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Magnetic resonance imaging (MRI) is increasingly used to triage patients for prostate biopsy. However, 9% to 24% of clinically significant (cs) prostate cancers (PCas) are not visible in MRI. We aimed to identify histomic and transcriptomic determinants of MRI visibility and their association to metastasis, and PCa-specific death (PCSD). We studied 45 radical prostatectomy-treated patients with csPCa (grade group [GG]2-3), including 30 with MRI-visible and 15 with MRI-invisible lesions, and 18 men without PCa. First, histological composition was quantified. Next, transcriptomic profiling was performed using NanoString technology. MRI visibility-associated differentially expressed genes (DEGs) and Reactome pathways were identified. MRI visibility was classified using publicly available genes in MSK-IMPACT and Decipher, Oncotype DX, and Prolaris. Finally, DEGs and clinical parameters were used to classify metastasis and PCSD in an external cohort, which included 76 patients with metastatic GG2-4 PCa, and 84 baseline-matched controls without progression. Luminal area was lower in MRI-visible than invisible lesions and low luminal area was associated with short metastasis-free and PCa-specific survival. We identified 67 DEGs, eight of which were associated with survival. Cell division, inflammation and transcriptional regulation pathways were upregulated in MRI-visible csPCas. Genes in Decipher, Oncotype DX and MSK-IMPACT performed well in classifying MRI visibility (AUC = 0.86-0.94). DEGs improved classification of metastasis (AUC = 0.69) and PCSD (AUC = 0.68) over clinical parameters. Our data reveals that MRI-visible csPCas harbor more aggressive histomic and transcriptomic features than MRI-invisible csPCas. Thus, targeted biopsy of visible lesions may be sufficient for risk stratification in patients with a positive MRI., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Hormonal therapies targeting androgen receptor (AR) are effective in prostate cancer (PCa), but often the cancers progress to fatal castrate-resistant disease. Improved understanding of the cellular events during androgen deprivation would help to identify survival and stress pathways whose inhibition could synergize with androgen deprivation. Toward this aim, we performed an RNAi screen on 2,068 genes, including kinases, phosphatases, epigenetic enzymes and other druggable gene targets. High-content cell spot microarray (CSMA) screen was performed in VCaP cells in the presence and absence of androgens with detection of Ki67 and cleaved ADP-ribose polymerase (cPARP) as assays for cell proliferation and apoptosis. Thirty-nine candidate genes were identified, whose silencing inhibited proliferation or induced apoptosis of VCaP cells exclusively under androgen-deprived conditions. One of the candidates, HSPB (heat shock 27 kDa)-associated protein 1 (HSPBAP1), was confirmed to be highly expressed in tumor samples and its mRNA expression levels increased with the Gleason grade. We found that strong HSPBAP1 immunohistochemical staining (IHC) was associated with shorter disease-specific survival of PCa patients compared with negative to moderate staining. Furthermore, we demonstrate that HSPBAP1 interacts with AR in the nucleus of PCa cells specifically during androgen-deprived conditions, occupies chromatin at PSA/klk3 and TMPRSS2/tmprss2 enhancers and regulates their expression. In conclusion, we suggest that HSPBAP1 aids in sustaining cell viability by maintaining AR signaling during androgen-deprived conditions., (© 2014 UICC.)

Patients with long-standing inflammatory bowel disease (IBD) have an increased risk for colorectal carcinoma (CRC). Earlier studies suggest that the severity of inflammation is an independent risk factor for CRC in ulcerative colitis (UC). We investigated the role of histological inflammation as a risk factor for colorectal dysplasia or CRC to better target dysplasia surveillance in IBD. By combining our hospital patient registry and pathology database between 1996 and 2008, we identified 183 IBD patients with dysplasia or CRC. The control group was collected from our registry of IBD patients. Histological severe inflammation was present in 41.4% of patients with dysplasia and in 24.1% of patients with CRC, but in only 4.3% of controls. Severe inflammation had an odds ratio (OR) of 31.8 [95% confidence interval (CI): 15.6-64.9] for dysplasia or carcinoma compared to patients with no inflammation. Among patients with mild to moderate inflammation, the OR was 2.6 (95% CI: 1.6-4.1). Disease duration increased the annual risk for dysplasia or CRC by 4.5%. Coexisting primary sclerosing cholangitis (PSC) did not elevate the risk, whereas use of thiopurines (OR = 0.09, 95% CI: 0.02-0.33) and also 5-aminosalicylic acid (OR 0.17, 95% CI: 0.017-1.01) protected against CRC. As conclusion, degree of inflammation and duration of disease cumulatively increase the risk for dysplasia and CRC. PSC was not identified as a risk factor. We demonstrated that use of thiopurines strongly protects against CRC. These results can be applied to better target dysplasia surveillance in IBD patients., (© 2013 UICC.)

Background: PSA is the most useful prostate cancer marker. However, its levels are increased also in some non-malignant conditions. In circulation, the majority of PSA is complexed with protease inhibitors, including α(1) -antichymotrypsin (ACT). The proportion of the PSA-ACT complex is higher in patients with prostate cancer than in controls without cancer. The expression of ACT has been shown to be higher in prostate cancer than in benign prostatic hyperplasia. However, results regarding the extent which PSA forms complexes within the prostate and whether there are differences in complex formation between normal and malignant prostatic tissue are inconsistent and limited., Methods: We studied complex formation of PSA secreted by cultured human prostate tissues and in the tissue by in situ proximity ligation assay (PLA). Free, total and active PSA, and the PSA-ACT complex were determined in tissue culture media by immunoassays, immunoblotting, and chromatographic methods., Results: The majority of PSA in tissue culture medium was free and enzymatically active. However, a significant proportion (1.6 ± 0.5%) of immunoreactive PSA was found to be complexed with ACT. Complex formation was confirmed by in situ PLA, which showed more intense staining of PSA-ACT in cancers with Gleason grade 3 than in adjacent benign tissues from the same patients., Conclusions: These results show that PSA forms complexes already within the prostate and that PSA-ACT levels are increased in moderately differentiated prostate cancer tissue. This may explain, at least partially, why the ratio of serum PSA-ACT to total PSA is increased in prostate cancer., (Copyright © 2012 Wiley Periodicals, Inc.)

High level of cyclin A promotes carcinogenesis, and overexpression of cyclin A has been associated with poor prognosis of cancer patients. We validated the prognostic role of cyclin A in gastric cancer and evaluated its correlation with expression of an mRNA stability factor HuR. From 342 consecutive histologically confirmed gastric cancer patients were obtained 325 representative tissue specimens for cyclin A and 316 for HuR immunohistochemistry. Specimens were stained by cyclin A and HuR specific monoclonal antibodies. Nuclear immunostaining detected in > or =5% of the tumor cells was considered the cut-off for cyclin A positivity. Positive HuR immunoreactivity was scored as nuclear or cytoplasmic. Associations between scores, clinicopathological factors and survival were calculated by the chi2-test, Fisher's exact test, Kaplan-Meier test and Cox model. Cyclin A detected in the nuclei of cancer cells was positive in 55% (179 of 325) of the specimens; 40% (127 of 316) of the specimens had cytoplasmic and 88% (279 of 316) nuclear immunoreactivity of HuR. Cyclin A expression was an independent prognostic factor for poor survival. Cyclin A immunoreactivity was associated with old age, high stage, proximal location of the tumor, intestinal type, noncurative resection, advanced penetration depth and with nodal metastases but not distant metastases. Furthermore, cyclin A expression was associated with cytoplasmic HuR expression, whereas no association with nuclear HuR was evident. Cyclin A is an independent prognostic factor in gastric cancer, and one mechanism for its overexpression may depend on cytoplasmic localization of HuR., (Copyright 2006 Wiley-Liss, Inc.)

Background: Prostate-specific antigen (PSA/KLK3) and human kallikrein 2 (hK2/KLK2) belong to the human kallikrein gene family. These two highly homologous genes are specifically expressed in the prostate under androgen control. Expression of these is regulated by similar mechanisms but changes in their relative expression have been observed in prostate cancer., Methods: We determined the relative levels of PSA and hK2 mRNA in benign and malignant prostate tissue using a quantitative reverse transcription-polymerase chain reaction (RT-PCR) method. The mRNA of PSA and hK2 are reverse transcribed and amplified in one reaction with the same primers., Results: The variation in the ratio of hK2/PSA mRNA was remarkably small, the difference between the highest and lowest values being three-fold. The ratio was significantly higher in WHO grade 2 compared to normal or benign prostatic hyperplasia tissue (P = 0.032 and P = 0.035, respectively) and in grade 3 compared to normal or benign prostatic hyperplasia tissue (P = 0.006 in both)., Conclusions: The new quantitative RT-PCR technique facilitates very accurate quantitation of the relative mRNA levels of homologous genes. Using this method we have shown that the ratio of hK2/PSA mRNA is higher in cancerous than in benign prostatic tissue., (Copyright 2004 Wiley-Liss, Inc.)

Background: The molecular mechanisms underlying the development and progression of prostate cancer have remained poorly understood. To find out potential genetic markers likely to underlie tumor progression, the pattern of allelic loss on chromosome arm 16q in matched primary, locally recurrent, and metastatic prostate cancer specimens was analyzed in the present study., Methods: The frequency of loss of heterozygosity (LOH) in 74 tumor specimens (62 primary cancer foci and 12 metastatic tumors) collected from 33 prostate cancer patients was determined by fragment analysis using 17 polymorphic microsatellite markers., Results: The overall frequency of patients showing allelic loss at one or more loci on 16q was 68% (21/31) in primary tumors and 90% (28/31) in recurrent tumors. Of the individual markers, D16S520, locating in region 16q24.3, exhibited a statistically significant development of LOH during disease recurrence (P < 0.01). Regarding distant metastases, instead, there seemed to be no allelic loss events exclusively typical of metastatic tumors at 16q., Conclusions: The data suggest the location of gene(s) related to prostate cancer progression at 16q24.3., (2004 Wiley-Liss, Inc.)

Expression of the free beta-subunit of human chorionic gonadotropin (hCGbeta) in malignant tumors is frequently associated with aggressive disease. We have shown previously that the pretreatment serum concentration of hCGbeta is an independent prognostic variable in patients with renal cell carcinoma (RCC). We now compare the serum levels with the expression of hCGbeta antigen and mRNA in tumor tissue and studied whether these are associated with the clinical outcome. Serum samples were collected before surgery from patients with RCC (n = 256) and from 84 apparently healthy controls. HCGbeta in serum was measured by a time-resolved immunofluorometric assay. Tissue expression was detected by immunohistochemical staining of a tissue microarray (TMA) comprising 229 samples, and in selected cases by reverse transcription polymerase chain reaction (RT-PCR) of hCGbeta mRNA (n = 20) from tumor tissue. The prognostic value of hCGbeta in serum and tissue and the association with usual clinicopathological variables was analyzed by the Kaplan-Meier method, the log-rank test, Cox multiple hazard regression, Mann-Whitney U-test or Kruskal-Wallis test. The serum concentrations of hCGbeta were increased in 27% of the RCC patients and patients with increased hCGbeta levels had significantly shorter survival time than those with levels below the median (cut-off 1.2 pmol l(-1), p = 0.0044). HCGbeta antigen was detected in 15% (35 of 229) of the tumors by immunohistochemistry, and hCGbeta mRNA in 8 of 20 samples (40%) by RT-PCR. Tissue positivity for hCGbeta antigen was not associated significantly with mRNA expression, serum concentrations of hCGbeta or survival. In multivariate analysis tumor stage, grade, size and serum hCGbeta were independent prognostic variables. The serum concentration of hCGbeta is an independent prognostic variable in RCC. Tissue expression of hCGbeta detected by immunohistochemistry occurs in 15% of RCCs but it is not significantly associated with prognosis. Expression at the mRNA level seems to be associated with other predictors of adverse outcome., (Copyright 2003 Wiley-Liss, Inc.)

We estimated resource use and costs in patients with Parkinson's disease (PD), thereby providing baseline data for future economic evaluations of therapeutic interventions. Data were collected from medical records of a South Swedish cohort of 127 PD patients during 1 year (1996) and a mailed questionnaire inquiring about cost-related consequences and resource use in 1996 and in 2000. Annual costs were calculated based on prevalence and expressed in SEK (monetary value of the year 2000). Direct health care costs averaged approximately SEK 29,000 ( approximately USD 2,900; EUR 3,200) per patient per year, of which drugs were the most costly component. Nonmedical direct costs were higher than direct health care costs, averaging approximately SEK 43,000 ( approximately USD 4,300; EUR 4,800) per patient per year, and costs due to lost production were approximately SEK 52,000 ( approximately USD 5,200; EUR 5,800) per patient per year. The mean total annual cost for PD in our sample approximated SEK 124,000 ( approximately USD 12,400; EUR 13,800) per patient. These findings are roughly within the same range as estimates from other countries and show that PD causes a considerable societal burden. In addition to other outcomes, evaluations of the economic implications of new therapeutic interventions are highly warranted. In this perspective, the present study provides valuable baseline data., (Copyright 2002 Movement Disorder Society)

Production of the glycoprotein hormone human chorionic gonadotropin beta (hCGbeta) has been associated with more aggressive behavior in non-trophoblastic tumors. In this study, the prognostic value of immunohistochemical hCGbeta expression was evaluated in 239 patients with colorectal cancer. Paraffin-embedded, formalin-fixed specimens were stained with hCGbeta-specific monoclonal antibody, and the results were compared with serum levels determined with an assay based on the same antibody. hCGbeta immunoreactivity was seen in 52 of 239 tumors (22%). The difference in survival time between patients with histologically hCGbeta-negative (median survival 94 months) and -positive (median survival 27 months) tumors was statistically significant (p = 0.014). The risk ratio during follow-up for patients with positive hCGbeta tissue expression was 1.65 (95% CI 1.11-2.46). In a Cox multivariate analysis, Dukes' stage, hCGbeta and age remained independent prognostic factors. There was moderate agreement between immunohistochemical and serum expression levels of hCGbeta (kappa = 0.30). Using a combination of histological and serum levels of hCGbeta, the difference between survival rates was highly significant (p < 0.001). The accuracy when predicting 5-year survival status with the combined results of serum and tissue expression was 1.3% higher compared to hCGbeta tissue expression alone. Our results show that hCGbeta expression in both tumor tissue and serum has prognostic significance independent of other clinicopathological variables. Positive tumor staining does not always occur together with elevated serum levels, and the prognostic accuracy can slightly be increased by combining the results., (Copyright 2001 Wiley-Liss, Inc.)

The prognostic value of the immunohistochemical expression of epithelial and stromal syndecan-1 was evaluated in 296 patients with gastric carcinoma. Formalin-fixed, paraffin-embedded specimens of gastric adenocarcinomas were stained with mouse monoclonal antibody B-B4 against human syndecan-1. Loss of immunoreactivity (syndecan-1 immunoreactivity correlated with a higher stage of disease (stages II-IV), tumour location in the upper third of the stomach, nodal metastases (N1 or N2), positive stromal syndecan-1 staining, deep tumour penetration (to subserosa or deeper = T2-T4), larger tumour size (> or = 5 cm) and intestinal type of cancer. No correlation between epithelial syndecan-1 immunoreactivity and age, gender, distant metastases, grade of differentiation or Borrmann classification was observed. Positive stromal syndecan-1 immunoreactivity correlated with decreased epithelial syndecan-1 expression, intestinal type of cancer and Borrmann type I. Patients with low epithelial syndecan-1 expression in cancer cells had worse overall survival than patients with strong epithelial syndecan-1 staining (p = 0.0012). Stromal syndecan-1-positive patients had a worse outcome than patients with syndecan-1-negative stroma (p = 0.0193). In Cox multivariate analysis, stromal syndecan-1 immunoreactivity was a prognostic factor independent of TNM stage, surgery for cure and tumour size. Thus, the immunohistochemical expression of syndecan-1 might be a predictor of outcome in patients with gastric adenocarcinoma., (Copyright 2001 Wiley-Liss, Inc.)

Chromosomal imbalances were studied by comparative genomic hybridization (CGH) on 27 specimens from 24 patients with plasmacytoma. All the specimens exhibited DNA copy number changes (mean, 7.7 aberrations/tumor; range, 2-15). The most recurrent change involved losses at 13q, found in 19 out of 24 patients. Other frequent losses were at 1p (42%), 14q (33%), X (33%), 8p (25%), and 6q (25%). Gains were frequent at 19p (58%), 9q (58%), 1q (58%), 7p (42%), 11q (38%), 15 (33%), 6p (25%), 8q (25%), and 5p (21%). High-level copy number increases were found at 1q, 5, 7, 8q, 9q, 11q, 15, and 19. The findings of highly recurrent chromosomal imbalances in plasmacytomas confirm the analytical power of CGH to detect chromosomal abnormalities in malignancies characterized by low mitotic activity. Our most striking finding, the losses in chromosome 13, provides a basis to investigate the role of the 13q loss in the tumorigenesis and progression of plasmacytoma and to evaluate the prognostic significance of this loss.

Our recent studies using comparative genomic hybridization showed that gain or amplification at the 17q12-q21 region is very common in the intestinal type of gastric cancer. Here, we describe a fluorescence in situ hybridization study with gastrin (GAS)-specific and ERBB2-specific probes on ten specimens of gastric carcinoma that, by using comparative genomic hybridization, showed 1) DNA copy number gain or amplification at 17q12-q21, a region known to harbor the GAS and ERBB2 genes (four cases); 2) gain of the entire chromosome 17 (three cases); or 3) normal copy number of chromosome 17 (three cases). GAS and ERBB2 protein expression was studied by Western immunoblotting from gastric cancer cell lines with or without gain at 17q12-q21 as well as a breast cancer cell line with ERBB2 amplification. Our results showed that simultaneous amplification of both GAS and ERBB2 was four- to ninefold in the tumors with the 17q12-q21 amplification. Both genes were amplified in the same nuclei, and the hybridization signals were localized to the same region of the nucleus. Overexpression of GAS and ERBB2 was observed by Western immunoblotting only in the gastric cancer cell line with gain at 17q12-q21. The ERBB2 amplification is also a recurrent change in breast cancer. To investigate whether the GAS amplification is unique in gastric cancer, fluorescence in situ hybridization analysis was performed on 40 breast cancer cell lines. The ERBB2 amplification was observed in 11 cell lines, but none of the lines showed the GAS amplification. This indicates that the formation of an amplicon, in which both the GAS and the ERBB2 genes are amplified, might be unique in gastric cancer, especially in its intestinal type, and that simultaneous amplification of both genes is important to the tumorigenesis of intestinal gastric cancer. We demonstrate here for the first time that a gene of a physiological hormone is amplified in tumors that originate from cells that normally secrete the hormone.

We studied DNA copy number changes in gastric cancer (GC) using comparative genomic hybridization (CGH) analysis on 35 resected gastric carcinomas (22 of the intestinal type and 13 of the diffuse type). Eighty-three percent of the cases showed DNA copy number changes. Gains were more common than losses (median of 3 and 1 in primary tumors of the intestinal and diffuse type, respectively). The most common gains were detected on 20q [46%; 12 intestinal type (55%) and four diffuse type (31%)], 8q [37%; 10 intestinal type (45%) and three diffuse type (23%)], and 17q12-21 [29%; all but one intestinal type (41%)]. The most frequent losses were detected on 18q [26%; all intestinal type (41%)] and on 4q [23%; all intestinal type (32%)]. High-level amplifications were observed in the intestinal type of tumors at 17q12-21 (three tumors), 20q (three tumors). 2q (one tumor), and 18q (one tumor). In the diffuse type, high-level amplification was detected once at 13q.

Protectin (CD59) inhibits homologous complement-mediated cytolysis by preventing formation of the membrane attack complex at the point of insertion and polymerization of C9 into cell membranes. The present study investigated the expression and function of CD59 on human prostatic tumor cells in situ and on 5 human prostate cell lines in vitro originating from either metastatic tumors or benign prostate hypertrophy epithelial cells. Immunohistochemical staining of prostate carcinoma tissue with monoclonal antibody (MAb) MEM43 revealed weak to moderately strong expression of CD59 by prostate glandular epithelial cells. Flow cytometry with MEM43 demonstrated that the 5 prostate cell lines expressed different relative quantities of CD59. Indirect immunofluorescence analysis revealed uniform membrane staining of DU145 and PC3 cell lines with no membranous granularity in the staining pattern. Western immunoblots with MAb BRIC 229 showed that PC3 and DU145 cells express CD59 with a m.w. of 18-25 kDa. Treatment of DU 145 and PC3 cells with phosphatidylinositol-specific phospholipase C caused a significant decrease of CD59 expression indicating that the CD59 expressed by prostate cancer cells is anchored to the cell membrane via a glycosylphosphatidylinositol (GPI) linkage. PC3 and DU145 cells were completely resistant to human complement-mediated cytolysis but became sensitive to killing in the presence of the CD59-neutralizing MAb YTH53.1. We conclude that malignant and benign human prostate cells express CD59 that is GPI-linked to the cell surface and that CD59 may regulate the immunological response to cancerous prostate cells by protecting the cells from the cytolytic activity of complement.

Twenty-three samples of benign and malignant bone tumors were studied with cytogenetic analysis, interphase cytogenetics (IC) using in situ hybridization with (peri)centromeric probes for chromosomes 1, 7, and/or 8, and DNA flow cytometry (FCM). Our aim was to compare these methods in the detection of numerical chromosome aberrations (NCA) and aneuploidy. IC detected aneuploidy in 91%, FCM in 73%, and cytogenetics in 27% of the malignant tumors. In benign tumors IC detected aneuploid by in 4(33%), FCM in 2(17%), and cytogenetic analysis in 1. All of the benign tumors aneuploid by IC, two of which were also aneuploid by FCM, were histologically potentially aggressive. The clonal aberrations detected with cytogenetics usually agreed with the IC and FCM findings. All malignant tumors which had a normal karyotype were aneuploid either by IC or FCM or by both. In conclusion, IC was the most sensitive method in the detection of NCA and aneuploidy even though it was usually performed with only two (peri)centromeric probes. Aneuploidy was detected by cytogenetic analysis alone in 4 samples (17%), by cytogenetic analysis and/or FCM in 11 samples (48%), and by cytogenetic analysis, FCM, and/or IC in 16 samples (70%). Thus, the combined use of all three methods increased the sensitivity of aneuploidy detection.

The applicability and reliability of estimates of proliferative activity in breast carcinomas using fine-needle aspiration (FNA) and needle-core biopsies (NC) was evaluated in 98 breast carcinoma patients. The Ki-67, Estrogen receptor (ER), and progesteron receptor (PR) immunolabelling of FNA and NC was compared with that of the surgical specimen. A statistically significant consistency between labelling was found in the Ki-67-NC (kappa = 0.474), ER-FNA (kappa = 0.318), ER-NC (kappa = 0.518), and PR-FNA (kappa = 0.404) groups. The consistency in the Ki-67-FNA group was less significant (kappa = 0.182), and there was no consistency in the PR-NC group (kappa = 0.062). There was a positive correlation of Ki-67 labelling in FNA and NC biopsies (Spearman rank, rho = 0.4; P = 0.0007), and also in ER labeling (Spearman rank rho = 0.6; P = 0.0001). These results indicate that NC and FNA can be used for preoperative assessment of proliferative activity and hormonal status in breast carcinoma.

Twelve variables were studied for possible prognostic value in 242 patients with adenocarcinoma of the stomach. Eight of these had a statistically significant effect on survival in univariate analyses. A multivariate analysis of 196 patients showed that the most significant differences in survival could be explained by 3 independent variables acting simultaneously, namely stage of disease, Sialyl Tn antigen (STn) expression and aneuploidy of the tumour cells. By adding scores for stage (1-4 points), STn expression (0-1 points) and ploidy (0-1 points) a risk score based on these 3 variables defined the patients into 6 different risk groups with statistically highly significant differences in survival (chi 2 = 107.74, DF = 1, p < 0.0001). Application of the risk score improves the prediction of outcome, may help in choosing patients for different treatment modalities, and allows more accurate stratification in clinical trials.

The prognostic value of the immunohistochemical expression of Sialyl Tn antigen (STn) was evaluated in 242 patients with gastric carcinoma. Formalin-fixed, paraffin-embedded specimens of gastric adenocarcinomas were stained with the monoclonal antibody C1282, produced by immunization with ovine submaxillary mucin (OSM). Positive immunoreactivity for STn was observed in 149 (62%) patients. The expression of STn did not correlate with stage of disease (TNM), tumour location, presence of lymph-node or distant metastases, histological type, age or gender. STn immunoreactivity correlated strongly with overall survival in univariate analysis. The median survival in the STn-positive group was 21 months, in comparison to 38 months in the STn-negative group. The difference in survival between STn-negative and STn-positive tumours was significant in patients with stage-I cancer, but not in patients with stage-II -III or -IV disease. STn immunoreactivity emerged as an independent prognostic factor in Cox multivariate analysis. It is concluded that the immunohistochemical expression of STn is a good marker in the prediction of survival in patients with stage-I gastric carcinoma.

Polyamines are found in all cells but their function is not fully understood. We have studied the effect of polyamines on the passage of cells through the cell cycle using a polyamine auxotrophic mutant, CHO-P22, which has no detectable ornithine decarboxylase activity. The ability of these cells to grow without serum allows efficient polyamine depletion. A flow cytometric analysis of DNA content and bromodeoxyuridine labeling showed that without added polyamines the cells accumulated in S-phase, the rate of DNA synthesis was retarded, and the entry into mitosis was blocked. Addition of polyamines to cultures deprived of polyamines induced cells in all phases of the cell cycle to reinitiate cycling. Earlier studies have shown that cells with damaged DNA are blocked from entering into mitosis but caffeine can partly overcome this block and induce premature chromosome condensation. Polyamine-depleted CHO-P22 cells responded to caffeine in the same way as cells with damaged DNA. These results show that polyamine depletion in CHO-P22 cells primarily affects DNA synthesis. The finding that polyamine-starved cells continuously take up bromodeoxyuridine without a corresponding increase in the amount of DNA is compatible with extensive repair of erroneous and/or damaged DNA. Polyamine auxotrophic Chinese hamster ovary (CHO) cells might be useful in studies on the regulation of mitosis in mammalian cells.

Twenty-eight partial nephrectomies were performed on nine pigs with a simultaneous, coaxial CO2-Nd:YAG laser at power settings of 20 W and 40 W, or with a steel scalpel. A vascular pedicle clamp was used without renal cooling. The time for hemostasis was 4.5 +/- 3.2 min (mean +/- SD) with the laser and 6.4 +/- 2.5 min with the steel scalpel (P = 0.064). There was no difference in the total operation time (10.4 +/- 3.5 min with the laser vs. 11.0 +/- 3.2 min with the steel scalpel, P = 0.470). The mean blood loss with the laser was 17.5 +/- 6.7 g and 22.1 +/- 15.2 g with the steel scalpel (P = 0.299). The number of ligatures needed for complete hemostasis was 2.9 +/- 2.1 with the laser and 5.0 +/- 2.3 with the steel scalpel (P = 0.011). The average thermal damage was 0.23 +/- 0.10 mm. It is concluded that the simultaneous CO2-Nd:YAG laser method can be used in partial nephrectomy and it offers better hemostasis than the conventional technique. Further studies with different power levels are needed.

The DNA content and S-phase fraction were measured by flow cytometry in 448 tumour biopsy specimens from transitional-cell bladder cancer (TCC). The samples were also analyzed for mitotic index, WHO grade and papillary status, and histological and flow cytometric data were then correlated to clinical behaviour of tumours during a mean follow-up period of 9.9 years. TNM classification, WHO grade, papillary status, mitotic index, DNA ploidy and S phase fraction were significantly interrelated. Twenty-four percent of tumours showed heterogeneous DNA indices when measured from multiple samples (measured in 94 cases). Of the histological parameters, independent predictors of progression in superficial tumours were the S-phase fraction and mitotic index. In superficial tumours, S-phase fraction and the mitotic index included all the available independent prognostic information in survival analysis, whereas in muscle-invasive tumours T category was the most important prognostic factor. The results suggest that DNA ploidy has no independent prognostic value in transitional-cell bladder cancer, whereas proliferation indices (SPF, mitotic index) are important prognostic factors. Accordingly, malignancy classification of papillary bladder tumours can be based on proliferation indices alone. Nodular tumours run an unfavourable course and their malignancy grading by flow cytometry or by mitotic index is not relevant.

A series of 327 breast cancers was analyzed for DNA ploidy by flow cytometry from paraffin-embedded tissue, and the resulting DNA histograms were classified independently by 6 researchers in the field as DNA diploid (Di), aneuploid (An), tetraploid (Te), multiploid (Mu), or technically uninterpretable. The frequency of diploid, aneuploid, tetraploid and multiploid cancers varied from 28 to 41%, 33 to 49%, 8 to 21% and 2 to 6%. According to the scale Di-An-Te-Mu, DNA ploidy was not significantly associated with breast-cancer mortality by 2 classifiers, but if DNA euploid cancers (Di+Te) were tested against non-euploid, or diploid cancers against non-diploid, all classifiers found DNA euploid and diploid cancers to have better prognosis. Mortality associated with diploid or tetraploid cancers decreased with improving histogram quality and increasing uniformity of classification, whereas that associated with aneuploid cancers remained unaltered. Among the cases where all classifiers agreed on ploidy, tetraploid, diploid and aneuploid cancers were associated with 100%, 88% and 68% 5-year survival rates. In this sub-set the S-phase fraction and possibly DNA ploidy were independent prognostic factors, together with histological grade, axillary node status, and primary tumor size.

The expression of the tumor marker antigen CA 50, defined by the monoclonal antibody (MAb) C 50, was studied by the immunoperoxidase technique in formalin-fixed, paraffin-embedded tissue sections from normal pancreata, from pancreata with pancreatitis and from benign and malignant pancreatic neoplasms. The results were compared with those obtained with Mab 1116 NS 19-9. The C 50 antibody reacts, like the 1116 NS 19-9 antibody, with sialosylfucosyllactotetraose (corresponding to sialylated blood group antigen Lewisa), but also with another sugar moiety, sialosyllactotetraose. Thirty-two of 37 well- to moderately-differentiated adenocarcinomas and all cystadenocarcinomas were positive for CA 50. The staining was most intense in the apical border of the cells, and in the intraluminal mucus. The number of positive cells was smaller in poorly differentiated adenocarcinomas and only occasional cells were stained in anaplastic carcinomas. In acute and chronic pancreatitis small terminal ducts, centro-acinar cells and some large ducts stained for CA 50. In normal pancreas only a few small terminal ducts were CA-19-9-positive, whereas both ducts and centro-acinar cells were C-50-positive. Normal pancreatic tissue adjacent to carcinoma usually stained more strongly for CA 50 than the carcinoma, whereas the opposite was true for CA 19-9. Eight out of 11 CA-19-9-negative carcinomas were CA-50-positive. Serous cystadenomas and malignant islet-cell tumors were focally positive for CA 50, but negative for CA 19-9. It seems apparent that the C 50 antibody reacts with another determinant than sialylated Lewisa in CA-19-9-negative specimens, serous cystadenomas and malignant islet-cell tumors. Serum CA 50 and CA 19-9 levels were determined in 29 patients with pancreatic cancer. The sensitivity was similar for both markers (76%), and there was a positive correlation between the serum levels. However, there was no correlation between the serum levels and the histological expression of the CA 50 and CA 19-9 antigens.

The nuclear DNA content of 38 malignant and 25 benign bone tumours was measured by flow cytometry. The specimens were taken either from biopsies or from surgical specimens. Seventeen of 26 primary malignant bone tumours were aneuploid, 15 had a single aneuploid DNA content, and 2 had a biclonal abnormality. Thirteen of 15 osteosarcomas were aneuploid, but only 2 of 6 chondrosarcomas showed an aneuploid DNA content. Six of 12 metastatic malignant bone tumours were also aneuploid. All 25 benign tumours had a diploid DNA content. Cell cycle analysis showed that the proportion of cells in S- and G2M-phases was higher in the malignant compared to benign tumours, indicating a higher proliferative activity. The increase was statistically significant (p less than 0.05) both in diploid and in aneuploid tumours. Among five tumours studied after chemotherapy, four displayed a marked hyperdiploid abnormality. Aneuploidy and high proliferative activity both were highly associated with malignant bone tumours, suggesting that DNA flow cytometry may be an adjunct in the assessment of malignancy of bone tumours.

The expression of a cell proliferation marker, the human transferrin receptor, was studied in ten human gastrointestinal tumors prior to and after implantation under the renal capsule in the mouse (1-6 days). These data were compared to the increase in tumor size in situ, and to the infiltration of inflammatory cells. All tumors studied expressed the transferrin receptor prior to implantation. Forty of 47 implants expressed the receptor, the strongest expression occurring on day 4, accompanied by a reorganization of tumor tissue to a morphology similar to that before implantation. On days 5 and 6 the expression of the transferrin receptor declined. Implants showed maximal increase in size on days 1 and 2, decreased in size on days 3 and 4, and increased again on days 5 and 6. The increase in the size of the implants on days 5 and 6 was accompanied by considerable infiltration of inflammatory cells, and was probably mostly a result of invading host cells and inflammation. If size alone is used as a criterion for tumor proliferation in this subrenal capsule assay, day 4 seems to be the most appropriate for evaluation. This is supported by a strong expression of a proliferation marker, the human transferrin receptor, during this time.