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Venous thromboembolism (VTE) is a well-known complication in adults receiving asparaginase (ASNase)-based intensification chemotherapy for acute lymphoblastic leukaemia (ALL). The optimal preventative strategy is unclear. Our objective is to determine the effects of low-molecular-weight heparin (LMWH) as primary VTE prophylaxis. A single-centred retrospective cohort study of adult patients with Philadelphia chromosome negative (Ph-) ALL who received ASNase-based intensification from 2001 to 2017, with prophylaxis given from 2011 to 2017. In all, 214 patients were included in this study with 99 in the historical control group and 125 in the prophylaxis group. The mean (range) enoxaparin dose was 0·79 (0·39-1·2) mg/kg. Of the 125 patients in the prophylaxis group 17 (13·6%) developed VTE during the intensification phase, while 27/99 patients (27·3%) in the control cohort experienced at least one thrombotic event (odds ratio [OR] 0·42, 95% confidence interval [CI] 0·21-0·83). Overall, the main sites of VTE incidences included deep vein thrombosis in the lower extremity (54·6%), pulmonary embolism (13·6%) and catheter-related thrombosis (22·7%). In addition, we found that after adjusting for age, T-phenotype ALL was associated with VTE development (OR 3·07, 95% CI 1·04-9·08). There was no documented major bleeding in the prophylaxis group. LMWH prophylaxis reduced the incidence of symptomatic VTE in adult patients with ALL receiving intensification chemotherapy with ASNase., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

We report the pharmaceutical stability of trastuzumab stored for a short time (12 h) at room temperature (RT; 20-25 °C) compared to trastuzumab stored at 2-8 °C. The physicochemical properties were evaluated by UV-visible and FTIR spectroscopy, SDS-PAGE and size-exclusion HPLC (SE-HPLC). Trastuzumab was reacted with benzylisothiocyanate diethylenetriaminepentaacetic acid (BzDTPA) to complex 111 In. The HER2-binding affinity of 111 In-BzDTPA-trastuzumab synthesised from trastuzumab stored at RT or at 2-8 °C was measured using HER2-positive SK-Br-3 human breast cancer (BC) cells. The tumour and normal tissue uptake of 111 In-BzDTPA-trastuzumab was studied by microSPECT/CT imaging and biodistribution studies in CD1 athymic mice with s.c. HER2-positive SK-Ov-3 human ovarian cancer xenografts. There were no differences in λ max or molar absorptivity (ε) values in the UV-visible spectra of trastuzumab stored at RT or at 2-8 °C. FTIR spectroscopy suggested no differences in secondary structure. SDS-PAGE revealed protein bands corresponding to the expected molecular weights. SE-HPLC showed identical properties for trastuzumab stored at RT or at 2-8 °C. The dissociation constant (K d ) for binding of 111 In-BzDTPA-trastuzumab to HER2 on SK-Br-3 cells (2.2-4.4 nM) was not significantly different when the radioimmunoconjugates were synthesised from trastuzumab stored at RT or at 2-8 °C. MicroSPECT/CT demonstrated high uptake in SK-Ov-3 tumours in mice that was not significantly different using trastuzumab stored at RT or at 2-8 °C (33.7 ± 8.8% vs. 22.2 ± 8.1% i.d./g, respectively; P = 0.36). There were no significant differences in normal tissue uptake or in tumour/normal tissue (T/NT) ratios. We conclude that short-term storage of trastuzumab at RT for 12 h did not affect the physicochemical or biological properties of the drug., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Routine VTE prophylaxis is recommended for hospitalized patients, but its effectiveness and safety in cancer patients is unclear. By observation, larger patients seemed poorly covered by the prophylaxis policy. The effectiveness and safety of VTE prophylaxis policy in the hospitalized patients, their potential risk factors such as BMI were examined. A retrospective chart review was conducted to determine VTE incidences, risk factors for VTE and major bleeding events between 2007 and 2016 on the solid tumor units (STU). Patients were divided into pre-policy (Pre-2012) or post-policy implementation groups (Post-2012). Descriptive statistics were used to evaluate effectiveness and safety of prophylaxis, while propensity score matching (1:3, VTE:Non-VTE) was used to reduce selection bias. The VTE incidence per patient was 1.30% (57/4392) pre-policy and 0.56% (18/3210) post-policy (p value = 0.0013). After propensity score matching, a reduction (32.3%) of VTE cases was observed after policy implementation (OR = 0.677, p = 0.32). BMI was found to be a significant predictor of VTE (OR = 1.094, 95% CI 1.021-1.172, p = 0.011). Between July 2014 and July 2016, 1.7% (19/1091) patients who received anticoagulants had a documented bleeding event. The policy positively impacted VTE events on the STU. A significant predictor of VTE was BMI and patients with high BMI may pose a risk of breaking through standard VTE prophylaxis dosing. There was no reported major bleeding for patients who developed an VTE event despite receiving prophylaxis in either the pre-policy or post-policy phase of the study, although a low incidence of minor bleeding was documented in the post-phase.

Despite the widespread use of 5-HT 3 antagonists as anti-emetic prophylaxis in patients with acute myeloid leukemia (AML) receiving induction chemotherapy, nausea and vomiting persist in many cases. We performed a Phase II single-arm study evaluating the use of aprepitant on days 1-5, in combination with a 5-HT antagonist on days 1-3, in AML patients undergoing induction chemotherapy with daunorubicin on days 1-3 plus cytarabine, given as a continuous infusion, on days 1-7. This was compared to a retrospective cohort of AML patients that received the same chemotherapy regimen with a 5-HT antagonist but without aprepitant. The cumulative incidence of vomiting/retching by the end of day 5 was significantly lower in the aprepitant vs. the control group (26.3 vs. 52.8%, p = 0.013). The cumulative incidence of nausea by the end of day 5 was 61% in the aprepitant group vs. 75% in the control group. The total use of supplemental anti-emetics on days 2-5 was also significantly lower in the aprepitant group (p = 0.01). In contrast, the cumulative incidence of vomiting/retching by the end of day 8, the incidence of vomiting/retching on days 6-8, and the use of anti-emetics on days 6-8, were not significantly different between the two groups. The results suggest that the use of aprepitant may be associated with a lower rate of emesis during aprepitant dosing days, but not afterward. However, this requires confirmation in a randomized trial.

Background Dysfunctional central venous catheter prohibits the administration of potential life-saving chemotherapy and the delivery of essential supportive care needs to patients. Sodium bicarbonate injection has been shown to impede against fibrin clot formation and prolong prothrombin time and thrombin clotting time. Sodium bicarbonate injection has been tried as a second-line agent with good results in a small number of patients (internal data not published) when alteplase failed. We assessed whether the pre-filled sodium bicarbonate injection in 5 mL syringes would not only preserve sterility and retain its pH and concentration but also amount to the potential cost savings for future use when stored in a refrigerated environment. Methodology Twelve pre-filled 5 mL syringes were prepared aseptically, of which four each were tested for pH, sodium bicarbonate injection concentration and sterility when stored in refrigerated temperature over a six-week period. A standard pH meter, enzymatic carbon dioxide analyzer, and a 14-day incubation for microbial detection were employed for this study. Results Sodium bicarbonate concentration measured in the form of carbon dioxide ranged from 923 mmol/L or (1846 mosol/L) to 1006 mmol/L or (2012 mosmol/L), and pH ranged from (7.88 to 8.05) were reported over the duration of the study period. The 14-day incubation period resulted in no microbial growth. Conclusion Our study results have indicated that the pH and sodium bicarbonate injection concentration values were stable and within range, comparable to those reported by the manufacturer within the study period. The contents of the subdivided sodium bicarbonate injection 5 mL syringes retained sterility over a 14-day incubation period.

Despite progressive treatments with tandem stem-cell transplantation, patients with incurable myeloma eventually succumb to relapsed or refractory disease if left untreated. Promising agents such as proteasome inhibitors and immunomodulating imide drugs (imids), including the newer-generation agent pomalidomide, in combination with lower-dose dexamethasone, have been shown to be effective and to significantly improve and prolong survival in pretreated patients. Although the incidence of pomalidomide hypersensitivity reaction (hsr) in this class of drugs is not as well known, we have documented cutaneous toxicity (grade 3 by the Common Terminology Criteria for Adverse Events, version 4) in 2 separate cases (not yet published). Because the imids are chemically, structurally, and pharmacologically similar, it is not unreasonable to consider possible cross-reactivity in pomalidomide recipients who developed hsr when receiving previous lines of imids. As a patient's advocate, it is only prudent to provide a responsible, and yet practical, means to better address cross-sensitivity for patients. Intervention with the use of a rapid desensitization program (rdp) as a preventive measure should be introduced before initiating pomalidomide. Such a proactive measure for the patient's safety will ensure a smooth transition into pomalidomide treatment. A hsr can be either related or non-related to immunoglobulin E. As imids become an essential treatment backbone for myeloma and other plasma-cell diseases, an increasing number of patients could experience skin and other life-threatening toxicities, resulting in unnecessary discontinuation of these life-prolonging agents. An extemporaneously prepared pomalidomide suspension developed at our centre enables patients to undergo rdp safely. Patients enjoy a good quality of life and clinical response after the rdp procedure.

Background: The addition of the immunostimulant plerixafor to the current standard-of-care regimens of granulocyte colony-stimulating growth factor with or without chemotherapy has improved clinical results in terms of successful stem cell mobilization and the outcomes of stem cell transplant in various settings. With this medical innovation has come an added financial cost for institutions where stem cell transplants are routinely performed, and there may be a further financial burden when the contents of partial vials of the drug are wasted, given that plerixafor vials (Mozobil, Sanofi-Aventis Canada Inc) are currently deemed suitable only for single use., Objective: To determine whether the portion of plerixafor remaining in an opened vial of the Mozobil product after administration of a single dose is chemically stable, by comparison with the original product., Methods: Stability testing of partial drug contents of an opened vial, stored at room temperature or under refrigeration (4°C), was conducted using liquid chromatography-tandem mass spectrometry analysis. The mean concentration of plerixafor (μmol/L), standard deviation, coefficient of variation, and bias were determined on days 2, 3, 11, 17, 24, and 31. Method validation included determination of precision, sensitivity, recovery, dilution linearity, and carryover., Results: Throughout the 4-week testing period, measured plerixafor concentration in aliquots stored at room temperature and under refrigeration, tested in series over time, appeared similar. The mean residual drug concentration after initial opening was slightly, but not significantly, higher for the sample designated for storage at room temperature than the one designated for refrigerated storage (40.4 versus 39.9 μmol/L; p = 0.37)., Conclusions: Residual plerixafor after initial opening of a vial of the Mozobil product remained chemically stable for at least 2 weeks both at room temperature and under refrigeration. The results of this study provide in vitro evidence to support multiple uses, instead of single use, of vials of this drug in an aseptic, controlled environment., Competing Interests: Competing interests: None declared.

Background: Venous thromboembolism (vte) is a recognized complication in patients treated with asparaginase-containing chemotherapy regimens; the optimal preventive strategy is unclear. We assessed the safety and efficacy of prophylaxis using low-dose low molecular weight heparin in adult patients with acute lymphoblastic leukemia in complete remission treated with an asparaginase-based post-remission chemotherapy regimen., Methods: As part of the intensification phase of the Dana-Farber Cancer Institute 91-01 regimen, asparaginase was administered weekly to 41 consecutive patients for 21-30 weeks; these patients also received prophylaxis with enoxaparin 40 mg daily (60 mg for patients ≥80 kg). Outcomes were assessed against outcomes in a comparable cohort of 99 patients who received the same chemotherapy regimen without anticoagulation prophylaxis., Results: The overall rate of symptomatic venous thrombosis was not significantly different in the prophylaxis and non-prophylaxis cohorts (18.92% and 21.74% respectively). Among patients receiving prophylaxis, vte occurred in higher proportion in those who weighed at least 80 kg (42.86% vs. 4.35%, p = 0.0070). No major bleeding complications occurred in the prophylaxis group (minor bleeding: 8.1%)., Conclusions: Prophylaxis with low-dose enoxaparin during the intensification phase was safe, but was not associated with a lower overall proportion of vte.

Background: Keratoconjunctivitis sicca from chronic graft-versus-host disease (cgvhd) after allogeneic stem cell transplantation is common, leading to severe corneal damage and blindness if not treated. We retrospectively examined the efficacy and safety of pooled human albumin eye drops (haeds) for symptom relief in 40 stem-cell transplantation patients after other alternatives had failed., Methods: The Common Terminology Criteria for Adverse Events (version 4.0) and the cgvhd grading scale were used to compare response in the patients during January 2000 and July 2013. In addition, on days 1 and 30, the haeds were subjected to quality assurance testing for sterility, oncotic pressure, albumin measurement, viscosity, pH, and purity by protein electrophoresis., Results: Use of haeds resulted in symptom relief for 37 patients (92.5%); 3 patients (7.5%) failed to improve with use of haeds (p ≤ 0.0001). Of the 37 patients having symptom relief, 7 (19%) improved from grade 3 to no dry eye symptoms. Proportionately, post-treatment symptom improvement by two grade levels, from 3 to 1 (70%), was significantly higher than improvement by one grade level, from 3 to 2 (11%) or from 2 to 1 (19%, p ≤ 0.0001). Time to symptom relief ranged from 2 weeks to 28 weeks. Of the 40 patients, 38 (95%) had no adverse reactions. Days 1 and 30 quality assurance testing results were equivalent., Conclusions: Complications of keratoconjunctivitis sicca were well managed and well tolerated with haeds when other remedies failed. Quality assurance testing confirmed that haeds were safe and stable in extreme conditions.

Invasive fungal infections cause significant morbidity and mortality in patients with concomitant underlying immunosuppressive diseases. The recent addition of new triazoles to the antifungal armamentarium has allowed for extended-spectrum activity and flexibility of administration. Over the years, clinical use has raised concerns about the degree of drug exposure following standard approved drug dosing, questioning the need for therapeutic drug monitoring (TDM). Accordingly, the present guidelines focus on TDM of triazole antifungal agents. A review of the rationale for triazole TDM, the targeted patient populations and available laboratory methods, as well as practical recommendations based on current evidence from an extended literature review are provided in the present document.

Background: Dermatologic toxicities from targeted agents such as panitumumab can interfere with cancer treatment., Objective: We sought to evaluate the rash assessment and management in a consecutive patient cohort who received panitumumab for colorectal cancer treatment., Methods: This was a retrospective chart review., Results: Skin toxicity, consisting of papulopustular rash, was experienced by 32 of 34 patients. The majority (85%) developed the rash by the end of the second infusion cycle. Patients presented with a mild (41%), moderate (38%), and severe (21%) rash, and progressed to an extensive rash without appropriate treatment. A grading system was used for 65% of patients to document severity., Limitations: Small sample size limited power in analysis. Rash severity had to be inferred based on rash description and management in 11 of the patients., Conclusion: Dermatologic toxicities related to panitumumab are common; however, the way they are reported and managed varies among physicians. To prevent progression, toxicities must be assessed and treated early and aggressively, according to severity grading. Dermatologists could aid oncologists in choosing the best management strategies., (Copyright © 2014 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Introduction: Voriconazole plasma concentrations have been correlated with oral dosing in healthy subjects, but have been poorly characterized in ill patients with hematological malignancies receiving intensive chemotherapy., Methods: The relationship between orally administered voriconazole, plasma concentrations and liver toxicity was examined in a cohort of 69 primarily acute leukemia patients undergoing intensive chemotherapy., Results: Oral administration of voriconazole was associated with significant interpatient variability, with voriconazole steady-state concentrations ranging from 0 μg/mL to 16.6 μg/mL. Approximately 20% of patients achieved steady-state concentrations <1 μg/mL. When adjusted for weight, patients receiving higher voriconazole doses tended toward higher plasma concentrations; however, there was no significant relationship between the plasma concentration and genotype, age, sex or use of concomitant proton pump inhibitors. Voriconazole concentrations were correlated with higher serum alkaline phosphatase levels at day 6 to 8, and with higher bilirubin and aspartate aminotransferase levels at day 14 to 16, but not with other liver enzyme levels., Conclusion: In ill patients with acute leukemia and related disorders undergoing treatment with oral voriconazole, there is a poor correlation between the voriconazole dose and plasma concentrations, and many patients achieve levels that are considered to be subtherapeutic. The findings support the routine use of therapeutic drug monitoring in these patients.

Introduction: Despite demonstrable risk of venous thromboembolism (VTE), thromboprophylaxis continues to be underutilized in hospitalized cancer patients. Our study evaluated institutional VTE prophylaxis rates after devising a series of strategic interventions to longitudinally improve adherence rates over a period of eight years., Methods and Materials: Between 2004 and 2012, a series of interventions were implemented to improve the thromboprophylaxis rate among patients with solid tumours hospitalized at our institution using quality improvement methodology. Interventions included development of guidelines and institutional policies coupled with educational in-services for physicians, nurses and pharmacists and engagement of the Cancer Quality Committee. Thromboprophylaxis rates were monitored to assess response to interventions., Results: At the outset in 2004, 11 of 57 (19.3%) eligible patients received appropriate pharmacological prophylaxis and formed the baseline of our analysis. Post-2009 policy implementation and educational sessions, 46.5% of an eligible 185 inpatients were administered thromboprophylaxis. Following a two-year grace period to allow for policy acceptance, three audits were conducted in 2011 for which an average prophylaxis rate of 62.3% resulted. In 2012, following another round of educational sessions, a 96.7% rate was achieved and maintained ten weeks later. Minimal bleeding risk was observed during this eight year initiative., Conclusion: A reproducible 96.7% prophylaxis uptake rate was the result of our perseverance and persistence in believing that culture change was inevitable through continuously collaborating with stakeholders at all levels., (© 2013. Published by Elsevier Ltd. All rights reserved.)

Background: Patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT), supported by complex drug regimens, are vulnerable to drug therapy problems (DTPs) at interfaces of care after discharge from hospital and may benefit from timely pharmacy interventions and education., Objective: To determine the effect on medication safety of, as well as potential barriers to, incorporating a pharmacist in the multidisciplinary team of an allo-HCT clinic., Methods: Two pharmacists rotated to attend the allo-HCT clinic of a tertiary care, university-affiliated cancer centre between January and June 2010 (coverage for 1 of 3 clinic days per week). For every patient who was seen by a pharmacist, all discharge medications were reconciled from the inpatient ward to the clinic. The pharmacists' primary task was to perform medication reconciliation and to identify and resolve DTPs. The pharmacists also provided medication education to patients and pharmacy consultations to clinic staff. Working with the outpatient pharmacy, the pharmacists helped to clarify prescriptions and drug coverage issues. Medication discrepancies identified and interventions performed by the pharmacists were recorded and were later graded for clinical significance by a panel of clinicians. Patient and staff satisfaction surveys were conducted at random during the study period. Barriers to the flow of patient care and other operational issues were documented., Results: The 2 pharmacists saw a total of 35 patients over 100 visits. They identified a total of 50 medication discrepancies involving 17 (49%) of the patients and 70 DTPs involving 23 (66%) of the patients. Thirty-one of the 70 DTPs resulted directly from a medication discrepancy. Twenty (95%) of the 21 unintentional medication discrepancies and 7 (70%) of the 10 undocumented intentional medication discrepancies were graded as clinically significant or moderately significant. Satisfaction surveys completed by patients and clinic staff yielded positive responses supporting pharmacists' participation., Conclusions: Pharmacists working as part of the multidisciplinary team identified and resolved medication discrepancies, thereby improving medication safety at the allo-HCT clinic.

Background: Use of combination antiretroviral therapy (cART) and cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) with or without rituximab for treatment of diffuse large B-cell lymphoma (DLBCL) in HIV substantially increases response rates but may also increase toxicity, possibly due to antiretroviral-antineoplastic drug interactions. The objective of this study was to evaluate the frequency of complete remission (CR) of DLBCL in patients treated with CHOP while receiving a protease inhibitor (PI) versus a non-PI-based cART., Methods: A retrospective multicentre pilot study was conducted in HIV-infected patients on cART treated for DLBCL with CHOP between 2002-2010 in three academic hospitals., Results: A total of 34 patients were included with 65% and 35% of patients receiving a PI and non-PI-based cART, respectively. Baseline characteristics between groups were similar; overall 85% were male, median age was 43 years, 50% had an International Prognostic Index (IPI) of 2-3 and median CD4(+) T-cell count was 225 cells/mm(3). CR was achieved in 77% and 58% of patients in the PI and non-PI groups, respectively (P=0.21), with 65% and 63% of patients achieving 2-year overall survival (P=1.00). A multivariate analysis showed that lower IPI score alone was significantly associated with higher CR rates (P=0.05). Toxicity was similar between both groups., Conclusions: Similar efficacy and toxicity of CHOP was observed in patients receiving a PI and non-PI-based cART.

Background: There is no consensus on a universal dosing method for calculating high-dose chemotherapy in allogeneic Stem Cell Transplant (SCT) patients. The Metropolitan Life (Met-Life) Insurance Company's weight-height tables have been used to determine body weight for chemotherapy dosing for SCT, however no formal study has been done to determine if the Met-Life weight- height tables can be used for chemotherapy dosing in SCT. We retrospectively studied the use of Met-Life weight-height tables for chemotherapy dosing in SCT. Our goal is to determine if patients with extremes of body size who had undergone an SCT and were dosed according to the Met-Life weight- height tables had an increase of Treatment Related Morbidity (TRM) or mortality or relapse., Patients and Methods: Patients were grouped into three different treatment regimens, cyclophosphamide/TBI, busulphan/cyclophosphamide, and AraC/cyclophosphamide/TBI. Patients in each treatment regimen were further divided into five equal groups based on weight. Treatment related morbidity and mortality was evaluated by comparing the lowest and highest quintiles to the middle quintiles within each treatment regimen., Result: Data from 262 patients was evaluated in this study. Overall, there was not an increase in TRM or mortality or in relapse in patients with extremes of body size., Conclusion: The Met-Life weight-height tables could be used to dose patients undergoing allogeneic SCTs. Additional prospective studies would need to be done comparing other chemotherapy dosing methods with the Met-Life weight-height tables to further validate this conclusion.

Purpose: The case of a patient who developed acute renal failure, gastrointestinal bleeding, and cardiac arrhythmia after receiving arsenic trioxide for the treatment of acute promyelocytic leukemia (APL) is described., Summary: An 84-year-old Caucasian woman with a history of osteoarthritis sought medical attention for relapse of her APL, which had initially been diagnosed approximately 30 months earlier. Complete remission was accomplished with three cycles of i.v. daunorubicin for 3 days and oral tretinoin for 28 days. After 19 months in remission, she was noted to have increased bruising and blood test values consistent with APL relapse. Two additional trials of oral tretinoin were unsuccessful, and arsenic trioxide was initiated at a daily dosage of 0.15 mg/kg of actual body weight. Less than 24 hours after receiving arsenic trioxide, the patient had "bile-like emesis" and her hemoglobin level decreased. Upper gastrointestinal bleeding was suspected and managed aggressively with transfusions of platelets and fresh frozen plasma and i.v. desmopressin. She became anuric, and her serum creatinine level more than doubled. Hemodialysis was started due to a sudden increase in potassium and fluid overload that did not respond to i.v. furosemide. One hour after hemodialysis, the patient was found pulseless and unresponsive by nursing staff. The cardiac arrest team rapidly responded and noted atrial fibrillation with a fast ventricular rate. Postresuscitation, the patient was transferred to the intensive care unit. Despite aggressive life-support therapy, the patient remained unresponsive., Conclusion: An 84-year-old woman developed acute renal failure, gastrointestinal bleeding, and cardiac arrhythmia after receiving arsenic trioxide for the treatment of APL.

Objective: To report 2 cases of acute tumor lysis syndrome (ATLS) associated with hydroxyurea treatment., Case Summary: A 79-year-old woman diagnosed with chronic lymphocytic leukemia presented with an acute blastic transformation. She was promptly hydrated, started on allopurinol, and treated with hydroxyurea. About 24 hours later, her biochemistry panel showed parameters consistent with ATLS when compared with pretreatment levels. The second case was a 76-year-old man newly diagnosed with acute myeloid leukemia presenting with high blast fraction. He was given appropriate hydration and allopurinol prophylaxis, and was started on high-dose hydroxyurea treatment. He became symptomatic after 12 hours and results of his blood work were consistent with ATLS., Discussion: ATLS is a well-known metabolic disturbance that occurs after cell destruction of rapidly growing tumors. In standard doses, hydroxyurea leads to cell death in the S phase and is not thought to cause significant cell lysis. However, in large doses, it possibly acts by a different mechanism and had a direct cytolytic effect associated with ATLS in our patients., Conclusions: Although ATLS caused by hydroxyurea appears to be rare, patients at risk should be closely monitored for this complication. An objective causality assessment using the Naranjo probability scale revealed that the adverse drug reaction was probable between ATLS and hydroxyurea therapy in these 2 patients.

Objective: To review the role of all-trans retinoic acid (ATRA) and arsenic trioxide in central nervous system (CNS) relapses of acute promyelocytic leukemia (APL)., Case Summary: A 69-year-old white man diagnosed with APL presented with bleeding diathesis. His molecular and cytogenetic studies were positive for promyelocytic leukemia-retinoic acid receptoralpha (PML-RARalpha) and t(15;17) transformation. Complete molecular and cytogenetic remission was achieved with ATRA, daunorubicin, and cytarabine. Within 6 months, the patient was readmitted for investigation of severe global headaches and an ataxic gait. His peripheral blood and cerebral spinal fluid were positive for PML-RARalpha fusion protein. Intrathecal chemotherapy and radiation, as well as ATRA, were the main treatment modalities provided. Molecular and cytogenetic remission was again obtained. Three months later, a second relapse occurred in the CNS and the peripheral blood., Discussion: APL is typically treated with anthacycline-based chemotherapy and ATRA. Approximately 85-95% of patients achieve complete remission (CR); however, the relapse rate has been reported to be about 30-40%. A thorough literature search (MEDLINE, EMBASE, CANCERLIT, 1966-January 2002) revealed only 54 cases of extramedullary disease, of which 35 involved the CNS., Conclusions: The introduction of ATRA has improved patient survival dramatically. APL relapse, in general, has been in part attributable to repetitive or prolonged exposure to ATRA and the possibility of additional chromosomal changes, making the disease more refractory to treat. Given the evidence, one could argue that, with repeated ATRA treatment, CR duration may be shortened. However, limited data are available to guide the appropriate management of APL relapsed to the CNS with either ATRA, chemotherapy, or arsenic trioxide. In our opinion, treatment using arsenic trioxide is an unconventional option worthy of exploring.

Objective: To seek an optimal treatment plan from the results of treatment for metastatic disease of the spine in children., Design: An 8-year retrospective study of children with metastatic disease of the spine. Imaging studies were reviewed and treatment modalities analysed., Setting: The divisions of pediatric orthopedics and pediatric neurosurgery at the Children's Hospital of Eastern Ontario, Ottawa., Patients: All children seen between April 1980 and December 1987 who had lesions metastatic to the spine by hematogenous or direct extension. There were 20 children (15 boys, 5 girls) with a mean age at the time of diagnosis of 9.5 years. Follow-up ranged from 2 weeks to 108 months. One child was lost to follow-up., Interventions: Eleven children underwent laminectomy and decompression. Of the 14 neurologically compromised children, 5 received chemotherapy and radiotherapy and 9 received chemotherapy, radiotherapy and surgery., Main Outcome Measures: Type of metastatic lesion, vertebrae involved and response to therapy., Results: Vertebrae involved with metastases were as follows: cervical (3), thoracic (5), lumbar (8) and multilevel (2). Meninges were involved in 2 cases. The most common causes of metastatic spinal involvement were neuroblastoma (4 cases) and astrocytoma (6 cases). Pathologic fractures occurred in 4 children and kyphoscoliosis in 4. Spinal cord paresis developed in 14 of the 20 children. Of the 6 children who survived from 48 to 108 months, 5 had tumours of neural origin, 4 being astrocytomas. Children with neuroblastoma or leukemic infiltration had a good initial response to chemotherapy. Five of the 6 surviving children had astrocytomas, and 5 were treated by surgical decompression., Conclusions: Metastatic disease of the spine in children secondary to astrocytoma should be treated aggressively, but from the experience gained from this study it is impossible to devise a rigid treatment plan for each type of metastatic tumour. The choice of chemotherapy, radiotherapy or surgery depends on the type of tumour, the age of the child and whether or not the spinal cord is compromised.