DNA aneuploidy in ulcerative colitis and in colorectal carcinoma--a comparative study.
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Adult↗
Biomedical subjects
R Stenling
Publications and source records attributed to R Stenling.
Prognostic significance of the Heidelberg classification of renal cell carcinoma.
OBJECTIVE: The specific genetic alterations characterising renal cell carcinoma (RCC) have lead to the recognition of distinctive types of tumours. In a large material of patients, the prognostic and clinical information of these different tumour types were evaluated. METHODS: Tumours from 186 patients were evaluated retrospectively according to the guidelines given by the Heidelberg Classification Conference. All patients were primarily nephrectomised and TNM staged, and the follow-up times for alive patients varied between 44 and 174 months. RESULTS: The material consisted of 145 conventional (non-papillary), 25 papillary, 12 chromophobe and 4 unclassified RCCs. There was no difference in tumour size between the different RCC types. Among patients with conventional RCC, 37% had distant metastases at the time of diagnosis, significantly more frequently than 16% in patients with papillary and 8% in chromophobe RCC (p = 0.044 and 0.048, respectively). Conventional RCC more frequently had vein invasion compared with papillary RCC (p = 0.009). Patients with chromophobe and papillary RCC survived significantly longer than patients with conventional RCC (p = 0.017 and 0.031, respectively). CONCLUSIONS: A significant difference in clinical behaviour between the different RCC types was found. Patients with conventional RCC had a higher incidence of metastases, vein invasion and had adverse survival compared with papillary and chromophobe RCCs. Thus, the RCC types recognised by specific genetic alterations seem to represent different malignant phenotypes.
Adult↗
Are lymph node micrometastases of any clinical significance in Dukes Stages A and B colorectal cancer?
PURPOSE: The aim was to investigate the significance of lymph node micrometastases in Dukes Stages A and B colorectal cancer. METHODS: Archival specimens were examined from 147 patients (96 colon, 51 rectum; 44 Stage A, 103 Stage B) who had surgery between 1987 and 1994. One lymph node section from each node (colon, 1-11; median, 4; rectum, 1-15; median, 3) was examined with use of an anticytokeratin antibody. RESULTS: Forty-seven (32 percent) patients had micrometastases. At follow-up in June 1996, 23 patients had died of cancer or with known tumor relapse, after a median time of 28 (range, 5-67) months; 8 of 47 (17 percent) patients had micrometastases, 15 of 100 (15 percent) did not. No statistically significant differences were observed according to micrometastases when the results were analyzed with respect to Dukes stage or survival time. The median survival time of living patients with micrometastases was 48 (range, 18-97) months, and for patients without micrometastases, 48 (range, 19-111) months. Six of 96 living patients had a tumor relapse; three of these displayed micrometastases. CONCLUSION: Lymph node micrometastases are not a useful prognostic marker in Dukes Stages A and B and do not imply different strategies for additional therapy or follow-up.
Adult↗
Factors influencing the estimates of proliferative labelling indices in rectal cancer.
PURPOSE: A detailed analysis was undertaken of some of the factors influencing the estimate of the labelling index (LI). MATERIALS AND METHODS: Thirty-three human rectal carcinomas were studied for their proliferative activity as measured by the fraction of cells labelled with a single injection of IdUrd 1-8 h before surgical resection. Adjacent specimens were stained both for histological examination and for flow cytometry (FCM) assessment of labelled nuclei. RESULTS: Two major differences were found. The superficial parts of each tumour almost always had significantly higher LI values than the deep part (34 versus 21%), yielding an average LI of 27%. The flow cytometry average value was much lower (17%). This was partly due to the influence of diploid tumours. There was a marked heterogeneity in the values, both within tumours, between tumours and between techniques. The average LI for the whole group differs by a factor of three, depending on the method of assessment. CONCLUSIONS: All these values indicate a varying but rapid proliferative turnover of cells, surprisingly being more marked in the superficial region, i.e. the opposite from the proliferation pattern of the normal rectal mucosa. A biopsy, if taken from the superficial part of the tumour, would therefore be biased toward higher values. This has implications for biopsy sampling for cell kinetic analysis. Histological assessment avoids the contaminating effect of stromal cells, allows architectural arrangements to be detected and is presumably a more realistic representation of proliferative activity.
Cell Division↗
Expression of cyclin D1 and retinoblastoma protein in colorectal cancer.
Abnormal expression of the retinoblastoma protein (pRb) and cyclin D1 have been reported in a variety of malignancies, but the frequencies of these deregulations and their relation to prognosis in colorectal cancer has not been clarified. We characterised 90 colorectal cancers with respect to immunohistochemical expression of cyclin D1, pRb and Ki-67. Two of 90 (2%) tumours lacked nuclear pRb staining, indicating inactivation of the protein, while 10 (11%) expressed high levels of pRb. Abnormal expression of pRb was significantly correlated to low levels of nuclear cyclin D1 observed in 32% of the tumours. Strong nuclear cyclin D1 expression was detected in 12% of the tumours. Cytoplasmic staining of cyclin D1 was observed in 17% of the tumours, showing an inverse relationship (P = 0.006) to the Ki-67 labelling index. Eight of 11 tumours with high nuclear overexpression of cyclin D1 and both tumours with pRb defects were located in the right colon in comparison with zero of 25 in the rectum (P = 0.009). Regarding prognosis, neither pRb nor cyclin D1 expression correlated with patient survival.
Adult↗
Systematic heterogeneity and prognostic significance of cell proliferation in colorectal cancer.
The prognosis of colorectal cancer has not significantly changed during the last 30 years. While evaluation of tumour cell proliferation may provide prognostic information, results obtained so far have been contradictory Heterogeneity in tumour cell proliferation may explain these contradictions. With in vivo injection of iododeoxyuridine (IdUrd), estimation of labelling index (LI), S-phase transit time (Ts) and potential doubling time (Tpot) may be performed from a single sample. A total of 109 colorectal cancers were studied after in vivo injection of IdUrd before surgical removal. From each cancer, four to eight samples were processed for both flow cytometrical (FCM) and immunohistochemical (IHC) visualization of IdUrd incorporation. LI/IHC was morphometrically quantified at both the luminal border and the invasive margin of these tumours. LI was significantly higher at the luminal border compared with the invasive margin, although they were correlated with each other. Using combined IHC and FCM methods, rapidly growing colorectal cancers (high LI and/or low Tpot) showed an increased survival (significant for LI at the invasive margin and for Tpot at both the invasive margin and the luminal border) in the entire unselected material and for radically removed Dukes' B tumours. FCM data alone did not discriminate for survival, with the exception of Ts in diploid and radically removed Dukes' B tumours.
Cecal Neoplasms↗
Recovery from Marie-Bamberger's syndrome and diabetes insipidus after removal of a lung adenocarcinoma with neuroendocrine features.
A 44-year-old woman with Marie-Bamberger's syndrome and diabetes insipidus had a lung tumour with mediastinal metastases, but no signs of metastases to the hypothalamus or pituitary gland. A week after removal of the tumour, the joint pain, polyuria and polydipsia disappeared. The tumour was diagnosed histopathologically as a moderately differentiated adenocarcinoma with focal neuroendocrine cell differentiation and dispersed cells reacting with antisera against neurone-specific enolase, S-100 protein, neuropeptide Y, follicle-stimulating hormone, substance P, vasoactive polypeptide (VIP), adrenocorticotropic hormone and pancreatic polypeptide (PP) as well as to one of three tested antisera raised against antidiuretic hormone (ADH). It was suggested that Marie-Bamberger's syndrome might be caused by one of these immunoreactive substances or by a substance that shares an amino acid sequence with one of these neuroendocrine peptides. It was also suggested that the tumour might produce an ADH-like substance which might have an ADH-antagonist effect.
Adenocarcinoma↗
Loss of heterozygosity at chromosome 3p correlates with telomerase activity in renal cell carcinoma.
Acquired loss of the entire or parts of the short arm of chromosome 3 is a frequent aberration in renal cell carcinoma as well as in other tumour types, indicating the presence of at least one tumour suppressor gene on 3p. Previous studies have defined the distal and proximal ends of one critical region to reside between 3p21 and 3p11, and one gene involved in von Hippel-Lindau disease has been identified at 3p25. Experimental in vitro data has suggested a negative regulator of telomerase activity on chromosome 3. In the present study we investigated the relationship between telomerase activity and loss of heterozygosity (LOH) on 3p in a series of renal cell carcinomas. Telomerase activity was evaluated using the telomeric repeat amplification protocol assay and LOH, by analysis of 17 polymorphic microsatellite markers. Twenty-nine out of 45 tumours (64%) demonstrated telomerase activity and 37 tumours (82%) showed allelic loss of single or multiple areas of chromosome 3p. A significant correlation between LOH of at least one of three markers localised within 4 cM in the region of 3p21.2-3p14.2 and telomerase activity was demonstrated (p=0.0031), as well as for three distal markers within 3 cM at 3p24.3-3p24.1 (p=0.0287). These data suggest the presence of at least two genes with regulatory function on the expression of telomerase. These genes can encode proteins of importance for senescence and/or immortalisation or have a more direct effect on activation of telomerase.
Carcinoma, Renal Cell↗
Predictive value of potential doubling time in head and neck cancer patients treated by conventional radiotherapy.
PURPOSE: The goal of this study was to investigate the clinical utility of pretreatment measurements of tumor cell kinetics to predict the outcome of patients with squamous cell carcinoma of the head and neck receiving conventional radiotherapy. METHODS AND MATERIALS: All patients received between 64 and 70 Gy as 2 Gy fractions, five fractions per week. Cell kinetics were assayed rapidly and quantitatively using flow cytometric evaluation of iododeoxyuridine (IdUrd) incorporation, in vivo, from a biopsy removed several hours after the administration of the DNA precursor to the patient prior to the start of treatment. RESULTS: The measured proliferation parameters were not related to the clinicopathological features of the tumors, emphasizing the independent nature of these parameters. In univariate analysis, nodal involvement was the most important clinical feature of the tumors related to local control followed by Tpot, DNA aneuploidy, and attainment of complete regression at 6 weeks. Of these only Tpot and nodal status maintained significance in multivariate analysis, with respect to loco-regional control. In subgroup analysis, Tpot was able to stratify patients into high or low rate of loco-regional control in node negative patients, in aneuploid tumors and in patients who did achieve complete regression at 6 weeks. For cause specific survival, N-stage was the only parameter that significantly discriminated the prognosis in these patients. CONCLUSIONS: The conclusion of this study is that Tpot provides clinically important information that can predict patients with a low probability of achieving long-term local control with conventional fractionation. Further improvements to the methodology to address the shortcomings of analyzing diploid tumors may increase the predictive power of the measurement.
Adult↗
Colonic endocrine cells in inflammatory bowel disease.
OBJECTIVES: To study colonic endocrine cell types in patients with ulcerative colitis (UC) and Crohn's disease (CD). SETTING: Departments of Medicine and Pathology, University Hospitals, Umeå and Uppsala, Sweden. SUBJECTS: Seventeen patients with UC (seven females and 10 males) and 11 patients with CD (five females and six males). Twenty-two patients (eight females and 14 males) operated on for colon carcinoma and without signs of inflammatory bowel disease were used as controls. MEASUREMENTS: The colonic endocrine cell types were identified by immunohistochemical methods and quantified by computed image analysis. RESULTS: The areas of the argyrophil cells as well as those immunoreactive to chromogranin A and serotonin were significantly increased in patients with both UC and CD, compared with those in the controls. In patients with CD, the areas of polypeptide YY(PYY)- and pancreatic polypeptide (PP)-immunoreactive cells were significantly reduced, whilst the area of enteroglucagon-immunoreactive cells was increased. There was no statistical difference in endocrine cell area between specimens with slight versus severe inflammation, except for PYY and enteroglucagon cell areas in patients with CD. Whilst the former cell area decreased, the latter increased in specimens with severe inflammation. The mean cellular area for each endocrine cell type did not differ between the controls and patients with UC or CD. CONCLUSIONS: The increase in the serotonin-immunoreactive cell area in patients with both UC and CD might be one of the factors causing reduced colonic contraction and increased intraluminal pressure observed in patients with inflammatory bowel disease. Furthermore, in patients with CD, the decreased PYY-immunoreactive cell area may explain the decreased absorption and increased secretion found in these patients.
Adolescent↗
Lateral rectal ligaments contain important nerves.
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Aged↗
Cell proliferation in renal cell carcinoma--a comparative study of cell kinetic methods.
Four different methods of assessing cell proliferation in renal cell carcinoma were compared in a total of 136 samples to analyze their degree of agreement and usefulness. The methods compared were flow cytometric S-phase (S-FCM) analysis, proliferating cell nuclear antigen expression detected by immunohistochemistry (PCNA-IHC), in vivo iododeoxyuridine incorporation analyzed with immunohistochemistry (IdUrd-IHC), and flow cytometry (IdUrd-FCM). The mean S-FCM fraction was 5.9%, compared with a mean PCNA-IHC labeling index of 4.7%. The mean labeling indices obtained by IdUrd-IHC and IdUrd-FCM were 1.2% and 1.7%, respectively. The four methods correlated well with each other. When the methods were compared according to Bland and Altman, good agreement was shown. A statistically significant difference in proliferation between diploid and aneuploid tumor samples was found with all methods (P < 0.001). The results showed that the four different methods provided comparable information on proliferative activity, although different cell cycle compartments were monitored.
Aneuploidy↗
Growth patterns and cell kinetics of human osteosarcoma xenografts in serial passages in nude mice analyzed by in vivo labelling with iododeoxyuridine.
A human osteoblastic osteosarcoma was transplanted in nude mice and followed in seven serial passages. Tumor cell kinetics was analyzed by in vivo labelling with the thymidine analogue iododeoxyuridine (IdUrd). Immunohistochemistry was used to measure the IdUrd labelling index. Duration of S phase (ts) was estimated by flow cytometry. From these two parameters potential doubling time (tpot) was calculated. Cell kinetic parameters showed low variations between passages and also between xenografts in same passage. Smaller variations of ts compared to labelling index and tpot were found. tpot was generally short with an interpassageal mean of 1.3 days and CV=14.8%. All xenografts showed DNA aneuploidy (mean DNA index --1.6). Homogeneous tumor growth was indicated by low variations of volume doubling time and lag time. There was no correlation between tumor growth and cell proliferation. Histopathological characteristics of the donor patients tumor were retained during serial transplantation.
Animals↗
Heterogeneity in renal cell carcinoma and its impact no prognosis--a flow cytometric study.
In the process of tumour progression genetic instability is the basis for the evolution of tumour cell clones with various genotypic and phenotypic characteristics causing heterogeneity. Renal cell carcinoma has a long prediagnostic growth period, which increases the probability of clonal evolution. We have studied 200 consecutive renal cell carcinomas, addressing the interrelationship between intratumour heterogeneity and clinicopathological factors. DNA ploidy patterns were analysed in multiple samples from each tumour using flow cytometry and compared with clinical stage, tumour invasion, metastatic rate and survival. Eighty-five of 192 evaluable tumours (44%) were homogeneous concerning DNA ploidy (62% diploid, 38% aneuploid). Among 107 heterogeneous tumours a majority (79%) contained aneuploid as well as diploid cell clones. Homogeneously diploid tumours had a lower incidence of local tumour spread compared with tumours with aneuploid cell clones (P < or = 0.001), but the frequency of distant metastasis at time of diagnosis was similar. The presence of aneuploidy in at least one sample from a tumour was a significant adverse prognostic factor (P < 0.001), whereas the degree of heterogeneity had no influence on survival. The frequent heterogeneity demonstrated indicates that multiple samples must be investigated to evaluate properly the malignant character of renal cell carcinoma.
Adult↗
Structure, growth and cell proliferation of human osteosarcoma and malignant fibrous histiocytoma xenografts in serial transplantation in nude mice.
Tumour specimens from one patient with osteosarcoma and one with malignant fibrous histiocytoma were transplanted in serial passages in nude mice. Structure, growth and cell kinetics of the xenografts were studied in order to assess the validity of the two tumour models. Cell proliferation was analysed using in vivo labelling with the thymidine analogue iododeoxyuridine (IdUrd) and the IdUrd labelling index (LI) was determined by immunohistochemistry. The DNA index (DI) was examined by flow cytometry. The c-myc oncoprotein expression was studied by immunohistochemistry. More intense proliferation was observed in the peripheral parts of the tumours. There was no correlation between tumour growth and cell proliferation in the two tumour groups. Stability of the tumour models was indicated by low intrapassage and interpassage variations of DI, LI, and volume doubling time, and also by retained histopathological characteristics and c-myc staining patterns of donor patients' tumours during serial transplantation.
Aged↗
Proliferating cell nuclear antigen expression in renal cell carcinoma. Prognostic implications.
The proliferating cell nuclear antigen (PCNA) is a nuclear protein associated with cells in active cell cycle. The expression of PCNA was evaluated immunohistochemically in 3-6 samples from 68 renal cell carcinomas. A total of 279 tumour samples were analysed using the monoclonal antibody PC-10, and the percentage of positively stained cell nuclei (PCNA-index) was determined. The tumour PCNA-index varied between 0.9-17.5%, with a mean value of 4.9%, significantly different from normal kidney cortex samples (p < 0.001). A significant difference in PCNA-index was found between the different tumour grades, whereas no significant difference was found between clinical stages. Concerning DNA ploidy, aneuploid tumours had a significantly higher PCNA-index compared with diploid tumours (p = 0.002). There was a significant survival advantage for patients with low tumour PCNA-indices (< 3.5%) compared with those with high indices (> 3.5%, p = 0.019), a difference also found for patients with non-metastatic disease (p = 0.012). Our data shows that PCNA expression can be analysed and that it may constitute an additional prognostic parameter for patients with renal cell carcinoma.
Adult↗
Peptidergic innervation of the human gallbladder.
The human gallbladder was investigated by means of immunohistochemical methods for the occurrence of peptidergic nerve fibres. In the gallbladder 11 types of peptidergic nerve fibres were observed. These were somatostatin-, pancreatic polypeptide (PP)-, peptide YY (PYY)-, neuropeptide Y (NPY)-, vasoactive intestinal peptide (VIP)-, gastric inhibitory peptide (GIP)-, neurotensin-, cholecystokinin (CCK)/gastrin C-terminus, substance P-, galanin- and serotonin-immunoreactive nerve fibres. NPY- and GIP-containing neurones were occasionally observed in the ganglionated plexus in the fibromuscular coat. Somatostatin-, NPY-, neurotensin-, and galanin-immunoreactive nerve fibres were abundant. The other nerve fibres were few. Peptidergic nerve fibres occurred in the lamina propria mucosae around and in close contact with the basement membrane of the epithelial cells. In the fibromuscular coat, they lied mainly around the muscle bundles. They showed no special arrangement in the perimuscular connective tissue. In both arteries and veins somatostatin-, neurotensin, and galanin nerve fibres were detected in both tunica media and tunica adventitia. NPY-nerve fibres were found in tunica media and substance P- and GIP- nerve fibres in tunica adventitia. The peptidergic nerve fibres observed in the gallbladder outnumbered those observed with the peripheral nerve markers used in this study. It has been speculated that this might be due to the coexistence of several neuropeptides in the same nerve fibre and/or the coexistence of these neuropeptides with a classical neurotransmitter.
Adult↗
p53 expression and cell proliferation in squamous cell carcinomas of the head and neck.
BACKGROUND: In squamous cell carcinoma of the head and neck (SCCHN), overexpression of the p53 protein has been found in 34-80% of the tumors studied. No data are available regarding p53 expression versus tumor cell proliferation and prognosis for this tumor type. METHODS: p53 protein levels were studied by immunohistochemical staining of 33 primary SCCHN using 3 antibodies (DO7, PAb 1801, and CM1) that react with different epitopes of the p53 protein. The cellular expression of p53 was compared with in vivo incorporation of the thymidine analog iododeoxyuridine (IdUrd) and expression of proliferating cell nuclear antigen (PCNA). RESULTS: Twenty-one tumors (64%) had a positive nuclear staining for p53 with the monoclonal antibody DO7, which reacts with a denaturation-resistant epitope in wild-type and mutant p53. PAb 1801 and CM1 reacted with 19 and 20 tumors, respectively, all of which were DO7-positive. No correlation was found between incorporation of IdUrd and p53 expression or between PCNA and p53 expression. The data indicate that intracellular accumulation of the p53 protein was related to tumor stage and localization of the tumor. No indication of a clinical or prognostic significance of p53 expression in SCCHN was found. CONCLUSIONS: No association between p53 deregulation and tumor cell proliferation was found.
Carcinoma, Squamous Cell↗