Does location matter? Rural vs urban outcomes after blood and marrow transplantation in a population-based Canadian cohort.

Specialized health services, such as blood and marrow transplantation (BMT), are usually based in large urban centers. Previous research has suggested that rural patients undergoing BMT have a higher risk of death. We performed a cohort study using data from both the Manitoba BMT Program and the provincial Cancer Registry to determine whether patients from the rural areas would have inferior survival after BMT and whether rural patients have reduced access to BMT. A total of 463 adult Manitobans, who underwent BMT between January 1990 and December 2006, were assessed. We analyzed area of residence (rural vs urban), disease and BMT characteristics, and calculated the OS. Patients undergoing autologous and allogeneic transplants were analyzed separately. When adjusted for gender, age at BMT and year of BMT, area of residence was not a significant predictor of mortality. A relative survival analysis was also conducted, and area of residence was again not a significant predictor of mortality. To measure access to BMT in urban vs rural patients, we evaluated all patients with newly diagnosed Hodgkin's Lymphoma (HL) during this same period. Of 432 Manitobans diagnosed with HL, 182 (42%) were rural and 250 (58%) were urban. In contrast, 69% of patients undergoing transplant for HL were urban. In conclusion, using population-based data from a Canadian province, we were unable to show a survival disadvantage for rural patients after controlling for other variables. BMT utilization in rural populations deserves further study.

Performance status, but not the hematopoietic cell transplantation comorbidity index (HCT-CI), predicts mortality at a Canadian transplant center.

The hematopoietic cell transplantation-specific comorbidity index (HCT-CI) was developed at a single center to predict outcomes for allogeneic transplant recipients who have comorbidities. The HCT-CI has not been widely validated in unselected transplant recipients. We evaluated whether the HCT-CI and other readily available pre-transplant variables predicted NRM and OS at a Canadian transplant center. Using a prospective cohort design, we analyzed consecutive adult allogeneic HCT recipients. Of 187 patients, HCT-CI risk was low in 22 (12%), intermediate in 50 (27%), high in 104 (55%) and undetermined in 11 (6%). Two-year OS was 45% (95% CI: 24-64%), 55% (95% CI: 40-68%) and 42% (95% CI: 32-51%) in the low, intermediate and high-risk HCT-CI groups, respectively. Two-year NRM was 36% (95% CI: 17-56%), 26% (95% CI: 15-39%) and 30% (95% CI: 22-39%) in the low, intermediate and high-risk HCT-CI groups, respectively. In multivariate analysis, the HCT-CI failed to predict OS or NRM. However, KPS of <90% at HCT was a strong predictor of NRM. In conclusion, the HCT-CI was not associated with NRM or OS. In contrast, KPS was an independent indicator of survival. International multi-center studies are required before the HCT-CI is used in clinical practice.

A prospective surveillance study of factor VIII inhibitor development in the Canadian haemophilia A population following the switch to a recombinant factor VIII product formulated with sucrose.

The introduction of new factor concentrates has, at times, resulted in an increase in inhibitor development; hence large systematic surveys of inhibitor development are necessary whenever new products are introduced. This study presents the results of a surveillance study conducted by the Inhibitor Subcommittee of the Association of Hemophilia Clinic Directors of Canada that evaluated inhibitor development in patients with haemophilia A following the switch to a second generation recombinant FVIII product (rFVIII-FS; Kogenate((R)) Bayer). Four hundred and sixty haemophilia A paediatric and adults patients from 17 Canadian Comprehensive Hemophilia Care Centers were enrolled in the study. Of these, 274 patients had evaluable data. Blood samples collected at baseline (prior to the switch to rFVIII-FS), and at 12 and 24 months following conversion were tested for inhibitors by the Nijmegen-modified Bethesda assay. Four subjects had positive inhibitor titres at baseline, with values ranging from 3.3 to 160 BU. Of the 274 patients who had baseline samples collected, 225 had postswitch samples collected at 12 months and 189 subjects had samples collected at 24 months. Only patients with positive baseline inhibitor titres (n = 4) had positive inhibitor titres at either the 12- or 24-month postswitch time points; therefore no de novo inhibitors developed over the 2-year evaluation period in this patient population. The results of this surveillance study suggest that the altered formulation of this recombinant FVIII concentrate was not associated with an increased incidence of inhibitor formation.

High rate of discordance between clinical and autopsy diagnoses in blood and marrow transplantation.

We analyzed autopsies performed in a Canadian blood and marrow transplantation (BMT) program. We aimed to assess variables that predict the performance of an autopsy, whether rates of autopsy are changing, and the rate of discordance between clinical and autopsy diagnoses. All deceased adult patients from January 1990 to December 2004 were reviewed. Autopsy rates were compared to a large teaching hospital. Of 476 myeloablative BMT patients, 225 died and 48 (27%) underwent autopsy. Autopsy was more likely in patients dying: <100 days post-BMT, in the intensive care unit, after allografting, and on weekends. Autopsy rates among BMT patients declined during the three time periods (1990-1994, 1995-1999, 2000-2004). The autopsy rate at the teaching hospital showed a similar downward temporal trend. Major and minor disagreements at autopsy were present in 16 (34%) and 14 (30%) of cases, respectively. There was no change in discordance rates over time. Thus, despite advances in diagnostic procedures, high levels of disagreement between clinical and autopsy diagnoses for BMT patients persist as autopsy rates decline. We recommend that the autopsy regains its role as a valuable investigation. This may become especially relevant in an era where patients with medical comorbidities are undergoing reduced-intensity BMT.

Optimising parameters for peripheral blood leukapheresis after r-metHuG-CSF (filgrastim) and r-metHuSCF (ancestim) in patients with multiple myeloma: a temporal analysis of CD34(+) absolute counts and subsets.

Patients (n = 69) with multiple myeloma undergoing peripheral blood stem cell collection (PBSC) were treated with cyclophosphamide and a combination of recombinant methionyl human granulocyte colony-stimulating factor (r-metHuG-CSF, filgrastim) and recombinant methionyl human stem cell factor (r-metHuSCF, ancestim). The objectives of this study were to determine: (1) The proportion of patients reaching a target yield of >or=5 x 10(6) CD34(+) cells/kg in one or two successive large-volume (20 liter) leukapheresis procedures; (2) the optimal collection time for leukapheresis; (3) mobilization kinetics of CD34(+) subsets in response to G-CSF/SCF. All patients were mobilized with cyclophosphamide (2.5 g/m(2)) on day 0 followed by filgrastim (10 microg/kg ) plus ancestim (20 microg/kg) commencing day 1 and continuing to day 11 or 12. Of the 65 evaluable patients, 57 were considered not heavily pretreated and 96.5% obtained a target of >or=5 x 10(6)/kg in one collection. The median CD34(+) cells/kg was 39.5 x 10(6) (range: 5.2-221.2 x 10(6)). Subset analysis demonstrated the number of CD38(-), CD33(-), and CD133(+) peaked at day 11; and CD34(+), CD90(+) cells peaked at day 10. The optimum day for leukapheresis was determined to be day 11. The median absolute peripheral blood CD34(+) cell numbers on day 11 was 665 x 10(6)/l (range: 76-1481 x 10(6)/l). Eight of the 10 heavily pretreated patients were evaluable: three achieved the target dose in one leukapheresis (37.5%) and three (37.5%) achieved the target dose with two leukaphereses. Use of this mobilization strategy allowed the collection of high numbers of CD34(+) cells and early progenitors and the ability to predictably schedule leukapheresis.

Does gastroenterology consultation change management of patients receiving hematopoietic stem cell transplantation?

Gastrointestinal complications following hematopoietic stem cell transplantations (HSCTs) are common, but it is unknown how often gastroenterology consultation (GEC) early post BMT leads to specific changes in patient management. We aimed to determine the reason(s) for GEC, the diagnoses found through GEC, whether the advice or intervention led to change(s) in management and if intervention led to any adverse outcome within the first 100 days post HSCT. We undertook a retrospective review of all patients at least 18 years old (n = 197) who underwent HSCT between November 1990 and April 1998. Of these, 79 patients had 92 consultations for a total of 163 separate GE problems within the first 100 days post HSCT. Data were obtained through chart review. It was determined whether the intervention or advice given by the consultant led to actual changes in patient management or outcome. We found that the characteristics more likely to be associated with GEC included female patient vs male (P = 0.03), allogeneic vs autologous transplants (P < 0.001), hematologic vs solid malignancies (P = 0.006), and leukemias vs lymphomas (P = 0.013). Overall, a definitive diagnosis for an identified complaint was made in 71% (range 25-87%). A change in management was effected in 54% of cases (range 0-59%). Endoscopy led to perforation and subsequent death in two patients (1.8%). Gastrointestinal disease was a direct cause of death in 2.5% of all patients. In conclusion, a definite diagnosis was reached in 71% of gastrointestinal problems and management was effected in 54% of cases. Since endoscopy was associated with a mortality of 1.8%, minimizing its use for the cases in which no impact is made, should be considered.

An epidemiological review of red cell transfusions in cancer chemotherapy.

OBJECTIVE: The objective of this chart review was to determine the frequency of transfusion and prevalence of anemia (hemoglobin result < 100 g/L) in patients receiving chemotherapy. DESIGN: This study was a retrospective review of medical charts. SETTING: Patients receiving chemotherapy were included from 12 tertiary care comprehensive cancer centres across Canada. MAIN OUTCOME MEASURE: The primary study outcome measure was red blood cell transfusion rate, controlling for patient variables. RESULTS: The 616 patients included had started chemotherapy in January-June 1992. For each subject, data collection finished 4 weeks after the end of the first regimen or after a maximum follow-up period of 26 weeks. Seventy-two patients (12%; 95% confidence interval 9.5% to 14.5%) were transfused for anemia (reasons other than blood loss), and 28% (95% confidence interval 24.5% to 31.5%) of the subjects were anemic during treatment. The univariate analyses of transfusion for anemia yielded significant associations with prognostic factors. In the multivariate analyses, platinum (odds ratio [OR] = 6.69) and anthracycline (OR = 3.56) chemotherapy, baseline hemoglobin (OR = 0.96) and disease stage (OR = 1.72) were statistically significant contributors. CONCLUSION: In this patient cohort, red blood cell transfusion was infrequent (12%). However, patient groups at high risk of transfusion could be identified, with platinum-based chemotherapy being the most significant contributing factor. The information obtained from this multicentre study may prove helpful in developing supportive care guidelines for the management of chemotherapy-related anemia requiring transfusion.

Remission induction therapy of untreated acute myeloid leukemia using a non-cytarabine-containing regimen of idarubicin, etoposide, and carboplatin.

BACKGROUND: The safety and efficacy of idarubicin, etoposide, and carboplatin as remission induction therapy for patients younger than 60 years with untreated acute myeloid leukemia was studied as an alternative to standard regimens based on cytarabine plus anthracycline. METHODS: Eligible patients received idarubicin (36-40 mg/m2), etoposide (500 mg/m2), and carboplatin (1000-1500 mg/m2) over 5 days. Those who achieved complete remission received a single course of cytarabine 1.5 gm/m2 every 12 hours for a total of 12 doses. D-xylose absorption was studied as a marker for cytotoxic therapy-induced gut mucosal damage. Cytogenetic and immunophenotyping studies were performed at the time of diagnosis and examined for prognostic importance. RESULTS: Remission was achieved in 29 (67%) of 43 patients with a single induction course. The median leukemia free and overall survival times were 15.4 months (95% CI 6.5-24.2) and 12.5 months (95% CI 5.9-19.1), respectively. Induction mortality was 14%. Karyotype (normal, simple, or complex vs. very complex) was the strongest predictor of remission (79% vs. 25%, P=0.01), leukemia free survival (odds ratio [OR] 19.3, 95% CI 2.7-138.9), and overall survival (OR 5.4, 95% CI 2.1-13.9). Dose-limiting gut mucosal toxicity was greatest during Weeks 2 and 3. Bloodstream infections occurred in 49% of patients at a median of 12 days. Grade 3-4 diarrhea, nausea, stomatitis, esophagitis/dysphagia, and vomiting developed in 33%, 26%, 23%, 9%, and 2% of cases, respectively, at a median of 17, 16, 11, 15.5, and 21 days, respectively. CONCLUSIONS: This regimen was active in adults younger than 60 years with untreated acute myeloid leukemia and normal, simple, or complex karyotypes. Remission duration was confounded by karyotype. Mucosal toxicity limited the tolerability of this regimen. These adverse effects might be overcome by increasing the intensity of postremission therapy and modifying the dosing schedule.

Expression of p53 predicts treatment failure in aggressive non-Hodgkin's lymphomas.

Approximately 50% of patients with aggressive non-Hodgkin's lymphomas (NHL) achieve a complete remission (CR) and cure with combination chemotherapy. The International Index is a useful clinical measure that predicts the patients' tolerance of therapy and likelihood of achieving CR, but it is not a direct measure of chemosensitivity. In this study we have investigated the predictive value of the tumor suppressor gene, p53, as a biological marker for response to treatment in the aggressive NHL. A retrospective study was carried out on 50 patients with aggressive NHL who were treated with CHOP chemotherapy. Treatment outcome was correlated with the expression of p53 in the lymphoma, as measured by routine immunohistochemistry using the monoclonal antibody Do-7. Forty percent of the lymphomas had >5% of the cells staining positively for p53 and this finding correlated significantly with response to treatment. Fifty percent of patients with p53 positive tumors achieved a CR versus 77% of patients with p53 negative tumors. In addition, the relapse rate and time to relapse were significantly different in the two groups. In the p53 positive group, 60% of patients relapsed in a median time of 6 months, whereas 26% of the p53 negative group relapsed with the time to relapse being >22 months. The overall survival of the p53 positive group (17 months) was significantly shorter than that of p53 negative group (>24 months). These results suggest that the immunohistochemical assessment of p53 is a simple and important prognostic measure for patients with aggressive NHL who are treated with CHOP chemotherapy.

Continuous infusion of porcine factor VIII in the management of patients with factor VIII inhibitors.

The effectiveness of continuous infusion porcine factor VIII (PFVIII) has been evaluated in the treatment of 7 consecutive patients with factor VIII(FVIII) inhibitors. Two patients had hemophilia A and five were nonhemophiliacs with acquired FVIII inhibitors. The median pretreatment anti-porcine FVIII titre was 0.2 (range: 0-15.0) Bethesda units (BU), and the anti-human FVIII titer was 12.0 BU (range: 2.4-50.0). All patients presented with major bleeding. Patients were given a bolus dose of PFVIII followed by continuous infusion. Six patients also received immunosuppressive therapy. Therapeutic FVIII levels (>0.5 U/ml) were achieved in 6 of 7 patients at a median time of 12.5 hr, and then maintained with continuous infusion PFVIII. Six patients were treated for more than 7 days, and in four of these there was a decline in FVIII recovery between days 7 to 11, presumably related to a rising antibody response to PFVIII. These four patients were plasmapheresed and the three patients with autoantibodies recovered therapeutic FVIII levels but this did not occur in the patient with hemophilia. Thrombocytopenia developed in 4 patients at days 18 to 24, with the platelet count falling to 11 to 87 x 10(9)/L, and the PFVIII was discontinued in 3 patients. All patients recovered from the acute bleeding events. With prolonged immunosuppressive therapy, the FVIII inhibitor disappeared in all patients with autoantibodies and there have been no relapses after a median follow-up period of 581 days. This study demonstrates that continuous infusion PFVIII is an effective therapy for patients with FVIII inhibitors, but that prolonged treatment is associated with the development of inhibitors to porcine FVIII and severe thrombocytopenia, which readily corrects with discontinuation of PFVIII.

Cytotoxic therapy-induced D-xylose malabsorption and invasive infection during remission-induction therapy for acute myeloid leukemia in adults.

PURPOSE: To study the sequential changes in the intestinal absorption of an oral pentose probe, D-xylose, in patients receiving therapy for untreated acute myeloid leukemia (AML), and to correlate these changes to infectious morbidity. PATIENTS AND METHODS: Serial D-xylose absorption studies were conducted in 110 consecutive adult patients admitted to a university-affiliated tertiary care hospital for remission-induction therapy for untreated newly diagnosed AML. Serial serum D-xylose levels were obtained 1 hour after a 5-g oral dose of D-xylose at baseline and weekly for 4 weeks until marrow recovery. These results were correlated with invasive infection using multivariate techniques. RESULTS: The mean (+/- SEM) serum D-xylose levels were 0.88 +/- 0.03, 0.69 +/- 0.03, 0.58 +/- 0.02, 0.53 +/- 0.02, and 0.73 +/- 0.02 mmol/L at baseline and weeks 1 to 4, respectively (P < .0001, analysis of variance [AN-OVA]). Time to malabsorption varied with induction regimen (P = .007, log-rank test). Bloodstream infections during week 2 correlated with malabsorption (P = .007). Neutropenic enterocolitis correlated independently with induction regimen (P = .009), malabsorption at week 2 (P = .02), and the development of candidemia (P = .005). Hepatosplenic fungal infection correlated with induction regimen (P = .03), malabsorption at week 2 (P = .02), and fever at diagnosis (P = .003). Malabsorption was unrelated to the duration of severe neutropenia and the administration of parenteral nutrition. CONCLUSION: Serial D-xylose absorption studies in subjects with AML produced a characteristic profile of cytotoxic therapy-related damage to the functional integrity of the intestinal epithelium that was regimen dependent, myelosuppression independent, and predictive for invasive infectious complications. Further study to validate these observations appears warranted.

Rhabdomyolysis induced by epsilon-aminocaproic acid.

OBJECTIVE: To report a case of rhabdomyolysis associated with epsilon-aminocaproic acid (epsilon-ACA). CASE SUMMARY: A 33-year-old female patient with chronic granulocytic leukemia was treated with epsilon-ACA for approximately 3.5 months for thrombocytopenic bleeding. The initial dosage was 4 g po q6h. One month after an increase in dosage to 5 g po 14h the patient developed severe lower extremity myalgia and marked weakness. Laboratory investigations revealed an elevated creatine kinase (CK), lactate dehydrogenase (LDH). aspartate aminotransferase (AST), and myoglobinemia. Epsilon-ACA was thought to be the causative agent and was discontinued. The patient received intravenous fluids to minimize renal damage due to myoglobin. Serum enzyme concentrations did not return to normal. The patient died of a central nervous system hemorrhage 1 week after the epsilon-ACA was discontinued. DISCUSSION: There were 31 cases of epsilon-ACA-induced myopathies published in the literature (MEDLINE) from 1972 to June 1995. Of these, 10 cases were reviewed. In all cases, patients received epsilon-ACA in doses ranging from 16 to 36 g/d for more than 28 days. Clinical findings varied from extreme muscle weakness to myopathic changes in electromyelograms. All patients recovered following discontinuation of epsilon-ACA. CONCLUSIONS: Long-term therapy with high-dose epsilon-ACA may produce muscle weakness or rhabdomyolysis. Patients who require long-term, high-dose epsilon-ACA therapy should be monitored for myoglobinuria and changes in serum CK, LDH, and AST, for myoglobinemia, for decreases in muscle strength, and/or for myalgia. Significant changes in these parameters compared with baseline values should suggest a need to discontinue epsilon-ACA therapy.

Multiple myeloma presenting clinically as lymphoma.

Multiple myeloma typically presents with monoclonal proteinemia, marrow plasmacytosis, anemia, bony involvement, hypercalcemia and renal insufficiency. Less frequent presentations include hepatic and splenic enlargement (5% of cases), lymphadenopathy (4%) and biclonal gammopathy (1%). Chemotherapy may produce remissions in 50% of cases, but relapses are the rule and mean survival is approximately 2.5 years. To improve survival, marrow transplantation is being explored as a therapeutic modality in younger patients. In this report we describe a unique case of multiple myeloma presenting clinically as lymphoma. The patient presented with fever, widespread lymphadenopathy and pleuropulmonary involvement and responded promptly to multiagent doxorubicin-based chemotherapy. This was followed by high-dose chemotherapy and allogeneic bone marrow transplantation and the patient remains in remission more than 36 months post transplant. This case report suggests that myeloma simulating lymphoma may be a chemosensitive and potentially curable myeloma variant.

In-vitro stability of porcine factor VIII (Hyate:C(®) ).

The stability of porcine factor VIII (Hyate:C(®) ) 30 units mL(-1) , 15 units mL(-1) and 5 units mL(-1) prepared aseptically in 0.9% sodium chloride injection was studied. Solutions were stored in plastic syringes at room temperature and ambient light, and at body temperature protected from light. Samples obtained immediately after mixing and at 4, 24, 48 and 72 h were assayed for FVIII activity using a one-stage FVIII assay. Samples were considered stable if FVIII activity did not decline more than 10% compared with baseline values. Hyate:C(®) 5 units mL(-1) stored at room temperature retained FVIII activity within 90% of baseline values for at least 24 h. When stored at body temperature, FVIII activity of Hyate:C(®) 5 units mL(-1) declined to less than 90% of baseline values within 4 h. Stability of Hyate:C(®) 15 units mL(-1) and 30 units mL(-1) stored at room temperature was retained for at least 72 h. When Hyate:C(®) 15 units mL(-1) and 30 units mL(-1) were stored at body temperature, stability was retained for 24 h. Results of this study will permit further evaluation of Hyate:C(®) stability when administered by ambulatory infusion pumps.

Pancreatitis post-bone marrow transplantation.

Pancreatitis has been reported as a rare complication after bone marrow transplantation (BMT). This paper reports a series of three cases of pancreatitis post-BMT and reviews the literature. Pancreatitis occurred in three of 68 (4.4%) of BMT cases in our transplant program. The etiology of such cases is multifactorial and includes drugs, graft-versus-host disease, infection, cholecystitis, and the lipid in total parenteral nutrition. Pancreatitis should be included in the differential diagnosis of abdominal pain post-BMT. The development of a pancreatic pseudocyst in an immunocompromised host may require surgical drainage since infected pseudocysts are not drained adequately by radiologically guided techniques.

Therapy of untreated acute myeloid leukemia in the elderly: remission-induction using a non-cytarabine-containing regimen of mitoxantrone plus etoposide.

PURPOSE: The University of Manitoba Adult Acute Leukemia Study Group sought to examine the safety, efficacy, and impact on quality of life of a non-cytarabine-containing remission-induction regimen followed by intermediate-dose cytarabine (IDARA-C) postremission therapy for the management of untreated acute myeloid leukemia (AML) in patients age 60 to 80 years. PATIENTS AND METHODS: Eligible patients received mitoxantrone 10 mg/m2 and etoposide 100 mg/m2 on days 1 to 5. Complete remitters received a single course of cytarabine 0.5 mg/m2 every 12 hours on days 1 to 6. Cytogenetic and immunophenotyping studies were performed at diagnosis and were examined for prognostic importance. The Functional Living Index-Cancer (FLI-C) was used in the longitudinal assessment of quality of life. RESULTS: A total of 37 (55%) of 67 eligible patients achieved remission, 34 (92%) of whom did so with a single course. The induction mortality rate was 12%. The median disease-free and overall survival times were 8.4 and 9.2 months, respectively. CD34 stem-cell phenotype, poor performance status, and high cytogenetic complexity score were independent covariates of failure to achieve remission. Very complex karotype combined with CD34 stem-cell phenotype to predict induction death in 67% of cases (P = .0003). Cytotoxic therapy-related gut epithelial damage was maximal during weeks 2 and 3 of therapy. Complete remitters and partial responders exhibited significantly improved global FLI-C scores following completion of therapy. CONCLUSION: Mitoxantrone plus etoposide was an effective and well-tolerated first-line induction regimen for AML in the elderly that should be studied further in comparison to the standard cytarabine/anthracycline-based therapy.

Social work in the academic medical center: advanced training--a necessity.

Although the total number of social workers within the academic medical center will probably decrease because of decreasing hospital bed usage, the role for those who remain will be that of a clinical specialist, a sophisticated and adaptable practitioner who can work flexibly under minimal supervision. The valued social work practitioner will be an independent player on the health care team who assumes a significant role which no other member of that team is equipped to take. Advanced training is more important today than ever before in the evolution of social work practice in academic health care. However, this training is not now available within the parameters of the two year master's program.

Metastatic extraskeletal myxoid chondrosarcoma. Successful therapy with interferon alfa-2b.

A patient with pulmonary metastatic extraskeletal myxoid chondrosarcoma (EMC), of unknown cause, responded dramatically to 16 months of therapy with interferon alfa-2b. This is the first report of a significant response of a patient with EMC to this novel treatment approach.