Accuracy of co-morbidity data in patients undergoing abdominal wall hernia repair: a retrospective study.

OBJECTIVES: To determine the baseline accuracy, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of routinely collected co-morbidity data in patients undergoing abdominal wall hernia repair. METHODS: All patients aged > 18 who underwent umbilical, para-umbilical, inguinal or incisional hernia repair between 1 January 2015 and 1 November 2016 were identified. All parts of the clinical notes were searched for co-morbidities by two authors independently. The following co-morbidities were considered: hypertension, ischaemic heart disease (IHD), diabetes, asthma, chronic obstructive pulmonary disease (COPD), cerebrovascular disease (CVD), chronic kidney disease (CKD), hypercholesterolemia, obesity and smoking. The co-morbidities data from clinical notes were compared with corresponding data in hospital episode statistics (HES) database to calculate accuracy, sensitivity, specificity, PPV and NPV of HES codes for co-morbidities. To assess the agreement between clinical notes and HES data, we also calculated Cohen's Kappa index value as a more robust measure of agreement. RESULTS: Overall, 346 patients comprising 3460 co-morbidity codes were included in the study. The overall accuracy of HES codes for all co-morbidities was 77% (Kappa: 0.13). When calculated separately for each co-morbidity, the accuracy was 72% (Kappa: 0.113) for hypertension, 82% (Kappa: 0.232) for IHD, 85% (Kappa: 0.203) for diabetes, 86% (Kappa: 0.287) for asthma, 91% (Kappa: 0.339) for COPD, 92% (Kappa: 0.374) for CVD, 94% (Kappa: 0.424) for CKD, 74% (Kappa: 0.074) for hypercholesterolemia, 71% (Kappa: 0.66) for obesity and 24% (Kappa: 0.005) for smoking. The overall sensitivity, specificity, PPV and NPV of HES codes were 9, 100, 100, and 77%, respectively. The results were consistent when individual co-morbidities were analyzed separately. CONCLUSIONS: Our results demonstrated that HES co-morbidity codes in patients undergoing abdominal wall hernia repair are specific with good positive predictive value; however, they have substandard accuracy, sensitivity, and negative predictive value. The presence of a relatively large number of false negative or missed cases in HES database explains our findings. Better documentation of co-morbidities in admission clerking proforma may help to improve the quality of source documents for coders, which in turn may improve the accuracy of coding.

The pharmacological sensitivity of a touchscreen-based visual discrimination task in the rat using simple and perceptually challenging stimuli.

RATIONALE: Cognitive testing with touchscreen-equipped operant boxes ('touchscreens') is becoming increasingly popular. Tasks, such as paired associate learning or reversal learning of visual stimuli, have the discrimination of visual stimuli as a fundamental component. However, the effect of drugs commonly used in the study of cognitive mechanisms has yet to be described in a visual discrimination. OBJECTIVE: The objective of the study was to profile a range of psychoactive agents (glutamatergic, dopaminergic, and cholinergic agonists and antagonists) known to be important in cognitive processing on visual discrimination performance using a touch sensitive computer monitor. METHODS: Male Lister Hooded rats were trained to a stable level of performance in a simple visual discrimination. In Experiment 1, the effect of MK-801, phencyclidine, memantine, dextroamphetamine sulphate (D-amphetamine) and scopolamine was assessed. In Experiment 2, the stimuli were blended together resulting in a perceptually more demanding discrimination and a reduction in accuracy. The rats used in Experiment 1 were then retested with these 'morphed' stimuli under the influence of the above compounds. RESULTS: MK-801, PCP, and D-amphetamine induced selective deficits in accuracy in both versions of the task. In contrast, scopolamine and memantine produced non-selective deficits in accuracy. Morphing the stimuli reduced accuracy, but did not alter the observed behavioural profile after compound administration. CONCLUSION: These data improve our understanding of the basic neuropharmacology of a visual discrimination in cognitive tests employing touchscreens and will aid in the interpretation of pharmacological studies with more cognitively demanding methodologies.

The range of the Oxford Shoulder Score in the asymptomatic population: a marker for post-operative improvement.

INTRODUCTION: The Oxford Shoulder Score (OSS) is a validated scoring system used to assess the degree of pain and disability caused by shoulder pathology. To date there is no knowledge of the range of the OSS in the healthy adult population. This study aimed to establish the range in asymptomatic individuals. METHODS: The OSS of 100 asymptomatic volunteers was compared with the pre-operative OSS of 100 symptomatic individuals who had had elective shoulder surgery performed at the Royal Preston hospital. RESULTS: The difference in mean scores in the operated group (36.7) and the asymptomatic group (15.3) was statistically significant (p<0.0001). There was, however, a substantial overlap between the scores of the two groups (operated group range: 19-55, asymptomatic group range: 12-47). Factors such as age, sex, body mass index, co-morbidities and smoking did not have a statistically significant impact on the eventual score in the asymptomatic group. CONCLUSIONS: This study has established the range of OSS in the asymptomatic adult population. Symptom scores can only be used effectively when the range in the asymptomatic population is known. This is so that disease severity can be gauged in the context of the normal population and post-operative improvements can be forecast more accurately.

Emergency medical service transport-induced stress? An experimental approach with healthy volunteers.

This randomized controlled trial was designed to evaluate the effects of simulated emergency medical service (EMS) transport related stress on hemodynamic variables, and catecholamine plasma levels. A total of 32 healthy male volunteers were randomized to being carried by paramedics from a third-floor apartment through a staircase with subsequent high-speed EMS transport with lights and sirens (stress; n = 16); or sitting on a chair for 5 min, and lying on a stretcher for 15 min (control; n = 16). Blood samples and hemodynamic variables were taken in the apartment before transfer, at the ground floor, and at the end of EMS transport in the stress group, and at corresponding time points in the control group. The stress versus control group had both significantly (P < 0.05) higher mean +/- SEM epinephrine (71 +/- 7 versus 37 +/- 3 pg/ml), and norepinephrine (397 +/- 29 versus 299 +/- 28 pg/ml) plasma levels after transport through the staircase. After EMS transport, the stress versus control group had significantly higher epinephrine (48 +/-6 versus 32 +/- 2 pg/ml), but not norepinephrine (214 +/- 20 versus 264 +/- 31 pg/ml) plasma levels. Heart rate increased significantly from 72 +/- 2 to 84 +/- 3 bpm after staircase transport, but not during and after EMS transport. In conclusion, volunteers being carried by paramedics through a staircase had a significant discharge of both epinephrine and norepinephrine resulting in increased heart rate, but only elevated epinephrine plasma levels during EMS transport. Transport through a staircase may reflect more stress than emergency EMS transport.

Practice guidelines for lipid-based amphotericin B in stem cell transplant recipients.

OBJECTIVE: To provide clinicians who practice in the stem cell transplantation (SCT) setting with practical guidelines for the use of lipid-based amphotericin B (AmB) formulations in SCT patients who have documented or probable invasive fungal infections, are experiencing neutropenic fever, or require secondary prophylaxis for fungal infections. DATA SOURCES: Recommendations are based on the results of a two-day consensus meeting that convened clinicians versed in the management of infectious complications in patients undergoing SCT. This meeting, which was held October 21-23, 1998, in Orlando, Florida, was sponsored by an educational grant from The Liposome Company. In addition, primary articles were identified by MEDLINE search (1980-December 1999) and through secondary sources. STUDY SELECTION AND DATA EXTRACTION: All of the articles identified from the data sources were evaluated, and all information deemed relevant was included in this review. DATA SYNTHESIS: Immunocompromised patients, particularly patients undergoing high-dose chemotherapy with SCT, experience a high degree of morbidity and mortality from invasive fungal infections. Historically, treatment for such infections with conventional AmB had been limited primarily by its associated nephrotoxicity. Lipid-based formulations of AmB have helped to advance the management of invasive fungal infections in the SCT population by offering a treatment alternative that allows for administration of adequate amounts of active drug to produce clinical and mycologic responses, compared with conventional AmB, in a delivery system that is less nephrotoxic. Unfortunately, these agents are relatively expensive. Therefore, patients who are candidates for lipid-based products must be selected carefully. CONCLUSIONS: Practical guidelines are provided for the use of lipid-based AmB formulations in SCT patients who have documented or probable invasive fungal infections, are experiencing neutropenic fever, or require secondary prophylaxis for fungal infections.

Lipid formulations of amphotericin B.

The incidence of systemic fungal infections, especially in immunocompromised patients, has continued to increase during the past few decades. Treatment with conventional amphotericin B has been the standard care for the majority of patients with invasive fungal infections, despite its associated toxicity. Three lipid formulations of amphotericin B have now been approved for use in the United States. The pharmacology, pharmacokinetics, clinical experience, toxicity, dosing strategies, and cost of these three preparations--amphotericin B lipid complex, amphotericin B colloidal dispersion, and liposomal amphotericin B--were reviewed in detail in this chapter. The clinical data indicate that lipid formulations of amphotericin B represent an important therapeutic modality in the management of invasive fungal infections.

A randomized, double-blind trial of filgrastim (granulocyte colony-stimulating factor) versus placebo following allogeneic blood stem cell transplantation.

Blood stem cell transplantation (BSCT) results in rapid hematopoietic recovery in both the allogeneic and autologous transplant settings. Because of the large numbers of progenitor cells in mobilized blood, the administration of growth factors after transplantation may not provide further acceleration of hematopoietic recovery. A randomized, double-blind, placebo-controlled study was performed to determine the effects of filgrastim (granulocyte colony-stimulating factor; G-CSF) administration on hematopoietic recovery after allogeneic BSCT. Fifty-four patients with hematologic malignancies undergoing a related, HLA-matched allogeneic BSCT were randomly assigned to receive daily filgrastim at 10 microg/kg or placebo starting on the day of transplantation. A minimum of 3 x 10(6) CD34(+) cells/kg in the allograft was required for transplantation. All patients received a standard preparative regimen and a standard regimen for the prevention of graft-versus-host disease (GVHD). The median time to achieve an absolute neutrophil count greater than 0.5 x 10(9)/L was 11 days (range, 9-20 days) for patients who received filgrastim compared with 15 days (range, 10-22 days) for patients who received placebo (P =.0082). The median time to achieve a platelet count greater than 20 x 10(9)/L was 13 days (range, 8-35 days) for patients who received filgrastim compared with 15.5 days (range, 8-42 days) for patients who received placebo (P =.79). There were no significant differences for red blood cell transfusion independence, the incidence of acute GVHD, or 100-day mortality between the groups. The administration of filgrastim appears to be a safe and effective supportive-care measure following allogeneic BSCT.

High-dose chemotherapy with autologous stem cell rescue in the outpatient setting.

Intensive outpatient care is rapidly becoming the primary mode of care for selected patients undergoing high-dose chemotherapy with autologous peripheral blood stem cell (PBSC) transplantation. Although the traditional inpatient model of care may still be necessary for high-risk patients, published data suggest that outpatient care is safe and feasible during or after administration of high-dose chemotherapy and autologous PBSC transplant. Blood and marrow transplant (BMT) centers have developed programs to provide more outpatient care under three basic models: an early discharge model, a delayed admission model, and a comprehensive, or total, outpatient model. This review will describe these models of care and address the elements necessary for the development of an outpatient BMT program, including patient selection, staff development, and patient and caregiver education. Available supportive care strategies to facilitate outpatient care will also be highlighted. Clinical outcome data and pharmacoeconomic analyses evaluating various outpatient BMT programs, as well as limited quality-of-life evaluations, will be reviewed.

Extending the spontaneous preference test of recognition: evidence of object-location and object-context recognition.

The natural preference for novel objects which is displayed by rats has been used as a behavioural index to test object recognition. In this series of experiments the standard spontaneous recognition task was extended to look at other types of recognition memory; memory for place (recognition that an object is in a location where previously there had been no object), memory for object in place (recognition that a specific object has changed position with another object) and memory for context (recognition that a familiar object is in a context different to that in which it was previously encountered). We also included a standard test of object recognition in which successful discrimination relied primarily on visual cues. In addition, we looked at how the differential exploration of objects varied within the 3 min of the test phase. The results showed that rats were sensitive to the changes made in all of the test conditions and that the level of discrimination varied within the 3 min test phase. In the standard condition and the context condition, the first 2 min were found to be the most sensitive period. In the two conditions involving a position change, discrimination was only evident in the first minute.

Safety and efficacy of a continuous infusion, patient controlled anti-emetic pump to facilitate outpatient administration of high-dose chemotherapy.

We evaluated the combination of diphenhydramine, lorazepam, and dexamethasone delivered as a continuous i.v. infusion via an ambulatory infusion pump with patient-activated intermittent dosing (BAD pump) for prevention of acute and delayed nausea/vomiting in patients receiving high-dose chemotherapy (HDC) for peripheral blood progenitor cell (PBPC) mobilization (MOB) or prior to autologous PBPC rescue. The BAD pump was titrated to patient response and tolerance, and continued until the patient could tolerate oral anti-emetics. Forty-four patients utilized the BAD pump during 66 chemotherapy courses, 34 (52%) for MOB and 32 (48%) for HDC with autologous PBPC rescue. The median number of days on the BAD pump during MOB and HDC was 3 (1-6) and 9 (2-19) days, respectively. Complete overall or complete emesis control occurred on 94% of MOB and 89% of HDC treatment days during chemotherapy administration and 72% and 43%, respectively, following chemotherapy administration. Eighty-three percent of MOB and 55% of HDC treatment days were associated with no nausea. While on the BAD pump, no patient experienced severe toxicity or required hospitalization for management of nausea/vomiting. The BAD pump was safe and effective in minimizing nausea and vomiting associated with HDC, and thus, eliminated the need for hospitalization for management of chemotherapy-induced nausea and vomiting.

Oral chemotherapy agents in the treatment of leukaemia.

Oral chemotherapy agents have been an important component of the treatment of leukaemia for many years. Obstacles such as poor or erratic bioavailability and noncompliance have often limited the utility of oral agents in the treatment of leukaemia. However, recent evaluations of new or existing oral agents have expanded the clinician's options and understanding of the use of these drugs in the treatment of leukaemia. One major advance is the use of tretinoin (all-trans retinoic acid) in the treatment of acute promyelocytic leukaemia (APL). Tretinoin, an oral vitamin A derivative that reverses abnormal differentiation in APL is now an essential component of first-line therapy for APL, replacing standard intravenous chemotherapy induction regimens. Other advances include an increased understanding of the pharmacokinetic and pharmacodynamic profile of oral chemotherapy agents such as etoposide and high dose busulfan, allowing for modifications or individualisation of administration regimens to enhance efficacy or minimise toxicity. Evaluations of noncompliance with oral agents in the treatment of leukaemia have also provided the clinician with important information on how this obstacle to oral therapy may be overcome or minimised.

Efficacy of low-dose dopamine in preventing amphotericin B nephrotoxicity in bone marrow transplant patients and leukemia patients.

This study evaluated the efficacy of low-dose dopamine for prevention of amphotericin B-induced nephrotoxicity in autologous bone marrow transplant and leukemia patients. Seventy-one patients undergoing cytoreductive therapy who required amphotericin B were randomly assigned in an unblinded fashion to a group receiving continuous-infusion low-dose dopamine (3 microgram/kg/min) or a group receiving no dopamine. Amphotericin B was dosed at 0.5 or 1.0 mg/kg/day based on computerized tomography scan results or presence of positive blood cultures. No patient received saline boluses. The rate of nephrotoxicity, severity as graded by Southwest Oncology Group toxicity criteria, and time to each grade of nephrotoxicity were compared between the two groups. Eighty percent of the no-dopamine group and 66.7% of the dopamine group developed nephrotoxicity, defined as a 1.5-fold or greater increase in baseline serum creatinine level (P = 0.20). No statistical difference was noted at any grade of nephrotoxicity between the two groups. Thirty-four percent of patients in the no-dopamine group versus 17.6% in the dopamine group had a 2.5-fold or greater increase in serum creatinine level, which was not statistically significant (P = 0.0888). Ten patients developed grade IV nephrotoxicity and were withdrawn from the study, 7 in the no-dopamine group and 3 in the dopamine group (P = 0.19). The time to each grade of nephrotoxicity was also not significantly different for the two groups. Eleven adverse drug reactions were reported in the dopamine group in comparison to one in the no-dopamine group. Thus, dopamine offers little in the way of prevention of nephrotoxicity associated with amphotericin B therapy. Although the significance of drug reactions in the dopamine group is not clearly established due to lack of cardiac monitoring in the no-dopamine group, dopamine therapy is not without complications.

An open-label dose comparison study of ondansetron for the prevention of emesis associated with chemotherapy prior to bone marrow transplantation.

Nausea and vomiting are significant side effects in bone marrow transplant (BMT) patients who receive high-dose preparative regimens. Higher than conventional ondansetron doses and continuous infusion might improve emetic control, because of the high doses and combinations of chemotherapy (CT) used in this setting. Our objective was to conduct a prospective, randomized study comparing two different administration methods of high-dose ondansetron during a BMT preparative regimen in breast cancer patients. Patients were eligible if they were nonpregnant women over 18 but under 65 years of age, undergoing highly emetogenic CT in preparation for autologous BMT. All patients received ondansetron as an intermittent (INT = 24 mg i.v. q 12 h/day) or continuous intravenous infusion (CIV = 8 mg i.v. loading dose followed by a continuous infusion of 2 mg/h per day). A total of 66 patients were enrolled in the study (n = 34, INT; n = 32, CIV). There was no statistical difference between treatment groups in the worst grade of emesis for the entire study period (P = 0.49). Greater than 90% of all patients were graded as failures (> or = 5 emetic episodes or need for rescue antiemetics). Complete control (no vomiting episodes) and complete plus major control (1-2 emetic episodes) per day ranged from 8% to 85% and 11% to 91%, respectively. There was no significant difference between the treatment arms in: grade of emesis, episodes of vomiting and retching, nausea scores, and mean number of rescue medications administered. There were no differences in efficacy when high-dose ondansetron was given as CIV or INT for the control of nausea and vomiting in breast cancer patients undergoing high-dose CT for autologous BMT. Ondansetron alone was not adequate to provide sustained control of CT-induced nausea and vomiting over the entire 5-day study period. A combination of antiemetics targeting various mechanisms of CT-induced nausea and vomiting may be necessary to improve response rates.

CCU patient survey tool: all-out recovery.

Studies show that patients' recall of their CCU stays is extremely limited due to various factors. To monitor patient satisfaction in this area, a team of CCU managers developed a survey and began an "All-Out Recovery Program."

Allogeneic bone marrow transplantation with matched unrelated donors for patients with hematologic malignancies using a preparative regimen of high-dose cyclophosphamide and fractionated total body irradiation.

Allogeneic bone marrow transplantation (BMT) from an HLA-identical sibling donor is effective therapy for patients with bone marrow failure states and those with hematologic malignancies. However, only a minority of them will have an HLA-identical sibling donor; unrelated donors, matched or partially mismatched, have been used successfully for patients lacking a related donor. Even though results with allogeneic transplants using unrelated donors are encouraging, the incidence of complications including graft-versus-host disease (GVHD) and graft rejection or late graft failure is increased compared to identical sibling transplants. The combination of cyclophosphamide and total body irradiation (TBI) has been used as an effective preparative regimen for allogeneic transplants, however, the total dosage and dosing schedule of both the cyclophosphamide and TBI has varied significantly among studies. To decrease the rate of graft rejection and late graft failure with volunteer donors, we evaluated a preparative regimen of high-dose cyclophosphamide (200 mg/kg over 4 consecutive days, days -8, -7, -6, -5) followed by fractionated TBI (1400 cGy administered in eight fractions over 4 days, days -4, -3, -2, -1). GVHD prophylaxis included FK506 and methotrexate. From July 1993 to January 1996, 43 adult patients, median age 38 years (range 18-58 years), were treated with this preparative regimen. Seventeen patients had low-risk disease and 26 had high-risk disease. Thirty-one donor/recipient pairs were matched for HLA-A, -B, and -DR by serology and molecular typing. Seven additional pairs were minor mismatched at the HLA-A or HLA-B loci. Four other donor/recipient pairs were HLA-A,-B, and -DR identical by serology but allele mismatched at either DRB1 or DQB. Forty patients were evaluable for myeloid engraftment. Engraftment occurred in all 40 patients at a median of 19 days. There were no cases of graft rejection or late graft failure. Nephrotoxicity was the primary adverse event with 26 patients (60%) experiencing a doubling of their creatinine. Hepatic veno-occlusive disease occurred in seven patients, six of whom had high-risk disease. All patients who had relapsed or refractory disease prior to BMT achieved a complete remission following BMT. Six patients transplanted for high-risk disease relapsed a median of 377 days post-BMT. None of the patients with low-risk disease have relapsed following transplant; the Kaplan-Meier survival for those patients with low-risk disease is 62% and 37% for those patients transplanted with high-risk disease (P = 0.0129). The median Karnofsky performance status is 100% (range 70-100%). Therefore, a preparative regimen of high-dose cyclophosphamide and fractionated TBI is an acceptable regimen for patients receiving an allograft from unrelated donors.

The outcome of unrelated donor bone marrow transplantation in patients with hematologic malignancies using tacrolimus (FK506) and low dose methotrexate for graft-versus-host disease prophylaxis.

Initial studies of FK506 combined with methotrexate (MTX) in patients receiving unrelated donor BMT have demonstrated a possible-decrease in the incidence of severe GVHD but high rates of severe stomatitis and nephrotoxicity. With this background, we undertook a pilot study evaluating FK506 in combination with a lower than usual dose of MTX in an attempt to improve the tolerability of this immunoprophylaxis regimen. Between July 1993 and October 1994, 26 consecutive adults receiving unrelated donor BMT at Emory University Hospital were enrolled on this study. All patients received FK506 intravenously at an initial dose of 0.03 mg/kg/day beginning day -1 and continuing until oral FK506 was tolerated. Patients also received MTX intravenously at 5 mg/m2 on days 1, 3, 6, and 11. The preparative regimen administered to all but one patient included cyclophosphamide at 200 mg/kg over 4 days followed by total body irradiation (TBI) at 1400 cGy in twice daily fractions over 4 days. The median age of patients was 31 years (range: 19 to 52). Sixteen donor/recipient pairs were matched for HLA-A, -B, and -DR by serology and molecular typing. Ten paris were minor mismatches at either class I or class II. Twenty-two of 26 patients (85%) completed four doses of MTX on schedule. Nephrotoxicity was the most common adverse event associated with the administration of FK506: 88% of patients experienced a doubling of their serum creatinine. One patient died of central nervous system hemorrhage prior to engraftment. Twenty-four of the remaining 25 patients (96%) engrafted. Fourteen of 24 patients (50%) evaluable developed grades 2-4 acute GVHD. The rate of severe (grades 3-4) acute GVHD was 25%. Chronic GVHD developed in 11 of 20 (55%) evaluable patients. At a median follow-up of 461 days, 14 patients (54%) are alive. All are relapse-free with a median Karnofsky performance status of 90% (range: 70-100%). The cumulative probability of 2-year disease-free survival is 50% (95% confidence interval [CI]: 0.33 to 0.77); for low risk patients 67% (95% CI: 0.47 to 0.95) and for high risk patients 23% (95% CI: 0.049 to 1.00). These preliminary data indicate that FK506-based immunosuppression following unrelated donor BMT is effective in preventing severe acute GVHD and warrants comparison to CSA-based regimens.

Isolation and characterization of fluconazole- and amphotericin B-resistant Candida albicans from blood of two patients with leukemia.

Infections with fluconazole-resistant Candida albicans isolate have rarely been described in clinical settings other than oropharyngeal candidiasis in patients with late-stage AIDS. We report on two patients with leukemia who developed fungemia caused by fluconazole-resistant C. albicans after receiving fluconazole prophylaxis (400 mg/day) and empiric amphotericin B therapy (0.5 mg/kg of body weight per day). The fluconazole MICs for the isolates were > or = 64 micrograms/ml, and the isolates were resistant to other azoles and had membrane sterol changes consistent with a mutation in the delta 5,6-sterol desaturase gene. The lack of ergosterol in the cytoplasmic membrane of the fluconazole-resistant strains also imparted resistance to amphotericin B. Both patients were successfully treated with high-dose amphotericin B (1 to 1.25 mg/kg/day) and flucytosine (150 mg/kg/day).

Cytokine therapy after bone marrow transplantation.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) have an important yet controversial role in the care of patients undergoing bone marrow transplantation (BMT). Numerous studies have documented acceleration of neutrophil recovery by the agents. Because of the differences and lack of published clinical outcomes and of direct comparisons of the two CSFs, coupled with limited data from phase III trials, it is difficult to draw conclusions from the literature on the use of the agents after BMT. Issues that must be critically evaluated are toxicity profile, dose, initiation and duration of administration, route of administration, and cost.

Minimal toxicity and mortality in high-risk breast cancer patients receiving high-dose cyclophosphamide, thiotepa, and carboplatin plus autologous marrow/stem-cell transplantation and comprehensive supportive care.

PURPOSE: To assess the clinical toxicity and outcome associated with a comprehensive supportive care approach in poor-risk breast cancer (BrCA) patients with high-dose chemotherapy (HDC). PATIENTS AND METHODS: One hundred twenty-five consecutive patients with stages II, III or metastatic breast cancer received HDC between February 1992 and June 1994. Recipients received 4 days of continuous infusion of cyclophosphamide 1.5 g/m2/d, thiotepa 125 mg/m2/d, and carboplatin 200 mg/m2/d followed by infusion of bone marrow or peripheral-blood stem cells (PBSC) and recombinant human growth factor (rhu-GF) support. Patients received similar supportive care that included administration of prophylactic antibiotics, management of neutropenic fevers, and transfusion support. RESULTS: There were 38 women with stage II or III (27 patients with > or = 10 lymph nodes), four with stage IIIB, and 83 with metastatic breast cancer. The median age was 44 years (range, 27 to 61). Grade II or greater nonhematologic toxicities included diarrhea (66%), stomatitis (33%), hepatic venoocclusive disease (VOD) (5%), and pulmonary toxicity (4%). Myeloid and platelet engraftment was comparable between bone marrow and PBSC recipients (P > .1). Infectious complications were rare and consisted of gram-negative bacteremia (1.6%), gram-positive bacteremia (1.6%), fungemia (1.6%), and documented or suspected aspergillosis infection (3%). There was one treatment-related death secondary to severe VOD. CONCLUSION: A comprehensive supportive care approach was associated with a low treatment-related mortality rate of less than 1%. With the observed reduction in treatment-related mortality, it is reasonable to evaluate the efficacy of HDC in women with less than 10 positive nodes and stage II disease in well-designed clinical trials.

Evaluation of the drug interaction between intravenous high-dose fluconazole and cyclosporine or tacrolimus in bone marrow transplant patients.

The purpose of this open-label, prospective study was to compare steady state concentrations and clearances of intravenously administered cyclosporine or tacrolimus with and without concomitant high-dose (400 mg/day) fluconazole in allogeneic BMT patients. Twenty-one patients were evaluable. The mean steady state cyclosporine and tacrolimus concentrations without fluconazole were 320.3 and 18.2 ng/ml and increased to 389.2 and 21.2 ng/ml, respectively, after the addition of fluconazole, corresponding to a 21% (P=0.031) and 16% (P=0.125) increase. The mean steady state clearance of cyclosporine and tacrolimus without fluconazole was 6.82 and 1.28 ml/min/kg, which decreased to 5.57 and 1.10 ml/min/kg with fluconazole, corresponding to a 21% (P=0.031) and 16% (P=0.125) decrease, respectively. The 21% difference in the cyclosporine concentration and clearance was not thought to be clinically significant. These results suggest that fluconazole's interaction with cyclosporine or tacrolimus may be a result of fluconazole's inhibition of gut metabolism, resulting in a greater extent of absorption.