Biomedical subjects

E Wilander

Publications and source records attributed to E Wilander.

At least 19 recordsLinked to original sources

PubMed2006

The carcinogenic role of oncogenic HPV and p53 gene mutation in cervical adenocarcinomas.

Thirty tumors were collected from our archive of cervical adenocarcinomas. They were examined with respect to the content of oncogenic HPV and presence of mutations in the p53 gene exons 5 through 8. Furthermore, available clinical information on the cases was reviewed. For the detection of p53 gene and presence of oncogenic HPV, PCR followed by direct sequence analysis of the amplified DNA was employed. Seventeen tumors were identified as HPV-positive, comprising both HPV types 18 and 16. Six cases showed a p53 gene mutation, of which five were of the missence and one of the silent type. No statistical correlation between the occurrence of oncogenic HPV and presence of p53 gene mutation (p = 0.67) was recorded. Among the tumors with p53 gene mutation, three were HPV-positive and three were HPV-negative. The determination of p53 gene mutations was not related to clinical findings such as the stage of the tumor or presence of metastases of the lymph nodes. However, p53 gene mutations were somewhat more prevalent in low differentiated tumors (p < 0.02). The results indicate that oncogenic HPV and p53 gene mutations have independent carcinogenic roles in cervical adenocarcinomas.

Adenocarcinoma↗

PubMed2005

High viral loads of human papillomavirus predict risk of invasive cervical carcinoma.

High loads of human papillomavirus (HPV) 16 and HPV 18/45 increase the risk of developing invasive cervical carcinoma, revealing higher risk in percentiles of highest viral loads for HPV 16 (odds ratio (OR) 58.7, 95% confidence interval (CI) 21.9-151.4) compared to HPV 18/45 (OR 3.3, 95% CI 1.5-7.2). Thus, HPV load is a type-dependent risk marker for invasive carcinoma.

Adult↗

PubMed2001

Human papillomavirus 16 E6 polymorphisms in cervical lesions from different European populations and their correlation with human leukocyte antigen class II haplotypes.

Infection with high-risk human papillomavirus (HPV) is necessary for the development of a cervical lesion, but only a fraction of precursor lesions progress to cancer. Additional factors, other than HPV type per se, are likely to increase the probability for progression. Intratype genome variations have been reported to be associated with viral persistence and the development of a major cervical disease. We have recently shown that the prevalence of specific HPV16-E6 variants in invasive cervical cancer (ICC) varies between Italian and Swedish women. To extend our initial study we have analyzed E6 variants in cervical lesions from Czech women, ranging from low-grade cervical intraepithelial neoplasia (LCIN) to ICC and scaled up the sample size of our initial study of Swedish and Italian women. In addition, we have correlated the cases of cancers with human leukocyte antigen (HLA) class II haplotypes. In line with our earlier observation, the distribution of specific HPV16-E6 genotypes in CIN and ICC varied in the 3 cohorts. For instance, the HPV16-E6 L83V variant, which has been found to be positively associated with ICC in Swedish women (p = 0.002), was more prevalent in LCIN than in ICC in Italian and Czech women (p = 0.01 and = 0.03, respectively). These data indicate that host genetic factors, such as HLA polymorphism, may determine the potential oncogenicity of the HPV16-E6 L83V variant. Indeed, the DR04-DQ03 haplotype, which is approximately 3-fold more abundant in the normal Swedish population than in those in Italy and the Czech Republic, was found to be positively associated with HPV16-E6 L83V in the 3 cohorts investigated (p = 0.01). This observation may explain why L83V is a risk factor more in Sweden than in the other 2 countries.

Cross-Sectional Studies↗

PubMed2001

The significance of p53 codon 72 polymorphism for the development of cervical adenocarcinomas.

Infection with the human papillomavirus is an important co-factor in the development of cervical carcinomas. Accordingly, HPV DNA is recognised in most of these tumours. Polymorphism of the p53 gene, codon 72, is also considered a risk factor in the development of cervical carcinoma. However, this finding is contradicted by several observers. In the present investigation, 111 cases of adenocarcinoma of the cervix collected through the Swedish Cancer Registry and 188 controls (females with normal cytology at organised gynaecological screening) were analysed with regard to p53, codon 72, polymorphism using a PCR- and SSCP-based technique. In the controls, 9% showed pro/pro, 44% pro/arg and 47% arg/arg, whereas in the invasive adenocarcinomas, the corresponding figures were 0%, 29% and 71%, respectively. The difference was statistically significant (P = 0.001). HPV DNA was identified in 86 tumours (HPV 18 in 48, HPV 16 in 31 and HPV of unknown type in 7 cases) and 25 tumours were HPV negative. The p53, codon 72, genotypes observed in HPV-positive and HPV-negative cervical adenocarcinomas were not statistically different (P = 0.690). The results indicate that women homozygotic for arg/arg in codon 72 of the p53 gene are at an increased risk for the development of cervical adenocarcinomas. However, this genetic disposition seems to be unrelated to the HPV infection.

Adenocarcinoma↗

PubMed2001

p53 codon 72 polymorphism and various human papillomavirus 16 E6 genotypes are risk factors for cervical cancer development.

Risk factors other than human papillomavirus (HPV) infection per se for cervical cancer development have been investigated recently. It was suggested that HPV 16 E6 variants and the p53 codon 72 arginine polymorphism could be progression markers. Indeed, it has been demonstrated that specific E6 variants and p53 arginine were both enriched in cancer. However, especially with regard to the latter, divergent results have been reported. Our aim was thus to investigate whether p53 arginine is important for cervical carcinogenesis by scaling up samples of the two European cohorts, the initial results of which were reported previously. In addition, we have assessed the occurrence of p53 codon 72 arginine, in combination with specific HPV 16 E6 genotypes. We found p53 arginine to be increased in cancer of both cohorts, consistent with our previous concept. Although specific E6 genotypes increased gradually with the severity of the lesion, p53 arginine was enriched in cancer only. Moreover, the frequency of the arginine allele was similar in groups with different E6 genotypes. It is concluded that p53 arginine is a risk factor for cervical cancer but probably acts independently of E6 variants.

Arginine↗

PubMed2001

The role of human papillomavirus in cervical adenocarcinoma carcinogenesis.

Human papillomavirus (HPV) is considered the single most important co-factor in the development of cervical squamous cell carcinomas. Adenocarcinomas of the cervix are also related to HPV, but the correlation is reported to be less pronounced. In the present study, 131 cervical adenocarcinomas were identified through the Swedish Cancer Registry, examined morphologically and then analysed with sensitive polymerase chain reaction (PCR)-based HPV methods for a study of age-related prevalence of HPV. HPV was identified in 64% of the tumours after PCR amplification of the HPV L1 gene only and in 71% following PCR amplification of both the L1 and E6 genes of HPV. HPV 18 was the most prevalent (52%), followed by HPV 16 (33%) and other types of HPV (15%). The prevalence of HPV was shown to be age-dependent. In women younger than 40 years, HPV was present in 89%, whereas in women 60 years and older, HPV was observed in only 43%. The difference was statistically significant, P<0.005. The HPV-positive adenocarcinomas were represented by an age distribution similar to that of cervical squamous carcinomas with a maximum age, in the 40-49 year old group, whereas the frequency of HPV-negative adenocarcinomas increased with age, typical of most carcinomas occurring in elderly women.

Adenocarcinoma↗

PubMed2001

Experience in treatment of metastatic pulmonary carcinoid tumors.

BACKGROUND: The only cure for patients with pulmonary carcinoids is surgery. In the present paper, we report the results of medical treatment of patients with metastatic tumors, their circulating hormone markers, and immunohistochemical profile of the tumors. PATIENTS AND METHODS/RESULTS: The response to systemic antitumoral treatment was studied in 31 patients with metastatic pulmonary carcinoids. Median survival from treatment start was 25 months. Alpha-interferon treatment has resulted in stable disease in 4 of 27 patients (median duration 15 months), while 23 patients showed progressive disease. Somatostatin analogues given as single drug treatment resulted in progressive disease. Streptozotocin and 5-fluorouracil resulted in progressive disease in seven of seven patients. Stable disease was obtained for 8 and 10 months respectively in two of two patients treated with streptozotocin + doxorubicin. Two of eight patients treated with cisplatinum + etoposide showed a significant decrease in tumor size lasting six and eight months respectively, and one displayed stable disease for seven months. Elevation of plasma chromogranin A was seen in 93%. CONCLUSIONS: The results of systemic antitumoral treatment of pulmonary carcinoids with distant metastases are generally discouraging. Chemotherapy with cisplatinum + etoposide, or doxorubicin combined with streptozotocin or paclitaxel may be of value. Alpha-interferon and octreotide offer efficient symptomatic relief, but stabilizes tumor growth in merely 15% of the cases. Plasma chromogranin A is the most frequently elevated tumor marker.

Adolescent↗

PubMed2001

Analysis of intratumoral heterogeneity of chromosome 3p deletions and genetic evidence of polyclonal origin of cervical squamous carcinoma.

Investigation on intratumoral genetic heterogeneity provides an important insight into the roles of genetic alterations in human carcinogenesis and clues to clonal origin of tumors. Intratumoral heterogeneity of genetic changes of cervical cancer has not been described so far. In this study, we analyzed the intratumoral heterogeneity of chromosome 3p deletions and X-chromosome inactivation patterns in multiple microdissected samples from each individual cervical cancer, attempting to understand the roles of 3p deletions in development of cervical cancer and its clonal origin. Totally, 120 normal and lesional samples from 14 cases of fresh cervicalcancers were analyzed. Frequency and patterns of allelic losses of 3p were assessed by polymerase chain reaction (PCR) amplification of 12 microsatellite markers flanking the frequently deleted regions of 3p, followed by Genescan analysis in an ABI 377 DNA sequencer. Loss of heterozygosity was recorded as heterogeneous pattern (LOH present in parts of samples or LOH involving different alleles among different samples) and homogeneous pattern (LOH involving identical alleles in all samples from the tumor). Allelic loss affecting at least one marker was detected in 8 of 14 cases (57%). Allelic losses, both homogeneous and heterogeneous, were frequently detected at FHIT gene region (D3S1300, 40% and 60%; D3S4103, 27.3% and 54.6%), 3p21.3-21.2 (D3S1478, 27.3% and 45.5%), and 3p24.2-22 (D3S1283, 30% and 50%). Seven of eight LOH-positive tumors exhibited homogeneous allelic loss involving at least one of these three 3p loci. Allelic losses were present in the CIN lesions synchronous with invasive lesions positive for LOH. Our findings suggest essential roles of genes on these 3p loci, particularly the FHIT gene in participating in clonal selection and early development of cervical cancer. Most interestingly, with the combination of LOH analysis and X-chromosome inactivation analysis, we provided the first clear genetic evidence of polyclonal origin of cervical invasive cancer in two of eight cases. This finding strongly suggests the importance of field defect (possible human papilloma virus) in cervical carcinogenesis.

Adult↗

PubMed2001

The level of the mitochondrial mutation A3243G decreases upon ageing in epithelial cells from individuals with diabetes and deafness.

We have in a longitudinal study determined the proportion of the mitochondrial A3243G mutation in DNA obtained from cervical cell samples collected from three individuals affected with mitochondrial diabetes and hearing loss during a period of up to 18 years. Using the minisequencing method we were able to sensitively determine the proportion between mutant and normal mitochondrial DNA. Our results demonstrate a constant decrease in the levels of the pathogenic mutation in mitotic tissues of affected individuals with time.

Adult↗

PubMed2001

Chromogranin A in human neuroendocrine tumors: an immunohistochemical study with region-specific antibodies.

Antibodies to six specific regions of the chromogranin A (CgA) molecule were used to study their immunoreactivity in human neuroendocrine (NE) tumors. Tissue specimens from endocrine pancreatic tumors (n = 14), duodenal carcinoids (n = 2), bronchial carcinoids (n = 5), ileal carcinoids (n = 5) appendix carcinoids (n = 2), medullary thyroid carcinomas (n = 6), parathyroid adenomas (n = 2), and pheochromocytomas (n = 8) were analyzed. The results showed that the NE tumor types expressed varying numbers of CgA fragments. A variation in frequency of the expression of immunoreactive cells was sometimes seen also within the same tumor type. The midportion fragment CgA 176-195 (chromacin) was the only fragment expressed in all tumors. Benign and malignant tumors expressed different patterns, being especially true of insulinomas and pheochromocytomas. These findings suggest that region-specific antibodies to CgA fragments can be used as a diagnostic tool for the characterization of NE tumors.

Adenoma↗

PubMed2000

Comparison of chromosome 3p deletions between cervical precancers synchronous with and without invasive cancer.

Cervical cancers are considered to originate from a series of pre-malignant lesions (cervical intra-epithelial neoplasia, CIN). The mechanisms behind these events are unknown. In addition to HPV infection, deletions of chromosome 3p have been found to be a frequent event in cervical cancer and likely play an important role in the transition of CIN to invasive cancer. To classify the potential role of 3p deletions in early-stage cervical carcinogenesis, we analyzed LOH of 3p in cervical precancers. Thirty cases with single or multiple CIN lesions were selected for the study, including 20 cases without and 10 cases with synchronous invasive cancers. Allelic losses on 1 or more 3p loci were recorded in 33% (3/9) of CIN II and 36% (5/14) of CIN III lesions from 20 cases without co-existing invasive cancer, whereas an increasing percentage of LOH was observed in the 10 precancerous lesions synchronous with invasive cancer, with 71% (5/7) CIN II and 76% (13/17) CIN III lesions. This result implies that 3p deletions have selective roles in early transition of pre-malignancy to invasive cancer. Comparing the LOH patterns between the 2 groups, genetic deletions in cases with invasive cancers involved extensive regions of 3p but were more localized in precancer cases without concomitant invasive cancer. Two interstitial regions, 3p22-21.3 around marker D3S1260 and 3p21.1 around markers D3S1289 and D3S1076, were most frequently deleted in both groups, suggesting that these 2 regions are novel tumor-suppressor loci which may play a role in early transition of cervical precancer to invasive cancer. Identical LOH patterns between multiple CIN lesions and synchronous invasive cancer in the same case suggests that different cervical precancers and invasive cancer are genetically linked and most likely originate from a single precursor cell.

Chromosome Deletion↗

PubMed2000

Clonality analysis of multifocal carcinoid tumours of the small intestine by X-chromosome inactivation analysis.

The clonality of intestinal carcinoids and the relationship between different tumour deposits of multiple intestinal carcinoids were investigated in this study. Six cases of multiple ileal carcinoids were selected for analysis and three independent carcinoid lesions from each case were microdissected. Clonality of the lesions was determined by polymerase chain reaction (PCR)-based X-chromosome inactivation of the human androgen receptor gene. Four out of six cases were heterozygous for microsatellite repeats within the androgen receptor gene and thus informative for the study. The results showed that all 12 lesions analysed had non-random X-chromosome inactivation (monoclonal) patterns, compared with the background normal intestinal mucosal tissues. This finding proves for the first time the monoclonal origin of human intestinal carcinoids, by X-chromosome inactivation analysis. More interestingly, identical X-chromosome inactivation patterns were found in different carcinoid lesions from each individual case. This evidence strongly indicates that multiple carcinoids of the small intestine were generated by metastasis of a primary tumour to different locations in the intestine, rather than being of multiple origin. This study provides an important insight into the carcinogenesis of intestinal carcinoids.

Carcinoid Tumor↗

PubMed2000

Streptozocin and o,p'DDD in the treatment of adrenocortical cancer patients: long-term survival in its adjuvant use.

BACKGROUND: To evaluate the efficacy of streptozocin and o.p'DDD (SO) in adrenocortical cancer (ACC) patients since other chemotherapeutic regimens have limited effects. PATIENTS AND METHODS: We performed a phase II study with SO therapy in 40 ACC patients (median age 44 years). Oral o,p'DDD administration (1-4 g/d, every day) was given together with intravenous streptozocin (1 g/d for five days, thereafter 2 g once every three weeks). 5HT3-receptor blocker was used as standard premedication for streptozocin. RESULTS: The SO therapy was found to have significant effects on disease-free interval (P = 0.02) as well as on survival (P = 0.01) in adjuvantly treated cases (n = 17) in comparison to the patients who did not get any therapy after complete resection (n = 11). Complete or partial response was obtained in 36.4% of patients with measurable disease (n = 22). The overall two-year and five-year survival rates were 70% and 32.5%, respectively. The presence of metastases at diagnosis was identified as a poor prognostic factor (P = 0.02). CONCLUSIONS: The present study necessitates further randomized clinical study of SO therapy in the treatment of ACC, mainly as adjuvant treatment immediately after curative intended surgery, and could be developed into a regular treatment regimen.

Adrenal Cortex Neoplasms↗

PubMed2000

Clonality of precursors of cervical cancer and their genetical links to invasive cancer.

Two problems were the focus of this study. (1) Is precancer and/or invasive cancer of the human cervix a poly- or monoclonal proliferation of neoplastic cells? (2) Are simultaneously present precancers and cancers of the cervix clonally related, or do they arise independently? Microdissection of 37 neoplastic lesions with different degrees of histologic severity in 22 patients followed by polymerase chain reaction-based analysis of X-chromosome inactivation was used as a principal method. Invasive cancers were interpreted as monoclonal because samples invariably showed monoclonal signals. In two thirds of these cases, simultaneously present precursors had the identical X-chromosome inactivation pattern, but in one third the pattern was different. Polyclonality was seen in a subgroup of precursors, where there was no simultaneous presence of invasive cancer. In contrast, when invasive cancer was present, no precursor signaled polyclonality. Data taken together indicate that the pathogenesis of cervical cancer is probably even more complicated than that of other cancers involving selection of subclones from originally polyclonal precursors and possibility of coexistence of precursors of different monoclonal composition. The study also observed that a large field of normal cervical squamous epithelium (approximately 500 basal squamous epithelial cells) with nonrandom X-chromosome inactivation was present. It remains to be further investigated whether this phenomenon represents an embryologic lyonization pattern of X-chromosome inactivation or postembryologic clonal expansion of submorphologically transformed cells.

Clone Cells↗

PubMed2000

Uneven distribution of HPV 16 E6 prototype and variant (L83V) oncoprotein in cervical neoplastic lesions.

A previous Swedish study revealed that both prototype and variant HPV16 E6 oncoprotein, occur in about equal numbers in high-grade cervical intraepithelial neoplasia (HCIN), whereas variant HPV16 predominates in invasive cervical squamous carcinoma. Most of the malignant HPV16 variants contain a common mutation, L83V, in the E6 oncoprotein. In the present investigation, 28 HPV16 positive, invasive cervical adenocarcinomas were collected from a total number of 131 adenocarcinomas. These HPV16-positive cases were evaluated with analysis of the E6 gene, using a recently described PCR-SSCP method for identification of the specific mutation (L83V) in the E6 gene. The results obtained were correlated to findings in 103 preinvasive, HCIN, and 31 invasive cervical squamous carcinomas also infected with HPV16. The HPV16 E6 variant L83V was present in 40% of the HCIN lesions, in 54% of the invasive adenocarcinomas, in comparison to 81% of the invasive squamous carcinomas. The difference between HCIN and squamous carcinomas was statistically significant, P < 0.001, whereas the difference between HCIN and invasive adenocarcinomas was not statistically significant, P = 0.604. Prototype HPV16 and its E6 variant L83V are both prevalent in preinvasive and invasive cervical lesions in Swedish women. However, the obvious predominance of HPV16 variant in squamous carcinomas was not seen in adenocarcinomas. A single amino-acid shift in the HPV16 E6 gene appears to result in a different transforming potential in squamous and glandular cervical lesions.

Adenocarcinoma↗

PubMed2000

Prognostic markers in patients with typical bronchial carcinoid tumors.

Typical bronchial carcinoids are usually considered fairly benign tumors. Metastases do however occur, and up to 10% of the patients ultimately die from their disease. To identify prognostic markers, we immunostained 43 typical bronchial carcinoids with antibodies against 8 possibly relevant hormones, oncogenes, tumor suppressor genes, adhesion molecules, and proliferation markers. Altogether 12 patients (28%) had metastatic disease, of whom 10 had regional lymph node metastases at diagnosis. Distant metastases have occurred in 5 patients (12%); all of these have died from their disease. Patients with high expression of Ki-67 had shorter survival time (P < 0.01). None of the immunostained hormones correlated to distant metastases or shorter survival time, but gastrin-releasing peptide correlated to metastatic disease (P < 0.05). All patients who died had CD44-negative tumors (P < 0.001). Nuclear nm23 staining correlated to decreased risk for metastatic disease and distant metastases per se (P < 0.01). Bcl-2 and p53 were associated with increased risk for distant metastases (P < 0.05 and P < 0.01, respectively). We conclude that some patients with typical bronchial carcinoids die from their disease and that gastrin-releasing peptide, Bcl-2, and p53 may be of importance for the malignant transformation of the tumor. Moreover, CD44, nm23, and Ki-67 may give valuable prognostic information and help identify the patients at risk of disease-related death.

Adolescent↗

PubMed1999

Decreased survival in patients with CD44-negative typical bronchial carcinoid tumors.

Tumor tissues from 43 patients with typical bronchial carcinoids have been immunostained with monoclonal antibodies (mAbs) against the standard form (CD44s) and the splice variants v4, v5, v6, v7, v7-8, v9 and v10 of the adhesion molecule CD44. The staining results were correlated with clinical data. Ten patients (23%) had regional lymph node metastases at diagnosis. Distant metastases have occurred in 12% of the patients; 9% died during the observation period of median 65 months (14-325). Positive staining for CD44s was correlated with decreased risk for distant metastases and disease related death. All patients with distant metastases were v6-negative. Patients with CD44v7-8-positive tumors had decreased risk for distant metastases, but the differences in mortality did not reach statistical significance. CD44v9 correlated significantly with decreased risk for distant metastases and death. The remaining CD44 variants (v4, v5 and v10) did not correlate significantly with clinical outcome. Our results confirm earlier observations that typical bronchial carcinoids are potentially malignant. However, positive staining for CD44s, v7-8 and v9 seems to be associated with a more favorable outcome, and may be taken into consideration in prognostic evaluation.

Adolescent↗

PubMed1999

HPV typing and HPV16 E6-sequence variations in synchronous lesions of cervical squamous-cell carcinoma from Swedish patients.

We microdissected 15 specimens of invasive cervical cancer co-existing with some of its precursors. Out of 15 cases, 10 carried HPV16, 2 HPV31, 1 HPV18 and 2 were HPV-negative. We found 3 HPV16 E6 variants among the 10 cases; one was A --> G in nt 131 (one case) and a second was A --> G in nt 276. The third, T;--> G in nt 350, was common, and was found in 5 of the 10 patients infected by HPV16. The type of HPV and the E6 variant were identical in all lesions within the same patient. Viral DNA present in normal epithelium was identical in type and E6 variant to HPV in the same patient's lesions. Multiple samples from invasive cancers with HPV were consistently positive. The data suggest that the originally infecting HPV, including its variant type in the E6 gene, persists unaltered in the whole series of CIN that precedes invasive cancer. Our data are compatible with an essential role of HPV manifested by persistence of the viral genome during the entire natural life history of cervical cancer. We did not confirm previous data on the specific association of invasive cancer with an HPV E6 variant (G at nt 350 rather than T). The discrepancy may depend on the relatively few cases investigated or selection of a special sub-set with progression from CIN to invasive cancer already manifest.

Adult↗