Biomedical subjects

C Behrens

Publications and source records attributed to C Behrens.

At least 19 recordsLinked to original sources

PubMed2005

Cellular and reticular variants of haemangioblastoma revisited: a clinicopathologic study of 88 cases.

The presence of histological variants of haemangioblastoma is well established, but data on the prognostic implications of histological subtyping are missing. We thus characterized clinical factors associated with histological subtypes, that is, of the cellular and reticular variant of haemangioblastoma, in a series of 88 consecutive primary haemangioblastomas of the central nervous system. Ten haemangioblastomas were classified as 'cellular' according to Cushing and Bailey. As compared to the more common 'reticular' variant (n = 78), the proportion of tumours containing glial fibrillary acidic protein-positive tumour cells (80% vs. 7%), as well as median Ki67 (MIB1) proliferation indices [4% (quartiles: 1-8%) vs. < 1% (<1-2%)], was significantly higher in cellular haemangioblastomas (P < 0.01). Recurrences were more frequent in the cellular variant [2/8 (25%) vs. 4/51 (8%)]. Kaplan-Meier analysis confirmed a significantly higher probability of recurrence in the cellular variant (Log-Rank test P < 0.01). Cox regression analysis not only confirmed the well established association of von Hippel-Lindau disease with tumour recurrence (P < 0.01), but also revealed an independent effect of histological subtype on the probability of recurrence (P < 0.05), whereas no significant influence of age, sex or tumour location was observed. To conclude, the results from this retrospective study suggest that histological subtyping of haemangioblastomas has prognostic implications and might contribute to identify patients at risk for recurrence.

Adolescent↗

PubMed2004

Mesalazine (5-aminosalicylic acid) micropellets show similar efficacy and tolerability to mesalazine tablets in patients with ulcerative colitis--results from a randomized-controlled trial.

BACKGROUND: Formulations containing 5-aminosalicylic acid, such as mesalazine, are the gold standard of treatment for mild-to-moderate ulcerative colitis. Current oral regimens require the use of large tablets and frequent dosing to reach the recommended treatment dose. Mesalazine micropellets were designed to allow less frequent dosing in an easier to swallow formulation. AIM: To compare the efficacy of mesalazine micropellets with the tablet formulation in patients with mild-to-moderate ulcerative colitis. METHODS: This phase 2, double-blind, active-controlled, parallel-group, multiple dose clinical trial randomized 362 patients to either mesalazine micropellets or tablets, at a dosage of 3 g/day. The primary efficacy end-point was the incidence of clinical remission within 8 weeks, defined as the sum of clinical activity index components 1-4 (CAI(C1-4)) < or = 2. RESULTS: CAI(C1-4) decreased significantly in both treatment groups within 8 weeks. The micropellet formulation showed confirmatory non-inferiority with statistical significance compared with the tablet formulation, with regard to the incidence of clinical remission (odds ratio in according-to-protocol population 1.008; 95% CI: 0.623-1.632). There was no significant difference in the incidence of adverse events. CONCLUSIONS: The mesalazine micropellet formulation is as effective as tablets in patients with mild-to-moderate ulcerative colitis, enabling a larger dose to be taken comfortably and conveniently, thereby potentially improving patient compliance, treatment response and quality of life.

Administration, Oral↗

PubMed2003

Combined scintigraphic and pharmacokinetic investigation of enteric-coated mesalazine micropellets in healthy subjects.

BACKGROUND: There is a growing clinical trend to increase the daily dose of mesalazine, which leads to significant compliance issues associated with multiple dosings of current preparations. AIM: To examine the gastrointestinal performance and systemic exposure of a 1.5 g sachet (micropellets) mesalazine formulation, compared with three enteric-coated tablets (500 mg each, Claversal). METHODS: A randomized, two-way, cross-over pharmacoscintigraphic (scintigraphy plus pharmacokinetics) study and a two-way, cross-over, pharmacokinetic-only study were performed in 24 healthy volunteers (12 subjects per investigation). RESULTS: The relative bioavailability of mesalazine was 92% comparing micropellets with Claversal tablets, and the cumulative urine excretion was c. 26% for both preparations, suggesting comparable systemic exposure for the two types of preparation. In the majority of subjects, drug release from the micropellet formulation occurred predominantly in the terminal ileum and ascending colon. The Claversal tablets disintegrated in comparable intestinal sites, albeit at slightly later time points than the micropellets, principally due to slower gastric emptying for the single-unit formulation. CONCLUSION: The 1.5 g micropellet formulation offers comparable delivery properties to the marketed tablets, but with greater convenience of dosing.

Administration, Oral↗

PubMed2003

Subacute sclerosing panencephalitis in two brothers.

We report the occurrence of subacute sclerosing panencephalitis (SSPE) in two brothers two years after measles infection. The diagnosis was confirmed by compatible data from medical history, occurrence of autochthonic measles virus (MV) IgG production in the central nervous system (CNS), and pathognomonic EEG changes. Pathogenetically, SSPE is caused by a genome mutation of intracellularly persisting MV, causing viral nucleocapsides to accumulate in the brain cells. A specific predisposing immune defect is not known. The occurrence of two cases in one family is suggestive of a genetic predisposing factor.

Child↗

PubMed2001

Impaired hyperpolarization in regenerated endothelium after balloon catheter injury.

Ca(2+)-activated K(+) (K(Ca)) channels control endothelial Ca(2+) homeostasis and the formation of vasodilators. After angioplasty, dysfunction of the regenerated endothelium leads to abnormal vasoregulation. In this study, we tested the expression and function of K(Ca) channels in regenerated endothelium at 6 weeks after balloon catheter injury of rat carotid arteries (CAs) by using single-cell reverse transcription-polymerase chain reaction, patch-clamp techniques, and analysis of vasoreactivity. In single regenerated endothelial cells (ECs), the percentage of ECs expressing the K(Ca) genes, rSK3 (12+/-8%) and rIK1 (22+/-9%), was significantly lower compared with the percentage of native ECs expressing these genes (rSK3 58+/-8%, rIK1 64+/-10%). In patch-clamp experiments, K(Ca) currents and acetylcholine-induced hyperpolarization were markedly reduced in regenerated ECs (shift of membrane potential -6+/-3 mV) compared with those in native ECs (shift of membrane potential -21+/-5 mV). In pressure myograph experiments, acetylcholine-induced dilation was impaired in reendothelialized CAs compared with normal CAs. Intraluminal application of the K(Ca) blocker apamin and charybdotoxin inhibited dilation by 30% in normal CAs but was without effect in reendothelialized CAs. Intraluminal application of 1-ethyl-2-benzimidazolinone (100 micromol/L), an opener of K(Ca) channels, evoked dilation by 29% in normal CAs but had no effect in reendothelialized CAs. In conclusion, the impaired expression of K(Ca) channels in regenerated endothelium results in defective hyperpolarization and impaired dilation. Thus, the impaired K(Ca) channel function contributes to functional alterations of regenerated endothelium after angioplasty.

Acetylcholine↗

PubMed2001

Molecular analysis of synchronous and metachronous tumors of the lung: impact on management and prognosis.

Patients with pulmonary neoplasms have an increased risk for developing a second tumor of the lung, either at the same time or different times. It is important to determine if the second tumor represents an independent primary tumor (ie, a synchronous or a metachronous tumor, depending on whether it is present at the same time or a later time) or recurrence/metastasis, because it will significantly change the management and prognosis. Because the two tumors from the same patient are often morphologically similar, histologic examination alone may not be sufficient to distinguish between the two possibilities. We have attempted to approach this problem by microdissecting malignant cells and comparing patterns of loss of heterozygosity of multiple genes and chromosomal loci between paired tumors. We found that primary tumors of the lung and their metastasis share nearly identical patterns of loss of heterozygosity. In contrast, most synchronous and metachronous tumors as defined by the current arbitrary criteria appeared to be genetically different; therefore, they likely represented independent primary tumors. Rare synchronous tumors had similar genetic profiles, raising the possibility of recurrence/metastasis. Our data suggest that molecular analysis can help fingerprint tumors and has the potential to significantly impact management and prognosis of patients.

Adenocarcinoma↗

PubMed2000

The relation between ion pair structures and reactivities of lithium cuprates

From Li+ well-solvating solvents or complex ligands such as THF, [12]crown-4, amines etc., lithium cuprates R2CuLi(*LiX) crystallise in a solvent-separated ion pair (SSIP) structural type (e.g. 10). In contrast, solvents with little donor qualities for Li+ such as diethyl ether or dimethyl sulfide lead to solid-state structures of the contact ion pair (CIP) type (e.g. 11). 1H,6Li HOESY NMR investigations in solutions of R2CuLi(*LiX) (15, 16) are in agreement with these findings: in THF the SSIP 18 is strongly favoured in the equilibrium with the CIP 17, and in diethyl ether one observes essentially only the CIP 17. Salts LiX (X=CN, Cl, Br, I, SPh) have only a minor effect on the ion pair equilibrium. These structural investigations correspond perfectly with Bertz's logarithmic reactivity profiles (LRPs) of reactions of R2CuLi with enones in diethyl ether and THF: the faster reaction in diethyl ether is due to the predominance of the CIP 17 in this solvent, which is the reacting species; in THF only little CIP 17 is present in a fast equilibrium with the SSIP 18. A kinetic analysis of the LRPs quantifies these findings. Recent quantum-chemical studies are also in agreement with the CIP 17 being the reacting species. Thus a uniform picture of structure and reactivity of lithium cuprates emerges.

Journal Article↗

PubMed2000

Evolutionarily conserved binding of ribosomes to the translocation channel via the large ribosomal RNA.

During early stages of cotranslational protein translocation across the endoplasmic reticulum (ER) membrane the ribosome is targeted to the heterotrimeric Sec61p complex, the major component of the protein-conducting channel. We demonstrate that this interaction is mediated by the 28S rRNA of the eukaryotic large ribosomal subunit. Bacterial ribosomes also bind via their 23S rRNA to the bacterial homolog of the Sec61p complex, the SecYEG complex. Eukaryotic ribosomes bind to the SecYEG complex, and prokaryotic ribosomes to the Sec61p complex. These data indicate that rRNA-mediated interaction of ribosomes with the translocation channel occurred early in evolution and has been conserved.

Animals↗

PubMed2000

High resolution chromosome 3p allelotyping of human lung cancer and preneoplastic/preinvasive bronchial epithelium reveals multiple, discontinuous sites of 3p allele loss and three regions of frequent breakpoints.

Allele loss involving chromosome arm 3p is one of the most frequent and earliest known genetic events in lung cancer pathogenesis and may affect several potential tumor suppressor gene regions. To further study the role of chromosome 3p allele loss in the pathogenesis of lung cancer, we performed high resolution loss of heterozygosity (LOH) studies on 97 lung cancer and 54 preneoplastic/preinvasive microdissected respiratory epithelial samples using a panel of 28 3p markers. Allelic losses of 3p were detected in 96% of the lung cancers and in 78% of the preneoplastic/preinvasive lesions. The allele losses were often multiple and discontinuous, with areas of LOH interspersed with areas of retention of heterozygosity. Most small cell lung carcinomas (91%) and squamous cell carcinomas (95%) demonstrated larger 3p segments of allele loss, whereas most (71%) of the adenocarcinomas and preneoplastic/preinvasive lesions had smaller chromosome areas of 3p allele loss. There was a progressive increase in the frequency and size of 3p allele loss regions with increasing severity of histopathological preneoplastic/preinvasive changes. In analyses of the specific parental allele lost comparing 42 preneoplastic/preinvasive foci with those lost in the lung cancer in the same patient (n = 10), the same parental allele was lost in 88% of 244 comparisons for 28 3p markers (P = 1.2 x 10(-36) for this occurring by chance). This indicates the occurrence of allele-specific loss in these foci similar to that seen in the tumor by a currently unknown mechanism. Analysis of all of the data indicated multiple regions of localized 3p allele loss including telomere-D3S1597, D3S1111-D3S2432, D3S2432-D3S1537, D3S1537, D3S1537-D3S1612, D3S4604/Luca19.1-D3S4622/Luca4.1, D3S4624/Luca2.1, D3S4624/Luca2.1-D3S1582, D3S1766, D3S1234-D3S1300 (FHIT/FRA3B region centered on D3S1300), D3S1284-D3S1577 (U2020/DUTT1 region centered on D3S1274), and D3S1511-centromere. A panel of six markers in the 600-kb 3p21.3 deletion region showed loss in 77% of the lung cancers, 70% of normal or preneoplastic/preinvasive lesions associated with lung cancer, and 49% of 47 normal, mildly abnormal, or preneoplastic/preinvasive lesions found in smokers without lung cancer; however, loss was seen in 0% of 18 epithelial samples from seven never smokers. The 600-kb 3p21.3 region and the 3p14.2 (FHIT/FRA3B) and 3p12 (U2020/DUTT1) regions were common, independent sites of breakpoints (retention of heterozygosity by some markers and LOH by other markers in the immediate region). We conclude that 3p allele loss is nearly universal in lung cancer pathogenesis; involves multiple, discrete, 3p LOH sites that often show a "discontinuous LOH" pattern in individual tumors; occurs in preneoplastic/preinvasive lesions in smokers with and without lung cancer (multiple lesions often lose the same parental allele); frequently involves breakpoints in at least three very small defined genomic regions; and appears to have allele loss and breakpoints first occurring in the 600-kb 3p21.3 region. These findings are consistent with previously reported LOH studies in a variety of tumors showing allele loss occurring by mitotic recombination and induced by oxidative damage.

Adult↗

PubMed2000

Two identical triplet sisters carrying a germline BRCA1 gene mutation acquire very similar breast cancer somatic mutations at multiple other sites throughout the genome.

Monozygotic twins, each of whom has breast cancer, offer a natural study population for gene-environmental interactions as causation of cancer, because they are genetically identical. If heritable factors play a large role in the origin of a neoplasm, disease concordance should be significant in monozygotic twins. Two monozygotic triplet sisters carrying a germline BRCA1 gene mutation (5382insC) who both developed breast cancer at early ages were studied for loss of heterozygosity (LOH) in their microdissected, paraffin-embedded tumors along with control blood and stromal breast tissue at 19 chromosomal arms using 161 microsatellite markers. Microdissected areas of normal lobular and ductal epithelium and ductal in situ carcinoma were also studied for LOH using a subset of microsatellite markers. The mother's DNA (extracted from peripheral blood lymphocytes) was analyzed to determine the parental allele under LOH in each case. Both tumors demonstrated similar histologic features suggestive of a secretory variant of ductal carcinoma. The tumors from both sisters had similar overall LOH frequency expressed by the fractional allelic loss (FAL) indices (0.56 vs. 0.60) and demonstrated concordance for loss or retention at 82 of 97 informative markers (85% correlation). In addition, detailed mapping analysis of several chromosomal arms revealed that identical breakpoints were detected in both tumors at several chromosome regions. Finally, in both sisters' tumors, when a chromosome exhibited allelic loss, all of the markers exhibited LOH of the same parental allele even when there were intervening regions of retention of heterozygosity. In contrast, 17 archival sporadic breast carcinomas demonstrated a wide range of FAL indexes and highly individual patterns of LOH. Our findings support the hypothesis that inherited factors play a role in the development of the multiple somatic deletions occurring in breast carcinomas. Whether one of these factors is the mutant BRCA1 allele or some other gene(s) remains to be determined. Genes Chromosomes Cancer 28:359-369, 2000.

Adult↗

PubMed2000

The dying cancer patient.

Cancer patients often die with serious unrelieved symptoms causing a distressing death for them and needless added suffering for their families. Many physicians have not been trained to care for the dying patient. This chapter reviews the common symptoms and describes the methods to control them and support the patient and family through this difficult time. These symptoms are so characteristic of the dying process that all physicians should recognize them, be skilled in providing appropriate care, and prepare for problems that may arise.

Attitude to Death↗

PubMed2000

Molecular changes in the bronchial epithelium of patients with small cell lung cancer.

To better understand the pathways involved in the pathogenesis of small cell lung carcinoma (SCLC), we compared the patterns of molecular changes present in these tumors and their accompanying bronchial epithelium with those present in the other two major types of lung cancer [squamous cell carcinoma (SQC) and adenocarcinoma (ADC)]. We obtained DNA from 68 microdissected invasive lung tumors (22 SCLCs, 21 ADCs, and, 25 SQCs) and 119 noncontiguous foci of histologically normal or hyperplastic epithelia from 10 tumors of each histological type. We determined loss of heterozygosity and microsatellite alterations at 12 chromosomal regions frequently deleted in lung cancers using 19 polymorphic microsatellite markers. Our major findings are as follows: (a) the mean index of allelic loss in SCLC (0.85) and SQC (0.71) tumors was higher than that in ADC (0.39) tumors; (b) although there was considerable overlap, each tumor type had a characteristic pattern of allelic loss; (c) most samples of bronchial epithelium accompanying SCLC (90%) had allelic loss at one or more loci compared with samples accompanying SQC (54%) or ADC (10%); (d) the mean index of allelic loss was much higher in bronchial epithelial samples from SCLC (0.27) than in those from SQC (0.08) or ADC (0.01); and (e) although the mean indices of microsatellite alterations in the tumor types were similar, the bronchial epithelial samples accompanying SCLC had a 10-fold higher mean index (0.063) than those accompanying SQC (0.006) or ADC (0.006). Our findings indicate that extensive genetic damage in the accompanying normal and hyperplastic bronchial epithelium is characteristic of SCLC tumors and suggest major differences in the pathogenesis of the three major lung cancer types.

Adenocarcinoma↗

PubMed2000

Molecular changes in second primary lung and breast cancers after therapy for Hodgkin's disease.

The risk of lung and breast cancer is significantly increased after therapy for Hodgkin's disease (HD), but there are few data that describe the molecular profiles of these tumors. We investigated the genetic abnormalities in second primary lung (n = 19) and breast cancers (n = 19) that follow therapy for HD ("post-HD cancers") and compared these with changes observed in corresponding tumor types (57 lung and 20 breast cancers) arising in the general population ("sporadic cancers"). DNA obtained from archival tissues was examined using PCR-based analyses for loss of heterozygosity and microsatellite alterations (MAs) at several chromosomal regions, TP53 and K-ras gene mutations, and frameshift mutations at minisatellite sequences at the coding regions of several genes (TGF-betaRII, IGFIIR, BAX, hMSH6, and hMSH3). The occurrence of loss of heterozygosity at all chromosomal regions taken together and frequencies at most individual areas were similar for the post-HD and sporadic cancers for both lung and breast sites. The overall frequency of MAs in the post-HD tumors was substantially greater (lung, 2.4-fold, P = 0.004; breast, 4.2-fold, P = 0.16) than that in the respective sporadic cancers. No differences in the pattern of TP53 and K-ras mutations were detected between post-HD and sporadic cancers. No mutations were detected at the minisatellite sequences examined. MAs, which reflect widespread genomic instability, occur at greatly increased frequency in post-HD lung and breast cancers. Although the mechanisms underlying the development of increased MAs are unknown, they have been associated with immunosuppression and radiation exposure. Future research should address the role that MAs, as well as other influences, may play in the development of neoplasias that occur after therapy for HD.

Adenocarcinoma↗

PubMed1999

K-ras and p53 mutations in the pathogenesis of classical and goblet cell carcinoids of the appendix.

BACKGROUND: Mutations in the K-ras oncogene and the p53 tumor suppressor gene are present in approximately 50% of colonic adenocarcinomas. Goblet cell carcinoids (GCCs) are uncommon neoplasms of the appendix that appear to be intermediate between carcinoid tumors and adenocarcinomas, both histologically and biologically. The current study was undertaken to examine the role of p53 and K-ras mutations in the pathogenesis of GCCs and typical carcinoids (TCs) of the appendix. METHODS: Archival materials from 22 GCCs and 18 TCs were analyzed. K-ras mutations in codons 12, 13, and 61 were studied by a polymerase chain reaction (PCR) based designed restriction fragment length polymorphism method using mismatched nested primers. Mutations in exons 5-8 of the p53 tumor suppressor gene were analyzed in 16 GCCs and 18 TCs by PCR and single-strand conformational polymorphism followed by direct sequencing. Immunostains for p53 and chromogranin were performed in all cases. RESULTS: K-ras mutations and nuclear accumulation of p53 by immunohistochemistry were not detected in any of the GCCs or TCs. p53 mutations were found in 4 of 16 GCCs (25%) and 8 of 18 TCs (44%). Immunoreactivity for chromogranin was seen in the vast majority of GCCs and TCs. CONCLUSIONS: p53 mutations appear to play a role in the pathogenesis of some GCCs and in approximately 50% of TCs of the appendix, whereas mutations in the K-ras oncogene do not appear to be important in the development of these tumors. The minimal cytologic atypia, low incidence of metastases, and lack of K-ras mutations in goblet cell appendiceal neoplasms suggest that they are variants of carcinoid tumors. Our findings lend support to the recommendation that the therapeutic guidelines applied to TCs of the appendix should be the same for GCCs.

Appendiceal Neoplasms↗

PubMed1999

Allelic losses at chromosome 8p21-23 are early and frequent events in the pathogenesis of lung cancer.

Allelic losses on the short arm of chromosome 8 (8p) have been reported as frequent events in several cancers, including lung. However, no comprehensive mapping analysis of chromosome 8p in lung cancer tumors has been performed, and no data are available about the stage at which these abnormalities occur during the multistage development of lung cancer. Using 26 microsatellite markers, we mapped the chromosome 8 regions frequently deleted in lung cancer in 13 small cell carcinoma and 17 non-small cell lung carcinoma cell lines and in 68 microdissected archival primary lung tumors (22 small cell lung carcinomas, 25 squamous cell carcinomas, and 21 adenocarcinomas). We also studied the role of 8p deletions in lung cancer pathogenesis by examining 95 microdissected normal epithelium and preneoplastic samples from 11 surgically resected squamous cell lung carcinomas and from 58 bronchoscopy biopsy samples obtained from 31 current and former smokers. High frequencies of deletions at 8p21-23 regions were detected in lung cancer cell lines and in primary lung tumors. Deletions commenced early during the multistage development of lung cancer at the hyperplasia/metaplasia stage in cancer patients and in smokers without cancer. Allelic deletions persisted for up to 48 years after smoking cessation. There was a progressive increase of the overall 8p21-23 loss of heterozygosity frequency and in the size of the deleted region with increasing severity of histopathological preneoplastic changes. In epithelial samples from resected squamous cell lung carcinomas, we compared the presence of loss of heterozygosity at 8p21-23 with deletions at chromosomes 3p and 9p. Of interest, the pattern of deletions was not random, and 8p21-23 allelic losses always followed 3p deletions and usually followed 9p deletions. We conclude that 8p21-23 deletions are frequent and early events in the pathogenesis of lung carcinomas.

Adult↗

PubMed1999

Sequential molecular abnormalities are involved in the multistage development of squamous cell lung carcinoma.

To understand the molecular pathways involved in the pathogenesis of squamous cell lung carcinoma, we obtained DNA from 94 microdissected foci from 12 archival surgically resected tumors including histologically normal epithelium (n=13), preneoplastic lesions (n=54), carcinoma is situ (CIS) (n=15) and invasive tumors (n=12). We determined loss of heterozygosity (LOH) at 10 chromosomal regions (3p12, 3p14.2, 3p14.1-21.3, 3p21, 3p22-24, 3p25, 5q22, 9p21, 13q14 RB, and 17p13 TP53) frequently deleted in lung cancer, using 31 polymorphic microsatellite markers, including 24 that spanned the entire 3p arm. Our major findings are as follows: (1) Thirty one percent of histologically normal epithelium and 42% of mildly abnormal (hyperplasia/metaplasia) specimens had clones of cells with allelic loss at one or more regions; (2) There was a progressive increase of the overall LOH frequency within clones with increasing severity of histopathological changes; (3) The earliest and most frequent regions of allelic loss occurred at 3p21, 3p22-24, 3p25 and 9p21; (4) The size of the 3p deletions increased with progressive histologic changes; (5) TP53 allelic loss was present in many histologically advanced lesions (dysplasia and CIS); (6) Analyses of 58 normal and non-invasive foci having any molecular abnormality, indicated that 30 probably arose as independent clonal events, while 28 were potentially of the same clonal origin as the corresponding tumor; (7) Nevertheless, when the allelic losses in the 30 clonally independent lesions and their clonally unrelated tumors were compared the same parental allele was lost in 113 of 125 (90%) of comparisons. The mechanism by which this phenomenon (known as allele specific mutations) occurs is unknown; (8) Four patterns of allelic loss in clones were found. Histologically normal or mildly abnormal foci had a negative pattern (no allelic loss) or early pattern of loss while all foci of CIS and invasive tumor had an advanced pattern. However dysplasias demonstrated the entire spectrum of allelic loss patterns, and were the only histologic category having the intermediate pattern. Our findings indicate that multiple, sequentially occurring allele specific molecular changes commence in widely dispersed, apparently clonally independent foci, early in the multistage pathogenesis of squamous cell carcinomas of the lung.

Aged↗

PubMed1999

Molecular abnormalities associated with endocrine tumors of the uterine cervix.

Objective. We studied the molecular abnormalities involved in the pathogenesis of endocrine tumors of the uterine cervix. Methods. We obtained DNA from precisely microdissected archival tissue from 15 endocrine tumors of the uterine cervix, consisting of 5 carcinoids (1 typical, 4 atypical), 2 large cell neuroendocrine carcinomas, and 8 small cell carcinomas. We investigated the presence of high-risk (types 16 and 18) and intermediate-risk (types 31 and 33) human papilloma virus (HPV) sequences, TP53 and K-ras gene mutations, and loss of heterozygosity (LOH) at 9 genes/chromosomal regions, including 3p14.2/FHIT, 3p14-p21, 3p21, 3p22-p24, 5q21-q22/APC-MCC region, 9p21/CDKN2, 11q23/MEN1, 13q/RB, and 17p/TP53. Results. HPV sequences were detected in 8 (53%) tumors, HPV 16 in 2 cases, and HPV 18 in 2 cases. LOH at 9p21 (43%) and localized 3p deletions (47%) were the most frequent allelic losses found. Allelic losses at 5q21-q22/APC-MCC region, 11q23/MEN1, and 13q/RB were infrequent. TP53 gene mutations were detected in 7 (47%) tumors (1 atypical carcinoid and 6 carcinomas). HPV sequences were demonstrated in 4 of the 7 cases with TP53 gene mutations. No K-ras mutations were detected. Conclusion. The molecular changes present in endocrine tumors of the uterine cervix have distinct features. They incorporate those present in the neuroendocrine tumors of the lung (high frequency of TP53 gene abnormalities and 9p21 deletions) with those detected in squamous cell carcinomas of the cervix (high-risk HPV sequences and localized 3p deletions).

Carcinoid Tumor↗

PubMed1999

Comparison of molecular changes in cervical intraepithelial neoplasia in HIV-positive and HIV-indeterminate subjects.

OBJECTIVE: HIV infection is associated with an increased incidence of cervical malignancy and its precursor lesions (CIN, cervical intraepithelial neoplasia) compared with the general population. We studied the molecular abnormalities in the development of HIV-associated CIN and compared them with those present in CINs arising in HIV-indeterminate subjects ("sporadic CIN"). METHODS: We investigated the presence of human papilloma virus (HPV) sequences, loss of heterozygosity (LOH), and microsatellite alterations (MAs) at five 3p chromosomal regions using 17 polymorphic markers in precisely microdissected archival tissues from 16 HIV-positive CINs and compared them with those present in 39 sporadic CINs. RESULTS: HPV sequences were detected in 36 of 55 (66%) CIN lesions, and high-risk oncogenic strains (HPV 16 and 18) accounted for 15 of them. No differences in the HPV frequencies were found between HIV-associated and sporadic CINs. Allelic losses at one or more chromosome 3p regions were frequently detected in CIN lesions (49%). The overall frequency of 3p LOH and the frequencies at all individual regions were similar in HIV-associated and sporadic CINs. The frequency of MA present in the HIV-associated CIN cases (0.093) was sixfold greater than in sporadic CINs (0.014; P = 0.0001). At least 1 MA was present in 11 (69%) of 16 HIV-associated vs. 5 of 39 (13%) sporadic CIN (P = 0.0006). Molecular changes were independent of the presence of HPV sequences. CONCLUSION: Chromosome 3p deletions are frequently detected in the precursor lesions of cervical carcinoma (CIN) and there are no differences in the 3p LOH frequencies between HIV-associated and sporadic CIN lesions. Microsatellite alterations, which reflect widespread genomic instability, occur at greatly increased frequency in HIV-associated CIN. Although the mechanism underlying the development of increased MAs is unknown, it may play a crucial role in the development of many HIV-associated neoplasias.

DNA Probes, HPV↗