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Biomedical subjects

T L Phillips

Publications and source records attributed to T L Phillips.

At least 145 records · Page 8Linked to original sources
PubMed1985

Misonidazole and hemibody irradiation in the palliation of widespread metastases. Final report of an RTOG study.

The radiation therapy oncology group conducted a phase I/II trial of hemibody irradiation combined with high-dose misonidazole in the management of metastatic solid tumors. Thirty-seven patients received 39 hemibody irradiation treatments, each preceded by 4 g/m2 or 5 g/m2 misonidazole orally. One fraction of 600 cGy was delivered to a half-body volume. Objective tumor response occurred in 21% of evaluable patients, including one complete response. Pain relief was documented in only 36%. Acute toxicity consisting of nausea and vomiting was significant; 54% of patients experienced severe or very severe reactions. Other toxicities were acceptable. The low response rate and high acute toxicity contraindicate the use of misonidazole with hemibody irradiation for palliation.

Administration, Oral↗
PubMed1985

Pre-enucleation irradiation of uveal melanoma.

The relative efficacy of various types of treatment in preventing metastatic uveal melanoma is unclear. We have performed a phase I-II non-randomised trial to determine if patients with large (greater than 15 mm in diameter or greater than 5 mm in thickness) uveal melanomas would benefit from pre-enucleation irradiation. Twenty-eight patients were treated between 1978 and 1983 by means of 5 X 5 cm anterior wedge pair ports on a 4 me V linear accelerator. Each patient received five 4 gray (400 rad) fractions over a five-day period for a total of 20 Gy. Enucleation was performed by a single surgeon within five days after treatment. The mean follow-up of the patients was 24 months (range 7-54 months). All melanomas were histologically confirmed. Four patients (14%) have developed metastatic tumour with a mean interval between diagnosis and death of 25 months. No significant perioperative or long-term morbidity was observed.

Clinical Trials as Topic↗
PubMed1985

Helium-ion radiation therapy at the Lawrence Berkeley Laboratory: recent results of a Northern California Oncology Group Clinical Trial.

We report on the first decade of the helium-ion radiotherapy clinical trial being carried out at the Lawrence Berkeley Laboratory. Over 500 patients have now been treated. We have had very good results to date in treating patients with small tumors critically located near a radiation-sensitive organ which would preclude delivering a curative dose with conventional radiotherapy. On the other hand, patients with larger tumors where the tumor dose cannot be increased more than 10% over conventional radiotherapy have not responded well to helium ion radiotherapy. This is illustrated by discussing selected patient groups in detail, namely those with uveal melanoma, small, low-grade tumors near the central nervous system, carcinoma of the pancreas, and carcinoma of the esophagus.

Adenocarcinoma↗
PubMed1985

Radiation brain damage induced by interstitial 125I sources: a canine model evaluated by quantitative computed tomography.

The canine brain is a good model of the human brain for studying radiation damage after megavoltage x-irradiation for brain tumors. We have further developed this model to study radiation damage induced by high activity interstitial 125I sources. Removable 125I sources were implanted in normal canine brains, and doses of 1,000 to 10,000 rads were delivered to a reference point at a 10-mm radius from the source; dose rates were 35 to 40 rads/hour at the reference point. Serial quantitative analysis of tissue damage (tissue density and contrast enhancement) was done using computed tomographic scanning up to 6 months after implantation and was compared to histopathological findings after the animals were killed. At doses greater than 19,000 rads (i.e., inside the reference point), frank coagulation necrosis was observed. Pronounced vessel-related changes, manifest as areas of contrast enhancement, corresponded to tissues receiving a minimum of 6,000 rads and a maximum of 19,000 rads. These results indicate that this model can be used in serial noninvasive studies to quantify the development of damage induced by interstitial irradiation and to provide dose-response information in individual animals.

Animals↗
PubMed1984

Regulation of intestinal goblet cells in situ, in mucosal explants and in the isolated epithelium.

Cholinergic secretagogues were previously shown to accelerate mucin secretion from intestinal goblet cells of adult rats and rabbits, both in vitro and in mucosal explants. This rapid secretory response occurs only in crypt cells; surface goblet cells are not affected. Rapid secretion involves the sequential fusion of secretory granule membranes with the plasma membrane and with each other, but does not require granule movement. In unstimulated cells, slow transport of secretory granules towards the luminal cell surface depends on functional microtubules. Goblet cells appear in the rat fetal intestine three to four days before birth but they are insensitive to cholinergic agents in the fetus and neonate. The secretory response of crypt goblet cells to carbachol, both in vivo and in mucosal slices in vitro, is established throughout the intestines only after weaning (20-25 days after birth). To determine whether acetylcholine from nerve endings in the intact mucosa may mediate a mucus secretory response in the absence of exogenous secretagogues, mucosal sheets were mounted in modified Ussing chambers and goblet cell secretion was assessed after electrical field stimulation. Electrical field stimulation elicited mucus secretion from crypt (but not surface) goblet cells. Secretion was inhibited by prior treatment of the mucosa with 500 nM-tetrodotoxin or 100 microM-atropine, but not by 10 microM-atropine. Thus, endogenous nerves may regulate mucus secretion from crypt goblet cells in the intact mucosa. When intact sheets of epithelium were isolated from adult rat ileum and colon, then maintained in vitro and exposed to 20 microM-carbachol, crypt goblet cells released mucin in response to the secretagogue but goblet cells in in portions of the epithelium derived from villi or mucosal surfaces were unresponsive. This suggests that crypt epithelial cells respond directly to cholinergic agents and that they lose this sensitivity as they migrate out of the crypts.

Animals↗
PubMed1984

Clinical trials with hypoxic cell sensitizers: time to retrench or time to push forward?

Results of world-wide clinical trials with misonidazole are discussed. An attempt is made to assess the reasons for the lack of positive results and the cost-benefit analysis is critically reviewed. The data on the clinical investigations of the second generation misonidazole analogues SR-2508 and RO-03-8799 are presented. Emphasis is placed on future work such as tumor selection for clinical trials, reduction of drug toxicity and methods to increase the drug radiosensitizing properties. Because of the large amount of knowledge, experience, productivity and good scientific clinical data accummulated with nitroimidazoles over the past five years, it is recommended that this is the time to push forward with the work on the newest, more efficient compounds.

Clinical Trials as Topic↗
PubMed1984

Is misonidazole neurotoxicity altered by the use of phenytoin and/or dexamethasone in RTOG 79-18 and RTOG 79-16?

An analysis of Misonidazole (MISO) neurotoxicity in RTOG 79-16 and RTOG 79-18 was undertaken to evaluate the incidence of neurotoxicity relative to dexamethasone dose and phenytoin use. MISO was administered as follows: 79-16 arm A, 1 gm/m2 5 days a week for a total of 10 gm/m2 in 2 weeks; 79-16 arm B, 2 gm/m2 twice weekly for a total of 12 gm/m2 in 3 weeks; and 79-18, 2.5 gm/m2 once a week for a total of 15 gm/m2 in 6 weeks. Practically all patients were on dexamethasone, and 240 out of 550 were on phenytoin for seizures. CNS toxicity and ototoxicity rates were no different between treatment groups with overall rates of 2.7 and 1.1%, respectively. Peripheral neuropathy (PN) was 5.1% in 79-16 arm A, 5.9% in 79-16 arm B, and 8.7% in 79-18. Phenytoin did not significantly alter CNS and PN toxicity rates. All ototoxicities occurred in patients not on phenytoin. There was no correlation between dexamethasone dose and incidence of neurotoxicity within each study. However, the incidence of (PN) for the combined studies was 6.4% (35/550) which is lower than 18.9% (85/449) for non-brain Phase III protocols where patients are rarely, if ever, on dexamethasone or other corticosteroids. Four hour and 24 hour plasma MISO levels, and 24 hour/4 hour MISO ratios did not correlate with toxicity.

Brain Neoplasms↗
PubMed1984

Chemical modifiers of cancer treatment.

It is clear that the investigators involved in chemical modification have reached an historical turning point in radiobiology. Studies in the 1960s concentrated on physical and chemical radiobiology, studying dose response relationships and initial chemical reactions. More recently, the area of biochemical radiobiology has been entered and studies of cellular modification of the initial events and cellular repair mechanisms have been initiated. The future would appear to belong to biochemical modulation. The ability to increase or decrease the various cellular components through enzyme blocking or stimulation gives much greater power to our abilities to chemically modify radiation and cytotoxic agents in the future. We are thus come from the winding country lane of sensitizer development to the complex city expressway of chemical modification. Non-nitro-compounds and pyrimidine analogs have entered the field, and cellular biochemistry has assumed a major role in our future progress. Although misonidazole has overall been a clinical failure, the investment in its laboratory and clinical study has opened up a whole new field of chemical modification based on sound biochemical principles.

Animals↗
PubMed1984

Brachytherapy of recurrent malignant brain tumors with removable high-activity iodine-125 sources.

Thirty-seven patients harboring recurrent malignant primary or metastatic brain tumors were treated by 40 implantations of high-activity iodine-125 (125I) sources. All patients had been treated with irradiation and most had been treated with chemotherapeutic agents, primarily nitrosoureas. Implantations were performed using computerized tomography (CT)-directed stereotaxy; 125I sources were held in one or more afterloaded catheters that were removed after the desired dose (minimum tumor dose of 3000 to 12,000 rads) had been delivered. Patients were followed with sequential neurological examinations and CT scans. Results of 34 implantation procedures were evaluable: 18 produced documented tumor regression (response) for 4 to 13+ months; five, performed in deteriorating patients, resulted in disease stability for 4 to 12 months. The overall response rate was 68%. In 11 patients, implantation did not halt clinical deterioration. At exploratory craniotomy 5 to 12 months after implantation, focal radiation necrosis was documented in two patients whose tumor had responded initially and then progressed, and in three patients whose disease had progressed initially (four glioblastomas, one anaplastic astrocytoma); histologically identifiable tumor was documented in two of these patients. All improved after resection of the focal necrotic mass and are still alive 10, 15, 19, 24, and 25 months after the initial implantation procedure; only one patient has evidence of tumor regrowth. The median follow-up period after implantation for the malignant glioma (anaplastic astrocytoma and glioblastoma multiforme) group is 9 months, with 48% of patients still surviving. While direct comparison with the results of chemotherapy is difficult, results obtained in this patient group with interstitial brachytherapy are probably superior to results obtained with chemotherapy.

Adolescent↗
PubMed1984

Promise of radiosensitizers and radioprotectors in the treatment of human cancer.

Over the past 30 years, as an understanding of radiation chemistry has developed, it has been possible to develop compounds which modify the initial radiochemical event. In addition, certain physiologic means such as hyperbaric oxygen or blood flow restriction have also been developed as methods to modify radiation response through the radiochemical processes. Following the success of certain hyperbaric trials, a great effort was made to develop chemical agents which would mimic oxygen in their sensitization of hypoxic cells. A large series of compounds have now been identified with such properties and several of these have entered clinical trial. The first compound to receive widespread testing, misonidazole, has proven too toxic to be used in adequate doses for clinically relevant sensitization. Two new nitroimidazole analogs, which are excluded from the central nervous system, promise to allow much higher degrees of sensitization in planned clinical trials and new non-nitro drugs are under development. Radioprotection can be achieved through various methods, including restriction in blood flow and the use of sulfhydryl-containing compounds which again modify the initial radiochemical events. To be successful in tumor therapy, such agents must be selective in protecting the normal tissues. One class of compounds, the thiophosphates, show differential protection of normal tissue vis-à-vis tumor through several mechanisms. After extensive animal testing, one of these compounds, WR 2721, is now in phase I clinical testing, with phase II evaluation planned for the near future. Other potential sensitizers with varying degrees of differential activity in tumor versus normal tissue are also discussed.

Clinical Trials as Topic↗
PubMed1984

Computed tomography analysis of the canine brain: effects of hemibrain X irradiation.

Radiation damage induced by megavoltage X irradiation in normal brain tissue can manifest as one of several pathologic processes depending upon the time of brain examination after irradiation. Serial quantitative computed tomography (QCT) analyses were used to study the development of radiation damage in the normal canine brain. Tissue density, volume of low density areas, magnitude and volume of contrast uptake, and ventricular volume were measured following hemibrain irradiation and were correlated with histopathology. Low density areas correlated with edema, demyelination, axonal swelling, and necrosis and appeared 3-4 months after irradiation. Large regions of contrast enhancement (coagulation necrosis and associated vascular changes) appeared 5-6 months after irradiation. Results from this study demonstrated that the pathologic changes induced in the dog brain after single doses of X rays were similar to the changes observed in nonhuman primates and man after exposure to radiation.

Animals↗
PubMed1984

Misonidazole neurotoxicity in rats: Part I. Evaluation of misonidazole neurotoxicity in rats by analysis of brain stem auditory and cortical evoked potentials.

The effects of misonidazole (MISO) on brain stem evoked potentials (BAEPs) and cortical evoked potentials (CEPs) were evaluated in 16 Sprague-Dawley rats treated with the agent. As found in previous studies, serial BAEP values were diagnostic of the onset of MISO toxicity before clinical signs and symptoms appeared. However, MISO had no effects on CEPs, which remained essentially unchanged through the course of the experiment. At histologic examination, significant changes were found in the area of the brain stem, but there was no histologic evidence of damage to cortical or subcortical structures caused by MISO administration. The results of this study suggest that the neurotoxic effects of MISO are species-specific, and that while the rat model may be useful for comparison of the relative toxic effects of nitroimidazole radiosensitizers, it is not a model suited for measurement of neurotoxicity caused by MISO in humans and nonhuman primates.

Animals↗
PubMed1984

Misonidazole neurotoxicity in rats: Part II. Effect of pre- and intermittent treatment with pentobarbital on misonidazole neurotoxicity in the rat.

Rats pretreated for 5 days with 50 mg/kg of pentobarbital tolerated statistically significant higher doses of misonidazole before the onset of misonidazole-induced neurotoxicity than rats treated intermittently with the same dose of pentobarbital. Presumably in pretreated rats, pentobarbital induced an increase in the activities of hepatic microsomal enzymes that led to a more rapid metabolism of misonidazole than in rats treated only intermittently.

Animals↗
PubMed1983

Evoked potentials in rats with misonidazole neurotoxicity. I. Brain stem auditory evoked potentials.

Central neurotoxicity produced in rats by daily administration of 300 mg/kg of misonidazole (MISO) 5 times/week for 4-5 weeks (total dose = 6.0 gm/kg) was evaluated weekly wit brain stem auditory evoked potentials (BAEPs). Compared to untreated control rats, all treated rats had a prolongation of the I-IV interpeak latency (p less than 0.005) at a mean of 13.2 +/- 2.7 days at a cumulative dose of approximately 4.0 gm/kg of MISO per rat. In some rats, the I-III and I-II interwave latencies were prolonged and waves III and IV were lost. Control rats did not show any significant alteration in BAEP latency or amplitude. Histopathologic examination of the brain stems of treated rats showed that necrotic lesions were present primarily in the nuclei of the tegmentum of the fourth ventricle, with scattered nuclear involvement in the cerebellar roof nuclei, inferior olive, and nucleus of the spinal tract of the trigeminal nerve. The cerebral cortex appeared to be normal in all treated rats. Changes in BAEPs caused by central neurotoxicity correlated with the histopathologic findings. We conclude that BAEPs are a sensitive method for evaluating MISO central neurotoxicity in the rat model.

Animals↗
PubMed1983

Desmoid tumors: local control and patterns of relapse following radiation therapy.

Desmoid tumors are benign neoplasms, arising from musculoaponeurotic tissues, which tend to be locally infiltrative, resulting in a high rate of local recurrence following surgical resection. Nineteen patients with desmoid tumors underwent radiation therapy at the University of California, San Francisco, between 1970 and 1980. Fifteen patients were referred with local recurrence following one or more surgical resections. Three patients were referred for initial radiation therapy with unresectable tumors, and one patient received planned postoperative irradiation following subtotal tumor resection. At the time of treatment, 8 patients had nonresectable disease measuring greater than 10 cm. Five patients had residual tumor masses measuring 4 to 6 cm, and six had only microscopic disease following resection. The majority of patients were treated to a tumor dose of 50-55 Gy at 1.6 to 1.8 Gy per fraction. With a median follow-up of 8 years, 13 patients remained free of recurrent disease following radiation therapy. The 5 year relapse free survival was 72% with 10 patients continuing to be free of disease 5 to 11 years following therapy. Local control was not related to the amount of disease present at the time of treatment. Of the 6 patients who developed recurrent disease, only 1 patient had a true in-field recurrence. Four patients recurred at the margin of the radiation field 1 to 5 years following therapy. Of these four patients, 3 were successfully salvaged while 1 died as a result of tumor extension into a major vessel. One patient with an extensive mesenteric mass did not respond to therapy and died 1 month post irradiation. The patient with the in-field recurrence and 1 patient with a marginal recurrence were successfully treated with combination chemotherapy. Moderate dose radiation therapy to desmoid tumors can result in lasting local control when surgical resection is not possible. Post operative radiation can improve the rate of local control for patients with a high risk of recurrence. As desmoid tumors tend to be locally infiltrative, fields must be very generous to prevent marginal recurrence. Systemic chemotherapy offers an alternative to ablative surgery in the event of local failure following radiation therapy.

Adolescent↗
PubMed1983

Helium charged-particle radiotherapy of locally advanced carcinoma of the esophagus, stomach, and biliary tract.

Sixty-five patients with squamous carcinoma of the esophagus (32 patients), carcinoma of the stomach (18 patients) and carcinoma of the biliary tract (15 patients) received from 6000 to 7000 equivalent rad (60-70 Gray-equivalents) of helium radiotherapy at 2.0 GyE per fraction, four fractions per day, using multiportal, spread-out Bragg peak therapy. All patients had locally advanced disease without evidence of distant metastases. Partial compensation for tissue inhomogeneities was accomplished. Although palliation of symptoms and regression of tumor was commonly seen, local failure occurred in most patients (77%). The median survival was 8 months. It does not appear that an increase in tumor dose relative to normal tissues can be achieved that would be high enough to increase locoregional control rates over historical control rates with low-LET irradiation. Further studies will be carried out with heavier particles such as neon or silicon in hopes of achieving greater biological effect on these difficult-to-control tumors.

Adenocarcinoma↗
PubMed1983

Periodic acid-Schiff positive deposits associated with aging in mouse brains.

Deposits which were heavily stained with periodic acid-Schiff's solution were observed in a serial study of mouse brain section. Their histochemical reactions to ferric acid, calcium, glycogen, amyloid, and mucopolysaccharide were negative. Many deposits were observed within 100 microns from the midline of the dorsal part of the ventral thalamic nucleus. The deposit sizes were directly related to the age of the mice (r2 = 0.99).

Aging↗