Incidence of HPV in primary and metastatic squamous cell carcinomas of the aerodigestive tract: implications for the establishment of clonal relationships.
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Carcinoma, Squamous Cell↗
Biomedical subjects
I Petersen
Publications and source records attributed to I Petersen.
Early exposure to smoking and future fecundity among Danish twins.
Several studies have examined the effect of in utero exposure to smoking and fecundity among the offspring but the findings are contradictory. We therefore studied the waiting time to first pregnancy (TTP) and exposure to smoking in utero and childhood among Danish twins born between 1931 and 1952. Information about TTP, exposure to mothers smoking in pregnancy, exposure to smoking in childhood and current smoking among the male twins and smoking in their own pregnancy among female twins was collected by interview. Fecundability odds ratio (FOR) estimating the odds of conception in a cycle among exposed compared to the unexposed were calculated separately for female and male twins. A total of 1653 female and 1598 male twins reported a TTP. Female twins, exposed in utero, had reduced fecundability after control for confounders (FOR = 0.81; 95% CI 0.67-0.99). A nonsignificant increase in fecundity among male twins exposed to smoking in utero was found (FOR = 1.12; 95% CI 0.89-1.40). Among dizygotic twins of opposite sex sharing the same in utero exposures, the future fecundity of the male twin was unaffected by in utero exposure (FOR = 0.97; 95% CI 0.60-1.55) whereas the female twin had reduced fecundity (FOR = 0.65; 95% CI 0.47-0.91). This study supports that smoking is hazardous to the female fetus not only in the short term but also affects her future ability to conceive and makes it even more important to advise pregnant women to stop smoking.
Adult↗
Prognostic impact of DNA-image-cytometry in neuroendocrine (carcinoid) tumours.
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Carcinoid Tumor↗
Risk and predictors of fatigue after infectious mononucleosis in a large primary-care cohort.
BACKGROUND: Fatigue has been found to complicate infectious mononucleosis (IM) when patients are directly asked about it. We do not know whether such fatigue is clinically significant, nor whether IM is a specific risk for fatigue (or whether it can follow other common infections). Various risk markers for post-infectious fatigue have been identified, but findings are inconsistent. AIM: To determine the risk of clinically reported fatigue (compared with depression) after IM (compared with both influenza and tonsillitis) in patients attending primary care, and to examine risk markers for post-IM fatigue. DESIGN: Comparison of matched primary-care cohorts. METHODS: We identified 1438 adult patients with a positive heterophil antibody test for IM from the UK General Practice Research Database. These patients were individually matched on age, sex and practice to two comparison groups; one with a clinical diagnosis of influenza and the other of tonsillitis. RESULTS: The odds ratios (ORs) (95%CI) for reported fatigue after IM vs. influenza and tonsillitis were 4.4 (2.9-6.9) and 6.6 (4.2-10.4), respectively. Risk markers for post-IM fatigue included female sex and premorbid mood disorder. By comparison, the ORs for depression after IM vs. influenza and tonsillitis were 1.6 (0.9-2.6) and 2.3 (1.4-3.9), respectively. DISCUSSION: IM is a specific and significant risk for clinically reported fatigue, which is both separate from, and more common than, depression. Female sex and premorbid mood disorder are risk markers for fatigue. These can be used both to target prevention strategies and to explore aetiological mechanisms.
Adolescent↗
[Malignant epithelioid hemangioendothelioma of the liver. Results of surgical treatment strategies].
BACKGROUND: Malignant epithelioid hemangioendothelioma is a rare vascular tumor described mostly in soft tissue, lungs, or liver. The outcome after a wide variety of therapeutic measures, ranging from extended surgical therapy to no therapy, is reported to be variable. Therefore, we reviewed our experience with resective therapy for this rare liver tumor, including orthotopic liver transplantation. MATERIAL AND METHODS: During a period of 5 years, seven patients with the histological diagnosis of hepatic epithelia hemangioendothelioma were seen. In five of them, the liver pathology was detected at random, and all patients were prospectively followed. The therapeutic measures and course of disease are given as case reports. RESULTS: Three patients received formal liver resection and two received liver grafts, one partial and one whole. One further patient is scheduled for transplantation and one is undergoing alternative therapy, with the tumor remaining stable. All resected patients recovered quickly and are alive and well 2 months to 4 years later without signs of tumor recidivism. CONCLUSION: Anatomic liver resection, or in the case of diffuse tumor spread, orthotopic liver transplantation, show favorable long-term results for the treatment of hepatic epithelioid hemangioendothelioma. Therefore, surgical therapy is proposed as the treatment of choice for this entity.
Adult↗
Parvovirus B19 infection associated with unilateral cervical lymphadenopathy, apoptotic sinus histiocytosis, and prolonged fatigue.
This report describes the case of a 16 year old girl with a history of high fever, prolonged fatigue, and cervical lymphadenopathy of the right side. In addition, the patient showed neutropenia, thrombopenia, and pronounced reticulopenia. Cervical ultrasound showed unilateral hypoechoic lymph nodes up to 23 mm in diameter suspicious for malignant lymphoma. Histology of a cervical lymph node specimen revealed massive nodular histiocytic proliferation and prominent apoptosis without necrosis. Parvovirus B19 was detected by polymerase chain reaction and immunohistochemistry in the lymph node. In summary, this case is an unusual presentation of parvovirus B19 infection. The virus was identified as the potential causative agent of unilateral cervical lymphoma and apoptotic sinus histocytosis, thus broadening the clinicopathological spectrum of parvovirus B19 induced diseases.
Adolescent↗
CD24 is an independent prognostic marker of survival in nonsmall cell lung cancer patients.
Originally identified as a B-cell marker, expression of the cell surface molecule CD24 has meanwhile been observed in a variety of human malignancies. It appears to function as a ligand of P-Selectin, an adhesion molecule that is present in activated platelets and endothelial cells. We aimed to determine the rate of CD24 expression in our nonsmall cell lung cancer (NSCLC) collection and to clarify its correlation with clinicopathological parameters including patients' survival. A total of 89 NSCLC were analysed immunohistochemically using a monoclonal CD24 antibody (clone 24C02) and a standard detection system (LSAB, DAKO) on NSCLC tissue microarrays (TMA). The staining was semiquantitatively scored (0, 1+, 2+, 3+) and grouped into high (2+, 3+)- and low (0, 1+)-level expression for statistical analysis. A high level of CD24 expression was observed in 45% of the cases, preferentially adenocarcinomas. Patients whose tumours had a high CD24 expression showed a significantly shorter median survival time of 23 months vs 38 months (P=0.033, log-rank test). Similarly tumour, grading, nodal status and clinical stage were significant prognostic markers in univariate survival analysis. Importantly, in the Cox regression-based multivariate analysis, CD24 expression (P=0.025) together with tumour stage (P=0.006) and grade (P=0.011) proved to be independent prognostic parameters. We hypothesise that the decreased survival of NSCLC patients with strongly CD24-positive tumours is related to an enhanced propensity of haematogenous metastasis formation, which might be P-Selectin mediated.
Adult↗
Gene expression profiles in human non-small and small-cell lung cancers.
Suppression subtractive hybridisation (SSH) was performed comparing normal bronchial epithelial cells with a lung squamous cell carcinoma (SCC) and a metastatic small-cell lung carcinoma (SCLC). The sequence analysis of four cDNA libraries revealed 869 individual sequences. Of these, 342 were tested using northern blots of lung cancer cell lines representing the three major subtypes (SCC, adenocarcinoma, SCLC) which confirmed the differential expression of 236 cDNAs. The extended analysis of 31 randomly chosen fragments confirmed the validity of the approach to identify genes associated with lung cancer development. Additionally, five novel full-length cDNA were isolated encoding the microtubule-associated proteins 1A/1B light chain 3, the epithelial V-like antigen 1 (EVA1), the GTP-binding protein SAR1, a new member of the S100-type calcium binding protein family and a new homeobox-containing gene.
Blotting, Northern↗
Genetic imbalances with impact on survival in colorectal cancer patients.
AIMS: To investigate the prognostic significance of chromosomal alterations in colorectal cancer patients. Histopathological tumour classification is still considered to be the gold standard for the characterization of solid tumours. However, it is well known that such established parameters do not satisfactorily predict the clinical outcome in individual cases. Markers that reliably predict survival are needed. These markers should guide the clinical treatment of neoplastic disease. METHODS AND RESULTS: Chromosomal imbalances in 61 colorectal carcinoma specimens in 37 patients determined by comparative genomic hybridization were correlated with patient survival using custom-made computer software which enabled the assessment of individual chromosomal loci. Kaplan-Meier analysis revealed that over-representations of 2p14-15, 6q23-6q24, 15q22-15q23, 22q11.2 and deletions of 1p36.1-36.2, 4q31.3, 4q35, 8q12-q21, 8p11.2 and 9p22 were significantly associated with shorter disease-specific survival, whereas over-expression of 20q13.3 and deletion of 18q11.2 were significantly associated with longer disease-specific survival in this collection of colorectal cancers. Multivariate Cox proportional hazards regression models consistently identified gains of 2p14-15, 15q22-23, 22q11.2 and losses of 1p36.1-36.2 and 4q35 as independent markers of shorter patient survival carrying greater significance than the classical clinicopathological parameters of nodal status and tumour grade. CONCLUSIONS: These five markers allow a molecular categorization of patients into high and low clinical risk groups. Thus, the genomic data have refined the histopathological classification highlighting the necessity for a supplementary genetically based stratification of colorectal cancer.
Adenocarcinoma↗
The gene ratios c-MYC:cyclin-dependent kinase (CDK)N2A and CCND1:CDKN2A correlate with poor prognosis in squamous cell carcinoma of the head and neck.
PURPOSE: Tumor-Node-Metastasis classification does not fully predict outcome of treatment and prognosis in patients with squamous cell carcinoma of the head and neck. Different biomarkers have been suggested to yield additional prognostic information, but no single marker has thus far been introduced in the clinic. The objective of the present study was to analyze the copy number of the frequently amplified oncogenes CCND1 and c-MYC in relation to the commonly deleted tumor suppressor gene cyclin-dependent kinase (CDK)N2A (p16) to enhance the clinical significance. EXPERIMENTAL DESIGN: Extracted DNA from diagnostic biopsies of 78 untreated patients were analyzed by real-time PCR with specific primers for c-MYC, CCND1, and CDKN2A. Gene copy number ratios were calculated by dividing the copy number of c-MYC or CCND1 with CDKN2A. Ratios > 2 were defined as enhanced. These data were related to disease-free interval and disease-specific survival. RESULTS: Enhanced gene ratio of c-MYC:CDKN2A was detected in 35 of 78 (45%) and enhanced ratio of CCND1:CDKN2A in 36 of 78 (46%) of the cases. The c-MYC:CDKN2A and CCND1:CDKN2A ratios correlated with disease-specific survival with respect to death (P = 0.042 and 0.049, respectively; Log-rank test). Furthermore, enhancement of c-MYC:CDKN2A was associated with a shorter disease-free interval as marked by the development of recurrences or metastases (P = 0.014; Log-rank test). CONCLUSIONS: We conclude that CCND1 and/or c-MYC amplification, when combined with CDKN2A deletion, yield additional prognostic information as compared with analysis of single genetic aberrations. These gene ratios, as analyzed by a sensitive method like real-time PCR on diagnostic biopsies, might help clinicians to individualize the treatment of squamous cell carcinoma of the head and neck as they reflect the biological properties of the tumors. This could be used as an adjunct to the Tumor-Node-Metastasis classification system.
Carcinoma, Squamous Cell↗
Grading of chronic synovitis--a histopathological grading system for molecular and diagnostic pathology.
The following is a proposition for a simple histopathological classification system to measure inflammation in synovial tissue. This synovitis-score is employed in conventionally stained routine sections, and is applicable to every kind of synovitis, irrespective of etiology and including the following relevant morphological alterations. First: hyperplasia/enlargement of synovial lining cell layer. Second: activation of resident cells/synovial stroma. Third: inflammatory infiltration. All defined histopathological qualities are graded from absent (0), slight (1) and moderate (2) to strong (3), with summaries ranging from 0 to 9. 0 to 1 corresponds to no synovitis (inflammatory grade = 0), 2 to 3 to a slight synovitis (inflammatory grade 1), 4 to 6 to a moderate synovitis (inflammatory grade 2), and 7 to 9 to a strong synovitis (inflammatory grade 3). Using this score, we analyzed 308 random specimens of synovial tissue from degenerative (osteoarthritis (OA)) and inflammatory joint diseases - reactive arthritis (ReA), psoriasis arthritis (PA) and rheumatoid arthritis (RA) - as well as synovial tissue from healthy individuals. The mean grade given to synovitis of RA turned out to be significantly higher than the mean grade of OA (p < 0.0005) and of healthy controls (p < 0.0005). On the contrary, no significant differences could be found between the mean grades of synovitis scores from patients with RA and those with PA and ReA. Another comparison between RA-synovitis types I and II according to the Stiehl classification resulted in type I (p < 0.0005), showing significantly higher values of inflammatory infiltration, and type II (p = 0.037), showing significantly higher values of stroma activation. Since in OA, synovitis is regarded as a result of degenerative cartilage destruction whereas in inflammatory joint diseases (RA, PA, ReA), synovitis is regarded to be the cause of cartilage destruction, it can be concluded that scores with considerable high values indicate the pathogenetic potential of synovitis and that the inflammatory score may be helpful in estimating the destructive potential of synovitis at the same time. Furthermore, the comparison of the score data with the Stiehl RA-synovitis types shows that the score enables us to discriminate the morphological peculiarities of the synovitis types. In experimental pathology, it could provide standardized information on molecular synovial tissue analyses where a correlation of molecular with morphological data is essential. In diagnostic pathology, this synovitis score (in combination with other typing systems) could provide basic and standardized information concerning the degree of inflammatory alterations in synovial tissue.
Arthritis↗
Diversity of gene expression in adenocarcinoma of the lung.
The global gene expression profiles for 67 human lung tumors representing 56 patients were examined by using 24,000-element cDNA microarrays. Subdivision of the tumors based on gene expression patterns faithfully recapitulated morphological classification of the tumors into squamous, large cell, small cell, and adenocarcinoma. The gene expression patterns made possible the subclassification of adenocarcinoma into subgroups that correlated with the degree of tumor differentiation as well as patient survival. Gene expression analysis thus promises to extend and refine standard pathologic analysis.
Adenocarcinoma↗
The American Brachytherapy Society recommendations for brachytherapy of soft tissue sarcomas.
PURPOSE: This report presents the American Brachytherapy Society (ABS) guidelines for the use of brachytherapy for patients with soft tissue sarcoma. METHODS AND MATERIALS: Members of the ABS with expertise in soft tissue sarcoma formulated brachytherapy guidelines based upon their clinical experience and a review of the literature. The Board of Directors of the ABS approved the final report. RESULTS: Brachytherapy used alone or in combination with external beam irradiation is an established means of safely providing adjuvant local treatment after resection for soft tissue sarcomas in adults and in children. Brachytherapy options include low dose rate techniques with iridium 192 or iodine 125, fractionated high dose rate brachytherapy, or intraoperative high dose rate therapy. Recommendations are made for patient selection, techniques, dose rates, and dosages. Complications and possible interventions to minimize their occurrence and severity are reviewed. CONCLUSION: Brachytherapy represents an effective means of enhancing the therapeutic ratio, offering both biologic and dosimetric advantage in the treatment of patients with soft tissue sarcoma. The treatment approach used depends upon the institution, physician expertise, and the clinical situation. Guidelines are established for the use of brachytherapy in the treatment of soft tissue sarcomas in adults and in children. Practitioners and cooperative groups are encouraged to use these guidelines to formulate their treatment and dose-reporting policies. These guidelines will be modified, as further clinical results become available.
Adult↗
Overexpression of c-erbB2 protein correlates with disease-stage and chromosomal gain at the c-erbB2 locus in non-small cell lung cancer.
Overexpression of the c-erbB2 protein is observed in a variety of malignancies including non-small cell lung cancer (NSCLC). We aimed to determine the rate of c-erbB2-overexpression in our tumour collection and to clarify its correlation with the chromosomal status at the c-erbB2 locus 17q21 in NSCLC. Eighty-nine NSCLC were analysed immunohistochemically using a polyclonal c-erbB2 antibody (DAKO). The staining was scored according to the guidelines of the Clinical Trial Assay recommendations (0-3+). Of these, 44 cases were also analysed by comparative genomic hybridisation (CGH). Overexpression was observed in 37% of the cases (score>1) which was associated with higher disease stages and a positive nodal status in adenocarcinomas. Chromosomal gains at 17q21 were clearly correlated with overexpression of the gene (P=0.009). In addition, there was a highly significant correlation between the c-erbB2 expression comparing the whole section immunostaining analysis and a 127 lung tumour tissue array which included 74 of the 89 cases that were analysed by the classical procedure. We conclude that c-erbB2 is a marker of tumour progression in NSCLC which can be observed on protein level and reflects chromosomal alterations at 17q21.
Adult↗
Towards a genetic-based classification of human lung cancer.
Lung cancer is a highly aggressive neoplasm which is reflected by a multitude of genetic aberrations being detectable on the chromosomal and molecular level. In order to understand this seemingly genetic chaos, we performed Comparative Genomic Hybridisation (CGH) in a large collective of human lung carcinomas investigating different tumor entities as well as multiple individual tumour specimens of single patients. Despite the considerable genetic instability being reflected by the well known morphological heterogeneity of lung cancer the comparison of different tumour groups using custom made computer software revealed recurrent aberration patterns and highlighted chromosomal imbalances that were significantly associated with morphological histotypes and biological phenotypes. Specifically we identified imbalances in NSCLC being associated with metastasis formation which are typically present in SCLC thus explaining why the latter is such an aggressive neoplasm characterized by widespread tumor dissemination. Based on the genetic data a new model for the development of SCLC is presented. It suggests that SCLC evolving from the same stem cell as NSCLC should be differentiated into primary and secondary tumors. Primary SCLC corresponding to the classical type evolved directly from an epithelial precursor cell. In contrast, secondary SCLC correlating with the combined SCLC develops via an NSCLC intermediate. In addition, we established libraries of differentially expressed genes from different human lung cancer types to identify new candidate genes for several of the chromosomal subregions identified by CGH. In this review, we summarise the status of our results aiming at a refined classification of lung cancer based on the pattern of genetic aberrations.
Carcinoma, Non-Small-Cell Lung↗
Analysis of the DMBT1 gene in carcinomas of the respiratory tract.
Loss of chromosome 10q is a critical step during the progression and metastasis formation of lung cancer. We recently defined 3 distinct regions of allelic imbalances and considered the DMBT1 gene at 10q25-q26 an interesting candidate for the most telomeric region. Therefore, we investigated DMBT1 in 25 cancer cell lines and 39 primary tumors of the respiratory tract. The analysis by RT-PCR and Northern blot hybridization revealed that the gene is expressed in all tumors and cell lines and diminished in the SCLC line H187, indicating that RT-PCR is critical when used as the single method for the evaluation of gene expression. No mutations were found by SSCP analysis of the cDNA and the partially known genomic sequence. Similarly, Southern blot hybridization was unable to detect homozygous deletions. Allelotyping of the markers D10S587, D10S1708 and D10S1723 located near or within the DMBT1 gene did not reach the peak incidence of the 3 minimally deleted regions that we recently defined. In summary, our data do not confirm previous findings reporting frequent loss of DMBT1 expression in lung cancer. However, they strengthen the notion that the responsible gene on chromosome 10q25-q26 mediating tumor progression and metastasis formation in respiratory tract cancer remains enigmatic.
Agglutinins↗
Patterns of chromosomal imbalances in invasive breast cancer.
Invasive breast carcinomas are characterized by a complex pattern of chromosomal alterations. We applied comparative genomic hybridization (CGH) to analyze 105 primary breast carcinomas using histograms to indicate the incidence of DNA imbalances of tumor subgroups and difference histograms to compare invasive ductal carcinomas (IDC) with lobular carcinomas (ILC), well and poorly differentiated carcinomas (G1/G3) and estrogen receptor-positive and -negative tumors (ER(+)/ER(-)). Only single imbalances showed a higher incidence in ILC compared with IDC, i.e., gains on chromosomes 4 and 5q13-q23 as well as deletions on chromosomes 6q, 11q14-qter, 12p12-pter, 16q, 17p, 18q, 19, and 22q. Of these, particularly gains of 4 and losses at 16q21-q23, and 18q12-q21 were statistically significant. For most loci, IDC showed more alterations providing a genetic correlate to the fact that ductal carcinoma overall is associated with a worse prognosis than ILC. Of these, many imbalances showing statistical significance were also observed in G3 and ER(-) tumors, i.e., deletions at 2q35-q37, 3p12-p14, 4p15-p16, 5q, 7p15, 8p22-p23, 10q, 11p, 14q21-q31, 15q, and gains at 2p, 3q21-qter, 6p, 8q21-qter, 10p, 18p11-q11, and 20q, suggesting that they contribute to a more aggressive tumor phenotype. By contrast, gains on chromosome 5q13-q23 as well as deletions at 6q, 16q and 22q were more prevalent in G1 and ER(+) tumors. The ratio profiles of all cases as well as histograms are accessible at our CGH online tumor database at http://amba.charite.de/cgh. Our results highlight distinct chromosomal subregions for cancer-associated genes. In addition, these imbalances may serve as markers for a genetic classification of invasive breast cancer.
Adult↗
Gene expression profiling of advanced lung cancer.
Lung cancer is a highly aggressive neoplasm with 85% mortality. To identify new tumor-associated genes, we compared the expression profile of a primary metastasizing adenocarcinoma with normal airway epithelial cells. Two cDNA libraries of up- and downregulated genes were generated, comprising 253 and 299 clones, respectively. The sequence analysis revealed 205 different known genes and 314 cDNA fragments of unknown functions. Northern-blot analysis of 167 clones confirmed differential expression in 58%, and indicated a similar expression pattern in additional lung-cancer cell lines for selected clones, strengthening the value of this model for the identification of new candidate genes in lung carcinogenesis.
Chromosome Mapping↗