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Biomedical subjects

W McCulloch

Publications and source records attributed to W McCulloch.

14 recordsLinked to original sources
PubMed1997

Testing technical skill via an innovative "bench station" examination.

BACKGROUND: A new approach to testing operative technical skills, the Objective Structured Assessment of Technical Skill (OSATS), formally assesses discrete segments of surgical tasks using bench model simulations. This study examines the interstation reliability and construct validity of a large-scale administration of the OSATS. METHODS: A 2-hour, eight-station OSATS was administered to 48 general surgery residents. Residents were assessed at each station by one of 48 surgeons who evaluated the resident using two methods of scoring: task-specific checklists and global rating scales. RESULTS: Interstation reliability was 0.78 for the checklist score, and 0.85 for the global score. Analysis of variance revealed a significant effect of training for both the checklist score, F(3,44) = 20.08, P <0.001, and the global score, F(3,44) = 24.63, P <0.001. CONCLUSIONS: The OSATS demonstrates high reliability and construct validity, suggesting that we can effectively measure residents' technical ability outside the operating room using bench model simulations.

Clinical Competence↗
PubMed1994

Amifostine (WR-2721) shortens the engraftment period of 4-hydroperoxycyclophosphamide-purged bone marrow in breast cancer patients receiving high-dose chemotherapy with autologous bone marrow support.

4-Hydroperoxycyclophosphamide (4-HC), a commonly used marrow-purging agent, is active against many tumors, but is also toxic to normal marrow progenitors. Amifostine (WR-2721) is a sulfhydryl compound with chemoprotectant activity. Preclinical studies using suspensions of bone marrow and breast cancer cells demonstrated that ex vivo treatment with amifostine followed by 4-HC resulted in protection of marrow progenitors, with no compromise in the antitumor effect of 4-HC. This fact stimulated the development of a clinical trial. Bone marrow was harvested from 15 poor-prognosis breast cancer patients and randomly assigned to ex vivo treatment with amifostine followed by 4-HC (amifostine + 4-HC), or treatment with 4-HC alone. High-dose chemotherapy was then administered followed by infusion of the purged autologous bone marrow support (ABMS). Leukocyte engraftment, defined as a white blood cell count > or = 1 x 10(9)/L, was achieved in an average of 26 days for patients whose marrow was purged with amifostine + 4-HC versus 36 days for patients whose marrow was purged with 4-HC alone (P = .032). The average number of platelet transfusions (12 v 29; P = .017) and days of antibiotic therapy (28 v 40; P = .012) were significantly less for patients whose marrow was exposed to amifostine + 4-HC, compared with 4-HC alone. Unpurged backup marrow fractions were infused into three patients whose marrow was purged with 4-HC alone, because of inadequate marrow recovery. None of the patients who received amifostine + 4-HC-purged marrow required a backup marrow fraction. Complete remissions were achieved in 83% of patients with measurable disease, with no difference between the two cohorts. Forty-three percent of patients remained alive and progression-free at a mean of 13 months posttransplant. There was no significant difference in the rate or pattern of relapse for patients whose marrow was purged with amifostine + 4-HC compared with those whose marrow was purged with 4-HC alone. Ex vivo treatment of marrow with amifostine significantly shortens the time to marrow recovery, thereby reducing the risk of myelosuppressive complications in breast cancer patients receiving high-dose chemotherapy and 4-HC-purged ABMS. Since supportive care requirements are also significantly decreased, amifostine may reduce the cost of such therapy.

Adult↗
PubMed1994

An in vivo comparison of oral 5-iodo-2'-deoxyuridine and 5-iodo-2-pyrimidinone-2'-deoxyribose toxicity, pharmacokinetics, and DNA incorporation in athymic mouse tissues and the human colon cancer xenograft, HCT-116.

5-iodo-2-pyrimidinone-2'-deoxyribose (IPdR) was recently reported to be converted to 5-iodo-2'-deoxyuridine (IUdR) by an aldehyde oxidase, most concentrated in liver tissue. We questioned whether IPdR could be used as a p.o. hepatotropic prodrug to increase the percentage of IUdR-DNA incorporation into liver tumors compared to normal liver with acceptable systemic toxicity. Athymic nude mice with human colon cancer (HCT-116) xenograft tumors as liver metastases and s.c. flank tumors received daily p.o. boluses (via gastric tubes) of IUdR or IPdR for 6 days. The maximum tolerated dose of IUdR was 250 mg/kg/day and was associated with a > 10% weight loss and a high percentage of IUdR-DNA incorporation (> 5%) into normal bone marrow and intestine. In contrast, animals tolerated escalating doses of IPdR to 1 gm/kg/day without weight loss and with less (1.5-4%) IUdR-DNA incorporation in normal tissues. Pharmacokinetic analysis of p.o. IPdR showed peak plasma levels of IPdR and IUdR within 15-45 min, suggesting efficient conversion of IPdR to IUdR. Aldehyde oxidase activity was found in normal liver tissue but not in other normal or tumor tissues. Additionally, we found a 2-3 times greater percentage of IUdR-DNA incorporation in tumor with IPdR than IUdR at the highest doses used. However, no differential effect in the percentage of IUdR-DNA incorporation was noted between liver metastases and s.c. tumors with either IPdR or IUdR. We conclude that p.o. IPdR offers a greater therapeutic index for tumor incorporation (and presumably radiosensitization) than a similar schedule of IUdR.

Administration, Oral↗
PubMed1994

Randomized clinical trial of mitomycin-C with or without pretreatment with WR-2721 in patients with advanced colorectal cancer.

The use of mitomycin for metastatic colorectal cancer has been limited by mitomycin's myelosuppressive potential. The objective of this randomized study was to determine whether WR-2721 would decrease the hematologic toxicity of mitomycin in patients with colorectal cancer resistant to fluorouracil-based therapy. Ninety-seven patients with refractory colorectal cancer were randomized to receive either mitomycin 20 mg/m2 only or the same dose of mitomycin after pretreatment with WR-2721, 910 mg/m2. The principal toxicity in both groups was thrombocytopenia. The platelet nadirs were lower in patients receiving single-agent mitomycin (P = 0.026). Surprisingly, no clinical complete or partial responses were noted in either group, and survival was not different between the two groups. Thus, while WR-2721 decreased the thrombocytopenia associated with mitomycin therapy, mitomycin was ineffective in the treatment of refractory colorectal carcinoma.

Adult↗
PubMed1992

A phase I study of WR-2721 in combination with total body irradiation (TBI) in patients with refractory lymphoid malignancies.

This Phase I study was designed to establish the maximum tolerated dose (MTD) of WR-2721 when given twice weekly with total body irradiation (TBI) in the treatment of patients with advanced refractory lymphoid malignancies and to define the toxicities of this combination and schedule. Patients eligible for this study had advanced recurrent indolent non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL). Patients had symptomatic or progressive disease, a performance status of 0, 1, or 2, and adequate bone marrow, hepatic, and renal function. Only patients failing one or two regimens of prior chemotherapy were eligible. Patients who had received prior extended field irradiation were ineligible. Patients received TBI twice weekly (Tuesday and Friday) to a total of 10 doses at 15 cGy/fx. WR-2721 was given intravenously over 15 min beginning 30 min before irradiation. The escalation of WR-2721 was Level 1: 740 mg/m2 and Level 2: 910 mg/m2. The MTD of WR-2721 was that dose which produced predictable and reversible toxicity and would not interfere with patient well-being. Seven patients were entered onto the study, three at 740 mg/m2 and four at 910 mg/m2. Five patients had CLL and two patients small lymphocytic NHL. No patient had hypotension or nausea requiring reduction in dose level or even interruption of infusion of WR-2721. At 740 mg/m2 no grade 3 or 4 toxicities related to WR-2721 were observed, but two patients could not complete treatment because of TBI-induced prolonged thrombocytopenia following treatments 5 and 8. One patient completed all 10 treatments. At 910 mg/m2 of WR-2721, two patients requested removal from study because of malaise, one after 5 cycles and one after 7 cycles. One patient completed all 10 treatments. One patient was treated with a modified schedule of 7 treatments of 20 cGy/fx and tolerated and completed all treatments but developed significant thrombocytopenia following completion of treatment. No patients had disease progression during treatment. The median survival was 11 months. This study indicates that WR-2721 given at 910 mg/m2 twice weekly with TBI is well tolerated for at least 5 treatments and that 910 mg/m2 of WR-2721 is the MTD with this regimen. In view of the importance of total radiation dose in achieving a response with TBI, a dose escalation study of TBI with 910 mg/m2 of WR-2721 should be performed in patients with indolent non-Hodgkin's lymphoma.

Amifostine↗
PubMed1992

Biochemical modulation of bolus fluorouracil by PALA in patients with advanced colorectal cancer.

PURPOSE: N-(phosphonacetyl)-L-aspartic acid (PALA) is a pyrimidine synthesis inhibitor that modulates fluorouracil (FU) cytotoxicity. Two previous studies of patients with colorectal carcinoma documented complete response (CR) and partial response (PR) rates of 40% and 43% using weekly low-dose PALA followed by a 24-hour FU infusion. We investigated whether comparable results could be obtained with biochemical modulation by low-dose PALA using bolus instead of infusional FU. PATIENTS AND METHODS: Forty-five patients without prior chemotherapy who had advanced colorectal carcinoma were treated with PALA 250 mg/m2 followed 24 hours later by bolus FU at three dose levels, 600, 700, 800 mg/m2, repeated weekly for 6 weeks followed by a 2-week break. RESULTS: The CR and PR rate was 15 of 43 patients or 35% (95% confidence interval [CI], 21% to 49%), with an overall median survival of 18 months. Grade 3 or 4 diarrhea was the major toxicity observed in 24% of patients receiving FU at 700 mg/m2 and in 43% of patients receiving 800 mg/m2. Hematologic toxicity was observed only with an FU dose of 800 mg/m2, and 29% (four of 14) of patients developed grade 4 leukopenia. We also noted the development of ascites in six patients, mild hyperbilirubinemia in 16 patients, and a decreased albumin level in 22 patients; these abnormalities occurred more frequently in responding patients. CONCLUSIONS: The observed response rate, median survival, and toxicity in this study are similar to those obtained with PALA plus infusional FU and with other methods of FU modulation. Larger phase III studies are needed to compare bolus FU/PALA regimens with other PALA and non-PALA-containing combinations. Our future focus will be attenuate this regimen's toxicity while maintaining or improving its response rates and survival.

Adenocarcinoma↗
PubMed1991

The role of hexamethylmelamine in the management of ovarian cancer.

Hexamethylmelamine has been recognized as having useful single-agent activity for the treatment of ovarian cancer for the past 25 years, with some patients surviving disease-free for periods in excess of 12 years. Data from recently analysed and mature trials demonstrate that the addition of hexamethylmelamine to first-line combination chemotherapy results in significant improvements in survival compared to what is achieved with regimens of cisplatin and cyclophosphamide with or without doxorubicin.

Altretamine↗
PubMed1991

New protective agents for bone marrow in cancer therapy.

WR-2721 is a unique bone marrow protective agent which also protects other normal tissues against the toxic effects of radiation therapy and chemotherapy, especially with cisplatin and alkylating agents. In addition to protection against acute toxicities, WR-2721 has also been shown to protect against mutagenesis, cell transformation, and carcinogenesis which might be termed subacute and late toxicities. The protective mechanisms are not fully elucidated but oxygen free radical scavenging certainly plays a role and effects of enzymatic DNA repair mechanisms have also been reported. In the field of reduction of toxicity from anticancer treatment modalities, the properties of CSFs and other substances have been contrasted with WR-2721 the former being stimulators of bone marrow (and the immune system) rather than true protectors. Nonetheless, they also have a clinical role and combinations of a protector and stimulator may prove useful in the future. WR-2721 offers the prospect of increasing the therapeutic index of current cancer treatment and may allow the administration of higher than currently would be considered maximal tolerated doses (MTD). This may, in turn, lead to improved efficacy and the full potential of this agent is now being explored in a variety of randomized, controlled clinical trials.

Amifostine↗
PubMed1989

Rhabdomyosarcoma in children: a histological and immunohistochemical study of 59 cases.

Recent studies have suggested that rhabdomyosarcoma can be divided into favourable and unfavourable histology groups. Those subtypes comprising the unfavourable histology group are alveolar, monomorphous round cell and anaplastic rhabdomyosarcoma, with a favourable histology group of embryonal rhabdomyosarcomas. An immunohistological study was undertaken on 59 childhood rhabdomyosarcomas, using antisera to keratin, S100 protein, vimentin, desmin, myoglobin, and troponin T. Our results suggest that desmin is the single most useful antibody in the diagnosis of rhabdomyosarcoma and was expressed in all our cases. The expression of troponin T in the majority of embryonal rhabdomyosarcomas but not in the other histological types has prognostic implications.

Child↗
PubMed1985

Effects of low dose oral triiodothyronine in myxoedema coma.

Some of the immediate cardiovascular changes and alterations in oxygenation occurring in a patient in myxoedema coma following the oral administration of a single dose of triiodothyronine (T3) (2.5 micrograms) are described. These included increases in oxygen consumption, oxygen delivery, cardiac output, heart rate and ventricular stroke work. Low dose oral T3 can be effective in myxoedema coma and these patients may benefit from the continuous, comprehensive monitoring which can be provided in an intensive care unit. Our observations suggest that over-vigorous attempts to reverse the hypothyroid state could precipitate tissue hypoxia and/or myocardial ischaemia.

Administration, Oral↗
PubMed1984

Evaluation of the human basophil degranulation test using the commercially available Baso-kit as a test of immediate-type hypersensitivity in hay-fever sufferers.

The basophil degranulation test (BDT) has failed to gain popular acceptance as a test of immediate-type hypersensitivity since its introduction in clinical medicine in 1961. Recent modification of this technique, however, seemed to have increased its reliability. We have studied a group of twenty-five hay-fever sufferers and a similar age- and sex-matched group of healthy controls to compare the sensitivity of a newly available commercial BDT kit (Baso-kit, Laboratoire des Stallergenes) with specific serum IgE levels and skin-prick tests to meadow-grass pollen. A quantitative correlation was found between the positive BDT (greater than 30% degranulation) and the skin tests, whereas only a qualitative relationship was obtained with specific IgE concentrations. The BDT also identified two subpopulations of responders and non-responders among a third group of hay-fever subjects who had previously been hyposensitized to mixed grass pollen. We conclude that the modified BDT provides a worthwhile addition to the in vitro testing of immediate-type hypersensitivity states.

Basophils↗
PubMedDate not supplied

Limb salvage surgery: an advance in surgical technique.

"Surgery is the primary and oldest treatment for malignant musculoskeletal tumors. Until the 1970's amputation was the accepted surgical procedure for patients with malignant tumors of the extremities. Recent advances in adjuvant treatment modalities such as chemotherapy and radiotherapy, bioengineering designs of internal prosthetic devices, radiographic workups, and bone and tissue transfers provide some individuals with the option of limb-preservation" (Lewis, 1992, p. 477-478). One limb salvaging technique uses a metallic implant to replace resected tumors of the bone. It is this surgical orthopaedic advancement that is currently being used in the resection of primary malignant bone tumors of the lower extremities at Mount Sinai Hospital, Toronto, Ontario. The objectives of this paper are to review the management of musculoskeletal tumors in "skeletally mature patients", and to review a system currently being utilized at Mount Sinai Hospital which provides a surgical option for resection and reconstruction of malignant bone tumors. The role the perioperative nurse plays in providing care to patients having limb salvage surgery will also be described. All three objectives will provide insight into the challenges facing orthopaedic oncology patients who are living with cancer.

Bone Neoplasms↗