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J R Benfield

Publications and source records attributed to J R Benfield.

At least 19 recordsLinked to original sources
PubMed1997

The alveolar type II cell is a pluripotential stem cell in the genesis of human adenocarcinomas and squamous cell carcinomas.

Studies in a canine bronchogenic carcinoma model indicate that alveolar type II cells may differentiate from carcinogen-exposed epithelium of larger bronchi and generate adenocarcinomas with bronchioloalveolar and other growth patterns. In this study, we investigated whether type II cells are one of the major proliferating cells (= stem cells) in the genesis of two major subsets of bronchogenic carcinoma in humans. Adenocarcinomas (17 bronchioloalveolar; 3 papillary; and 10 other) and squamous cell carcinomas (n = 27) as well as (pre)neoplastic lesions in adjacent bronchi and bronchioles were examined for the presence of type II cell markers and cellular proliferation markers (PCNA; Ki-67) using light and electron microscopy and immunohistochemistry. Distinctive features of type II cells, which do not depend upon the degree of cell maturity, are the approximately cuboid shape, large and roundish nucleus, cytoplasmic staining for surfactant protein A (SP-A), and presence of multilamellar bodies or their precursory forms. Cells with this phenotype were found in early progressive (i.e., dysplastic, in situ, microinvasive) lesions in conducting airways and in all the carcinomas investigated, although with a much greater abundance among glandular lesions compared to squamous lesions. The most consistent sites of type II cells were the basal and adjacent epithelial layers. Nuclear PCNA (Ki-67) expression usually predominated in the same region. None of the lesions displayed specific Clara cell features. Our findings strongly suggest that the type II cell is a pluripotential stem cell in human lung carcinogenesis. Based on our findings in humans and dogs, we postulate that type II tumor stem cells may originate from one of two sources: (1) normal bronchial epithelium (by an oncofetal mechanism of differentiation); and (2) normal alveolar type II cells.

Adenocarcinoma↗
PubMed1996

Bronchial carcinogenesis in syngeneic hamsters.

Endobronchial sustained release implants of carcinogen were placed in males (m) and females (f) of four varieties of syngeneic hamsters: BIOF1D; BIO87.20; BIO1.5; BIO15.16. The sequential progression of carcinogenesis that occurred was faster for 1.5m than for 1.5f (P = 0.01) and less rapid for 15.16m than for 87.20m and F1Dm (P < 0.05). Fewer invasive cancers occurred in 15.16m than in the other male varieties (P < 0.01), in 1.5m than in 87.20m (P < 0.05), and in 87.20f than in 87.20m (P < 0.05). Adenocarcinoma occurred with greater frequency in the 1.5 variety than in the F1D variety (P < 0.05). Significant variability in susceptibility, incidence, and types of invasive cancers formed exists, providing new opportunities for further study of bronchial carcinogenesis.

Animals↗
PubMed1996

Comparison of DNA topoisomerase II alpha expression in small cell and nonsmall cell carcinoma of the lung. In search of a mechanism of chemotherapeutic response.

BACKGROUND: Small cell carcinoma of the lung (SCLC) is distinguished from nonsmall cell carcinoma (NSCLC) by its exquisite initial sensitivity to chemotherapy. Antineoplastic drugs effective against SCLC include doxorubicin, etoposide, and others. Recently, the molecular target of these drugs has been identified as the alpha form of DNA topoisomerase II, which is important in DNA replication and in the separation of chromosomes during normal cellular division. In this study we compared DNA topoisomerase II alpha expression in SCLC and NSCLC by immunohistochemistry. We hypothesized that the sensitivity of SCLC and relative insensitivity of NSCLC to these chemotherapeutic agents stem from different frequencies of DNA topoisomerase II alpha expression. METHODS: DNA topoisomerase II alpha expression was analyzed in 17 cases of SCLC and 24 cases of NSCLC by immunohistochemistry utilizing a monoclonal antibody recognizing the alpha isoform of DNA topoisomerase II. A topo II index was determined by dividing the number of tumor nuclei expressing DNA topoisomerase II by the total number of tumor nuclei counted. RESULTS: A significantly higher frequency of DNA topoisomerase II alpha expression was identified in SCLC (P < 0.001). The average topo II index for SCLC was 0.60 (range: 0.45-0.76) compared with NSCLC, 0.31 (range: 0.05-0.75). CONCLUSIONS: We conclude that DNA topoisomerase II alpha is expressed at a higher frequency in SCLC than in NSCLC, and that this expression is possibly involved in the response of SCLC to chemotherapeutic agents.

Antigens, Neoplasm↗
PubMed1996

Alveolar stem cells in canine bronchial carcinogenesis.

Alveolar type II cells are not present in normal epithelium of canine segmental bronchi but after carcinogen exposure they do occur in intra-epithelial lesions with all degrees of atypia and in invasive lesions with different glandular growth patterns. Immunohistochemistry for proliferation markers (PCNA; Ki-67) strongly suggest that such novel type II cells are pluripotential stem cells in canine bronchial carcinogenesis. Very likely, bronchial carcinogenesis is subject to an oncofetal mechanism of differentiation: bronchial epithelial retrodifferentiation followed by novel differentiation of alveolar tumor stem cells.

Animals↗
PubMed1996

Multimodality therapy in stage III non-small cell lung cancer.

BACKGROUND: Non-small cell lung cancer commonly presents as locally advanced disease. This category of tumors is heterogeneous. Although some patients clearly benefit from operative management alone, the vast majority (more than 90%) will succumb to their disease within 5 years. In the past decade a large clinical research effort has been undertaken in an attempt to improve on this outcome using a combination of chemotherapy, radiotherapy, and operation. METHODS: The English-language literature was reviewed using the headings for lung neoplasms and text words combined modality therapy and multimodality therapy. In addition, the bibliographies of relevant articles were reviewed. Emphasis was placed on prospective randomized trials and large phase II studies. We review the rationale, design, and outcome of these trials, including both operative and nonoperative approaches. RESULTS: Several prospective, randomized trials now demonstrate an advantage to combined modality management over radiotherapy or operation alone when a cisplatin-based chemotherapy regimen is incorporated into the treatment plan. This advantage was seen using both operative and nonoperative approaches. CONCLUSIONS: Combined modality therapy offers an improved outcome for patients with stage III non-small cell lung cancer. Whether both operation and radiotherapy are needed for local control, the best sequence of treatment and the optimal chemotherapy regimen remain to be defined.

Carcinoma, Non-Small-Cell Lung↗
PubMed1996

Metamorphosis.

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Societies, Medical↗
PubMed1996

Surgical management and treatment of esophageal fistula.

Esophageal fistula may involve the respiratory or cardiovascular system. Fistulas involving the respiratory system which originate from esophageal cancers are the most common. Diagnosis is best made with barium esophagogram. ERF of any cause usually leads to repetitive contamination of the respiratory tract, resulting in sepsis and death of the patient if untreated. In the case of MERF, whether from esophageal or lung cancer, only palliative treatment is usually possible. Better results, including cure, may be expected when a MERF is caused by lymphoma. Curative operation with closure of the fistula is usually possible for BERF if the fistula is identified and treated before irreversible damage has been done by infection, sepsis, and malnutrition. Esophagocardiovascular fistulas occur infrequently in comparison with ERF. These may involve the aorta, usually as a result of a thoracic aneurysm. Rarely one may encounter esophageal fistula to the pericardium or heart. Few survivors have been reported, but successful management is possible if early diagnosis is made and prompt surgical management is undertaken.

Aortic Diseases↗
PubMed1995

Loss of nm23 and Alu DNA in human lung cancer propagated in nude mice.

Freshly resected human non-small cell lung cancer (NSCLC) has been successfully transplanted and propagated subcutaneously in nude mice (Cancer Letters 61 (1991) 53-60). We used this model to study the changes of the human metastasis suppressor genes, nm23-H1 and nm23-H2, through the process of propagation and metastasis of human NSCLC. Using a non-radioisotopic Southern analysis, the nm23-H1 and nm23-H2 genes were detected without evidence of deletion in the early generations of the tumor grafts. These genes, however, were absent from the tumor grafts sampled past 4 generations of propagation and from all the propagated metastases originated from the subcutaneous grafts. Further restriction analysis revealed that only mouse DNA, but no human Alu DNA, was present in the tumor specimens which lacked the human nm23 genes. Thus, there is a loss of human DNA but a gain of mouse DNA in the propagated tumors originated from the transplanted human NSCLC. The mechanisms of loss of human DNA in these propagated tumors in nude mice have yet to be delineated.

Animals↗
PubMed1995

Histogenesis of adenosquamous bronchogenic carcinoma.

In our hamster lung cancer model studies, among 463 non-small-cell lung cancers (NSCLC), there were 47 adenosquamous neoplasms. In 24 of 27 lesions with diameters of less than 3.0 mm, the adenocarcinoma and the squamous cell carcinoma components arose as separate, spatially discrete lesions, but these were separate in only 7 of 20 lesions with diameters of 30 mm or greater. Co-infiltration of the components became more frequent as tumor size increased. The usual adenosquamous variety of NSCLC is likely a collision tumor, with each component possessing separate biological characteristics. Thus, future prognostically directed studies of this variety of NSCLC must recognize that these neoplasms have two components, each of which needs to assessed.

Adenocarcinoma↗
PubMed1995

Successful xenotransplantation of human lung cancer correlates with the metastatic phenotype.

BACKGROUND: Occult micrometastases could explain deaths from stage I non-small cell lung cancer (NSCLC) after complete resections. If patients who have occult metastases could be identified, systemic therapy might be beneficial. METHODS: Non-small cell lung cancers from 81 patients in stages I, II, and III were transplanted to nude beige mice. Mean follow-up was 22.5 months (2 to 61 months). RESULTS: Twenty-one xenotransplants successfully took, and seven metastasized in the nude mice. Neither the predominant cell type nor the incidence of lymph node metastases correlated with the results of xenotransplantation. Of the 21 patients whose NSCLCs took in xenotransplantation, 13 (61.9%) have had development of metastases, and 9 (42.9%) have died of the cancer. Among the 57 patients whose NSCLCs did not take, 14 (24.6%) have had development of metastases, and 9 (15.8%) have died of their cancer. The higher incidence of metastases in association with xenotransplant take is significant (p = 0.0032). CONCLUSIONS: Patients whose NSCLCs take in xenotransplantation are at high risk for metastases. The xenotransplantation model is a step toward facilitating precise cellular biologic definition of the metastatic propensity of human NSCLC:

Animals↗
PubMed1994

Varied sign language systems and their mediating effects on WISC-R Verbal subtests of profoundly deaf students: a replication.

This study replicated the 1984 work of Miller who reported a normal mean Verbal IQ of profoundly deaf students. To 27 profoundly deaf students the WISC--R Verbal Scale was administered using one of three signed language systems. The means do not support Miller's findings and raise some doubt about the mediating effects of language systems among profoundly deaf students.

Adolescent↗
PubMed1994

In favour of an oncofoetal concept of bronchogenic carcinoma development.

Our recent studies in a heterotopic model of non-small cell lung cancer in dogs (subcutaneous bronchial autografts treated with 3-methylcholanthrene) have provided evidence that alveolar type II cells may newly arise during initial phases of bronchial carcino-genesis. In the light of these novel findings, which are in agreement with our observations in human non-small cell lung cancer, and in view of present insights into embryonic lung differentiation, we discuss evidence that favours a new, oncofoetal concept of bronchogenic carcinoma development. According to this concept, the primary cells of origin for these tumors are undifferentiated primordial-like cells that derive from bronchial epithelial cells present in major bronchi or their divisions by retrodifferentiation. Such primordial-like cells of origin undergo novel differentiation into the potential (alveolar, bronchial or primordial) tumor stem cells, which occupy the dividing cellular layers of the (pre)neoplastic lesions and constitute the actively dividing and invading part of the neoplasm. Examples of tumors that may originate from alveolar tumor stem cells are carcinomas of the bronchiolo-alveolar, papillary, acinar, and adenoid-cystic types. Squamous cell carcinomas could possibly belong to this group as well, but much more evidence is required to reach conclusions regarding this type of cancer. We suggest that epithelial retrodifferentiation followed by novel differentiation (oncofoetal mechanism) is fundamental in bronchial carcinogenesis.

Animals↗
PubMed1993

A step section method for full histopathological assessment of carcinogen-affected target tissue during respiratory carcinogenesis.

Studies of carcinogenesis that are not limited to overt neoplasms but also involve evaluations of preneoplastic stages require histopathological assessment of the entire carcinogen-affected tissue so that the true nature and sequence of the progressive process can be determined. The customary serial sectioning approach achieves this goal, but at an inordinate logistic cost. In studies of hamster bronchial carcinogenesis, a step section method was compared to a quasi-random approach and to the customary serial section method. The step section method achieved the same diagnostic completeness as serial sectioning, but at a two orders of magnitude reduction in costs.

Animals↗
PubMed1993

Hamster bronchial carcinogenesis induced by carcinogen-containing sustained release implants placed endobronchially: a clinically relevant model.

For several widely appreciated reasons, the Syrian hamster has been the most frequently used experimental animal in investigations of conducting airway carcinogenesis. To develop a model where bronchogenic cancer arises focally at a predetermined site, we used the Laskin-Kuschner self-retaining intrabronchial pellet principle, employing a carcinogen-containing silastic polymer sustained release implant (SRI). The SRI is placed in the right lower lobe bronchus via tracheostomy; when modified, the SRI can be removed without loss of the animal. Special preparation of the SRI implant site after fixation but prior to paraffin embedding allows for full histopathological examination of the carcinogen-affected target tissue. Logistic regression analysis of histological findings provides valid quantitative inter-regimen comparisons of histomorphic classifications suitable for determining modulation of carcinogenesis by external influences. Using this model, we demonstrated that the sequential progression of carcinogenesis (SPC) in hamster bronchus is similar to that which occurs in humans and in dogs, including both the ploidy increases that are progressive during the SPC, and the histological patterns of the induced cancers. We have shown genetic variation in susceptibility to carcinogenesis among inbred hamster strains, and have assessed effects of Bacillus Calmette-Guerin (BCG) immunostimulation on the SPC. Time/dose response studies were performed, as were comparisons between four polycyclic aromatic hydrocarbon carcinogens. Systemic administration of 5-azacytidine (AZC) soon after SRI placement was found to inhibit the SPC, to alter the ploidy changes during the SPC and in the eventual cancers, and to affect the degree of differentiation of the cancers. Studies using removable SRIs have assessed the duration of carcinogen exposure required to induce a neoplastic transformation that proceeds to cancer without further carcinogen exposure. Serial syngeneic transplantation of cancers arising in inbred animals has shown that the degree of tumor differentiation is affected by the extent of host immunocompetence, and has also led to development of models for study of the processes of metastasis.

Animals↗