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Biomedical subjects

J R Benfield

Publications and source records attributed to J R Benfield.

At least 55 records · Page 3Linked to original sources
PubMed1991

Variable regression of experimental bronchial preneoplasia during carcinogenesis.

It has been thought that squamous severe atypical metaplasia of the bronchus is reliably precancerous. The canine subcutaneous bronchial autograft model for studying the progression of epidermoid carcinogenesis (normal----regular squamous metaplasia----mild, moderate, and severe atypical metaplasia----squamous cell carcinoma) provides evidence that severe atypical metaplasia of the bronchial epithelium is reversible. Among 148 subcutaneous bronchial autografts that had serial sampling of the epithelium and exposure to implants of methylcholanthrene, severe atypical metaplasia was noted in 28 that received only a single implant. During the total carcinogen exposure (median 24.5 months), 9 of 28 (32%) developed squamous cell cancer, and 19 of 28 (68%) regressed toward normal. Severe atypical metaplasia was noted in 34 subcutaneous bronchial autografts that received two or more carcinogen implants: epidermoid cancer developed in 26 of 34 (76.5%), and regression toward or to normal occurred in 8 of 34 (23.5%). Severe atypical metaplasia was not detected in 53 subcutaneous bronchial autografts: 19 that received only a single implant and 34 that received two or more implants. Progression and regression occurred among these subcutaneous bronchial autografts in proportions similar to those found in subcutaneous bronchial autografts wherein severe atypical metaplasia was seen. Among 33 subcutaneous bronchial autografts initially studied after 6 months of exposure to carcinogen, progression to severe atypical metaplasia was seen 3 months later in 19 of 33 that had additional exposure; in the same interval regression of epithelial abnormalities occurred in 14 of 33 subcutaneous bronchial autografts that had no additional exposure (p less than 0.05). We have presented evidence that severe atypical metaplasia includes at least three cell populations: one committed to cancer without further stimulus, one that regresses despite further carcinogen exposure, and one that requires additional carcinogen to progress to cancer. At least in this model, severe atypical metaplasia is not inexorably precancerous. The subcutaneous bronchial autograft model is suitable for seeking biologic indicators of irreversibility.

Animals↗
PubMed1990

Bronchiolo-alveolar regions in adenocarcinoma arising from canine segmental bronchus.

Adenocarcinomas induced in canine bronchial segments placed subcutaneously have bronchiolo-alveolar regions. Immunocytochemistry and routine staining of adjacent sections strongly suggests that the lining of these regions consists of type II cells. These regions may thus represent true prospective alveolar regions, as also seen in embryonic lungs. This first observation of bronchoalveolar cancer arising from a major bronchus indicates that the carcinogen-induced neoplastic progression in bronchial epithelium may lead to type II cell differentiation and type II cell tumor development. The preservation of cell properties in serial nude mouse transplants suggests that it is a stable type II cell population.

Adenocarcinoma↗
PubMed1990

Effects of 5-azacytidine in Syrian golden hamsters: toxicity, tumorigenicity, and differential modulation of bronchial carcinogenesis.

5-Azacytidine (AZC) was studied in a lung cancer model in outbred and syngeneic (F1D) hamsters wherein benzol[a]pyrene (BP) from sustained release implants (SRI) induces preneoplastic mucosal changes which progress to bronchogenic cancer. In pilot studies to evaluate AZC toxicity, a dose schedule of 5 mg/kg biweekly was found suitable and was then used for long-term administration in all subsequent studies. Three groups of outbred hamsters were studied: BP SRi alone (n = 60), BP SRI + AZC (n = 60), and AZC alone (n = 54). AZC treatment was begun 3-5 days after SRI placement. Sixty-one days after the start of the experiment, seven or eight hamsters were sacrificed from each group. Later sacrifices were at 3-week intervals in groups receiving BP SRI and at 6-week intervals in the AZC only group. Four groups of F1D syngeneic hamsters were studied: BP SRI alone (n = 50); BP + AZC starting 3-5 days after SRI placement and continuing until death (n = 52); BP + AZC from 3 to 5 days until 75 days after SRI placement (n = 49); BP + AZC starting 80 days after SRI placement and continuing until death (n = 52). Hamsters (n = 9-14) from each group were sacrificed at 120, 150, 180, and 220 days after SRI implantation. AZC alone was not carcinogenic under these conditions. Both outbred and F1D hamsters treated with early or continuous AZC had slower rates of neoplastic change from BP SRI than did animals receiving BP SRIs alone or BP + late AZC. The incidence of epidermoid cancer were the same for all regimens, but the tumors in those receiving AZC early in carcinogenesis were smaller than in those receiving late or no AZC. The incidences of nonepidermoid cancer were lower in those receiving AZC during early carcinogenesis, and larger tumors were noted in the absence of AZC. Thus, within the study period in this unique hamster lung cancer model, AZC given early in carcinogenesis inhibited only the later (promotional) phase of BP epidermoid carcinogenesis, but inhibited all phases of nonsquamous cancer development induced by BP. This differential modulation of bronchial carcinogenesis, which occurs from AZC given during preneoplastic stages, may prove useful for delineating molecular mechanisms underlying specific phenotypic types of bronchogenic cancers.

Animals↗
PubMed1990

Quantitative DNA alterations during 5-azacytidine-induced differential modulation of benzo(a)pyrene carcinogenesis in hamster bronchi.

Sustained release implants (SRI) containing 10% benzo(a)pyrene (BP) were placed endobronchially into outbred and syngeneic (F1D) hamsters. Randomly selected OB and F1D hamsters also received 5-azacytidine (AZC), 5 mg/kg i.p., twice weekly until death (AZC-CONT); two more groups of F1D hamsters were given the same AZC dose either for the first 75 days of SRI implantation (AZC-EARLY) or from 80 days after SRI placement until death (AZC-LATE). OB Hamsters were sacrificed at regular intervals from 62 to 189 days of SRI exposure. F1D Hamsters were sacrificed in groups after 120, 150, 180, and 220 days of SRI exposure. The bronchial mucosa at the SRI site was examined cytologically and histologically, as were the tumors that developed. Mean quantitative total cellular DNA values (QDNA) were measured by image analysis. For both varieties of hamster given AZC, QDNA values were higher in early carcinogenesis (CG) and lower in the late stage of CG than in hamsters that did not get AZC (P less than 0.001). QDNA values were lower in epidermoid than in non-epidermoid cancers (P less than 0.001); for both types of cancer, QDNA was lower in AZC-treated hamsters (P less than 0.01). Cancers induced under the influence of AZC included more epidermoid cancers (P less than 0.01) and were of a higher degree of differentiation (P less than 0.01) than those induced by BP alone, especially when AZC was given early in CG. There was no consistent relationship between QDNA and degree of differentiation in tumors. These differential effects of AZC given early during CG suggest that 1) for epidermoid bronchial CG, some of the molecular alterations involved in hyperploidy and in differentiation occur early in the sequential progression of carcinogenesis; and 2) for both epidermoid and non-epidermoid bronchial CG, the necessary changes must occur in a fixed sequence instead of as random events, until all needed changes have occurred.

Animals↗
PubMed1988

Non-small cell lung cancer in autogenous subcutaneous bronchial grafts in dogs.

The progression of preneoplasia into lung cancer can be serially studied in a new canine model that is simpler and more cost effective than previously reported methods of orthotopic endobronchial carcinogenesis. Short segments of bronchus, obtained by pneumonectomy, were placed on the back of 10 dogs in the form of subcutaneous bronchial autografts. These autografts (12 to 14 per dog) became vascularized and lined with normal respiratory epithelium. Four to 12 weeks after autograft implantation, 10% methylcholanthrene in crystalline form was put into 57 autografts and 10% methylcholanthrene in a silicone polymer sustained-release implant was placed into 54 autografts. Ten autografts without carcinogen (one per dog) served as controls. Serial samplings of each autograft during 9 to 97 weeks of carcinogen exposure showed the neoplastic progression from normal bronchial cells to invasive cancer through stages such as atypical squamous metaplasia and carcinoma in situ. To date, cancers have been histologically proved in 60 autografts; 36 were induced by implants and 24 by the crystalline form. Thirty-nine cancers were epidermoid, and the remainder were either adenocarcinomas (n = 3) or poorly differentiated spindle cell cancers (n = 18). The sustained-release implant method resulted in larger autografts with a greater tendency to progress to cancer than the crystalline carcinogens (p greater than 0.025). Therefore, the sustained-release implant is now considered the preferred method. Measurement of nuclear deoxyribonucleic acid by image analysis of nine histologic cancers demonstrated hyperploidy. Deoxyribonucleic acid from the L1 repeated sequence family was demonstrably hypomethylated in spindle cell tumors. Curettement of individual autografts yielded sheets of respiratory epithelium from which 43.5 to 409.5 micrograms of deoxyribonucleic acid was isolated. For the first time, deoxyribonucleic acid from each stage of the neoplastic progression in non-small cell lung cancer is available in adequate quantities for serial biochemical and therapeutic analysis.

Animals↗
PubMed1988

Biochemical and cytogenetic studies of human lung cancers.

In ongoing studies, we have tested resected lung cancers from 41 men and 49 women; of those with primary lung cancer, 46 patients are free of disease and 35 have died of cancer or have persistent disease. Measurements and studies were as follows: total cellular deoxyribonucleic acid content by image analysis (n = 77); total genomic deoxyribonucleic acid methylation state and banding patterns from probed Southern blots (n = 36); radioimmunoassay for motilin, bombesin, gastrin, vasoactive intestinal peptide, and cholecystokinin (n = 18); and cytogenetic analysis (n = 39). All lung cancers were hyperploid. Adenocarcinomas and epidermoid carcinomas were generally hexaploid to nearly septaploid; comparisons by stage and histologic features suggested potential prognostic correlations. There was general hypomethylation of deoxyribonucleic acid (p less than 0.001). Deoxyribonucleic acid digests from restriction endonuclease Hpa II, when probed with deoxyribonucleic acid homologous to KPN, showed banding patterns that separated histologically indistinguishable primary adenocarcinomas and metastatic adenocarcinomas from one another. Cancers studied with radioimmunoassay were all negative for polypeptide hormones. Five cancers grew adequately in vitro to permit study of 190 detailed karyotypes (20 to 50 per tumor). Chromosome modal numbers ranged from 49 to 109. There were from 4 to 20 clearly abnormal marker chromosomes per tumor; abnormality derived from chromosome 1 was prevalent. Ten of 19 tumors xenotransplanted to nude mice were carried through two to five transplant generations without a change in histologic patterns.

Animals↗
PubMed1987

Differential susceptibility to bronchial carcinogenesis in syngeneic hamsters.

Previous studies of chemical carcinogenesis in the lung of Syrian golden hamsters have utilized outbred (nonsyngeneic) animals. Using the endobronchial sustained release implant technique, which causes focally originating cancers in outbred hamsters, we studied the course of bronchial carcinogenesis in two varieties of syngeneic Syrian golden hamsters, the LSH and the F1D strains (BIO 15.16 male X BIO 87.20 female). With either 10% benzo(a)pyrene or 10% methylcholanthrene sustained release implants the time course of epithelial transition from normal to neoplastic was the same for F1D hamsters as previously described for outbred hamsters. Using 10% benzo(a)pyrene sustained release implants the incidence of cancers as a function of time was significantly lower (P less than 0.001) in LSH hamsters as compared to outbred and F1D animals. Of 19 tumors transplanted into syngeneic F1D hamsters, 16 have been successfully propagated by serial transplantation. We conclude that (a) F1D hamsters are comparable to outbred animals in the response of their bronchial epithelium to endobronchial benzo(a)pyrene and methylcholanthrene, (b) there are significant differences in susceptibility to bronchial chemical carcinogenesis among hamster strains, thereby giving opportunity to study potential genetic control mechanisms during bronchial carcinogenesis, and (c) F1D hamsters are suitable for studies of lung cancer biology using tumor transplantation methods.

Animals↗
PubMed1987

Surgical management of lymphomas involving the chest.

The efficacy of surgical judgments in the management of thoracic lymphoma was studied through review of 34 patients with primary mediastinal lymphomas, 30 patients who needed one or more thoracic operations after treatment of extrathoracic lymphomas, and 5 patients with primary lymphocytic infiltrates (PLI) of the lung. In all patients with primary lymphocytic infiltrates of the lung, thoracotomies were required in order to establish the correct diagnosis. Patients with primary mediastinal lymphoma required 74 surgical procedures (2.2 per patient) to establish the correct diagnosis. In retrospect, 40 operations were not beneficial. The procedures that provided diagnostic samples were 15 anterior mediastinotomies, 8 full thoracotomies, 3 median sternotomies, and 8 lesser procedures such as mediastinoscopy. Patients who needed thoracic procedures after treatment of extrathoracic lymphomas had 41 thoracic operations (1.37 per patient). Five operations were needed to manage complications of thoracic lymphoma or its therapy. To evaluate new radiographic findings, there were 35 operations (1.3 per patient) at a mean interval of 5.0 years following initial treatment; the findings were recurrent lymphoma in 62% and new lesions in 38% of patients. Among new lesions, there were 2 bronchogenic cancers; 9 enlarging mediastinal-pleural masses were not caused by lymphoma. The accurate diagnosis of thoracic lymphoma or new thoracic lesions in patients with lymphomas usually requires enough tissue for immunophenotyping. Providing adequate tissue samples and treating new lesions that are not lymphomas often require major thoracomediastinotomies for immunophenotyping.

Adolescent↗
PubMed1986

Occult primary adenocarcinoma with axillary metastases.

The medical charts of 20 women with occult primary adenocarcinoma with axillary metastases were reviewed. An extensive radiologic workup in search of the primary lesion had a less than 7 percent positivity rate in the 74 studies carried out. Eleven patients were treated with mastectomy, 5 of whom were found to have carcinoma (49 percent). Four of the 11 patients, all with 14 or more positive axillary lymph nodes, died from breast cancer. Seven patients with no evidence of disease had an average of 4.6 positive axillary lymph nodes. Seven patients did not receive mastectomy, and one died from breast cancer. There was no significant difference in survival between the group treated with mastectomy and the group treated with axillary dissection. We conclude that mastectomy is unnecessary for patients with adenocarcinoma in axillary nodes but no apparent primary tumor.

Adenocarcinoma↗
PubMed1986

Pneumothorax associated with lymphoma.

Pneumothorax in patients with lymphoma has rarely been reported. We have encountered 8 patients with lymphoma with 17 episodes of pneumothorax; these episodes occurred 3 months to 8 yr in 7 patients after the diagnosis of Hodgkin's disease (HD) and in 1 patient with non-Hodgkin's lymphoma (NHL). The observed incidence of pneumothorax among 1,977 patients with lymphoma was 10-fold higher than expected; this included a significantly higher incidence in patients younger than 30 versus those older than 30 yr of age (1:552 versus 1:5,788 patient-years, p less than 0.001), and a higher incidence in patients with HD than in those with NHL (1:708 versus 1:5,072 patient-years, p less than 0.005). There was a strong suggestion of increased risk for pneumothorax in patients treated with radiotherapy as compared with patients treated without irradiation (1:1,016 versus 0:1,963 patient-years, p = 0.065). Apparent additional contributing factors in 6 patients were lung involvement with lymphoma (n = 2), radiation fibrosis (n = 3), and infection (n = 1). Pneumothorax was persistent in 5 patients, bilateral in 4, and recurrent in 2. The occurrence of pneumothorax in 2 patients heralded death. Management commonly required placement of chest tube (n = 9) or major surgical procedures (n = 5). We conclude that pneumothorax may be more common among patients with lymphoma than previously appreciated. Young age, HD, and probably radiotherapy are predisposing factors. The pneumothoraces associated with lymphoma are more complex and ominous and more difficult to manage than the usual spontaneous pneumothorax. In patients with lymphoma, pneumothorax is likely to be secondary to underlying abnormality of the lung.

Adolescent↗
PubMed1986

Differential interaction of normal and preneoplastic hamster bronchi with adriamycin.

Advanced bronchogenic carcinoma in humans is notoriously resistant to the cytocidal actions of cancer chemotherapy. The experiments reported here were undertaken as a first step in examining the mechanisms of resistance of carcinogen-altered bronchus to the actions of the commonly used cancerocidal agent Adriamycin. Syrian Golden hamsters were treated with an endobronchial carcinogen in order to produce bronchial neoplasms or with no carcinogen as controls. Hamsters were then given i.v. Adriamycin, and the amounts and metabolism of bronchial Adriamycin were determined. Peak uptake values were found 5 min after Adriamycin administration, and the amounts of Adriamycin in normal and carcinogen-altered bronchi were found to be similar. Whereas no metabolism of Adriamycin was observed in normal bronchi, 40-60% of total Adriamycin fluorescence was found to be due to Adriamycinol and Adriamycin aglycones in bronchi with premalignant changes. In separate experiments, the susceptibility of normal and carcinogen-altered bronchial extracts to drug-induced lipid peroxidation was measured in vitro. A 50% decrease was found in the ability of carcinogen-altered bronchi to act as a substrate for lipid peroxidation mediated by Adriamycin and an approximately 30% decrease for lipid peroxidation induced by t-butyl-hydroperoxide. These results demonstrate two different mechanisms by which bronchogenic carcinomas might become resistant to the chemotherapeutic actions of Adriamycin. These are by the carcinogen induction of metabolism of Adriamycin to less toxic products and by resistance of the bronchi to free radical damage.

Animals↗
PubMed1986

Carcinogenesis in heterotopic respiratory epithelium in canine subcutaneous bronchial autografts.

Short bronchial segments obtained by pneumonectomy were implanted, 9-12 per dog, in the subcutaneous tissues of the back of seven dogs. These subcutaneous bronchial autografts (SBA) became vascularized, and they contained viable, histologically normal respiratory epithelium 4 wk after implantation. From 1-3 mo after implantation, 10% methylcholanthrene in steroid suspension medium was instilled into 21 SBAs, and 10% methylcholanthrene in a silicone polymer sustained release implant was placed in 22 SBAs. Ten SBAs were left carcinogen free as controls. SBA contents were examined cytologically at 3-mo intervals. Biopsies were done from 2-32 mo after carcinogen implantation. Progressive preneoplastic changes were noted in all five dogs which received carcinogen. Curetments of five SBAs after 14-mo exposure to methylcholanthrene yielded 10(4)-10(5) cells from each SBA; 40-70% of the cells obtained were at the same stage of atypical squamous metaplasia. At least one SBA in each dog yielded cancer cells by cytological criteria by 19-29 mo after instillation. Biopsy of a grossly abnormal SBA revealed well-differentiated epidermoid carcinoma at 32 mo. The multiple SBA method provides isolated portions of canine respiratory epithelium for the study of chemical carcinogenesis and for the production of sizable preneoplastic cell populations.

Animals↗
PubMed1986

Bronchogenic carcinoma associated with upper aerodigestive cancers.

Of 1,450 patients with upper airway cancers, 189 (13%) had additional cancers. There were 60 cases in which lung cancer occurred after upper airway cancer and a single case in which it preceded upper airway cancer. The occurrence of upper airway plus lung cancer in 61 patients was referred to as multiple airway cancers. The overall incidence of multiple airway cancers was 4.1%, or 1:112 patient-years at risk. The highest incidence of lung cancer was 1:70 patient-years, and this was associated with laryngeal cancer. The mean diagnostic interval between upper airway and lung cancers was 6.1 (0 to 23) years, including nine cases (14.8%) in which the two were synchronous. Triple endoscopy revealed occult lung cancer only once. The use of mediastinoscopy (n = 9) and other surgical staging procedures (n = 9) was limited, because previous treatment of upper airway cancers made such procedures impractical and also because interpretation of findings would have been difficult. Past reports have indicated that lung cancer in association with upper airway cancer is almost invariably squamous cell and almost always develops in men. By contrast, among our 61 patients, the incidence of adenocarcinomas was 24%, and 16 patients or 26% were women. Among patients whose records could be evaluated in this regard, symptoms were present in 27 of 55 (49%); the cancers were in Stage III at presentation in 51%. Outcome was related to symptomatology and to lung cancer stage. The median survivals for symptomatic and asymptomatic patients were 6 and 25 months, respectively (p less than 0.001); the median survivals for patients with Stage I, II, and III lesions were 26, 9, and 6 months, respectively (p less than 0.05). Post-thoracotomy management after surgical-radiation therapy of upper airway cancers (n = 22) was inordinately challenging because of preexisting impairment of the upper airways. We have reached the following conclusions: Patients with upper airway cancer are at high risk for lung cancer of all cell types. When multiple airway cancers occur together, the prognosis is poor; nonetheless, cure of each cancer can be achieved if it is completely and adequately treated. When multiple airway cancers occur synchronously, the more life-threatening cancer should be treated first. When the option exists, the lung cancer should be treated before the upper airway cancer to avoid the impact of previous irradiation and/or surgical treatment of the upper airway cancer upon post-thoracotomy management.

Adenocarcinoma↗