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Biomedical subjects

W Hrushesky

Publications and source records attributed to W Hrushesky.

17 recordsLinked to original sources
PubMed2001

Premenopausal status accelerates relapse in node positive breast cancer: hypothesis links angiogenesis, screening controversy.

Much attention has been given to determining the benefit of mammographic screening to reduce breast cancer mortality. Eight randomized clinical trials have been conducted in four countries: the US, Canada, Scotland and Sweden. Trials report an early and stable 30% reduction in breast cancer mortality for women aged 50-59. For women under 50, unexpectedly, the early years of screening produce a disadvantage to the screened population. Only in later years does an advantage appear. To help understand this, we studied relapse patterns using a breast cancer database of 1,173 pre- and postmenopausal, node negative and positive patients treated with surgery only and having 16-20 years of follow-up. This approach is relevant since at least five of the eight screening trials began before the widespread use of adjuvant chemotherapy in the 1980s. Surgical cure rates were independent of menopausal status. However, a major difference in early relapse rate was found. In premenopausal and node positive patients, 27% of all distant relapses occurred within the first 10 months following resection. This is twice the early relapse frequency of any other clinical group. Using computer simulation, we interpret that these early relapses probably result from a disadvantage induced at surgery. A disinhibition or surgery/wounding induced angiogenic surge might be responsible. Disinhibition is known to occur in animal models such as Lewis lung where lung metastases are avascular and dormant until the primary is removed. Sudden outgrowth of tumor after wounding has been observed for a century. According to the simulation, in breast cancer this induction apparently accelerates inevitable relapses by a median of two years. This is offset in later years with a balancing reduction in relapses. These data suggest that the angiogenic switch may be upregulated more frequently among premenopausal women, perhaps depending upon the sex hormones. The acceleration would cause 0.11 deaths per 1,000 screened aged 40-49 subjects in years 2-3, a value comparable to the early year excess mortality in trials of a significant 0.15 deaths per 1,000 subjects. Equal screening advantage is predicted for node negative (but not node positive) pre- and postmenopausal patients. The acceleration of relapse after surgery may explain the paradoxical effect of mammographic screening for women under 50.

Adult↗
PubMed2000

Investigation of the comparative toxicity of 5-FU bolus versus 5-FU continuous infusion circadian chemotherapy with concurrent radiation therapy in locally advanced rectal cancer.

PURPOSE: To compare the relative toxicities of bolus versus infusional 5-FU chemotherapy administrated concurrently during external beam irradiation in patients with locally advanced rectal cancer following surgical extirpation. METHODS: A total of 26 eligible patients were retrospectively identified as having been treated for rectal adenocarcinoma at the Stratton VAMC between 1989 and 1997. A comparative analysis of treatment dose intensities, treatment delays and toxicities in these patients was performed. RESULTS: Significantly less WBC toxicity was observed in the patients receiving infusional 5-FU chemotherapy. The other toxicities, with the exception of skin toxicity, were generally less frequent in the 5-FU infusional group. When the toxicities were corrected for 5-FU dose intensity, to yield toxicity per mg of 5-FU, statistically significant differences were found for hematological toxicity (WBC and platelets), and for gastrointestinal toxicity (frequency and severity of diarrhea and weight loss). The majority of patients receiving infusional 5-FU therapy were treated using a circadian pattern of treatment peaking around the time of the radiation therapy. Patients receiving infusional 5-FU were able to tolerate over twice the dose intensity as those receiving bolus administration. Local recurrence rate in all patients was 3.8% comparing favorably to other reported studies. Distant recurrence frequency was also acceptable at 34.6% for the group. CONCLUSION: Infusional 5-FU chemotherapy compared with bolus therapy during pelvic radiation minimizes toxicity to the patient while maximizing the dose of 5-FU that can be delivered. As infusional 5-FU therapy during radiation has previously been shown to increase disease free duration and survival, infusional 5-FU should be considered as an acceptable standard of care to prevent local recurrence of rectal adenocarcinoma following its resection. Shaping this infusional 5-FU chemotherapy within the day so that most of the daily dose is delivered around the time of the radiation therapy may further modify the toxic therapeutic ratio of combined modality therapy.

Adult↗
PubMed1984

Peripheral sensory neuropathy and cisplatin chemotherapy.

Patients with advanced cancer, previously untreated, were given 60 mg/m2 cisplatin plus 60 mg/m2 adriamycin by monthly intravenous injections. Signs and symptoms of a predominantly sensory peripheral neuropathy developed in 92% of the patients. Patients complained of dysesthesias and paresthesias in hands and feet. Clinically, there was progressive decrease or loss of tendon reflexes, decreased vibratory sense, and mild decrease in light touch and pin sensation. Distal sensory latencies became prolonged or dropped out completely, but there was little change in motor nerve conduction velocities or motor unit action potentials. Sural nerve biopsies showed loss of large-diameter nerve fibers, with axonal and myelin degeneration.

Carcinoma↗
PubMed1979

Chronic lymphocytic leukemia in association with a second lymphoproliferative disorder: response to chemotherapy in two cases.

The development of either histiocytic lymphoma or Hodgkin disease in association with pre-existing chronic lymphocytic leukemia has been described in the literature as a terminal event. We describe two patients in whom the diagnosis of a second malignant lymphoma was made during life and who achieved objective clinical response after a change in therapy to a more aggressive combination of drugs. We conclude that patients with chronic lymphocytic leukemia who have had a sudden change in their clinical course should have thorough reevaluation, looking specifically for the development of a second lymphoproliferative disorder. If this is discovered, more aggressive therapy should be initiated.

Aged↗
PubMedDate not supplied

Cancer-associated alteration of circadian rhythms in carcinoembryonic antigen (CEA) and alpha-fetoprotein (AFP) in humans.

A circadian rhythm of serum concentrations of two tumor markers (CEA and AFP) was demonstrated in individuals not suffering from cancer. These rhythms exhibited a diurnal peak with a nocturnal dip. They disappeared in cancer groups. However, in some cancer subjects, a circadian activity was still detectable, but with quite different characteristics (time of peak, amplitude) of rhythms when compared to controls. The importance of such findings is discussed with regard to the circadian kinetics of cancer cells, to time scheduled cancer treatments and to the detection of cancer.

Carcinoembryonic Antigen↗
PubMedDate not supplied

Time-varying effects in mice and rats of several synthetic ACTH preparations.

Circadian stage-dependent effects characterize synthetic ACTH 1-17 preparation (HOE 433 = Synchrodyn 1-17), tested in mice and rats, with reference notably to corticosterone and aldosterone production in vitro and to the behavior of rhythms in these two corticoids as an aspect of the adrenal cortical pacemaker of the circadian system. The possibility to advance or delay the rhythm in serum corticosterone by ACTH 1-17 also is demonstrated, as is a differential behavior of the circadian rhythm in serum aldosterone. Differences in timing of circadian corticosterone and aldosterone responses also are described and await further scrutiny for ultradian and infradian (notably circannual) modulation.

Adrenocorticotropic Hormone↗
PubMedDate not supplied

Synthetic adrenocorticotropin for optimizing murine circadian chronotolerance for adriamycin.

An attempt to pre-set the circadian rhythm in murine chronotolerance for adriamycin (ADR) given i.p. or i.v. with ACTH was performed in three studies. In CDF1 mice standardized in LD12:12, it was demonstrated that 1) the circadian rhythm in murine chronotolerance for ADR exhibits a different timing depending upon whether the intravenous or intraperitoneal route is used for the administration of this anticancer agent; 2) ACTH or saline pretreatment does not enhance optimal circadian-stage-qualified ADR tolerance, whatever its route of injection, with any of the circadian stages and schedules explored; 3) near-optimal tolerance can be achieved by a fixed 'best' interval (among those investigated) between ACTH and ADR, irrespective of circadian stage. Tolerance equivalent to optimal circadian-stage-qualified ADR tolerance results from the administration of ACTH 1-17 (HOE433 = Synchrodyn) 24 hours before ADR injection; 4) and acrophase advance of over 6 hours of the tolerance rhythm results from ACTH 1-17 administration at 6 HALO. The acrophase changes do not directly account for an optimal ADR tolerance at a fixed interval of 24 hours after ACTH 1-17. Thus, ACTH may be considered a potential relative chronizer of murine chronotolerance for ADR.

Adrenocorticotropic Hormone↗