Evaluation of medical decision support systems (DDX generators) using real medical cases of varying complexity and origin.

BACKGROUND: Medical decision support systems (CDSSs) are increasingly used in medicine, but their utility in daily medical practice is difficult to evaluate. One variant of CDSS is a generator of differential diagnoses (DDx generator). We performed a feasibility study on three different, publicly available data sets of medical cases in order to identify the frequency in which two different DDx generators provide helpful information (either by providing a list of differential diagnosis or recognizing the expert diagnosis if available) for a given case report. METHODS: Used data sets were n = 105 cases from a web-based forum of telemedicine with real life cases from Afghanistan (Afghan data set; AD), n = 124 cases discussed in a web-based medical forum (Coliquio data set; CD). Both websites are restricted for medical professionals only. The third data set consisted 50 special case reports published in the New England Journal of Medicine (NEJM). After keyword extraction, data were entered into two different DDx generators (IsabelHealth (IH), Memem7 (M7)) to examine differences in target diagnosis recognition and physician-rated usefulness between DDx generators. RESULTS: Both DDx generators detected the target diagnosis equally successfully (all cases: M7, 83/170 (49%); IH 90/170 (53%), NEJM: M7, 28/50 (56%); IH, 34/50 (68%); differences n.s.). Differences occurred in AD, where detection of an expert diagnosis was less successful with IH than with M7 (29.7% vs. 54.1%, p = 0.003). In contrast, in CD IH performed significantly better than M7 (73.9% vs. 32.6%, p = 0.021). Congruent identification of target diagnosis occurred in only 46/170 (27.1%) of cases. However, a qualitative analysis of the DDx results revealed useful complements from using the two systems in parallel. CONCLUSION: Both DDx systems IsabelHealth and Memem7 provided substantial help in finding a helpful list of differential diagnoses or identifying the target diagnosis either in standard cases or complicated and rare cases. Our pilot study highlights the need for different levels of complexity and types of real-world medical test cases, as there are significant differences between DDx generators away from traditional case reports. Combining different results from DDx generators seems to be a possible approach for future review and use of the systems.

[Fine-needle aspiration (FNA) of the thyroid gland : Analysis of discrepancies between cytological and histological diagnoses]. / Feinnadelaspiration (FNA) der Schilddrüse : Analyse diskrepanter zytologischer und histologischer Diagnosen.

BACKGROUND: Diagnostic problems of thyroid cytology are frequently discussed, but relevance and causes of discrepant cytological and histological diagnoses are rarely studied in detail. OBJECTIVES: Investigation of causes and relevance of discrepant diagnoses. MATERIALS AND METHOD: The analysis includes 297 patients who had thyroid resection after prior fine needle aspiration (FNA) and is based on the cytological and histological reports. In special cases, cytological and histological specimens were re-examined. RESULTS: Malignant tumors were found in 45 patients (15.1 %). In 5 patients the cytological diagnosis was "false negative". Three of these 5 tumors were papillary carcinomas (PTC) of ≤10 mm, one an obviously nonmalignant papillary proliferation of the thyroidal epithelium and one a malignant lymphoma complicating autoimmune thyreoiditis (AIT). In 11 of the 35 patients with a FNA diagnosis "suspicious of malignancy" or "malignant," 1 AIT, 4 goiter nodules, and 6 adenomas were diagnosed histologically. However, since distinct nuclear atypia was found in three of five false positive diagnoses, there still remains doubt in their benignity. CONCLUSIONS: Carcinomas of ≤10 mm incidentally detected in the resected thyroid tissue may not be relevant to the patient and do not reduce the high negative predictive value of FNA. The final diagnosis on the resected tissue should include the cytological findings. Discrepant findings should be commented in the report to the clinician.

[A plea for cytopathology]. / Ein Plädoyer für die Zytopathologie.

Compared to other European and non-European countries the benefits of cytopathology for the diagnosis of many tumors is still underestimated in Germany for traditional reasons. Cytological methods provide excellent material from many organs for morphological, immunochemical and molecular examinations so that a definitive diagnosis is cytologically possible in many cases and the number of exploratory surgical operations could therefore be reduced. Improvements in this deplorable situation will only be possible if a standardized training period in cytology is consistently included in the training of general pathologists. This requires organizational and infrastructural changes within the institutes of pathology. In this respect, the university institutes as important training institutions should lead the way.

[Cytology of the urinary tract: Between uncertainty and clarity]. / Zytologie der ableitenden Harnwege: Zwischen Zweifel und Gewissheit.

Reliable detection of poorly differentiated urothelial carcinoma and the detection of carcinoma in situ, which is often invisible by cystoscopy, are the undisputed strength of urinary cytology. In contrast, well-differentiated urothelial tumors are often missed by cytology. We suggest the following classification: negative, questionable, suspicious, and positive. Due to the complex clinico-pathological associations, the classification should always be accompanied by an appropriate commentary. The WHO 2004 classification separates the clinically less important low-grade tumors from the clinically relevant high-grade tumors, usually classified as "positive" by cytology. A cytological diagnosis of low-grade tumors by cytology is of minor clinical importance. Most urothelial neoplasias are characterized by chromosomal aberrations. This makes multi-target fluorescence in situ hybridization (FISH) assay suitable for the clarification of non-definitive cytology. In contrast, positive cytology does not need further confirmation by FISH analysis. Standardized diagnosis and the possibility for supplementary analyses increase the diagnostic value of urinary cytology.

A phase I study of adenovirus-mediated wild-type p53 gene transfer in patients with advanced non-small cell lung cancer.

Mutations of the tumor suppressor gene p53 are the most common genetic alterations observed in human cancer. Loss of wild-type p53 function impairs cell cycle arrest as well as repair mechanisms involved in response to DNA damage. Further, apoptotic pathways as induced by radio- or chemotherapy are also abrogated. Gene transfer of wild-type p53 was shown to reverse these deficiencies and to induce apoptosis in vitro and in preclinical in vivo tumor models. A phase I dose escalation study of a single intratumoral injection of a replication-defective adenoviral expression vector encoding wild-type p53 was carried out in patients with incurable non-small cell lung cancer. All patients enrolled had p53 protein overexpression as a marker of mutant p53 status in pretreatment tumor biopsies. Treatment was performed either by bronchoscopic intratumoral injection or by CT-guided percutaneous intratumoral injection of the vector solution. Fifteen patients were enrolled in two centers, and were treated at four different dose levels ranging from 10(7) to 10(10) PFU (7.5 x 10(9) to 7.5 x 10(12) particles). No clinically significant toxicity was observed. Successful transfer of wild-type p53 was achieved only with higher vector doses. Vector-specific wild-type p53 RNA sequences could be demonstrated in posttreatment biopsies of six patients. Transient local disease control by a single intratumoral injection of the vector solution was observed in four of those six successfully transduced patients. There was no evidence of clinical responses at untreated tumor sites. Wild-type p53 gene therapy by intratumoral injection of a replication-defective adenoviral expression vector is safe, feasible, and biologically effective in patients with advanced non-small cell lung cancer.

Frequent TP53 gene alterations (mutation, allelic loss, nuclear accumulation) in primary non-small cell lung cancer.

Mutations of the TP53 tumour suppressor gene have been reported for many human cancers. A variety of TP53 mutations have also been reported for both primary non-small cell lung cancer (NSCLC) and associated metastases. To assess the pathogenetic significance of TP53 gene alterations in NSCLC, 24 paired samples of primary NSCLC and the corresponding normal lung tissue were analysed for mutations of the TP53 gene (exons 5-8) using exon-specific PCR, single-strand conformation polymorphism PCR (SSCP-PCR) and direct DNA sequencing; for p53 protein accumulation by immunohistochemistry and for 17p allelic loss using restriction fragment length polymorphism (RFLP) probes on Southern blots and amplified fragment length polymorphism-PCR. TP53 point mutations were observed in 9/24 (38%) tumours encompassing a total of 14 mutations. Two tumours displayed the same double mutation while a third harboured four different mutations. Seventeen of 24 NSCLCs (71%) overexpressed p53 protein and all 17 immunopositive tumours (100%) showed a mutation and/or allelic loss at the D17S30 locus. Of the 17 NSCLCs informative at the DS17S30 locus, 10 (59%) showed allelic loss, of which five (50%) were also mutated on the remaining TP53 allele. These results suggest that TP53 gene alterations are involved in the pathogenesis of primary NSCLC and that such alterations may serve a selective role in the development of NSCLC by diminishing the apoptotic potential of bronchial epithelial cells heterozygous for a TP53 point mutation. This may also explain the accumulation of multiple TP53 point mutations in 3/24 of our NSCLC samples.

Polyomavirus disease under new immunosuppressive drugs: a cause of renal graft dysfunction and graft loss.

BACKGROUND: Manifest polyomavirus (PV) renal graft infection is a rare complication. We diagnosed 5 cases among 70 kidney recipients undergoing transplants since December 1995; however, there were no cases at our institution before December 1995. METHOD: To identify risk factors promoting manifest PV graft infection, we compared those 5 patients with kidney recipients who had signs of PV replication but no manifest graft infection (n=23, control group). PV replication was judged by the presence of intranuclear inclusion cells in the urine. RESULTS: Before the infection, five of five patients had recurrent rejection episodes. All were switched from cyclosporine A to high dose tacrolimus as rescue therapy. Infection was diagnosed histologically 9+/-2 months posttransplantation; it persisted and led to graft loss in four of five patients. In control patients, graft function was stable, 1 of 23 patients were switched to tacrolimus as rescue therapy, and graft loss occurred in 4 of 23 patients. CONCLUSION: Recurrent rejection episodes and high dose immunosuppressive therapy, including tacrolimus, are risk factors for manifest PV kidney graft infection, which has an ominous prognosis.

Pulmonary cytomegalovirus infection in immunocompromised patients.

BACKGROUND: Cytomegalovirus (CMV) infection and CMV disease are frequent complications in immunocompromised patients. In this study, the incidence of pulmonary CMV infection was analyzed in different groups of immunocompromised patients and the diagnostic value of immunostaining with anti-CMV antibodies in BAL cells was evaluated in regard to the diagnosis of CMV pneumonitis. METHODS: Five hundred eighty consecutive BAL procedures were analyzed prospectively in 442 immunocompromised and 126 nonimmunocompromised control subjects. CMV culture in BAL fluid was performed by shell vial assay and immunostaining using three monoclonal anti-CMV antibodies. RESULTS: The incidence of culture results positive for CMV in the BAL fluid varied from 20 to 30% in HIV-positive patients, in patients following stem cell or renal transplantation, and in patients with autoimmune disease or lung fibrosis treated with immunosuppressive agents. CMV was cultured from 4.4% of BALs in patients treated with high-dose chemotherapy and from 2.4% of control subjects. CMV disease developed in 37 patients; in 18 of these patients, CMV pneumonitis was present. The results of CMV immunostaining were positive in a total of 22 BALs, all in patients with CMV disease. The sensitivity, specificity, and positive and negative predictive values of positive CMV immunostaining results for the diagnosis of CMV pneumonitis were 88.9%, 98.6%, 72.7%, and 99.5%, respectively. CONCLUSION: The incidence of pulmonary CMV infection is similar in different groups of immunocompromised patients except for patients following high-dose chemotherapy. CMV immunostaining in the BAL fluid is a very helpful method to diagnose CMV pneumonitis in these patients.

Evaluation of a new self-expandable silicone stent in an experimental tracheal stenosis.

STUDY OBJECTIVES: To assess the usefulness of an animal model for testing new tracheobronchial stents. SETTING: Animal laboratory of a university hospital. ANIMALS AND INTERVENTIONS: In a series with 12 mini-pigs, we induced a stable fibromalacic tracheal stenosis that was 50% to 70% of the normal tracheal diameter. After dilation we inserted a 16 x 40-mm self-expandable silicone stent into the stenotic part of the trachea in 10 of the mini-pigs. Five of the stents had a smooth outer surface, and five had additional silicone retaining spikes. Because of a long stenosis in two of the mini-pigs, two overlapping stents (one smooth and one with spikes) were inserted. MEASUREMENTS AND RESULTS: Stent deployment was successful and resulted in the disappearance of the slight to moderate stridor in all of the mini-pigs. Over a mean (+/- SD) observation period of 24 days (range, 10 to 41 days), all of the mini-pigs redeveloped stridor. Three of them died unexpectedly of suffocation: in all three a smooth stent had migrated, leading to total obstruction of the stenosis. In total, five of the six smooth stents migrated, and only one of the six spiked stents migrated. There was considerable granulation tissue formation at the ends of all of the stents. In the two control mini-pigs, a 12 x 35-mm Dumon stent was inserted. Both Dumon stents migrated, and one of them had considerable granuloma formation at its ends. At the end of the observation period, all stents were removed endoscopically and were found not to have deteriorated over time. CONCLUSIONS: Our model proved to be suitable for the evaluation of the technical aspects of the Polyflex stent. Spikes on the outer stent surface are more effective in preventing migration than smooth-surface stents. Long-term compatibility, however, seems to be difficult to test with our model because both the Polyflex and the Dumon stents had excessive granulation tissue formation at both ends, a factor which--in the case of the Dumon stent--does not occur to such a degree in benign human airway stenoses. Our results indicate a need for prospective long-term studies in benign human airway stenoses.

The value of transbronchial needle aspiration in the diagnosis of peripheral pulmonary lesions.

BACKGROUND: Transbronchial needle aspiration (TBNA) is a bronchoscopic sampling technique used for the diagnostic workup of mediastinal lymph nodes, but the value of its routine use in evaluating peripheral pulmonary lesions is not yet firmly established. DESIGN: Retrospective analysis of routine diagnostic bronchoscopies. SETTING: University teaching hospital. PATIENTS AND METHODS: One hundred seventy-two consecutive patients (126 with malignant and 46 with nonmalignant disease) who underwent bronchoscopy for a peripheral pulmonary lesion. RESULTS: In 87 patients (51%), a final diagnosis was established by bronchoscopy; diagnoses included 81 malignant lesions (69 lung cancer and 12 pulmonary metastases) and 6 benign lesions (all tuberculosis). TBNA was used in 152 of the 172 patients (89%). Other endoscopic techniques included bronchial washing (100%), bronchial brushing (45%), and transbronchial biopsy (TBB) (27%). Concerning the different bronchoscopic sampling techniques, TBNA showed a positive result in 35% of cases, in comparison to 17% for TBB, 22% for bronchial washing, and 30% for bronchial brushing. While TBNA was diagnostic in 27.5% of the malignant lesions < 3 cm in diameter, the success rate in lesions > 3 cm was 65.5% (p = 0.03). Endoscopy-related complications included pneumothorax (n = 1), self-limiting bleeding (n = 12), prolonged coughing (n = 2), and vasovagal reactions (n = 2). None of these complications required further treatment. CONCLUSION: TBNA is an effective bronchoscopic sampling technique in the diagnosis of peripheral pulmonary lesions. In our study, the use of TBNA increased the diagnostic yield of bronchoscopy from 35 to 51% without additional risk. The use of TBNA in the clinical routine should be encouraged.

Diagnostic yield of bronchoscopy in histologically proven invasive pulmonary aspergillosis.

Invasive pulmonary aspergillosis (IPA) is a life-threatening infectious complication in neutropenic patients after high-dose chemotherapy or hematopoietic stem cell transplantation. Its diagnosis is mainly based on clinical symptoms, and radiological signs on thoracic CT scan. The value of bronchoscopy is controversial. We analyzed the diagnostic yield of bronchoscopy in 23 consecutive patients with histologically proven invasive pulmonary aspergillosis. In seven patients (30%) bronchoscopically obtained specimens were diagnostic for pulmonary fungal infection. Typical hyphae were detected by cytology in six patients and fungal cultures were positive in four cases. Patients with a positive bronchoscopic result presented more often with multiple changes on thoracic CT scan (71%; 5/7), but had received a lower median cumulative dose of amphotericine B (300 mg; 168-3010 mg) compared to patients with non-diagnostic bronchoscopy (25% multiple lesions (4/16); amphotericine dose 1100 mg, 260-2860 mg). The diagnostic yield of bronchoscopy was not associated with clinical symptoms or duration of neutropenia. Bronchoscopy allows the diagnosis of IPA in about one third of patients. Fungal cultures and cytological examination of intrabronchial specimens obtained during bronchoscopy have a high specificity, but its sensitivity is low. It is advisable to perform diagnostic bronchoscopy before starting antifungal therapy. Better diagnostic tools are urgently needed.

Multiprobe FISH for enhanced detection of bladder cancer in voided urine specimens and bladder washings.

The aim of this study was to evaluate the UroVysion (Vysis, Downers Grove, IL) fluorescence in situ hybridization (FISH) test for improved detection of bladder cancer in urinary specimens. Three groups of specimens were examined, including voided urine specimens (1) collected before resection of bladder cancer, (2) from cystoscopically negative bladders of patients with previous bladder cancer, and (3) from patients with benign prostatic hyperplasia (controls). FISH positivity was defined as more than 2 urothelial cells with an abnormal signal copy number of at least 1 of the 4 probes. FISH was positive in 1 of 27 control specimens and in 33 (73%) of 45 pTa, 12 (100%) of 12 pT1, and 13 (100%) of 13 pT2-4 tumors. The results were similar in a series of 68 bladder washings. In addition, FISH of voided urine specimens was positive in 5 of 10 patients with negative follow-up cystoscopy results. Subsequent recurrence was found in 4 of these patients but in none of 5 patients with FISH-negative results. Multiprobe FISH markedly improves the sensitivity and specificity of cytology for the detection of bladder cancer in urine specimens.

Severe bronchiolitis in acute Mycoplasma pneumoniae infection.

We report on a 17-year-old patient with severe bronchiolitis due to Mycoplasma pneumoniae infection. Despite an early 10-day course of clarithromycin, she developed progressive dyspnea, cough, fever, and severe obstructive ventilatory impairment. Sixteen days after onset of the disease a severe hemolytic anemia developed with only cold agglutinins positive at serologic screening. Thoracoscopic lung biopsy revealed diffuse bronchiolitis with suppurative intrabronchiolar inflammation, lymphohistiocytic "cuffing" of the bronchioli, and foam cell aggregates within neighboring alveoli. The infiltrate consisted mainly of CD3+, CD8+ lymphocytes and CD68+ macrophages. The diagnosis of Mycoplasma pneumoniae bronchiolitis was based on repeated complement fixation tests, which turned strongly positive only at day 74 after onset of the disease. Pulmonary function improved slowly under long-term prednisone treatment.

DNA aneuploidy, S-phase fraction, nuclear p53 positivity, and survival in non-small-cell lung carcinoma.

Inactivation of the p53 gene plays a key role in tumour biology, probably through a disturbed cell cycle control and an increased genetic instability in p53-inactivated tumours. To learn more about the relationship between p53 alterations, proliferation and genetic instability (DNA aneuploidy) in lung cancer patients, specimens of 220 surgically resected lung carcinomas with clinical follow-up information were examined by immunohistochemistry (p53; CM1) and flow cytometry. Nuclear p53 positivity--found in 49.5% of the tumours--was associated with both high S-phase fraction (SPF) and DNA ploidy aberrations. SPF was higher in p53-positive tumours (15.9 +/- 10.2) than in p53-negative tumours (10.3 +/- 8.7; P = 0.03). The rate of p53 positivity was higher in 101 DNA-aneuploid and DNA-multiploid tumours (55%) than in 27 diploid and peridiploid carcinomas (33%; P = 0.0512). These results are consistent with an in vivo role of p53 inactivation for increased proliferative activity and development of genomic instability in lung cancer. There was no association between SPF and prognosis. Although prognosis was worse in DNA-aneuploid and multiploid tumours than in diploid, peridiploid and tetraploid carcinomas (P = 0.029), DNA ploidy was not an independent predictor of poor prognosis in multivariate analysis. These data show that DNA-flow cytometry has little prognostic value for patients with resected non-small-cell lung carcinoma.

Immunocytochemistry in diagnostic cytology.

As the decision for immunocytochemistry is usually made on the basis of findings in Papanicolaou-stained smears and uncovering of the smears takes time, the immunocytochemical results are often reported with some delay. But they are of clinical interest only if reported within a short time. Therefore, immunocytochemistry on cytologic preparations must be carefully organized. The decision for immunocytochemistry must be made before the mounting medium has completely hardened to keep the time of uncovering short. The method of immunocytochemistry should fulfill the following prerequisites: 1. Cell sampling and fixation should be easy to handle for the clinician who sends the specimen to the laboratory. 2. Unspecific background staining, especially in cytologic preparations rich in blood and protein, should not occur. 3. The immunostaining method should be applicable to all kinds of cytologic material, fixed and stained smears included. 4. The nuclear structure of tumor cells should not be destroyed by the immunocytochemical procedure so that tumor cells after incubation are clearly distinguishable from normal cells showing a similar reaction as the tumor cells. There has hitherto been no such all-round method fulfilling all these prerequisites since the properties of the antigenic epitopes of the cells and of the antibodies recognizing them are too heterogeneous. Therefore several methods have to be considered and a variety of technical aspects such as fixation, storage of cytologic material, properties of tinctorial stains, of antibodies and of the antigenic epitopes must be studied to find out the two or three standard methods which meet the requirements in most cases. We recommend the ABC method for Papanicolaou-stained smears and the APAAP method for demonstration of lymphocyte markers. The indication of immunocytochemistry in diagnostic cytology is restricted by the limited number of specimens. Therefore, the following rules have to be observed: 1. The conventional light-microscopic examination must have priority over the immunocytochemical examination. 2. The cytologic specimens assigned for immunocytochemical examination must have been adequately fixed and stored. 3. As the number of smears is limited, the immunocytochemical examinations must be carefully planned and restricted to the absolutely necessary incubations. If possible, an informative smear has to be spared for documentation and future training of cytologists and cytotechnicians. 4. Immunocytochemical examinations in cytology are only justified if the diagnostic problem can be clearly defined. 5. The panel of antibodies should be selected carefully so that the results may give an answer to alternative questions. At least two antibodies should be applied.(ABSTRACT TRUNCATED AT 400 WORDS)

Invasive pulmonary aspergillosis: effects of early resection in a neutropenic rat model.

OBJECTIVE: Invasive pulmonary aspergillosis is frequent in neutropenic patients. Usually localized in the beginning, the disease spreads and mortality is high despite antifungal treatment. The role of early adjuvant surgery is not clear. Surgery may help to confirm fungal disease, may control fungal disease locally and may prevent systemic spreading. This study examines effects of early resection on survival and dissemination in a rat model of localized invasive pulmonary aspergillosis. METHODS: Forty persistently neutropenic male albino rats were challenged with standardized conidial aspergillus inoculum injected into peripheral lung tissue of the right upper lobe under direct vision. Animals were divided into four groups. Twenty animals were treated with amphotericin B at 1 mg/kg per day beginning 48 h after inoculation, 20 animals were left untreated. In each group half the animals underwent early resection of localized invasive aspergillosis by lobectomy. Animals were checked daily and mortality was recorded up to 28 days after which surviving animals were sacrificed. RESULTS: Significantly higher survival was observed in resected animals in the non-Am B groups (survival: 10 +/- 19% without early resection and 50 +/- 32% with early resection; P = 0.044). However, early resection did not lead to improved survival in animals treated with amphotericin B (survival 70 +/- 29% without early resection and 50 +/- 32% with early resection; P = 0.316). CONCLUSIONS: In this rat model of localized invasive pulmonary aspergillosis effects of early resection on survival could be demonstrated only in animals not receiving amphotericin B treatment.

Lung biopsy: methods, value, complications, timing, and indications.

Six methods of lung biopsy are discussed on the basis of literature reports: 1. Aspiration biopsy by fine needle, 2. split needle biopsy (Vim-Silverman), 3. cutting needle biopsy (Travenol), 4. trephine biopsy by rotating needle, 5. transbronchial biopsy, 6. open biopsy. Because of the high risk, biopsies with thick needles (methods 2--4) should be abandoned. Transbronchial biopsy is renounced because reliable results are only achieved in sarcoidosis which can be clearly diagnosed in high percentage of cases by other less dangerous procedures. In solitary tumors which could not be diagnosed by any other means aspiration biopsy is indicated because of its low risk and its diagnostic accuracy of more than 80%. In disseminated pulmonary disorders which cannot be diagnosed by any other means open lung biopsy is the most reliable method. The lung specimens can be taken under eye control. They should contain tissue from the transitional zone between diseased and unchanged areas, however. The specimens are usually big enough for additional electron and fluorescence microscopic examinations as well as dust analyses. The pathologist must be aware of all clinical data including X-ray pictures, laboratory findings, case history, and history of occupational and nonoccupational dust exposure. If these conditions are fulfilled and adequate methods are applied, lung biopsy provides diagnosis and prognosis, makes causal therapy possible, and amplifies the medical knowledge of pulmonary diseases.

Morphologic findings in central bronchi correlated to lung function data in obstructive airways disease.

Quantitative analyses of morphologic findings are the condition of clinico-pathological correlation studies. These quantitative analyses are possible by morphometry. The present correlation study shows that morphometry may therefore contribute to understanding the pathogenesis of obstructive airways disease: decreasing bronchial lumen and increasing volume of grandular ducts are correlated to increasing airways resistances (clinical parameters: RAW, FEV1). Increasing volume of bronchial muscles is correlated with resistance of airways at quiet breathing (RAW) and less with increasing residual volume (RV). Increasing volume of bronchial glands and glandular ducts is correlated with increasing resistance at forced expiration which is clinically shown by decreasing FEV1. These findings can be interpreted as follows. Airway resistances are mainly influenced by airway narrowing. At quiet breathing, muscle constriction is an additional cause of increasing airflow resistance due to bronchial narrowing. At forced expiration, however, mucus plugs probably limit the airflow because thickening of bronchial glands points to increased secretory activity. Until now it is not possible to understand why bronchial muscle volume correlates with residual volume.

Combined immunoreaction and Papanicolaou's stain on cytological smears.

The method described below combines an immunoreaction with Papanicolaou's stain on cytological smears. For the immunoreaction, the avidin-biotin-complex (ABC) method was used. The method was tested on various cytological material with the monoclonal antibody lu-5 and two polyclonal antibodies (anti-keratin and anti-chymotrypsin). Wet fixation of the smears with a modified Delaunay's solution is recommended. Drying of the material impairs immunoreactivity. The main advantages of the technique are the clear-cut permanent immunostaining and the preservation of the nuclear structure, permitting a combined immuncytological characterization of cellular products and conventional cyto-diagnosis.

A simple "expert system" for morphometric evaluation of cells in pleural effusions.

Quantitation in diagnostic pathology serves to improve both diagnostic reliability and the prognosis of various malignant tumors. Unfortunately, flexible, user-friendly, reasonably priced and compatible morphometric systems are hardly available on the market. A modular Apple II PC-based system was therefore developed in-house. It records stereologic, planimetric and digital image analysis data and calculates secondary parameters. Detailed statistical analyses can be performed, after data transfer, on larger computers. A typical application of diagnostic morphometry is to determine whether, and with which probability a patient with an unclear histopathologic finding can be assigned to one or more groups of patients with known diseases and prognoses. To this end morphometric data of the patient under investigation are compared with other patient data stored in an expert system. This paper describes the concept of an expert system carried out on the Apple II PC system mentioned above and outlines the evaluation procedures. Invariant moments were used to describe nucleus textures. Results obtained from the cytological analysis of pleural effusions demonstrate that with this approach it is possible to differentiate between normal mesothelium, mesothelioma and metastases of adenocarcinomas.