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J R Benfield

Publications and source records attributed to J R Benfield.

At least 37 records · Page 2Linked to original sources
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↗
PubMed1993

Regression of bronchial epithelial cancer in hamsters.

For bronchogenic carcinoma, if and when the sequential process of carcinogenesis is reversible is fundamental to chemoprevention research. In our hamster model, focally originating non-small cell lung carcinoma (NSCLC) develops via a reproducible sequential process of carcinogenesis by 180 days after endobronchial sustained-release implants (SRIs) of 10% benzo(a)pyrene. In this study, 114 hamsters received removable 10% benzo(a)pyrene SRIs. Short-term controls were sacrificed in 3 groups at 50, 65, and 80 days after SRI placement. Three experimental groups had SRIs removed at 50, 65, and 80 days after placement, and sacrifice was delayed until 100 to 180 days later. Long-term controls retained SRIs until sacrifice at 180 or 240 days after SRI placement. All long-term controls had NSCLC. Preneoplastic change was more common in 50- and 65-day controls, as compared with hamsters with equal duration of SRI exposure whose sacrifice was delayed until 100 to 180 days after SRI removal (p < 0.05). The 56% incidence of early NSCLC in hamsters sacrificed after 80 days of SRI exposure decreased to 5% in hamsters that had delayed sacrifice after SRI removal after 80 days of exposure. At the 10% benzo(a)pyrene dose used, hamster bronchial epithelium requires more than 80 days of continuous exposure to become irreversibly committed to NSCLC uniformly. Microinvasive NSCLC in hamsters often regresses, and it is not necessarily a precursor of overt invasive cancer. The removable SRI model provides new opportunities to evaluate chemoprevention of NSCLC and the related molecular-genetic control mechanisms.

Animals↗
PubMed1993

Surgical resection of stage IIIA and stage IIIB non-small-cell lung cancer after concurrent induction chemoradiotherapy. A Southwest Oncology Group trial.

UNLABELLED: Recent studies suggest that preoperative induction chemotherapy +/- radiotherapy can improve the historically poor resectability and survival of patients with stage IIIA non-small-cell lung cancer, but sometimes with significant associated morbidity and mortality. Such treatment has not been studied in stage IIIB non-small-cell lung cancer, usually considered unresectable. This multiinstitutional phase II trial tested the feasibility of concurrent preoperative chemoradiotherapy for stages IIIA and IIIB non-small-cell lung cancer. METHODS: Eligible patients had pathologically documented T1-4 N2-3 disease (without pleural effusions). Induction therapy was cisplatin, 50 mg/m2, days 1, 8, 29, and 36 plus VP-16, 50 mg/m2, days 1 to 5, and 29 to 33 plus concurrent radiotherapy (4500 cGy, 180 cGy fractions). Resection was attempted 3 to 5 weeks after induction if the response was stable, partial, or complete. Complete nodal mapping at thoracotomy was required. RESULTS: One hundred forty-six patients were entered. This interim analysis is based on the first 75 eligible patients for whom complete surgical data are available. There were 49 men and 26 women, median age 58 years (range 32 to 75 years). Sixty-eight of (91%) patients were eligible for operation, and 63 of 75 patients (84%) underwent thoracotomy. Fifty five of 75 patients (73%), including 12 of 16 with a stable response, had a complete resection. Four of 63 patients died postoperatively (6%). Approximately one third required a "complex" resection, for example, lobectomy plus chest wall or spine resection, but mean operating time was 3.2 hours and mean blood loss was less than 1000 ml for both stages IIIA and IIIB. Complete pathology data are currently available from 53 patients: 11 (21%) had no residual tumor; 20 (30%) had rare microscopic foci of residual cancer. The 2-year survival is 40% for both stages IIIA and IIIB. CONCLUSIONS: This combined modality therapy has been well tolerated and has been associated with high response and resectability rates in both stage IIIA and stage IIIB non-small-cell lung cancer. Current survival is significantly better than survivorship among historical control patients and provides a firm basis for subsequent phase III clinical trials.

Adult↗
PubMed1993

Expression of alveolar type II cell markers in acinar adenocarcinomas and adenoid cystic carcinomas arising from segmental bronchi. A study in a heterotopic bronchogenic carcinoma model in dogs.

The type II alveolar epithelial cell is one of two pluripotential stem cell phenotypes in normal mammalian lung morphogenesis; cells manifesting this phenotype have been found to constitute bronchioloalveolar regions of canine adenocarcinomas. We now studied type II cell expression in canine acinar adenocarcinomas and adenoid cystic (bronchial gland) carcinomas, using the same bronchogenic carcinoma model (subcutaneous bronchial autografts treated with 3-methylcholanthrene). Distinctive features of type II cells are the approximately cuboid cell shape, large and roundish nucleus, immunofluorescent staining of the cytoplasm for the surfactant protein SP-A, and presence of multilamellar bodies or their precursory forms. Cells with these type II cell characteristics were found in the basal epithelial layer of all tumor lesions and in upper layers as far as the lumen, singly or in clusters; they were also found in early invasive carcinomatous lesions but not in bronchial glands or bronchial epithelium before carcinogen exposure. Immunoblots of tumor homogenates showed reactive proteins within size classes of SP-A (28 to 36 kd) or its dimeric form (56 to 72 kd). These findings and those previously reported are consistent with the concept that chemical carcinogenesis in the adult bronchial epithelium may lead to type II cell carcinomas of varying glandular (acinar, adenoidcystic or bronchioloalveolar) growth patterns.

Animals↗
PubMed1992

Bronchial and pulmonary carcinogenesis at focal sites in dogs and hamsters.

Models of the sequential process of lung carcinomas have been developed in dogs and hamsters. The bronchial mucosa, or the pulmonary parenchyma, was exposed at selected focal sites to polycyclic aromatic hydrocarbons [most often benzo(a)pyrene or methylcholanthrene]. In hamsters, sustained release implants that contained carcinogen were implanted into the right lower lobe bronchus. In dogs, for orthotopic carcinogenesis the carcinogens were repeatedly injected into the bronchial submucosa or topically applied to the bronchus; sustained release implants were implanted into the pulmonary parenchyma. Heterotopic focal canine bronchial carcinogenesis was accomplished by exposing s.c. bronchial autografts (8-12/dog) to methylcholanthrene. In both species a predictable, reproducible, preneoplastic continuum that leads to bronchial squamous cell carcinoma that metastasizes has been characterized; serial measurements of total cellular DNA showed that ploidy increased in proportion to the stage of preneoplasia. In both species there were adenocarcinomas, including bronchiolar (bronchioloalveolar) carcinomas and other varieties of non-small cell cancers. Different susceptibility to carcinogenesis has been demonstrated among different inbred strains of hamsters; 58% of cancers were adenocarcinomas in one strain. From these models, specimens that are not readily available from humans can be obtained for the study of cellular events during lung carcinogenesis. In parallel with studies in humans, these animal models can be used to evaluate methods of possible chemoprevention and early detection.

Animals↗
PubMed1991

Metastases from fresh human non-small cell lung cancers propagated in nude mice.

Specimens from 69 freshly resected human non-small cell lung cancers (NSCLC) were transplanted into nude mice. Twelve mice died before the transplants were evaluable. There were 4 takes of 12 evaluable transplants into untreated athymic nude mice and 24 takes of 45 evaluable transplants into nude mice with decreased natural killer (NK) cell activity. Fourteen tumor lines were propagated into 2 or more successive transplant generations. Distant metastases occurred from the mid-dorsal transplant site in 8 of 81 (9.88%) recipients of 4 of those tumor lines, after 3-9 consecutive tumor growth cycles. Xenotransplantation of freshly resected human NSCLC provides a model with potential for serial assessment of cellular changes related to metastatic capability.

Adenocarcinoma↗
PubMed1991

Lung cancer model for study of the metastatic process.

In our hamster model of focal, chemically induced nonsmall cell lung cancer (NSCLC), we studied metastases in autochthonous hamster hosts (n = 300) and in syngeneic hamster and nude mice recipients (n = 230) of serial tumor transplants. Metastases in autochthonous hosts and transplant recipients occurred in regional lymph nodes, liver, and adrenals. In autochthonous host hamsters no metastases were noted from microinvasive (n = 112) or visible cancer less than 3.0 mm in diameter (n = 66); the incidence of metastasis was 8.2% (4/49) from 3- to 10-mm cancers and 22% (16/73) from cancers 10 mm in diameter or larger (p less than 0.05). Serial transplants were used to evaluate the metastatic propensity of 20 primary and six metastatic NSCLCs. Six primary NSCLCs that metastasized in the autochthonous host and six metastatic NSCLCs all metastasized promptly in recipients. This expression of metastatic potential was significantly different (p less than 0.05) from 14 primary cancers without autochthonous host metastases. Eight of the 14 caused no metastases in recipients, even after 5 to 11 tumor growth cycles; metastases occurred from the other six primary NSCLC after 3 to 12 tumor growth cycles in transplant recipients. Primary hamster NSCLCs metastasize in the autochthonous host with a frequency and a distribution pattern similar to human NSCLCs. A new model to study serially the cellular changes that govern the process of metastasis in NSCLC has been developed.

Animals↗