Stimulated Raman Histology Interpretation by Artificial Intelligence Provides Near-Real-Time Pathologic Feedback for Unprocessed Prostate Biopsies.

PURPOSE: Stimulated Raman histology is an innovative technology that generates real-time, high-resolution microscopic images of unprocessed tissue, significantly reducing prostate biopsy interpretation time. This study aims to evaluate the ability for an artificial intelligence convolutional neural network to interpretate prostate biopsy histologic images created with stimulated Raman histology. MATERIALS AND METHODS: Unprocessed, unlabeled prostate biopsies were prospectively imaged using a stimulated Raman histology microscope. Following stimulated Raman histology creation, the cores underwent standard pathological processing and interpretation by at least 2 genitourinary pathologists to establish a ground truth assessment. A network, trained on 303 prostate biopsies from 100 participants, was used to measure the accuracy, sensitivity, and specificity of detecting prostate cancer on stimulated Raman histology relative to conventional pathology. The performance of the artificial intelligence was evaluated on an independent 113-biopsy test set. RESULTS: Prostate biopsy images obtained through stimulated Raman histology can be generated within a time frame of 2 to 2.75 minutes. The artificial intelligence system achieved a rapid classification of prostate biopsies with cancer, with a potential identification time of approximately 1 minute. The artificial intelligence demonstrated an impressive accuracy of 96.5% in detecting prostate cancer. Moreover, the artificial intelligence exhibited a sensitivity of 96.3% and a specificity of 96.6%. CONCLUSIONS: Stimulated Raman histology generates microscopic images capable of accurately identifying prostate cancer in real time, without the need for sectioning or tissue processing. These images can be interpreted by artificial intelligence, providing physicians with near-real-time pathological feedback during the diagnosis or treatment of prostate cancer.

Preliminary experience with a novel method of three-dimensional co-registration of prostate cancer digital histology and in vivo multiparametric MRI.

AIM: To assess a novel method of three-dimensional (3D) co-registration of prostate cancer digital histology and in-vivo multiparametric magnetic resonance imaging (mpMRI) image sets for clinical usefulness. MATERIAL AND METHODS: A software platform was developed to achieve 3D co-registration. This software was prospectively applied to three patients who underwent radical prostatectomy. Data comprised in-vivo mpMRI [T2-weighted, dynamic contrast-enhanced weighted images (DCE); apparent diffusion coefficient (ADC)], ex-vivo T2-weighted imaging, 3D-rebuilt pathological specimen, and digital histology. Internal landmarks from zonal anatomy served as reference points for assessing co-registration accuracy and precision. RESULTS: Applying a method of deformable transformation based on 22 internal landmarks, a 1.6 mm accuracy was reached to align T2-weighted images and the 3D-rebuilt pathological specimen, an improvement over rigid transformation of 32% (p = 0.003). The 22 zonal anatomy landmarks were more accurately mapped using deformable transformation than rigid transformation (p = 0.0008). An automatic method based on mutual information, enabled automation of the process and to include perfusion and diffusion MRI images. Evaluation of co-registration accuracy using the volume overlap index (Dice index) met clinically relevant requirements, ranging from 0.81-0.96 for sequences tested. Ex-vivo images of the specimen did not significantly improve co-registration accuracy. CONCLUSION: This preliminary analysis suggests that deformable transformation based on zonal anatomy landmarks is accurate in the co-registration of mpMRI and histology. Including diffusion and perfusion sequences in the same 3D space as histology is essential further clinical information. The ability to localize cancer in 3D space may improve targeting for image-guided biopsy, focal therapy, and disease quantification in surveillance protocols.

Impact of delay after biopsy and post-biopsy haemorrhage on prostate cancer tumour detection using multi-parametric MRI: a multi-reader study.

AIM: To assess impact of haemorrhage and delay after biopsy on prostate tumour detection using multi-parametric (MP) magnetic resonance imaging (MRI) assessment. MATERIALS AND METHODS: Forty-four patients underwent prostate MRI at 1.5 T using a pelvic phased-array coil, including T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), diffusion-weighted imaging (DWI), and dynamic contrast-enhanced (DCE) imaging, before prostatectomy. Three radiologists independently reviewed images during four sessions [T2WI, DWI, DCE, and all parameters combined (MP-MRI)] to assess for tumour in each sextant. In a separate session, readers reviewed T1WI to score the extent of haemorrhage per sextant. Accuracy was assessed using logistic regression for correlated data. RESULTS: There was no significant difference in accuracy between readers for any session (p ≥ 0.166), and results were averaged across the three readers for remaining comparisons. Accuracy was significantly greater for MP-MRI than for any parameter alone (p ≤ 0.020). For T2WI alone, there was a trend toward decreased sensitivity in sextants with extensive haemorrhage (p = 0.072). However, accuracy, sensitivity, and specificity were otherwise similar for sextants with and without extensive haemorrhage for all sessions (p = 0.192-0.934). No session showed a significant improvement in accuracy, sensitivity, or specificity in cases with delay after biopsy of over 4 weeks compared with shorter delay. CONCLUSION: Extensive haemorrhage and short delay after biopsy did not negatively impact accuracy for tumour detection using MP-MRI. Further studies using MP-MRI protocols and interpretation schemes from other institutions are required to confirm these observations.

Contributions to the history of ocular toxoplasmosis in Southern Brazil.

The evolution of knowledge regarding ocular toxoplasmosis over the last 30 years is described based on studies and observations performed in Southern Brazil. The isolation of Toxoplasma gondii established the definitive diagnosis of the disease. It was proven that in most cases, the disease was acquired after birth, a concept supported by the description of numerous familial cases and observation of the disease many years after primary infection. Epidemiological studies showed important regional variations in the prevalence of the disease due to different factors, including the types of strains involved, of which type I predominates. The large number of patients also enabled detailed study of the different forms of clinical presentation of the disease and its complications. New parameters have been established for the use of steroids and the management of pregnant women with active lesions. Studies on the epidemiology of toxoplasmic infection in pregnant women and newborns showed a high prevalence of infection. The different factors of exposure to infection have also been studied. Gradually, preventive actions have been developed in the sphere of public health, although they have not been sufficiently effective. Trends for future research over the next few years are also outlined.

Inhibition of phagocytosis of complement C3- or immunoglobulin G-coated particles and of C3bi binding by monoclonal antibodies to a monocyte-granulocyte membrane glycoprotein (Mol).

Events that lead to phagocytosis of complement (C3)- or IgG-coated particles after their interaction with specific cell surface receptors are poorly understood. Two mouse monoclonal antibodies (an IgM and an IgG2a) to a human granulocyte-monocyte surface membrane differentiation antigen (Mol) inhibited ingestion by granulocytes both of oil Red O particles opsonized with normal human serum or with IgG and of sheep erythrocytes sensitized with IgG. In addition, they specifically inhibited rosetting between phagocytes and sheep erythrocytes coated with C3bi, a fragment of the complement component C3, generated by cleaving C3b with C3b inactivator and beta IH protein. These monoclonal anti-Mol antibodies did not inhibit IgG Fc, C3b or C3d receptor-mediated binding of erythrocytes coated with the respective proteins. The Fab fragment of the IgG2a monoclonal antibody inhibited noncytotoxic enzyme release from granulocytes when these cells were stimulated with zymosan coated with C3bi. Electrophoretic transfer of polymorphonuclear leukocyte detergent lysates to nitrocellulose, followed by immunofixation with monoclonal antibody, showed that these antibodies were directed to a 155,000-mol wt glycoprotein. This surface membrane structure appears to be involved in Fc and C3 receptor-dependent phagocytosis and closely associated with the C3bi receptor.

Practical aspects of planning, building, and interpreting tissue microarrays: the Cooperative Prostate Cancer Tissue Resource experience.

This is a review of several new approaches developed at or adopted by the Cooperative Prostate Cancer Tissue Resource (CPCTR) to resolve issues involved in tissue microarray (TMA) construction and use. CPCTR developed the first needle biopsy TMA, allowing researchers to obtain 200 or more consecutive cancer sections from a single biopsy core. Using radiographs of original paraffin blocks to measure tissue thickness we developed a method to produce TMAs with a larger number of usable sections. The modular approach to plan TMA construction is also a novel concept wherein TMAs of different types, such as tumor grade TMAs, metastasis TMA and hormone refractory tumors TMA can be combined to form an ensemble of TMAs with expanded research utility, such as support for tumor progression studies. We also implemented an open access TMA Data Exchange Specification that allows TMA data to be organized in a self-describing XML document annotated with well-defined common data elements. It ensures inter-laboratory reproducibility because it offers information describing the preparation of TMA blocks and slides. There are many important aspects that may be missed by both beginners and experienced investigators in areas of TMA experimental design, human subjects protection, population sample size, selection of tumor areas to sample, strategies for saving tissues, choice of antibodies for immunohistochemistry, and TMA data management.

Identification of a high affinity nucleocapsid protein binding element within the Moloney murine leukemia virus Psi-RNA packaging signal: implications for genome recognition.

Murine leukemia virus (MLV) is currently the most widely used gene delivery system in gene therapy trials. The simple retrovirus packages two copies of its RNA genome by a mechanism that involves interactions between the nucleocapsid (NC) domain of a virally-encoded Gag polyprotein and a segment of the RNA genome located just upstream of the Gag initiation codon, known as the Psi-site. Previous studies indicated that the MLV Psi-site contains three stem loops (SLB-SLD), and that stem loops SLC and SLD play prominent roles in packaging. We have developed a method for the preparation and purification of large quantities of recombinant Moloney MLV NC protein, and have studied its interactions with a series of oligoribonucleotides that contain one or more of the Psi-RNA stem loops. At RNA concentrations above approximately 0.3 mM, isolated stem loop SLB forms a duplex and stem loops SL-C and SL-D form kissing complexes, as expected from previous studies. However, neither the monomeric nor the dimeric forms of these isolated stem loops binds NC with significant affinity. Longer constructs containing two stem loops (SL-BC and SL-CD) also exhibit low affinities for NC. However, NC binds with high affinity and stoichiometrically to both the monomeric and dimeric forms of an RNA construct that contains all three stem loops (SL-BCD; K(d)=132(+/-55) nM). Titration of SL-BCD with NC also shifts monomer-dimer equilibrium toward the dimer. Mutagenesis experiments demonstrate that the conserved GACG tetraloops of stem loops C and D do not influence the monomer-dimer equilibrium of SL-BCD, that the tetraloop of stem loop B does not participate directly in NC binding, and that the tetraloops of stem loops C and D probably also do not bind to NC. These surprising results differ considerably from those observed for HIV-1, where NC binds to individual stem loops with high affinity via interactions with exposed residues of the tetraloops. The present results indicate that MLV NC binds to a pocket or surface that only exists in the presence of all three stem loops.

Allelic loss on chromosome 13q in human prostate carcinoma.

To clarify the role in prostate tumorigenesis played by loss of the three known or putative tumor suppressor loci on the centromeric portion of chromosome 13q, we examined 80 clinically localized and 15 advanced prostate carcinomas for allelic loss at microsatellite markers mapped to this region, including markers tightly linked to the BRCA-2, retinoblastoma (Rb), and DBM (deleted in B-cell malignancy) loci. Among the 80 clinically localized cases, 24 showed allelic loss at one or more 13q loci. In all cases with loss, the Rb and/or DBM loci were lost. No cases were found with loss of Rb without loss of DBM or loss of DBM without loss of Rb, implying a role for both the Rb and DBM loci in clinically localized prostate cancer. Loss of the BRCA-2 locus was less common (4 of 55 informative cases) and was always associated with loss of Rb and/or DBM loci. Thus, the BRCA-2 locus does not appear to play as important a role in clinically localized prostate cancer as the Rb and/or DBM loci. Allelic loss on 13q was extremely common in the clinically advanced cases; it was present in 14 of the 15 cases. The rate of allelic loss at each of the three tumor suppressor loci was increased significantly in the advanced cases (P < 0.01, Fisher's exact test). Thus, loss of heterozygosity on 13q is very common in prostate cancer and occurs at all three known or putative tumor suppressor loci on the centromeric portion of chromosome 13q.

Initial clinical evaluation of radiolabeled MX-DTPA humanized BrE-3 antibody in patients with advanced breast cancer.

To evaluate radiometal-labeled humanized BrE-3 (huBrE-3) monoclonal antibody as a radioimmunolocalization and therapeutic agent in breast cancer patients, tumor localization, pharmacokinetics, radiation dosimetry, and immunogenicity of (111)In-labeled combined 1-p-isothiocyanatobenzyl 3-methyl- and 1-p-isothiocyanatobenzyl 4-methyldiethylenetriamine pentaacetic acid (MX-DTPA) huBrE-3 were studied. Seven women with BrE-3 antigen-positive, metastatic breast carcinoma underwent (111)In huBrE-3 infusion (5 mCi; 50 mg), followed by serial gamma camera imaging and plasma sampling. Region of interest analysis of images was used to make radiation absorbed dose estimates for (111)In huBrE-3. Data were extrapolated to 90Y huBrE-3. Human anti-human antibody (HAHA) response was measured in serum samples obtained up to 3 months after infusion. Patients tolerated infusions well. Seventy-six percent of 105 known sites of disease were identified on planar and single-photon emission computed tomography scans. For six of seven patients, a biexponential model fit the plasma time-activity curve best with an average T1/2alpha=10.6+/-8.5 (SD) h and average T1/2beta=114.2+/-39.2 h. Radiation absorbed dose estimates for (111)In huBrE-3 for whole body averaged 0.53+/-.08 rads/mCi. Dose estimates for 90Y huBrE-3 for marrow averaged 8.4+/-11.9 rads/mCi, and for tumors, 70+/-31.5 rads/mCi. Liver radioactivity uptake averaged 19.7+/-8.8% injected dose at 24 h after infusion, translating into an average radiation absorbed dose 21.1+/-12 rads/90Y mCi administered. Only one of seven patients demonstrated a low level of HAHA response. Although the plasma half-lives are longer and marrow dose higher for radiolabeled huBrE-3 compared with the murine construct, the excellent tumor localization, good tumor dosimetry, and low immunogenicity support the use of 90Y-huBrE-3 antibody for radioimmunotherapy of breast cancer.

Tobacco smoking, occupation, and p53 nuclear overexpression in early stage bladder cancer.

Epidemiological studies show an increased risk of bladder cancer associated with tobacco smoking and occupational exposures. Certain carcinogens in tobacco and occupational exposures cause DNA damage and may produce specific mutations. TP53 is considered a common target for carcinogenic agents, and mutations of this gene are reported to be the most frequent nuclear abnormalities in human cancer. In order to investigate the relationship between tobacco smoking, occupations, and altered patterns of p53 expression, we have analyzed a group of 109 incident patients with superficial transitional cell carcinoma of the bladder. We assessed p53 nuclear overexpression by the use of anti-p53 antibody PAb1801 and immunohistochemistry, and identified 45 of 109 patients (41%) displaying p53-positive phenotype. We observed a significant association between the number of cigarettes smoked per day and p53 nuclear overexpression (p = 0.02). The odds ratios were 2.3 for those smoking 1-2 packs per day and 8.4 for smoking more than 2 packs per day. Similar estimates were obtained after controlling for age, sex, and race. Elevated odds ratios were also observed for dye-/ink-related (odds ratio = 2.0; 95% CI, 0.4-9.4) and cooking-related occupations (1.8, 0.6-5.0), although those were not statistically significant. These data support the hypothesis that certain carcinogens derived from cigarette smoking and occupations may induce TP53 mutations, which in turn are involved in early steps of bladder carcinogenesis.

Choriocarcinoma as a cause of thyrotoxicosis.

Three patients with choriocarcinoma had clinical and biochemical evidence of hyperthyroidism. Diminution in the thyrotoxicosis closely paralleled the fall in human chorionic gonadotrophin (hCG) levels. Three patients originally presented to internal medicine units as a problem of hemoptysis. Thyroid-stimulating hormone bioassay activity was demonstrated in the serum of all three patients prior to therapy. Recently evidence has been presented that hCG has intrinsic thyrotropic activity and that in conditions, such as hydatidiform mole, in which serum hCG levels are grossly elevated this thyrotropic activity can be sufficient to produce hyperthyroidism. Two of our cases supported the concept that hCG was also the substance with thyroid-stimulating activity in patients with choriocarcinoma. The third case left open the possibility that, in addition to the thyroid-stimulating activity of hCG, there may also be the production of a true ectopic thyroid-stimulating hormone (TSH). It is considered that the development of biochemical and clinical thyrotoxicosis in patients with choriocarcinoma depends upon the duration of the choriocarcinoma and the level of hCG.

PIP: The cases of 3 patients with advanced metastatic choriocarcinoma and biochemical and clinical evidence of hyperthyroidism are reported. The thyroid-stimulating hormone (TSH) bioassay activity was increased in all 3 patients before chemotherapy. All patients had clinical signs and symptoms of overt thyrotoxicosis although goiter was present in only 1. Sinus tachycardia was present in all. The 1st symptom in all 3 cases was hemoptysis. An X-ray appearance of multiple pulmonary metastases was also present. There was biochemical evidence of improvement in thyrotoxicosis after chemotherapy. This improvement paralleled the fall in urinary human chorionic gonadotropin (HCG). As treatment, intermittent oral 5-day courses of methotrexate and iv actinomycin D were given at 3-week intervals. In 2 of the cases the ratio of bioassayable thyrotropic activity to HCG found in the serum was similar to the ratio in patients with hydatidiform moles. In the other case the ratio was much higher. It appears that the development of biochemical and clinical hyperthyroidism in patients with choriocarcinoma depends on the duration of the choriocarcinoma and the serum level of HCG. Findings suggest that there may be production of another TSH in addition to the thyrotropic activity of high HCG levels.

Adenovirus colitis in human immunodeficiency virus infection: an underdiagnosed entity.

Adenovirus infection of the gastrointestinal tract in human immunodeficiency virus (HIV)-infected patients is rarely reported, probably because of a lack of familiarity of most pathologists with diagnostic criteria during routine light microscopy and possible misidentification as cytomegalovirus infection. We studied colonoscopic biopsy specimens from 135 HIV-infected patients with clinically suspected cytomegalovirus colitis during a 4.5-year period to morphologically identify the presence of adenovirus infection. Immunohistochemical staining for adenovirus was performed for confirmation on all suspected cases. Adenovirus infected cells showed characteristic amphophilic or eosinophilic nuclear inclusions, predominantly affecting the surface epithelium and characteristically involving goblet cells. Sixteen cases showed morphologic features of adenovirus infection, all confirmed by immunohistochemistry. Twelve cases also showed cytomegalovirus infection, whereas 4 showed adenovirus alone. In 10 cases, adenovirus colitis was not recognized during initial routine histopathologic diagnostic evaluation. Adenovirus inclusions also were discovered in the stomach, the duodenum, and the liver in single cases. Conclusions are as follows: (1) Adenovirus colitis has been underdiagnosed at our institution and, we suspect, in general. (2) The morphologic features and nuclear inclusions of adenovirus colitis are characteristic and can be identified reliably by routine light microscopy. (3) Adenovirus infection also may be diagnosed morphologically in extracolonic sites, such as the stomach, the small intestine, and the liver. (4) Coinfection of adenovirus with cytomegalovirus and other agents is seen frequently, but, less frequently, adenovirus may be identified as a sole pathogen.

Renal myxoma. A report of two cases and review of the literature.

Renal myxomas are rare neoplasms. Seven cases have been reported, of which only two are convincingly diagnosed as myxoma; the remaining cases exhibit features of sarcoma, fibroepithelial polyp, or myxolipoma. We report two additional cases; one in a 52-year-old man and another in a 68-year-old woman. They were discovered incidentally by radiological examination. The resected kidney in both patients contained a well-demarcated gelatinous intraparenchymal tumor, which consisted of occasional slender spindle cells scattered in an abundant myxoid stroma, closely resembling myxomas of other sites. The tumor cells showed immunoreactivity for vimentin but not for S-100 protein, epithelial membrane antigen (EMA), CAM 5.2, HHF-35, or smooth muscle actin. Ultrastructural features were of fibroblast-like cells with an elaborate network of cytoplasmic processes. The differential diagnosis of myxoid tumors of the kidney includes myxoid variants of renal sarcomas and carcinomas, renomedullary interstitial cell tumors, and fibroepithelial polyps. It is important to recognize the existence of a renal myxoma, to avoid confusing this benign tumor with the malignant neoplasms with secondary myxoid features that may involve the kidney.

Clinical and pathobiological effects of neoadjuvant total androgen ablation therapy on clinically localized prostatic adenocarcinoma.

Neoadjuvant total androgen ablation therapy leads to involutional changes in prostatic carcinoma and may have the potential to downstage operable prostate cancers. We studied 27 clinically localized prostatic carcinomas after 3 months of combined treatment with a luteinizing hormone-releasing hormone agonist, goserelin acetate, and the antiandrogen flutamide, followed by radical retropubic prostatectomy, for changes in the serum prostate-specific antigen (PSA) level, changes in prostatic volume, therapy-induced histopathologic changes, DNA ploidy, and proliferative activity. Ten hormonally untreated, grade-matched prostatic adenocarcinomas served as controls. The mean pretherapy serum PSA level was 17.5 ng/ml, and posttherapy PSA levels were all < 4.0 ng/ml, with 18 men having undetectable levels. The mean reduction in prostatic volume following hormonal therapy was 37% (range 16-52%). Pathologic staging confirmed 20 pT2N0, six pT3N0, and one pT3N1. All prostates showed residual adenocarcinoma (extremely focal in seven cases [26%] with loss of glandular architecture, cytoplasmic vacuolization, and nuclear pyknosis. High-grade adenocarcinoma was nondiploid in 25% of hormonally treated prostates and 80% of 10 untreated controls. Immunostaining for proliferating cell nuclear antigen showed > 10% nuclear reactivity in 33% of treated carcinomas and 90% of untreated carcinomas. In conclusion, 3 months of neoadjuvant androgen ablation for localized prostatic carcinoma significantly lowers serum PSA and prostatic volume and produces involutional changes in residual carcinomas that mimic high-grade disease. However, pretreated carcinomas have predominantly a diploid DNA content and low proliferative activity as opposed to untreated carcinomas. Thus, grading of pretreated adenocarcinomas by conventional methods may be misleading. Preoperative total androgen ablation has a profound effect on a subset of prostatic carcinoma cells, possibly by facilitating programmed cell death.

Benign proliferative nipple duct lesions frequently contain CAM 5.2 and anti-cytokeratin 7 immunoreactive cells in the overlying epidermis.

Benign proliferative nipple duct lesions (PNDLs) pose a diagnostic problem for clinicians and pathologists. Clinically, they may be associated with skin changes typically present in Paget's disease of the nipple. The identification of numerous scattered cells in the epidermis that are immunoreactive for low-molecular-weight cytokeratin may lead to further confusion with Paget's disease. We studied the nipple epidermis in nine cases of PNDL and compared them with 26 histologically normal nipples from mastectomy specimens. CAM 5.2 and anticytokeratin 7 (CK7) immunoreactive cells were identified in the epidermis of seven of nine nipples associated with PNDL. The cytokeratin-positive cells appeared cytologically benign and were dispersed singly (scattered in seven of seven cases and frequent in four of seven cases) or formed small aggregates with occasional tubular structures (three of seven cases) in the basal and middle layers of the epidermis. In two of seven cases, these epidermal immunoreactive cells showed continuity with the underlying PNDL, suggesting the spread or continuation of lesional cells to the epidermis. Dispersed single immunoreactive cells were identified in small numbers (scattered) in the basal layer of the epidermis in 12 of 26 normal nipples and more frequently in 1 of 12 cases. In all cases, the intraepidermal cells were negative for carcinoembryonic antigen (CEA) and Her-2/neu. We conclude that intraepidermal CAM 5.2 and anti-CK7 immunoreactive cells, which are normally present in the nipple epidermis, may proliferate and form aggregates when there is an underlying PNDL. The presence of these cells does not imply Paget's disease when the intraepidermal cells have a bland cytologic appearance, fail to overexpress Her-2/neu, and there is no carcinoma within the PNDL or elsewhere in the breast.

P53 nuclear overexpression and disease progression in ta-bladder carcinoma.

This study investigates the prevalence and clinical relevance of nuclear overexpression of the p53 protein, as detected by antibody PAb1801, in 54 patients with pathologically confirmed Ta bladder carcinomas obtained by transurethral resection at Memorial Sloan-Kettering Cancer Center between 1972 and 1980. No patient received any prior adjuvant therapy. Clinical and histopathological prognostic variables such as age, sex and tumor grade were also analyzed. The median follow-up was 110 months. Patients were stratified into two groups according to the percent of tumor cells with nuclear overexpression of the p53 protein. Group A included carcinomas with less than 20% (n=42) and Group B with 20% or more (n=12) of tumor cells with positive nuclear immunoreactivity. Five patients of Group A (12%) developed tumor progression as did 7 (58%) patients of Group B (p=0.002). Three (7%) patients of Group A and 3 (25%) patients of Group B died of bladder cancer (p=0.12). This study demonstrates a relatively low prevalence of altered p53 expression in this early stage of bladder cancer (22%). Nuclear overexpression of the p53 protein in greater-than-or-equal-to 20% tumor cells,was highly associated with tumor grade (p=0.01), but the former was the only independent marker of tumor progression (p=0.0008) on the basis of the multivariate analysis performed. It was also the only independent variable . associated with death due to bladder cancer (p=0.04). We conclude that p53 nuclear overexpression is a prognostic indicator in this disease, and may be useful for selection of therapy for patients with non-invasive papillary superficial bladder carcinoma.

Morphological and biological characteristics of mammogram-detected invasive breast cancer.

Thirty-nine mammographically detected, (M-detected) small invasive carcinomas of the breast (< or = 5 mm) were compared with 78 consecutive clinical cancers (> or = 10 mm) for a variety of morphological and biological markers of prognostic importance. There were more tubular carcinomas in the M-detected group (12.8% v 3.8%), but this did not reach statistical significance. Incidences of other histological types were similar. The types of associated in situ component were similar in the two groups. M-detected cancers were of lower overall grade (P < .001), lower architectural and nuclear grades (P = .0164 and P < .0001 respectively), and had fewer mitotic cells (P < .0001). None showed positive lymph nodes (P < .0001). Estrogen and progesterone receptor expression was similar in both groups. M-detected cancers expressed p53 nuclear protein less frequently than clinical cancers (P = .0398), had lower levels of microvessel density (P = .0001), and were more often diploid (P = .0131). S-phase of diploid tumors in the two groups was similar, but S-phase of aneuploid tumors was lower in the M-detected group (P = .0057). Ki67 expression was lower in M-detected cancers (P < .0001). In conclusion, M-detected small breast cancers, although invasive, represent an evolutionary phase of breast cancer that generally lacks morphological and biologic markers of aggressive behavior. The presence or absence of these markers, collectively, may explain the influence of tumor size on survival in patients with breast cancer.

Renal pathology of essential hypertension.

Microscopic analysis of over 2,000 renal biopsies taken at surgical sympathectomy operations has been correlated with blood pressures in essential hypertension. Statistically significant relationships exist between the average diastolic pressure and the degree of afferent renal arteriolar thickening and narrowing. Postoperative prognosis was favorable with all but the most severe and diffuse arteriolar sclerosis, and vascular fibrinoid necrosis did not affect survival. Juxtaglomerular cell hyperplasia and inferred renin hypersecretion were significantly involved in the kidney biopsies of essential hypertension. Diabetic juxtaglomerular cell atrophy and sclerosis reduced this component of hypertension. After age 80, kidneys at autopsy showed no evident relation between arteriolar lesions and hypertension.

Immunohistochemical detection of hepatitis C antigen by monoclonal antibody TORDJI-22 compared with PCR viral detection.

We sought to determine the sensitivity and specificity of immunohistochemistry using the TORDJI-22 MoAb (BioGenex, San Ramon, Calif), which is specific for the C-100 protein of the hepatitis C virus, compared with reverse transcriptase-polymerase chain reaction (RT-PCR) of tissue for viral RNA. RT-PCR had been performed on 52 fixed tissue specimens. Immunohistochemistry was performed using prediluted antibody with the alkaline phosphatase/fast red (BioGenex) technique. Predigestion with Protease XXIV (BioGenex) and other procedures followed the manufacturer's protocols. Positive immunohistochemistry was narrowly defined as tightly clumped, perinuclear red granules in hepatocytes. Of the specimens, 28 were positive by RT-PCR. With RT-PCR as the standard of comparison, immunohistochemistry yielded a sensitivity of 70% and specificity of 84%. Positive cells, when present, were usually very rare. With stringent criteria, immunohistochemistry with the TORDJI-22 monoclonal antibody is a very specific, fairly sensitive diagnostic test for hepatitis C virus in fixed liver tissues.