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Biomedical subjects

H I Pass

Publications and source records attributed to H I Pass.

At least 37 records · Page 2Linked to original sources
PubMed1999

Asbestos induction of extended lifespan in normal human mesothelial cells: interindividual susceptibility and SV40 T antigen.

Normal human mesothelial cells from individual donors were studied for susceptibility to asbestos-induction of apoptosis and generation of an extended lifespan population. Such populations were generated after death of the majority of cells and arose from a subset of mesothelial cultures (4/16) whereas fibroblastic cells (5/5) did not develop extended lifespan populations after asbestos exposure. All mesothelial cultures were examined for the presence of SV40 T antigen to obtain information on (i) the presence of SV40 T antigen expression in normal human mesothelial cells and (ii) the relationship between generation of an extended lifespan population and expression of SV40 T antigen. Immunostaining for SV40 T antigen was positive in 2/38 normal human mesothelial cultures. These cultures also had elevated p53 expression. However, the two isolates expressing SV40 T antigen did not exhibit enhanced proliferative potential or develop an extended lifespan population. Asbestos-generated extended lifespan populations were specifically resistant to asbestos-mediated but not to alpha-Fas-induced apoptosis. Deletion of p16Ink4a was shown in 70% of tumor samples. All mesothelioma cell lines examined showed homozygous deletion of this locus which extended to exon 1beta. Extended lifespan cultures were examined for expression of p16Ink4a to establish whether deletion was an early response to asbestos exposure. During their rapid growth phase, extended lifespan cultures showed decreased expression of p16Ink4a relative to untreated cultures, but methylation was not observed, and p16Ink4a expression became elevated when cells entered culture crisis. These data extend the earlier observation that asbestos can generate extended lifespan populations, providing data on frequency and cell type specificity. In addition, this report shows that generation of such populations does not require expression of SV40 T antigen. Extended lifespan cells could represent a population expressing early changes critical for mesothelioma development. Further study of these populations could identify such changes.

Adult↗
PubMed1999

Emerging translational therapies for mesothelioma.

Malignant pleural mesothelioma remains a therapeutic and diagnostic problem. Translational mechanisms for treatment of the disease are emerging from newly learned characteristics of the tumor on a molecular, cellular, and extracellular basis. Although slow to reach the clinical arena, these potential strategies do show proof of principle in the in vitro and in vivo settings, and some, including adenoviral molecular chemotherapy, have completed phase I testing. This review describes the rationale and status of these newer treatment ideas.

Adenoviridae↗
PubMed1999

Simian virus 40 is present in most United States human mesotheliomas, but it is rarely present in non-Hodgkin's lymphoma.

Simian virus 40 (SV40) causes mesotheliomas, osteosarcomas, ependymomas, choroid plexus tumors, and lymphomas in hamsters. In humans, SV40 has been detected in tumors of the first four types. Using the polymerase chain reaction (PCR), we tested 29 non-Hodgkin's lymphomas (intermediate and high-grade), 25 posttransplant lymphoproliferative disorders, and 5 AIDS lymphomas for SV40 DNA. PCR analysis revealed that 3 of 29 lymphomas, 6 of 25 posttransplant lymphoproliferative disorders, and 2 of 5 AIDS lymphomas contained SV40 sequences corresponding to the retinoblastoma (RB)-pocket binding domain of SV40 tumor antigen (Tag). However, among positive samples, only one posttransplant lymphoproliferative disorder and one AIDS lymphoma contained the SV40 regulatory region, which suggest a higher viral load in these patients. In parallel experiments, 8 of 12 mesotheliomas tested positive for SV40 for both the RB-pocket binding domain of Tag and the SV40 regulatory region. These data confirm the presence of SV40 in most United States mesotheliomas and indicate that in human non-Hodgkin's lymphomas, the prevalence of SV40 is low.

Animals↗
PubMed1999

Migration of mesothelioma cells correlates with histotype-specific synthesis of extracellular matrix.

Three human pleural malignant mesothelioma cell cultures (MM) of epithelioid (E1), fibrous (F1) and byphasic (B1) histotype were studied in their synthesis of the extracellular matrix (ECM) components laminin (LM), fibronectin (FN), type IV collagen (cIV), and in their chemotactic and haptotactic migration towards the ECM produced proteins. MM-B1 showed the highest FN synthesis and release; MM-E1 produced the highest quantity of basement membrane constituents LM and cIV; MM-F1 weakly produced and released FN, LM and cIV. MM-B1 had the highest chemotactic and haptotactic motility, MM-F1 migrated toward the lowest concentration of LM while had reduced chemotactic activity toward FN and cIV; MM-E1 had the lowest migratory activity toward each ECM substrate. We demonstrated that three MM of different histotype are characterized by different ECM production and that these differences determine a variable ability of each MM to spread and migrate towards ECM substrates.

Cell Movement↗
PubMed1999

Modulation of integrin expression on mesotheliomas: the role of different histotypes in invasiveness.

The in vitro and in vivo integrin expression in human pleural malignant mesothelioma (MM) of three different histotypes was studied. Cell lines from MM of epithelioid (E1), fibrous (F1), byphasic histotype (B1) and normal mesothelial cells (NM) were analysed for the surface expression of alpha2, alpha3, alpha4, alpha5, alpha6, alphav, beta1, beta3, beta4 subunits and alphavbeta5 integrins. We found that alpha6, beta4 subunits and alphavbeta5, weakly detectable on NM cells, were expressed on MM cells. The beta3 subunit, well expressed on NM cells, was absent on MM cells. Differential expression among histotypes was observed, the MM-E1 was the least and the MM-B1 the most positive. Specimens for each MM histotype, were analysed by immunohistochemistry. The alpha6 and alphav subunits were more evident on the epithelioid histotype. Intense staining for beta3 and beta4 subunits, was found in all MM, particularly in invading cells, while the alpha5, and alphavbeta5 integrins were variously expressed. The different histotypes can affect the in vitro integrin expression and may indicate a preferential involvement of some subunits in vivo during MM tumor progression.

Humans↗
PubMed1999

Simian virus 40 (SV40)-like DNA sequences not detectable in finnish mesothelioma patients not exposed to SV40-contaminated polio vaccines.

Occupational asbestos exposure can be demonstrated in 80% of mesothelioma cases. A possible role of simian virus 40 (SV40) in the etiology of mesothelioma was raised because several studies reported the presence and expression of SV40-like DNA sequences in human mesotheliomas. It is also known that expression of SV40 large T antigen inhibits cellular Rb and p53. This suggests that SV40 might render infected cells more susceptible to asbestos carcinogenicity. The SV40-like sequences are suggested to have arisen from contaminated polio vaccines. Millions of people in the United States and most European countries were inoculated with SV40-contaminated polio vaccine in 1955-1963. However, in Finland, where polio vaccination started in 1957, no SV40-contaminated vaccine was used. We used a polymerase chain reaction-based method to test for the presence of SV40-like sequences in DNA extracted from the frozen tumor tissues of 49 Finnish mesothelioma patients, most of whom had been occupationally exposed to asbestos. All of the Finnish tumor tissues tested negative for SV40-like sequences. The results suggest that the SV40-like sequences detected in mesothelioma tissue in some previous studies may indeed originate from SV40-contaminated polio vaccines. It is a matter of speculation whether the absence of SV40 infection has contributed to the relatively low incidence of mesothelioma in Finland (1/10(5) in 1990-1995).

Adult↗
PubMed1999

Principles of chemoradiation: theoretical and practical considerations.

Chemotherapy agents known to enhance the effects of radiation in preclinical studies have been used concurrently with radiotherapy in numerous clinical trials with the prospect of further enhancing radiation-induced local tumor control. While some success in several tumor histologies has been achieved using this approach, a major concern has been enhancement in normal tissue toxicity. This brief review addresses both theoretical and practical issues with respect to chemoradiation clinical trials. Recommendations for clinical trials are provided that, if implemented, can increase our understanding of basic mechanisms (in patients) and provide a more rational approach for future trials.

Animals↗
PubMed1998

Reoperative pulmonary metastasectomy for sarcomatous pediatric histologies.

BACKGROUND: The role for reoperative pulmonary metastasectomy in patients with "pediatric sarcomas" (osteosarcoma, nonrhabdomyosarcoma-soft tissue sarcoma, and Ewing's sarcoma) is undefined. METHODS: We reviewed our results for patients with these histologic presentations (median age, 17.5 years; range, 6 to 32 years) having two (70), three (27), or four (10) metastasectomies between January 1965 and March 1995 to define postresection survival and potential prognostic factors. Simple wedges (88 thoracotomies, 84%) were performed more frequently than anatomic (17 thoracotomies, 16%) resections. RESULTS: With a median potential follow-up of 12.7 years, median survival was 2.25, 3.60, and 0.96 years from the second, third, and fourth explorations, respectively. Primary tumor site, sex, histology, age, maximal metastasis size, and systemic chemotherapy did not influence survival. Resectability was the most important prognostic factor (5.6 versus 0.7 years, 5.2 versus 2.5 years, 2.2 versus 0.2 years, resectable versus unresectable, median survival from second, third, and fourth thoracotomy, respectively). Unresectability, disease-free interval less than 6 months between initial (ie, first) pulmonary resection and the second thoracotomy, and two or more preoperative nodules noted on the right were simultaneously negatively associated with survival from the second thoracotomy. Unresectability or finding two or more metastases negatively affected survival from the third thoracotomy. CONCLUSIONS: These data imply that repeat metastasectomy can salvage a subset of patients with sarcomatous pediatric histologic presentations who retain favorable prognostic determinants.

Adolescent↗
PubMed1998

Human mesotheliomas contain the simian virus-40 regulatory region and large tumor antigen DNA sequences.

BACKGROUND: A cohort (20%) of patients with mesothelioma will not have an exposure to asbestos. Recently, a DNA tumor virus (simian virus 40) has been shown to cause hamster mesotheliomas; we previously described simian virus 40-like DNA amino terminus sequences in 29 of 48 mesotheliomas. We analyzed an additional 42 mesotheliomas to determine (1) whether our initial observations were durable and (2) the extent to which the simian virus 40 genome is present in mesotheliomas. METHODS: Genomic DNA was extracted from snap frozen mesothelioma tumor samples and from the simian virus 40-induced hamster mesothelioma tumor H9A. Polymerase chain reaction primers were used to amplify various simian virus 40 large T-antigen regions including a 105-base pair amino terminus fragment, a 281-base pair carboxyl terminus fragment, and a 310-base pair fragment of the enhancer promoter region. Endonuclease digestions and Southern blotting were used to verify the expected product. RESULTS: Thirty of the 42 (71%) samples amplified T-antigen amino sequences, and specificity was verified by Southern hybridization. Sixteen of 42 samples (38%) amplified the appropriate size fragment for the carboxyl terminus, and digestion with BsaB1 matched that of H9A. Twenty-two of 42 samples (52%) amplified simian virus 40 regulatory sequences and Fok1 digestion matched that of the hamster control tumor. Sequence analysis (4 patients) revealed 100% homology with the regulatory region of simian virus 40 strain 776. CONCLUSIONS: These data suggest an association between the simian virus 40 virus and human mesothelioma that could be exploited for diagnostic/therapeutic options including early detection and potential vaccination strategies.

Animals↗
PubMed1998

Preoperative tumor volume is associated with outcome in malignant pleural mesothelioma.

OBJECTIVES: Our objective was to analyze the impact of preoperative and postresection solid tumor volumes on outcomes in 47 of 48 consecutive patients undergoing resection for malignant pleural mesothelioma who were treated prospectively and randomized to photodynamic therapy or no photodynamic therapy. METHODS: From July 1993 to June 1996, 48 patients with malignant pleural mesothelioma had cytoreductive debulking to 5 mm or less residual tumor by extrapleural pneumonectomy (n = 25) or pleurectomy/decortication (n = 23). Three-dimensional computed tomographic reconstructions of preresection and postresection solid tumor were prospectively performed and the disease was staged postoperatively according to the new International Mesothelioma Interest Group staging. RESULTS: Median survival for all patients is 14.4 months (extrapleural pneumonectomy, 11 months; pleurectomy/decortication, 22 months; p2 = 0.07). Median survival for preoperative volume less than 100 was 22 months versus 11 months if more than 100 cc, p2 = 0.03. Median survival for postoperative volume less than 9 cc was 25 months versus 9 months if more than 9 cc, p2 = 0.0002. Thirty-two of forty-seven (68%) had positive N1 or N2 nodes. Tumor volumes associated with negative nodes were significantly smaller (median 51 cc) than those with positive nodes (median 166 cc, p2 = 0.01). Progressively higher stage was associated with higher median preoperative volume: stage I, 4 cc; stage II, 94 cc; stage III, 143 cc; stage IV, 505 cc; p2 = 0.007 for stage I versus II versus III versus IV. Patients with preoperative tumor volumes greater than 52 cc had shorter progression-free intervals (8 months) than those 51 cc or less (11 months; p2 = 0.02). CONCLUSIONS: Preresection tumor volume is representative of T status in malignant pleural mesothelioma and can predict overall and progression-free survival, as well as postoperative stage. Large volumes are associated with nodal spread, and postresection residual tumor burden may predict outcome.

Combined Modality Therapy↗
PubMed1998

Surgical management of pulmonary metastases.

The management of pulmonary metastases remains controversial. More information is available, however, on outcomes in larger series of patients undergoing metastasectomy as well as the indications for the procedure. The role of video-assisted thoracic surgery for the diagnosis and management of these patients is being scrutinized carefully. Isolated perfusion techniques for treating patients with unresectable pulmonary metastases have been applied in phase I and II trials at selected institutions. More data regarding clinical outcomes are necessary, however, before widespread adaptation of this experimental form of treatment is accepted as standard practice.

Humans↗
PubMed1998

Pharmacokinetics of fentanyl during hyperthermic, isolated lung perfusion.

BACKGROUND: Hyperthermic, isolated pulmonary perfusion with tumor necrosis factor is a surgical procedure that isolates the pulmonary vasculature from the systemic circulation in patients with unresectable primary or metastatic disease confined to the chest. High drug levels are delivered to the perfused organ, avoiding systemic toxicity, and preventing loss of active drug through metabolism. METHODS: The pharmacokinetics of fentanyl are evaluated in three patients while the operative lung is hyperthermic, ventilated, and perfused with an asanguineous solution during nonpulsatile bypass. A loading dose of fentanyl, 1.5 microg/kg to 2.5 microg/kg, was given during the induction of anesthesia followed by a continuous infusion of 150 microg/hr. RESULTS: Results showed no difference in mean plasma fentanyl concentrations before, during, or after bypass and was consistent with clearance values previously reported in healthy adult surgical patients in the absence of an extracorporeal circuit. CONCLUSIONS: Adjustments in fentanyl dosing are not required before, during, or after hyperthermic, isolated pulmonary perfusion is established and a steady state of fentanyl is achieved.

Adult↗
PubMed1998

Biology of metastatic disease.

Metastasis is highly organized and organ selective, a process involving multiple sequential steps. It occurs through complex interactions between tumor cells and the host. The surviving metastatic cells have heterogeneous biologic and antigenic or immunogenic properties, and the metastatic cells take over the homeostatic mechanisms of the host. Investigations at the genetic level are necessary to make advances in the early diagnosis, treatment, and prevention of metastatic disease.

Antigens, Neoplasm↗
PubMed1998

Genetic polymorphism of CYP2D6 and lung cancer risk.

Previous reports of the association of extensive debrisoquine metabolism, controlled by the cytochrome P450 CYP2D6, with increased lung cancer risk have been conflicting. We examined the hypothesis that genetic polymorphism at the CYP2D6 locus identifies individuals at increased risk for lung cancer in a case-control study of 98 incident Caucasian lung cancer patients and 110 age-, race-, and sex-matched controls conducted at the National Naval Medical Center, Bethesda, MD. Using germ line DNA, we identified inactivating mutations at the CYP2D6 locus (CYP2D6*3, CYP2D6*4, CYP2D6*5, and CYP2D6*6A), as well as those mutations that impair but do not abolish enzyme activity (CYP2D6*9 and CYP2D6*10A). Compared to subjects with homozygous inactivating mutations, no association with lung cancer was observed for those with homozygous or heterozygous functional alleles (odds ratios were 0.4 and 0.7, respectively). Furthermore, no excess risk was seen in any histological group or smoking category, and adjustment for smoking and sociodemographic characteristics did not alter the findings. Although the concept that genetic polymorphisms may contribute to differential lung cancer susceptibility is sound, these data do not support the role of CYP2D6 as a marker for elevated lung cancer risk.

Adenocarcinoma↗
PubMed1998

The biological activities of simian virus 40 large-T antigen and its possible oncogenic effects in humans.

Simian virus 40 (SV40) is an oncogenic virus which induces tumors in hamsters and transforms human cells in tissue culture. Between 1955 and 1963, polio vaccines and adenovaccines were contaminated with SV40; therefore, millions of people were exposed to this oncogenic virus. The SV40 proteins responsible for in vivo oncogenesis and in vitro cell transformation are encoded by the early region of the virus. These proteins are called T (tumor) antigens (Tags), because animals with tumors induced by SV40 have antibodies against these viral proteins. Recently, we and other research laboratories have found SV40 in specific types of human tumors: mesothelioma, ependymoma and choroid plexus tumors, osteosarcoma and sarcoma. The same tumor types will develop in hamsters which have been injected systemically with SV40. SV40 causes cell transformation in tissue culture and tumors in animals, because SV40 Tag binds and inactivates the cellular tumor suppressor gene products, Rb and p53. We found that SV40 Tag binds p53 and Rb in human mesotheliomas, possibly contributing to the malignant phenotype.

Animals↗
PubMed1998

Evidence for and implications of SV40-like sequences in human mesotheliomas and osteosarcomas.

Pleural mesotheliomas and osteosarcomas develop in hamsters injected intracardially with SV40. Using primers specific for the RB-pocket binding domain of SV40 we analysed with the polymerase chain reaction frozen specimens from 48 human mesotheliomas and 145 human bone tumours. We found that 60% of human mesotheliomas and 33% of human bone tumours contained SV40-like DNA. Immunostaining, Western blot and RNA in situ hybridization experiments revealed SV40 Tag expression in human mesotheliomas. Osteosarcomas were not studied for Tag expression because not enough material was available. Finally, antibodies anti-Tag were detected in the sera collected from patients with mesothelioma. These data indicate that SV40, or a closely related virus, is/are present in human mesothelioma and osteosarcoma.

Animals↗
PubMed1998

Simian virus 40 oncogenesis in hamsters.

Simian virus 40 (SV40) is a DNA tumour virus which is highly oncogenic in hamsters. Only specific histologic types of tumours develop in hamsters injected with SV40, and these are influenced by the route of virus inoculation. When SV40 is injected systemically to expose most different cell types to the virus, the animals develop mesotheliomas, osteosarcomas, sarcomas, and lymphomas within six months. When the virus is injected subcutaneously, sarcomas at the site of injection develop. If hamsters are injected intracranially with SV40, they develop ependymomas. These same tumour types have been found to contain SV40.

Animals↗