Purpose: Renal cell carcinoma (RCC) is the most common malignancy of the kidney composed of specific tumor types. The sporadic conventional
RCCs are, in contrast to the other RCC types, characterized ...by a high rate of von Hippel-Lindau (VHL) mutations and hypermethylation.
The majority of these tumors lack functional VHL protein (pVHL) that leads to increased hypoxia-inducible factor 1α (HIF-1α)
expression. The pVHL is the physiologic regulator of the activity of HIF-1α by targeting it to the proteasome for degradation
under normoxia. Both pVHL and HIF-1α target other genes that are important for cancer survival and proliferation. Expression
of HIF-1α has been linked to poor prognosis in different malignancies, although few studies have been done on the relation
between HIF-1α and clinical variables in RCC.
Experimental Design: HIF-1α protein expression was analyzed in tumor tissue from 92 patients with RCC. HIF-1α was quantified by Western blot relative
to a positive control.
Results: The HIF-1α protein was expressed as two bands which strongly correlated ( r = 0.906, P < 0.001); therefore, they were added and the sum evaluated against clinicopathologic variables. There was no association
between HIF-1α and gender, stage, grade, tumor size, or vein invasion. Conventional RCCs had significantly higher HIF-1α expression
compared with papillary and chromophobe RCCs and kidney cortex. In conventional RCC, HIF-1α was an independent prognostic
factor.
Conclusion: HIF-1α levels varied significantly between the different RCC types. In conventional RCC, HIF-1α was an independent prognostic
factor. These data indicate that HIF-1α is involved in tumorogenesis and progression of RCC. Evaluation of other HIF target
gene products and correlation to angiogenesis seems warranted.
OBJECTIVE
To evaluate the prognostic information of carbonic anhydrase (CA) IX expression in patients with renal cell carcinoma (RCC), as increased expression of CA IX is correlated with a worse ...prognosis in several malignancies.
PATIENTS AND METHODS
CA IX expression was assessed in RCC tumours from 228 patients, using a tissue microarray technique on archival material. The expression was related to RCC cell type, Tumour‐Node‐Metastasis (TNM) stage, nuclear grade and survival.
RESULTS
CA IX expression was significantly higher (P < 0.001) in 183 conventional than in 31 papillary RCC and 14 chromophobe RCC. For conventional RCC there was no correlation of CA IX expression with TNM stage or nuclear grade. To evaluate the prognostic information conventional RCC tumours were subdivided arbitrarily into three groups according to the CA IX expression, of 0–10%, 11–90% and 91–100% expression, respectively. Patients with tumours with 0–10% expression had a less favourable prognosis than those with 11–90% and 91–100% expression (P = 0.012, and 0.001), respectively. A multivariate analysis of prognostic factors for patients with conventional RCC showed that TNM stage, nuclear grade and CA IX were independent predictors of prognosis.
CONCLUSION
These results show that CA IX expression is higher in conventional than other RCC cell types; furthermore, patients with conventional RCC with low CA IX expression had a less favourable prognosis.
Primary mesothelioma of the pericardium is a rare tumor and carries a dismal prognosis. This case report presents a 38-year-old man who suffered from recurrent pericardial fluid. Initial symptoms ...were unspecific, with dry cough and progressing fatigue. Pericardiocentesis was performed, but analyses for malignant cells and tuberculosis were negative. After recurrence a pericardiectomy was planned. At operation, partial resection of tumor tissue surrounding the heart was performed. Histopathologic examination including immunohistochemical staining for calretinin showed a biphasic mesothelioma. During the postoperative period the patient’s condition ameliorated, but symptoms recurred and the patient died 3 months after diagnosis and 15 months after the first symptoms. At autopsy, the pericardium was transformed by the tumor that also expanded into the mediastinum and had set metastases to the liver. A review of 29 cases presented in the recent literature indicates a higher incidence of malignant pericardial mesothelioma among men than women. Median age was 46 (range, 19–76) years. In pleural mesotheliomas, exposure to asbestos is a known risk factor. However, in primary pericardial mesotheliomas the evidence for asbestos as an etiologic factor seems to be less convincing (3 exposed among 14 cases). Symptoms are often unspecific and cytologic examination of pericardial fluid is seldom conclusive (malignant cells demonstrated in 4/17 cases). Partial resection of the tumor can give a period of symptom reduction. Only a few patients have been treated with chemotherapy. Median survival of patients with pericardial mesotheliomas is approximately 6 months.
OBJECTIVES
To examine vascular endothelial growth factor (VEGF), VEGF‐receptor‐(R)1, and R2 mRNA levels in renal cell carcinoma (RCC), a tumour generally refractory to most medical therapy, but for ...which a potentially useful therapeutic alternative is inhibition of angiogenesis.
PATIENTS AND METHODS
VEGF, VEGF‐R1 and ‐R2 mRNA levels were analysed using the quantitative reverse transcription‐polymerase chain reaction. RNA was extracted from 84 conventional (clear cell) RCCs (cRCC), 20 papillary (pRCC), six chromophobe (chRCC), and 27 corresponding kidney cortex tissues, obtained from 110 patients in whom high‐quality RNA was available from the tumours (53 women and 57 men, mean age 64.7 years, range 25–85).
RESULTS
The VEGF, VEGF‐R1, and ‐R2 mRNA levels were higher in tumour than in kidney cortex tissues. Among the RCC types, cRCC had higher VEGF levels than pRCC. In cRCC, VEGF‐R2 levels were higher in stage I–II than in more advanced stages. In pRCC, VEGF and VEGF‐R2 levels were higher in stage III than in stage I–II tumours. In cRCC, patients with VEGF levels below the median had a significantly shorter survival time than those with higher levels. By contrast, in pRCC, VEGF, VEGF‐R1 and ‐R2 RNA levels above the median were related to adverse survival. Using multivariate analysis in cRCCs, VEGF‐R1 mRNA level was the last factor to be omitted after stepwise elimination analysis.
CONCLUSION
VEGF and its receptors were associated with tumour stage and survival, but were not independent prognostic factors. Different RCC types had different expression patterns of VEGF and receptor mRNA levels. We conclude that different pathways might be involved in regulating angiogenesis in the specific RCC types. Detailed knowledge of angiogenesis in RCC is essential when designing new treatment trials where angiogenesis inhibition is used.
Lung cancer is the most common cause of cancer death worldwide, with over one million cases annually. To identify genetic factors that modify disease risk, we conducted a genome-wide association ...study by analysing 317,139 single-nucleotide polymorphisms in 1,989 lung cancer cases and 2,625 controls from six central European countries. We identified a locus in chromosome region 15q25 that was strongly associated with lung cancer (P = 9 × 10-10). This locus was replicated in five separate lung cancer studies comprising an additional 2,513 lung cancer cases and 4,752 controls (P = 5 × 10-20 overall), and it was found to account for 14% (attributable risk) of lung cancer cases. Statistically similar risks were observed irrespective of smoking status or propensity to smoke tobacco. The association region contains several genes, including three that encode nicotinic acetylcholine receptor subunits (CHRNA5, CHRNA3 and CHRNB4). Such subunits are expressed in neurons and other tissues, in particular alveolar epithelial cells, pulmonary neuroendocrine cells and lung cancer cell lines, and they bind to N′-nitrosonornicotine and potential lung carcinogens. A non-synonymous variant of CHRNA5 that induces an amino acid substitution (D398N) at a highly conserved site in the second intracellular loop of the protein is among the markers with the strongest disease associations. Our results provide compelling evidence of a locus at 15q25 predisposing to lung cancer, and reinforce interest in nicotinic acetylcholine receptors as potential disease candidates and chemopreventative targets.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Conventional renal cell carcinoma (cRCC) accounts for most of the deaths due to kidney cancer. Tumor stage, grade, and patient performance status are used currently to predict survival after surgery. ...Our goal was to identify gene expression features, using comprehensive gene expression profiling, that correlate with survival.
Gene expression profiles were determined in 177 primary cRCCs using DNA microarrays. Unsupervised hierarchical clustering analysis segregated cRCC into five gene expression subgroups. Expression subgroup was correlated with survival in long-term follow-up and was independent of grade, stage, and performance status. The tumors were then divided evenly into training and test sets that were balanced for grade, stage, performance status, and length of follow-up. A semisupervised learning algorithm (supervised principal components analysis) was applied to identify transcripts whose expression was associated with survival in the training set, and the performance of this gene expression-based survival predictor was assessed using the test set. With this method, we identified 259 genes that accurately predicted disease-specific survival among patients in the independent validation group (p < 0.001). In multivariate analysis, the gene expression predictor was a strong predictor of survival independent of tumor stage, grade, and performance status (p < 0.001).
cRCC displays molecular heterogeneity and can be separated into gene expression subgroups that correlate with survival after surgery. We have identified a set of 259 genes that predict survival after surgery independent of clinical prognostic factors.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Purpose: To evaluate mortality rate and causes of death in patients with pituitary adenomas. Material & Methods: Five hundred seventy-two patients with pituitary adenomas were identified in ...the Regional Cancer Registry in Umeå in northern Sweden between 1958 and 2007. Four hundred eighty-nine patients with a follow-up time ≤ 12 months from diagnosis of pituitary adenoma were included. Patients were followed until time of death, or the end of year 2007 through connection with the Swedish Population Register. During follow-up 228 patients (47 %) died. The primary causes of death were identified from the Swedish National Board of Health and Welfare's Cause of Death Register. The person-years at risk were calculated from the time of diagnosis of the pituitary adenoma until time of death. Standard mortality ratios (SMR) between observed and expected causes of death were calculated. Results: Two hundred twenty-eight patients (138 men, 90 women) died during follow-up. The expected number of deaths were 103, SMR = 2.22 (CI 1.94-2.52). Increased mortality was seen both in men, SMR = 1.98 (CI 1.66-2.34) and women, SMR = 2.71 (CI 2.18-3.33). The median age of death was 77 years (range, 14-94). The median follow-up was 13 years (range, 1-47), giving a total of 3 439 person-years. One hundred forty-eight patients had non-secreting adenomas, 41 patients had hormonally secreting adenomas and in 39 patients the type of adenoma was unknown. One hundred sixty-eight patients had their pituitary adenoma surgically resected, 158 patients received radiotherapy to the pituitary and 2 patients received neither surgery or radiotherapy. In 28 patients the treatment was unknown. One hundred twenty-two patients died in disorders of the circulatory system. The expected number of patients was 54, SMR = 2.26 (CI 1.88-2.70). Sixteen patients died in disorders of the respiratory system, 7 expected, SMR = 2.20 (CI 1.26-3.57). Seven patients died in disorders of the nervous system, 1 expected, SMR = 4.85 (CI 1.94-10.00). Six patients died in infectious diseases, 1 expected, SMR = 6.98 (CI 2.55-15.20). No increased mortality rate was seen in 28 patients who died from malignant tumours. The expected number was 24, SMR = 1.17 (CI 0.78-1.70). An increased mortality rate in cerebrovascular disorders was seen in both men and women who received radiotherapy to the pituitary. Twenty-nine patients (15 men and 14 women) who received radiotherapy died of cerebrovascular disorders. The expected number of patients was 6, SMR = 4,56 (CI 3.05-6.55). In patients who did not receive radiotherapy, the cerebrovascular mortality did not differ from the general population. Conclusions: Patients with pituitary adenomas had a two-fold increased mortality rate, compared to the general population. Patients who received radiotherapy to the pituitary had an increased mortality rate in cerebrovascular disorders compared to the general population and compared to patients who did not receive radiotherapy.
Citation Format: {Authors}. {Abstract title} abstract. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 739. doi:1538-7445.AM2012-739
Results from case‐control and prospective studies suggest a moderate positive association between obesity and height and differentiated thyroid carcinoma (TC). Little is known on the relationship ...between other measures of adiposity and differentiated TC risk. Here, we present the results of a study on body size and risk of differentiated TC based on a large European prospective study (EPIC). During follow‐up, 508 incident cases of differentiated TC were identified in women, and 58 in men. 78% of cases were papillary TC. Cox proportional hazard models were used to estimate hazard ratios (HRs). In women, differentiated TC risk was significantly associated with body mass index (BMI, kg/m2) (HR highest vs lowest quintile = 1.41, 95% CI: 1.03–1.94); height (HR = 1.61; 95% CI: 1.18–2.20); HR highest vs lowest tertile waist (HR = 1.34, 95% CI: 1.00–1.79) and waist‐to‐hip ratio (HR = 1.42, 95% CI: 1.05–1.91). The association with BMI was somewhat stronger in women below age 50. Corresponding associations for papillary TC were similar to those for all differentiated TC. In men the only body size factors significantly associated with differentiated TC were height (non linear), and leg length (HR highest vs. lowest tertile = 3.03, 95% CI: 1.30–7.07). Our study lends further support to the presence of a moderate positive association between differentiated TC risk and overweight and obesity in women. The risk increase among taller individuals of both sexes suggests that some genetic characteristics or early environmental exposures may also be implicated in the etiology of differentiated TC.
Abstract
We analysed the incidence of second primary intracranial tumours in patients with pituitary adenomas treated with radiotherapy compared to the risk of patients not exposed to irradiation and ...to the general population. Materials and methods. This retrospective cohort study includes 298 patients with pituitary adenomas that received radiotherapy to the pituitary from 1960 to 2007. The patients were recruited from the Cancer Registry of northern Sweden and the local radiotherapy-registry of the University Hospital in Umeå. Only patients with ≥12 months follow-up after diagnosis of pituitary adenoma were included. A cohort of 131 patients with pituitary adenomas not treated with radiotherapy was used as reference. Standard incidence ratios (SIR) between observed and expected number of second primary intracranial tumours were calculated. Results. The median observation time after diagnosis of pituitary adenoma in 298 patients treated with radiotherapy was 14 years, and the total number of person-years at risk was 4 784. Six (2.0%) of the patients developed second primary intracranial tumours between 7 and 31 years after radiotherapy. Two patients had gliomas and four had meningiomas. The expected number of intracranial tumours was 1.15 giving a SIR of 5.20 (95% CI 1.90-11.31). No significant correlations were found between radiation technique or administered dose and the risk of developing a second primary intracranial tumour. The cumulative risk for second intracranial tumours at 10 and 20 years was 1.3%. Patients not treated with radiotherapy were followed 1 601 years and no second primary intracranial tumour occurred. Discussion. The results indicate an increased risk of second primary intracranial tumours in patients treated with radiotherapy for pituitary adenomas, compared to patients not exposed to irradiation and to the general population. Meningiomas were more frequent than gliomas and the median time interval between radiotherapy and second intracranial tumour was 17 years.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Cortisol and dehydroepiandrosterone (DHEA) and its sulphate (DHEAS) are the major steroid hormones produced by the human adrenal cortex. The serum levels of cortisol and DHEAS were analysed in 211 ...consecutive patients with renal cell carcinoma before initiation of therapy. Serum cortisol was significantly higher in patients with renal cell carcinoma compared with that in patients with benign cysts (p<0.0001). Serum cortisol was independent of disease stage, but positively correlated to tumour diameter and grade. The serum levels of DHEAS were higher in men than in women, and decreased with age, but did not correlate with disease stage, tumour diameter or grade. The prognosis of patients with elevated serum cortisol tended to be poorer (p=0.06) than the prognosis of those with lower levels. In a multivariate analysis, disease stage and tumour grade were independent predictors of prognosis. Age, gender and serum levels of cortisol and DHEAS were of limited value for prognosis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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