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Biomedical subjects

T L Phillips

Publications and source records attributed to T L Phillips.

At least 127 records · Page 7Linked to original sources
PubMed1988

Phase III trial of irradiation plus chemotherapy for patients with hepatic metastases and hepatoma: experience of the Northern California Oncology Group.

The effects of iv or intra-arterial chemotherapy added to hepatic irradiation were evaluated in a 3-arm randomized trial. Patients with predominantly hepatic metastases or with hepatoma were eligible. They were randomized to receive 2,100 cGy in seven fractions alone or with 5-fluorouracil given either intra-arterially or by iv infusion; doxorubicin and mitomycin were given by bolus simultaneously with the radiation in a single course. A total of 166 patients were entered in the study. Toxicity was acceptable, with no sign of enhanced radiation damage. Response was evaluated 4-6 weeks after treatment. No complete responses were seen, but partial responses greater than or equal to 50% were observed in the groups treated with radiation only (17%), radiation plus drug given iv (25%), and radiation plus drug given intra-arterially (20%) (P greater than .3). Disease progression occurred in a larger number of patients who received radiation only (29%) at 6 weeks than in the other 2 groups (7% and 18%, respectively; P less than .03). Thus, in terms of local response duration, the addition of chemotherapy enhanced the effect of the radiation. Survival was not different among the 3 groups.

Adult↗
PubMed1987

Transport of membrane-bound macromolecules by M cells in follicle-associated epithelium of rabbit Peyer's patch.

M cells in Peyer's patch epithelium conduct transepithelial transport of luminal antigens to cells of the mucosal immune system. To determine the distribution of specific lectin-binding sites on luminal membranes of living M cells and to follow the transport route of membrane-bound molecules, lectin-ferritin conjugates and cationized ferritin were applied to rabbit Peyer's patch mucosa in vivo and in vitro. The degree to which binding enhances transport was estimated by comparing quantitatively the transport of an adherent probe, wheat germ agglutinin-ferritin, to that of a nonadherent BSA-colloidal gold probe. When applied to fixed tissue, the lectins tested bound equally well to M cells and columnar absorptive cells. On living mucosa, however, ferritin conjugates of wheat germ agglutinin and Ricinus communis agglutinins I and II bound more avidly to M cells. Absorptive cells conducted little uptake and no detectable transepithelial transport. Lectins on M cell membranes were endocytosed from coated pits, rapidly transported in a complex system of tubulocisternae and vesicles, and remained adherent to M cell basolateral membranes. Cationized ferritin adhered to anionic sites and was similarly transported, but was released as free clusters at M cell basolateral surfaces. When applied simultaneously to Peyer's patch mucosa, wheat germ agglutinin-ferritin was transported about 50 times more efficiently than was bovine serum albumin-colloidal gold.

Animals↗
PubMed1987

Macromolecules can pass through occluding junctions of rat ileal epithelium during cholinergic stimulation.

Crypt, but not villus, goblet cells in the ileum accelerate their secretion of mucus within 5 min following cholinergic stimulation. This study was done to determine whether the macromolecular permeability and structure of occluding junctions in the ileum are altered during accelerated secretion. Rats were injected intravenously with horseradish peroxidase followed by carbachol (250 micrograms/kg, subcutaneous) and the intestinal mucosa was fixed 3-12 min later. In control mucosa (saline-injected), peroxidase filled lateral intercellular spaces up to the occluding junctions of both crypt and villus epithelium, but did not enter occluding junctions or pass into the lumen. In 3 of 8 carbachol-stimulated rats, peroxidase was present within occluding junctions in crypt epithelium and in the crypt lumen, although all intermembrane junctional fusion sites appeared intact. Villus epithelial occluding junctions, in contrast, continued to exclude peroxidase. In freeze-fracture replicas of crypt cells prepared after carbachol stimulation, we detected no structural changes in strand networks of occluding junctions that could account for increased paracellular permeability.

Animals↗
PubMed1987

A comparison of misonidazole sensitized radiation therapy to radiation therapy alone for the palliation of hepatic metastases: results of a Radiation Therapy Oncology Group randomized prospective trial.

Between May 1980 and July 1983, the RTOG conducted a randomized prospective study comparing external radiation therapy and misonidazole to radiation therapy alone for patients with hepatic metastases. Two hundred fourteen patients were accessioned to this study of whom 187 were evaluable. Radiation therapy was delivered to the whole liver to a dose of 21.0 Gy in 7 fractions. Misonidazole was administered orally, 1.5 gm/m2 daily 4-6 hr before each treatment. Patients in the two treatment groups were evenly distributed with respect to stratification variables including primary site, extent of metastatic disease, and Karnofsky Performance Score (KPS). End points examined included amelioration of hepatic pain, improvement of KPS and alkaline phosphatase, decrease in liver and tumor size, and survival. The addition of misonidazole did not significantly improve the therapeutic response to radiation therapy in any of the parameters studied. Hepatic irradiation was effective in relieving abdominal pain with 80% of the symptomatic patients achieving improvement following therapy. Pain was completely relieved in 54% of these patients. Patients with liver metastases from colon carcinoma improved more frequently than those with metastases from other primary tumor sites (p = 0.02). Relief of pain occurred more frequently in patients treated with radiation therapy and misonidazole (87%) compared with radiation therapy alone (74%) (p = 0.08). Palliation of pain was prompt, occurring within a median of 1.7 weeks from the initiation of treatment, and 94% of patients who improved did so within 6 weeks of treatment. The median duration of response was 13.0 weeks in the symptomatic patients; 52% of those surviving 3 months remained improved. KPS improved in 28% of patients. Serial CT scans revealed a partial response in 7% and a marginal response in 13% of patients. One patient had a complete response to treatment. The median survival of patients treated in this series was 4.2 months with no difference between the two treatment groups. Patients with metastases from colon carcinoma and an initial KPS of 80 or more (48% of the patient population) had a median survival of 5.8 months with radiation therapy alone compared with 6.6 months with radiation therapy and misonidazole (p = 0.36). There was no significant treatment related morbidity. Radiation therapy remains an excellent palliative tool for the management of patients with symptomatic hepatic metastases. Further research must continue to identify new methods of selectivity enhancing the tumor response to radiation therapy.

Alkaline Phosphatase↗
PubMed1987

Combined radiotherapy and chemotherapy with bleomycin and methotrexate for advanced inoperable head and neck cancer: update of a Northern California Oncology Group randomized trial.

Between 1978 and 1984, the Northern California Oncology Group (NCOG) conducted a randomized trial to study the efficacy of combined radiotherapy (RT) and chemotherapy (CT) for stage III or IV inoperable head and neck cancer. One hundred four patients were randomized to receive: (1) RT alone, or (2) RT plus CT. RT consisted of 7,000 cGy to the involved areas and 5,000 cGy to uninvolved neck at 180 cGy/fraction, five fractions/wk. CT consisted of bleomycin, 5 U intravenously (IV), twice weekly during RT, followed by bleomycin, 15 U IV, and methotrexate, 25 mg/m2 IV weekly for 16 weeks after completion of RT. Fifty-one patients in the RT alone group and 45 in the combined treatment group were evaluable. The local-regional complete response (CR) rate was 45% v 67% (P = .056); the 2-year local-regional control rate, including salvage surgery, was 26% v 64% (P = .001); and the incidence of distant metastasis was 24% v 38% (P greater than .25), for the RT alone and RT plus CT groups, respectively. The relapse-free survival curves were significantly different (P = .041), favoring the combined treatment. However, the survival curves were not significantly different (P = .16). Patient compliance to maintenance CT was poor. Bleomycin significantly increased the acute radiation mucositis, although the difference in late normal tissue toxicity was not statistically significant. Thus, bleomycin and concurrent RT produced a more favorable CR rate, local-regional control rate, and relapse-free survival, but the difference in survival was not statistically significant.

Adult↗
PubMed1987

[Heavy particle radiotherapy at the University of California Lawrence Berkeley Laboratory. Clinical studies by the Northern California Oncology Group].

At the university of California Lawrence Berkeley Laboratory, patients have been irradiated for 10 years with heavy ions (He, C, Ne, Si). Due to the biologic efficacy of this type of radiation as well as the possibility of a precise dose application, the tumors can be irradiated with very high doses without exposing the surrounding tissues. The experience gained in the treatment of more than 800 patients is presented. It shows that this radiation can be used to localize tumors situated near to particularly radiosensitive organs such as skull base, paraspinal region, and the eye.

Humans↗
PubMed1987

Pathology of delayed radiation brain damage: an experimental canine model.

Delayed radiation damage of normal brain can be a devastating complication of radiation therapy and generally occurs months to years after the initiation of therapy. Primarily restricted to the white matter, radiation damage is characterized by a number of histopathologic changes including coagulation necrosis, vascular alterations with fibrinoid necrosis, edema, and demyelination. Normal dogs were exposed to either 10, 15, or 30 Gy of X rays to a single hemisphere and the gross and histopathologic changes were evaluated qualitatively. A spectrum of changes was observed ranging from white matter edema to extensive white matter necrosis, and the extent, location, and type of damage were dependent upon radiation dose. Histopathologic changes were separated into three major categories based on the character and size of the lesions, with the most severe changes being similar to the types of changes described in human patients who have developed delayed radiation necrosis. Less severe forms of damage such as multifocal, sometimes confluent areas of microscopic necrosis with spongiotic borders and edema with severe axonal swelling were also observed. These latter changes are not well recognized as being due to radiation. The findings of this study also indicate that many of the changes ascribed to combined treatment with methotrexate and radiation in humans are induced in the normal dog brain by radiation alone. The results of his study show that the dog is a suitable model of the human brain for studying radiation brain injury and may be useful for investigation of drug-radiation interactions.

Animals↗
PubMed1986

Phase I trial of the hypoxic cell radiosensitizer SR-2508: the results of the five to six week drug schedule.

Sixty-five patients were entered on the long schedule of the Phase I trial of SR-2508. The planned total doses ranged from 30 to 40.8 g/m2 using various treatment schema including daily, split course, and every-other-day schedules. The individual dose size was 2 g/m2 for 56 patients and 1.7 g/m2 for nine. In contrast to misonidazole and desmethylmisonidazole, more SR-2508 can be administered as the duration of therapy is lengthened. All six patients on the 30 g/m2 step tolerated the drug without toxicity. This total dose was not achievable in the three week schedule. Additionally, a number of patients did not develop neuropathy at a cumulative dose of 40.8 g/m2. Although the analysis is not yet complete, a given patient's drug exposure as measured by their total AUC (mMxhr), defined as the area-under-the-curve of serum concentration of SR-2508 vs. time for a single dose times the number of doses given, is useful in predicting toxicity for that patient. The recommended starting schedule for the Phase II and III trials is 34 g/m2 over a 6 week period (2 g/m2 every other day). A total AUC of approximately 39 mMxhr should be tolerable. The drug regimen must be altered for patients who have a high AUC. Therefore, it is mandatory to have an accurate and rapid pharmacokinetic analysis for each patient. The clinical efficacy of the hypoxic cell sensitizers remains to be proven. However, using the guidelines derived from the Phase I trial, SR-2508 should be a relatively safe drug, producing minor or no toxicity.

Drug Administration Schedule↗
PubMed1986

The relationship of SR-2508 sensitizer enhancement ratio to cellular glutathione levels in human tumor cell lines.

We have recently demonstrated that intracellular elevation of glutathione (GSH) by oxothiazolidine 4-carboxylate lessens SR-2508 hypoxic cell radiosensitization in Chinese hamster cells. This observation, coupled with the fact that GSH depletion potentiates SR-2508 hypoxic radiosensitization, prompted a study of human tumor cell lines whose inherent GSH levels are high compared to normal human cell lines or rodent cell lines. Sensitizer enhancement ratios (SER) for a range of SR-2508 concentrations were determined for human tumor cell lines varying in inherent GSH levels. The SER (at the 1% survival level) for 1 mM SR-2508 was found to decrease as the inherent intracellular GSH level increased, particularly for clinically relevant SR-2508 concentrations. All human tumor cell lines studied yielded lower SER values than Chinese hamster V79 cells over the SR-2508 concentrations studied. GSH depletion by buthionine sulfoximine (BSO) of a human tumor line (A549) particularly high in GSH resulted in potentiation of SR-2508 effects. Maximal sensitization occurred when extremely low GSH levels were attained; however, enhancement was observed for a drop of only 30% in GSH levels. Should these high GSH levels seen in human tumor cell lines also apply to clonogenic or potentially clonogenic cells in human tumors in vivo, these findings might explain, in part, the negative results of some human nitroimidazole clinical trials.

Cell Line↗
PubMed1986

Variation in sensitizing efficiency for SR 2508 in human cells dependent on glutathione content.

The observation by several authors and ourselves that manipulation of glutathione (GSH) levels in cultured cells would change the relative sensitization of hypoxic cells by nitroimidazole sensitizers led to the hypothesis that natural variation in GSH level could influence the sensitizer enhancement ratio (SER). Since many human tumor cell lines have shown high GSH levels, the A549 lung line, the HeLa line and a skin fibroblast line, the AG1522, were studied in monolayer culture in glass flasks. The GSH levels (nmol/mg protein) measured were 324 for A549, 103 for HeLa, and 32 for 1522 cells. For V-79 cells the level was 25 nmol/mg. In control experiments there was no effect of up to 10 mM SR 2508 in air but BSO (D,L-buthionine-S-R-sulfoximine) treatment modestly sensitized the A549 in air and nitrogen. Calculation of SER values at 1% survival revealed very little sensitization at 0.1, 0.5, and 1.0 mM SR 2508 for A549 cells (SER not significantly different than 1). At 5 mM the SER was 1.5 and at 10 mM 1.65. In contrast, the SER for fibroblasts was 1.65 at 0.5 mM and 2.2 at 1.0 mM SR 2508. The results for HeLa were intermediate, 1.25 and 1.45 at the same concentrations. Thus, the SER relates to the GSH levels in the cells. Treatment with BSO increased the sensitization of A549 to a level similar to that seen for AG1522 at 0.5 and 1.0 mM. These findings could explain the negative results of some sensitizer clinical trials.

Cell Line↗
PubMed1986

Heavy charged particle therapy of bone and soft tissue sarcoma. A phase I-II trial of the University of California Lawrence Berkeley Laboratory and the Northern California Oncology Group.

At the University of California Lawrence Berkeley Laboratory and the Northern California Oncology Group, a preliminary study of heavy charged particle radiotherapy in soft tissue and bone sarcoma has been carried out. Fifty-two patients with bone or soft tissue tumors were treated wholly or in part with heavy charged particles from 1978 to 1985. Eleven patients, considered inevaluable for purposes of this analysis, received less than 50 Gray-equivalents (GyE) because of the following: progressive disease (three patients); palliative treatment due to recurrent disease after previous radiation therapy (three patients); or since they were part of preliminary studies of relative biological effectiveness (RBE) (five patients). Forty-one patients received from 50 to 78.5 GyE, with a mean of 65 GyE. They had an average of 23 months follow-up, ranging from 4 to 78 months. In patients with paraspinal chondrosarcoma 9 of 11 had local control, with a mean follow-up time of 32 months. In the remaining patients with other histologies, 19 of 30 were controlled within the irradiated area, with a mean follow-up time of 20 months. Serious complications were encountered in the CNS (four patients), in the bowel (one patient), and in bone (one patient). Heavy charged particle radiotherapy appears to be of value in treating bone or soft tissue sarcoma; further trials are planned.

Actuarial Analysis↗
PubMed1986

Normal brain iodine-125 radiation damage: effect of dose and irradiated volume in a canine model.

High-activity iodine-125 sources in plastic catheters were surgically placed in the cerebral white matter of healthy beagle dogs and later removed. Reference doses, calculated at a point 0.75 mm from the source, ranged from 10 to 40 Gy. Necrosis, vascular-related damage, and edema were quantified by computed tomography. Volumetric analyses were used to derive the relationship of dose and dose rate to necrosis and contrast enhancement. The extent of necrosis was related to irradiated volume; a minimum effective dose averaging 180-200 Gy was required to induce this type of damage. Contrast enhancement was less dependent on irradiated volume or total dose. The extent of radiation-induced edema was directly related to the volumes of necrosis plus contrast enhancement. Noninvasive serial studies in a well-characterized in vivo model can address specific clinically related questions on damage to normal tissue after interstitial irradiation.

Animals↗
PubMed1986

Early results of ion beam radiation therapy for sacral chordoma. A Northern California Oncology Group Study.

The authors report on eight patients with sacral chordoma treated with ion beam radiation therapy. Ion beams have favorable physical and biological characteristics when compared to conventional radiation therapy beams of x-rays, gamma rays, or electrons. This treatment technique has been developed to exploit those advantages. With this technique it is possible to deliver a much higher tumor dose than that usually given with conventional beams, and to date no significant normal-tissue morbidity has been noted. Seven of the eight patients currently have local control of their tumor; however, follow-up time is too short to judge the long-term local control rate of this treatment technique.

Adult↗
PubMed1985

A phase I-II trial of heavy charged particle irradiation of malignant glioma of the brain: a Northern California Oncology Group Study.

Thirty-nine patients with primary or recurrent glioma of the brain were irradiated wholely or in part with heavy charged particle beams at the University of California Lawrence Berkeley Laboratory in a Phase I-II clinical trial of the Northern California Oncology Group. During the course of this trial, treatment techniques have been developed and tumor doses have been escalated in order to obtain data on normal brain toxicity and response of malignant glioma of the brain. Toxicity has been acceptable with a low level of brain injury. Survival and tumor control has been approximately the same as historical results in glioma of the brain. Further dose escalation is planned together with possible trial of combined modality therapy.

Adult↗
PubMed1985

Precision, high dose radiotherapy. II. Helium ion treatment of tumors adjacent to critical central nervous system structures.

In this paper we present a technique for treating relatively small, low grade tumors located very close to critical, radiation sensitive central nervous system structures such as the spinal cord and the brain stem. A beam of helium ions is used to irradiate the tumor. The nearby normal tissues are protected by exploiting the superb dose localization properties of this beam, particularly its well defined and controllable range in tissue, the increased dose deposited near the end of this range (i.e., the Bragg peak), the sharp decrease in dose beyond the Bragg peak, and the sharp penumbra of the beam. To execute this type of treatment, extreme care must be taken in localization of the tumor and normal tissues, as well as in treatment planning and dosimetry, patient immobilization, and verification of treatment delivery. To illustrate the technique, we present a group of 19 patients treated for chordomas, meningiomas and low grade chondrosarcomas in the base of the skull or spinal column. We have been able to deliver high, uniform doses to the target volumes (doses equivalent to 60 to 80 Gy of cobalt-60) while keeping the doses to the nearby critical tissues below the threshold for radiation damage. Follow-up on this group of patients is short, averaging 22 months (2 to 75 months). Currently, 15 patients have local control of their tumor. Two major complications, a spinal cord transection and optic tract damage, are discussed in detail. Our treatment policies have been modified to minimize the risk of these complications in the future, and we are continuing to use this method to treat such patients. We are enthusiastic about this technique, since we believe there is no other potentially curative treatment for these patients.

Aged↗