = 0.0007) and the need to inform the driving licence authority (P = 0.032). Interobserver reliability ranged from Kappa = -0.10 to 0.35 for disability benefit decision and from Kappa = -0.26 to 0.36 for handicap benefit decision. The raw agreement on driving licence decision ranged from 73% to 100% (Kappa not calculable). Spearman's correlation between percentages of disability and patients' features showed correlations with age, daytime naps, sleepiness, cataplexy and quality of life. This first interobserver reliability study on social benefit decisions for narcolepsy shows the difficulty of reaching an agreement in this field, mainly because of variance in interpretation of the assessment criteria. The minimum set of indicators of disease severity correlating with patients' self assessments encourages a disability classification of narcolepsy.     

A method for checking interobserver reliability in observational sleep studies

Disturbances of the sleep/wake cycle occur frequently in nursing home residents. Because of the many technical difficulties in studying sleep and rhythms in such patients, systematic behavioral observations offer an alternative approach. In this study we describe a method for determining interrater reliability of such observations. Two individuals observed 39 nursing home residents four times per hour during daytime and nighttime hours. Results indicated high interrater reliability for both sleep/wake and the presence of apnea during sleep. Both day and night observations were made reliably. We found only 101 discrepancies of 1.160 tandem observations. These results suggests that behavioral observations are a viable approach in the study of the sleep/wake cycle in nursing home settings.     

Interpretation of subjective symptoms in double-blind placebo-controlled food challenges - interobserver reliability

BACKGROUND: Subjective symptoms after food challenges are difficult to interpret and no standard is available. We discuss a strategy for how to interpret a diary. Furthermore, the interobserver reliability is evaluated. METHODS: Diaries for 32 patients with subjective symptoms were used. The diaries were re-evaluated with a predefined strategy by three independent observers. RESULTS: The proportion of positives was 21.9% among the old diagnoses, according to the new approach 34.4% (observers I and II) and 37.5% (observer III) were positive. The new approach had high interobserver reliability (97 and 100%). CONCLUSIONS: The proportion of positives depends on how subjective symptoms are interpreted. Interpretations of subjective symptoms in diaries could be made with high interobserver reliability.     

Tumor budding in colorectal carcinoma: An institutional interobserver reliability and prognostic study of colorectal adenocarcinoma cases

BackgroundColorectal carcinomas are one of the most commonly diagnosed malignancies. There are many prognostic factors relating to clinical course and disease progression, including tumor stage, metastasis, and tumor budding. In 2016, the International Tumor Budding Consensus Conference (ITBCC) created a system to uniformly assess tumor budding. This system includes a 3-tier system for the grading of tumor budding. In the past, there lacked uniform consensus, however the general grading practice was based on a 2-tiered system. Given that tumor budding is considered to have prognostic value, the accuracy and reproducibility of its assessment is vital. Our study aims to look at interobserver agreement in the scoring of tumor budding.DesignA total of 233 cases of colorectal carcinoma diagnosed in our health system were retrospectively analyzed and routine H&E stained slides of these cases were collected. A representative slide for tumor budding was selected per case. Four investigators with different levels of experience and expertise evaluated the selected slide of each case for tumor budding. Scoring was based on the ITBCC protocol. Clinico-pathological data was collected for each case and analyzed with tumor budding scores. Tumor budding scores per individual investigator and consensus tumor budding score were compared to patient and tumor characteristics including patient survival, tumor grade, tumor stage, and lymph node status.ResultsInter-observer agreement was calculated using Gwet's Agreement Coefficient (AC₁) and associated 95% confidence intervals was used to compare the ratings made by 4 pathologists. Overall, there was variation among pathologists in tumor budding score (Gwet's agreement coefficient = 0.25 and 0.326 for 3-tier and 2-tier grading system, respectively). Results show higher reliability with the 2-tier system compared to the 3-tier system. Tumor stage was significantly associated with budding score for all individual investigators and the consensus value (p value < 0.001).ConclusionThere is low inter-observer agreement in the assessment of tumor budding in colorectal carcinoma. This suggests that it is difficult to uniformly grade tumor budding and that our classification system needs improvement. We found that the older 2-tier system (Hase et al.) results in slightly higher inter-observer agreement than the recently proposed 3-tier grading system (ITBCC, 2016), though both systems lead to suboptimal agreement. Worth noting is that observers with subspecialty GI training and more work experience had higher inter-observer agreement. Our results showed that subspecialty training tends to increase agreement more than overall work experience. In addition, our exploratory results showed that there is an association of tumor budding score to tumor stage. While increasing refinement in classification, the 3-tiered system resulted in decreased agreement in tumor budding assessment. Clearly, there is more work to be done in the identification and quantification of tumor buds.     

ICSD diagnostic criteria for narcolepsy: interobserver reliability. Intemational Classification of Sleep Disorders

STUDY OBJECTIVES: To estimate the reliability of the diagnosis of narcolepsy after clinical interview and polysomnographic evaluation among sleep medicine doctors, before and after training in application of the International Classification of Sleep Disorders (ICSD). SETTING: Videotaped semi-structured interviews of 10 patients complaining of daytime sleepiness of different etiologies. Questions referred to ICSD criteria for narcolepsy. A further series of 10 cases of narcolepsy without cataplexy were simulated, with at least a random one to three of the ICSD polysomnographic criteria at pathological levels. PARTICIPANTS AND DESIGN: Seventeen doctors were required to classify each videotaped case as "ascertained," "possible," or "excluded" narcolepsy, in two sessions: one before and one after discussion of ICSD criteria. The observers were invited to confirm or exclude the diagnosis of narcolepsy in the 10 simulated cases, according to the given polysomnographic findings, before and after an agreed proposal of the interpretation of ICSD polysomnographic criteria. Interobserver reliability was calculated using Kappa statistics. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Interobserver reliability of clinical judgement improved from "substantial" at baseline (Kappa 0.61) to "almost perfect" after training (Kappa 0.95). Interobserver reliability of polysomnographic findings was "fair" at baseline (Kappa 0.24), unanimous after the proposed interpretation of ICSD polysomnographic criteria. CONCLUSIONS: Baseline reliability of diagnostic judgement in suspected narcolepsy was found satisfactory among Italian sleep medicine doctors. Educational training, based on discussion of ICSD criteria, further improved agreement. Diagnosis based on polysomnographic findings, not reliable at baseline, needed a strict interpretation of ICSD criteria to attain standardization.     

Breast carcinoma with basal differentiation: a proposal for pathology definition based on basal cytokeratin expression

AIM: To assess the expression and coexpression of a range of different biomarkers that have been used to define breast carcinomas with a basal phenotype (BP) and their relationship with prognosis in an attempt to refine the definition of BP and to evaluate the reliability of using a single biomarker to identify these tumours. METHODS AND RESULTS: The expression pattern of basal cytokeratins (CK5/6 and CK14), oestrogen, progesterone and androgen receptors, epidermal growth factor receptor, HER2, BRCA1, P-cadherin and myoepithelial markers (smooth muscle actin and p63) were studied in a well-characterized series of invasive breast carcinoma (1872 cases) with long-term follow-up using immunohistochemistry and tissue microarray. Although the additional markers were associated with basal CK expression, they did not serve to improve recognition of cases with differing outcome when compared with basal CKs alone and, if used to define cases, reduced considerably the proportion of cases allocated to this poor prognostic type of breast cancer. CONCLUSION: BP can be defined based on the expression of basal CKs regardless of the expression of other markers.     

Basal plate plaque: a novel organising placental thrombotic process

In contrast to thrombi and haematomas at other body sites, thrombi in the placental intervillous space are not traditionally known to undergo organisation. This report presents 11 examples of a form of organising thrombotic process that develops as a plaque on the foetal aspect of the basal plate. Originally identified in the placenta of a foetus showing severe intrauterine growth restriction, further examples of this lesion, which we term a 'basal plate plaque', show a spectrum of placental involvement. Small lesions appear to occur at points of localised stasis at the basal plate (eg, at edges of anchoring villi or in small basal plate depressions). Large areas of involvement, as seen in the original case, may be pathological markers of more generalised disturbances in placental circulation or of hypercoagulability in the intervillous space. Large basal plate plaques may therefore prove to be diagnostically significant and should be reported.     

Observer reliability in assessing placental maturity by histology.

AIMS--To evaluate the ability of five experienced perinatal pathologists to assess placental maturity reliably by histology. METHODS--Twenty four haematoxylin and eosin slides, six each from placentas of 27, 31, 35, and 39 weeks' gestation, were circulated to five pathologists on three separate occasions. The slides were labelled with the correct or incorrect gestational ages. RESULTS--The mean absolute error over all 360 readings was 2.72 weeks. Only 54% of the slides were assessed within two weeks of the correct gestation. Pathologist tended to overestimate younger gestations and underestimate older gestations. Two, and possibly three, pathologist were influenced by the gestational age state on the label. One pathologist, who did not appear to be influenced by the label, was more accurate in diagnosing gestation of the placentas than other colleagues. CONCLUSIONS--Experienced pathologists can have difficulty in assessing the villous maturity of placentas by histology. They can also be influenced by clinical information provided, such as gestational age. Other observer reliability studies must address the issue of the influence of labelled information on observer variation. A difference in maturation would have to be of a six week magnitude to have a chance of being detected by current methods. This may limit the value of the histological diagnosis of placental dysmaturity as a surrogate marker for uteroplacental ischaemia.     

Use of the ThinPrep method in bile duct brushings: analysis of morphologic parameters associated with malignancy and determination of interobserver reliability

Recent work suggests the ThinPrep method can improve diagnostic sensitivity and accuracy in bile duct brushings. However, the proportion of atypical and suspicious diagnoses remains high. The aim of this study was to identify the most useful morphologic features in ThinPrep bile duct cytology and evaluate interobserver reliability. We evaluated 100 bile duct brushings prepared by ThinPrep, all with either histology or long term clinical follow-up (55 malignant, 45 benign). Morphologic features were evaluated by four experienced cytopathologists blind to clinical information and follow-up diagnoses. These features included cellularity, blood or diathesis, mitoses, inflammation, three-dimensional groups, discohesive atypical cells, macronucleoli, well-defined cytoplasmic borders, and nuclear features of malignancy (nuclear membrance irregularity, chromatin clumping). The data were analyzed by intraclass correlation (ICC) and stepwise multiple logistic regression. Reviewers showed unanimous agreement in 29% of cases, one degree of disagreement in 58% of cases, and full disagreement in 13% of cases. Of benign cases, 38% were thought to be diagnostic of malignancy by at least one of the four reviewers. Sensitivity for the morphologic parameters varied from 18 to 67%; the highest sensitivity was for discohesive atypical cells, well-defined cytoplasmic borders, nuclear features of malignancy, and cellularity (67, 62, 51 and 46%, respectively). Specificity of parameters varied from 16 to 100%; the highest specificity was for mitoses, three-dimensional groups, nuclear features of malignancy, and macronucleoli (100, 98, 93, and 93%, respectively). Interobserver reliability (ICC) was very good for specimen cellularity (0.72) and nuclear features of malignancy (0.60). In logistic regression analysis, only nuclear features of malignancy and increasing patient age separated benign from malignant. On ThinPrep bile duct brushings, nuclear features of malignancy are most useful in distinguishing benign from malignant, and interobserver reliability for this parameter is very good. Discohesive atypical cells show moderate sensitivity and specificity, while three dimensional clusters and macronucleoli are specific but not sensitive for malignancy, and are not significant in multivariate logistic regression models. The relatively high proportion of benign cases thought to be diagnostic of malignancy by at least one reviewer argues for a consensus approach to this diagnosis.     

Intra- and interobserver reliability and agreement in three-dimensional computed tomography measurements of component positions after total knee arthroplasty

BackgroundAccurate evaluation of the postoperative position of total knee arthroplasty (TKA) components is crucial in the analysis of the association of alignments with clinical outcomes. The aim of this study was to investigate the reliability of measurements of component positions after TKA using three-dimensional computed tomography (3D-CT) reconstruction.MethodsTwo independent orthopedic surgeons (an attending surgeon and a fellow) examined 30 knees after primary TKA. The coronal, sagittal, and rotational positions of the femoral and tibial components were measured twice at an interval of six weeks on 3D-CT images reconstructed using ZedKnee software. Mean intra- and interobserver differences of measured angles were calculated, and the intra- and interobserver reliability was determined using intraclass correlation coefficients (ICCs), with agreement assessed by Bland–Altman analysis.ResultsThe mean intraobserver difference between alignment measurements for femoral and tibial components was < 2° (range 0.23–1.17°) and the mean interobserver difference was < 1° (range 0.22–0.97°). The intra- and interobserver ICCs were > 0.8 for all component positions. The only systematic bias found in the intra- and interobserver agreements occurred for the sagittal position of the femoral component.ConclusionThree-dimensional-CT measurements of component positions after TKA showed good intra- and interobserver reliability for the femoral and tibial components in coronal, sagittal and rotational positions. The intra- and interobserver agreements were favorable for all but the sagittal position of the femur. These results suggest that 3D-CT can be used to evaluate the alignment of all TKA components except for the sagittal position of the femur.     

Chronic histiocytic intervillositis: a placental lesion associated with recurrent reproductive loss

Chronic (histiocytic) intervillositis (CHIV), defined for the purposes of this study as diffuse histiocytic infiltration of the intervillous space without villitis, is an idiopathic lesion seen in the chorionic sacs of some spontaneous abortion specimens and placentas. In this retrospective study, we evaluated all patients diagnosed with CHIV from 2 hospitals between 1993 and 2000, plus 1 additional patient from 1977. Histopathology, phenotype of the leukocytic infiltrate, perinatal outcome, and other associated clinical features were assessed by review of clinical records and all available pathology specimens plus immunohistochemical staining. CHIV was found in 31 of 45 specimens examined from 21 patients (23 of 31 first trimester, 3 of 5 second trimester, and 5 of 9 third trimester). Recurrence rate was 67% for patients with more than one specimen reviewed. Overall perinatal mortality rate was 77%, and only 18% of pregnancies reached 37 weeks. Eight of 19 patients with 3 or more pregnancies had recurrent spontaneous abortion (RSA); 5 with primary RSA (> or = 3 consecutive spontaneous abortions (SAB) with no living children) and 3 with secondary RSA (> or = 3 consecutive SAB with 1 or more living children). Severe intrauterine growth restriction was seen in 5 of 8 second- and third-trimester placentas with CHIV. Patients were generally not of advanced maternal age (mean, 29.8 +/- 6.2 years), and there was no obvious racial predisposition. Autoimmune or allergic phenomena were identified in 11 patients. Immunohistochemical staining of the intervillous infiltrate showed a near uniform population of monocyte-macrophages at varying stages of maturity and activation: more than 90% CD45Rb and CD68 positive, 30% to 40% MAC387 positive, less than 5% CD3 positive, and CD1a, CD20, CD30, and CD56 negative. We conclude that CHIV is an uncommon but important cause of recurrent spontaneous abortion and, in some cases, loss at later gestational ages. HUM PATHOL 31:1389-1396.     

Intraobserver and interobserver reliability of radial torsion angle measurements by a new and alternative method with computed tomography

OBJECTIVE:

To evaluate the intraobserver and interobserver reliability of radial torsion angle measurement using computed tomography.

METHODS:

Twelve pairs of cadaver radii and 116 forearms from 58 healthy volunteers were evaluated using axial computed tomography sections measured at the level of the bicipital tuberosity and the subchondral region of the radius. During digital imaging, the angle was formed by two lines, one diametrically perpendicular to the radial tubercle and the other tangential to the volar rim of the distal joint surface. Measurements were performed twice each by three observers.

RESULTS:

In cadaveric bones, the mean radial torsion angle was 1.48° (‐6° ‐ 9°) on the right and 1.62° (‐6° ‐ 8°) on the left, with a mean difference between the right and left sides of 1.61° (0° ‐ 8°). In volunteers, the mean radial torsion angle was 3.00° (‐17° ‐ 17°) on the right and 2.91° (‐16°‐ 15°) on the left, with a mean difference between the sides of 1.58° (0° ‐ 7°). There was no significant difference between each side. The interobserver correlation coefficient for the cadaver radii measurements was 0.88 (0.72 ‐ 0.96) and 0.81 (0.58 ‐ 0.93) for the right and left radius, respectively, while for the volunteers, the difference was 0.84 (0.77 – 0.90) and 0.83 (0.75 – 0.89), respectively. Intraobserver reliability was high.

CONCLUSION:

The described method is reproducible and applicable even when the radial tubercle has a rounded contour.     

Distribution and characterization of anionic sites in trophoblast and capillary basal laminas of human placental villi

The distribution of anionic sites was studied in the trophoblastic and fetal capillary basal laminas of developing human placental villi with the cationic stain ruthenium red. At 7-12 weeks of gestation the trophoblastic basal lamina (TBL) contained ruthenium red-positive granules in a quasi-regular array throughout the lamina densa or sometimes concentrated at the interstitial surface of the lamina densa. The capillary basal lamina (CBL) (and anionic sites) were not present at this age. Anionic sites were also associated with collagen or reticular fibrils. At term, the TBL was largely devoid of anionic sites except for some distributed along its interstitial surface. The CBL was present in later gestation and sometimes had arrays of anionic sites. In order to characterize the anionic sites, minced pieces of villi were incubated in the presence or absence of either chondroitinase ABC, heparitinase, neuraminidase, or Streptomyces hyaluronidase in appropriate buffer systems. Incubation of early villi with heparitinase resulted in the disappearance of the TBL-associated sites. Chondroitinase ABC appeared to reduce staining of collagen-associated sites. In term villi, heparitinase removed those few sites still associated with the TBL but did not affect sites associated with the CBL or collagen. Chondroitinase ABC resulted in the disappearance of all anionic sites. In later gestation, a number of developmentally important macromolecules are transported across the trophoblast and enter the fetal capillaries. We conclude that the absence of an array of polyanionic sites from the term placenta TBL and the reduction in the amount of extracellular matrix intervening between the trophoblast and capillaries are adaptations to enhance the exchange of macromolecules across the placenta.     

Telecytology: Intraobserver and interobserver reproducibility in the diagnosis of cervical-vaginal smears

Telecytologic diagnosis of cervical-vaginal smears is potentially useful because it could allow more efficient use of cytopathologist resources and expertise. A pathologist in one location could, in principle, review cytotechnologists' findings using a video display hundreds or thousands of miles away. Currently, bandwidth restrictions limit practical implementation of such a system to review of fields that had been selected for review by the cytotechnologist. The purpose of our investigation was to evaluate how well this type of review correlates with a review in which the entire slide is available for examination by the pathologist. We prospectively selected 100 consecutive cervical-vaginal smears over an 11-day period in August 1999. For each smear, 4 to 12 fields containing abnormal cells from each slide were digitally imaged. Each of 3 pathologists reviewed all digitized images and all glass slides. Diagnoses based on selected digitized images were compared with those based on conventional pathologist review. The kappa statistic, a measure of chance-corrected agreement (reproducibility), was calculated in each setting. Overall, intraobserver and interobserver reproducibility of cervical-vaginal smear diagnoses is fair to excellent. The use of remote digital images for pathologist review did not introduce large (2-step) diagnostic disagreements. The disagreement between a pathologist's glass slide and digital diagnoses is less than that for different pathologists reviewing glass slides, although interobserver differences were even greater in the interpretation of digital images.     

Genetic origin and proportion of basal plate surface-lining cells in normal and abnormal pregnancies

The human placenta is a transient organ, the villous surface of which is in direct contact with the maternal circulation during pregnancy. Thus, the syncytiotrophoblast and the basal plate-lining cells are considered continuous with the endothelial layer of the maternal vasculature. Two types of cells are found on the surface of the basal plate: trophoblasts (of fetal origin) and endothelial cells of putative maternal origin. Histologic abnormalities have been described in the basal plate of the placenta obtained from patients with preeclampsia and intrauterine growth restriction. Moreover, endothelial cell dysfunction and intravascular inflammation are key features of preeclampsia. The objectives of this study were to: (1) determine the origin of the endothelial cells located in the basal plate surface of the placenta (from male fetuses); and (2) analyze the relative proportion of the intervillous surface of the basal plate occupied by trophoblasts and endothelial cells. Immunohistochemistry and morphometry were performed in placentas from women in the following clinical groups: (1) normal-term pregnancies (n = 15); (2) severe preeclampsia at term (n = 15); (3) small-for-gestational-age (SGA) neonates delivered at term (n = 15); (4) preterm deliveries (<37 weeks) without inflammation (n = 5); and (5) preterm preeclampsia (n = 5). Laser capture microdissection and polymerase chain reaction were used to determine the allelic pattern of the amelogenin gene of the endothelial cells on the intervillous surface of the basal plate. Our results showed that: (1) the endothelial cells lining the basal plate in placentas of male fetuses were uniformly of maternal origin; and (2) in placentas from uncomplicated pregnancies, the median proportion of trophoblasts and endothelial cells covering the surface of the basal plate were 27.7% and 46.5%, respectively. The remaining area of the intervillous surface of the basal plate was composed of fibrin and anchoring villi. Of interest, placentas from women who delivered an SGA neonate had a higher proportion of trophoblasts and a lower proportion of endothelial cells lining the basal plate than those from normal pregnancies (P < .05). The same tendency was observed in placentas from patients with preeclampsia. This study demonstrates that endothelial cells of maternal origin cover the intervillous surface of the basal plate of the placenta, along with trophoblasts of fetal origin. The proportion of this surface lined by trophoblasts is greater in placentas from SGA and preeclampsia than in normal pregnancy. We propose that this change reflects a compensatory mechanism whereby the basal plate surface covered by injured endothelial cells is replaced by trophoblasts or results from a failure of trophoblastic involution in abnormal pregnancies. Our observations also suggest that the lining of the basal plate can provide information about the pathology of endothelial cells in complications of pregnancy.     

Glutamate cycling may drive organic anion transport on the basal membrane of human placental syncytiotrophoblast

Key points

• The placenta removes waste products, drugs and environmental toxins from the fetal circulation and two of the transport proteins responsible for this are OAT4 and OATP2B1 localised to the basal membrane of placental syncytiotrophoblast.
• We provide evidence that OAT4 and OATP2B1 mediate glutamate efflux when expressed in Xenopus oocytes and that in the perfused placenta, bromosulphothalein (an OAT4 and OATP2B1 substrate) stimulates glutamate efflux.
• Furthermore the efflux of glutamate can only be seen in the presence of aspartate, which will block glutamate reuptake by the placenta, consistent with cycling of glutamate across the basal membrane.
• We propose that glutamate efflux down its transmembrane gradient drives placental uptake via OAT4 and OATP2B1 from the fetal circulation and that reuptake of glutamate maintains this driving gradient.

Abstract

The organic anion transporter OAT4 (SLC22A11) and organic anion transporting polypeptide OATP2B1 (SLCO2B1) are expressed in the basal membrane of the placental syncytiotrophoblast. These transporters mediate exchange whereby uptake of one organic anion is coupled to efflux of a counter‐ion. In placenta, these exchangers mediate placental uptake of substrates for oestrogen synthesis as well as clearing waste products and xenobiotics from the fetal circulation. However, the identity of the counter‐ion driving this transport in the placenta, and in other tissues, is unclear. While glutamate is not a known OAT4 or OATP2B1 substrate, we propose that its high intracellular concentration has the potential to drive accumulation of substrates from the fetal circulation. In the isolated perfused placenta, glutamate exchange was observed between the placenta and the fetal circulation. This exchange could not be explained by known glutamate exchangers. However, glutamate efflux was trans‐stimulated by an OAT4 and OATP2B1 substrate (bromosulphothalein). Exchange of glutamate for bromosulphothalein was only observed when glutamate reuptake was inhibited (by addition of aspartate). To determine if OAT4 and/or OATP2B1 mediate glutamate exchange, uptake and efflux of glutamate were investigated in Xenopus laevis oocytes. Our data demonstrate that in Xenopus oocytes expressing either OAT4 or OATP2B1 efflux of intracellular [¹⁴C]glutamate could be stimulated by conditions including extracellular glutamate (OAT4), estrone‐sulphate and bromosulphothalein (both OAT4 and OATP2B1) or pravastatin (OATP2B1). Cycling of glutamate across the placenta involving efflux via OAT4 and OATP2B1 and subsequent reuptake will drive placental uptake of organic anions from the fetal circulation.

Abbreviations

BM

basal membrane

BSP

bromosulphothalein

DHEAS

dehydroepiandrosterone‐3‐sulfate

OAT

organic anion transporter

OATP

organic anion transporting polypeptide

PAH

para‐aminohippuric acid

     

Malignant mesothelioma of the pleura: interobserver variability.

AIMS--To assess the consistency of histopathological diagnosis of pleural malignant mesothelioma by estimating interobserver agreement between five pathologists. METHODS--Eighty eight histological sets pertaining to original diagnoses of pleural malignant mesothelioma were reviewed separately by each pathologist. Diagnostic likelihood was graded as definite (A), probable (B), possible (C), improbable (D), and definitely not (E) malignant mesothelioma. The following indexes were estimated: observed proportion of agreement (Po), kappa statistics and proportion of agreement for "positive" (Ppos) and "negative" (Pneg) diagnoses. RESULTS--Sixty cases (68.2%) were rated by at least three reviewers as A or B and by none of the others as D or E. Five (5.7%) were rated by at least two reviewers as D or E and by none of the others as A or B. Nine (10.2%) showed a serious disagreement, rated A or B and D or E. Agreement for sets obtained at necropsy/surgery (median kappa w = 0.57) was similar to that for endoscopic material (median kappa w = 0.54). Agreement was poor on material obtained by needle biopsy (median kappa w = 0.21). The median value of Ppos varied between 0.94 (necropsy/surgery) and 0.67 (needle biopsy) and that of Pneg between 0.78 (necropsy/surgery) and 0.34 (unspecified biopsy). Interobserver agreement on histological typing was good overall (median kappa = 0.59). CONCLUSIONS--Of the original histological diagnoses, 70% were consistently reproduced through panel review. Most indexes of agreement between pathologists ranged from poor (needle biopsy) to moderate (necropsy/surgery). Agreement in confirming malignant mesothelioma was greater than that regarding exclusion of this diagnosis. Of the cases finally considered to have malignant mesothelioma, the reproducibility of histological typing was relatively satisfactory.     

Smears diagnosed as ASCUS: interobserver variation and follow-up

The purpose of this study was to apply atypical squamous cells of undetermined significance (ASCUS) criteria from the Bethesda System for Reporting Cervical/Vaginal Cytologic Diagnoses (TBS) to the rescreen of cases previously diagnosed as ASCUS, to compare initial and rescreen diagnoses, and to analyze agreement with follow-up (cytology or histology). Two cytotechnologists (S.B. and M.J.M.) and one cytopathology fellow (M.A.) rescreened 632 cervicovaginal specimens diagnosed as ASCUS between June 1, 1992-December 31, 1995. Age and LMP were provided. Rescreen diagnoses were categorized as within normal limits (WNL), ASCUS, low-grade squamous intraepithelial lesions (LSIL), high-grade squamous intraepithelial lesions (HSIL), or carcinoma (CA). Complete agreement was found in 200 specimens (32%): 31 (15%) WNL; 91 (45%) ASCUS; 77 (38.5%) SIL; and one (0.50%) CA. Follow-up revealed no abnormality in 67% of the cases reclassified as WNL, 49% of the cases reclassified as ASCUS, and 48% of the cases reclassified as squamous intraepithelial lesions (SIL). SIL was found in 29% of cases reclassified as WNL, 29% of specimens rediagnosed as ASCUS, and 34% of cases reclassified as SIL. Partial agreement was found in 391 specimens (62%). In 41 specimens (6%), rescreeners were in complete disagreement, and follow-up revealed 9/41 (22%) SIL or worse; 21/41 (51%) WNL; and 4/41 (10%) inconclusive. Applying established criteria, 14% (91/632) of cases diagnosed as ASCUS resulted in complete agreement, and 30% (190/632) resulted in partial agreement. Follow-up of cases initially diagnosed as ASCUS revealed SIL or CA in 30% of cases. ASCUS is a significant diagnosis warranting careful patient follow-up.