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Biomedical subjects

P Rubin

Publications and source records attributed to P Rubin.

At least 19 recordsLinked to original sources
PubMed1992

Interruptions adversely affect local control and survival with hyperfractionated radiation therapy of carcinomas of the upper respiratory and digestive tracts. New evidence for accelerated proliferation from Radiation Therapy Oncology Group Protocol 8313.

Hyperfractionated radiation therapy (HFX) attempts to overcome tumor proliferation during treatment by permitting higher total doses in the same overall time as standard fractionation. Whereas interruptions, including splits, reduce local control with standard fractionation in carcinoma of the upper respiratory and digestive tracts, HFX might compensate for interruptions. Patients were randomized to receive total doses of 6720, 7200, 7680, and 8160 cGy, using 120 cGy twice daily, 5 days per week. Those analyzed received +/- 4% of assigned total dose and lived 90 days or more. Treatment was completed within 5 days of the time specified for each treatment arm in 233 patients; 48, 80, and 131 patients had delays 14, 10, and 5 days or more, respectively. Locoregional control and survival were significantly (P less than or equal to 0.03) reduced with delays of 5 days or more when corrected for prognostic factors. Late effects of radiation therapy were not affected by interruptions. These data support the hypothesis that proliferation (possibly accelerated) of tumor clonogens during treatment influences the outcome.

Aged↗
PubMed1992

The discovery and development of zileuton: an orally active 5-lipoxygenase inhibitor.

The enzyme 5-lipoxygenase is a key target in the effort to discover drugs which inhibit the pathophysiology associated with the formation of leukotrienes. The research efforts of these laboratories have focused on the discovery of direct enzyme inhibitors of 5-lipoxygenase. In particular, compounds with hydroxamate or N-hydroxyurea functionalities have proven to be potent inhibitors of leukotriene biosynthesis in vitro and more importantly in vivo. One of these compounds, zileuton (N-(1-benzo-[b]-thien-2-ylethyl)-N-hydroxyurea) has been shown recently to be an effective leukotriene inhibitor in man. The critical approaches and breakthroughs in the discovery and development of zileuton are described. In addition, some recent results with zileuton in animals and man are detailed.

Animals↗
PubMed1992

A report of RTOG 8206: a phase III study of whether the addition of single dose hemibody irradiation to standard fractionated local field irradiation is more effective than local field irradiation alone in the treatment of symptomatic osseous metastases.

Hemibody irradiation (HBI) in a single exposure is an effective and safe technique for palliation of symptoms due to widespread bony metastases (RTOG 78-10). The present study (82-06) sought to explore the possibility that HBI added to local-field irradiation might delay the onset of metastases in the hemibody effected, as assessed by bone scans and X rays, and decrease the frequency of further treatment. The results of this clinical trial establish that 800 cGy of HBI is indeed causes micro-metastases to regress, perhaps completely. A total of 499 patients were randomized to receive either HBI or no further treatment following completion of standard palliative local field irradiation (300 cGy x 10) to the symptomatic site. Improvement was seen in time-to-disease progression at one year, 35% for local + HBI versus 46% on the local-only control arm. Time-to-new disease in the targeted hemibody was also improved. At one year, 50% of patients on the local + HBI arm showed new disease compared to 68% on the local-only arm. Furthermore, the median time-to-new disease within the targeted HBI area was 12.6 months for the local + HBI arm versus 6.3 months for patients in the local-only arm. Time-to-new treatment within the hemibody segment was also delayed. At one year, 76% of the local only group had been retreated versus 60% in the local + HBI arm. There were no fatalities and no radiation pneumonitis was seen in the local + HBI arm. Overall, the incidence of toxicities was low (5-15%). The occurrence of severe hematopoetic toxicities were significantly different in the local + HBI arm, but they were transitory. One life-threatening thrombocytopenia occurred, for a limited time, indicating excellent tolerance to HBI. This clinical trial demonstrates that HBI has the potential to be used to treat systemic and occult metastases, particularly if both halves of the body can be treated.

Aged↗
PubMed1992

Comparison of pathologic and clinical evaluation of lymph nodes in prostate cancer: implications of RTOG data for patient management and trial design and stratification.

RTOG 77-06 and 75-06 were studies of nodal irradiation in prostate cancer, for which the status of nodes was determined by lymph node dissection (LND), lymphangiography (LAG), or computer assisted tomography (CT) based on investigator preference. Actuarial 5 year endpoints of survival, NED survival, local recurrence and distant metastasis have been determined by stage for 805 eligible patients with a comparison of pathologic vs clinical (imaging test) determined nodal status. Patients with pathologically negative lymph nodes show significantly improved 5 year survival (Stage T-2 (B) 84% vs 77%, Stage T-3,4 (C) 82% vs 65%) and NED survival (Stage T-2 (B) 72% vs 63%, Stage T-3,4 (C) 64% vs 44%) compared to patients clinically negative. Free of metastasis rates are increased in Stage T-3,4 (C) pathologic negative patients compared to imaging negative patients (75% vs 60%). A comparison of clinical positive versus clinical negative patients shows no difference in survival, NED survival or rate of metastasis, while a similar comparison of pathologic positive versus pathologic negative shows significant difference for all three endpoints (survival: Stage T-2 (B) 84% vs 61%, Stage T-3,4 (C) 82% vs 66%, NED survival: Stage T-2 (B) 72% vs 32%, Stage T-3,4 (C) 64% vs 32%; free of metastasis: Stage T-2 (B) 82% vs 64%, Stage T-3,4 (C) 75% vs 44%). The clinical determination of nodal status, therefore, has no prognostic value in contrast to pathologic determination and should not be used for stratifying patients in clinical trials. The CT scans often used to evaluate nodal status are more useful if delayed until they can be done as part of the treatment planning process where the CT has value. When imaging tests suggest positive lymph nodes in prostate cancer patients, the imaging finding is confirmed by biopsy.

Humans↗
PubMed1992

Logistics in designing clinical trials for etanidazole (SR 2508): an RTOG experience.

In a Phase II study of etanidazole (SR 2508), the dose of 17 x 2 g/m2 (total drug dose: 34 g/m2) was tested in 33 patients and the toxicity was deemed acceptable. A Phase III trial is now in progress comparing conventional radiotherapy with conventional radiotherapy plus etandizole (2 g/m2 i.v. 30 to 60 min before radiotherapy each Monday, Wednesday, and Friday to 34 g/m2 in 17 doses) in patients with unresectable head and neck carcinomas. A recent analysis showed only 14.7% grade 1 and 3.9% Grade 2 peripheral neuropathy. In the initial study design, 133 evaluable patients per treatment arm could achieve an 80% level of power of detecting a 15% difference in local-regional control rates between the radiotherapy arm (25% local-regional control at 2 years) and the radiotherapy plus etanidazole arm (assuming a 40% rate). Allowing for 20 ineligible cases in each arm, a total number of 306 was required. An interim analysis showed that 27% of the patients assigned to radiotherapy plus etanidazole are receiving less than 14 doses of the drug. It is assumed that less than 14 drug doses will not produce any therapeutic gain, therefore, a true 40% local-regional control rate in the radiotherapy plus etanidazole arm will be observed as a 36% rate when analyzed by assigned treatment. Using this information, the study was modified to have an 80% level of power in detecting a difference between a 25% local-regional control rate in the radiotherapy group and a 36% rate in the radiotherapy plus etanidazole group. Allowing for a 10% patient ineligibility rate, 518 patients are required. With 12 patients entered per month, it is estimated that patient accrual to this study will continue through October 1991.

Carcinoma, Squamous Cell↗
PubMed1992

Radiation oncology residents' computer workstation.

We are investigating the feasibility of using the Macintosh computer as a workstation platform for radiation oncology residents because of its ease of use, graphics capability, and low cost. Hypercard was chosen as the programming environment because it easily mixes graphics, text, and control functions in an integrated screen display. Furthermore, it results in a system that can be relatively easily extended and customized by individual users with varying degrees of computer skills. We have developed several software modules in order to test the ability of this environment to support the demands of such a workstation. Modules created thus far include various clinical physics aids and tutorials, treatment planning guides, oncology databases, and others. The software runs on all Macintosh configurations, but calculation speeds are improved when a 68020 or greater processor is used. In general, we have been pleased with the implementation thus far. Graphics display capability is good, but design and entry of graphics have proved labor-intensive. Searching is fast and text is easily entered and manipulated. Finished modules can be customized with minimal computer training, but implementing complex new functions requires familiarity with Hypercard's programming language. New modules, once developed, are easily integrated into the workstation universe, suggesting that cooperative development of the workstation by multiple contributors is realistically achievable.

Computer Graphics↗
PubMed1992

Molecular biology mechanisms in the radiation induction of pulmonary injury syndromes: interrelationship between the alveolar macrophage and the septal fibroblast.

Pulmonary fibrosis is a crippling, essentially lethal chronic disease due to an interplay of events following irradiation between the pneumonitic and fibrotic phases. In this series of experiments it is demonstrated that there is no latent period after irradiation, but an immediate intercellular communication system which springs into action to initiate recovery. Latency was only a function of our inability to uncover the molecular events that precede and underlie the clinical pathologic course of organ/tissue irradiation. Current advances in understanding the production of growth factors by different cells provides new insights to autocrine, paracrine and endocrine messages as a basis for understanding radiation pathophysiology as a progressive process that is amplified by other injurious events such as chemotoxicity. This is the first demonstrated release of trophic factors (cytokines) after in vivo irradiation that persists up to a month after exposure, suggesting that the persistence of a small incremental stimulus during a silent "latent" period can be the basis for the clinical pathologic expression of a late radiation effect, that is, pulmonary interstitial fibrosis.

Animals↗
PubMed1992

Comparative study of pressor and heart rate responses to angiotensin II and noradrenaline in pregnant and non-pregnant women.

1. Twenty-eight healthy non-pregnant women and 28 women in the first or second trimester of pregnancy were studied. They were given an incremental intravenous infusion of either noradrenaline or angiotensin II. Pressor and heart rate responses were documented. 2. Dose-pressor response curves were constructed for the two agents in pregnant and non-pregnant women (n = 14 in each group). The regression parameters of slope and intercept were calculated, and were used to derive the variables of dose required to elicit a 10 mmHg rise in systolic or diastolic blood pressure. 3. The pressor response to angiotensin II was diminished in pregnancy, with approximately twice the dose being required to raise the systolic or diastolic arterial blood pressure as in non-pregnant subjects. 4. The systolic pressor response to noradrenaline was slightly diminished in pregnancy, but the diastolic pressor response was unchanged. There were no significant differences between the doses of noradrenaline required to elicit a 10 mmHg rise in systolic or diastolic arterial blood pressure in pregnant or non-pregnant subjects. 5. There was a diminution in the bradycardia evoked in response to both hormones in pregnancy. 6. We conclude that the well-documented pressor insensitivity to angiotensin II during pregnancy is a specific phenomenon, not a manifestation of a generalized reduction in vascular reactivity.

Angiotensin II↗
PubMed1992

Zileuton, a 5-lipoxygenase inhibitor in rheumatoid arthritis.

The effects of zileuton, a new 5-lipoxygenase inhibitor, on leukotriene generation and clinical response in rheumatoid arthritis (RA) was studied in a 4-week randomized double blind placebo controlled study at 2 academic rheumatology centers. Zileuton decreased the mean (+/- SEM) ionophore induced synthesis of leukotriene B4 at Week 1 by 70% from 191.2 +/- 28.5 to 57.5 +/- 17.0 ng/ml. A parallel suppression of all major 5-lipoxygenase pathway products was observed. An improvement in clinical variables was observed in the zileuton and placebo treated population. No unique toxicity was identified in this study. Zileuton inhibited 5-lipoxygenase in RA with a suggestion of clinical response with limited toxicity.

Adult↗
PubMed1992

Phase II study of the safety and efficacy of a 5-lipoxygenase inhibitor in patients with ulcerative colitis.

We examined the effects of an inhibitor of 5-lipoxygenase (A-64077) in 11 patients with mild to moderately active ulcerative colitis (UC). Treatment was a daily oral dose of 800 mg for 28 days. Physicians global rating (scale 1-50) included stool characteristics, rectal bleeding, abdominal and rectal pain, urgency, and general well being; sigmoidoscopic evaluation (scale 1-15) included mucosal vascular pattern, erythema, granularity/ulcerations, friability, and exudate. All of the patients experienced a decrease in discomfort of their disease, and the gross appearance in the sigmoidoscopy improved in eight of them, but were not accompanied by histologic improvement. No significant side effects occurred. A long-term controlled double-blind and dose-effect trial using 5-lipoxygenase inhibitors is needed which may lead to a new therapeutic approach in UC.

Administration, Oral↗
PubMed1992

Prevention of heterotopic ossification with irradiation after total hip arthroplasty. Radiation therapy with a single dose of eight hundred centigray administered to a limited field.

Sixty-two hips in fifty-five patients who were considered to be at risk for postoperative heterotopic ossification were randomly divided into two groups: one received a single 800-centigray dose of limited-field radiation and the other, 1000 centigray of limited-field radiation in divided doses. The risk for heterotopic-bone formation was identified on the basis of previously described criteria, which included previous heterotopic ossification after an operation about the hip, hypertrophic osteoarthritis or post-traumatic osteoarthrosis characterized by formation of extensive osteophytes, radiographic evidence of diffuse idiopathic skeletal hyperostosis, ankylosing spondylitis, and male sex. The treatment portals excluded prosthetic surfaces that were intended for biological fixation by ingrowth of bone. At a minimum six-month follow-up, progression of heterotopic ossification had occurred in seven (21 per cent) of thirty-four hips in the first group and in six (21 per cent) of twenty-eight hips in the second group. The ossification had advanced more than one grade in only one hip. Extra-field ossification occurred in fifteen (43 per cent) of thirty-five hips that had not had previous heterotopic ossification. Since the time of the study, the treatment portal has been modified to include the lateral aspect of the greater trochanter, so that the risk of bursitis associated with ossification in this area is minimized. Single-dose limited-field radiation is effective for the prevention of heterotopic ossification, without compromise of early fixation of an uncemented implant.

Adult↗
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↗