Biomedical subjects
Publications and source records attributed to R F Morton.
Thirty patients with recurrent primary brain tumors were treated with a combination of 5-fluorouracil and leucovorin. There were three responses seen. Toxicity consisted of stomatitis, diarrhea, and hematological suppression. 5-fluorouracil and leucovorin would appear to be minimally effective in recurrent brain tumors.
An increase in the proportion of advanced malignancies among rural residents has been noted and may be due to a combination of factors, including availability of screening services, demographic characteristics, and access to health care facilities. A cross-sectional study was conducted in 33 nonmetropolitan Iowa counties among randomly selected middle-aged farm and rural nonfarm adults to compare utilization of cancer early detection services. A total of 1,126 adults in 600 farm households and 1,092 adults in 589 rural nonfarm households provided information through a 155-item in-home interview. Differences in income, age, and health insurance coverage (including preventive services) between the farm and nonfarm study populations were found. Although farm men were less likely to have had a checkup during the past year than men in the nonfarm population, no difference was found for women. Overall, differences in screening behaviors were small. Larger differences between both populations were observed for use of mammograms, prostate examinations among men age 50 and older, use of sigmoidoscopy among women age 50 and older, and skin cancer examinations among both sexes. When controlling for demographic characteristics and insurance coverage, members of the farm and rural nonfarm population were equally likely to use multiple screenings according to ACS guidelines. Because of the increased risk of breast cancer, interventions aimed at increasing utilization of mammography among women age 50 and older should be implemented. Although the farm population was more likely to use skin examinations, prevalence should be increased substantially to counteract the continuing rise in skin cancer.
Experiments were carried out to characterize the cardiorespiratory reflex responses to intravenous injection of lactic acid and to determine the involvement of vagal bronchopulmonary C-fiber afferents in eliciting these responses in anesthetized rats. Bolus injection of lactic acid (0.2 mmol/kg i.v.) immediately elicited apnea, bradycardia, and hypotension, which were then followed by a sustained hyperpnea. The immediate apneic and bradycardiac responses to lactic acid were completely abolished by bilateral vagotomy and were absent when the same dose of lactic acid was injected into the left ventricle. The subsequent hyperpneic response was substantially attenuated by denervation of carotid body chemoreceptors. After a perineural capsaicin treatment of both vagus nerves to block the conduction of C fibers, lactic acid no longer evoked the immediate apnea and bradycardia, whereas the hyperpneic response became more pronounced and sustained, presumably because of the removal of the inhibitory effect on breathing mediated by pulmonary C-fiber activation. Single-unit electrophysiological recording showed that intravenous injection of lactic acid consistently evoked an abrupt and intense burst of discharge from the vagal C-fiber afferent endings in the lungs. In conclusion, the cardiorespiratory depressor responses induced by lactic acid are predominantly elicited by activation of vagal pulmonary C fibers.
OBJECTIVE: To characterize a clinical syndrome that occurs in some women who have undergone breast or axillary lymph node biopsy or partial mastectomy. MATERIAL AND METHODS: Six case reports are presented, the clinical and histopathologic findings are described, and the implications for recognition of this entity are discussed. RESULTS: Patients who had undergone partial mastectomy, breast biopsy, or axillary lymph node excision shortly thereafter had clinical signs (most notably, erythema and edema) suggestive of infectious mastitis or inflammatory breast cancer. Representative histologic sections of involved skin revealed dilated dermal vessels without specific evidence of infection or cancer. Although antibiotic therapy was generally ineffective, the clinical findings resolved with time (from 2 months to 1 year). This condition should be considered in the differential diagnosis when this circumscribed patient population has such intervention-related symptoms. CONCLUSION: This clinical syndrome may mimic an infectious or neoplastic process, but we hypothesize that it is due to interruption of lymphatic vessels. Appropriate recognition may alter the use of antibiotic therapy or surgical intervention.
This intergroup trial was developed to determine the toxicity of relatively low doses of difluoromethylornithine (DFMO) administered to humans for 1 year. The goal was to find an appropriate DFMO dose for use in human chemoprevention trials. Patients with resected superficial bladder cancers were studied. Following stratification, they were randomized to daily DFMO doses of 0.125, 0.25, 0.5, or 1.0 g/day for a planned period of 1 year. Patients were followed closely for evidence of drug toxicity. Seventy-six patients were evenly randomized (19 per group) to receive each dose of DFMO. Forty-nine patients received DFMO for more than 200 days while 35 received the drug for > or = 350 days. No substantial drug-related toxicity was observed at any dose. DFMO doses of > or = 1 g/day for periods up to 1 year appear to be without significant toxicity in most patients. This dose range may be appropriate for use in future human cancer chemoprevention trials.
We prospectively treated 46 patients with favorable myelodysplastic syndrome classified as refractory anemia (RA), refractory cytopenia (RC), or refractory anemia with ringed sideroblasts (RARS). These patients received one of two schedules of 13-Cis-Retinoic Acid (low dose 80 mg daily for 6 months vs. high dose 200 mg po daily for 3 months), or Danazol (800 mg po daily for 3 months), and were crossed over to the alternative drug in the absence of response or at progression. Using strict criteria of response we found little objective evidence of activity for either compound. Only two minor responses were seen among 22 patients treated with low dose 13-CRA, 1 response among 20 cases that received high dose 13-CRA, and 1 partial response and 1 minor response to Danazol among 34 cases. Neither 13-Cis-Retinoic Acid nor Danazol appear active enough in patients with favorable myelodysplastic syndrome to justify their use.
Amonafide, a novel imide derivative with broad preclinical antitumor activity, achieves significant cerebrospinal fluid levels in animal models. In order to test its antitumor activity in patients with recurrent diffuse infiltrative glioma of the astrocytic and oligodendroglial type, we performed a phase II clinical trial. Of the 22 eligible and evaluable patients treated, 2 (9%) experienced tumor regression lasting more than one year. No other patients experienced tumor regression; one remained stable more than six months. Toxicities consisted primarily of myelosuppression, vomiting, and venous irritation at the infusion site. We conclude that amonafide has minimal activity in recurrent glioma patients. Further investigations are not warranted in this study population.
Stimulation of vagal pulmonary C-fiber afferents by chemical irritants is believed to be responsible for eliciting the pulmonary chemoreflex (apnea, bradycardia, and hypotension). This study was carried out in anesthetized Sprague-Dawley rats to determine whether the pulmonary chemoreflex was altered by prostaglandin E2 (PGE2), which is one of the major inflammatory mediators in the lungs and is known to enhance the sensitivity of C-fiber afferents in several other organ systems. Capsaicin injected at a dose just above the stimulation threshold (0.25 or 0.5 microgram/kg i.v.) elicited a very mild respiratory and cardiovascular depression. In sharp contrast, during a constant infusion of PGE2 (1.5 micrograms.kg-1.min-1 i.v.), the same dose of capsaicin triggered a long apnea, with the expiratory duration reaching 843% of the baseline expiratory duration, accompanied by intense bradycardia and hypotension. Similarly, the pulmonary chemoreflex response elicited by a bolus injection of phenyl biguanide (1 or 2 micrograms/kg i.v.) was also greatly augmented by PGE2. These enhanced responses were completely abolished, by a perineural capsaicin treatment of both cervical vagi to selectively block the conduction of C fibers, suggesting the involvement of these afferents. Electrophysiological recording of pulmonary C-fiber afferent activity further supported our conclusion that the sensitivity of these sensory endings to capsaicin challenge was potentiated by PGE2.
PURPOSE: We conducted a randomized prospective trial in selected patients with fully resected high-risk stage I and II malignant melanoma. PATIENTS AND METHODS: Interferon alfa-2a (IFN-alpha 2a) 20 x 10(6) U/m2 was administered three times each week for 12 weeks by the intramuscular route. Both the treatment group (n = 131) and the control group (n = 131) were evenly balanced with regard to relevant prognostic discriminants. RESULTS: The median disease-free survival (DFS) time was 2.4 years for the IFN-alpha 2a group and 2.0 years for the observation group (log-rank P = 0.19). The median survival times were 6.6 years for IFN-alpha 2a and 5.0 years for observation (log-rank P = .40). For stage I patients (n = 102), there was no apparent therapeutic advantage from IFN-alpha 2a therapy. The DFS for stage II patients was a median of 10.8 months in the control group versus 17 months in the treatment group. The overall survival time was 4.1 years for the treatment group versus 2.7 years for the control group. The differences in DFS for stage II patient were significant in a Cox model. These results must be interpreted cautiously because of subset analysis. A severe flu-like toxicity occurred in 44% of patients, 13% lost at least 10% of their baseline weight, and 45% experienced a worsening of Eastern Cooperative Oncology Group (ECOG) performance score. CONCLUSION: Our findings indicate trends that suggest a possible benefit for selected patients with high-risk malignant melanoma. The results will require further study in a larger patient population for confirmation.
BACKGROUND: Long-term survival with extensive stage small cell lung cancer is rare. There have been no major advances in the treatment of this stage of disease in the last 15-20 years. New agents with activity against this malignancy are needed. This study was designed to evaluate the efficacy of edatrexate against small cell lung cancer in a Phase II trial. METHODS: This was a multicenter cooperative oncology group trial. Patients were either previously untreated or had failed only one prior chemotherapy regimen. All previously untreated patients had extensive stage disease. Patients in whom prior therapy had been unsuccessful had either limited or extensive stage disease. All cases had histologic documentation. Patients received edatrexate (80 mg/m2) intravenously over 20-30 minutes every 7 days. Previously untreated patients with disease progression at any time or stable disease after 6 weeks of treatment were crossed over to treatment with cisplatin and etoposide. The primary end points of the study were clinical response and toxicity to edatrexate. All patients were observed for survival. RESULTS: Eleven previously untreated and 22 previously treated patients were enrolled. A median of five doses of chemotherapy was given to each group. No major clinical response was observed in either group. The median survival time for the 11 previously untreated patients was 9.8 months versus 3.7 months for individuals who had received prior therapy. Myelosuppression and stomatitis were the primary toxicities, and both were infrequent. CONCLUSIONS: Edatrexate is inactive against small cell lung cancer.
Several randomized, placebo-controlled clinical trials have demonstrated that megestrol acetate therapy can result in appetite stimulation and nonfluid weight gain in patients with cancer anorexia/cachexia. The present trial was designed to compare megestrol acetate doses ranging from 160 to 1,280 mg/day. day. This trial randomly assigned 342 evaluable patients with cancer anorexia/cachexia to receive oral megestrol acetate at doses of 160, 480, 800 and 1,280 mg/day. Patients were evaluated monthly by history, examination and patient-completed questionnaires, as well as by serum albumin levels. The data demonstrate a positive dose-response effect for megestrol acetate on appetite stimulation (p = 0.02). there was a trend for more nonfluid weight gain with higher drug doses. Megestrol acetate was well tolerated in this group of patients with advanced malignant disease. The positive dose-response effect observed for megestrol acetate on appetite stimulation supports both the prestudy hypothesis and findings in the literature. The optimal dose in this study seemed to be 800 mg/day; no further benefit was derived from using the higher dose. Nonetheless, it may be reasonable to start with lower initial doses in routine clinical practice, taking into account dosage form, availability and cost of therapy.
Effects of histamine on the base-line activity of vagal pulmonary C-fibers and their responses to chemical and mechanical stimulations were studied in anesthetized, open-chest dogs. Histamine aerosols (5 breaths, 1% solution) increased the change in tracheal pressure per breath (delta Pt) to 53 +/- 9% (mean +/- SE) above its base line, whereas an accompanying increase in activity was found in only 27% of the C-fibers studied and hence the overall afferent activity was not significantly different from the control. After Pt returned toward the base line in several minutes, the receptor activity evoked by right atrial injection of capsaicin (0.8-4.0 micrograms/kg) increased from a base line of 0.43 +/- 0.02 imp/sec to 8.12 +/- 1.16 imp/sec (averaged over 10 sec), which was markedly greater and longer lasting than the response triggered by the same dose of capsaicin after phosphate buffer aerosols (4.72 +/- 0.71 imp/sec). Furthermore, pretreatment with histamine aerosols also enhanced the afferent responses of these receptors to static lung inflation (Pt = 20 cmH2O). We conclude that the low dose of histamine aerosols alone did not consistently stimulate the vagal pulmonary C-fibers, but it potentiated the stimulatory effects of both capsaicin and lung inflation on these receptors.
To determine whether the irritant effect of cigarette smoke on breathing was affected by chronic exposure to smoke, two groups of sixteen young male Sprague-Dawley rats were exposed daily to fresh cigarette smoke (treated group) or air (control group) for 4-8 wk. Acute ventilatory response to cigarette smoke (50% concn, 6 ml volume) inhaled via a tracheal cannula was then studied under anesthesia and compared between the two groups. Inhalation of either cigarette smoke or gas phase smoke induced an immediate and transient apnea or bradypnea that was completely abolished by bilateral vagotomy in both groups, suggesting the involvement of vagal bronchopulmonary afferents. However, the apneic response was markedly attenuated in the treated group. Inhalation of cigarette smoke, but not the gas phase smoke, also induced a delayed tachypneic response after the initial apnea. The tachypneic response was again significantly smaller in treated rats, and this difference between the two groups was eliminated after vagotomy. On the basis of these results, we suggest that a reduced stimulatory effect on vagal bronchopulmonary sensory receptors was responsible for the attenuated ventilatory responses to smoke observed in treated rats.
PURPOSE: Several placebo-controlled randomized clinical trials have demonstrated that megestrol acetate can result in appetite stimulation and nonfluid weight gain in patients with cancer anorexia/cachexia. The present trial was designed to compare megestrol acetate doses ranging from 160 to 1,280 mg/d. METHODS: This trial randomized 342 assessable patients with cancer anorexia/cachexia to receive oral megestrol acetate at doses of 160, 480, 800, or 1,280 mg/d. Patients were evaluated monthly by history, examination, patient-completed questionnaires, and serum albumin levels. RESULTS: The data demonstrate that there is a positive dose-response effect for megestrol acetate on appetite stimulation (P < or = .02). In concert, there was a trend for more nonfluid weight gain with higher drug doses. Megestrol acetate was well tolerated in this group of patients with advanced malignant disease. CONCLUSION: The positive dose-response effect that we observed for megestrol acetate on appetite stimulation supports both our prestudy hypothesis and other available literature. Nonetheless, based primarily on the cost and inconvenience associated with the use of higher doses of this drug, it is reasonable to use 160 mg/d for the initial treatment of cancer anorexia/cachexia in routine clinical practice.
One hundred forty-two patients with progressive, hormonally refractory advanced prostate carcinoma who had not received prior chemotherapy were randomized to receive either combination chemotherapy with 5-fluorouracil (5-FU), doxorubicin, and mitomycin C (FAM) or sequential chemotherapy with the same agents, i.e., mitomycin C, followed by doxorubicin on disease progression, followed by 5-FU. Objective tumor regressions were observed in 10 of 70 (14%) patients receiving the FAM treatment arm and 10 of 72 (14%) patients initially receiving mitomycin C. Of the 24 patients who received secondary therapy with doxorubicin alone, 3 (12.5%) achieved objective tumor regression. There were no responses among five patients who received tertiary therapy with 5-FU alone. The median survival time for all patients treated with the combination arm was 8.7 months, compared with 7.1 months for patients who received the FAM arm (P = 0.025). However, this modest survival advantage in favor of the FAM treatment arm must be weighed against significantly more myelosuppression experienced by these patients. The chemotherapeutic regimens used in this study have only minor clinical value in the treatment of hormonally refractory advanced prostate cancer.
Spontaneous inhalation of acrolein vapor (350 ppm, 1 ml/100 g body wt) elicited an immediate and transient inhibitory effect on breathing in anesthetized rats, characterized by a prolongation of expiratory duration and accompanied by a bradycardia; ventilation was reduced by 47 +/- 6%, which returned to baseline after three to seven breaths. When both vagi were cooled to 6.6 +/- 0.1 degrees C, the reflex apneic response to lung inflation was completely abolished but the bradypneic response to acrolein was not affected. After perineural capsaicin treatment of both cervical vagi to selectively block the capsaicin-sensitive C-fiber afferents, acrolein no longer evoked an inhibitory effect on breathing; conversely, an augmented inspiration was consistently elicited with the first breath of acrolein inhalation, which was subsequently abolished by cooling both vagi to 6.5 degrees C. The inhibitory effect of inhaling acrolein at a lower concentration (200 ppm) was not detectable, whereas that of a higher concentration (600 ppm) was more intense and prolonged. All these responses were completely eliminated by bilateral vagotomy. These results suggest that inhaled acrolein activated both vagal C-fiber endings and rapidly adapting irritant receptors in the airways, but the acrolein-induced inhibitory effect on breathing was elicited primarily by the C-fiber afferent stimulation.
The objective of this study was to determine the effect of circulated nicotine on rapidly adapting receptors (RARs) in canine lungs. Afferent activities of RARs were studied with a single fiber recording technique in 10 anesthetized, open-chest and artificially ventilated dogs. Bolus injection of nicotine (10 micrograms/kg) into either right or left atrium did not activate the RARs in the first two breaths, but it consistently evoked a mild stimulatory effect beginning approximately 3-6 breaths after the injection, accompanied by a mild increase in tracheal pressure (Pt). There was no significant difference between the receptor responses to nicotine injected via these two different routes in either the peak discharge or the latency time. By contrast, nicotine delivered by cigarette smoke directly into the airways triggered an intense burst of activity upon the very first breath of smoke delivery. Taken together, these results suggest that the sensory endings of RARs are located near the surface of airway epithelium, more easily accessible from the luminal side of the airways. The delayed stimulation of RARs following the nicotine injection was probably activated by the bronchoconstrictive effect of nicotine.
OBJECTIVE: To compare the survival of patients with medically inoperable or unresectable stage III non-small cell lung cancer treated with thoracic radiotherapy alone or in combination with chemotherapy. DESIGN: Randomized, prospective phase III trial. SETTING: Multi-institutional cooperative oncology group. PATIENTS: A total of 121 patients were enrolled in the study, of whom 7 (5.8%) were ineligible. All patients were ambulatory and had measurable or evaluable disease. Before they were randomized, patients were stratified by ECOG performance score, histologic type, maximum tumor diameter, and NCCTG institution. INTERVENTIONS: Radiotherapy consisted of a total of 5000 cGy in 5 weeks with a 1000 cGy boost in 5 fractions to a small tumor field. Combined modality therapy was MACC which is intravenous methotrexate, intravenous doxorubicin, intravenous cyclophosphamide, and oral lomustine (CCNU), on day 1 and 28. Chemotherapy was followed by identical thoracic radiotherapy 4 weeks after the second cycle of chemotherapy. Four weeks after thoracic radiotherapy was completed, patients received another two cycles of identical chemotherapy. Patients who had progression of disease after chest irradiation only were treated with MACC chemotherapy. MAIN RESULTS: Major clinical responses were observed in 31 of 56 (55%; 95% Cl, 42% to 68%) patients treated with combination therapy and 37 of 58 (64%; Cl, 51% to 76%) treated with radiation only (P greater than 0.2). The median time to progression was 192 days with radiotherapy only compared with 199 days for combined modality therapy (P greater than 0.2). The median survival time was 313 days compared with 317 days, respectively (P greater than 0.2). The 1-, 2-, and 5-year survival rates after thoracic radiation only were 45% (Cl, 32% to 58%), 16% (Cl, 6% to 25%), and 7%. With chemoradiotherapy, the survival rates were 46% (Cl, 33% to 60%), 21% (Cl, 11% to 32%), and 5%, respectively. Myelosuppression was significantly greater for the combined modality therapy arm (P = 0.002). CONCLUSION: Chemotherapy with MACC, in combination with thoracic radiotherapy, did not result in significant survival advantage compared with radiation alone (P greater than 0.2) in patients with medically inoperable or unresectable stage III non-small cell lung cancer.