Biomedical subjects

Arndt Hartmann

Publications and source records attributed to Arndt Hartmann.

67 records · Page 4Linked to original sources

PubMed2003

Cancer of unknown primary: clinicopathologic correlations.

Cancer of unknown primary origin (CUP) accounts for 5-10% of all malignant tumors at presentation and remains the death certificate diagnosis in 0.5-5% of patients. We investigated CUP patients whose primary site remained unknown throughout the entire clinical course. We reviewed 9,436 consecutive autopsies performed between 1984 and 1999 at the Mayo Clinic, matched with 177,167 cancer patients treated in the same time period. Sixty-four patients who died of CUP underwent postmortem examination. Antemortem pathologic diagnoses were obtained in 57 patients, agreed with postmortem diagnoses in 98%, and included adenocarcinoma (n=44), undifferentiated carcinoma (n=7), squamous cell carcinoma (n=3), and others (n=3). Autopsy located the primary site in 35 patients (55%). Common primary sites were lung (n=8), the pancreaticobiliary (n=13) and GI tracts (n=9). Of 43 patients evaluated for tumor-specific therapy, only six received no further oncologic treatment and untreated patients survived a median of 57 (range 10-280) days, compared with 225 (range 19-1,129) days for patients treated with chemotherapy and/or radiotherapy (n=37). Our findings show that (1) autopsy studies provide a valuable tool for quality control in the setting of CUP, and (2) treated patients have a small but significant survival benefit.

Adenocarcinoma↗

PubMed2003

Molecular genetic analysis excludes implantation metastasis of basal cell carcinomas.

Basal cell carcinoma (BCC) of the skin is the most common tumor in the white population. A 66-year-old man developed 2 BCCs at the left parietal region of the head and at the helix of the left ear. The 2 lesions matched exactly when pressing the ear against the head, suggesting an implantation metastasis mechanism. Molecular genetic techniques were used to confirm or exclude such a mechanism in this rare clinical constellation. Tumor tissues were precisely microdissected for DNA isolation. Exons 5-9 of the p53 tumor suppressor gene were directly sequenced. In addition, loss of heterozygosity analysis of chromosome 9q was performed using 5 polymorphic microsatellite markers. The BCC of the ear revealed a p53 mutation at codon 273, whereas the other one lacked this mutation. In addition, the smaller BCC of the ear showed loss of heterozygosity at 9q33.3, in contrast with the larger BCC. Interestingly, histologically normal skin of the ear distant from the small BCC had the same deletion, indicating a field defect of this skin patch at 9q33.3. Molecular genetic analysis clearly demonstrated different genetic alterations of the two BCCs and therefore most likely excludes a mechanism of implantation metastasis.

Aged↗

PubMed2003

Hereditary nonpolyposis colorectal cancer syndrome in a patient with urothelial carcinoma of the upper urothelial tract.

Urothelial carcinoma of the upper urinary tract is relatively uncommon but may develop as a manifestation of the hereditary nonpolyposis colorectal cancer syndrome (HNPCC), which is characterized by mutations in a number of DNA mismatch repair genes and detectable as microsatellite instability or loss of the respective protein by immunostaining. No well-established screening test is available for urothelial carcinomas of the upper urinary tract, and little is known of the clinical impact of screening for HNPCC in patients with upper urinary tract cancer. We describe herein a patient with a urothelial carcinoma of the ureter and a strongly positive history of cancer, who was subsequently found to have HNPCC. Our findings reinforce the importance of obtaining a comprehensive history of cancer in patients with urothelial carcinoma of the renal pelvis and ureter. Subsequent identification of individuals with HNPCC enables the patient and at-risk relatives to benefit from targeted surveillance and management programs.

Colectomy↗

PubMed2003

Microsatellite instability at chromosome 8p in non-small cell lung cancer is associated with lymph node metastasis and squamous differentiation.

Genetic alterations at chromosome arm 8p are associated with advanced disease and poor patient outcome in several types of malignant tumors. We studied the frequency of microsatellite instability (MSI) and loss of heterozygosity (LOH) at chromosome 8p in early stage non-small cell lung cancer (NSCLC) of 47 patients with stage I or II disease (25 squamous cell carcinomas and 22 adenocarcinomas). Microsatellite analysis was performed after laser microdissection using 5 polymorphic tetranucleotide microsatellite markers and 4 dinucleotide markers at chromosome 8p. A pentanucleotide repeat marker at the chromosomal locus 17p13.1 (TP53.Alu) was also analyzed. Expression of the mismatch repair (MMR) proteins hMSH2, hMSH6 and hMLH1 was evaluated by immunohistochemistry. Microsatellite instability (MSI) in at least 2 markers was detected in 9 of 47 patients (19.1%) and was predominantly found at tetranucleotide repeats. Sixteen of 47 (34.0%) NSCLC demonstrated LOH at chromosome 8p. All MSI-positive tumors showed normal expression of the MMR proteins. The presence of MSI at chromosome 8p was associated with lymph node metastasis (p=0.02), squamous differentiation (8/25; 32%-p=0.03), and the presence of LOH at the p53 locus (p=0.06). None of the other investigated clinical, pathologic or molecular factors correlated with MSI. Our study showed that an elevated MSI at selected tetranucleotide sequences (EMAST) on chromosome 8p is frequent in early stage squamous cell carcinomas of the lung with lymphatic spread. The tetranucleotide marker panel used in this study was able to indicate lymph node metastasis and high risk disease in patients with resectable squamous cell lung cancer.

Adaptor Proteins, Signal Transducing↗

PubMed2002

Frequent microsatellite instability in sporadic tumors of the upper urinary tract.

Urothelial carcinoma of the renal pelvis and ureter may develop sporadically or as a manifestation of hereditary nonpolyposis colorectal cancer. The majority of hereditary nonpolyposis colorectal cancer is caused by mutation of the human DNA mismatch repair (MMR) genes and is detected by associated microsatellite instability (MSI). Seventy-three unselected urothelial carcinomas of the ureter and/or renal pelvis were screened for MSI using the National Cancer Institute-designated reference panel (plus BAT40). Instability of at least two microsatellite markers (MSI-high) was detected in 15 samples (21%). Immunohistochemical staining of the MMR proteins (hMSH2, hMLH1, or hMSH6) was absent in 13 of 15 (87%) MSI tumors, and alteration of coding sequence microsatellites (TGFbetaRII, Bax, hMSH3, and hMSH6) was found at frequencies of 7-33% in these samples. Tumors with MSI had significantly different clinical and histopathological features including higher prevalence in female patients, low tumor stage and grade, and a papillary and frequently inverted growth pattern. Our results suggest a molecular pathway of tumorigenesis that is similar to MMR-deficient colorectal cancers and consistent with the notion that the site distributions of hereditary or sporadic MSI-high tumors may reflect tissue-specific susceptibility to lesions processed by the MMR machinery.

Adaptor Proteins, Signal Transducing↗

PubMed2002

Clonality of multifocal urothelial carcinomas: 10 years of molecular genetic studies.

Multifocal occurrence and frequent recurrence are characteristic features of urothelial carcinomas of both the urinary bladder and the upper urinary tract. To describe the clonal nature of these tumors, 2 theories have been proposed. The monoclonality hypothesis describes the multiple tumors as descendants of a single genetically transformed cell spreading throughout the urothelium. In contrast, field cancerization caused by carcinogen exposure of the urothelium may lead to independent development of synchronous or metachronous nonrelated tumors at different sites of the urothelial tract. In the last 10 years, a multitude of molecular genetic studies have investigated the clonality of multifocal urothelial carcinomas. The majority of studies revealed a monoclonal origin of the multiple tumors. However, most of these studies investigated advanced invasive carcinomas. A small but significant proportion of multifocal urothelial carcinomas appear to arise from different clones, supporting the field-cancerization hypothesis. Oligoclonal tumors might be more common in precursor lesions and early tumor stages. The frequent monoclonality found in patients with advanced tumors could be due to outgrowth of 1 tumor cell clone with specific genetic alterations. Two important mechanisms appear to be important for the spread of malignant cells: intraluminal seeding and intraepithelial migration. Investigation of the entire urothelial lining in patients with urothelial tumors should provide further insight into the development of multifocal urothelial carcinomas.

Animals↗

PubMed2002

Occurrence of chromosome 9 and p53 alterations in multifocal dysplasia and carcinoma in situ of human urinary bladder.

To define the genetic changes of flat urothelial lesions, carcinoma in situ (CIS) and moderate dysplasias (DII) were investigated for alterations in the two chromosomal regions most frequently involved in bladder cancer. Overall, 33 CIS and 16 DII from 21 patients were used to microdissect urothelium. Dual color fluorescence in situ hybridization (FISH) using gene locus probes of 9q22 (FACC), 9p21 (CDK), 17p13 (p53), and related centromeric probes was applied on interphase nuclei. In parallel, preamplified DNA of these samples was used for loss of heterozygosity (LOH) analyses with eight microsatellite markers on chromosomes 9p, 9q and 17p, and for sequencing of exons 5-9 of p53. Data indicated nearly identical deletion frequencies for chromosomes 9 and 17 for CIS (chromosome 9, 86%; p53, 84%). DII showed a lower deletion rate in comparison with CIS (chromosome 9, 75%; p53, 53%). A very high correlation between the results of FISH and LOH analyses was found. p53 mutations were detected in 12 of 15 patients (CIS, 72%; DII, 67%). In three of 16 patients with multifocal tumors, oligoclonal lesions were identified by LOH analyses, a finding further supported by sequencing of p53, by which two different p53 deletions were detected in two cases. In conclusion, data from microdissected flat urothelial lesions indicate that chromosome 9 deletions cannot be regarded as indicators of papillary growth, because they are found frequently in both types of flat lesions of the urothelium: those associated with papillary tumors and those that are not. The similar distribution and lower amount of genetic changes in DII render DII a possible precursor lesion of CIS.

Aged↗

PubMed2002

Ultraviolet-excited (308 nm) autofluorescence for bladder cancer detection.

OBJECTIVES: To assess the ability of ultraviolet laser-induced autofluorescence for the diagnosis of transitional cell carcinoma of the bladder. METHODS: We studied 43 patients undergoing transurethral resection with recurrent transitional cell carcinoma of the bladder. Guided through 5-aminolevulinic acid-induced fluorescence endoscopy, the autofluorescence of the red fluorescing areas and the adjacent tissue and inconspicuous-appearing mucosa were measured spectroscopically. The autofluorescence excitation was carried out with a xenon chloride excimer laser operating at 308 nm (AF308). For the evaluation of the autofluorescence spectra, an intensity ratio (335/430 nm) was calculated and correlated with the histologic results of the biopsies taken. RESULTS: We analyzed the AF308 spectra of 114 biopsies (21 malignant, 93 benign). The autofluorescence intensity ratios for the benign lesions were a factor of 2 to 7 higher than carcinoma in situ and neoplastic tissue. Therefore, 20 of 21 neoplastic lesions were detected as true positive by AF308. A sensitivity and specificity for AF308 of 95% and 77%, respectively, could be calculated. The sensitivity and specificity for 5-aminolevulinic acid-induced fluorescence endoscopy was 90% and 61%, respectively. By combining the two methods, we calculated a sensitivity of 90% and a specificity of 84%. CONCLUSIONS: The combination of a sensitive imaging technique such as 5-aminolevulinic acid-induced fluorescence endoscopy and a more specific spectral fluorescence probe technique with autofluorescence at 308 nm is a very efficient procedure in the detection of transitional cell carcinoma of the bladder.

Aged↗

PubMed2002

Histologic-genetic mapping by allele-specific PCR reveals intraurothelial spread of p53 mutant tumor clones.

Common and clinically important features of urothelial carcinomas are multifocality and a high rate of recurrence. Molecular studies demonstrated that multifocal tumors are frequently composed of one tumor clone spreading throughout the urothelial tract. A combination of histologic and genetic mapping of cystectomy specimens from bladder cancer patients is a valuable tool to study bladder carcinogenesis and tumor cell spread by correlating urothelial morphologic features and defined genetic alterations. In the present study, the primary tumors of 14 cystectomy specimens were investigated for p53 protein overexpression by immunohistochemistry and p53 gene mutation by genomic sequencing. Seven tumors showed a strong nuclear staining for the p53 protein. In six of seven tumors, a p53 gene mutation was detected. Allele-specific PCR of defined p53 mutations was established in five of six cases with a p53 mutation. Subsequent screening of the entire urothelial lining of each cystectomy specimen by allele-specific PCR revealed p53-mutant cell clones in urothelial patches with carcinoma in situ and dysplasia, but also frequently in histomorphologically normal urothelium adjacent to the tumor. The pattern of tumor cell spread indicated a continuous intraurothelial growth of the p53-mutant clone. P53 immunohistochemistry visually confirmed the presence of mutant cells in most of these samples. We conclude that allele-specific PCR is a highly sensitive and reliable method for tracking specific p53 mutant clones in the urothelium. Moreover, the detection of p53-mutant cells in histologically normal or preneoplastic urothelial areas in four patients with invasive bladder cancer indicates an extensive intraurothelial tumor cell spread. The excellent correlation of immunohistochemically positive urothelial patches with the presence of a specific mutation highlights the biologic significance of p53-positive cells in the urothelium of tumor patients.

Aged↗

PubMed2002

Upper tract urothelial carcinoma: a clinicopathologic study including microsatellite instability analysis.

Urothelial carcinoma of the renal pelvis and ureter may develop as a manifestation of the hereditary nonpolyposis colorectal cancer syndrome that is characterized by mutations in a number of DNA mismatch repair genes and detectable as microsatellite instability. In this study, we examined microsatellite instability and the clinicopathologic features of urothelial carcinoma of the renal pelvis (n = 61) and ureter (n = 53) from 114 consecutive patients surgically treated from 1985-1992. Clinical data were obtained through chart review. Matched normal and tumor DNA was extracted from paraffin-embedded tissue, and a panel of six microsatellite loci was analyzed. The male-female ratio was 2.8:1 with a median age of 70 years (range, 28 to 92 y). Microsatellite analysis was successful in 67 tumors, and 21 (31.3%) patients had tumors that exhibited microsatellite instability. Patients with microsatellite-unstable tumors were significantly more likely to have additional nonurologic cancers (P =.015) including colorectal carcinoma (P =.001) compared with patients with tumors that did not exhibit microsatellite instability. In addition, patients with microsatellite-unstable tumors showed more colorectal cancers in their family (P =.026) and were more likely to have higher grade urothelial carcinoma of the upper tract (P =.028). Grade and stage, but not microsatellite status, were the strongest predictors of cancer-specific survival. This study found the highest frequency of microsatellite instability in upper urothelial tract carcinomas reported to date and highlights upper tract urothelial carcinoma as a marker of the hereditary nonpolyposis colorectal cancer syndrome in some patients. These findings reinforce the importance of obtaining cancer histories in patients with upper tract urothelial carcinoma to subsequently identify individuals with the hereditary nonpolyposis colorectal cancer syndrome and at-risk relatives for surveillance and management programs.

Adult↗

PubMed2002

Molecular genetic evaluation of fluorescence diagnosis in bladder cancer.

Fluorescence diagnosis of superficial bladder cancer using 5-aminolevulinic acid (ALA) is a highly sensitive technique (95%). However, the specificity is only 60-70% due to false-positive results after histopathological examination. We hypothesized that the biopsies in fluorescence endoscopy could represent early preneoplastic lesions not detectable by histopathology. In order to evaluate the specificity of fluorescence endoscopy at the molecular genetic level we performed comparative genomic hybridization (CGH) and investigated telomerase activity of ALA-positive tissue samples. For CGH, DNA was isolated from 5-10 frozen sections. Tumor and normal (control) DNAs were amplified by DOP-PCR and labeled with biotin-dUTP and digoxigenin-dUTP, respectively. Hybridization and detection were carried out according to standard protocols. Telomerase activity was analyzed using a non-radioactive system (TRAP-assay). In 33 out of 118 bladder cancer cases (28%) detected by conventional cystoscopy, additional suspicious areas were found using ALA. CGH revealed genetic changes in 27% of samples with non-malignant histological diagnoses. Telomerase activity was found in 59% of these samples. Tumor samples showed genetic alterations in 84% and in 69% telomerase activity occurred. The type of genetic alterations in the normal biopsies was identical to the tumors. Based on these molecular data, the portion of false-positive results obtained by fluorescence diagnosis is lower than defined by histopathology alone. Genetic alterations and activation of telomerase activity are early events of tumor development in bladder cancer occurring earlier than histological features of neoplasia. The clinical importance of fluorescence diagnosis and the possible reduction of the recurrence rate have to be shown in ongoing clinical studies.

Biotinylation↗

PubMed2002

No evidence for involvement of beta-catenin and APC in urothelial carcinomas.

The wnt pathway plays an important role in embryonal patterning and cell fate determination, involving stabilization of nuclear and cytoplasmic beta-catenin (CTNNB1) mediated by APC, axin, and other proteins. Uncomplexed beta-catenin binds to TCF/LEF transcription factors and activates the expression of growth regulatory target genes such as c-myc or cyclin D1. In colorectal and other cancers, constitutive wnt signaling results frequently from mutations in one or more pathway components, e.g. APC and beta-catenin, resulting in nuclear and/or cytoplasmic accumulation of beta-catenin. In the present study, the most frequent alterations in the CTNNB1 and APC genes were investigated in primary urothelial bladder tumors and cell lines. Snap-frozen bladder tumors (n=99) of different stages and grades and 4 cell lines (RT4, RT112, J82, UROtsa) were investigated for APC allelic deletions by loss of heterozygosity (LOH) analysis. The most frequent mutated regions of CTNNB1 (degradation box in the third exon) and APC (mutation cluster region) were directly sequenced. Beta-catenin expression was analyzed by immunofluorescence in the cell lines. LOH at the APC gene locus on chromosome 5q21 was found in 7 of 72 (10%) of the informative cases. No mutations were found in either CTNNB1 or APC. A previously described polymorphism at codon 1493 of the APC gene was detected in 8 tumors and 3 cell lines. All cell lines showed normal membranous beta-catenin staining without evidence for nuclear or cytoplasmic accumulation. Alteration of APC and beta-catenin, which are the most frequent wnt pathway alterations in many tumor types, are rare events in urothelial carcinomas. Other wnt pathway members, such as axin, may play an important role in urothelial carcinogenesis.

Adenomatous Polyposis Coli Protein↗

PubMedDate not supplied

Low frequency of human polyomavirus BKV and JCV DNA in urothelial carcinomas of the renal pelvis and renal cell carcinomas.

Human polyomaviruses BKV and JCV establish a persistent infection in the kidney and possess oncogenic potential in experimental animal models. Their possible involvement in the pathogenesis of human urogenital tumors has been suggested by several studies but is not conclusively resolved. For the present study, highly sensitive quantitative TaqMan PCR assays were developed to detect BKV and JCV DNA sequences in matched pairs of human tumors and surrounding normal tissue. Samples from 55 patients with renal pelvic urothelial carcinomas and from 83 patients with renal cell carcinomas of all histologic subtypes were investigated. Human polyomavirus DNA was detected in renal pelvis samples with a frequency of 16% (BKV) and 15% (JCV), and in kidney samples with a frequency of 1% (BKV) and 23% (JCV), respectively. However, viral sequences were not present more often in tumors than in normal tissue. There was no integration of the potentially oncogenic viral large T-antigen in the tumors, and the viral concentration of both BKV and JCV was not higher in DNA extracted from tumors compared to normal tissue. These data provide no evidence for a causative role of the human polyomaviruses BKV and JCV in the development of tumors of the renal pelvis and the kidney.

Adult↗