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P Rubin

Publications and source records attributed to P Rubin.

At least 181 records · Page 10Linked to original sources
PubMed1991

Altered modulation of prefrontal and subcortical brain activity in newly diagnosed schizophrenia and schizophreniform disorder. A regional cerebral blood flow study.

To measure prefrontal and subcortical activity during a cognitive task, we examined 19 newly diagnosed schizophrenics and patients with schizophreniform psychosis. Seven healthy volunteers served as controls. The patients were drug naive or had received neuroleptics for a few days only. Cerebral blood flow distribution was depicted by single photon emission computed tomography at rest and during activation with the Wisconsin Card Sorting Test. A significant relative activation deficit in the left inferior-prefrontal region was revealed during the Wisconsin Card Sorting Test in the patient group. Furthermore, the patients had impaired striatal suppression on the left side during the cognitive task. The test performance was significantly impaired in the patients. The inability to reduce striatal activity may be due to a lack of corticostriatal feedback during prefrontal activation.

Adult↗
PubMed1991

Effect of Zileuton (A-64077) on the 5-lipoxygenase activity of human whole blood ex vivo.

The potency and reversibility of a new orally active 5-lipoxygenase (5-LO) inhibitor were evaluated in human volunteers. Zileuton (A-64077) 600 mg q.i.d. was administered to volunteers for 14 days in a phase I study, and blood samples were withdrawn, stimulated with ionophore A23187 and LTB4 levels were determined using both reverse phase high performance liquid chromatography (RP-HPLC) and radioimmunoassay (RIA). The drug significantly inhibited (above 70%) LTB4 biosynthesis in whole blood stimulated with A-23187 throughout the 14 days. The activity of 5-LO was also measured one week after stopping the medication and was returned to control levels. Measurement of LTB4 levels using either RP-HPLC or RIA gave similar percentage of inhibition although RIA appeared to underestimate by half the absolute amounts of LTB4 in the blood samples. These results show that Zileuton is a highly active and reversible 5-LO inhibitor in human.

Adolescent↗
PubMed1991

Simultaneous presentation of adenocarcinoma of prostate and transitional cell carcinoma of bladder.

Simultaneous presentation of transitional cell carcinoma of the bladder and adenocarcinoma of the prostate is not uncommon. Twenty-two patients were diagnosed as having simultaneous or concurrent presentation of prostate and bladder carcinomas between January 1970 and July 1986. The overall five-year survival was 40 percent, with patients presenting with prostate cancer doing better (50%) than those with bladder cancer (32%). Retrospective review of these cases suggests that primary therapy should be directed to the most advanced cancer. Incidental prostate cancer may be "cured" with a cystoprostatectomy and, when indicated, radiation therapy added postoperatively for the bladder cancer. Eleven patients presented with Stage A prostate cancer: 10 of the 11 were treated for their bladder cancer. Treatment was usually radical cystoprostatectomy with or without postoperative radiation. None died of prostate cancer. Patients presenting with advanced stage prostate cancer have had recurrence or have died of the cancer.

Adenocarcinoma↗
PubMed1991

Interleukin 1 alpha stimulates hemopoiesis but not tumor cell proliferation and protects mice from lethal total body irradiation.

Interleukin 1 alpha (IL-1) is a polypeptide/glycoprotein growth factor with multiple functions including the modulation of hematopoietic cell proliferation and differentiation. In vivo studies were performed with C57BL/6J mice injected with 0, 0.2, or 2.0 micrograms of IL-1 24 hr before or after lethal total body irradiation (TBI) (9.5 Gy). More mice in the groups administered IL-1 before TBI survived (90% of the 2.0 micrograms group) than those treated 2 or 24 hr after TBI, which was still slightly superior to the uninjected group, which all died within 15 days (p = .0001). Proliferation of bone marrow granulocyte/macrophage colonies following split dose TBI was also greatest for mouse groups treated with IL-1 prior to TBI. These experiments support data from other investigators that IL-1 stimulation of BM is related to IL-1 timing with respect to TBI. Stimulation of hemopoiesis was also assessed in terms of changes in peripheral blood and BM cell numbers and cell cycle kinetics using an electronic particle counter and flow cytometric techniques. Mice injected with 2 micrograms of IL-1 showed an initial decline (at 3-6 hr) and then a selective proliferation (24-48 hr) of early and more committed progenitor cells to 125% and 200% of control values, respectively. Peripheral blood counts rose accordingly. Cells in S and G2/M phases increased over 10 hr and then declined in number. It thus appeared that some synchronization of cell cycling occurred, which might place cells in a more radioresistant phase of the cell cycle. The glutathione (GSH) content and synthesis in BM cells were measured by isocratic paired-ion high performance liquid chromatography and 35S-labelled cysteine incorporation into the GSH tripeptide. An increase in cellular GSH content and synthesis was demonstrated following IL-1 which lasted 24 hr, suggesting a possible mechanism for the radioprotection by IL-1. To determine the potential for achieving a favorable therapeutic ratio, KHT tumor-bearing mice were injected with 2.0 micrograms IL-1. No change in tumor diameters or weights or tumor cell clonogenicity between IL-1 treated or untreated animals was observed. These experiments strongly support a role for IL-1 in stimulating bone marrow to overcome the myelosuppressive effects of irradiation.

Animals↗
PubMed1991

Elapsed treatment days--a critical item for radiotherapy quality control review in head and neck trials: RTOG report.

For all randomized trials since 1978, the Radiation Therapy Oncology Group has required the study chairman for radiation therapy to review the treatment given to each patient. The chairman scores the compliance of the treatment borders, total dose, fraction, and total elapsed time relative to the protocol prescription at the primary site, regional nodes, and any critical structure. The individual parameters are then considered together to derive an "overall" treatment score. For two RTOG head and neck studies in patients with moderately and very advanced carcinomas, the "overall" treatment was classified as unacceptable if the treatment at primary was scored unacceptable with respect to dose, fractionation, and field borders. However, prolonged elapsed treatment was not included. Analysis of these studies with 426 evaluable patients was performed to assess the relationship of unacceptable "overall" treatment compliance with outcome. Patients with prolonged treatment elapsed days (14 days beyond the protocol prescription) exhibited significantly poorer loco-regional control (13% vs. 27% at 3 years with p = .007) and absolute survival (13% vs. 26% at 3 years with p = .01). As a result, the criteria for unacceptable "overall" treatment were revised to include prolonged elapsed treatment days. Further multivariate analyses showed the revised criteria identified patients with significantly poorer loco-regional control and absolute survival even after adjusting for other prognostic factors.

Carcinoma, Squamous Cell↗
PubMed1991

ASTRO plenary: interfraction interval is a major determinant of late effects, with hyperfractionated radiation therapy of carcinomas of upper respiratory and digestive tracts: results from Radiation Therapy Oncology Group protocol 8313.

A prospective, randomized, multi-institutional, Phase I(LE)/II trial of HFX was conducted by the RTOG between 1983 and 1987. Patients with histologically proven, inoperable squamous cell carcinoma of the upper respiratory and digestive tracts stratified by site, nodal status, and performance status, were assigned to one of three arms, were assigned to one of three arms, 67.2 Gy, 72.0 Gy, or 76.8 Gy. Fractions of 1.2 Gy were given twice daily, 5 days per week: intervals of 4 to 8 hours were permitted between fractions. After acceptable rates of acute normal tissue effects were found, the randomization was changed to evaluate a new higher total dose, 81.6 Gy. Of 479 patients entered, 447 were analyzed, 63 on 67.2 Gy, 129 on 72.0 Gy, 117 on 76.8 Gy, and 138 on 81.6 Gy. The treatment arms were well balanced with respect to pretreatment characteristics. Acute reactions consisted almost entirely of pseudomembranous inflammation. "Severe" (Grade 3) acute reactions were reported in 33% to 41% and grade 4 reactions were found in 0 to 3% of patients, with no differences in frequencies among the four arms. Toxicities that developed or persisted beyond 90 days after the first treatment (408 patients evaluable greater than 90 days) did not differ among arms: grade 3+ reactions occurred in 10% to 14%, and grade 4+ effects (necroses) were reported in 5% at 67.2 Gy, 3% at 72.0 Gy, 7% at 76.8 Gy, and 2% at 81.6 Gy. Grade 3+ acute reactions occurred in 40% of patients when the interfraction interval was less than or equal to 4.5 hours versus 31% with greater than 4.5 hours (p = .03). Interfraction intervals less than or equal to 4.5 hours were associated with higher frequencies of grade 4+ late effects in all four arms, 8% of 197 patients with less than or equal to 4.5 hours versus 1% of 211 patients with greater than 4.5 hours. Estimates of late toxicity at 1, 2, and 3 years were 5.5%, 9.8%, and 15.4% with intervals less than or equal to 4.5 hours, versus 1.7% at all three periods for greater than 4.5 hours (p = .006). Local-regional control at 2 years was 25% for the assigned dose of 67.2 Gy compared to 43% to 45% for the three higher doses (p = .01), but a similar comparison for survival showed no significant difference (p = .35). There was no evidence for an effect of interfraction interval on either local-regional control (p = .38) or survival (p = .28).(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1991

The effect of overall treatment time on the outcome of definitive radiotherapy for localized prostate carcinoma: the Radiation Therapy Oncology Group 75-06 and 77-06 experience.

From 1976 to 1983, 1091 patients were entered into RTOG protocols 75-06 and 77-06. Of these, 780 patients complied with protocol requirements, received a minimum tumor dose of greater than or equal to 6500 cGy, and received no endocrine therapy. There were 78, 342, and 360 patients with localized prostate carcinoma, Stages T1b(A2), T2(B), and T3,4(C), respectively. The potential follow-up period ranges from 6 years 5 months to 13 years 3 months, with a median follow-up of 9 years. This study examines the influence of overall treatment time on the outcome of definitive radiotherapy for localized prostate carcinoma in this patient population. Within each stage, patients were divided into three groups according to the total number of elapsed days while on treatment: within 49 days (less than or equal to 7 weeks); 50 to 63 days (8 to 9 weeks); and greater than or equal to 64 days (greater than 9 weeks). Based on actuarial analysis, within each stage, the overall treatment time did not have any impact on the following: overall survival, NED survival, or local/regional control. When grouped under different histologic grades, that is, Gleason scores 2-5, 6-7, and 8-10, the actuarial local/regional control showed no statistical difference among the three groups. The actual local/regional failures were analyzed and stratified by stage and Gleason scores, and no statistical difference was noted among the three groups for each stratification. The range of local/regional failure rates among the three groups for T1b(A2), T2(B), and T3,4(C) disease were 0%-8%, 16%-23%, and 24%-27%, respectively. The corresponding range of local/regional failure rates for patients with Gleason scores of 2-5, 6-7, and 8-10 were 13%-14%, 18%-22%, and 22%-33%, respectively. The incidence of late complications was not related to the number of elapsed treatment days. Therefore, the overall treatment time does not have an impact on the outcome of definitive radiotherapy for localized prostate carcinoma. It is hypothesized that prostate carcinoma behaves as late-reacting tissue in which there is little, if any, accelerated repopulation of clonogenic tumor cells during the later half of a protracted course of radiotherapy. This observation is in direct contrast to that suggested for head and neck carcinoma and bears important implications in daily radiotherapeutic management of patients with prostate carcinoma.

Follow-Up Studies↗
PubMed1991

Outcome for lymph node dissection negative T-1b, T-2 (A-2,B) prostate cancer treated with external beam radiation therapy in RTOG 77-06.

One hundred four patients with stage T-1b, T-2 N-O M-O prostate cancer were treated with external beam irradiation as part of RTOG 77-06. Lymph nodes were negative by lymph node dissection in 16 patients with T-1b and 88 patients with T-2 cancers. Survival exceeds age matched expected survival for the 10 years of observation (63% vs 59% at 10 years). Patterns of failure at 10 years show 87% of patients were free of isolated local recurrence, 79% free of metastatic failure, 67% free of any failure, and cause specific survival shows 86% free of cancer death at 10 years. The outcome of this group is equal or superior to reports of radical prostatectomy in similar stage patients.

Aged↗
PubMed1991

Randomized phase III study comparing irradiation and hyperthermia with irradiation alone in superficial measurable tumors. Final report by the Radiation Therapy Oncology Group.

A total of 307 patients with superficial measurable tumors were registered on a Radiation Therapy Oncology Group (RTOG) protocol involving fractionated radiation therapy, either alone or followed immediately by hyperthermia (42.5 degrees C, 45-60 min). Overall complete response (CR) was observed in 30% of the lesions treated with radiotherapy (RT) and 32% of those receiving RT and heat. Response was found to be significantly related to both maximum tumor diameter (less than 3 or greater than or equal to 3 cm) and site/histology (breast/adenocarcinoma, head and neck/squamous, or other site/histologies). In tumors less than 3 cm in diameter in the breast, trunk, and extremities, a better CR rate was noted with irradiation and heat (62 and 67%) than with irradiation alone (40 and 0%). However, in the head and neck there was only minimal difference in CR with irradiation alone or combined with hyperthermia (50 vs 38%). In lesions less than 3 cm treated with irradiation and heat, there was improved local control. In lesions greater than 3 cm, there was no difference in local control between the two treatment arms. The higher response rate in patients with smaller lesions (less than 3 cm) may be explained by the fact that these tumors are easier to heat. Problems in correlating tumor response with quality of heating include less than optimal heating in larger lesions and the limited ability of current thermometry to map the temperature distribution in a tumor. Acute and late toxicities in both treatment arms were comparable, except for an overall 30% incidence of thermal blisters in the heated tumors.

Adenocarcinoma↗
PubMed1991

Efficacy of intraarterial heparin in maintaining microvascular patency: an experimental model.

Human-grade sodium heparin was studied to determine thrombosis model patency rates between an intraarterial infusion versus an intravenous method of delivery in a rabbit model. Specific differences in patency and partial thromboplastin times were studied in each group and compared with a saline-perfused group. Three animal groups (New Zealand white rabbits) were established (total = 35 animals). Standardized femoral arterial 5-mm inversion grafts (AIG) were done in each animal in each group. The animals in the control group received intravenous saline infusion, while the two treatment groups received intravenous heparin (12 animals) or intraarterial heparin (12 animals minus 1 anesthesia death). The route of instillation of the infusate was selected at random after completing the inversion grafts. A proximal epigastric branch was utilized for access in those animals randomized to the intraarterial group. Intravenous delivery was accomplished by means of a femoral venous catheter in the vena cava. A 72-hour period of infusion was used in all animals. A dose of 45 units per hour of heparin following a 500-unit bolus was used in the intravenous group. After an identical bolus dose, 25 units per hour of heparin was administered in the intraarterial group. The control (saline group) was given 1 cc saline (in a volume equal to the heparin-dosed groups) daily for 3 days. Arterial inversion graft patency rates were assessed by direct inspection at day 5. Systemic and regional (i.e., distal to the inversion graft) partial thromboplastin times (PTT) were measured in representative control, IV, and intraarterial heparin-treated groups. Complications were recorded.(ABSTRACT TRUNCATED AT 250 WORDS)

Anastomosis, Surgical↗
PubMed1991

Effect of a 5-lipoxygenase inhibitor on leukotriene generation and airway responses after allergen challenge in asthmatic patients.

The effect of a single oral dose (800 mg) of zileuton (A-64077), a specific 5-lipoxygenase inhibitor, on the early and late airway responses to inhaled allergen was studied in a randomised, double blind, placebo controlled, and crossover trial in nine subjects with atopic asthma. Leukotriene generation was also assessed in vivo by measuring urinary leukotriene (LT) E4 excretion, and ex vivo by measuring calcium ionophore stimulated whole blood LTB4 production. Zileuton almost completely inhibited ex vivo LTB4 production but reduced urinary excretion of LTE4 by only about half. There was a trend for the early asthmatic response to be less on the day of zileuton treatment, but this did not reach statistical significance (p = 0.08). The zileuton induced reduction in maximum fall in FEV1 in the early asthmatic response was, however, significantly related to the reduction in urinary LTE4 excretion (r = 0.8), but not to the reduction in LTB4 generation ex vivo. There was no significant change in the allergen induced late asthmatic response, or in the increase in airway responsiveness to methacholine following antigen. The results provide some support for the hypothesis that the cysteinyl leukotrienes have a role in the allergen induced early asthmatic response. More complete in vivo inhibition of 5-lipoxygenase may be needed to produce a significant reduction in airway response to allergen challenge.

Adult↗
PubMed1991

Pharmacokinetics, safety, and ability to diminish leukotriene synthesis by zileuton, an inhibitor of 5-lipoxygenase.

Zileuton is a potent and specific inhibitor of 5-lipoxygenase, the first dedicated enzyme in the metabolism of arachidonic acid to the leukotrienes. The leukotrienes have been implicated in numerous pathological conditions. Zileuton was given to normal human volunteers in single doses of 200 mg to 800 mg. Results of these studies indicated that zileuton was well absorbed orally with an elimination half-life of approximately 2.5 hours. Leukotriene B4 production by ex vivo calcium ionophone stimulated whole blood was inhibited by up to 80% of baseline and correlated with plasma concentrations. Zileuton did not significantly inhibit cyclooxygenase as demonstrated by thromboxane B2 levels. There were no safety concerns that would preclude development.

Adolescent↗
PubMed1990

The effects of a 5-lipoxygenase inhibitor on asthma induced by cold, dry air.

BACKGROUND: The enzyme 5-lipoxygenase catalyzes the metabolism of arachidonic acid to form products that have been implicated in the airway obstruction of asthma. We hypothesized that if products of the 5-lipoxygenase pathway are important in mediating this obstruction, then prevention of their formation should decrease the severity of an induced asthmatic response. METHODS: In a randomized, double-blind, placebo-controlled, crossover study, we examined the effect of A-64077, a 5-lipoxygenase inhibitor, on the bronchoconstriction induced by hyperventilation of cold, dry air in 13 patients with asthma. The completeness of 5-lipoxygenase inhibition was confirmed by examining the profile of eicosanoids produced in whole blood ex vivo after activation with the calcium ionophore A-23187. RESULTS: A-64077 decreased the mean (+/- SEM) ionophore-induced synthesis of leukotriene B4, a 5-lipoxygenase product, by 74 percent (from 265.3 +/- 30.3 to 69.5 +/- 21.5 ng per milliliter, P less than 0.001), but it did not affect the ionophore-induced synthesis of thromboxane B2, a cyclooxygenase metabolite of arachidonic acid (80.0 +/- 17.1 ng per milliliter before A-64077 vs. 75.8 +/- 14.3 ng per milliliter after A-64077). In concert with the selective inhibition of 5-lipoxygenase by A-64077, the amount of cold, dry air (expressed as respiratory heat exchange) required to reduce the forced expiratory volume in one second by 10 percent was increased by 47 percent after A-64077 (3.0 kJ per minute for placebo vs. 4.4 kJ per minute for A-64077, P less than 0.002). Similar results were obtained when minute ventilation was used as an indicator of outcome (27.5 liters per minute for placebo vs. 39.8 liters per minute for A-64077, P less than 0.005). CONCLUSIONS: Selective inhibition of 5-lipoxygenase by A-64077 is associated with a significant amelioration of the asthmatic response to cold, dry air, suggesting that 5-lipoxygenase products are involved in this response. This approach may be useful in the treatment of asthma.

Asthma↗
PubMed1990

Dose-response for local control with hyperfractionated radiation therapy in advanced carcinomas of the upper aerodigestive tracts: preliminary report of radiation therapy oncology group protocol 83-13.

A prospective, randomized Phase Ilate/II trial of hyperfractionated radiation therapy was conducted: 1.2 Gy minimum tumor dose was administered twice daily with a minimum interval of 4 hr, 5 days per week. Patients with Stage III and IV carcinomas of the oral cavity, oropharynx, nasopharynx, hypopharynx, and supraglottic larynx were stratified by site, presence or absence of nodal metastases, and performance status. They were assigned to four total doses between 67.2 Gy and 81.6 Gy to all known tumors. The highest dose arm was opened after preliminary assessment indicated acceptable late morbidity rates with the three lower doses. Of 479 patients entered, 260 patients were randomized to the three lower total doses and 237 were analyzed for this preliminary report: 63 were assigned to receive 67.2 Gy, 58 to 72.0 Gy, and 116 to 76.8 Gy. Estimates of grade 4 necrosis at 2 years were 10.0%, 5.1%, and 13.9%, respectively, for patients who received total doses of 67.2 Gy, 72.0 Gy, and 76.8 Gy. There was a suggestion of a trend toward increased local control at 24 months (Kaplan-Meier estimates of 25% for 67.2 Gy, 37% for 72.0 Gy, and 42% for 76.8 Gy) (p = .08). No difference was observed in survival. Assessment of the results using Cox regression models to correct for slight inequalities of pretreatment prognostic variables supported a total dose-tumor control relationship (p = .054). Results for the lowest dose arm were comparable to previous RTOG studies of common fractionation with similar total doses. The higher local control rates with 72.0 and 76.8 Gy using hyperfractionated radiation therapy suggest an improvement in outcome with radiation therapy for advanced carcinomas of the upper aerodigestive tracts. These preliminary findings have led to a Phase III comparison of hyperfractionated radiation therapy with 1.2 Gy b.i.d. with standard fractionation.

Adult↗
PubMed1990

The use of postoperative irradiation for the prevention of heterotopic bone after total hip replacement with biologic fixation (porous coated) prosthesis: an animal model.

Radiation has been shown to be effective in the prevention of heterotopic bone. The exact etiology of heterotopic bone is unknown. Total Hip prosthetic devices that do not depend upon bone cement for fixation have become increasingly popular. The mechanism by which the bone forms around the prosthesis is similar to the process by which fractures heal which has been shown to be sensitive to irradiation. Using a rabbit model we have undertaken a study to investigate the effect of irradiation on the bony ingrowth on porous coated implants. Forty-five rabbits had porous coated implants surgically placed in the tibiae bilaterally. Each rabbit had one tibae randomly irradiated with 1,000 cGy in 5 fractions starting on the first post-operative day. Animals were sacrificed weekly starting 2 weeks post-operatively and the tibae were sent for pullout studies. The amount of force necessary to pullout the treated tibae was statistically less than the amount of force necessary to remove the untreated tibae at 2 weeks. From 3 weeks on there was no difference in the force necessary to remove the prosthesis from the untreated or treated tibae. Histologically, the untreated tibae showed bone formation while the treated tibae did not. Because of these results, it is suggested that the treatment of patients at risk for development of heterotopic bone be modified to only include the area between the femur and pelvis avoiding treatment of the prosthetic device.

Animals↗