Large Cumulative Doses Research Articles

Use of propofol anesthesia and adjunctive treatment with levetiracetam and gabapentin in managing status epilepticus in a patient of acute intermittent porphyria

Use of propofol anesthesia and adjunctive treatment with levetiracetam and gabapentin in managing status epilepticus in a patient of acute intermittent porphyria

Multiple spontaneous dislocations in a patient with Ehlers–Danlos syndrome

Ehlers–Danlos syndrome (EDS) consists of a heterogeneous group of inherited connective tissue disorders, characterised by generalised joint hypermobility, hyperextensibility of the skin, dystrophic scars, and a tendency to excessive bleeding....

Analgesic nephropathy

Analgesic nephropathy

Long‐term outcome of therapy for 59 cats and 11 dogs with cryptococcosis

To determine the outcome of therapy in cats and dogs with naturally occurring cryptococcosis. Design Retrospective study of 59 cats and 11 dogs at the University Veterinary Centre Sydney from 1986 to 2004. Following detailed analysis of case notes potential associations between patient characteristics, cryptococcal species, retroviral status (cats), disease severity and type of therapy were examined in relation to duration and success of therapy. Treatment protocols based on amphotericin B, fluconazole and itraconazole were compared. Seventy-six percent of feline patients were successfully treated. For cats, the presence of central nervous system disease was the only factor found to influence outcome. Cats with neurological involvement, disseminated disease or refractory disease treated with amphotericin B containing protocols did as well, on average, as cats with less severe disease treated with azole monotherapy. Amphotericin B was thus an effective agent for treating severe cases of cryptococcosis. The median cumulative dose of amphotericin B for cats cured at the first attempt was 16 mg/kg (range 7 to 23 mg/kg). The median duration of treatment required to effect a cure at first attempt was significantly shorter for fluconazole (4 months; range 1 to 8 months) than for itraconazole (9 months; range 3 to 24 months; P = 0. 0191; Mann Whitney U test). The success rate for treatment of canine cases was 55%. No factor appeared to influence disease outcome in dogs. Large cumulative doses of amphotericin B could be administered via the subcutaneous route in both species and generally with minimal nephrotoxicity. Recrudescence occurred in a significant proportion of animals, in some cases despite a reduction of serum latex cryptococcal antigen agglutination test to zero. Although the prognosis of cryptococcosis should be described as guarded, a majority of the canine and especially feline patients can be expected to be cured, although treatment is protracted and expensive.

Brief review: Nondepolarizing neuromuscular blocking drugs and critical illness myopathy

Critically-ill patients who receive nondepolarizing neuromuscular blocking drugs (NMBDs) may be at risk of developing profound muscle weakness that may last for months after the NMBD is discontinued, especially when large cumulative doses of NMBDs and corticosteroids are co-administered to septic, mechanically ventilated patients. This review focuses on the etiology and clinical features of critical illness myopathy (CIM), summarizes specific risk factors for its development, and discusses strategies that might be used to attenuate or even prevent the development of this potentially devastating syndrome. The etiology of CIM is unknown. Whether it can develop in at-risk patients who undergo lengthy operations during which they receive NMBDs is also unknown. In some patients following exposure to NMBDs their motor systems are impaired secondary to loss of thick (myosin) filaments that render the muscle unexcitable to direct electrical stimulation, while the sensory system is spared. Management of patients who develop NMBD myopathy is supportive, consisting of nutritional support, physical therapy, and daily trials of decreased ventilatory support. Recent guidelines recommend that NMBDs be used in critically ill patients only when absolutely necessary, that the depth of muscle paralysis be monitored to avoid overdosing and metabolite accumulation, and that drug administration be curtailed periodically to allow interruption of sustained NMBD effect.

Sudden cardiac death and antipsychotics Part 2: Monitoring and prevention

Cardiac safety of antipsychotic drugs continues to be a concern for both typical and atypical antipsychotics. Risk appears greatest in those with pre-existing cardiac disease but many patients may have occult cardiovascular disease. In addition, several drugs appear to increase the likelihood of diabetes and weight gain, which may have an additive adverse effect. On the basis of risk of sudden cardiac death and risk of QTc prolongation we suggest considering antipsychotics in two categories – higher and lower risk. Of most concern is the use of large cumulative doses of antipsychotics that are sometimes given inadvertently by different prescribers. Clinicians need to be aware how to read an ECG, and how to monitor physical parameters and interpret the significance of QTc prolongation in relation to antipsychotic prescribing. We suggest provisional guidance on antipsychotic monitoring in relation to cardiac safety but acknowledge that future studies will help clarify which antipsychotic drugs and which concomitant risk factors are most important for those with and without established cardiac disease.

Chronic disseminated candidiasis in patients with acute leukemia: emphasis on diagnostic definition and treatment

Background: Chronic disseminated candidiasis (CDC) is a form of invasive fungal infection that occurs most commonly in patients with acute leukemia treated with chemotherapy. Recent studies have provided evidence for diagnostic alternatives to invasive procedures and more therapeutic options for the management of this complication. In order to put diagnostic criteria and methodological approach to the disease into the perspective of developing strategies for therapy, all relevant studies published in the English literature over the last 30 years were examined. Materials and methods: The English-language articles located through MEDLINE (1966 to present) and from selected bibliographies. Results: There is increased recognition of CDC as complication of treatment with chemotherapy in patients with acute leukemia. Liver biopsy may not always be revealing or feasible to perform in some patients. Among the imaging modalities, magnetic resonance imaging has obtained preeminence as a non-invasive tool for the diagnosis of hepatosplenic fungal infections. Administration of amphotericin B (Amp B) in relatively large cumulative doses is needed to ensure appropriate control of the infection and prevention of future relapse. Patients intolerant of, or refractory to conventional Amp B have been successfully salvaged using fluconazole or lipid formulations of Amp B. A constellation of clinical, laboratory and radiologic parameters should be used to determine response and efficacy of therapy. There is sufficient evidence to support the safety and feasibility of continuing chemotherapy for acute leukemia in conjunction with antifungal treatment in patients diagnosed with CDC. Conclusion: The development of CDC in patients with acute leukemia does not preclude further chemotherapy or constitute contraindication for bone marrow transplantation. Knowledge of the course and pattern of evolution of the disease and adopting aggressive therapeutic approach will likely reduce the morbidity and mortality from this complication.

Chronic Steroid and Immunosuppressant Therapy in Children

1. Abraham Gedalia, MD* 2. Avinash K. Shetty, MD† 1. *Professor of Pediatrics and Head, Division of Pediatric Rheumatology, Louisiana State University Health Sciences Center and Children’s Hospital, New Orleans, La 2. †Assistant Professor of Pediatrics, Division of Infectious Diseases, Wake Forest University School of Medicine, Winston-Salem, NC After completing this article, readers should be able to: 1. Describe the mechanism of action, list indications for therapy, and discuss the adverse effects of corticosteroid therapy in children. 2. Delineate the mechanism of action and adverse effects of other immunosuppressive agents frequently used in children. 3. Discuss the immunization recommendations for children receiving immunosuppressive therapy. Corticosteroids are the most potent, naturally occurring anti-inflammatory agents known. Despite more than 50 years of controversy regarding their clinical use, risks, and benefits, corticosteroids still play a significant role in the management of a wide variety of diseases. They have reduced the morbidity and mortality significantly in children afflicted with leukemia, asthma, rheumatic diseases, and other inflammatory disorders. In this article, we review the mechanism of action, clinical indications, and adverse effects of corticosteroids and other commonly used immunosuppressive agents in children. We also review immunization recommendations for children receiving immunosuppressive therapy. Corticosteroids have a diverse role in the human body at the physiologic level. The actions of glucocorticoids include: 1) negative feedback modulation of corticotropin-releasing factor and adrenocorticotropic hormone; 2) regulation of blood glucose and liver glycogen levels; 3) maintenance of water-electrolyte homeostasis; 4) influence on the metabolism of protein, fat, and purine; 5) maintenance of normal cardiovascular, central nervous system (CNS), and renal functions; 6) influence on circadian rhythmicity; 7) maintenance of bone and muscle work capacity; and 8) protection of the body against moderate stress. Glucocorticoids also have pharmacologic properties that are used in the treatment of rheumatic and other inflammatory diseases. Cellular receptors for cortisol are ubiquitous in cell cytoplasm, reflecting the critical role of the hormone in maintaining cell homeostasis. The type 1 glucocorticoid receptor, known as the mineralocorticoid receptor, has high affinity for aldosterone. The type 2 glucocorticoid receptor, known as the glucocorticoid receptor, exhibits strong affinity for dexamethasone. Although …

Favorable Impact of T Cell Depleted PBSCT on Transplant Outcomes Despite Delayed Donor T Cell Engraftment.

Although T cell depleted stem cell transplantation can reduce risks from GVHD, it is associated with incomplete engraftment and higher relapse rates. To mitigate these negative effects we evaluated a T cell depleted PBSCT protocol followed by delayed add-back of donor T cells. Between 2001–2004, 56 patients with hematological malignancies received a preparative regimen of total body irradiation 12Gy, fludarabine 125mg/m2, and cyclophosphamide 120mg/kg followed by a T cell depleted PBSCT from an HLA identical sibling. The T cell dose was adjusted to 2 x 104/kg in all patients. Patients not developing grade <II GVHD received 107CD3 cells/kg between days 45–100. Lineage-specific T cell and myeloid chimerism was monitored day 14, 30, 45, 60 and 90 post-transplant. Patients were aged between 11–56 (median 30y). Twenty six with CML in CP, acute leukemia in first remission, or MDS RA were designated as standard risk (SR) for transplant outcome. Thirty with more advanced or refractory disease were designated high risk (HR). Overall survival was 65±7% at a median of 1 year. Disease risk was the major factor affecting outcome with lower relapse and transplant-related mortality (TRM) and higher disease-free survival (DFS) in SR versus HR patients (3.5±3.5 vs. 42±11%, 7.5±4 vs. 17.5±8% and 85±7 vs 36±9% respectively, p< 0.0001). One patient rejected the transplant and died following two further transplant attempts. The remaining patients achieved rapid 100% donor myeloid engraftment, sustained unless relapse occurred. Donor T cell engraftment was incomplete. 0nly 12.5% of patients had full donor T cell chimerism (>95% donor T cells) on day 14, rising to 50% of patients by day 90, with persistent mixed chimerism in some patients beyond 6 months. Predictably, acute GVHD grade I–IV by d60 was significantly correlated with full T cell chimerism (p< 0.0001). There was no significant difference in day 30 lymphocyte count, CMV reactivation or transplant CD34 dose between fully or partially T cell chimeric recipients at any time point. Full T cell chimerism was significantly more frequent in HR vs SR patients (on day 90: 82 vs 24%, p= 0.002). Kaplan-Meier outcome estimates for mixed vs full T cell chimerism were therefore analyzed separately for SR and HR patients. All outcomes (relapse, TRM and DFS) were more favorable (but not significantly so) for patients who had mixed chimerism at any time point between d14–90: of 13 evaluable HR patients fully chimeric at d30 there was a 74% probability of relapse vs a 58% relapse for15 mixed chimeric patients (p=NS). No patient with SR disease relapsed. There was a non-significant DFS advantage for d30 mixed vs full chimeric patients: 95% vs 85%, and 40% vs 20% for SR and HR patients respectively. These results indicate 1) full T cell chimerism is more frequent in HR patients (who have received large cumulative doses of prior chemotherapy) 2) T cell depleted PBSCT have a high frequency of prolonged mixed T cell chimerism. This does not predispose to late graft rejection, is favorable for reducing GVHD and does not negatively affect CMV reactivation, relapse, TRM and DFS.

Pharmacokinetics of pegylated liposomal Doxorubicin: review of animal and human studies.

Pegylated liposomal doxorubicin (doxorubicin HCl liposome injection; Doxil or Caelyx) is a liposomal formulation of doxorubicin, reducing uptake by the reticulo-endothelial system due to the attachment of polyethylene glycol polymers to a lipid anchor and stably retaining drug as a result of liposomal entrapment via an ammonium sulfate chemical gradient. These features result in a pharmacokinetic profile characterised by an extended circulation time and a reduced volume of distribution, thereby promoting tumour uptake. Preclinical studies demonstrated one- or two-phase plasma concentration-time profiles. Most of the drug is cleared with an elimination half-life of 20-30 hours. The volume of distribution is close to the blood volume, and the area under the concentration-time curve (AUC) is increased at least 60-fold compared with free doxorubicin. Studies of tissue distribution indicated preferential accumulation into various implanted tumours and human tumour xenografts, with an enhancement of drug concentrations in the tumour when compared with free drug. Clinical studies of pegylated liposomal doxorubicin in humans have included patients with AIDS-related Kaposi's sarcoma (ARKS) and with a variety of solid tumours, including ovarian, breast and prostate carcinomas. The pharmacokinetic profile in humans at doses between 10 and 80 mg/m(2) is similar to that in animals, with one or two distribution phases: an initial phase with a half-life of 1-3 hours and a second phase with a half-life of 30-90 hours. The AUC after a dose of 50 mg/m(2) is approximately 300-fold greater than that with free drug. Clearance and volume of distribution are drastically reduced (at least 250-fold and 60-fold, respectively). Preliminary observations indicate that utilising the distinct pharmacokinetic parameters of pegylated liposomal doxorubicin in dose scheduling is an attractive possibility. In agreement with the preclinical findings, the ability of pegylated liposomes to extravasate through the leaky vasculature of tumours, as well as their extended circulation time, results in enhanced delivery of liposomal drug and/or radiotracers to the tumour site in cancer patients. There is evidence of selective tumour uptake in malignant effusions, ARKS skin lesions and a variety of solid tumours. The toxicity profile of pegylated liposomal doxorubicin is characterised by dose-limiting mucosal and cutaneous toxicities, mild myelosuppression, decreased cardiotoxicity compared with free doxorubicin and minimal alopecia. The mucocutaneous toxicities are dose-limiting per injection; however, the reduced cardiotoxicity allows a larger cumulative dose than that acceptable for free doxorubicin. Thus, pegylated liposomal doxorubicin represents a new class of chemotherapy delivery system that may significantly improve the therapeutic index of doxorubicin.

High Dose Spatially Fractionated Radiation (GRID): a new paradigm in the management of advanced cancers

Purpose: In the early 1940’s, the concept of using spatially fractionated radiation (SFR) to treat advanced cancers was well established. Large cumulative doses (>100 Gy) of ortho-voltage radiation were delivered to overcome the problems of skin tolerance in an effort to deliver higher dose at depth. SFR has been proven to be safe and effective. SFR has been adapted to megavoltage beams using a specially constructed Grid to achieve a physical dose distribution simulating virtual high dose rate brachytherapy. This study evaluates the toxicity and effectiveness of this approach in treatment of advanced and bulky (>8 cm) cancers.

Nutritional Issues in the Management of Advanced Liver Disease

AbstractPatients with advanced liver disease require aggressive management of the protein‐calorie malnutrition associated with the diagnosis. However, toxicity and tolerance thresholds for nutritional intervention are very low. These thresholds are defined largely by the failing liver's metabolic derangements. Attention needs to be given to ensuring optimal amino acid nutriture without precipitating hepatic encephalopathy. Adequate calorie provision is necessary for maximal use of the administered protein. Micronutrient disposition in the chronic liver disease patient is compromised for metals, necessitating monitoring of iron status and possibly that of copper. Vitamin A status also may need to be determined, especially in light of its implicated hepatotoxin status with large cumulative doses. The iatrogenic liver disease induced by long‐term total parenteral nutrition is relatively rare but frequently amenable to refinement of the regimen, in addition to intervention with carnitine supplementation in select cases. The above insights are important in tailoring the nutritional plan and will lead to better patient outcomes in concert with medical intervention.

Recombinant VIIa concentrate in the management of bleeding following prothrombin complex concentrate‐related myocardial infarction in patients with haemophilia and inhibitors

Prothrombin complex concentrates (PCCs) and, more recently, activated prothrombin complex concentrates (APCCs), are widely used for the treatment of active bleeding in haemophiliacs with inhibitors. Myocardial infarction (MI), associated with the use of these concentrates, is a well-recognized, but uncommon, complication. We review the 14 previous cases published in the literature and describe two additional patients. MI related to the use of activated and non-activated PCCs predominantly affects young patients who often have no preceding history of, or risk factors for, MI and tends to be associated with large cumulative doses of concentrate. The most frequent pathological finding is myocardial haemorrhage, with no evidence of coronary artery atheroma or thrombosis. The management of further bleeding in these patients is difficult. We have safely used recombinant factor VIIa to treat bleeding in the immediate and long-term period following PCC-related MI.

Therapy-related acute myeloid leukemia and myelodysplasia after high-dose chemotherapy and autologous stem cell transplantation

Therapy-related myelodysplasia (t-MDS) and acute myeloid leukemia (t-AML) after high-dose chemotherapy (HD-CT) and autologous stem cell transplantation (ASCT) for malignant diseases have become an important problem. The actuarial risk has varied, but has often been high if compared to the risk after conventional therapy. Prior chemotherapy with large cumulative doses of alkylating agents is the most important risk factor. In addition, patient age and previous radiotherapy, particularly the use of total body irradiation (TBI) in the preparative regimen for ASCT, have been identified as risk factors. In 3 studies, patients transplanted with CD34+ cells from peripheral blood after chemotherapy priming showed a higher risk of t-MDS or t-AML than patients transplanted with cells isolated from the bone marrow without priming. To what extent this higher risk relates to the prior therapy with a different contamination with preleukemic, hematopoietic precursors of the CD34+ cells obtained by the 2 methods, or is a direct result of chemotherapy priming, or of an increasing awareness of these complications, remains to be determined. The latent period from ASCT to t-MDS and t-AML has often been short, 12 months or less in 27% of the patients. Bone marrow pathology of early cases of t-MDS after ASCT has often been neither diagnostic nor prognostic, but most patients presented chromosome aberrations, primarily deletions or loss of the long arms of chromosomes 5 and 7. The prognosis was in general poor, although 17% with indolent t-MDS survived more than 18 months from diagnosis, and most of these presented a normal karyotype or a single chromosome aberration.

High-dose spatially-fractionated radiation (GRID): a new paradigm in the management of advanced cancers

Purpose: With the advent of megavoltage radiation, the concept of spatially-fractionated (SFR) radiation has been abandoned for the last several decades; yet, historically, it has been proven to be safe and effective in delivering large cumulative doses (> 100 Gy) of radiation in the treatment of cancer. SFR radiation has been adapted to megavoltage beams using a specially constructed grid. This study evaluates the toxicity and effectiveness of this approach in treatment of advanced and bulky cancers. Methods and Materials: From January 1995 through March 1998, 71 patients with advanced bulky tumors (tumor sizes > 8 cm) were treated with SFR high-dose external beam megavoltage radiation using a GRID technique. Sixteen patients received GRID treatments to multiple sites and a total of 87 sites were irradiated. A 50:50 GRID (open to closed area) was utilized, and a single dose of 1,000–2,000 cGy (median 1,500 cGy) to D max was delivered utilizing 6 MV photons. Sixty-three patients received high-dose GRID therapy for palliation (pain, mass, bleeding, or dyspnea). In 8 patients, GRID therapy was given as part of a definitive treatment combined with conventionally-fractionated external beam irradiation (dose range 5,000–7,000 cGy) followed by subsequent surgery. Forty-seven patients were treated with GRID radiation followed by additional fractionated external beam irradiation, and 14 patients were treated with GRID alone. Thirty-one treatments were delivered to the abdomen and pelvis, 30 to the head and neck region, 15 to the thorax, and 11 to the extremities. Results: For palliative treatments, a 78% response rate was observed for pain, including a complete response (CR) of 19.5%, and a partial response (PR) of 58.5% in these large bulky tumors. A 72.5% response rate was observed for mass effect (CR 14.6%, PR 52.9%). The response rate observed for bleeding was 100% (50% CR, 50% PR) and for dyspnea, a 60% PR rate only. A relatively higher response rate (CR 23.3%, PR 60%) was observed in patients who received GRID treatment in the head and neck area. No grade 3 late skin, subcutaneous, mucosal, GI, or CNS complications were observed in any patient in spite of these high doses. In the 8 patients who received GRID treatment for definitive treatment, a clinical CR was observed in 5 patients (62.5%) and a pathological complete response was confirmed in the operative specimen in 4 patients (50%). Conclusion: The efficacy and safety of using a large fraction of SFR radiation was confirmed by this study and substantiates our earlier results. In selected patients with bulky tumors (> 8 cm), SFR radiation can be combined with fractionated external beam irradiation to yield improved local control of disease, both for palliation and selective definitive treatment, especially where conventional treatment alone has a limited chance of success.

Elucidating the mechanism of cesium-induced sustained monomorphic ventricular tachycardia in rabbits.

The mechanisms of sustained ventricular tachycardia (VT) induced by large cumulative dose of cesium chloride (Cs) remains unclear. Seven anesthetized rabbits were intravenously injected with Cs (1 mmol/kg) 3 times at 20-min intervals. The surface ECG and monophasic action potential of the left ventricular endocardium were simultaneously recorded. In another 12 rabbits, transmembrane action potentials of right ventricular muscles were recorded with glass microelectrodes. In experiments in vivo, sustained monomorphic VT was induced after the third injection of Cs, whereas the early afterdepolarization (EAD)-related nonsustained polymorphic VT was induced after the second injection. Overdrive pacing during the sustained VT resulted in postdrive acceleration. The pacing and recovery cycle lengths showed an inverse relation. In experiments in vitro, preparations were superfused with Tyrode's solution containing 7.5 mM Cs. Cs initially induced EADs. Additional exposure to Cs depolarized the membrane potential, which consequently attained threshold, producing spontaneous activities. Further exposure resulted in an induction of sustained rhythms that were accelerated by overdrive pacing. Our results indicate that the sustained rhythms at low membrane potential induced by a long exposure to Cs in vitro may underlie an electrophysiologic mechanism for the sustained VT induced after large cumulative dose of Cs in vivo.

Accounting for errors in dose estimates used in studies of workers exposed to external radiation.

This paper discusses approaches for accounting for errors in dose estimates used in dose-response analyses of data from epidemiologic studies of workers exposed to external radiation and illustrates these approaches with analyses of data on workers at the Hanford site. In these analyses, estimates of the excess relative risk are corrected for bias in recorded doses as estimates of organ dose, and confidence intervals reflect uncertainty in the correction factors. For the Hanford data, these procedures did not greatly modify results for all cancer excluding leukemia, but the upper confidence limit for leukemia was increased by about 40%, a difference that is of some importance in comparing worker-based estimates and confidence intervals with estimates that serve as the basis of radiation protection standards. It is argued that aside from taking account of uncertainty in correction factors, no additional corrections are needed to address random errors resulting from variation in exposure energies and geometries. In addition, it is shown that because the larger cumulative doses, which are most influential in dose-response analyses, are the sums of large numbers of independent dosimeter readings, random errors resulting from variation in laboratory measurements are unlikely to be important for epidemiologic purposes. It is hoped that the approaches illustrated in this paper will be applied to future analyses of data from worker studies, especially combined analyses of data from several countries. Taking account of uncertainty in factors that correct for systematic bias will be especially important as uncertainty resulting from sampling variation decreases.

Paclitaxel with mitoxantrone, fluorouracil, and high-dose leucovorin in the treatment of metastatic breast cancer: a phase II trial.

Paclitaxel is a highly active single agent in the treatment of breast cancer. However, its optimal incorporation into combination regimens awaits definition. In this phase II study, we added paclitaxel, administered by 1-hour infusion, to a previously described combination regimen that included mitoxantrone, fluorouracil (5-FU), and high-dose leucovorin (NFL). Forty-six patients with metastatic breast cancer received the following regimen as first- or second-line treatment: paclitaxel 135 mg/m2 by 1-hour intravenous (i.v.) infusion on day 1, mitoxantrone 10 mg/m2 by i.v. bolus on day 1, 5-FU 350 mg2/m by i.v. bolus on days 1, 2, and 3, and leucovorin 300 mg i.v. over 30 to 60 minutes immediately preceding 5-FU on days 1, 2, and 3. Courses were administered at 3-week intervals for a total of eight courses in responding patients. Twenty-three of 45 assessable patients (51%) had major responses. Previous chemotherapy, and in particular previous treatment with doxorubicin, did not affect response rate. The median response duration was 7.5 months. Myelosuppression was moderately severe, with 76% of courses resulting in grade 3 or 4 leukopenia. Hospitalization for treatment of fever during neutropenia was required in 13% of courses, and two patients died as a result of sepsis. Two patients developed severe congestive heart failure after a large cumulative anthracycline dose. This combination regimen was active as first- or second-line therapy for metastatic breast cancer, although its activity compared with other combination regimens or with paclitaxel alone is unclear. Myelosuppression was more severe than anticipated based on previous results with the NFL regimen or with paclitaxel administered at this dose and schedule as a single agent. The infrequent development of cardiotoxicity in these patients suggests that the paclitaxel/mitoxantrone combination may not share the problems previously reported with the paclitaxel/doxorubicin combination.

Ifosfamide tolerance in osteosarcoma patients previously treated with cis-Diamminedichloroplatinum-II: Renal, hematologic, and neurologic observations

We attempted to ascertain renal, hematologic, and neurologic tolerance to ifosfamide (IFX) in pediatric patients previously treated with large single and cumulative doses of cis-Diamminedichloroplatinum-II (CDP) for osteosarcoma (OS). Twenty OS patients were treated with CDP: initially 150 mg/m2 was administered every 2 weeks for a maximum of seven courses. Later, other agents, including additional CDP, were also administered. Twelve patients were treated with intra-arterial CDP, one with intra-arterial, and later intravenous CDP, and seven with intravenous CDP. Patients who relapsed were treated with IFX. Renal function was monitored by measuring creatinine clearance, serum electrolytes, total protein, albumin and CO2 content, and urine analysis during IFX therapy. Prior to initiation of IFX, creatinine clearance was above 60 ml/min/m2 in all except one patient who had developed a hemolytic uremic syndrome (HUS). Cumulative CDP doses ranged from 300 to 22,500 mg/m2, and cumulative IFX doses 12 to 128 gm/m2. Myelosuppression was monitored by obtaining routine hemograms midway between each course of treatment. Neurologic tolerance was assessed by reviewing the medical records for any abnormality. The interval between CDP and IFX ranged from 1 to 64 months. All patients experienced a progressive reduction in creatinine clearance with CDP. The reduction in creatinine clearance, measured from base-line after three to four courses varied from 10 to 53.7%, after four to seven courses from 19 to 78%, and after seven courses from 12 to 80.5%. In all patients except five, including the HUS patient, creatinine clearance remained above 60 ml/min/m2 during IFX therapy. Twelve patients developed hypo-magnesemia in the vicinity of 1.4 to 1.6 mg/dl during CDP treatment and required magnesium supplementation. They were asymptomatic and the abnormality did not affect IFX tolerance. Fourteen patients intermittently displayed variable degrees of glycosuria, phosphaturia, and/or proteinuria during IFX therapy. This was considered to be a forma frustre type of Fanconi's syndrome. Approximately 80% of courses of IFX were associated with reversible myelosuppression. No neurologic abnormalities were detected. The abnormalities detected during IFX treatment were not major, did not give rise to symptomatology, and did not require discontinuation of therapy. Renal abnormalities were considered a forma frustre type of Fanconi's syndrome. Provided a creatinine clearance of 60 ml/min/m2 is accepted as a prerequisite for treatment, and no major preexisting renal disease is present, IFX is well tolerated by most patients previously exposed to very high cumulative doses of CDP.

Tolerance of high doses of amphotericin B by infusion of a liposomal formulation in children with cancer.

Conventional amphotericin B (Amph-B) is the drug of choice for treating systemic fungal infections. Recently, a new formulation has become available, encapsulated in liposomes (Amph-lip). This new form of administration was developed in order to lower the acute side effects and to offer the possibility of administering high doses of amphotericin B. Experience with Amph-lip is limited, especially in children. We treated four children with documented systemic fungal infections with Amph-lip and administered it empirically to 12 children. Fifteen of these 16 children were severely granulocytopenic oncologic patients. One 3-month-old baby suffered from systemic candidiasis. Amph-lip was preferred to conventional Amph-B in children with organ dysfunction developing as a consequence of conventional chemotherapy or bone marrow transplantation, after failure of conventional Amph-B to improve a fungal infection, and after adverse drug reactions had occurred. The daily doses of Amph-lip ranged from 1 to 6 mg/kg (median 3 mg/kg), the cumulative doses from 13 to 311 mg/kg (median 75 mg/kg). Acute adverse reactions or organ function abnormalities attributable to Amph-lip did not occur in 402 administrations. Amph-lip has proven to be well tolerated by children in terms of acute toxicity and in the long term. Although large cumulative doses were given, organ function abnormalities attributable to Amph-lip doses were not detected in any of ten long-term survivors over a median observation time of 36 months (range 30-44 months). Amph-lip appears to be a promising alternative antifungal treatment, especially for patients with impaired organ function, when high doses of amphotericin B are necessary.