Considerable Interobserver Variability Research Articles

An Interobserver Study of Prostatic Fossa Clinical Target Volume Delineation in Clinical Practice

To study interphysician variability of delineation of the prostatic fossa clinical target volume (pfCTV) to be irradiated in patients with residual or recurrent microscopic prostate cancer following radical prostatectomy and to estimate the risk for a geographical miss. Thirty-eight pfCTV were delineated on postradical prostatectomy computerized tomography scans of 8 patients by 5 observers. To estimate the risk of a geographical miss, a high risk volume (HRV) was defined and the percentage of "missed" HRV was calculated for each pfCTV. Interphysician variability was considerable with a mean pfCTV of 39.09 cm (range, 11.8-72.5 cm). At least 25% of the HRV at the bladder neck/anastomosis and the retro-vesical space was excluded in 11 pfCTVs. The mean "missed" HRV was 27.5% (range, 2.3%-78.7%). A pfCTV of less than 30 cm was associated with a geographical miss in 66% of cases versus 17.2% for pfCTV of 30 cm or more (P = 0.006). Observer identity was significantly associated with excluded HRV (P = 0.03). pfCTV delineation is subject to considerable interobserver variability associated with a significant risk of inadequate targeting of the anastomosis/bladder neck region and the retrovesical space. The failure to recognize regions at high risk for harboring microscopic disease may be due to a lack of familiarity with tissue redistribution following radical surgery, and a lack of literature-based guidelines for pfCTV delineation. A strategy to improve pfCTV delineation is proposed.

Interobserver variation in reporting CT arthrograms of the shoulder

Computed tomography (CT) arthrography of the shoulder is an imaging modality of great diagnostic accuracy with regard to glenohumeral instability and in particular labral lesions. Interpretation of the scans is made difficult by the frequent occurrence of normal anatomic variants and the complexity of injuries to the bone and soft tissues. We selected a continuous sample of 50 CT arthrograms of the shoulder and they were reported by two consultant musculoskeletal radiologists. The results were collated and analysed for the level of agreement. Hill-Sachs showed Kappa (K) statistic to be 0.37 (fair agreement), soft tissue Bankart 0.32 (fair agreement), bony Bankart 0.61 (substantial agreement), anterior capsular laxity 0.41 (moderate agreement) and glenohumeral osteoarthritis 0.20 (slight agreement). All the results were significant with a p value of <0.05. Nine (18%) of the 50 scans were in complete agreement. The results demonstrate that there can be considerable interobserver variation (IOV) in the reports of a CT arthrogram of a shoulder. They highlight the potential difficulties in reporting such images and suggests ways in which the report could be more focussed to provide a clinically reliable report and one which matches the surgical findings accurately.

Detection rates of cancer, high grade PIN and atypical lesions suspicious for cancer in the European Randomized Study of Screening for Prostate Cancer

The aim of the study This article presents the incidence of prostate cancer, isolated high grade prostatic intraepithelial neoplasia (PIN) and atypical lesions suspicious for prostate cancer (LSPC) during subsequent screening rounds in the centres of five of the countries participating in the European Randomized Study of Screening for Prostate Cancer (ERSPC). The incidence and predictive value of high grade PIN and LSPC for prostate cancer in subsequent biopsy following these diagnoses were evaluated. Patients and methods Study group consisted of 56,653 screened men in the ERSPC centres of Finland, Italy, Netherlands, Sweden and Switzerland, who underwent 3–7 screening rounds at 2–4 year interval. Data for prostate cancer were obtained from the ERSPC central database. Data for high grade PIN and LSPC were gathered from each ERSPC centre. Detection rates of subsequent prostate cancer in the first re-biopsy after these diagnoses were determined. Results The average cancer detection rate was 3.5%, 3.2% and 3.5% for the completed rounds 1, 2 and 3, respectively, in all five centres. Incidence of high grade PIN increased from 1.5% in the first round to 5.0% in the third round, varying among centres in the first round between 0.8% and 7.6%. The cancer detection rate in the first re-biopsy after the diagnosis of high grade PIN was 12.9%. Incidence of LSPC was 2.4%, 2.7%, 2.2% and 2.6% in the first, second, third and fourth round, respectively. The cancer detection rate at the first re-biopsy after the diagnosis of LSPC was in average 33.8%. Conclusions Cancer detection rate was stable during the three screening rounds. The wide variation in frequency in particular of high grade PIN among the ERSPC centres suggests a considerable inter-observer variation. The average comparatively low detection rate of isolated high grade PIN in the first screening round may be screening-related, while its consistent increase during three screening rounds could be the consequence of a.o. previous screening and ageing of the population. The observed low risk of prostate cancer after isolated high grade PIN in this screening setting is in line with the current recommendation to abstain from early repeat biopsies after this diagnosis. The association of LSPC with high incidence of prostate cancer in re-biopsies confirms the need for early repeat biopsies and follow-up of these men. The low percentage of LSPC (<3% of biopsies) throughout all rounds is reassuring as it limits the biopsy burden in a screening setting.

Diagnostic Challenges in the Pathologic Evaluation of Barrett Esophagus

Barrett esophagus represents an unstable epithelium resulting from chronic gastroesophageal reflux disease. Patients with Barrett esophagus routinely undergo endoscopic examination to detect dysplasia and early carcinoma. Although appropriate classification of Barrett esophagus and neoplasia is usually straightforward, persistent esophageal inflammation may induce epithelial changes that mimic, or mask, dysplasia. Recent data also indicate that specific molecular changes occur in nondysplastic Barrett mucosa and herald the development of dysplasia and/or carcinoma. To describe problematic aspects of biopsy interpretation in tissue samples of the gastroesophageal junction and distal esophagus, including the diagnostic criteria for Barrett esophagus, the importance of the gastric cardia, and pitfalls to the diagnosis of dysplasia. Ancillary studies that have recently emerged as potential adjuncts to the evaluation of patients with Barrett esophagus will be briefly discussed. A comprehensive review of the relevant literature indexed in PubMed (National Library of Medicine) was performed. Barrett esophagus is currently defined as the presence of intestinal metaplasia in samples obtained from an endoscopically evident abnormality in the distal esophagus. Diagnosis and grading of dysplasia in mucosal biopsies remain the most reliable method to assess risk for neoplastic progression, but its classification may be hindered by superimposed inflammatory changes and suffers from considerable interobserver variability. Therefore, immunohistochemical studies and molecular assessment for TP53, CDKN2A , and DNA content abnormalities have emerged as potential adjuncts to the detection of dysplasia.

P16/CDKN2A and Ki-67 Enhance the Detection of Anal Intraepithelial Neoplasia and Condyloma and Correlate With Human Papillomavirus Detection by Polymerase Chain Reaction

The classification of anal intraepithelial neoplasia (AIN) in mucosal biopsies is subject to considerable interobserver variability. Previous studies have shown that Ki-67 and p16/CDKN2A immunostains aid detection of dysplasia in biopsy samples from the uterine cervix. The aim of this study was to determine whether Ki-67 and p16/CDKN2A immunolabeling enhanced diagnostic accuracy in the assessment of anal mucosal biopsies from patients with suspected human papillomavirus (HPV) infection. The study consisted of 75 cases that were originally interpreted to represent normal anal transitional zone (n=15), fibroepithelial polyp (n=10), condyloma accuminatum (n=10), low-grade AIN (AIN1, n=20), and high-grade AIN (n=20), including 10 cases each of AIN2 and AIN3. The histologic features of all cases were re-reviewed and categorized based upon consensus agreement, which resulted in reclassification of 16 cases. Thus, the final study group consisted of 17 samples of normal anal transition zone, 14 fibroepithelial polyps, 6 condylomata accuminata, and 38 cases of AIN (11 AIN1, 16 AIN2, and 11 AIN3). Each case was tested for the presence of HPV DNA by a SPF10 polymerase chain reaction and LiPA25 genotyping assay and immunostained for Ki-67 and p16/CDKN2A. A positive Ki-67 result was defined as the presence of a cluster of at least 2 strongly stained epithelial nuclei in the upper two-thirds of the epithelial thickness. A positive result for p16/CDKN2A was defined as diffuse moderate-to-strong cytoplasmic and nuclear staining. None of the anal transition zone samples or fibroepithelial polyps showed Ki-67 or p16/CDKN2A staining. All condylomata and samples of AIN contained HPV DNA and showed positive Ki-67 labeling. All cases of high-grade AIN showed positive p16/CDKN2A staining. We conclude that Ki-67 labeling detects anal HPV-related changes with a high degree of sensitivity and specificity, whereas increased p16/CDKN2A staining is strongly associated with high-grade squamous neoplasia. These results indicate that a combination of these markers may aid interpretation of anal mucosal biopsy samples.

Comparison of Provider-Assessed and Patient-Reported Outcome Measures of Acute Skin Toxicity During a Phase III Trial of Mometasone Cream Versus Placebo During Breast Radiotherapy: The North Central Cancer Treatment Group (N06C4)

Considerable interobserver variability exists among providers and between providers and patients when measuring subjective symptoms. In the recently published Phase III N06C4 trial of mometasone cream vs. placebo to prevent radiation dermatitis, the primary provider-assessed (PA) endpoint, using the Common Toxicity Criteria for Adverse Events (CTCAE), was negative. However, prospectively planned secondary analyses of patient-reported outcomes (PROs), using the Skindex-16 and Skin Toxicity Assessment Tool (STAT), were positive. This study assesses the relationship between PA outcomes and PROs. Pearson correlation coefficients were calculated to compare the three tools. Statistical correlations were defined as follows: <0.5, mild; 0.5-0.7, moderate; and >0.7, strong. CTCAE dermatitis moderately correlated with STAT erythema, and CTCAE pruritus strongly correlated with STAT itching. CTCAE pruritus had a moderate correlation with Skindex-16 itching. Comparing the 2 PRO tools, Skindex-16 itching correlated moderately with STAT itching. Skindex-16 burning, hurting, irritation, and persistence all showed the strongest correlation with STAT burning; they showed moderate correlations with STAT itching and tenderness. The PRO Skindex-16 correlated well with the PRO portions of STAT, but neither tool correlated well with CTCAE. PROs delineated a wider spectrum of toxicity than PA measures and provided more information on rash, redness, pruritus, and annoyance measures compared with CTCAE findings of rash and pruritus. PROs may provide a more complete measure of patient experience than single-symptom, PA endpoints in clinical trials assessing radiation skin toxicity.

The Physical Exam and Other Forms of Fiction

The traditional physical diagnosis course taught in the first two years of medical school has changed little in over half a century, and it deserves some scrutiny, if only because it is quite out of step with what students see when they begin on the wards during their clinical years. They are surprised to find that the house staff and attending staff carry very few of the instruments the student has acquired: reflex hammers are occasionally spotted, but ophthalmoscopes are quite rare. Even more vexing for the student is the realization that the currency on the ward, the “clinical skill” they were so anxious to acquire, does not involve the patient as much as it involves finesse and efficiency on the computer in ordering tests, in discharging patients and in completing notes-throughput. Indeed, one could make the case that it is time to dispense with the physical exam course altogether because the physical exam is being dispensed with altogether. It would appear that the two-dimensional rendering of the patient through imaging occupies us more than the three dimensional reality of the patient.

P57KIP2 immunohistochemical expression: a useful diagnostic tool in discrimination between complete hydatidiform mole and its mimics

The purpose of this study was to evaluate the results of immunohistochemical expression of p57KIP2 in the complete hydatidiform mole (CHM) and other types of hydropic pregnancy. Classification of molar pregnancies is typically defined by histologic and genetic criteria. The histologic criteria are subjective and demonstrate considerable interobserver variability. Several studies have recently shown that immunohistochemical detection of p57KIP2 expression in molar pregnancies is a useful ancillary diagnostic tool. The p57KIP2 gene is strongly paternally imprinted and maternally expressed. The villous cytotrophoblastic cells of complete hydatidiform mole (CHM) lack the maternal genome, that's why they reveal negative immunostaining for p57KIP2. On the contrary, in villous cytotrophoblastic cells of partial hydatidiform mole (PHM) and hydropic abortion, immunohistochemical staining for this marker is positive. We performed p57KIP2 immunohistochemical staining in 89 cases in four histological diagnostic categories as follows: "CHM" (n = 22), "PHM" (n = 32), "hydatidiform mole (HM)" (where the histological features were insufficient to differentiate between CHM and PHM) (n = 20), and "suggestive for PHM" (n = 15). p57KIP2 expression in villous cytotrophoblasts and stromal cells was absent or markedly reduced in 22 of 22 "CHMs", 7 of 32 "PHMs", 15 of 20 "HMs", and 1 of 15 "suggestive for PHMs" (P < 0.001). In all cases, maternal decidua and syncytiotrophoblast, respectively, showed diffuse and strong p57KIP2 expression, and negative p57KIP2 expression. This study confirms that negative p57KIP22 immunostaining may reliably identify CHM irrespective of gestational age and can be used in association with the histological findings to distinguish CHM from its mimics in challenging cases.

Causality Assessment in Drug-Induced Liver Injury Using A Structured Expert Opinion Process: Comparison to the Roussel-Uclaf Causality Assessment Method

Drug-induced liver injury (DILI) is largely a diagnosis of exclusion and is therefore challenging. The US Drug-Induced Liver Injury Network (DILIN) prospective study used two methods to assess DILI causality: a structured expert opinion process and the Roussel-Uclaf Causality Assessment Method (RUCAM). Causality assessment focused on detailed clinical and laboratory data from patients with suspected DILI. The adjudication process used standardized numerical and descriptive definitions and scored cases as definite, highly likely, probable, possible, or unlikely. Results of the structured expert opinion procedure were compared with those derived by the RUCAM approach. Among 250 patients with suspected DILI, the expert opinion adjudication process scored 78 patients (31%) as definite, 102 (41%) as highly likely, 37 (15%) as probable, 25 (10%) as possible, and 8 (3%) as unlikely. Among 187 enrollees who had received a single implicated drug, initial complete agreement was reached for 50 (27%) with the expert opinion process and for 34 (19%) with a five-category RUCAM scale (P = 0.08), and the two methods demonstrated a modest correlation with each other (Spearman's r = 0.42, P = 0.0001). Importantly, the RUCAM approach substantially shifted the causality likelihood toward lower probabilities in comparison with the DILIN expert opinion process. The structured DILIN expert opinion process produced higher agreement rates and likelihood scores than RUCAM in assessing causality, but there was still considerable interobserver variability in both. Accordingly, a more objective, reliable, and reproducible means of assessing DILI causality is still needed.

Intraobserver and interobserver agreement of the interpretation of pediatric chest radiographs

The objective of this study is to quantify the magnitude of intraobserver and interobserver agreement among physicians for the interpretation of pneumonia on pediatric chest radiographs. Chest radiographs that produced discordant interpretations between the emergency physician and the radiologist's final interpretation were identified for patients aged 1-4 years. From 24 radiographs, eight were randomly selected as study radiographs, and 16 were diversion films. Study participants included two pediatric radiologists, two senior emergency medicine physicians, and two junior fellowship-trained pediatric emergency medicine physicians. Each test included 12 radiographs: the eight study radiographs and four randomly interspersed diversion radiographs, and each radiograph was paired with a written clinical vignette. Testing was repeated on four occasions, separated by > or =2 weeks. The dependent variable was the interpretation of presence or absence of pneumonia; primary analysis done with Cohen's kappa (95% confidence intervals). Intraobserver agreement was good for pediatric radiologists (kappa = 0.87; 95% CI 0.60-0.99) for both but was lower for senior emergency physicians (mean kappa = 0.68; 95% CI 0.40-0.95) and junior pediatric emergency physicians (mean kappa = 0.62; 95% CI 0.35-0.98). Interobserver agreement was fair to moderate overall; between pediatric radiologists, kappa = 0.51 (0.39-0.64); between senior emergency physicians, kappa = 0.55 (0.41-69), and between junior pediatric emergency medicine physicians, kappa = 0.37 (0.25-0.51). Practicing emergency clinicians demonstrate considerable intraobserver and interobserver variability in the interpretation of pneumonia on pediatric chest radiographs.

Ten reasons why we should NOT use severity scores as entry criteria for clinical trials or in our treatment decisions*

Severity scores such as Acute Physiology and Chronic Health Evaluation II have been advocated as entry criteria for clinical trials and in clinical decision-making. We present ten reasons why we believe this approach is not appropriate and may even be detrimental. Available relevant literature from authors' personal databases and personal knowledge of past and future clinical trial development. Severity scores were not designed for use in individual patients or for therapeutic decision-making for specific interventions. Difficulties with the time window needed to calculate these scores and the need to administer therapies early further limit their use in this context. The complex nature of the scores makes it difficult to use them at the bedside and there is considerable interobserver variability in score calculation. Inclusion of chronic health and age points in severity scores may prevent younger, previously healthy patients, with similar acute physiological dysfunction and therefore total lower severity scores, from trial inclusion or from receiving therapies that may be beneficial. We believe severity of illness scores are poor surrogates for risk stratification and should not be used as a criterion for patient enrollment into clinical trials or as the basis for individual treatment decisions.

The impact of inter-observer variation in pathological assessment of node-negative breast cancer on clinical risk assessment and patient selection for adjuvant systemic treatment

BackgroundIt is well known that there is considerable inter-observer variability in assessment of the pathological parameters that are used to select node-negative breast cancer patients for adjuvant systemic treatment. There are only limited data available as to in how many patients this leads to differences in treatment decisions. MethodsClinical and pathological data of 694 patients <61 years with primary unilateral T1–4N0M0 breast cancer were analysed. Grade, estrogen receptor (ER) status and human epidermal growth factor receptor 2 (HER2) status were first assessed locally; subsequent central re-evaluation of these parameters was carried out. Clinicopathological low or high risk was assessed using national Dutch guidelines and the Adjuvant! Online (www.adjuvantonline.com). ResultsThe local pathological examination was discordant with central review for grade, ER and HER2 in 28% (kappa 0.56; grade 2 tumours 35% discordant), 5% (kappa 0.85) and 4% (kappa 0.81) of patients, respectively. If clinical risk were assessed based on Dutch guidelines or Adjuvant! Online, respectively, 15% (one of seven patients; kappa 0.70) or 8% (kappa 0.83) of patients would have been assigned to a different clinical risk group. ConclusionInter-observer variation in pathological examination of breast carcinomas results in significant differences in grade, ER status, HER2 status, clinicopathological risk and subsequently in adjuvant systemic treatment advice.

Multimodality Noninvasive Imaging for Assessment of Congenital Heart Disease

Major advances in the field of pediatric cardiology and cardiac surgery over the last several decades have led to a dramatic improvement in survival rates for most forms of congenital heart disease (CHD). For example, hypoplastic left heart syndrome, a previously lethal defect, now has early survival rates up to 90% at major centers.1 These improved outcomes have produced a growing population of survivors with complex CHD who are now reaching adulthood (Figure 1). During this period, improvements in surgical and medical treatments have been accompanied by developments in diagnostic modalities. Echocardiography has replaced catheterization as the primary diagnostic modality, and it is now uncommon for newborn infants to undergo catheterization for purely diagnostic purposes. Although echocardiography remains the bedrock of noninvasive cardiac imaging, the array of diagnostic modalities and techniques available continue to grow and this has spawned the specialty of “noninvasive cardiac imaging” and the need for the “cardiac imager” to be adept in all the different modalities. Figure 1. Percentage of patients under the age of 1 year (grey bars) and over the age of 18 years (black bars) undergoing echocardiography at Children’s Hospital Boston from 1983 through 2006. Note the reverse trends of these age groups reflecting the steady increase in the proportion of adult patients with congenital heart disease. Although the absolute number of infants undergoing echocardiography during this time period has increased, their proportion has steadily declined. Echocardiography, cardiac magnetic resonance (CMR), and cardiac computed tomography (CCT) are the primary modalities used for noninvasive cardiac imaging in patients with CHD. Nuclear scintigraphy is used in selected circumstances. The Table summarizes the strengths and weaknesses of each modality. Figure 2 shows temporal trends in utilization for the various noninvasive cardiac imaging techniques at our center. It is clear that echocardiography is the most frequently …

Interobserver and Intraobserver Variation Among Experts in the Diagnosis of Thyroid Follicular Lesions With Borderline Nuclear Features of Papillary Carcinoma

Distinguishing follicular variant of papillary carcinoma (FVPC) from follicular adenoma and follicular carcinoma can be difficult if nuclear features of papillary carcinoma are not well developed or only focally present. We assessed interobserver and intraobserver agreement among 6 thyroid experts by using 15 cases in which original pathologists suspected FVPC. There was unanimous expert agreement in diagnosing FVPC in only 2 cases (13%) and majority agreement in 6 cases (40%). Unanimous agreement on benign and malignant diagnoses was seen in 4 cases (27%) and majority agreement on malignancy in 8 cases (53%). Intraobserver agreement ranged from 17% to 100%. Histologic features considered most helpful in diagnosing FVPC were nuclear clearing, nuclear grooves, nuclear overlapping and crowding, nuclear membrane irregularity, and nuclear enlargement. This considerable interobserver and intraobserver variability in the diagnosis of FVPC seems to result from lack of agreement on the minimal criteria needed to diagnose FVPC, even among experts.

Blinded comparison of faecal loading on plain radiography versus radio-opaque marker transit studies in the assessment of constipation

To compare faecal loading on plain radiography versus radio-opaque marker transit studies in the assessment of constipation. The study group was a convenience sample of patients attending the Durham Constipation Clinic. All patients underwent transit studies according to an established protocol, and severity of constipation was assessed contemporaneously using a validated questionnaire (PAC-SYM). Transit studies were performed using radio-opaque markers that were ingested over 3 consecutive days, with a radiograph taken on the fourth day. Digital images of the radiograph were digitally altered to remove all traces of the transit markers without affecting the underlying pattern of faecal loading. Four observers assessed faecal loading independently; two clinicians (C1 and C2) and two radiologists (R1 and R2). C1 and R1 used a previously described formal scoring method of assessing faecal loading, whereas C2 and R2 assessed the images as if they were in a clinic or reporting session, grading the faecal loading as mild, moderate, or severe. One hundred patients were recruited out of 186 presenting in a 2-year period. All patients completed assessments. The correlation between observers was only fair to moderate (r ranging from 0.34-0.51). There were some surprisingly marked disagreements in 10-18% of assessments. The correlation between faecal loading and transit was weak for all observers (r ranging from 0.261-0.311). Symptom severity did not correlate with faecal loading. These results suggest that there is considerable inter-observer variation in the radiological assessment of faecal loading, irrespective of the training or method used by the observer, and that there is very poor correlation with colonic transit. The diagnosis of constipation, and the assessment of severity, is best performed clinically.

Inter‐observer variability in chest radiograph reading for diagnosing acute lung injury in children

Acute lung injury (ALI), including its most serious form called acute respiratory distress syndrome (ARDS), is a devastating disease that can occur at any age. ALI/ARDS accounts for only 5-8% of admissions to pediatric intensive care units (PICUs) but is fatal in 30-60% of cases. International multicenter prospective studies are needed to better understand pediatric ALI/ARDS. However, a reproducible definition of ALI/ARDS is crucial to ensure that study populations are homogeneous. We designed a retrospective review to test the inter-observer variability of chest radiograph interpretation for presence of the American-European Consensus Conference (AECC) radiographic criterion for ALI/ARDS. The medical files of 24 children ventilated for ALI/ARDS in our PICU between January 1993 and December 2002 were reviewed. Five pediatric radiologists and five pediatric intensivists interpreted one frontal chest radiograph (FCR) per patient taken on the day of ALI/ARDS diagnosis. Each reader indicated whether the radiograph showed the AECC radiographic criterion for ALI/ARDS. Data analysis involved comparing each reader to all the others based on the raw agreement and Kappa coefficient (kappa). Features in the 24 patients were consistent with earlier studies. Global inter-observer agreement beyond chance was fair (kappa = 0.29 +/- 0.02) among the five radiologists (kappa = 0.26 +/- 0.05) and among the five intensivists (kappa = 0.29 +/- 0.05). Thus, considerable inter-observer variability occurred in assessing the radiographic criterion for ALI/ARDS, as previously shown in adults. Given the low incidence of ALI/ARDS in children, this variability may have a large impact in studies of pediatric ALI/ARDS.

Perspectives for Improved and More Accurate Classification of Thyroid Epithelial Tumors

Histologic examination of thyroid nodules is the current standard to distinguish benign from malignant thyroid epithelial tumors and to classify histologic subtypes. This review analyzes the problems in histological differential diagnosis as well as contradictions between histology and molecular data and describes possibilities to combine histology with molecular data in an effort to more accurately classify thyroid epithelial tumors. Published literature, addressing the current recommendations for thyroid tumor classification, as well as literature on the application of histology and molecular studies on the etiology of thyroid tumors is analyzed. The current histologic criteria to classify thyroid tumors, especially follicular-patterned tumors, are hampered by considerable interobserver variability. The detection of somatic mutations via genotyping and the definition of potentially informative gene expression signatures by microarray analyses, which can distinguish cancer subtypes as well as low- and high-risk cohorts, have recently demonstrated significant diagnostic potential. Moreover, in a routine diagnostic setting, micro-RNA profiling appears most promising due to their relative stability and the high accuracy of their expression profiles. It is very likely that molecular definitions of thyroid tumors mentioned in the current World Health Organization classification will be further developed, leading to future progress in defining thyroid tumor types by an integrated histologic and molecular approach. These integrated classifications need to be evaluated for their specific impact on thyroid tumor diagnosis and prognosis.

Differentiated Intraepithelial Neoplasia of the Vulva

We present the clinical and pathological findings of 6 women with intraepithelial neoplasia of differentiated or simplex type (DVIN). The mean age was 68 years (range 55-82). One lesion was still in situ, whereas 5 were associated with squamous carcinoma, 4 of well-differentiated keratinizing type and 1 of poorly differentiated spindle-cell type. The invasive depth of the squamous carcinomas ranged from 0.6 to 8 mm and the surgical margins of all of the resection specimens were uninvolved by neoplastic cells. In contrast, DVIN involved the surgical margins in 5 specimens while the remaining specimen had normal surgical margins. In all 6 vulvar specimens, DVIN showed intense immunoreactivity for Ki-67 in the basal and parabasal cells while only 4 specimens showed reactivity for p53. In 5 surgical specimens with DVIN the number of CD1a cells was increased but little if any immunoreactivity could be found amongst the corresponding invasive neoplastic cells. Four squamous carcinomas also showed diffuse p53 reactivity. There was little difference in the pattern of Ki-67 expression between DVIN and squamous carcinoma. For a number of reasons, DVIN present diagnostic difficulty and considerable interobserver variation also exists. Our study suggests that Ki-67 and p16 are useful for distinguishing DVIN and classical VIN 3, whereas p53 and CD1a are useful for distinguishing DVIN and invasive squamous carcinoma. Furthermore, p53 appears to have higher specificity than sensitivity for distinguishing DVIN from normal squamous epithelium.

Diagnosis of ventilator-associated pneumonia: a systematic review of the literature.

IntroductionEarly, accurate diagnosis is fundamental in the management of patients with ventilator-associated pneumonia (VAP). The aim of this qualitative review was to compare various criteria of diagnosing VAP in the intensive care unit (ICU) with a special emphasis on the value of clinical diagnosis, microbiological culture techniques, and biomarkers of host response.MethodsA MEDLINE search was performed using the keyword 'ventilator associated pneumonia' AND 'diagnosis'. Our search was limited to human studies published between January 1966 and June 2007. Only studies of at least 25 adult patients were included. Predefined variables were collected, including year of publication, study design (prospective/retrospective), number of patients included, and disease group.ResultsOf 572 articles fulfilling the initial search criteria, 159 articles were chosen for detailed review of the full text. A total of 64 articles fulfilled the inclusion criteria and were included in our review. Clinical criteria, used in combination, may be helpful in diagnosing VAP, however, the considerable inter-observer variability and the moderate performance should be taken in account. Bacteriologic data do not increase the accuracy of diagnosis as compared to clinical diagnosis. Quantitative cultures obtained by different methods seem to be rather equivalent in diagnosing VAP. Blood cultures are relatively insensitive to diagnose pneumonia. The rapid availability of cytological data, including inflammatory cells and Gram stains, may be useful in initial therapeutic decisions in patients with suspected VAP. C-reactive protein, procalcitonin, and soluble triggering receptor expressed on myeloid cells are promising biomarkers in diagnosing VAP.ConclusionAn integrated approach should be followed in diagnosing and treating patients with VAP, including early antibiotic therapy and subsequent rectification according to clinical response and results of bacteriologic cultures.

Detektion pneumonischer Infiltrate bei ambulant erworbener Pneumonie: Übereinstimmung in der Befundung der Röntgen-Thoraxaufnahme

To assess interobserver agreement (IOA) in the diagnosis of pulmonary infiltrates on chest x-rays for patients with community-acquired pneumonia (CAP). From 7/2002 to 12/2005, 806 adults with CAP were included in the multicenter study "CAPNETZ" (7 hospitals). Inclusion criteria were clinical signs of pneumonia and pulmonary opacification on chest x-rays. Each x-ray was reevaluated by two radiologists from the university hospital in consensus reading against the interpreter at the referring hospital in regard to: presence of infiltrate (yes/no/equivocal), transparency (<or=/>50%), localization, and pattern of infiltrates (alveolar/interstitial). The following parameters were documented: digital or film radiography, hospitalization, fever, findings of auscultation, microbiological findings. The overall IOA concerning the detection of infiltrates was 77.7% (n=626; CI 0.75-0.81), the infiltrates were not verified in 16.4% (n=132) by the referring radiologist with equivocal findings in 5.9% (n=48). The IOA of the different clinical centers varied between 63.2% (n=38, CI 0.48-0.78) and 92.3% (n=65, CI 0.86-0.99). The IOA for the diagnosis of infiltrates was significantly higher for inpatients with 82.6% (n=546; CI 0.80-0.85) than for outpatients with 55.2 % (n=80; CI 0.47-0.63), p<0.0001. The IOA of infiltrates with a transparency >50% was 95.1% (n=215; CI 0.92-0.98) versus 80.4% (n=403; CI 0.77-0.84) for infiltrates with a transparency >50% (p<0.0001). In patients with positive auscultation, the IOA was higher (p=0,034). Chest x-rays of patients with antibiotic therapy or an alveolar infiltrate showed more equivocal findings compared to patients without these features. There is considerable interobserver variability in the diagnosis of pulmonary infiltrates on chest radiographs. The IOA is higher in more opaque infiltrates, positive auscultation and inpatients.