ICORG 10-14: NEOadjuvant trial in Adenocarcinoma of the oEsophagus and oesophagoGastric junction International Study (Neo-AEGIS).

BACKGROUND: Neoadjuvant therapy is increasingly the standard of care in the management of locally advanced adenocarcinoma of the oesophagus and junction (AEG). In randomised controlled trials (RCTs), the MAGIC regimen of pre- and postoperative chemotherapy, and the CROSS regimen of preoperative chemotherapy combined with radiation, were superior to surgery only in RCTs that included AEG but were not powered on this cohort. No completed RCT has directly compared neoadjuvant or perioperative chemotherapy and neoadjuvant chemoradiation. The Neo-AEGIS trial, uniquely powered on AEG, and including comprehensive modern staging, compares both these regimens. METHODS: This open label, multicentre, phase III RCT randomises patients (cT2-3, N0-3, M0) in a 1:1 fashion to receive CROSS protocol (Carboplatin and Paclitaxel with concurrent radiotherapy, 41.4Gy/23Fr, over 5 weeks). The power calculation is a 10% difference in favour of CROSS, powered at 80%, two-sided alpha level of 0.05, requiring 540 patients to be evaluable, 594 to be recruited if a 10% dropout is included (297 in each group). The primary endpoint is overall survival, with a minimum 3-year follow up. Secondary endpoints include: disease free survival, recurrence rates, clinical and pathological response rates, toxicities of induction regimens, post-operative pathology and tumour regression grade, operative in-hospital complications, and health-related quality of life. The trial also affords opportunities for establishing a bio-resource of pre-treatment and resected tumour, and translational research. DISCUSSION: This RCT directly compares two established treatment regimens, and addresses whether radiation therapy positively impacts on overall survival compared with a standard perioperative chemotherapy regimen Sponsor: Irish Clinical Research Group (ICORG). TRIAL REGISTRATION: NCT01726452 . Protocol 10-14. Date of registration 06/11/2012.

Vasorelaxant properties of isolated human radial arteries: comparison with internal mammary arteries.

Radial arteries, used in revascularisation surgery, are prone to spasm. We have examined the ability of nitrovasodilators, calcium channel blockers, and K(ATP) channel openers to cause vasodilation, and to attenuate contractions due to depolarisation and receptor activation in radial and mammary arteries used in coronary artery bypass graft surgery. Two to three millimetre rings of artery obtained from patients at surgery were studied in organ baths in vitro. Constriction to KC1 and phenylephrine was examined before and again after treatment of the rings with drug or vehicle. Calcium channel blockers were the only compounds to inhibit contractions to both KC1 and phenylephrine. Sodium nitroprusside attenuated constriction to phenylephrine but not KC1 in both vessels. K(ATP) channel openers similarly attenuated constriction to phenylephrine in radial arteries but were much less effective in mammary arteries. These studies support the continued use of calcium blockers after revascularisation with radial artery but suggest that other classes of drug may be as effective at minimising spasm due to receptor mediated constriction.

Prediction of prostate carcinoma stage by quantitative biopsy pathology.

BACKGROUND: Considerable evidence has shown that the use of computational algorithms to combine pretreatment clinical and pathology results can enhance predictions of patient outcome. The aim of this study was to prove that the application of such methods to predict patient-specific likelihoods of organ-confined (OC) prostate carcinoma (PCA) may be helpful to patients and physicians when they are choosing an optimal treatment for carcinoma of the prostate. METHODS: The authors used clinical and quantitative pathology results from the biopsy specimens of 817 PCA patients who had been evaluated at a large national pathology reference laboratory. The pathology parameters that were measured included the number of positive cores, Gleason grades and score, percentage of tumor involvement, and the tumor location. The pathologic stage of these cases, as determined by results from radical prostatectomy, lymphadenectomy, or bone scan, categorized the PCA as either OC, non-OC due to capsular penetration only (NOC-CP) or advanced disease with metastasis (NOC-Mets), i.e., seminal vesicle and/or lymph-node positive or bone-scan positive. There were a total of 481 OC cases, 185 NOC-CP cases, and 151 NOC-Mets cases. Patient-specific prediction models were trained by ordinal logistic regression (OLOGIT) and genetically engineered neural networks (GENNs), and the resulting trained models were validated by biopsy information from an independent set of 116 PCA patients. RESULTS: When the authors applied a cutoff of >or= 35% for the n = 817 training set of OC, NOC-CP, and NOC-Mets predictive probabilities, the OLOGIT model predicted OC PCA with an accuracy of 91%, whereas the GENN model predicted the same with an accuracy of 95%. When the authors employed the n = 116 validation set (76 OCs, 31 NOC-CPs, and 9 NOC-Mets), the OLOGIT and GENN models correctly identified OC PCA with 91% and 97% accuracy, respectively. CONCLUSIONS: The value of combining patient pretreatment diagnostic pathology parameters to make predictions concerning the postoperative extent of pathology was illustrated clearly in this study. This finding further confirms the need to pursue such approaches for PCA disease management in the future, especially with the increasing prevalence of clinical T1c (American Joint Committee on Cancer, 1977) disease.

Contemporary use of complexed PSA and calculated percent free PSA for early detection of prostate cancer: impact of changing disease demographics.

OBJECTIVES: To assess the diagnostic performance of complexed prostate-specific antigen (cPSA), total PSA (tPSA), and calculated free/total PSA (f/t PSA) ratios in the differentiation of benign disease from prostate cancer (CaP) using a contemporary patient cohort. METHODS: The cPSA, tPSA, and calculated fPSA values were determined using the Bayer Immuno-1 system. To validate our calculated f/t PSA ratio, we also retrospectively measured fPSA using the Abbott AxSYM immunoassay system in archival pretreatment sera obtained between 1990 and 1997 from 362 men with clinically and biopsy-confirmed benign prostatic hyperplasia (n = 179) or CaP (n = 183). The diagnostic utility of tPSA, cPSA, and the calculated f/t PSA ratio was assessed using a contemporary test population consisting of sera prospectively collected between June 1999 and June 2000 from 3006 men who had recently undergone a systematic biopsy by urologists in clinical practices throughout the United States. This contemporary patient sample had biopsy diagnoses of either no evidence of malignancy (n = 1857) or CaP (n = 1149). All serum samples had tPSA values between 2.0 and 20.0 ng/mL. RESULTS: The measured versus calculated f/t PSA ratios had a Pearson's correlation coefficient of 0.9130 in the retrospectively studied population of 362 men. The areas under the receiver operating characteristic curves (ROC-AUCs) for the measured and calculated f/t PSA ratios were indistinguishable (69.6% versus 69.2%, respectively). In the contemporary population (n = 3006), the ROC-AUC for tPSA, cPSA, and the calculated f/t PSA ratio was 52.2%, 53.9%, and 58.4%, respectively. We also compared the diagnostic performance using published cutoffs for tPSA (greater than 4.0 ng/mL), cPSA (greater than 3.8 ng/mL), and the f/t PSA ratio (greater than 15% and greater than 25%) in tPSA reflex ranges of 2 to 20 ng/mL and 2 to 10 ng/mL. We found that both cPSA and the f/t PSA ratio (greater than 25% cutoff) outperformed tPSA and yielded similar results in terms of biopsies spared and cancers missed. CONCLUSIONS: The calculated f/t PSA ratio and cPSA perform equally well in terms of the improvement of specificity in the discrimination of benign disease and CaP. The f/t PSA ratio and cPSA provide clinical benefits over the use of tPSA alone, such as an increased sparing of unnecessary biopsies performed with a manageable degree of risk of delayed cancer detection.

Analysis of repeated biopsy results within 1 year after a noncancer diagnosis.

OBJECTIVES: A prostate biopsy data base derived from patients referred to private practice urologists was analyzed for the cancer diagnosis rates of the "initial" biopsy and the repeated biopsy performed within 1 year for those patients with a noncancer diagnosis. METHODS: A retrospective analysis assessed 132,426 prostate biopsies received and processed by a single pathology laboratory between March 1994 and September 1998; none had had a previous biopsy processed at this laboratory. Prostate cancer was diagnosed in 50,521 of the patients (38.2%). The remaining 81,905 patients (61.8%) had a noncancer diagnosis of either no evidence of malignancy (NEM), high-grade prostatic intraepithelial neoplasia (HGPIN), small acinar glands suspicious for cancer (suspicious), or suspicious with HGPIN (Susp-HGPIN). We identified 6380 (7.8%) of these "noncancer" patients who underwent a repeated biopsy within 1 year. RESULTS: The incidence of NEM, HGPIN, suspicious, and Susp-HGPIN biopsy diagnoses in the "noncancer" patients (81,905) was 55.3%, 3.7%, 2.5%, and 0.3%, respectively. The rate at which these "noncancer" patients (81,905) underwent a repeated biopsy was 4.8% for patients with a diagnosis of NEM, 26.6% for HGPIN, 40.4% for suspicious, and 47.5% for Susp-HGPIN. The overall cancer diagnosis rate in the repeated biopsy patient sample (6380) was 25.7%. When stratified by the initial biopsy diagnosis, the cancer diagnosis rate for the repeated biopsies was 19.8%, 22.6%, 40.0%, and 53.1%, for the patients with NEM, HGPIN, suspicious, and Susp-HGPIN, respectively. The repeated biopsy diagnosis rates did not vary dramatically when analyzed at 3-month intervals during the 1-year period. Also, a strong correlation (79%) was observed between the number of tissue samples obtained at the initial and repeated biopsy procedures. In a subset of patients with free and total prostate-specific antigen (PSA) results obtained before the repeated biopsy (n = 813), we were able to construct a multivariate logistic regression algorithm using the patients' age, initial biopsy diagnosis, total PSA, and free/total PSA ratio that could predict the likelihood of cancer on the repeated biopsy with an accuracy of 70%. CONCLUSIONS: Men who have an initial noncancerous biopsy diagnosis remain at risk of prostate cancer, especially if the initial diagnosis was suspicious or Susp-HGPIN. These data suggest that the initial biopsy strategy needs to be improved and/or expanded to increase the overall cancer detection rate in the primary biopsy. In addition, combining factors such as the initial biopsy diagnosis, family history, digital rectal examination results, prostate gland volume, age, total PSA, and free/total PSA ratio could provide valuable information for predicting the likelihood of cancer.

beta-catenin expression in primary and metastatic colorectal carcinoma.

beta-catenin plays a fundamental role in the regulation of the E-cadherin-catenin cell adhesion complex. It also functions in growth signalling events, independently of the cadherin-catenin complex, and these signalling pathways are disturbed in colorectal cancer. Mutations in either the APC or beta-catenin genes in colorectal cancer cells result in up-regulation of protein expression and subsequent cytoplasmic and nuclear distribution of beta-catenin. In this study, we examined beta-catenin expression in 47 primary colorectal tumors and the corresponding liver metastases. Immunohistochemical studies demonstrated loss of membranous beta-catenin expression in 26% of primary tumors and 60% of liver metastases and a concomitant increase in cytoplasmic and nuclear staining. Widespread nuclear expression of beta-catenin was found in 64% of primary tumors and 21% of liver metastases. No associations were found between any form of beta-catenin expression and either tumor stage or tumor grade. Cellular distribution of beta-catenin was also examined by detergent extraction and Western blot analysis in 16 primary tumors and 23 liver metastases. This analysis showed that most tumors demonstrated reduced beta-catenin in the cytoskeletal fraction and increased beta-catenin in the cytosolic fraction. Furthermore, 3 liver metastases were found to contain a truncated beta-catenin protein of approximately M(r) 80,000. Immunoprecipitation studies showed that the truncated beta-catenin proteins only bound weakly to E-cadherin and beta-catenin compared with non-truncated beta-catenin. These results demonstrate gross alterations in the cellular distribution of beta-catenin in primary colorectal cancers with metastatic potential, as well as in the metastatic tumors. These changes may be the consequence of APC or beta-catenin gene mutations, or possibly result from a post-translational modification of the E-cadherin-catenin complex.

Most prostate cancers missed by raising the upper limit of normal prostate-specific antigen for men in their sixties are clinically significant.

OBJECTIVES: To evaluate the efficacy of applying an age-specific prostate-specific antigen (PSA) reference range to determine whether prostate biopsies are warranted in men 60 to 69 years of age. We estimated the incidence of clinically significant prostate cancer in men in their sixties with PSA levels of 4.01 to 4.50 ng/mL and normal digital rectal examinations (DRE). METHODS: We reviewed 203 sextant prostate biopsies of men in their sixties with PSA levels of 4.01 to 4.50 ng/mL and normal DRE. Tumors were considered clinically significant if the cancer on biopsy was poorly differentiated (Gleason score of 7 or more), involved more than one core, or included a single focus measuring more than 3 mm. RESULTS: The positive biopsy rate was 31.5%. More than 80% of the cancers detected satisfied criteria that almost always predict clinically significant cancer. Thus, among men in their sixties with PSA levels of 4.01 to 4.50 ng/mL and normal DRE, the risk of detecting clinically significant cancer on biopsy was approximately 25%. CONCLUSIONS: Most nonpalpable cancers detected by sextant biopsies in men 60 to 69 years of age with PSA levels of 4.01 to 4.5 ng/mL are clinically significant. Applying an age-specific PSA reference range that increases the upper limit of normal PSA to 4.5 ng/mL results in the failure to detect a substantial number of clinically significant cancers.

The complement regulatory proteins CD46 and CD59, but not CD55, are highly expressed by glandular epithelium of human breast and colorectal tumour tissues.

Three of the proteins protecting cells from autologous lysis by complement are: membrane cofactor protein (MCP; CD46), an inhibitor of the membrane attack complex formation (CD59), and decay accelerating factor (DAF; CD55). We have investigated the expression of these proteins in breast and colorectal carcinoma by immunohistochemistry and immunoblotting of breast tissue for CD46. CD46 was consistently and strongly expressed in the epithelial compartment in 26/28 ductal carcinomas of the breast, 9/9 fibroadenomas, and 9/11 cases of control non-neoplastic breast tissue. CD59 showed a similar degree of expression in the fibroadenomas (9/9), but was less strongly expressed in carcinomatous (22/28) and control (5/11) tissues. In marked contrast, no CD55 expression was detected in tissue from 15 ductal carcinomas. Immunoblotting of breast tissue for CD46 showed the same size of the molecule as for lymphocytes. It had however considerably stronger expression in tumour tissue than in non-neoplastic tissue. CD46 and CD59 were either lacking or only weakly expressed in the epithelial component of control colorectal mucosa: 2/15 and 5/15, respectively. In contrast, tissue samples from colorectal adenocarcinomas showed clear staining for both CD59 (10/18) and, more markedly, CD46 (15/18). There was no association between the pattern or intensity of CD46 and CD59 expression and tumour differentiation. As the complement regulatory proteins CD46 and CD59 are also strongly expressed by trophoblast at the feto-maternal tissue interface, these results support the concept that similar mechanisms are employed both by the genetically dissimilar fetus and certain tumours to evade immune attack by their host.

The role of biopsy pathology, quantitative nuclear morphometry, and biomarkers in the preoperative prediction of prostate cancer staging and prognosis.

The focus of this review is to survey pretreatment biopsy and patient-derived information applicable to predicting pathological stage and prognosis of men with a diagnosis of prostate cancer. Various sources of clinical and pathological information that may contribute to building decision support tools (DSTs) for application by the urologist to manage prostate cancer patients are presented. These DSTs use serum biomarkers and objective, well-established, pathology information extracted by experienced pathologists from needle-core tissue samples that describe tumor size, grade, and location. Other valuable data can be derived from the biopsy tissue, such as computer-assisted image cytometry-derived DNA ploidy and nuclear morphometry informatics, as well as select tissue biomarker results that may provide supplemental prognostic information. Also discussed are the technical and clinical limitations of these DSTs with respect to the prediction accuracy. A commercially available pretreatment prediction algorithm (UroScore, Oklahoma City, OK) was applied to predict the disease organ confinement status of the prostate cancer test case. Finally, the authors present existing and future applications of computer-derived computational solutions for incorporating all patient history, clinical laboratory, and pathology information into algorithms that can generate patient-specific predictive probability estimates of stage, recurrence, and progression.

Positive prostate biopsy rate consistently increases with age at the same prostate-specific antigen level in patients with normal digital rectal examination.

OBJECTIVES: To examine the relationship between positive prostate biopsy rates and age over the range of serum prostate-specific antigen (PSA) concentrations of 4 to 10 ng/mL. METHODS: The rates for adenocarcinoma were calculated for prostate biopsy specimens received at UroCor Inc., Oklahoma City, Oklahoma between April 1995 and June 1997. The selection criteria were as follows: men between 50 and 79 years of age, normal digital rectal examination (DRE), prebiopsy PSA level between 4.01 and 10.0 ng/mL obtained within a 4-month period prior to receipt of biopsy, and no previous prostate biopsy. Five thousand six cases were selected out of 81,545 prostate biopsy specimens submitted by office-based urologists. The rates of positive prostate biopsies were stratified by age in decade increments and by PSA in increments of 1 ng/mL. The P values were calculated by the chi-square test. RESULTS: The patient mean age was 65.8 years. An overall increase in the positive prostate biopsy rate for men between 50 and 79 years of age as serum PSA increases from 4.01 to 10.0 ng/mL (P = 0.047) was found; however, this increase was less significant than the increase found in positive biopsy rates caused by age alone (P <0.0001). CONCLUSIONS: Undetected prostate cancer appears to be a major cause of the increasing serum PSA seen with advancing age.

Value of computer-assisted quantitative nuclear grading in differentiation of normal urothelial cells from low and high grade transitional cell carcinoma.

OBJECTIVE: To evaluate the ability of computer-assisted quantitative nuclear grading (QNG) using a microspectrophotometer and morphometry software to differentiate Feulgen-stained nuclei captured from normal urothelium, low grade transitional cell carcinoma (LG-TCC) and high grade transitional cell carcinoma (HG-TCC) cytology specimens. STUDY DESIGN: Feulgen-stained nuclei from a series of normal volunteers (urologic disease-free history) and from biopsy-confirmed cases of LG-TCC and HG-TCC were evaluated using a CAS-200 image analysis system. Thirty-eight nuclear morphometric descriptors (NMDs) were measured for each nucleus using a software conversion system. Backwards stepwise logistic regression analysis was applied to assess which of the NMDs contributed to QNG statistical models that could differentiate between nuclei from normals vs. LG-TCC, normals vs. HG-TCC, and LG-TCC vs. HG-TCC. Receiver operating characteristic curves and areas under the curve (AUC), as well as cell classification accuracy, were used to assess these differences. RESULTS: Statistically significant differences (P < .0001) were observed between all three categories. In the LG-TCC vs. normals, the QNG solution model required 16/38 features, with an AUC = 93%, a sensitivity = 85%, specificity = 86%, positive predictive value (PPV) = 87% and negative predictive value (NPV) = 84%. The QNG solution model for normals vs. HG-TCC required 12/38 nuclear features yielding an AUC = 99%, sensitivity = 99%, specificity = 98%, PPV = 98% and NPV = 99%. The QNG solution model for LG-TCC vs. HG-TCC required 17/38 nuclear features, with an AUC = 99%, sensitivity = 96%, specificity = 97%, PPV = 97% and NPV = 96%. CONCLUSION: Computer-assisted QNG cell classifiers based upon the measurement of 38 nuclear features, including size, shape and chromatin organization, are capable of differentiating normal urothelial nuclei from LG-TCC and HG-TCC nuclei as well as LG-TCC from HG-TCC nuclei. The QNG cell classifier has shown conclusively that there are morphometric differences between normal urothelial and LG-TCC nuclei that may not be apparent to the naked eye and that it may be useful in helping the pathologist determine the presence or absence of LG-TCC in bladder cytology specimens.

Observations on pathology trends in 62,537 prostate biopsies obtained from urology private practices in the United States.

OBJECTIVES: To evaluate pathology trends of 62,537 first-time prostate needle-core biopsies submitted by office-based urologists, processed at a single pathology laboratory. METHODS: Prostate biopsy cases obtained over a 2-year period were assessed. Patient information included age, digital rectal examination (DRE) status, and prostate-specific antigen (PSA) serum levels. Biopsy pathology results included the number of tissue samples per case, Gleason score, presence of Gleason grades 4 or 5, percent of biopsy length with evidence of cancer, number of samples with cancer per biopsy, and determination of DNA ploidy status using microspectrophotometry. RESULTS: Adenocarcinoma, suspicious lesions, and isolated high-grade prostatic intraepithelial neoplasia (PIN) were diagnosed in 38.3%, 2.9%, and 4.1% of the biopsies, respectively. For each serum PSA and age range assessed, the positive biopsy rate and incidence of critical pathologic features increased consistently. The average percentage of biopsy length with evidence of tumor, the percentage of cases with Gleason grades 4 or 5, and the percentage of cases with an abnormal DNA ploidy all decreased significantly over the 2-year period (P <0.01). CONCLUSIONS: The number of tissue cores and anatomic sites (locations) being sampled per biopsy are increasing. The tumor size detected and percentage of cases with Gleason grades 4 and 5 are decreasing. There has been a slight increase in the number of biopsies performed on men younger than 60 years of age and a slight decrease in biopsies performed on men older than 70 years of age. The decline in meaningful pathologic features observed in biopsies over time may be clinically relevant to improved disease management.

Comparative analysis of DNA content in polyomavirus-infected urothelial cells, urothelial dysplasia and high grade transitional cell carcinoma.

OBJECTIVE: To characterize the DNA content pattern in cytologically confirmed polyomavirus (PV)-infected urothelial cells and to compare it with DNA ploidy changes in cytologically diagnosed urothelial dysplasia and high grade transitional cell carcinoma. STUDY DESIGN: We selected 200 bladder cytology specimens consisting of four groups with 50 patients each in the following cytologic categories: (1) no evidence of malignancy or dysplasia (controls), (2) PV, (3) urothelial dysplasia (UD), and (4) high grade transitional cell carcinoma (TCC-HG). For each case, two slides with 25-mm filter imprints were stained, one using the Papanicolaou method and the other using the Feulgen staining method. The DNA index (DI), proliferative activity (S + G2M) and degree of hyperploidy (> 5C) were evaluated using an image analysis system. RESULTS: Using the Wilcoxon rank-sum test, statistically significant differences in the DI were found between the PV and UD groups (P = .008) and between the PV and TCC-HG groups (P < .0001). There was no significant difference in the DI between the PV and control groups. The S + G2M fraction for the PV group significantly differed from the control, UD and TCC-HG groups (all P < .0001). Between all four groups, the degrees of hyperploidy were significantly different as well (all P < .0001). CONCLUSION: Cytologically confirmed PV-infected urothelial cells demonstrated a unique DNA content pattern with mildly elevated proliferative activity and a significantly dispersed hyperploid DNA content pattern. DNA analysis can help to differentiate PV infection from dysplasia and high grade carcinoma.

Update on the appropriate staging evaluation for newly diagnosed prostate cancer.

PURPOSE: Prostate cancer clinical staging methods and decision support tools were reviewed to assess their accuracy to predict pathological staging results and determine what comprises an appropriate clinical staging evaluation. MATERIALS AND METHODS: The MEDLINE data base was searched and 238 abstracts were obtained. Data were extracted from 142 articles that evaluated the preoperative accuracy of digital rectal examination, prostate specific antigen, prostatic acid phosphatase, systematic biopsy parameters (including Gleason scoring), seminal vesicle biopsy, various imaging studies and pelvic lymphadenectomy versus pathological staging results. The sensitivity, specificity and accuracy rates were calculated and tabulated from the reported data on each method or decision support tools for organ confined, nonorgan confined and lymph node metastatic tumor. RESULTS: Decision support tools based on logistic regression analysis, which combine several statistically independent staging parameters, had greater accuracy than any single clinical staging method alone. The most accurate decision support tools for clinical staging combined digital rectal examination (T stage), systematic biopsy parameters (including Gleason scoring) and prostate specific antigen. CONCLUSIONS: The components that comprise the most accurate decision support tools for clinical staging represent an appropriate staging evaluation for the newly diagnosed prostate cancer patient in 1997. Limited use of radiographic imaging and seminal vesicle biopsy may be indicated in select patients to detect bone metastases, and plan pelvic lymphadenectomy and surgical therapy.

Deoxyribonucleic acid ploidy enhances the cytological prediction of recurrent transitional cell carcinoma of the bladder.

PURPOSE: We determined whether deoxyribonucleic acid (DNA) ploidy analysis by image analysis cytometry enhances the cytological diagnosis of recurrent transitional cell carcinoma of the bladder. MATERIALS AND METHODS: A retrospective study was performed during a 5-year period to evaluate the cytological diagnosis and DNA ploidy analysis of 469 patients with previously diagnosed superficial transitional cell carcinoma. Cytological and DNA ploidy analysis was performed on 1,034 urine and bladder wash specimens, and the patients were monitored with cystoscopy and biopsies as clinically indicated. Cytology results were classified as normal, atypical, dysplastic or cancerous, and DNA ploidy was defined as normal if the diploid index was 1.2 or less, the S phase+G2M fraction was less than 21% or if there were 3% or less hyperploid cells, or abnormal if there was an increased S phase+G2M fraction, an aneuploid peak on the histogram or tetraploidy or hyperploidy was present. RESULTS: The majority of patients (85 of 88, 97%) with a cytological diagnosis of cancer had an abnormal DNA ploidy, and in 60 of 85 of these patients (71%) recurrence was diagnosed within 6 months. Only 5 of 284 specimens (2%) with normal cytology had abnormal DNA ploidy and 1 of these 5 (20%) heralded transitional cell carcinoma recurrence. However, in 145 patients with atypical cytological findings 29 (20%) with abnormal DNA ploidy had a recurrence, compared to 20 of 391 (5%) with normal DNA ploidy (p < 0.0001). Similarly, in 101 patients with dysplastic cytological findings 39 (39%) with abnormal DNA ploidy had transitional cell carcinoma recurrence compared to 4 of 25 with normal ploidy (p = 0.033). CONCLUSIONS: Abnormal DNA ploidy determined by image analysis significantly enhances the detection of bladder tumor recurrence in patients with atypical or dysplastic cytology but not in those with normal cytology or frank carcinoma on cytological findings.

c-erbB2 and p53 expression are not associated with stage progression of gastric cancer in Britain or Japan.

The results of surgical treatment for gastric cancer are apparently better in Japan than in Western countries. It has been proposed that this is because of a biological difference between the tumours in Japan and in the West. We have previously reported very similar frequencies of positive immunohistochemical staining for the c-erbB2 oncogene and mutant p53 proteins in British and Japanese gastric cancers, findings which do not seem to support the 'biological difference' hypothesis. We realized that these studies did not rule out differences in the mechanism of cancer progression which might show themselves by a different association between p53 and c-erbB2 expression and stage in the two populations. We therefore re-analysed our data to look for differences in the frequency of p53 and c-erbB2 expression in the British and Japanese populations. Comparison of fixed tissue from 88 British and 89 Japanese tumours showed no significant association of c-erbB2 or p53 with stage progression in either population. Logistic regression showed no difference between the two populations in the relationship between stage and oncogene expression. These results do not support the idea of biologically different cancers in Japan and Britain. Other possible explanations for the difference in results such as the stage migration effect, better efficacy of Japanese-style surgery, or a difference in the host resistance to cancer in the two countries should be considered.

Differential excretion of leucocyte granule components in inflammatory bowel disease: implications for pathogenesis.

1. Faecal excretion of the leucocyte primary granule component, myeloperoxidase, and of the secondary granule component, lactoferrin, were compared in inflammatory bowel disease and infective diarrhoea. 2. Faecal lactoferrin correlated with faecal myeloperoxidase in both inflammatory bowel disease (P = 0.0018; n = 32) and infective diarrhoea (P = 0.00013; n = 37), but inflammatory bowel disease was associated with a much higher faecal excretion of lactoferrin but lower excretion of myeloperoxidase than infective diarrhoea. As a consequence, the median ratio of lactoferrin/myeloperoxidase excretion (both expressed as ng/mg of protein) for inflammatory bowel disease was 7.5 (range 3.5-21.3) with similar values for ulcerative colitis (n = 18) and Crohn's disease (n = 14) compared with only 0.9 (range 0.4-2.3; P < 0.0001) for infective diarrhoea. In inflammatory bowel disease faecal lactoferrin and myeloperoxidase excretion remained increased even in clinical remission. 3. In subsequent immunohistochemical studies to assess the possible explanation for these findings, lactoferrin and myeloperoxidase were demonstrated within crypt abscesses and surface mucus, both in inflammatory bowel and in infective diarrhoea mucosal samples. There was a slight increase in the number of lactoferrin-containing cells in the mucosal samples from ulcerative colitis and in the submucosa of samples from Crohn's disease compared with infective diarrhoea, but these changes were not sufficient to account for the marked increase in faecal lactoferrin excretion in inflammatory bowel disease. 4. In all mucosal samples, including those from normal mucosa, lactoferrin was also shown to be contained within mast cells. 5. These results could best be explained by a different mechanism for leucocyte activation in inflammatory bowel disease compared with infective diarrhoea, and are compatible with selective secretion of secondary granule components, which include lactoferrin but not myeloperoxidase, as a result of leucocyte activation by N-formylated bacterial peptides in inflammatory bowel disease.

An algorithm for predicting nonorgan confined prostate cancer using the results obtained from sextant core biopsies with prostate specific antigen level.

PURPOSE: We determined the enhanced ability to predict nonorgan confined prostate cancer using several histopathological and quantitative nuclear imaging parameters combined with serum prostate specific antigen (PSA). MATERIALS AND METHODS: Several independent pathological and quantitative image analysis variables obtained from sextant biopsy specimens, as well as preoperative PSA were used. The study population included 210 patients with pathologically staged disease (192 with PSA). All variables were examined by univariate and multivariate logistic regression analyses to assess ability to predict disease organ confinement status. RESULTS: Univariate logistic regression analysis demonstrated that, in decreasing order, quantitative nuclear grade, preoperative PSA, total percent tumor involvement, number of positive sextant cores, preoperative Gleason score and involvement of more than 5% of a base and/or apex biopsy were significant (p < or = 0.006) for prediction of disease organ confinement status. Backward stepwise logistic regression was applied to these univariately significant variables, including deoxyribonucleic acid ploidy, to calculate a multivariate model for prediction of disease organ confinement status. This algorithm had a sensitivity of 85.7%, specificity 71.3%, positive predictive value 72.9%, negative predictive value 84.7% and area under the receiver operating characteristic curve 85.9%. CONCLUSIONS: Information from pathological study of sextant prostate biopsies, preoperative PSA blood test and a new image analysis variable termed quantitative nuclear grade can be combined to create a multivariate algorithm that can predict more accurately nonorgan confined prostate cancer compared to previously reported methods.