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Biomedical subjects

B A Werness

Publications and source records attributed to B A Werness.

At least 37 records · Page 2Linked to original sources
PubMed1998

Importance of lymph node metastases in primary peritoneal carcinoma.

BACKGROUND AND OBJECTIVES: The incidence and significance of lymph node involvement in patients with primary peritoneal adenocarcinoma (PPA) are unknown. The aim of the current study is to report on the incidence and significance of clinically or surgically detectable lymphadenopathy in women with PPA. METHODS: The study is a retrospective clinical review of patients with the confirmed diagnosis of PPA treated at Roswell Park Cancer Institute between 1982 and 1996. Patients with clinically or surgically detectable lymphadenopathy confirmed on histologic examination to be secondary to metastases from PPA were identified and compared to patients with negative lymph nodes with regard to clinicopathologic characteristics, treatment, response to treatment, and survival. RESULTS: Seventy-two patients with PPA were identified. Pelvic and periaortic lymph node biopsies or sampling were performed in 35% of the patients. In 8/72 patients (11%), lymphadenopathy was one of the presenting clinical or surgical findings. The clinicopathologic features, treatment, response to first-line chemotherapy, and estimated median overall survival were not different in patients with or without lymph node involvement (71.4% vs. 69.7%, P = 1.0, and 21.5 vs. 23.5 months, P = 0.14). CONCLUSIONS: Lymph node involvement is not an infrequent occurrence in patients with PPA and does not seem to be of adverse prognostic significance.

Adenocarcinoma↗
PubMed1998

Prognostic factors in extraovarian primary peritoneal carcinoma.

OBJECTIVE: To determine the pathological, clinical, and therapeutic factors which had prognostic significance in women with extraovarian primary peritoneal carcinoma (EOPPC). METHODS: A retrospective, clinicopathologic study was conducted of 75 women diagnosed with EOPPC. Diagnosis and assessment of prognostic pathological factors were based on the Gynecologic Oncology Group (GOG) criteria. Univariate and multivariate analyses were used to assess the following factors for their effect on overall survival: age, parity, presenting symptoms and signs, ascites, CA 125 level, history of oophorectomy, maximum ovarian dimension, histologic type, architectural and nuclear grades, number of mitosis and psammoma bodies, depth of ovarian invasion, estrogen and progesterone receptors (positive, negative), p53 overexpression (present, absent), performance status (GOG criteria), stage (FIGO criteria for ovarian cancer), debulking surgery (optimal versus suboptimal), first-line chemotherapy (platin-based without paclitaxel versus platin/paclitaxel), secondary cytoreduction, and second-line chemotherapy (paclitaxel-based versus no paclitaxel). RESULTS: The median overall survival of all patients was 23.5 months (95% CI 18.6, 39.8 months). The 5-year survival was 26.5% (SE 6.7%). p53 overexpression and estrogen and progesterone receptor positivity were demonstrated in 42.4, 50.0, and 6.3%, respectively. In univariate analysis, performance status, primary debulking surgery, stage, and age were significant on overall survival (P < 0.001, <0. 001, 0.004, and 0.012, respectively). In multivariate analysis, only performance status (P < 0.001) and primary debulking surgery (P = 0. 03) were independent prognostic factors. Conclusions. Overall survival in women with EOPPC is affected significantly by performance status and primary debulking surgery as independent variables. To improve survival, efforts should be made to achieve optimal tumor cytoreduction at primary surgery.

Adult↗
PubMed1998

Correlation of TP53 mutations and p53 expression in ovarian tumors.

To characterize the involvement of the TP53 tumor suppressor gene in ovarian cancer, mutation analysis of exons 2-11 of TP53 and immunodetection of its protein product, p53, were done in 48 ovarian tumors. Normally, p53 is not immunodetectable. Missense TP53 mutations have been reported to result in p53 accumulation and detection, but mutations generating premature stop codons have not. Mutations were identified in 19 of 41 malignant tumors but not in 5 benign tumors and 2 tumors of low malignant potential. Fifteen of the 19 tumors with mutations also stained positively by immunohistochemistry or Western blot or both. They included 11 missense mutations, 1 in-frame duplication (474ins6), and 3 frameshift mutations generating premature stop codons. The three tumors with frameshifts also had a wild-type TP53 allele and displayed normal size but not truncated p53 by Western blot. This indicates that these tumors express wild-type p53. The significance of TP53 mutations in the development of the three tumors is questionable unless there is a mechanism for inactivating wild-type p53. Nine of the 19 mutations found here, including the 3 frameshifts, were previously not reported in ovarian cancer. Thirteen of the 19 mutations were single nucleotide substitutions with 6 transitions and 7 transversions. The ratio of transversions to transitions (1.2) was different from literature reports (0.5) (P < 0.01). Thus, the spectrum of TP53 mutations in our study differed from other ovarian tumor reports. This difference may be due to population-based differences in the molecular epidemiology of TP53 mutations.

Blotting, Western↗
PubMed1998

Mutations in BRCA1 from fixed, paraffin-embedded tissue can be artifacts of preservation.

DNA isolated from paraffin-embedded tissues has been used for analysis of DNA alterations in disease states. Use of archival tissue can expedite the gathering of large numbers of specimens from rare disease subtypes that would take years to accumulate prospectively. Therefore, archival tissues from 70 ovarian cancer cases diagnosed before or at age 40 were retrieved for analysis of BRCA1 mutations. DNA was isolated from paraffin-embedded tissue of 70 ovarian cancer cases diagnosed before or at age 40. BRCA1 mutation analysis was conducted by single-strand conformation polymorphism analysis and DNA sequencing. Fifty-eight BRCA1 mutations were found in 34 of the 70 ovarian cancer cases. Twenty-two cases had one mutation each and 12 cases had multiple mutations. Multiple mutations found in histologically normal tissue of 2 cases were not present in matched tumor tissue. For another case, DNA from two separate blocks of normal tissue contained different mutations. These observations were anomalous and suggested that mutations detected in fixed tissues may be artifacts of tissue preservation and not present in the original unfixed tissues. To test this suggestion, blood was obtained from 2 patients for whom mutations were found in fixed, normal tissue. DNA from their unfixed lymphocytes did not contain the mutations found in fixed normal tissue. Thus, mutations found in fixed, paraffin-embedded tissues can be artifacts of tissue preservation. The reliability of DNA sequence data derived from such tissues must be questioned in the absence of corroborating data from unfixed tissues. This severely limits the use of fixed tissues as a source of DNA for retrospective research and for clinical genetic testing in families for which a disease-affected member is not alive.

Adult↗
PubMed1998

HsMCM2/BM28: a novel proliferation marker for human tumors and normal tissues.

HsMCM2/BM28 is a member of the family of minichromosome maintenance (MCM) proteins, which play a critical role in DNA replication by helping to ensure that DNA is replicated once and only once per cell cycle. The association of HsMCM2 with DNA replication suggested to us that it might prove useful as a new marker for cell proliferation. To test this possibility, we employed immunohistochemistry and immunoblotting to study HsMCM2 expression in both normal human tissues and primary human tumors. We found that HsMCM2 was detectable by immunoblotting in 97% of the studied tumors but in only 27% of the corresponding normal tissues. In normal tissues, the immunoblot signal was weaker than in tumors. Immunohistochemistry revealed that in normal tissues HsMCM2 is present only in proliferating cell nuclei. In most cases, tumor cell nuclei produced a stronger HsMCM2 signal than normal proliferating cell nuclei. Comparative studies revealed that antibodies against HsMCM2 stained fewer nuclei than antibodies against proliferating cell nuclear antigen but usually more than antibodies against Ki-67 (another proliferation-related antigen). Thus, the correlations between proliferation and antigenic signal are different for these three proteins. These results indicate that HsMCM2 is, indeed, a novel marker for proliferating cells. Further studies are required to determine whether the fact that HsMCM2 has a different correlation with proliferation and elevated staining intensity in tumor nuclei (compared to nuclei in normal proliferating cells) will permit it to be a more useful diagnostic and prognostic marker than proliferating cell nuclear antigen and Ki-67.

Biomarkers↗
PubMed1998

Metachronous benign solitary fibrous tumours of the pleura (localized "mesotheliomas"): a case report.

Solitary fibrous tumours are uncommon pleural tumours that are not related to mesotheliomas. They are typically benign and pedunculated and may grow to massive sizes. Surgical resection is usually curative. Tumour recurrence and metachronous development of multiple tumours are unusual. In this report a patient was treated for 3 benign solitary fibrous tumours of the pleura over 23 years. The authors hypothesize that this represents multifocal tumorigenesis as opposed to local tumour recurrence. The importance of complete surgical excision and lifelong radiographic follow-up are stressed.

Aged↗
PubMed1997

Activation of the focal adhesion kinase signal transduction pathway in cervical carcinoma cell lines and human genital epithelial cells immortalized with human papillomavirus type 18.

The inappropriate activation of protein-tyrosine kinases (PTKs) has been associated with initiation and progression of several types of human cancers. We therefore postulated that immortalization by DNA tumor viruses results in the induction of PTKs fundamental to these processes. An RT-PCR-based screen was thus used to identify PTKs that were abundantly expressed in HPV-18-immortalized epithelial cells and HPV-containing carcinoma cell lines. One of the genes isolated in this screen was the focal adhesion kinase (FAK; pp125FAK), a cytoplasmic protein kinase that is activated in v-src transformed cells or by stimulation with mitogenic polypeptides. FAK also becomes catalytically active upon integrin engagement with extracellular matrix proteins, such as fibronectin. We found that FAK expression and activity were significantly elevated in HPV-18 E6/E7-immortalized human genital epithelial cells relative to their primary cell counterparts. Protein expression and tyrosine phosphorylation of the putative FAK substrate, paxillin, were also notably increased upon HPV-18 immortalization of genital epithelial cells and in HPV-containing cervical carcinoma cell lines. Most significantly, these cells expressed markedly higher levels of both intracellular and extracellular fibronectin, thus providing a mechanism for activation of FAK and increased tyrosine phosphorylation of paxillin. These findings suggest a role for the integrin/FAK-mediated signaling pathway in cervical carcinogenesis and represent one of the first demonstrations of a tyrosine kinase whose activity is elevated following viral immortalization.

Cell Adhesion Molecules↗
PubMed1997

Primary peritoneal adenocarcinoma metastatic to the brain.

Primary peritoneal adenocarcinoma is a relatively newly identified disease entity whose clinical behavior is not fully recognized. We report a case of a patient with progressive primary peritoneal adenocarcinoma who developed brain metastases and died shortly afterward. The incidence of central nervous system metastases in 72 patients with documented primary peritoneal adenocarcinoma was 1.4%. The risk factors, clinical behavior, and prognosis of patients with primary peritoneal adenocarcinoma metastatic to the central nervous system seem to be similar to those of patients with epithelial ovarian cancer metastatic to the central nervous system.

Adenocarcinoma↗
PubMed1997

Identical, unique p53 mutations in a primary ovarian mucinous adenocarcinoma and a synchronous contralateral ovarian mucinous tumor of low malignant potential suggest a common clonal origin.

The origin of malignant ovarian epithelial tumors is uncertain and has been the subject of considerably controversy. Some favor the theory of origin in precursor lesions such as benign cystadenomas or tumors of low malignant potential (LMP; borderline tumors), whereas others favor the concept of an independent origin of carcinomas from the ovarian surface epithelium or inclusion cysts. Recently, the demonstration of identical molecular alterations in morphologically benign and malignant areas within the same ovarian tumor have suggested the possibility that the malignant epithelium had undergone differentiation to a benign appearance. Because both areas were present in the same tumor, however, the possibility of progression of the morphologically benign component could not be excluded. We present a case of simultaneous mucinous carcinoma and contralateral tumor of LMP which exhibited identical, unique mutations of the p53 gene, suggesting a clonal origin. Because these were separate and distinct tumors, we believe this case provides strong support for the differentiation hypothesis. We also provide evidence for markedly different levels of p53 expression in areas with identical p53 mutations.

Adenocarcinoma, Mucinous↗
PubMed1997

Expression of the p53 induced tumor suppressor p21waf1/cip1 in ovarian carcinomas: correlation with p53 and Ki-67 immunohistochemistry.

Mutations of the p53 gene are the most common genetic alteration in malignant human tumors, including ovarian carcinomas of surface epithelial origin. A cyclin-dependent kinase inhibitor, p21waf1/cip1, is thought to be an important mediator of p53-induced cell cycle arrest. Although numerous studies have reported p53 expression and mutation in ovarian tumors, none have correlated p53 expression with that of its downstream effector, p21waf1/cip1. We studied p53 and p21waf1/cip1 expression by immunohistochemistry in 44 ovarian carcinomas of different histologic types and correlated these findings with each other and with proliferation as measured by expression of the Ki-67 nuclear antigen. Fifty percent of tumors expressed p53, whereas 34% expressed p21waf1/cip1. Clear cell carcinomas expressed p21waf1/cip1 significantly more often than other histologic types, and tumors with squamous differentiation showed higher p21waf1/cip1 expression in these areas. There was no correlation of p21waf1/cip1 expression with p53 expression, p53 mutation, or Ki-67 expression. p21waf1/cip1 appears to be induced independently of p53 in these tumors and may be associated with differentiation rather than proliferation.

Cell Differentiation↗
PubMed1997

Tumor of the broad ligament in von Hippel-Lindau disease of probable mullerian origin.

A rare neoplasm seen in women with von Hippel-Lindau disease is the papillary cystadenoma of the broad ligament, only three cases of which have been reported. All three exhibited characteristic histologic features identical to those of epididymal tumors that occur in affected patients, and were presumed to be of wolffian origin. This is the case of a broad ligament tumor in a woman with von Hippel-Lindau disease that had features more consistent with a mullerian rather than wolffian origin. This is the first report of a broad ligament tumor of probable mullerian origin in von Hippel-Lindau disease.

Adult↗
PubMed1997

p53-independent expression of p21waf1/cip1 in preinvasive and invasive squamous neoplasms of the uterine cervix.

Although mutations of the p53 gene are the most common genetic alteration in human tumors, they are relatively rare in cervical carcinomas, possibly because human papillomaviruses of the oncogenic type encode for an oncoprotein that leads to the ubiquitin-mediated destruction of p53. An important mediator of p53-induced cell-cycle arrest is p21waf1/cip1, and although several studies evaluated invasive and preinvasive cervical lesions for p53 expression, none has studied expression of this important downstream effector. We examined normal cervical squamous epithelium, squamous cell carcinomas, and a range of preinvasive cervical lesions for expression of p53, p21waf1/cip1, and the proliferation-associated antigen, Ki-67, by immunohistochemical analysis. p53 expression was absent in normal squamous epithelium and all dysplasias regardless of severity, consistent with the presence of predominantly wild-type p53. Invasive carcinomas were mostly negative but contained occasional small nests of cells immunoreactive for p53. p21waf1/cip1, on the other hand, was expressed in all normal squamous epithelium and all preinvasive and invasive lesions. In normal squamous epithelium, the basal and immediate parabasal layers were negative, with the early differentiating layers positive. Expression was increased in dysplasias compared with normal squamous epithelium, both in number of immunoreactive nuclei and intensity of staining. The highest expression was seen in high-grade dysplasias and invasive carcinomas. Ki-67 expression also increased with increasing severity of the lesion, but p21waf1/cip1 and Ki-67 seemed to be expressed in different cells, a fact that was confirmed by double immunohistochemical staining for these two proteins on the same sections. This paradoxical increase in p21waf1/cip1 expression and mutually exclusive expression might be related to the role of p21waf1/cip1 in differentiation.

Adult↗
PubMed1996

Luteinized thecoma with sclerosing peritonitis.

Clement and colleagues recently described a group of six patients who had spindle cell proliferations of the ovary resembling luteinized thecomas. A fatal case of extensive sclerosing peritonitis associated with an identical ovarian proliferation is reported. In addition, several other cases in the literature that almost certainly represent the same disease entity have been identified. To our knowledge, this report increases the number of cases to 13. The extensive peritoneal disease along with the high mitotic activity of the ovarian tumor resulted in the diagnosis of peritoneal dissemination of an ovarian cancer in some cases, including the one currently described. Awareness of this newly described condition, which may be more common than previously thought, may help prevent further misdiagnosis.

Adult↗
PubMed1990

The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53.

The E6 protein encoded by the oncogenic human papillomavirus types 16 and 18 is one of two viral products expressed in HPV-associated cancers. E6 is an oncoprotein which cooperates with E7 to immortalize primary human keratinocytes. Insight into the mechanism by which E6 functions in oncogenesis is provided by the observation that the E6 protein encoded by HPV-16 and HPV-18 can complex the wild-type p53 protein in vitro. Wild-type p53 gene has tumor suppressor properties, and is a target for several of the oncoproteins encoded by DNA tumor viruses. In this study we demonstrate that the E6 proteins of the oncogenic HPVs that bind p53 stimulate the degradation of p53. The E6-promoted degradation of p53 is ATP dependent and involves the ubiquitin-dependent protease system. Selective degradation of cellular proteins such as p53 with negative regulatory functions provides a novel mechanism of action for dominant-acting oncoproteins.

Antigens, Polyomavirus Transforming↗
PubMed1990

Association of human papillomavirus types 16 and 18 E6 proteins with p53.

Human papillomavirus type 16 (HPV-16) is a DNA tumor virus that is associated with human anogenital cancers and encodes two transforming proteins, E6 and E7. The E7 protein has been shown to bind to the retinoblastoma tumor suppressor gene product, pRB. This study shows that the E6 protein of HPV-16 is capable of binding to the cellular p53 protein. The ability of the E6 proteins from different human papillomaviruses to form complexes with p53 was assayed and found to correlate with the in vivo clinical behavior and the in vitro transforming activity of these different papillomaviruses. The wild-type p53 protein has tumor suppressor properties and has also been found in association with large T antigen and the E1B 55-kilodalton protein in cells transformed by SV40 and by adenovirus type 5, respectively, providing further evidence that the human papillomaviruses, the adenoviruses, and SV40 may effect similar cellular pathways in transformation.

Adenovirus Early Proteins↗
PubMed1989

Complex formation of human papillomavirus E7 proteins with the retinoblastoma tumor suppressor gene product.

The E7 proteins encoded by the human papillomaviruses (HPVs) associated with anogenital lesions share significant amino acid sequence homology. The E7 proteins of these different HPVs were assessed for their ability to form complexes with the retinoblastoma tumor suppressor gene product (p105-RB). Similar to the E7 protein of HPV-16, the E7 proteins of HPV-18, HBV-6b and HPV-11 were found to associate with p105-RB in vitro. The E7 proteins of HPV types associated with a high risk of malignant progression (HPV-16 and HPV-18) formed complexes with p105-RB with equal affinities. The E7 proteins encoded by HPV types 6b and 11, which are associated with clinical lesions with a lower risk for progression, bound to p105-RB with lower affinities. The E7 protein of the bovine papillomavirus type 1 (BPV-1), which does not share structural similarity in the amino terminal region with the HPV E7 proteins, was unable to form a detectable complex with p105-RB. The amino acid sequences of the HPV-16 E7 protein involved in complex formation with p105-RB in vitro have been mapped. Only a portion of the sequences that are conserved between the HPV E7 proteins and AdE1A were necessary for association with p105-RB. Furthermore, the HPV-16 E7-p105-RB complex was detected in an HPV-16-transformed human keratinocyte cell line.

Amino Acid Sequence↗
PubMed1989

Genital human papillomavirus infections.

Genital human papillomavirus (HPV) infection is an increasingly common sexually transmitted disease that has been associated with carcinoma of the cervix. Genital warts are easily diagnosed by clinical criteria; however, the more prevalent subclinical infections generally require laboratory diagnosis. Satisfactory methods for culture of HPV do not exist, and cytologic and histopathologic methods are the most widely available diagnostic techniques. Detection of HPV DNA is a more sensitive method, but its role in the clinical laboratory remains to be defined.

Antibodies, Viral↗