ArticleLiterature Review

Tumour lysis syndrome: New therapeutic strategies and classification

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Abstract

Tumour lysis syndrome (TLS) describes the metabolic derangements that occur with tumour breakdown following the initiation of cytotoxic therapy. TLS results from the rapid destruction of malignant cells and the abrupt release of intracellular ions, nucleic acids, proteins and their metabolites into the extracellular space. These metabolites can overwhelm the body's normal homeostatic mechanisms and cause hyperuricaemia, hyperkalaemia, hyperphosphaetemia, hypocalcaemia and uraemia. TLS can lead to acute renal failure and can be life-threatening. Early recognition of patients at risk and initiation of therapy for TLS is essential. There is a high incidence of TLS in tumours with high proliferative rates and tumour burden such as acute lymphoblastic leukaemia and Burkitt's lymphoma. The mainstays of TLS prophylaxis and treatment include aggressive hydration and diuresis, control of hyperuricaemia with allopurinol prophylaxis and rasburicase treatment, and vigilant monitoring of electrolyte abnormalities. Urine alkalinization remains controversial. Unfortunately, there have been few comprehensive reviews on this important subject. In this review, we describe the incidence, pathophysiological mechanisms of TLS and risk factors for its development. We summarise recent advances in the management of TLS and provide a new classification system and recommendations for prophylaxis and/or treatment based on this classification scheme.

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... STLS requires clinical correlation with the patient's known malignancy, the likelihood for lysis, and laboratory studies. Current guidelines reflect that of the Cario-Bishop guidelines [12,13]. If the laboratory studies reveal at least two abnormalities, the patient may be diagnosed with TLS. ...
... If the laboratory studies reveal at least two abnormalities, the patient may be diagnosed with TLS. Abnormalities noted by current Cario-Bishop guidelines classify patients with TLS or STLS have a serum uric acid level ≥8 mg/dL, or a 25% increase from baseline; a serum potassium level ≥6 mmol/L, or a 25% increase from baseline; serum phosphate levels ≥4.5 mg/dL in adults, or a 25% increase from baseline; and a serum calcium level ≤7 mg/dL, or a 25% decrease from baseline [12][13][14] In addition, these abnormalities must have occurred three days prior to or within seven days following the beginning of chemotherapy treatment to be considered for a diagnosis of TLS [12,13]. However, as this patient has not started any cytotoxic therapy, the evidence is clear that the patient was experiencing steroid-induced TLS given recent steroid use. ...
... If the laboratory studies reveal at least two abnormalities, the patient may be diagnosed with TLS. Abnormalities noted by current Cario-Bishop guidelines classify patients with TLS or STLS have a serum uric acid level ≥8 mg/dL, or a 25% increase from baseline; a serum potassium level ≥6 mmol/L, or a 25% increase from baseline; serum phosphate levels ≥4.5 mg/dL in adults, or a 25% increase from baseline; and a serum calcium level ≤7 mg/dL, or a 25% decrease from baseline [12][13][14] In addition, these abnormalities must have occurred three days prior to or within seven days following the beginning of chemotherapy treatment to be considered for a diagnosis of TLS [12,13]. However, as this patient has not started any cytotoxic therapy, the evidence is clear that the patient was experiencing steroid-induced TLS given recent steroid use. ...
Article
We present a case of a 66-year-old male with a past history of newly diagnosed non-Hodgkin lymphoma, diabetes, and recent surgical splenectomy secondary to splenic infarct who presented to the Emergency Department (ED) with several nonspecific symptoms that were consistent with tumor lysis syndrome. This case report discusses the clinical presentation, diagnosis, and management of spontaneous tumor lysis syndrome.
... The incidence of TLS varies greatly across different cancer types, occurring in over 20% of hematologic cancers [31] while being so rare in sarcomas and other tumor types as to have no reported incidence [30,32]. Multiple classification systems exist [33][34][35], though the commonly used standard for identifying TLS is the Cairo-Bishop classification [35], which takes into account a patient's baseline metabolic panel and categorizes TLS as laboratory TLS (LTLS) or clinical TLS (CTLS). LTLS is defined by two or more of either absolute changes (uric acid ≥ 8.0 mg/dL, potassium ≥ 6.0 mEq/L, phosphorus ≥ 0.5 mg/dL, and/or calcium ≤ 7.0 mg/dL) or expected changes in these laboratory values >25% from baseline within a 24-hour period, 3-7 days after chemotherapy initiation. ...
... The incidence of TLS varies greatly across different cancer types, occurring in over 20% of hematologic cancers [31] while being so rare in sarcomas and other tumor types as to have no reported incidence [30,32]. Multiple classification systems exist [33][34][35], though the commonly used standard for identifying TLS is the Cairo-Bishop classification [35], which takes into account a patient's baseline metabolic panel and categorizes TLS as laboratory TLS (LTLS) or clinical TLS (CTLS). LTLS is defined by two or more of either absolute changes (uric acid ≥ 8.0 mg/dL, potassium ≥ 6.0 mEq/L, phosphorus ≥ 0.5 mg/dL, and/or calcium ≤ 7.0 mg/dL) or expected changes in these laboratory values >25% from baseline within a 24-hour period, 3-7 days after chemotherapy initiation. ...
... The patient in this report had both clinical and laboratory TLS per Cairo-Bishop criteria [35] with increased uric acid and phosphate, the development of an AKI, and a fatal cardiac arrhythmia. This medical emergency was promptly recognized and treated; unfortunately, the patient died despite maximal medical therapy. ...
Article
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Background Tumor lysis syndrome is an oncologic emergency that involves multiple metabolic abnormalities and clinical symptoms such as acute renal failure, cardiac arrhythmias, seizures, and multiorgan failure, and may be fatal if not promptly recognized. Tumor lysis syndrome occurs most often in patients with hematologic malignancies, and relatively few cases have been described in patients with sarcoma. Case presentation A 64-year-old male of Asian heritage presented to his primary care physician with a right lower-extremity mass and was ultimately diagnosed with widely metastatic osteosarcoma. He was treated with one cycle of cisplatin and doxorubicin that was complicated by hypervolemia and hypoxic respiratory failure. Given concerns for volume overload, therapy was changed to single-agent, dose-reduced ifosfamide. After receiving one dose of ifosfamide 1 g/m² (1.8 g total) intravenously over 1 hour, the patient developed renal failure, hyperuricemia, hyperkalemia, hyperphosphatemia, and lactic acidosis. The patient ultimately died from severe electrolyte abnormalities associated with tumor lysis syndrome. Conclusion This is the first instance of tumor lysis syndrome described in a patient with osteosarcoma undergoing ifosfamide monotherapy. Clinicians must be vigilant in identifying tumor lysis syndrome regardless of the malignancy type or chemotherapy regimen in order to prevent potentially fatal complications.
... Tumor lysis syndrome (TLS) is a hematologiconcologic emergency requiring immediate recognition and treatment. It is the consequence of spontaneous or therapy-related rapid cellular death leading to the release of a waste amount of intracellular ions and metabolic products of purine bases into the bloodstream [1,2]. The incidence of TLS varies between different types of tumors and depends on patient and tumor characteristics. ...
... Rapid spontaneous or, more frequently, therapyrelated cell death occuring in the first few days after treatment leads to the release of intracellular contents of malignant cells into the bloodstream [2]. The characteristic metabolic derangement in TLS comprises hyperkalemia, hyperphosphatemia, hyperuricemia, and usually secondary hypocalcemia. ...
... Hyperuricemia is caused by the catabolism of purine bases into hypoxanthine and xanthine, and then to uric acid via xanthine oxidase. Uric acid is poorly soluble in water, leading to crystal formation and deposition in distal tubules, especially in acid-ic urine [2]. On the other hand, uric acid causes endothelial dysfunction, inflammation, and oxidative stress contributing to kidney damage [2,9]. ...
Article
Introduction. Tumor lysis syndrome is an emergency condition requiring prompt recognition and treatment. It?s a consequence of spontaneous or therapy-induced cellular death leading to the release of intracellular ions and metabolic products of purine bases into the bloodstream. Pathophysiology. The characteristic metabolic derangement comprises hyperkalemia, hyperphosphatemia, hyperuricemia, and hypocalcemia. These metabolic changes can lead to kidney failure, arrhythmia, and seizures. Epidemiology, classification and risk assessment. The incidence of tumor lysis syndrome varies between different types of tumors, but it is most common in hematologic malignancies. According to Cairo - Bishop Classification, tumor lysis syndrome can be defined as laboratory tumor lysis syndrome and clinical tumor lysis syndrome. Preventive measures and treatment of tumor lysis syndrome. Frequent laboratory monitoring is obligatory in patients with intermediate and high risk of tumor lysis syndrome. Preventive measures are based on vigorous hydration and administration of medication to control serum uric acid levels. When clinical tumor lysis syndrome develops, additional treatment, including renal replacement therapy, is needed for the correction of metabolic disturbances. Conclusion. Tumor lysis syndrome is a potentially fatal complication in patients with suffering from malignancies. Early recognition of patients at risk and administration of prophylactic and therapeutic measures improves outcomes for these patients.
... Tumour lysis syndrome (TLS) is an oncological emergency resulting from massive tumour cell lysis leading to life-threatening metabolic derangements. Although TLS can occur spontaneously, it usually occurs after therapy for aggressive haematological malignancies, including acute leukaemias with very high white blood counts and high-grade lymphomas along with rapidly proliferating solid tumours 229 . TLS is caused by the rapid release of intracellular contents into the bloodstream, including nucleic acids, potassium, lactate dehydrogenase and phosphorus, following cancer cell death (Fig. 6). ...
... All patients with pronounced electrolyte abnormalities should have an electrocardiogram to exclude serious arrhythmias and conduction abnormalities. The Cairo-Bishop definition provides specific laboratory criteria for the diagnosis and grading of TLS to help delineate the degree of severity of TLS 229 . ...
... The lysis of cancer cells releases enzymes and DNA, leading to a cascade of inflammatory and procoagulant enzymes, an increase in purines and resulting uric acid and its metabolic products, and to a release of phosphorus that may precipitate with calcium and contribute to nephropathy along with the increase in uric acid. Tumour lysis syndrome is managed with intensive hydration, diuresis, and agents such as allopurinol and rasburicase 229 . ...
Article
Despite the enthusiasm surrounding novel targeted agents and immunotherapies, chemotherapy remains the mainstay treatment for most human malignancies, either alone or in combination. Yet, the burden of chemotherapy-associated adverse events (CAAEs) remains high and, importantly, is associated with considerable morbidity, mortality and costs that affect patients across multiple dimensions, including physical, emotional and social functioning. CAAEs can directly affect patient outcomes and indirectly increase the risk of cancer recurrence by compromising treatment intensity and continuity. Systematic efforts to identify and critically summarize the evidence on management approaches for CAAEs remain limited. Herein, we review the most common acute CAAEs having a major effect on survival, quality of life, function and/or continuation of optimal therapy. We focus on selected acute toxicities that occur during treatment, summarizing their underlying pathophysiology, multifactorial aetiologies, evidenced-based treatments, prevention strategies and management recommendations. We also summarize the available evidence on risk factors, validated risk assessment tools and other efforts to optimize symptom control in patients most likely to benefit in order to personalize the prevention and treatment of acute CAAEs. Finally, we discuss innovative symptom monitoring and supportive care interventions that are under development to further improve the outcomes of patients with cancer.
... The traditional way of urinary alkalisation is considered controversial these days as urinary alkalinisation with sodium bicarbonate may lead to metabolic alkalosis and/or xanthine obstructive uropathies. The solubility of xanthine and hypoxanthine significantly decreases at an alkaline urine pH (≥6.5), leading to the development of urinary xanthine crystals during and after allopurinol therapy [8]. ...
... Allopurinol is a competitive inhibitor of xanthine oxidase and prevents the formation of uric acid (Figure 1). Allopurinol can be administered orally 24-48 hours before the initiation of chemotherapeutic drugs [8]. The major disadvantage of allopurinol is its delayed onset of action and that it does not reduce the amount of urate already present in the body. ...
... The combination of refractory hyperkalaemia, oliguria, central nervous system (CNS) toxicity secondary to uraemia, metabolic acidosis and fluid overload unresponsive to diuretics is an indication for haemodialysis. TLS is also an indication for haemodialysis in isolation [8,17]. ...
Article
Tumour lysis syndrome (TLS) is an onco-metabolic emergency seen in rapidly proliferative malignancies resulting from the destruction of tumour cells, resulting in an electrolyte and metabolic derangement. TLS is usually associated with high-grade haematological malignancies and rarely with solid tumours. TLS can be therapy induced or might occur spontaneously. Here, we present a case of a 61-year-old male patient with newly diagnosed mantle cell lymphoma (MCL) admitted for elective chemotherapy, who went into sudden spontaneous tumour lysis before the administration of cytotoxic chemotherapy. The laboratory investigations were consistent with hyperkalaemia, hyperuricaemia, hyperphosphatemia and acute kidney injury. The patient was managed with aggressive intravenous hydration and rasburicase, and his hyperkalaemia was managed in the ward. He was taken to the intensive care unit (ICU) for consideration of haemofiltration. Unfortunately, the patient went into multi-organ failure soon after and died. This case emphasises the need to recognise and treat this complication quickly as it can have fatal consequences. Additionally, it stresses the necessity to vigorously screen patients admitted with malignancy and high tumour burden for TLS, even when they do not receive cytotoxic treatment. TLS management includes adequate hydration, the use of uric acid-lowering therapies and minimisation of potassium intake.
... They used some specific parameters of which variation are usually observed during the first four days after starting antineoplastic therapy. Their definition was not including patients with spontaneous TLS, and it was modified by Cairo and Bishop in 2004 by summing up the clinical and laboratory changes that appear within 3 to 7 days after the initiation of chemotherapy, thus including patients who already have TLS at presentation, as well as those who are developing it later on (Table 1) [20]. Additionally, it is necessary to exclude other causes of AKI. ...
... They used some specific parameters of which variation are usually observed during the first four days after starting antineoplastic therapy. Their definition was not including patients with spontaneous TLS, and it was modified by Cairo and Bishop in 2004 by summing up the clinical and laboratory changes that appear within 3 to 7 days after the initiation of chemotherapy, thus including patients who already have TLS at presentation, as well as those who are developing it later on (Table 1) [20]. Additionally, it is necessary to exclude other causes of AKI. ...
... Additionally, it is necessary to exclude other causes of AKI. [20]). • changes of the laboratory parameters must be simultaneous within 24 h because the patient may develop one abnormality, and later on another, unrelated to TLS (e.g., hypocalcemia associated with sepsis); • symptomatic hypocalcemia has to be a criterion for clinical TLS, even when the decrease in calcium level is less than 25% of baseline; • a 25% variation of a parameter is significant for the diagnosis only if it causes symptoms or if the value is not within the normal range [3]. ...
Article
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Tumor lysis syndrome (TLS) is a common cause of acute kidney injury in patients with malignancies, and it is a frequent condition for which the nephrologist is consulted in the case of the hospitalized oncological patient. Recognizing the patients at risk of developing TLS is essential, and so is the prophylactic treatment. The initiation of treatment for TLS is a medical emergency that must be addressed in a multidisciplinary team (oncologist, nephrologist, critical care physician) in order to reduce the risk of death and that of chronic renal impairment. TLS can occur spontaneously in the case of high tumor burden or may be caused by the initiation of highly efficient anti-tumor therapies, such as chemotherapy, radiation therapy, dexamethasone, monoclonal antibodies, CAR-T therapy, or hematopoietic stem cell transplantation. It is caused by lysis of tumor cells and the release of cellular components in the circulation, resulting in electrolytes and metabolic disturbances that can lead to organ dysfunction and even death. The aim of this paper is to review the scientific data on the updated definition of TLS, epidemiology, pathogenesis, and recognition of patients at risk of developing TLS, as well as to point out the recent advances in TLS treatment.
... On the other hand, clinical TLS is defined as laboratory TLS plus one or more of the above-mentioned clinical criteria. [6] Acute kidney injury (AKI) is the most common clinical complication of TLS. AKI in TLS is multifactorial and is linked to both uric acid and calcium phosphate deposition in renal tubules. ...
... Reference hematological malignancies. [6] Of note, when assessing the risk of TLS in any patient with hematological malignancy, patients, tumors, and therapy-specific factors should be considered. [1] STLS has been rarely reported in both hematological and solid malignancies. ...
Article
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Rationale: Tumor lysis syndrome (TLS) is an oncological emergency that occurs due to diffuse tumor cell destruction with the massive release of intracellular electrolytes. Spontaneous tumor lysis syndrome (STLS) is the development of TLS before the commencement of chemotherapy. To the best of our knowledge, there are no reported cases of STLS in the chronic or accelerated phase of chronic myeloid leukemia (CML). Patient concerns: A 37-year-old woman of Arabic descent with a history of CML presented with a 3-day history of nausea and abdominal pain. She had not started any new treatment for CML within the last 3 months of presentation. Diagnosis: The patient was diagnosed with hyperuricemia, hyperphosphatemia, hypocalcemia, and acute kidney injury. A peripheral blood smear confirmed the accelerated CML phase. Our patient met the criteria for clinical TLS, specifically, STLS. She was also diagnosed with autoimmune hemolytic anemia. Interventions: The patient was started on intravenous normal saline (200 mL/h) and rasburicase (6 mg/d). In addition, hydroxyurea was used as a cytoreductive agent. Outcomes: The creatinine level returned to normal within 48 hours of rasburicase initiation. Lessons: Any patient with hematological malignancy should be monitored for TLS even before the initiation of chemotherapy. The exact mechanism of spontaneous TLS remains unknown, and further studies are needed to explain the pathophysiology of this condition. Rapid initiation of rasburicase, in addition to vigorous hydration, is effective in the treatment of acute kidney injury associated with TLS. Abbreviations: AIHA = autoimmune hemolytic anemia, AKI = acute kidney injury, CML = chronic myeloid leukemia,STLS = spontaneous tumor lysis syndrome,TLS = tumor lysis syndrome.
... This syndrome is caused by the release of the contents from destroyed cells, inter alia intracellular ions, nucleic acids, proteins, and their metabolites. Substances such as uric acid and phosphate may contribute to the damaging of renal tubules when they precipitate, which in consequence leads to renal function impairment [165,166]. Other possible mechanisms of nephrotoxicity of CAR-T therapy are associated with the consequences of the development of hemophagocytic lymphohistiocytosis (HLH) in which AIN or TMA may be identified [167][168][169]. ...
... Renal adverse drug reactions of BsAbs are hardly known [165][166][167][168][169]. Considering the large number of ongoing trials assessing the safety and efficacy of different new BsAbs [160], their impact on kidneys should be described soon. ...
Article
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Modern oncological therapy utilizes various types of immunotherapy. Immune checkpoint inhibitors (ICIs), chimeric antigen receptor T cells (CAR‐T) therapy, cancer vaccines, tumortargeting monoclonal antibodies (TT‐mAbs), bispecific antibodies and cytokine therapy improve patients’ outcomes. However, stimulation of the immune system, beneficial in terms of fighting against cancer, generates the risk of harm to other cells in a patient’s body. Kidney damage belongs to the relatively rare adverse events (AEs). Best described, but still, superficially, are renal AEs in patients treated with ICIs. International guidelines issued by the European Society for Medical Oncology (ESMO) and the American Society of Clinical Oncology (ASCO) cover the management of immune‐related adverse events (irAEs) during ICI therapy. There are fewer data concerning real occurrence and possible presentations of renal adverse drug reactions of other immunotherapeutic methods. This implies the need for the collection of safety data during ongoing clinical trials and in the real‐life world to characterize the hazard related to the use of new immunotherapies and management of irAEs.
... For diagnosis of TLS, the Cairo and Bishop scoring system was adopted [ Table 1]. [6] The patients were then risk stratified according to the recommendations by expert panel consensus by Cairo et al. summarized in Table 2. [7] Definitions Hyperkalemia was defined potassium >5.5 mmol/L, hyperphosphatemia phosphate >1.9 mmol/L, hypocalcemia calcium <2.0 mmol/L, hyperuricemia uric acid > 416.5 umol/L, blood urea nitrogen and serum creatinine more than institutionally sex/age -defined upper limit of normal. The CTCAE v4.0 was used for pretreatment and postchemotherapy AKI. ...
... Definitions of laboratory and clinical tumor lysis syndrome[6] ...
Article
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BACKGROUND: Tumor lysis syndrome (TLS) is a common complication of hematological malignancies and consists of either hyperkalemia, hyperphosphatemia, hyperuricemia, or hypocalcemia. These metabolic derangements may result in clinical tumor lysis syndrome in the form of acute kidney injury (AKI), arrhythmias, seizures, and sudden death. OBJECTIVES: This study was conducted to determine the incidence and outcome of TLS and to identify local risk factors in children with hematological malignancies. PATIENTS AND METHODS: This was a retrospective chart review of children ≤18 years diagnosed with acute lymphoblastic leukemia (ALL), acute myeloid leukemia, or non-Hodgkin lymphoma between 2014 and 2018. TLS was diagnosed and stratified according to the risk of developing tumor lysis using the Cairo and Bishop definition and Cairo stratification. RESULTS: Among 180 patients, only 11 patients (6%) developed TLS. Four patients had laboratory TLS (LTLS) (36.3%) and six had CLTS (54.5%). The male-to-female ratio was high (2.4:1 in the TLS group). Hyperphosphatemia and hypocalcemia were the most frequently occurring criteria for LTLS (81.8%). The strongest predictors for TLS were hyperuricemia and hypocalcemia at presentation (P < 0.001) followed by diagnosis of T-cell ALL, preceding AKI splenomegaly, high initial white blood cell, and lactate dehydrogenase, with P < 0.05. AKI secondary to tumor lysis occurred in six patients (54.5%), of which five needed dialysis. One patient had seizures secondary to tumor lysis (9.1%) and no patient died from TLS. CONCLUSION: There is a wide variation in reported incidence of TLS from 6% to 45%, likely due to different TLS definitions applied, diverse cohorts and duration. A universal definition and risk-stratified approach to prevent tumor lysis in patients with hematologic malignancies is needed to help in proper comparison between studies.
... 7 Our patient fulfilled both the laboratory criterial for TLS as evidenced by elevated potassium, uric acid and phosphate levels and the clinical criteria for TLS, as evidenced by raised creatinine. 8 The majority of TLS occurs post-chemotherapy, while spontaneous TLS is much rarer and is characterised as TLS occurring in the absence of active chemotherapy. 6 Risk factors for TLS in solid tumours include high tumour volume with metastasis, liver metastasis, and high pre-treatment LDH, uric acid, and renal insufficiency. ...
Article
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Tumour lysis syndrome is common in haematological malignancies but is rarely reported in solid tumours. Peripheral blood lymphocytosis is an autoimmune feature of thymomas. We report a 63-year-old female who presented with a mediastinal mass, spontaneous tumour lysis syndrome and a leukoerythroblastic picture on peripheral blood film. Bone marrow aspiration and trephine biopsy ruled out haematological malignancy. Subsequent biopsy of the mediastinal mass confirmed thymoma. This is the first reported case of thymoma with peripheral blood lymphocytosis presenting with spontaneous tumour lysis syndrome. Clinicians are reminded that solid tumours may masquerade as haematological malignancies in the presence of peripheral blood lymphocytosis, hence careful clinical evaluation is needed to differentiate between the two diagnoses.
... Supportive care and prevention of TLS were managed according to recommendations [26]. TLS was diagnosed according to international definition including hyperuricemia, hyperkaliemia, hyperphosphatemia, hypocalcemia and uremia [27]. DIC was diagnosed based on laboratory tests including platelets, fibrinogen level, D-dimer, prolonged Prothrombin Time (PT), according to international recommendations [28]. ...
Article
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Introduction Patients with hyperleukocytic (HL) acute myeloid leukemia (AML) are at higher risk of early death. Initial management of these patients is challenging, not fully codified and heterogenous. Retrospective studies showed that several symptomatic measures might decrease early death rate but long-term data are scarce. We aimed to analyze whether the therapeutic measures carried out urgently at diagnosis may influence the outcome among HL AML patients having achieved who survived inaugural complications. Methods We retrospectively reviewed all medical charts from patients admitted to Saint-Louis Hospital between January, 1 st 1997 and December, 31st 2018 with newly diagnosed AML and white blood cell (WBC) count above 50x10 ⁹ /L. Outcome measures were cumulative incidence of relapse (CIR), treatment-related mortality (TRM) defined as relapse-free death, and overall survival. Univariate and multivariate analyses were performed using Cox proportional hazards models. Results A total of 184 patients with HL AML in complete remission (CR) were included in this study. At 2 years after CR. 62.5% of patients were alive, at 5 years, cumulated incidence of relapse was 55.8%. We found that every therapeutic measure, including life-sustaining therapies carried out in the initial phase of the disease, did not increase the relapse risk. The use of hydroxyurea for more than 4 days was associated with a higher risk of relapse. At the end of the study, 94 patients (51.1%) were still alive including 23 patients out of 44 aged less than 60 yo that were able to return to work. Conclusion We show that the use of emergency measures including life sustaining therapies does not come at the expense of a higher risk of relapse or mortality, except in the case of prolonged use of hydroxyurea. Patients with HL AML should be able to benefit from all available techniques, regardless of their initial severity.
... КСЛП) ознаками (за M.S.Cairo, M. Bishop, 2004). Відповідно до критеріїв Cairo і Bishop[14] діагноз СЛП за лабораторними ознаками встановлюється, якщо при госпіталізації вміст 2 речовин і більше (сечової кислоти, калію, фосфату або кальцію) вище або нижче норми або якщо вони змінилося на 25% в межах 3 діб до початку лікування або 7 діб після нього. ...
... Tumor Lysis Syndrome (TLS) is an oncological emergency caused by massive tumor cell destruction leading to a release of cellular content into the blood stream. The Cairo-Bishop definition provides specific criteria for the diagnosis ( Table 1), which is characterized by laboratory findings of hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia (5). ...
Article
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Tumor lysis syndrome (TLS) is a life-threatening oncological emergency rarely seen in solid tumors and is a complication of cancer therapy for rapidly proliferating tumors with devastating outcomes. BRAF and KRAS are two key oncogenes in the MAPK signaling pathway that are routinely examined for mutations to predict resistance to anti-EGFR therapy. Concomitant KRAS and BRAF mutations in GI tumors are rare, occurring in less than 0.001% of cases and are associated with an aggressive tumor behavior. We report an unusual case of a young male patient diagnosed with locally advanced duodenal mucinous adenocarcinoma harboring concomitant KRAS and BRAF mutations. This unique genetic profile generated hyperactivation of the EGFR signaling pathway. Following day-1 of mFOLFOX-6 chemotherapy protocol, the patient developed TLS. Clinical resolution was achieved using high volume hydration. Unfortunately, the patient passed away 10 days later during anesthesia induction.
... Clinical TLS, on the other hand, is the presence of laboratory TLS plus an increased creatinine level, seizures, cardiac dysrhythmia, or death. 1 The incidence of TLS ranges from 4 to 42% and usually occurs early in the administration of chemotherapy or radiotherapy. The mortality rate of TLS can be as high as 15% among confirmed cases, and thus requires a high index of suspicion for diagnosis. ...
Article
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Although prevention is vital in managing tumor lysis syndrome (TLS), no study directly compares various regimens. This study compared the effectiveness and safety of urate-lowering agents in preventing TLS. Databases were searched for randomized controlled trials involving adults with hematologic or solid malignancies on chemotherapy or cytoreductive agents given allopurinol, febuxostat, or rasburicase alone or in combination at any dose, form, or frequency published in English by December 2021. Outcomes included laboratory and clinical TLS expressed as relative risks, adverse events as described by authors, and mean serum uric acid (sUA) as mean differences of area under the curve. A network of meta-analysis and post-hoc meta-analysis based on TLS risk using a random-effects model was done using Stata 14.0 and Review Manager 5.3, respectively. Certainty of evidence was assessed using the GRADE approach. Three studies with a total of 633 participants given allopurinol, febuxostat, rasburicase, or rasburicase combined with allopurinol were included. Rasburicase is more effective than allopurinol in preventing laboratory TLS (relative risk: 0.51; 95% confidence interval [CI]: 0.32–0.81) based on moderate quality evidence. No significant differences were observed in clinical TLS. Adverse events were attributable to toxicities of chemotherapy. Rasburicase alone or in combination with allopurinol was better than allopurinol or febuxostat alone in reducing sUA level. Febuxostat is more effective than allopurinol in lowering sUA levels among patients at high-risk of TLS (mean difference −125.75; 95% CI: −223.47 to −28.02). Rasburicase may be the most effective agent in preventing laboratory TLS and maintaining low sUA levels.
... This condition is most often diagnosed in patients with leukemia and an exceedingly high white blood cell count. 6 In this condition, kidney damage occurs via uric acid obstructive uropathy; potassium and phosphorus build-up can cause fatal arrhythmias and hypocalcemia, respectively. ...
Article
Introduction: Emergency physicians must maintain a broad differential when seeing patients in the emergency department (ED). Occasionally, a patient may have an undiagnosed, life-threatening medical condition not related to the presenting chief complaint. It is imperative to review all ordered laboratory tests and any available previous laboratory values to assess for any abnormalities that may warrant further evaluation. Case report: This case report is regarding the missed diagnosis of acute leukemia and subsequent disseminated intravascular coagulation in a 27-year-old male who presented to multiple EDs with the unrelated chief complaint of finger ring entrapment. This patient ultimately succumbed to his illness. Conclusion: When evaluating patients in the ED, it is important to review any prior available test results for abnormalities, even if the results do not specifically correlate with the chief complaint. Emergency physicians must remain vigilant to avoid missing a critical diagnosis.
... Tumor lysis syndrome (TLS) is an important, frequent cause of AKI, counted among oncologic emergencies, characterized by metabolic abnormalities leading to organ failure (12)(13)(14)(15). Furthermore obstructive nephropathy, disseminated intravascular disease, chemotherapyinduced nephrotoxicity were described among the other causes of AKI in malignity's (16). ...
Article
Bu yazıda akut böbrek hasarını (ABH) takiben tanı alan bir kronik myeloid lösemi (KML) vakası bildirilmiştir. 80 yaşında erkek hasta, oligüri ve serum kreatinin düzeylerinde yükselme ile kliniğe başvurdu. Akut böbrek hasarı (ABH) teşhisi kondu ve destekleyici tedavi verildi,kısmen iyileşme sağlandı,renal replasman tedavisi gerekmedi. Dört ay sonra persistan lökositoz nedeniyle tekrar kliniğe başvurdu; periferik yayma,kemik iliği biyopsisi ve BCR-ABL gen tarama incelemesi sonrasında kronik myeloid lösemi tanısı kondu.
... 6 The diagnosis of TLS is based on the Cairo-Bishop criteria, which include laboratory (hyperuricemia, hyperphosphatemia, hyperkalemia, and hypocalcemia) and clinical (Increased creatinine, cardiac arrhythmia/sudden death, and seizure) findings. 7 Unlike most TLS cases, our patient presented hypercalcemia in initial laboratory tests instead of hypocalcemia, which could be related to nature of plasma cell dyscrasias, particularly in this case, primary PCL. In these hematologic malignancies, malignant cells produce substances that induce osteoclasts to accelerate the rate of bone break down. ...
Article
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Tumor lysis syndrome (TLS) is an oncologic emergency in which tumor cells undergo lysis either spontaneously or due to the initiation of cancer therapy typically presenting with hypocalcemia. We described a 62‐year‐old male patient with spontaneous TLS and hypercalcemia without a known malignancy, who is later discovered to have plasma cell leukemia. A high level of suspicion is needed for spontaneous tumor lysis syndrome to be diagnosed in early stages to provide a better chance of more immediate and effective treatments, especially in invasive malignancies such as plasma cell leukemia.
... Tumor lysis syndrome was assessed according to the Cairo and Bishop criteria. 19 Septic shock was defined following the International Pediatric Sepsis Consensus Guidelines. 20 ...
Article
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Objective: To identify the risk factors and describe the outcomes of patients who developed acute kidney injury (AKI)during treatment for myeloid leukemia of Down syndrome (ML-DS).Material and Methods: The medical records of 23 Down syndrome patients under the age of 15 who had been diagnosedwith acute myeloid leukemia (AML) and were being treated at a major tertiary care referral facility in Southern Thailandwere reviewed. The identification of factors associated with AKI was done using logistic regression. The Kaplan-Meiermethod was used to calculate survival probabilities.Results: Eight (34.8%) patients developed AKI during their course of chemotherapy with a median time from the firstvisit to the AKI event of 1.1 (IQR 0.7, 3.1) months. Higher levels of blast cells (OR: 1.19, 95% CI: 1.05-1.98) and septicshock during the course of chemotherapy (OR: 621.1, 95% CI: 2.40-Inf.) were independently associated with AKI. The1-year overall survival rate was 26.1%. The median survival times among those who developed AKI and those who didnot were 1.94 and 10.7 months, respectively.Conclusion: About one-third of the cases with ML-DS in our cohort developed AKI during the course of chemotherapy.The risk factors of AKI were higher peripheral blast count and septic shock during chemotherapy.
... This condition is most often diagnosed in patients with leukemia and an exceedingly high white blood cell count. 6 In this condition, kidney damage occurs via uric acid obstructive uropathy; potassium and phosphorus build-up can cause fatal arrhythmias and hypocalcemia, respectively. ...
Article
Introduction: Emergency physicians must maintain a broad differential when seeing patients in the emergency department (ED). Occasionally, a patient may have an undiagnosed, life-threatening medical condition not related to the presenting chief complaint. It is imperative to review all ordered laboratory tests and any available previous laboratory values to assess for any abnormalities that may warrant further evaluation. Case Report: This case report is regarding the missed diagnosis of acute leukemia and subsequent disseminated intravascular coagulation in a 27-year-old male who presented to multiple EDs with the unrelated chief complaint of finger ring entrapment. This patient ultimately succumbed to his illness. Conclusion: When evaluating patients in the ED, it is important to review any prior available test results for abnormalities, even if the results do not specifically correlate with the chief complaint. Emergency physicians must remain vigilant to avoid missing a critical diagnosis.
... TLS is an oncological emergency that needs to be recognized urgently, and if treated early, complications can be prevented, thereby improving the outcomes [15]. The Cairo-Bishop laboratory and clinical criteria are used to diagnose TLS ( Table 1) [16]. The presence of two or more laboratory abnormalities starting either three days before or seven days after treatment of the tumor can be used to define laboratory TLS. ...
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Tumor lysis syndrome (TLS) in patients with solid tumors is a rare and potentially fatal condition associated with anti-cancer treatment. Its outcome depends on awareness, identification of high-risk patients, and implementation of appropriate preventive measures. A systematic review was conducted according to PRISMA guidelines of case reports describing the occurrence of TLS in patients with solid tumors, primarily to identify potentially unrecognized or unusual clinical findings and outcomes. We searched the PubMed, EMBASE, and Cochrane databases and conference abstracts and performed manual searches for case reports and case series published in English and describing patients who developed TLS. A total of 124 studies (118 case reports and six case series) describing the findings for 132 patients were included. The most common cancers were hepatocellular carcinoma (17%, n = 22), lung cancer (13%, n = 17), and melanoma (10%, n = 13). The most common risk factor was metastatic disease (75%, n = 100). TLS was induced by chemotherapy in 48% (n = 64) of the patients. Clinical manifestations of TLS developed within three days of anti-cancer treatment in 37% of the patients (n = 49), while 52% (n = 68) received the full dose of anti-cancer treatment. Gastrointestinal symptoms occurred in 33% of the patients (n = 44), hyperuricemia in 95% (n = 125), and elevated creatinine level occurred in 85% of the patients (n = 112), While 58% (n = 77) of the patients received intravenous fluids, only 49% received allopurinol, and 24% (n = 32) received rasburicase. A total of 101 patients (77%) were treated in the ward, and 54% (n = 71) died. The mortality rate associated with TLS in patients with solid tumors remains high. Adequate management requires awareness, early recognition, and identification of patients at high risk. Interdisciplinary team management is essential to reduce mortality.
... Feinstein et al. proposed that urinary insulin growth factor 1 excretion and its impacts on higher tubular phosphate retention could be a potential mechanism of phosphorus level elevation in such children [35]. However, as seen in rhabdomyolysis and tumor lysis syndrome, increased cellular mass catabolism could be [36]. Medications like steroids and diuretics may have a role in uric acid metabolism [10,37]. ...
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Background Nutritional status assessment in children with nephrotic syndrome (NS) is critical for identifying patients who are at risk of protein-energy wasting (PEW) and for determining their nutritional needs and monitoring nutritional intervention outcomes. Methods In a case–control study, we enrolled 40 children (age range: 2–16 years) with NS and 40 apparently healthy children (age and sex-matched) as a control group. Anthropometric data, as well as demographic, clinical, and laboratory data, were collected. A dietary intake assessment using a 3-day food intake record was done, and the quadriceps rectus femoris thickness (QRFT) and quadriceps vastus intermedius thickness (QVIT) were assessed using B-mode ultrasound and compared between both groups. Results Children with NS had lower QRFT and QVIT measurements than control groups ( p < 0.001). Inadequacy in protein intake occurred in 62.5% and 27.5% of the NS and control groups, respectively ( p = 0.002). The thickness of the rectus and vastus muscles by ultrasound was significantly associated with the percentage of protein intake ( p < 0.001). The ROC curve revealed that the best cutoff value of QRFT for the prediction of the patient at risk of malnutrition was ≤ 1.195 with an area under curve of 0.907, with p < 0.001. Conclusion In children with NS, skeletal muscle ultrasound is a simple and easy-to-use bedside technique for the identification of patients at risk of malnutrition. Graphical abstract
... To prevent lethal complications, fast and effective leukoreduction is intended. However, tumor lysis syndrome in children (3,4) as well as its clinical complications (renal dysfunction, cardiac arrhythmia, seizures), induced by too aggressive cytoreduction should be avoided as well. Therefore, intensive supportive care to prevent bleeding, leukostasis and kidney failure is essential. ...
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Twelve to 22% of pediatric acute myeloid leukemia (AML) patients present with hyperleukocytosis, which is one of the main risk factors of early death due to its clinical complications: leukostasis, causing pulmonary or central nervous system injuries, tumor lysis syndrome, and disseminated intravascular coagulation. Sorafenib is a multi-kinase inhibitor that blocks the Fms-Related Tyrosine Kinase 3 receptor ( FLT3 ) in AML patients with a FLT3 -internal tandem duplication ( FLT3 -ITD), leading to a reduction of proliferation. Here we report four de novo diagnosed or relapsed pediatric FLT3 -ITD–positive AML patients with hyperleukocytosis, which were treated with sorafenib in combination with cytoreductive chemotherapy prior to the start of the induction phase. We observed a fast reduction of white blood cells in peripheral blood and bone marrow. This resulted in a rapid clinical stabilization of the patients. Adverse side effects—such as dermatologic toxicity, elevation of transaminases and hypertension—occurred but were mild and inductive chemotherapy could be started in parallel or subsequently. This implies sorafenib as a safe and effective treatment option in combination with chemotherapy during cytoreductive prephase for children with this life-threatening condition.
Article
High serum lactate dehydrogenase (LDH) levels are typically associated with a poor prognosis in many cancer types. Even the most effective drugs, which have radically improved outcomes in patients with melanoma over the past decade, provide only marginal benefit to those with high serum LDH levels. When viewed separately from the oncological, biochemical, biological and immunological perspectives, serum LDH is often interpreted in very different ways. Oncologists usually see high serum LDH only as a robust biomarker of a poor prognosis, and biochemists are aware of the complexity of the various LDH isoforms and of their key roles in cancer metabolism, whereas LDH is typically considered to be oncogenic and/or immunosuppressive by cancer biologists and immunologists. Integrating these various viewpoints shows that the regulation of the five LDH isoforms, and their enzymatic and non-enzymatic functions is closely related to key oncological processes. In this Review, we highlight that serum LDH is far more than a simple indicator of tumour burden; it is a complex biomarker associated with the activation of several oncogenic signalling pathways as well as with the metabolic activity, invasiveness and immunogenicity of many tumours, and constitutes an extremely attractive target for cancer therapy.
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Acute kidney injury (AKI) is common and associated with high morbidity and mortality. It is expensive to manage and has a major impact on healthcare costs. Yet, despite several guidelines and new initiatives to prevent and mitigate AKI, their implementation into clinical care remains suboptimal.Given the global and individual impact of AKI, we, as nephrologists, have a responsibility in the development of systematic and robust mechanisms to identify patients at risk across all specialities and mitigate the risk of AKI by targeted prophylaxis, prevention and timely management of established AKI.This chapter covers risk stratification, generic and specific prophylaxis, generic and specific treatment of established AKI and specific management of AKI in conditions that benefit from unique treatments.KeywordsAKI preventionProphylaxisAKI managementAminoglycosidesTumour lysis syndromeContrast nephropathySnakebiteRenal replacement therapy
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A 48-year-old gentleman who had recently commenced chemotherapy for diffuse B-cell lymphoma was admitted to hospital with nausea and generalised weakness. He developed abdominal pain and oliguric acute kidney injury with multiple electrolyte derangements and was transferred to the intensive care unit (ICU). His condition deteriorated, requiring endotracheal intubation and renal replacement therapy (RRT). Tumour lysis syndrome (TLS) is a common and life-threatening complication of chemotherapy and represents an oncological emergency. TLS affects multiple organ systems and is best managed in the ICU with closer monitoring of fluid balance, serum electrolytes, cardiorespiratory and renal function. TLS patients may go on to require mechanical ventilation and RRT. TLS patients require input from a large multidisciplinary team of clinicians and allied health professionals.
Chapter
The rate of cancer patients will continue to increase in the coming decades. Additionally, new treatments will continue to emerge. The increased survival rates and the anti-tumour medications used will without doubt contribute to an increased rate of patients with oncological emergencies. Patients with oncologic emergencies will foremost seek care at an emergency department, but physicians at other clinics should also be familiar with the initial management of these patients. The initial management of any critically ill and instable patient, including those presenting with an oncologic emergency, should be based on the O-ABCDE approach and aimed at countering established or potentially life-threatening conditions. Oncologic emergencies can be divided into several different categories. This chapter focuses on five different oncologic emergency categories: metabolic, haematological, cardiovascular, neurologic, as well as treatment related. While all critically ill patients with an oncologic emergency must be attended to based on the O-ABCDE approach; it is of vital importance for the treating physician to also treat the patients symptomatically and at the same time rule in or rule out other differential diagnosis.
Article
Background: Effective treatments for hematologic malignancies include therapies that target tyrosine kinase (TK) signaling pathways. Tumor lysis syndrome (TLS) is an oncologic emergency that can occur due to rapid turnover following the initiation of treatments for hematologic malignancy. The incidence of TLS is under-reported and it is unclear as to whether TK inhibitors (TKIs) are associated with TLS. Objective: To conduct a systematic review to determine the incidence of TLS with TKIs. Methods: A search was performed using EMBASE, MEDLINE, and Web of Science electronic databases, as well as a manual search of American Society of Hematology and American Society of Clinical Oncology abstract databases. Keywords included: (1) "tumor lysis syndrome", (2) "tyrosine kinase inhibitors", (3) "lymphoma", (4) "leukemia". Results: We identified a total of 57 publications that commented on the incidence of TLS with TKIs for hematologic malignancy. 39 of those publications reported TLS as an adverse event. TLS was described as an adverse event among essentially all the sub-classes of TKIs that are used to manage hematologic malignancies. Conclusion: The overall number of articles commenting on TLS as an adverse event is sparse and there needs to be more transparency regarding the incidence of TLS when employing newer targeted therapies. Physicians should consider the risk of TLS on an individual basis and the added risk of TLS when using TKIs to treat hematologic malignancy. This article is protected by copyright. All rights reserved.
Article
Transient abnormal myelopoiesis (TAM) is a unique disease occurring in Down syndrome (DS) infants from which most patients have spontaneous remission. This study aimed to evaluate the incidence and outcomes of TAM in a tertiary center in Thailand. We reviewed the records of 997 DS patients diagnosed between June 1993 and October 2019. From the 997 DS patients, 32 had been diagnosed with TAM. The incidence of TAM was 3.2% and an overall survival rate of 87.5%. A total of 2/28 who survived (7.1%) subsequently developed AML-DS at the ages of 2.1 and 4.5 years, respectively. The risk factors related with death included maternal multiparity, sepsis, skin bleeding, subcutaneous nodules, high WBC count, low hemoglobin, and elevated AST level.Abbreviations.
Article
Background The pathophysiology of AKI during tumor lysis syndrome (TLS) is not well understood due to the paucity of data. We aimed to decipher crystal-dependent and crystal-independent mechanisms of TLS-induced AKI. Methods Crystalluria, plasma cytokine levels, and extracellular histones levels were measured in two cohorts of patients with TLS. We developed a model of TLS in syngeneic mice with acute myeloid leukemia, and analyzed ultrastructural changes in kidneys and endothelial permeability using intravital confocal microscopy. In parallel, we studied the endothelial toxicity of extracellular histones in vitro. Results The study provides the first evidence that previously described crystal-dependent mechanisms are insufficient to explain TLS-induced AKI. Extracellular histones that are released in huge amounts during TLS caused profound endothelial alterations in the mouse model. The mechanisms of histone-mediated damage implicates endothelial cell activation mediated by Toll-like receptor 4. Heparin inhibits extracellular histones and mitigates endothelial dysfunction during TLS. Conclusion This study sheds new light on the pathophysiology of TLS-induced AKI and suggests that extracellular histones may constitute a novel target for therapeutic intervention in TLS when endothelial dysfunction occurs.
Chapter
This chapter reviews some of the less frequent causes of acute kidney injury (AKI): acute interstitial nephritis (AIN), atheroembolic renal disease, cast nephropathy, crystalline nephropathies, and renovascular syndromes. AIN is a hypersensitivity reaction that causes AKI by immune‐mediated tubular injury localized to the kidney interstitium with sparing of the glomeruli. The classical signs and symptoms of drug‐induced AIN include a triad of rash, fever, and eosinophilia, which suggests an allergic type reaction. Urinalysis in patients suspected to have AIN often show hematuria and sterile pyuria. Kidney imaging may reveal normal to large kidneys with increased echogenicity, although this is a nonspecific finding. Given the polymorphic nature of the disease and the multiple potential causative agents, AIN does not have a uniform course or response to treatment. Atheroembolic renal disease causes progressive AKI and acute kidney disease resulting from inflammation in the renal microvasculature caused by cholesterol crystals and lipid debris.
Article
Objectives To analyze clinical features associated to mortality in oncological patients with unplanned admission to the Intensive Care Unit (ICU), and to determine whether such risk factors differ between patients with solid tumors and those with hematological malignancies. Design An observational study was carried out. Setting A total of 123 Intensive Care Units across Spain. Patients All cancer patients with unscheduled admission due to acute illness related to the background oncological disease. Interventions None. Main variables Demographic parameters, severity scores and clinical condition were assessed, and mortality was analyzed. Multivariate binary logistic regression analysis was performed. Results A total of 482 patients were included: solid cancer (n = 311) and hematological malignancy (n = 171). Multivariate regression analysis showed the factors independently associated to ICU mortality to be the APACHE II score (OR 1.102; 95% CI 1.064–1.143), medical admission (OR 3.587; 95% CI 1.327–9.701), lung cancer (OR 2.98; 95% CI 1.48–5.99) and mechanical ventilation after the first 24 h of ICU stay (OR 2.27; 95% CI 1.09–4.73), whereas no need for mechanical ventilation was identified as a protective factor (OR 0.15; 95% CI 0.09–0.28). In solid cancer patients, the APACHE II score, medical admission, antibiotics in the previous 48 h and lung cancer were identified as independent mortality indicators, while no need for mechanical ventilation was identified as a protective factor. In the multivariate analysis, the APACHE II score and mechanical ventilation after 24 h of ICU stay were independently associated to mortality in hematological cancer patients, while no need for mechanical ventilation was identified as a protective factor. Neutropenia was not identified as an independent mortality predictor in either the total cohort or in the two subgroups. Conclusions The risk factors associated to mortality did not differ significantly between patients with solid cancers and those with hematological malignancies. Delayed intubation in patients requiring mechanical ventilation might be associated to ICU mortality.
Article
Patients with hematological malignancies, both treated and untreated, or solid tumors undergoing treatment are at risk of life-threatening complications, which may present in the emergency department (ED). Such emergencies are diverse in etiology and often require prompt treatment. Traditional complications, such as febrile neutropenia, have had recent guideline updates, which incorporate new evidence and a new validated risk stratification tool. In addition, newer approaches to treatment, such as chimeric antigen receptor (CAR) T-cell therapy, are becoming more widely available and have unique associated toxicities. This review discusses the management of the following hematological and oncological emergencies likely to be encountered in the ED: febrile neutropenia, CAR T-cell toxicities, differentiation syndrome, tumor lysis syndrome, hypercalcemia of malignancy, and hyponatremia.
Article
Patients with advanced cancer generate 4 million visits annually to emergency departments (EDs) and other dedicated, high‐acuity oncology urgent care centers. Because of both the increasing complexity of systemic treatments overall and the higher rates of active therapy in the geriatric population, many patients experiencing acute decompensations are frail and acutely ill. This article comprehensively reviews the spectrum of oncologic emergencies and urgencies typically encountered in acute care settings. Presentation, underlying etiology, and up‐to‐date clinical pathways are discussed. Criteria for either a safe discharge to home or a transition of care to the inpatient oncology hospitalist team are emphasized. This review extends beyond familiar conditions such as febrile neutropenia, hypercalcemia, tumor lysis syndrome, malignant spinal cord compression, mechanical bowel obstruction, and breakthrough pain crises to include a broader spectrum of topics encompassing the syndrome of inappropriate antidiuretic hormone secretion, venous thromboembolism and malignant effusions, as well as chemotherapy‐induced mucositis, cardiomyopathy, nausea, vomiting, and diarrhea. Emergent and urgent complications associated with targeted therapeutics, including small molecules, naked and drug‐conjugated monoclonal antibodies, as well as immune checkpoint inhibitors and chimeric antigen receptor T‐cells, are summarized. Finally, strategies for facilitating same‐day direct admission to hospice from the ED are discussed. This article not only can serve as a point‐of‐care reference for the ED physician but also can assist outpatient oncologists as well as inpatient hospitalists in coordinating care around the ED visit.
Article
In combination with immune checkpoint inhibitors, photodynamic therapy can induce robust immune responses capable of preventing local tumor recurrence and delaying the growth of distant, untreated disease (ie. the abscopal effect). Previously, we found that repeated photodynamic therapy (R-PDT) using porphyrin lipoprotein (PLP) as a photosensitizer, without the addition of an immune checkpoint inhibitor, can induce the abscopal effect. To understand why PLP mediated R-PDT alone can induce the abscopal effect, and how the addition of an immune checkpoint inhibitor can further strengthen the abscopal effect, we investigated the broader immune mechanisms facilitated by R-PDT and combination R-PDT + anti-PD-1 monoclonal antibody (αPD-1) in a highly aggressive, subcutaneous AE17-OVA mesothelioma dual tumor-bearing C57BL/6 mice. We found a 46.64-fold and 61.33-fold increase in interleukin-6 (IL-6) after R-PDT and combination R-PDT + αPD-1 relative to PBS respectively, suggesting broad innate immune activation. There was a greater propensity for antigen presentation in the spleen and distal, non-irradiated tumor draining lymph nodes, as dendritic cells and macrophages had increased expression of MHC class II, CD80, and CD86, after R-PDT and combination R-PDT + αPD-1. Concurrently, there was a shift in the proportions of CD4⁺ T cell subsets in the spleen, and an increase in the frequency of CD8⁺ T cells in the distal, non-irradiated tumor draining lymph nodes. While R-PDT had an acceptable safety profile, combination R-PDT + αPD-1 induced 1.26-fold higher serum potassium and 1.33-fold phosphorus, suggestive of mild laboratory tumor lysis syndrome. Histology revealed an absence of gross inflammation in critical organs after R-PDT and combination R-PDT + αPD-1 relative to PBS-treated mice. Taken together, our findings shed light on how the abscopal effect can be induced by PDT and strengthened by combination R-PDT + αPD-1, and suggests minimal toxicities after R-PDT.
Chapter
Tumor lysis syndrome (TLS) is one of the most common oncologic emergencies. It is caused by the inability of the body’s homeostatic mechanisms to handle the massive release of intracellular contents (potassium, phosphate and nucleic acids) from disintegrating tumor cells into the blood stream. Catabolism of nucleic acids to uric acid leads to urate deposition in renal tubules, resulting in acute kidney injury (AKI) and its associated complications. These metabolic disturbances can lead to clinical toxic effects including cardiac arrhythmia, seizures, multi organ dysfunction and death. This chapter outlines the epidemiology, risk factors, clinical features and principles of preventing and managing TLS.
Chapter
Oncological emergencies in children have comparatively favorable outcome with prompt recognition and institution of treatment. The common situations in children with cancer requiring critical care are either disease related emergencies or therapy related complications. Common oncological emergencies in children include hyperleukocytosis, tumor lysis syndrome, superior vena cava syndrome/superior mediastinal syndrome and malignant spinal cord compression. Hyperleukocytosis affects lungs and central nervous system due to increase in blood viscosity while tumor lysis syndrome causes metabolic derangements due to rapid turnover and cell lysis with subsequent renal failure or cardiac-arrythmias. Management of hyperleukocytosis and tumor lysis syndrome is directed towards aggressive hydration, monitoring and management of electrolyte disturbances, management of uric acid and blood product support. Superior vena cava syndrome in children is often due to a malignant mediastinal mass. It is managed with prompt initiation of steroids even on empiric basis. Use of sedatives is to be strictly avoided and diagnosis is to be established quickly and non-invasively. Recognition of malignant spinal cord compression in younger children is often delayed. Rapid initiation of steroid is essential in suspected cord compression to ensure neurological recovery. Neurosurgical intervention is necessary especially for intradural lesions whereas multi-modality therapy can be considered for extra-dural lesions.
Article
Onco-nephrology focuses on the care of patients with cancer and kidney disease. Patients with acute kidney injury, tumor lysis syndrome, and malignancy-associated hypercalcemia are frequently treated in a critical care setting. Oncological emergencies can have a high mortality rate when not promptly recognized and appropriately treated. The critical care nurse should be knowledgeable regarding the risk factors, clinical manifestations, and laboratory abnormalities of common renal manifestations of malignancy and oncological emergencies to optimize care and improve patient outcomes.
Article
The incidence of hematologic malignancies is on the rise worldwide. Kidney disease is ubiquitous in patients with hematologic malignancies, encompassing a wide spectrum of disorders involving each kidney compartment, including the vasculature, tubules, interstitium, and glomerulus, and there is significant overlap of kidney involvement with each hematologic malignancy. Vascular disorders include both microvascular and macrovascular damage, via thrombotic microangiopathy, hyperleukocytosis, hyperviscosity, and cryoglobulinemia. The tubulointerstitial compartment may be affected by prerenal azotemia and acute tubular injury, but malignant infiltration, tumor lysis syndrome, extramedullary hematopoiesis, cast nephropathy, granulomatous interstitial nephritis, and lysozymuria should be considered in certain populations. Obstructive uropathy may occur due to nephrolithiasis or retroperitoneal fibrosis. Glomerular disorders, including membranoproliferative, membranous, minimal change, and focal segmental glomerulosclerosis, can rarely occur. By understanding how each compartment may be affected, care can best be optimized for these patients. In this review, we summarize the widely varied etiologies of kidney diseases stratified by kidney compartment and hematologic malignancy, focusing on demographics, pathology, pathophysiology, mechanism, and outcomes. We conclude with common electrolyte abnormalities associated with hematologic malignancies.
Article
Sodium and potassium disorders are pervasive in patients with cancer. The causes of these abnormalities are wide-ranging, are often primary or second-order consequences of the underlying cancer, and have prognostic implications. The approach to hyponatremia should focus on cancer-related etiologies, such as syndrome of inappropriate antidiuretic hormone, to the exclusion of other causes. Hypernatremia in non-iatrogenic forms is generally due to water loss rather than excessive sodium intake. Debilitated or dependent patients with cancer are particularly vulnerable to hypernatremia. Hypokalemia can occur in patients with cancer due to gastrointestinal disturbances, resulting from decreased intake or increased losses. Renal losses can occur as a result of excessive mineralocorticoid secretion or therapy-related nephrotoxicity. The approach to hyperkalemia should be informed by historical and laboratory clues, and pseudohyperkalemia is particularly common in patients with hematological cancers. Hyperkalemia can be seen in primary or metastatic disease that interrupts the adrenal axis. It can also develop as a consequence of immunotherapy, which can cause adrenalitis or hypophysitis. Tumor lysis syndrome (TLS) is defined by the development of hyperkalemia and is a medical emergency. Awareness of the electrolyte abnormalities that can befall patients with cancer is vital for its prompt recognition and management.
Article
We report the case of a 76-year-old female with diffuse large B cell lymphoma who developed tumor lysis syndrome (TLS) and subsequent acute kidney injury (AKI) due to massive hyperphosphatemia during the prophylactic use of rasburicase. Our case showed no hyperphosphatemia before chemotherapy but had elevated uric acid and creatinine levels and unilateral hydronephrosis due to paraaortic lymphadenopathy. TLS risk was classified as high risk because of bulky mass, LDH elevation, and renal disturbance. With rasburicase use, uric acid was completely controlled but massive hyperphosphatemia and, subsequently, AKI developed. Immediate kidney replacement therapy led to improvement of hyperphosphatemia and AKI. In the rasburicase era, hyperphosphatemia has been a key target for preventing and treating TLS. Renal replacement therapy is the only effective option for lowering hyperphosphatemia and treating AKI.
Article
Clinical Practice Points •Lurbinectedin is an intravenous alkylating drug approved by the U.S. Food and Drug Administration (FDA) under accelerated approval on June 15, 2020, for the treatment of adult patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy. •During routine pharmacovigilance monitoring, the FDA identified safety signals for new adverse events (AE)s with lurbinectedin: extravasation, rhabdomyolysis, and tumor lysis syndrome (TLS). •Further evaluation of these AEs led to their addition to the lurbinectedin U.S. prescribing information (USPI). •Clinicians should be aware of these safety issues and implement mitigation strategies to minimize the potential risk of these AEs.
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Cancer and its treatment can lead to oncologic emergencies. This article discusses the approach to acute emergency problems in cancer patients. A list of emergent problems has been selected for focused discussion. Sudden cardiopulmonary arrest is discussed along with considerations in resuscitation of cancer patients. Arrhythmia, superior vena caval syndrome, pericardial tamponade, and acute hemorrhage are important cardiovascular emergencies. Tumor lysis syndrome can be rapidly fatal, and early recognition and treatment are very important in preventing disastrous outcomes. Pulmonary problems include airway obstruction, pleural effusion, hemoptysis, pneumothorax, and pulmonary embolism. Neurological emergencies include spinal cord compression, brain herniation, and status epilepticus. Neutropenic fever is perhaps the most frequently discussed important topic in oncologic emergency. Other important issues such as immune‐related adverse effects of cancer immunotherapy, anaphylaxis, and cytokine release syndrome are also discussed. Oncologists and emergency physicians must be aware of these potentially serious acute complications of cancer patients in order to initiate appropriate treatments in a timely manner.
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El síndrome de lisis tumoral es una emergencia oncológica causada por destrucción de la célula tumoral, de forma espontánea o secundaria a la quimioterapia, que libera el contenido intracelular al torrente sanguíneo y produce hiperuricemia, hiperfosfatemia, hipocalcemia e hiperkalemia. Para su diagnóstico se debe tener un alto grado de sospecha y aplicar los criterios de Cairo-Bishop y Howard. Se presenta caso de un paciente de 35 años de edad, con antecedente de seminoma no gonadal retroperitoneal estadio IIC. Ingresó remitido desde consulta externa por intolerancia a la vía oral, deshidratación y parestesias a nivel de miembros inferiores, hiperkalemia, hipocalcemia e hiperuricemia, además de elevación de creatinina sérica. Se consideró diagnóstico de síndrome de lisis tumoral, y se trató con fluidoterapia agresiva a dosis de 2-3 L/m2/día de solución salina normal. También se indicó rasburicasa y se corrigieron las alteraciones electrolíticas. Una vez se tuvo la función renal por encima de 60 mL/min/1,73 m3, se inició tratamiento citorreductor con cisplatino, etopósido y bleomicina. Se concluye la importancia de tener sospecha diagnóstica en pacientes oncológicos, incluso en neoplasias de bajo riesgo. Asimismo, se resalta que, en las revisiones de la literatura, su incidencia está sujeta a reportes de caso.
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Electrolyte disturbances in leukemia can be the result of the disease process or drug therapy. One group of electrolyte abnormalities is related to the stage of the leukemic process. Included in this group are newly diagnosed patients who may show elevated serum potassium, phosphorus, and magnesium--a result of their release from malignant cells after cytotoxic therapy or their accumulation due to urate nephropathy. Patients in remission usually have normal serum electrolyte concentrations, but acute leukemia patients during relapse may have hypokalemia, hypophosphatemia, and hypomagnesemia. This imbalance may be related to cellular uptake of these electrolytes in the presence of inadequate dietary intake. Other factors contributing to electrolyte derangements, and related to the leukemic process, include hyponatremia and hypochloremia secondary to the SIADH, hypokalemia in acute monocytic or acute myelomonocytic leukemia due to lysozyme-induced tubular damage, hypercalcemia possibly secondary to leukemic infiltration of bone or parathyroid glands (with PTH release), or production of a PTH-like substance by leukemic cells. Nonspecific factors related to the disease process which may aggravate the electrolyte imbalance include gastrointestinal loss through nausea, vomiting, and malnutrition. The drug-related electrolyte abnormalities include cyclophosphamide- and vincristine-induced SIADH; decreased serum sodium, chloride, potassium, and calcium concentrations as a result of polymyxin B nephrotoxicity; hypokalemia and hypomagnesemia secondary to amphotericin B; hypocalcemia, hypophosphatemia, and hyperphosphaturia due to L-asparaginase-induced hypoparathyroidism; hypokalemia due to a nonreabsorbable anion effect of antibiotics in the distal tubule or changes in membrane ionic transport of all cells by large doses of antibiotics. Electrolyte disturbance in leukemia thus have a multifactorial pathogenesis which can best be delineated according to the stage of the leukemic process and the drugs being used. Recognition of the cause or causes in a particular patient is essential for an effective approach to management. This review emphasizes the need for routine measurement of serum electrolytes during all phases of the leukemic process.
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Amino acid sequencing of peptides obtained after proteolytic hydrolysis of Aspergillus flavus urate oxidase (uricase) permitted the design of oligodeoxynucleotide probes that were used to obtain 1.2- and 5-kilobase pair DNA fragments from A. flavus cDNA and genomic libraries, respectively. The cDNA fragment contained the entire coding region for uricase, and comparison with the genomic fragment revealed the presence of two short introns in the coding region of the gene. A. flavus uricase has around 40% overall identity with uricases from higher organisms but with many conserved amino acids. Hitherto highly conserved consensus patterns found in other uricases were found to be modified in the A. flavus enzyme, notably the sequence Val-Leu-Lys-Thr-Thr-Gln-Ser near position 150, which in the filamentous fungus is uniquely modified to Val-Leu-Lys-Ser-Thr-Asn-Ser. Silent mutations were introduced by cassette mutagenesis near the 5'-extremity of the coding sequence in order to conform with Escherichia coli codon usage, and the uricase was expressed in the E. coli cytoplasm in a completely soluble, biologically active form.
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We report a 4-year-old boy who developed tumor lysis syndrome complicated by severe hyperphosphatemia and acute renal failure, following chemotherapy for T-cell acute lymphoblastic leukemia. Despite successful treatment of hyperphosphatemia with hemodialysis, there was an immediate rebound in the high serum phosphorus level. The patient underwent a second treatment with hemodialysis which was then followed by continuous veno-venous hemofiltration (CVVH). CVVH maintained his serum phosphorus at a stable level until his renal function improved. CVVH can be used in conjunction with hemodialysis to successfully treat the hyperphosphatemia associated with tumor lysis syndrome.
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We report on a 14-year-old boy with acute lymphoblastic leukemia (lymphoma-leukemia) who had two episodes of acute tumor lysis syndrome during induction of remission with oral prednisolone alone and oral prednisolone, intravenous vincristine, and doxorubicin, respectively. Subsequently he had severe hyperphosphatemia (29.3 and 14.1 mg/dl; 9.46 and 4.55 mmol/L), hypocalcemia, hyperuricemia, hyperkalemia, and azotemia. Multiple stones and tumor cells infiltration were demonstrated in both kidney. He responded favorably to hemodialysis.
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Standard prophylaxis and treatment of malignancy-associated hyperuricemia in the USA has been allopurinol with vigorous hydration, urinary alkalinization and osmotic diuresis. Urate oxidase, the enzyme that converts uric acid to allantoin (a readily excreted metabolite that has 5- to 10-fold higher solubility than uric acid), is an alternative therapy; however, few published findings support this practice. Between February 1994 and December 1996, we administered non-recombinant urate oxidase (Uricozyme) to 126 children with newly diagnosed non-B cell acute lymphoblastic leukemia (ALL) during the first 5 days of chemotherapy with methotrexate, 6-mercaptopurine or both. Their blood levels of uric acid and other indicators of tumor lysis were measured at diagnosis and during treatment and then compared with findings in 129 similarly treated historical controls who had received allopurinol to control hyperuricemia. Clinical responses to urate oxidase were also determined in eight patients with newly diagnosed B cell ALL or advanced-stage non-Hodgkin lymphoma. Patients treated with urate oxidase had rapid and significantly greater decreases in their blood uric acid levels than did the historical controls (median maximal level during treatment, 2.3 vs 3.9 mg/dl, P < 0.001). They also had lower creatinine (0.6 vs 0.7 mg/dl, P = 0.01) and blood urea nitrogen (11 vs 24 mg/dl, P < 0.001) levels. Similar findings were made in the eight cases of B cell ALL or non-Hodgkin lymphoma. None of the patients required dialysis for acute renal failure. Six (4.5%) of the 134 children given urate oxidase had allergic reactions, manifested primarily by urticaria, bronchospasm and hypoxemia. Thus, non-recombinant urate oxidase is a more effective uricolytic agent than allopurinol but is associated with acute hypersensitivity reactions, even in patients without a history of allergy.
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Standard therapy in the United States for malignancy-associated hyperuricemia consists of hydration, alkalinization, and allopurinol. Urate oxidase catalyzes the enzymatic oxidation of uric acid to a 5 times increased urine soluble product, allantoin. Rasburicase is a new recombinant form of urate oxidase available for clinical evaluation. This multicenter randomized trial compared allopurinol to rasburicase in pediatric patients with leukemia or lymphoma at high risk for tumor lysis. Patients received the assigned uric acid-lowering agent for 5 to 7 days during induction chemotherapy. The primary efficacy end point was to compare the area under the serial plasma uric acid concentration curves during the first 96 hours of therapy (AUC(0-96)). Fifty-two patients were randomized at 6 sites. In an intent-to-treat analysis, the mean uric acid AUC(0-96) was 128 +/- 70 mg/dL.hour for the rasburicase group and 329 +/- 129 mg/dL.hour for the allopurinol group (P <.0001). The rasburicase versus allopurinol group experienced a 2.6-fold (95% CI: 2.0-3.4) less exposure to uric acid. Four hours after the first dose, patients randomized to rasburicase compared to allopurinol achieved an 86% versus 12% reduction (P <.0001) of initial plasma uric acid levels. No antirasburicase antibodies were detected at day 14. This randomized study demonstrated more rapid control and lower levels of plasma uric acid in patients at high risk for tumor lysis who received rasburicase compared to allopurinol. For pediatric patients with advanced stage lymphoma or high tumor burden leukemia, rasburicase is a safe and effective alternative to allopurinol during initial chemotherapy.
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To evaluate the frequency of metabolic complications and dialysis due to tumor lysis syndrome in patients with B-cell advanced-stage non-Hodgkin's lymphoma (NHL) and L3 leukemia at initiation of chemotherapy including the use of urate-oxidase. Retrospective review of the clinical records of 410 patients with stage III and IV B-cell NHL and L3 leukemia treated in France and prospectively registered in the LMB89 protocol. During the first week of chemotherapy, only 34 of 410 patients recorded metabolic problems that included hypocalcemia (< 70 mg/dl) in 24 patients, hyperphosphatemia (> 6.5 mg/dl) in 28 and elevation of creatinine > or = 2 SD in 16. Six patients underwent dialysis for life-threatening problems and a seventh as a preventive measure. In the other 27 cases, metabolic problems were successfully resolved using urate-oxidase in combination with alkaline hyperhydration. Among the 410 patients, one case of hemolysis was reported and there was no severe allergic reaction to urate-oxidase. Only 1.7% of patients in our study receiving urate-oxidase during their induction chemotherapy needed renal dialysis. Urate-oxidase was well tolerated, and used as prophylaxis and/or treatment of hyperuricemia and tumor lysis syndrome consistently gave a lower rate of renal and metabolic complications than in other series of similar patients.
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Electrolyte disturbances in leukemia can be the result of the disease process or drug therapy. One group of electrolyte abnormalities is related to the stage of the leukemic process. Included in this group are newly diagnosed patients who may show elevated serum potassium, phosphorus, and magnesium--a result of their release from malignant cells after cytotoxic therapy or their accumulation due to urate nephropathy. Patients in remission usually have normal serum electrolyte concentrations, but acute leukemia patients during relapse may have hypokalemia, hypophosphatemia, and hypomagnesemia. This imbalance may be related to cellular uptake of these electrolytes in the presence of inadequate dietary intake. Other factors contributing to electrolyte derangements, and related to the leukemic process, include hyponatremia and hypochloremia secondary to the SIADH, hypokalemia in acute monocytic or acute myelomonocytic leukemia due to lysozyme-induced tubular damage, hypercalcemia possibly secondary to leukemic infiltration of bone or parathyroid glands (with PTH release), or production of a PTH-like substance by leukemic cells. Nonspecific factors related to the disease process which may aggravate the electrolyte imbalance include gastrointestinal loss through nausea, vomiting, and malnutrition. The drug-related electrolyte abnormalities include cyclophosphamide- and vincristine-induced SIADH; decreased serum sodium, chloride, potassium, and calcium concentrations as a result of polymyxin B nephrotoxicity; hypokalemia and hypomagnesemia secondary to amphotericin B; hypocalcemia, hypophosphatemia, and hyperphosphaturia due to L-asparaginase-induced hypoparathyroidism; hypokalemia due to a nonreabsorbable anion effect of antibiotics in the distal tubule or changes in membrane ionic transport of all cells by large doses of antibiotics. Electrolyte disturbance in leukemia thus have a multifactorial pathogenesis which can best be delineated according to the stage of the leukemic process and the drugs being used. Recognition of the cause or causes in a particular patient is essential for an effective approach to management. This review emphasizes the need for routine measurement of serum electrolytes during all phases of the leukemic process.
Article
Purpose To evaluate the frequency of metabolic complications and dialysis due to tumor lysis syndrome in patients with B-cell advanced-stage non-Hodgkin’s lymphoma (NHL) and L3 leukemia at initiation of chemotherapy including the use of urate-oxidase. Patients and methods Retrospective review of the clinical records of 410 patients with stage III and IV B-cell NHL and L3 leukemia treated in France and prospectively registered in the LMB89 protocol. Results During the first week of chemotherapy, only 34 of 410 patients recorded metabolic problems that included hypocalcemia (<70 mg/dl) in 24 patients, hyperphosphatemia (>6.5 mg/dl) in 28 and elevation of creatinine ≥2 SD in 16. Six patients underwent dialysis for life-threatening problems and a seventh as a preventive measure. In the other 27 cases, metabolic problems were successfully resolved using urate-oxidase in combination with alkaline hyperhydration. Among the 410 patients, one case of hemolysis was reported and there was no severe allergic reaction to urate-oxidase. Conclusions Only 1.7% of patients in our study receiving urate-oxidase during their induction chemotherapy needed renal dialysis. Urate-oxidase was well tolerated, and used as prophylaxis and/or treatment of hyperuricemia and tumor lysis syndrome consistently gave a lower rate of renal and metabolic complications than in other series of similar patients.
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Allopurinol [4-hydroxypyrazolo(3,4-d)pyrimidine], a potent inhibitor of xanthine oxidase, was given orally to patients with leukemia and lymphoma in whom marked hyperuricemia was present or was to be expected as a result of cytolytic therapy. There was a decrease in serum uric acid in each patient, and a decrease in urine uric acid excretion in each of the ten patients in whom it was measured. This was accompanied by only a moderate increase in urinary oxypurines and no evidence of renal, hematologic, gastrointestinal, or hepatic toxicity.
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Tumor lysis syndrome refers to the metabolic disturbances (hyperuricemia, hyperphosphatemia, hyperkalemia, and hypocalcemia) associated with lymphoproliferative malignancies which occur secondary to cell lysis. In some patients, tumor lysis results in acute renal failure. The nature and severity of the metabolic alterations are variable and may be influenced by the timing and intensity of chemotherapy, the magnitude of cell lysis, and the general condition of the patients with respect to hydration and glomerular filtration rate. Not only do hyperuricemia and hyperphosphatemia result from tumor lysis syndrome, they also contribute to oliguric acute renal failure in patients with tumor lysis. The pathogenesis of tumor lysis syndrome and current therapeutic strategies are discussed.
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We measured serial urine levels of hypoxanthine, xanthine, and uric acid in 19 children with acute lymphocytic leukemia (ALL) receiving allopurinol therapy during tumor lysis: four of these children developed acute renal failure. The urinary excretion of uric acid rose moderately from 447±251 μg/dl glomerular filtrate before chemotherapy to 778±463 μg/dl glomerular filtrate during tumor lysis (P<0.05) whereas the urinary excretion of hypoxanthine (17.9±15 to 292±213 μg/dl glomerular filtrate) and xanthine (74±62 to 1091±1085 μg/dl glomerular filtrate) rose dramatically (P<0.001). The urinary excretion of uric acid, hypoxanthine, and xanthine per deciliter of filtrate was significantly higher (P<0.001) in those who developed acute renal failure than in those who did not, but the highest urine concentration of these purine metabolites did not differ in the two groups. In all 19 children, the highest urine concentration of uric acid and hypoxanthine during tumor lysis did not exceed the solubility limit of each in an alkaline urine specimen. In contrast, the peak urine concentration of xanthine exceeded its solubility limit in an alkaline urine specimen in 16 of 19 children. The urine sediment during the period of tumor lysis was examined by diffuse refiectance infrared spectroscopy; precipitated xanthine was found in sediment from eight of the 19 children, was significantly (P<0.001) associated with a urine xanthine level >350 mg/dl, and occurred with equal frequency in those who did or did not develop acute renal failure. We conclude that urinary excretion of hypoxanthine and xanthine increases dramatically whereas uric acid excretion rises moderately in children undergoing tumor lysis while receiving allopurinol, that acute renal faulire occurs in children with a higher purine load per decilliter of glomerular filtrate, but that factors other than tubular precipitation of purine metabolites are likely to be involved in the pathogenesis of renal failure during tumor lysis.
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The paper reviews methods of studying cell kinetics in man, cell population kinetics of human tumors and bone marrow, drug interactions and the cell cycle, and possible applications to chemotherapy. The conclusions drawn are: (1) Cell cycle time and S-phase duration for proliferating granulocyte precursors in human bone marrow are poorly defined but are probably shorter than median values for most human tumors, including leukemia. (2) Most drugs have greater toxicity for cycling cells and some variation in toxicity at different phases of the cell cycle. There is a special need for chemotherapy directed at slowly proliferating and hypoxic tumor cells. (3) Pretreatment indices of tumor cell kinetics are of little value in choosing drugs or in predicting response. (4) Experiments in animals have demonstrated that therapeutic index may depend on schedule. Knowledge of cell kinetics in animals rarely allows prediction of the optimal schedule and is unlikely to do so in man. Optimal schedules in mice are not directly relevant to man. (5) Measurement of tumor labeling index or DNA histogram by flow microfluorimetry to detect cell synchrony is of little benefit in scheduling if concurrent changes in bone marrow are ignored; these methods are invalid at short intervals after treatment because surviving clonogenic cells are indistinguishable from a larger number of drug-damaged cells prior to their lysis. (6) The major factor determining the outcome of chemotherapy is the availability of drugs with activity for the tumor and acceptable host toxicity. Claims that complex schedules using several drugs are effective because of synchrony or kinetic differences of tumor and normal tissue are at present unsubstantiated.
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COMPOUNDS that inhibit the enzyme, xanthine oxidase, are useful in the treatment of disorders of purine metabolism. They are of particular value in disorders resulting from the overproduction of uric acid. Xanthine oxidase is inhibited by both allopurinol (4-hydroxypyrazolo [3,4-d] pyrimidine), an analogue of hypoxanthine, and oxypurinol (4,6-dihydroxypyrazolo [3,4-d] pyrimidine), which is an analogue of xanthine. Xanthine oxidase catalyzes the conversion of hypoxanthine to xanthine to uric acid. It also catalyzes the conversion of allopurinol to oxypurinol. A major percentage of administered allopurinol is rapidly oxidized to oxypurinol.1 After the administration of a xanthine oxidase inhibitor such as allopurinol or . . .
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Nucleotide sequences of portions of second and fifth exons of urate oxidase encoding gene (UOX) of chimpanzee, gorilla, orangutan, rhesus monkey and squirrel monkey obtained following amplification by polymerase chain reaction have been compared with corresponding sequences of human, baboon and rat UOX. Two or more nonsense mutations are found in the coding regions of this UOX gene thus far analyzed in human, chimpanzee, gorilla and orangutan, but not in the baboon, rhesus monkey and squirrel monkey. Of these nonsense mutations, the stop codon at amino acid position 33 is constant in the human and the three great apes suggesting that this may be the original mutation responsible for the inactivation of the UOX gene during hominoid evolution.
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Patients experiencing acute tumor lysis syndrome require expert and immediate medical and nursing intervention. Attempts are made to minimize possible complications by early management of metabolic abnormalities. The patient who presents with renal failure before treatment may require dialysis before chemotherapy begins. The metabolic disturbances resulting from tumor lysis syndrome usually endure 5 to 7 days because of the "finite period of cytolysis." Proactive preventative therapy may minimize or avert the life-threatening complications of tumor lysis syndrome.
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The management of tumour lysis syndrome remains problematic despite the rigorous use of preventative measures. Continuous arteriovenous haemofiltration (CAVH) is well suited to its use in both the prevention and treatment of metabolic abnormalities and renal insufficiency associated with tumour lysis. We report the successful use of CAVH in the treatment of a patient with tumour lysis syndrome.
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As antineoplastic therapy improves, patients with cancer will have the potential for prolonged survival. Tumor products may produce metabolic complications, such as hypercalcemia, hyponatremia, and hypoglycemia, and these conditions must be promptly recognized so that treatment can be initiated before severe or life-threatening symptoms occur. Tumor-lysis syndrome is a metabolic complication that occurs most frequently when effective treatment for rapidly proliferating tumors is initiated. It is a syndrome that can be prevented or ameliorated with appropriate anticipatory treatment. Recognition of metabolic emergencies common to cancer patients will improve quality of life and improve survival, allowing patients to benefit from definitive cancer treatment.
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Four children with acute lymphoblastic leukemia received a controlled dietary intake of protein, calcium and phosphorus to study prospectively the changes in the serum and urinary calcium and phosphorus values, which occur during therapy of the disease. Two 12-hour urine collections were obtained daily for determinations of phosphorus, calcium, uric acid and creatinine. Serum creatinine, urea nitrogen, calcium, phosphorus and uric acid were measured midway through each collection. Hyperphosphatemia (values of 5.7 to 9.4 mg per 100 ml), hypocalcemia (values of 6.6 to 8.3 mg per 100 ml) and marked hyperphosphaturia were observed within 24 to 48 hours of the initiation of chemotherapy. The tubular reabsorption of phosphorus decreased to levels that were 20 to 70 per cent of pretreatment base-line values. Symptomatic hypocalcemia is most common in patients with exceptionally high peripheral lymphoblast counts and some degree of renal insufficiency. These events may be caused by the increased endogeno...
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This article has no abstract; the first 100 words appear below. ALLOPURINOL is an agent of proved value for the treatment of hyperuricemic and hyperuricosuric states.¹,² Both allopurinol and its principal metabolic product, oxypurinol, inhibit the enzyme xanthine oxidase that normally converts hypoxanthine to xanthine, and xanthine to uric acid.¹,² In hematopoietic cancer uric acid excretions may be increased two to four times.¹ Hyperuricemia and hyperuricosuria may become even more marked after therapy with anticancer agents or radiation. The rapid lysis of cells can lead to abrupt elevation of serum uric acid, hyperuricosuria, urinary-stone formation and urinary-tract obstruction. In these patients the prophylactic use of allopurinol is generally advised, the drug . . . *From the Department of Medicine, University of Alberta (address reprint requests to Dr. Band at the Division of Hematology and Clinical Oncology, Department of Medicine, University of Alberta, Edmonton, 61, Alberta, Canada). We are indebted to Miss Mina Ann Bossenberry for technical assistance and to Miss Geraldine D. Shantz for performing the xanthine-stone analysis.
Article
This article has no abstract; the first 100 words appear below. UROLITHIASIS and renal insufficiency, associated with hyperuricemia, are well known complications of certain neoplastic disorders, particularly leukemia and lymphoma.¹,² Irradiation or chemotherapy, by increasing elevated serum levels of uric acid, may precipitate acute uric acid nephropathy. This has been cited as the most frequent cause of acute renal failure in patients with leukemia,³ and occasionally may be the presenting manifestation of the disease.⁴ In the past, prevention and treatment of this complication were attempted by increasing the solubility of the increased uric acid load presented to the renal tubules with vigorous hydration, urinary alkalinization and osmotic diuresis. In desperate situations . . . *From the Section of Clinical Pharmacology and Chemotherapy, departments of Medicine and Pharmacology, Yale University School of Medicine. Supported by grants (CA-05944, T4 CA 5138 5 MO1-FR-00038 and CA 8341–01) from the United States Public Health Service. Source Information NEW HAVEN, CONNECTICUT †United States Public Health Service trainee in Clinical Pharmacology and Chemotherapy. ‡Associate professor of medicine and pharmacology, Yale University School of Medicine; Burroughs Wellcome Scholar in Clinical Pharmacology.
Article
The early metabolic events in 33 patients with non-Hodgkin lymphoma were analyzed in the present study. Twenty-three patients had Burkitt lymphoma, 3 had non-Burkitt undifferentiated lymphoma and 7 had lymphoblastic lymphoma. Eight patients developed azotemia prior to starting chemotherapy while five did so during the first treatment week. All the patients but two who developed azotemia had stage C or D disease. Serum LDH prior to chemotherapy correlated well with the stage of disease and predicted the serum levels of creatinine, uric acid and phosphorus in the post-treatment period. Surgical excision of the main tumor mass was associated with a low incidence of azotemia and other metabolic derangements. Hyperuricemia and occasionally obstruction were encountered as the causes of azotemia in the pre-treatment period. Hyperuricemia and/or hyperphosphatemia were presumed responsible for the development of azotemia in the post-chemotherapy period. Two patients were dialyzed for renal failure due to hyperuricemia and one for renal failure due to hyperphosphatemia which developed shortly after starting chemotherapy. The patterns of renal and metabolic disturbances observed during treatment of these patients were characterized by the following profiles: 1. Azotemia due to hyperuricemia prior to treatment. 2. Hyperuricemia without azotemia in the pre-treatment period with azotemia due to hyperphosphatemia in the post-treatment period. 3. Azotemia due to combined hyperphosphatemia and hyperuricemia developing gradually in post-treatment period. 4. Increased urine phosphorus excretion in both non-azotemic and azotemic patients.
Article
ONE OF THE COMPLICATIONS of the initial phase of acute leukemia therapy is uric acid-induced nephropathy caused by massive cell lysis. Prophylactic therapy has included the use of allopurinol, a xanthine-oxidase inhibitor, and of fluids, bicarbonate, and diuretics (acetazolamide).' Urate-oxidase, an enzyme which converts uric acid into allantoin, is claimed to be particularly useful in the prevention of this complication, but there are few published data regarding its use. We have studied the efficacy of urate-oxidase therapy for the prevention of uric acid induced nephropathy in the initial phase of antineoplastic treatment in a homogeneous group of pediatric patients with acute leukemia.
Article
The urinary excretion of hypoxanthine, xanthine, and uric acid was measured prior to and following chemotherapy in 11 patients with rapidly growing chemotherapy-sensitive lymphomas who were receiving concomitant allopurinol therapy. Mean maximal total dairy urinary excretions of these purines postchemotherapy were: uric acid, 807 mg/day; hypoxanthine, 343 mg/day; and xanthine, 638 mg/day. The mean maximal postchemotherapy urinary concentrations of uric acid, hypoxanthine, and xanthine were 288, 115, and 179 mg/liter, respectively. Mean total daily urinary excretion of uric acid, hypoxanthine, and xanthine rose 2.2-, 6.6-, and 6.9-fold, respectively, following initiation of antineoplastic therapy. Although standard doses of allopurinol did not prevent a postchemotherapy increase in the excretion of uric acid or hypoxanthine, the urinary concentrations of both compounds remained below their solubility in urine at pH 7 in all 11 patients studied. However, the urinary concentration of xanthine exceeded its solubility in urine at pH 7 in six of the 11 patients. In three of the six patients whose urinary concentration of xanthine concentration exceeded its solubility in urine, transient renal failure developed in association with the increased excretion of xanthine. These studies indicate that, despite the use of conventional doses of allopurinol, the urinary excretion of uric acid may still increase following massive tumor lysis, and urinary excretion of xanthine can increase to concentrations potentially causing xanthine nephropathy.
Article
Renal and metabolic complications of tumor lysis during 46 episodes of remission induction chemotherapy were reviewed in 37 patients with American Burkitt's lymphoma. Azotemia occurred in 14 patients, preceding chemotherapy in eight. All of these patients had abdominal tumors. Pretreatment azotemia was associated with elevated lactic dehydrogenase (LDH) and uric acid levels, and sometimes extrinsic ureteral obstruction by tumor. Two patients required dialysis for uric acid nephropathy before chemotherapy was initiated. Following chemotherapy, major complications of tumor lysis (hyperuricemia, hyperkalemia and hyperphosphatemia) were associated with very large tumors, high LDH levels and inadequate urinary output. In patients undergoing diuresis and receiving allopurinol, hyperkalemia or hyperuricemia developed infrequently unless concomitant renal failure ensued. Hyperphosphatemia, which occurred only after chemotherapy, developed in 10 of 32 (31 per cent) nonazotemic and in all azotemic patients. Hemodialysis was required in three post-treatment patients for control of azotemia, hyperuricemia, hyperphosphatemia and/or hyperkalemia. Because of the potential for renal failure caused by precipitation of phosphate, severe hyperphosphatemia is an additional criterion for dialysis in patients with acute tumor lysis syndrome.
Article
Renal and metabolic complications of tumor lysis syndrome (TLS) were recognized frequently in the 1960s and 1970s. Strategies were designed to prevent TLS. We conducted a retrospective chart review study to identify the current TLS risk in children with acute leukemia. Children were considered to have "laboratory tumor lysis syndrome" (LTLS) if two of the following metabolic changes occurred within 4 days of the start of chemotherapy: a 25% increase in serum phosphate, potassium, uric acid, or blood urea nitrogen levels, or a 25% decline in serum calcium concentration. Clinical TLS (CTLS) was defined as LTLS plus a serum potassium level higher than 6.0 mmol/L or acute renal failure. Twenty-one of 30 children developed LTLS; one developed CTLS. Absolute blast count, pretreatment white blood cell count, pretreatment lactic dehydrogenase, and sex or tumor DNA index did not correlate with the development of LTLS. LTLS is still frequent in children undergoing chemotherapy for acute leukemia; CTLS, however, is much less common.
Article
Tumor lysis syndrome (TLS) is a complication associated with electrolyte abnormalities that is observed in patients with acute leukemia who are receiving intense doses of chemotherapy. Forty-one patients with acute leukemia were treated with high-dose combination chemotherapy and were evaluated for TLS. A grading system developed for the evaluation of these patients was applied. Grade I tumor lysis was observed in 22 patients, grade II TLS in 2 patients and grade III in 1 patient. All patients were treated with intravenous fluids, mannitol, allopurinol and in some patients, aluminum-based antacids. Treatment for TLS prior to intensive chemotherapy reduced morbidity and mortality associated with high-dose chemotherapy for acute leukemias.
Article
To identify patients with lymphoma at risk for tumor lysis after chemotherapy. The case records of 102 patients receiving combination chemotherapy for non-Hodgkin's lymphoma (intermediate to high-grade histology) were reviewed. Patients were considered to have "laboratory tumor lysis" if two of the following metabolic changes occurred within 4 days of treatment: a 25% increase in the serum phosphate, potassium, uric acid, or urea nitrogen concentrations, or a 25% decline in the serum calcium concentration. "Clinical tumor lysis" was defined as laboratory tumor lysis plus one of the following: a serum potassium level greater than 6 mmol/L, a creatinine level greater than 221 mumol/L, or a calcium level less than 1.5 mmol/L, the development of a life-threatening arrhythmia, or sudden death. Laboratory tumor lysis occurred in 42% of patients and clinical tumor lysis in 6%. There was no statistical difference in the frequency of either tumor lysis syndrome among lymphoma subgroups. Clinical tumor lysis occurred more frequently in patients with pretreatment renal insufficiency (serum creatinine level greater than 132 mumol/L) than in patients with normal renal function (36% versus 2%; p = 0.01). The development of azotemia correlated with high pretreatment serum lactate dehydrogenase concentrations (p < 0.01; r2 = 0.11). Clinically significant tumor lysis is a rare occurrence in patients with lymphoma when they are receiving allopurinol. However, tumor lysis can occur in patients with all types of moderate to high-grade non-Hodgkin's lymphoma. Patients with a high serum lactate dehydrogenase level or renal insufficiency are at increased risk for metabolic complications after chemotherapy and should be closely monitored.
Article
The prognosis for the child with cancer has improved dramatically over the past decades. With this success comes the need for recognition and proper treatment of emergencies. Respiratory or circulatory failure may arise from compression of the SVC or airway. Epidural spinal cord compression by tumor may lead to irreversible paraplegia or urinary incontinence if intervention is not rapid. Raised intracranial pressure may be a life-threatening presentation of a brain tumor. Bone marrow failure, with anemia and thrombocytopenia, is associated with malignant infiltration of the marrow. Hyperleukocytosis carries a high risk of thrombotic events if not treated promptly. Coagulation abnormalities are seen in many childhood cancers at the time of diagnosis. Life-threatening metabolic abnormalities are observed at presentation in children with leukemia and lymphoma. Hypercalcemia, although rare, may be a difficult situation to correct. Immediate attention to these emergencies and appropriate treatment may save the life of a child with cancer or make his or her subsequent course just a little smoother.
Article
To tabulate data obtained over a 21-year period to determine the efficacy and safety of an intravenous (IV) allopurinol preparation. IV allopurinol was provided on a compassionate plea basis to patients of any age in whom xanthine oxidase inhibitor therapy was indicated as an adjunct to chemotherapy and for whom oral intake was restricted. Three hundred twenty-seven investigators at multiple hospitals in the United States treated 1,172 patients with IV allopurinol. The vast majority of these patients had a malignancy and were in danger of developing tumor lysis syndrome (TLS) and subsequent acute uric acid nephropathy (AUAN) and were unable to take oral allopurinol. Data referable to the time period of IV allopurinol administration were collected, collated, and analyzed retrospectively. There was no randomization. In patients initiating treatment for an elevated serum uric acid (SUA), the SUA normalized or improved in 87% of adult patients and normalized or improved in 95% of pediatric patients. IV allopurinol, administered prophylactically to patients at high risk of developing hyperuricemia and TLS, prevented an increase in SUA levels in 93% of adults and 92% of children. Toxicities caused by IV allopurinol were minimal and consisted of 10 instances of mild to moderate skin or allergic reactions. IV allopurinol is as efficacious and safe as oral allopurinol and will be of significant benefit to patients at risk of TLS and AUAN and unable to take oral medication.
Article
To improve the control of hyperuricemia in patients with leukemia or lymphoma, we tested a newly developed uricolytic agent, recombinant urate oxidase (SR29142; Rasburicase; Sanofi-Synthelabo, Inc, Paris, France), which catalyzes the oxidation of uric acid to allantoin, a highly water-soluble metabolite readily excreted by the kidneys. We administered Rasburicase intravenously, at 0.15 or 0.20 mg/kg, for 5 to 7 consecutive days to 131 children, adolescents, and young adults with newly diagnosed leukemia or lymphoma, who either presented with abnormally high plasma uric acid concentrations or had large tumor cell burdens. Blood levels of uric acid, creatinine, phosphorus, and potassium were measured daily. The pharmacokinetics of Rasburicase, the urinary excretion rate of allantoin, and antibodies to Rasburicase were also studied. At either dosage, the recombinant enzyme produced a rapid and sharp decrease in plasma uric acid concentrations in all patients. The median level decreased by 4 hours after treatment, from 9.7 to 1 mg/dL (P =.0001), in the 65 patients who presented with hyperuricemia, and from 4.3 to 0.5 mg/dL (P =.0001) in the remaining 66 patients. Despite cytoreductive chemotherapy, plasma uric acid concentrations remained low throughout the treatment (daily median level, 0.5 mg/dL). The urinary excretion rate of allantoin increased during Rasburicase treatment, peaking on day 3. Serum phosphorus concentrations did not change significantly during the first 3 days of treatment, decreased significantly by day 4 in patients presenting with hyperuricemia (P =.0003), and fell within the normal range in all patients by 48 hours after treatment. Serum creatinine levels decreased significantly after 1 day of treatment in patients with or without hyperuricemia at diagnosis (P =.0003 and P =.02, respectively) and returned to normal range in all patients by day 6 of treatment. Toxicity was negligible, and none of the patients required dialysis. The mean plasma half-lives of the agent were 16.0 +/- 6.3 (SD) hours and 21.1 +/- 12.0 hours, respectively, in patients treated at dosages of 0.15 or 0.20 mg/kg. Seventeen of the 121 assessable patients developed antibodies to the enzyme. Rasburicase is safe and highly effective for the prophylaxis or treatment of hyperuricemia in patients with leukemia or lymphoma.
Article
Tumor lysis syndrome (TLS) is a constellation of metabolic disturbances observed in tumors with high cell turnover. It is associated with significant morbidity and mortality. TLS is characterized by the increased release of intracellular contents (uric acid, potassium, phosphorus) into the extracellular compartment, which can overwhelm the body's capacity for clearance. TLS is usually caused by response to chemotherapy; however, it may also occur spontaneously. Because uric acid, potassium, and phosphorus are excreted primarily by the kidneys, TLS can lead to hyperuricemia, hyperkalemia, and hyperphosphatemia with accompanying renal compromise. The pathophysiology of TLS-associated acute renal failure is probably multifactorial. Potential etiologies include intravascular volume depletion, urinary precipitation of nucleic acid metabolites and calcium phosphate, and malignancy-associated nephrotoxins. Despite prophylactic therapy with allopurinol and volume repletion, patients may still develop TLS with acute renal failure. While reducing the risk of uric acid precipitation, allopurinol and alkalinization increase the risk of xanthine and calcium phosphate crystals, respectively. Aggressive hydration might lead to volume overload, specifically in older patients. Novel approaches in the management of TLS include the use of urate oxidase, which can provide effective treatment with an acceptable safety profile.
Article
The study of purine and pyrimidine metabolism, and particularly of its inborn errors in man, "experiments in nature", has led to a number of major conceptual and practical advances in biology and medicine. In this review, the major progress which has been accomplished since the First International Symposium on Human Purine and Pyrinaidine Metabolism, held in Tel-Aviv in 1973, will be surveyed. Important unresolved questions, as well as new orientations in the field, will also be briefly presented.
Article
Rasburicase (Fasurtec, Elitek, Sanofi-Synthelabo) is a new recombinant urate oxidase developed for the prevention and treatment of hyperuricaemia. It has a half-life of 17-21 h and produces rapid (within 4 h) and pronounced reductions in plasma uric acid concentrations. To date, rasburicase has been tested in four clinical trials conducted in patients with cancer (primarily haematological malignancies). It successfully alleviated hyperuricaemia in 98% of patients and prevented this complication in 99.6% of those who were at risk. In a stratified, randomised trial, rasburicase was more effective than allopurinol. Most patients had improved or stabilised renal function during rasburicase treatment, despite ongoing chemotherapy-induced tumour lysis. Except for occasional instances of haemolytic anaemia and methemoglobinaemia in patients with glucose-6-phosphate dehydrogenase deficiency, rasburicase was well-tolerated, with a low frequency of mild adverse events. Rasburicase is a safe and effective agent in the prevention or treatment of hyperuricaemia in cancer patients.
Article
Hyperuricemia is a common manifestation of lymphoid malignancies at diagnosis or after the start of chemotherapy. When accompanied by other metabolic abnormalities and/or organ failure, hyperuricemia may be a manifestation of tumor lysis syndrome (TLS). Patients at particularly high risk of such complications include those with acute lymphoblastic leukemia and advanced stage non-Hodgkin's lymphoma. Conventional measures to prevent hyperuricemia and TLS are comprised of hydration, alkalinization of body fluids, and administration of allopurinol. Although these measures are usually effective in preventing or managing hyperuricemia, approximately 20% of patients at high risk of TLS require dialysis, and many cannot receive chemotherapy as planned. Rasburicase, a recombinant form of the enzyme urate oxidase, has recently become available and may further reduce the morbidity of hyperuricemia and TLS. In this review, we provide an overview of hyperuricemia and TLS and discuss the impact of rasburicase in the overall management of these complications.
Biochemistry of uric acid and its relationship to gout
  • Seegmiller