Immunohistochemical studies and fluorodeoxyglucose uptake on positron emission tomography in pharyngeal cancer for predicting radiotherapy-based treatment outcomes.

OBJECTIVES: This study correlated immunohistochemical studies with fluorodeoxyglucose (FDG) uptake on positron emission tomography-computed tomography (PET-CT) and identified prognostic factors for radiotherapy (RT)-based treatment outcomes in patients with squamous cell carcinoma of the oropharynx and hypopharynx. METHODS: Genomic data from pre-treatment biopsy specimens (Glut1, CAIX, VEGF, HIF-1α, EGFR, Ki-67, Bcl-2, CLAUDIN-4, YAP-1, c-Met and p16) of 76 patients were analysed using tissue microarrays. FDG uptake was evaluated using the maximum standardised uptake value (SUVmax), metabolic tumour volume (MTV) and total lesion glycolysis (TLG). RESULTS: The overexpression of Glut1 positively associated with increased values of the SUVmax, MTV and TLG, whereas VEGF and HIF-1α expression with the MTV and TLG, respectively. A VEGF immunoreactive score (IRS) >2 (P = 0.001, hazard ratio [HR] = 3.94) and an MTV defined by an SUV of 2.5 (MTV2.5) >14.5 mL (P = 0.004, HR = 3.31) were prognostic factors for low cause-specific survival, whereas a VEGF IRS >2 (P = 0.02, HR = 2.83) for low primary relapse-free survival. CONCLUSION: The overexpression of Glut1, VEGF and HIF-1α associated with increased FDG uptake. For patients with pharyngeal cancer requiring RT, the treatment outcome can be stratified by VEGF and MTV2.5.

Overexpression of the RNA-binding proteins Lin28B and IGF2BP3 (IMP3) is associated with chemoresistance and poor disease outcome in ovarian cancer.

BACKGROUND: RNA-binding proteins have an important role in messenger RNA (mRNA) regulation during tumour development and carcinogenesis. In the present study, we examined the insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs; hereafter refered to as IMPs) and Lin28 family expressions in epithelial ovarian carcinoma (EOC) patients and correlated their expression levels with the response to chemotherapy, hCTR1 expression and patient survival. METHODS: Patients clinical information, real-time RT-PCR, immunohistochemistry, western blot, Transwell migration invasion assays, and cytotoxicity assays were used. RESULTS: From 140 EOC patients, high expression of IMP3 or Lin28B was associated with poor survival, and women diagnosed at advanced stages with elevated IMP3 and Lin28B were at higher risk of developing chemoresistance. High IMP3 levels combined with high Lin28B levels significantly correlated with the poorest 5-year survival rates. Knockdown of IMP3 or Lin28B decreased cell proliferation, migration, and invasion, and increased the platinum sensitivity, but not taxol sensitivity, of ovarian cancer cells through increased expression of hCTR1, a copper transporter involved in platinum uptake. High expression of hCTR1 correlated with low expression of IMP3/Lin28B and better progression-free survival in advanced-stage EOC patients. CONCLUSION: Testing for a combination of elevated IMP3 and Lin28B levels could further facilitate the identification of a patient subgroup with the worst prognosis.

Identifying LRRC16B as an oncofetal gene with transforming enhancing capability using a combined bioinformatics and experimental approach.

Oncofetal genes are expressed in embryos or fetuses, are downregulated or undetectable in adult tissues, and then re-expressed in tumors. Known oncofetal genes, such as AFP, GCB, FGF18, IMP-1 and SOX1, often have important clinical applications or pivotal biological functions. To find new oncofetal-like genes, we used the public information of expressed sequence tags to systematically analyze gene expression patterns and identified a novel oncofetal-like gene, LRRC16B. It increased the proliferation, anchorage-independent growth and tumorigenesis of transformed cells in xenografts, possibly through its effects on cyclin B1 protein levels. These findings exemplify the feasibility of using bioinformatics to find new oncofetal-like genes and suggest that more genes with important functional roles will be uncovered in the candidate gene list.

Co-expression of RON and MET is a prognostic indicator for patients with transitional-cell carcinoma of the bladder.

Recepteur d'Origine Nantais (RON) is a distinct receptor tyrosine kinase in the c-met proto-oncogene family. We examined the mutational and expression patterns of RON in eight human uroepithelial cell lines. Biological effects of RON overexpression on cancer cells were investigated in vitro, and the prognostic significance of RON and/or c-met protein (MET) expression was analysed in a bladder cancer cohort (n=183). There was no evidence of mutation in the kinase domain of RON. Overexpression of RON using an inducible Tet-off system induced increased cell proliferation, motility, and antiapoptosis. Immunohistochemical analysis showed that RON was overexpressed in 60 cases (32.8%) of primary tumours, with 14 (23.3%) showing a high level of expression. Recepteur d'Origine Nantais expression was positively associated with histological grading, larger size, nonpapillary contour, and tumour stage (all P<0.01). In addition, MET was overexpressed in 82 cases (44.8%). Co-expressed RON and MET was significantly associated with decreased overall survival (P=0.005) or metastasis-free survival (P=0.01) in 35 cases (19.1%). Recepteur d'Origine Nantais-associated signalling may play an important role in the progression of human bladder cancer. Evaluation of RON and MET expression status may identify a subset of bladder-cancer patients who require more intensive treatment.

Molecular diagnosis of primary liver cancer by microsatellite DNA analysis in the serum.

Frequent loss of heterozygosity of microsatellites markers on specific chromosomal region have been reported in various types of primary human cancer. The same loss of heterozygosity has also been identified in the matched plasma/serum DNA. Using 109 microsatellite markers representing 24 chromosomal arms, we have examined the loss of heterozygosity in 21 cases of hepatocellular carcinoma, six of cholangiocarcinoma, and 27 cases of chronic hepatitis or cirrhosis. All cases of the hepatocellular carcinoma showed deletion from two to 10 chromosomal arms, while deletion of chromosomes from two to eight regions was detected in five of six cholangiocarcinoma patients. One or more loss of heterozygosity in the paired serum DNA could be detected in 16 of 25 (76.2%) hepatocellular carcinoma patients. In contrast, no alterations in serum DNA test could be found in cholangiocarcinoma patients. Five of seven (71.4%) hepatocellular carcinoma patients with alpha-fetoprotein levels less than 20 ng ml(-1) produced positive serum DNA test. The profiles of 19 microsatellite markers gave a 100% positive predictive value and an 80.8% negative predictive value for hepatocellular carcinoma. In conclusion, we have determined a profile of microsatellite markers appropriate for differential diagnosis of primary liver cancer. The discovery may permit a high-throughput screening of hepatocellular carcinoma at an early stage of disease.

Investigation of the prognostic value of coexpressed erbB family members for the survival of colorectal cancer patients after curative surgery.

Epidermal growth factor receptor (EGFR), erbB2, erbB3 and erbB4 are four transmembrane glycoproteins belonging to the subtype I tyrosine kinases. They share structure homologies and are believed to direct cellular growth through the ligand-stimulated tyrosine phosphorylation of intracellular substrate. The overexpression of these tyrosine kinases has been linked to various cancers. To examine the role of the erbB family in the neoplastic transformation of the human colon, we analysed the protein expression of these four members by immunohistochemistry in paraffin-embedded specimens from 125 resected colorectal cancers. Our data showed that for EGFR expression, 62 (50%) were scored as '+', and 2 (2%) as '++'. For erbB2 expression, 39 (31%) were classified as '+', and 5 (4%) as '++'. For erbB3 expression, 43 (34%) were scored as '+', and 3 (2%) as '++'. A significantly higher percentage of overexpressed erbB3 was observed in early stage carcinomas (Dukes' stage A or B) (50%) than in advanced stage cancers (Dukes' stage C or D) (15%) (P<0.0001). For erbB4 expression, 22 (18%) were scored as '+', and 5 (4%) as '++'. Early stage patients had a lower percentage of erbB4 overexpression than the late stage ones (18% versus 28%). Concomitant overexpression of erbB2 and erbB3 occurred in 21% (16/78) of the early stage carcinomas, whereas it occurred in only 2% (1/47) of the late stage ones (P=0.003). Conversely, simultaneous overexpression of erbB2 and erbB4 occurred in 17% (8/47) of the late stage carcinomas but in only 4% (3/78) of the early stage ones (P=0.02). Overexpression of EGFR, erbB2, erbB3 or erbB4 alone was not significantly associated with a shortened survival. However, patients with a simultaneous overexpression of erbB2 and erbB4 had a shorter overall survival time than others in the univariate analysis (P=0.01). This significance disappeared after adjustment for Dukes' staging in the Cox model. In conclusion, overexpressed erbB3 was common in early stage colorectal cancers, but its prevalence was significantly reduced in late stage ones. The percentage of its coexpression with erbB2 was significantly higher in early stage than in late-stage cancers. Heterodimerisation between erbB2 and erbB4 may play a role in the late stages of carcinogenesis.

Clinical comparison of high-dose interferon-alpha2b with or without ribavirin for treatment of interferon-relapsed chronic hepatitis C.

BACKGROUND: Interferon a with ribavirin combination therapy is effective but still unsatisfactory in the treatment of patients with interferon-relapsed chronic hepatitis C. AIMS: To compare, in a randomized, double blind, placebo-controlled study, high-dose interferon-alpha2b with or without ribavirin in the treatment for interferon-relapsers. PATIENTS: A total of 52 patients with interferon-relapsed chronic hepatitis C were randomly assigned to receive 24-week treatment with interferon-alpha2b (6 MU three times per week) combined with either ribavirin (1,000 to 1,200 mg per day) or a matched placebo and then followed for an additional 24 weeks. METHODS: Hepatitis C virus RNA was detected by reverse-transcription polymerase chain reaction. For determining viral concentration, the commercial bDNA Quantiplex hepatitis C virus-RNA 2.0 assay was used. Genotyping was performed by reverse hybridization assay RESULTS: At the end of treatment, no detectable hepatitis C virus RNA levels were observed in 92% (24/26) of patients on interferon alpha2b/ribavirin and 81% (21/26) of patients on interferon alpha2b/placebo. At the end of the follow-up, a higher sustained virological response rate was seen in patients treated with interferon alpha2b/ribavirin than those treated with interferon alpha2b/placebo (69% vs 23%, p < 0.001). Patients with either initially high levels of viral concentration or with genotype 1 responded poorly. Patients who received interferon-alpha2b/ribavirin treatment and in whom no hepatitis C virus RNA was detected at 4th week after treatment had 90% chance to achieve sustained virological response. CONCLUSIONS: High-dose interferon-alpha2b plus ribavirin treatment is highly effective in interferon-relapsed patients.

Long-term evaluation of recombinant interferon alpha2b in the treatment of patients with hepatitis B e antigen-negative chronic hepatitis B in Taiwan.

The effect of interferon (IFN) on hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) has not been fully investigated in Chinese patients. We enrolled 58 HBeAg-negative CHB Chinese patients with hepatitis B viremia in Taiwan to evaluate the response to IFN. 30 patients received recombinant IFN 5 million units 3 times weekly for 6-10 months, and 28 patients who refused IFN treatment served as controls. Rates of virological response and biochemical response were higher in the treated group at the end of treatment (57% vs 18%, P = 0.006, and 73% vs 29%, P = 0.002, respectively). Both effects were superior in the treated group at 6 months after IFN withdrawal (virological: 30% vs 7%, P = 0.06; biochemical: 47% vs 7%, P = 0.002). Improvement of liver histological activities with persistently biochemical response was found in 65% of the treated patients. After a mean of 32 months' follow-up, virological response was rarely maintained (17% vs 4%, P = 0.228) but biochemical response was better in the treated group (27% vs 4%, P = 0.039). None of the treated patients but five controls developed severe complications of CHB during the follow-up period. A larger total IFN dosage or a younger age (< or = 40 years) were associated with 'sustained' virological response. Younger age and higher baseline alanine transaminase values (> or = 120 Ul(-1)) were related to 'sustained' biochemical response.

Molecular detection of prostate cancer in urine by GSTP1 hypermethylation.

Novel approaches for the early detection and management of prostate cancer are urgently needed. Clonal genetic alterations have been used as targets for the detection of neoplastic cells in bodily fluids from many cancer types. A similar strategy for molecular diagnosis of prostate cancer requires a common and/or early genetic alteration as a specific target for neoplastic prostate cells. Hypermethylation of regulatory sequences at the glutathione S-transferase pi (GSTP1) gene locus is found in the majority (>90%) of primary prostate carcinomas, but not in normal prostatic tissue or other normal tissues. We hypothesized that urine from prostate cancer patients might contain shed neoplastic cells or debris amenable to DNA analysis. Matched specimens of primary tumor, peripheral blood lymphocytes (normal control), and simple voided urine were collected from 28 patients with prostate cancer of a clinical stage amenable to cure. Genomic DNA was isolated from the samples, and the methylation status of GSTP1 was examined in a blinded manner using methylation-specific PCR. Decoding of the results revealed that 22 of 28 (79%) prostate tumors were positive for GSTP1 methylation. In 6 of 22 (27%) cases, the corresponding urine-sediment DNA was positive for GSTP1 methylation, indicating the presence of neoplastic DNA in the urine. Furthermore, there was no case where urine-sediment DNA harbored methylation when the corresponding tumor was negative. Although we only detected GSTP1 methylation in under one-third of voided urine samples, we have demonstrated that molecular diagnosis of prostate neoplasia in urine is feasible. Larger studies focusing on carcinoma size, location in the prostate, and urine collection techniques, as well as more sensitive technology, may lead to the useful application of GSTP1 hypermethylation in prostate cancer diagnosis and management.

Expression of oncogene products HER2/Neu and Ras and fibrosis-related growth factors bFGF, TGF-beta, and PDGF in bile from biliary malignancies and inflammatory disorders.

The expression of several growth factors and K-ras gene mutation in bile were studied to better understand the pathogenesis and improve early diagnosis of bile duct cancers. Bile samples were collected from 12 cholangiocarcinomas (CLC), 10 ampullary cancers (APC), 3 gallbladder cancers (GBC), 7 pancreatic cancers (PNC), 9 biliary tract infection (BTI), 8 biliary stone disease (ST), and 5 normal controls (NC). The highest mean value of TGF-beta in bile was in patients with BTI; the mean levels of bFGF and PDGF were highest in CLC, and patients with APC and CLC had higher expression of HER2/Neu than other groups. In bile, a K-ras gene codon 12 mutation was found in 5 of 6 (83%) cases of CLC by the PCR-RFLP method. The results suggest overexpression of bFGF, PDGF, and HER2/Neu and the presence of K-ras mutation are important for carcinogenesis of bile duct cancers, and detection of the above abnormalities in bile is helpful for early diagnosis.

Clinicopathologic correlation of serum tissue polypeptide specific antigen in hepatocellular carcinoma.

OBJECTIVE: Recently, tissue polypeptide specific antigen (TPS) has been introduced as a cell proliferation marker. Little is known about its clinical significance in hepatocellular carcinoma (HCC). This study aimed to clarify serum TPS levels and tumor invasiveness of HCC. METHODS: Serum TPS levels were determined with a monoclonal TPS IRMA assay in 69 patients with HCC. A correlation between serum TPS levels and clinical, biochemical, and pathological features was sought and compared with that of alpha-fetoprotein (AFP). In 57 healthy subjects, 56 patients with biopsy-proven chronic hepatitis and in 49 patients with liver cirrhosis, serum TPS levels were assayed and compared. RESULTS: Serum TPS levels were significantly correlated with glutamic oxalacetic transaminase (p < 0.0001), glutamic pyruvic transaminase (p < 0.001), and lactate dehydrogenase (p = 0.027). There tended to be a positive relationship between serum TPS levels and tumor size, histological differentiation, capsular invasion, portal invasion, and clinical staging, although it did not reach statistical significance. A significant correlation, however, was observed between AFP and tumor size (p = 0.01), number (p = 0.042), histological grading (p = 0.028), portal invasion (p = 0.009), and clinical staging (p = 0.03). Patients with HCC had significantly higher TPS than healthy subjects (p < 0.001). However, there was substantial overlap between patients with HCC, chronic hepatitis, and liver cirrhosis. CONCLUSIONS: Our data suggest that serum TPS is not significantly related to tumor invasiveness in patients with HCC. Serum TPS levels are affected by the proliferative activity of the underlying chronic liver disease, which is frequently associated with HCC in Chinese patients. As a cell proliferation marker, serum TPS should be interpreted cautiously in the presence of chronic liver disease.

Expression profiles of ErbB family receptors and prognosis in primary transitional cell carcinoma of the urinary bladder.

In vitro experiments have demonstrated that epidermal growth factor (EGF)-related peptides activate distinct subsets of ErbB receptors and differ in their biological activities. The implications of cross-talk among ErbB family receptors in human cancer, however, remain to be clarified. This cohort study was performed to examine the expression patterns of ErbB receptors by immunohistochemistry in primary human bladder cancer (n = 245) and compared with conventional biological indicators for their prognostic significance. Expression of individual EGF receptor (EGFR) and ErbB2, ErbB3, or ErbB4 receptors was detected in 72.2, 44.5, 56.3, and 29.8% of bladder cancer cases, respectively. Expression of two of the receptors varied from 14.7 to 42.4%, of three of the receptors between 11.0 and 22.0%, and of all four of the ErbB receptors by 8.6%. Important indicators in association with patient survival were tumor staging (P = 0.017), ErbB2 (P = 0.018), EGFR-ErbB2 (P = 0.023), and ErbB2-ErbB3 (P = 0.042). In the subset of grade-2 tumors, EGFR-ErbB2-ErbB3 and EGFR-ErbB2 predicted the development of second recurrence (P = 0.026 and 0.039, respectively), and ErbB2-ErbB3 tended to correlate with patient survival (P = 0.09). The results indicate that a combination of EGFR, ErbB2, and ErbB3 expression profile may be a better prognostic indicator than any family member alone. Given that ErbB2 is the preferred coexpression partner of ErbB family members, expression of other ErbB receptors may significantly affect the prognostic implication of ErbB2 for bladder cancer patients.

Clinical relevance of vascular endothelial growth factor for thyroid neoplasms.

Angiogenesis is of vital importance during the development and progression of solid tumors. Vascular endothelial growth factor (VEGF) is a major regulator of angiogenesis and could be produced by some cancer cells. To investigate the clinical relevance of VEGF in the tumorigenesis of human thyroid, an immunohistochemical study was performed on archival materials of follicular adenomas (n = 13), Hürthle cell adenomas (n = 6), papillary carcinomas (n = 76), follicular carcinomas (n = 12), Hürthle cell carcinomas (n = 2), and anaplastic carcinomas (n = 8). Patterns of VEGF expression were analyzed in relation to histologic subtypes of thyroid tumors and were correlated to biologic indicators of papillary carcinoma. All papillary carcinomas and Hürthle cell neoplasms revealed a strong, diffuse staining reaction, whereas anaplastic carcinoma usually exhibited weak and infrequent immunoreactivity. VEGF levels were usually higher in follicular adenomas than in follicular carcinomas. With regard to prognostic value, VEGF expression did not correlate with tumor size, extent of invasion, or scores on the AGES system (i.e., patient age, tumor size, histologic grade, tumor extent, distant metastasis) or the MACIS system (i.e., metastasis, age, completeness of resection, invasion, tumor size) for papillary carcinomas (p > 0.05, respectively). The results of the current study indicate that VEGF may play a role in the development of human thyroid cancer. Determination of the angiogenic phenotype may have limited prognostic value for patients with papillary carcinoma.

Age-associated changes in collagen content and its subtypes within rat corpora cavernosa with computerized histomorphometric analysis.

OBJECTIVES: To study the age-associated changes in the percentage of collagen and subtypes I, III, and IV within the corpora cavernosa in a rat model. METHODS: The corpora cavernosa tissues were obtained from 30 male Wistar rats at three different ages. Processed with Masson's trichrome staining for collagen and with immunohistochemical staining for the collagen subtypes, the values of the collagen percentage, the percentage of area, and relative proportion of each collagen subtype within the rat corpora cavernosa were measured using an automatic image analysis system. The relationships between an increase in age and these parameters were analyzed. RESULTS: The percentage of collagen within the corpora cavernosa was higher in the old rats (80 weeks) than in the young (20 weeks) and intermediate-age (40 weeks) rats (P = 0.02 and P = 0.25, respectively) and significantly increased with age (P = 0.021). The values of the percentage of area of collagen subtypes III and IV also increased significantly with age (P = 0.039 and P = 0.019, respectively). The value of the percentage of area of collagen subtype I was not significantly increased (P = 0.159). Also, no significant differences were found in the relative proportions of all three collagen subtypes with age among the three age groups. CONCLUSIONS: The percentages of collagen within rat corpora cavernosa significantly increased, but not strongly, with age, especially collagen subtypes III and IV. However, the relative proportion of each subtype did not change with age. Therefore, we conclude that the amount of collagen may only partly contribute to erectile dysfunction in the aging process of the rat.

Hepatic angiomyolipoma with concomitant hepatocellular carcinomas.

Angiomyolipoma is a rare lipomatous tumor in the liver. Definitive preoperative diagnosis is becoming easier by the use of ultrasonography, computed tomography, and magnetic resonance imaging techniques. Nonsurgical treatment has been advocated for its benign nature. However, recently we encountered one case of hepatic angiomyolipoma with two concomitant hepatocellular carcinomas on a hepatitis B carrier. Although his serum alpha-fetoprotein was normal, under the above impression these lesions were resected. The pathologic findings showed a typical angiomyolipoma and two well-differentiated hepatocellular carcinomas with marked fatty metamorphosis. This is the first report of angiomyolipoma with concomitant hepatocellular carcinomas in the literature. Nonsurgical treatment of angiomyolipoma in an endemic area for hepatocellular carcinoma should proceed with caution because cases of fat-rich minute hepatocellular carcinomas will make the diagnosis difficult.

Reappraisal of the role of NM23-H1 in colorectal cancers.

BACKGROUND AND OBJECTIVES: A number of evidence indicate that downregulation of the nm23-H1 gene may be relevant to metastatic progression of many kinds of human cancer. However, its role in colorectal cancers remains controversial. To address the issue, this study was performed to investigate the clinical relevance of nm23-H1 in patients with colorectal cancers. METHODS: Immunohistochemical expression of nm23-H1 protein product (NM23-H1) was studied in a total of 146 colorectal cancer patients and compared for its prognostic value at a mean follow-up of 54 months. RESULTS: There was no apparent correlation between NM23-H1 expression and clinicopathological indicators, including Dukes category, lymphatic metastasis, distant metastasis, histological grading, and tumor location (P < 0.1, respectively). In addition, determination of NM23-H1 expression status did not provide independent prognostic information compared with conventional pathological staging. CONCLUSIONS: The results indicate that nm23-H1 gene does not play an important part in the progression of colorectal carcinogenesis.

Expression of nm23-H1 in transitional cell carcinoma of the upper urinary tract.

Transitional cell carcinoma of the upper urinary tract is an uncommon neoplasm. Relatively little information is available regarding the clinical relevance of molecular markers. This study was performed to examine the importance of nm23-H1 gene expression (NM23-H1) in this type of tumors. Immunohistochemical expression of NM23-H1 was analyzed in 90 cases of upper urinary tract cancer, and was compared for its prognostic significance with conventional biological indicators. High expression of NM23-H1 was found in 7 cases (8%), intermediate expression in 32 cases (36%), and low expression in 51 cases (57%). Reduced NM23-H1 (defined as intermediate or low level of expression) was associated with a higher histological grading (p=0.002), invasive tumor growth (p=0. 002), or an increased proliferating cell nuclear antigen labeling index (p=0.004). NM23-H1 tended to inversely relate to later recurrence or long-term survival (p=0.06), but, only tumor staging was found to be significant in predicting clinical outcome (p=0.002). nm23-H1 appears to function as a tumor suppressor for upper urinary tract cancer, however, evaluation of NM23-H1 provides limited prognostic information.

Immunohistochemical analysis of epidermal growth factor receptor family members in stage I non-small cell lung cancer.

BACKGROUND: To elucidate the relationship between the expression of epidermal growth factor receptor family members (ErbB-1, neu/ErbB-2, ErbB-3, and ErbB-4) and tumor recurrence. METHODS: We used immunohistochemistry to examine the expression of four epidermal growth factor receptor family members in 73 patients with stage I non-small cell lung cancer. RESULTS: Using Cox univariate analysis, we determined that angiolymphatic tumor emboli and non-well-differentiated tumor cells were two significant conventional pathologic predictors of tumor recurrence, and that ErbB-1 and ErbB-3 were also significant predictors. Co-expression of ErbB-1+, -3+, or expression of three or more epidermal growth factor receptor family members had a significant effect on lung cancer recurrence. A stepwise multivariate Cox proportional hazards regression analysis provided a predictive model for tumor recurrence. CONCLUSIONS: The present study shows that in patients with a non-well-differentiated tumor, overexpression of ErbB-3 is a useful marker for predicting tumor recurrence. The present study also confirmed that ErbB-1 expression increased in proportion to the loss of tumor differentiation. The correlation between ErbB-3 and distant metastasis was good.

Papillary urothelial hyperplasia is a clonal precursor to papillary transitional cell bladder cancer.

Papilloma and papillary hyperplasia (PH) have been proposed to be the putative precursor lesions of papillary transitional-cell carcinoma of the urinary bladder. We examined 15 PH lesions and 4 papillomas for loss of heterozygosity (LOH) at 17 microsatellite markers on 9 chromosomal arms. Eight of 15 (53%) PHs were clonal, demonstrating LOH of at least 1 microsatellite marker. In contrast, none of the papillomas showed any genetic changes among the markers tested. In PH, chromosomal arm 9q was the most frequently lost (4/15), followed by 9p and 18q (n = 2) and, less frequently, 8p, 10q, 11p and 17p (n = 1). Furthermore, 2 hyperplastic lesions demonstrated LOH at 9q only, confirming the notion that allelic loss on chromosomal arm 9q is among the earliest events in bladder-cancer progression. In 1 patient, identical LOH patterns were observed between PH and a recurrent transitional-cell carcinoma. Our molecular data demonstrate that at least a proportion of PHs represent pre-cancerous lesions of the bladder that subsequently progress to papillary bladder cancer. Moreover, chromosomal arm 9q may harbor a tumor-suppressor gene(s) inactivated in the earliest stages of human bladder tumorigenesis.