Evaluation of the efficacy and safety of deferiprone compared with deferasirox in paediatric patients with transfusion-dependent haemoglobinopathies (DEEP-2): a multicentre, randomised, open-label, non-inferiority, phase 3 trial.

BACKGROUND: Transfusion-dependent haemoglobinopathies require lifelong iron chelation therapy with one of the three iron chelators (deferiprone, deferasirox, or deferoxamine). Deferasirox and deferiprone are the only two oral chelators used in adult patients with transfusion-dependent haemoglobinopathies. To our knowledge, there are no randomised clinical trials comparing deferiprone, a less expensive iron chelator, with deferasirox in paediatric patients. We aimed to show the non-inferiority of deferiprone versus deferasirox. METHODS: DEEP-2 was a phase 3, multicentre, randomised trial in paediatric patients (aged 1 month to 18 years) with transfusion-dependent haemoglobinopathies. The study was done in 21 research hospitals and universities in Italy, Egypt, Greece, Albania, Cyprus, Tunisia, and the UK. Participants were receiving at least 150 mL/kg per year of red blood cells for the past 2 years at the time of enrolment, and were receiving deferoxamine (<100 mg/kg per day) or deferasirox (<40 mg/kg per day; deferasirox is not registered for use in children aged <2 years so only deferoxamine was being used in these patients). Any previous chelation treatment was permitted with a 7-day washout period. Patients were randomly assigned 1:1 to receive orally administered daily deferiprone (75-100 mg/kg per day) or daily deferasirox (20-40 mg/kg per day) administered as dispersible tablets, both with dose adjustment for 12 months, stratified by age (<10 years and ≥10 years) and balanced by country. The primary efficacy endpoint was based on predefined success criteria for changes in serum ferritin concentration (all patients) and cardiac MRI T2-star (T2*; patients aged >10 years) to show non-inferiority of deferiprone versus deferasirox in the per-protocol population, defined as all randomly assigned patients who received the study drugs and had available data for both variables at baseline and after 1 year of treatment, without major protocol violations. Non-inferiority was based on the two-sided 95% CI of the difference in the proportion of patients with treatment success between the two groups and was shown if the lower limit of the two-sided 95% CI was greater than -12·5%. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with EudraCT, 2012-000353-31, and ClinicalTrials.gov, NCT01825512. FINDINGS: 435 patients were enrolled between March 17, 2014, and June 16, 2016, 393 of whom were randomly assigned to a treatment group (194 to the deferiprone group; 199 to the deferasirox group). 352 (90%) of 390 patients had ß-thalassaemia major, 27 (7%) had sickle cell disease, five (1%) had thalassodrepanocytosis, and six (2%) had other haemoglobinopathies. Median follow-up was 379 days (IQR 294-392) for deferiprone and 381 days (350-392) for deferasirox. Non-inferiority of deferiprone versus deferasirox was established (treatment success in 69 [55·2%] of 125 patients assigned deferiprone with primary composite efficacy endpoint data available at baseline and 1 year vs 80 [54·8%] of 146 assigned deferasirox, difference 0·4%; 95% CI -11·9 to 12·6). No significant difference between the groups was shown in the occurrence of serious and drug-related adverse events. Three (2%) cases of reversible agranulocytosis occurred in the 193 patients in the safety analysis in the deferiprone group and two (1%) cases of reversible renal and urinary disorders (one case of each) occurred in the 197 patients in the deferasirox group. Compliance was similar between treatment groups: 183 (95%) of 193 patients in the deferiprone group versus 192 (97%) of 197 patients in the deferisirox group. INTERPRETATION: In paediatric patients with transfusion-dependent haemoglobinopathies, deferiprone was effective and safe in inducing control of iron overload during 12 months of treatment. Considering the need for availability of more chelation treatments in paediatric populations, deferiprone offers a valuable treatment option for this age group. FUNDING: EU Seventh Framework Programme.

Agranulocytosis Induced by Sinomenine Hydrochloride.

BACKGROUND Sinomenine hydrochloride is an alkaloid that is extracted from the Chinese herbal plant Sinomenium acutum, and is used as a herbal medicine in the treatment or rheumatic disease. This report is the first to describe a case of sinomenine hydrochloride-induced agranulocytosis. CASE REPORT A 44-year-old woman with systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) was treated with sinomenine hydrochloride and developed agranulocytosis with a neutrophil count of 0.01×10^9/L. She subsequently developed an opportunistic bacterial infection. Bone marrow aspiration showed a severe reduction in the proportion of mature granulocytes. The patient discontinued sinomenine hydrochloride therapy and was treated with granulocyte colony-stimulating factor (G-CSF) and antibiotics. The patient showed a return to normal granulocyte levels within ten days of discontinuing treatment with sinomenine hydrochloride. CONCLUSIONS The findings of this case report show that monitoring of bone marrow function and granulocyte levels should be performed during treatment with sinomenine hydrochloride.

Graves' disease in a 3 year-old patient with agranulocytosis due to anti-thyroid drugs: Radioiodine ablation therapy as an effective alternative. / Enfermedad de Graves en un paciente de 3 años con agranulocitosis asociada a fármacos antitiroideos: terapia ablativa con radioyodo como una alternativa eficaz.

The case is presented of a 3 year-old girl with mitochondrial disease (subacute necrotizing encephalomyelopathy of Leigh syndrome), v-stage chronic kidney disease of a diffuse mesangial sclerosis, as well as developmental disorders, and diagnosed with hyperthyroidism Graves-Basedow disease. Six weeks after starting the treatment with neo-carbimazole, the patient reported a serious case of agranulocytosis. This led to stopping the anti-thyroid drugs, and was treated successfully with 131I ablation therapy. The relevance of the article is that Graves' disease is uncommon in the paediatric age range (especially in children younger than 6 years old), and developing complications due to a possible late diagnosis. Agranulocytosis as a potentially serious adverse effect following the use of anti-thyroid drugs, and the few reported cases of ablation therapy with 131I at this age, makes this case unique.

Exploring an animal model of amodiaquine-induced liver injury in rats and mice.

Amodiaquine (AQ) is associated with a relatively high incidence of idiosyncratic drug-induced liver injury (IDILI) and agranulocytosis. A previous study reported that a combination of high dose AQ and glutathione (GSH) depletion led to liver injury. However, the characteristics of this toxicity were very different from AQ-induced liver injury in humans. We developed a model of AQ-induced liver injury with characteristics similar to the injury in humans by treating mice with lower doses of AQ for several weeks. In this study we found that not only did GSH depletion not increase AQ covalent binding to hepatic proteins at this lower dose, but also it paradoxically prevented the liver injury. We extended the model to rats and found AQ treatment led to a mild delayed onset liver injury that resolved despite continued treatment with AQ. Immunohistochemistry indicated the presence of Kupffer cell activation, apoptosis and hepatocyte proliferation in the liver. There was also an increase in serum IL-2, IL-5, IL-9, IL-12, MCP-1 and TGFß, but a decrease in leptin. Coincident with the elevated serum ALT, the number of liver CD4(+) T-cells, IL-17 secreting cells and TH17/Treg cells increased at Week 3 and decreased during continued treatment. Increases in NK1.1+ cells and activated M2 macrophages were also observed during liver injury. These results suggest that the outcome of the liver injury was determined by the balance between effector and regulatory cells. Co-treatment with cyclosporin prevented AQ-induced liver injury, which supports an immune mechanism. Retinoic acid (RA), which has been reported to enhance natural killer (NK) cell activity, exacerbated AQ-induced liver injury. These results suggest that AQ-induced IDILI is immune mediated and the subsequent adaptation appears to represent immune tolerance.

A Case of Fatal Agranulocytosis That Developed in a Patient with ß-Thalassemia Major Treated with Deferiprone.

A 29-year-old male with transfusion-dependent ß-thalassemia major (ß-TM), splenectomized and on chelation therapy with deferiprone (DFP or L1) due to heart and liver hemosiderosis, presented with high fever and agranulocytosis. Deferiprone was discontinued and a broad spectrum antibiotic therapy was started intravenously. The patient remained febrile and showed no recovery of neutrophil count even after the initiation of granulocyte colony-stimulation factor (G-CSF). After 12 days at the hospital, he developed respiratory failure and was transferred to the intensive care unit (ICU) where he developed multi-organ failure and died 3 days later. To investigate the mechanism of agranulocytosis, bone marrow mononuclear cells of a healthy volunteer were plated on culture dishes, with or without the patient's serum. The observation of colony forming units of progenitor cells in dishes that contained the patient's serum, provided inconclusive explanation of the possible mechanism of DFP-induced agranulocytosis. This is a case of fatal agranulocytosis developing in a patient being treated with DFP, a well recognized but rare complication of this drug. Further studies are required in order to elucidate the possible pathogenic mechanism of agranulocytosis due to DFP and to provide clear guidelines in order to best care for the patient.

Safety Profile of Oral Iron Chelator Deferiprone in Chinese Children with Transfusion-Dependent Thalassaemia.

UNLABELLED: There is a lack of knowledge regarding the incidence of serious adverse drug reactions (ADR) to the oral iron chelator deferiprone in Chinese children with transfusion-dependent thalassaemia. In this retrospective population-based cohort study, paediatric thalassaemia patients in Hong Kong were screened for serious and medically important adverse events related to deferiprone therapy using diagnosis codes, laboratory data and hospital admissions. Potential ADRs were assessed by reviewing concomitant medications, diagnoses and laboratory data and evaluated using standardised causality assessment. Eighty-seven patients contributing 169.8 person-years were included. Thirty ADRs were identified in 21 patients. Most ADRs (56.0%) occurred in the first three months of therapy. Neutropenia occurred in 11 patients (12.6%; incidence rate 6.5 per 100 patient-years) and severe neutropenia (agranulocytosis) was observed in 5 patients (5.7%, incidence rate 2.9 per 100 patient-years). Other identified ADRs involve severe arthropathy, elevated liver enzymes and mild thrombocytopenia. In conclusion, the safety profile of DFP therapy in Chinese children suffering from transfusion-dependent thalassaemia is in line with previous studies of non-Chinese children. However, unlike previous studies, we observed a relatively high incidence of agranulocytosis and neutropenia in patients with simultaneous combined therapy. Hence close monitoring for white blood cell counts is advised in Chinese children under combined iron chelation therapy. Further prospective clinical and pharmacogenetic studies are required to better evaluate this important safety signal. KEY POINTS: • Half of the identified ADRs related to deferiprone therapy occurred during the first three months of treatment. • A relatively high incidence of agranulocytosis and neutropenia. Hence close monitoring for white blood cell counts is advised in Chinese children under combined iron chelation therapy.

Deferiprone versus deferoxamine in thalassemia intermedia: Results from a 5-year long-term Italian multicenter randomized clinical trial.

In patients with thalassemia intermedia (TI), such as beta-TI, alpha-thalassemia (mainly HbH disease and mild/moderate forms of HbE/beta-thalassemia), iron overload is an important challenge in terms of diagnosis, monitoring, and treatment. Moreover, to date, the only possible chelators available are deferoxamine, deferasirox, and deferiprone. Here, we report the first 5-year long-term randomized clinical trial comparing the effectiveness of deferiprone versus deferoxamine in patients with TI. Body iron burden, which was determined by measuring serum ferritin levels in the same patient over 5 years and analyzed according to the generalized linear mixed model (GLMM), showed a linear decrease over time in the mean serum ferritin levels in both treatment groups (P-value = 0.035). The overall period of observation was 235.2 person-years for the deferiprone patients compared with 214.3 person-years for the deferoxamine patients. The results of the log-rank test suggested that the deferiprone treatment did not affect survival compared with the deferoxamine treatment (P-value = 0.360). The major adverse events observed included gastrointestinal symptoms and joint pain or arthralgia. Neutropenia and agranulocytosis were also detected, suggesting needing of strict hematological control. In conclusion, long-term iron chelation therapy with deferiprone is associated with an efficacy and safety similar to that of deferoxamine, suggesting that this drug is an alternative option in cases in which deferoxamine and deferasirox are contraindicated.

Clostridium difficile infection induced by pregabalin-associated agranulocytosis.

A 33-year-old man who had recently undergone surgery for cervical spondylotic myelopathy was prescribed pregabalin for neuralgia, and the dose was increased to 600 mg/day during hospitalization. However, the patient was diagnosed with a Clostridium difficile infection on day 34 after admission. A complete blood count showed agranulocytosis (neutrophil count: 105/µL). We did not observe any changes in vital signs, a relative increase in band cells, or intestinal edema. The patient's agranulocytosis resolved after withdrawing pregabalin. This is the first reported case of agranulocytosis associated with pregabalin. Periodic monitoring of the white blood cell count is therefore considered to be useful in patients receiving high-dose pregabalin therapy.

The impact of previous or concomitant IFN therapy on deferiprone-induced agranulocytosis and neutropenia: a retrospective study.

OBJECTIVE: Although IFN therapy is known to cause neutropenia, data on the risk of deferiprone (DFP)-induced haematological complications in patients receiving IFN are lacking. RESEARCH DESIGN AND METHODS: This was a retrospective single-centre study to assess the association between exposure to IFN for hepatitis C virus treatment and haematological side effects of DFP therapy in patients with thalassemia major and intermedia using a large database spanning 2001 ­ 2008. During observation time, a total of 66 patients, including 63 affected by thalassemia major and 3 by thalassemia intermedia, were treated with chelation DFP-based regimens. A subset of 25 patients was treated at least for 3 months also with IFN (6 were cotreated and 19 were pretreated). RESULTS: Overall, the incidence of neutropenia and agranulocytosis was 9.83 and 1.14/100 patient/year, respectively. Receipt of IFN was significantly associated with increased risk of haematological complications of DFP therapy: among patients receiving IFN, 48 and 12% experienced at least one episode of neutropenia and agranulocytosis, respectively. CONCLUSIONS: These results suggest that IFN therapy may increase the risk of complications of DFP-based iron chelation therapy in patients with thalassemia. Further research is needed to assess whether the association observed in this retrospective single-centre observational study is due to IFN or other factors.

Long-term response to deferiprone therapy in Asian Indians.

Deferiprone (L1) has been used in several countries for iron chelation therapy for over one decade. Long-term results on the drug are lacking. In the present study, data of 110 patients on deferiprone (L1) for up to 17 years were analyzed. On a mean L1 dose of 70.2 mg/kg/day (range 44-100), serum ferritin level showed a very steady decrease with time from an initial mean (+/-SD) of 3,033.61 +/- 1,468.04 ng/ml to final of 1,665.08 +/- 949.93 ng/ml after a mean (+/-SD) of 6.1 +/- 3.8 years. In total, 13 patients discontinued L1 therapy. Major complications of L1 requiring permanent discontinuation of treatment included arthropathy (n = 8, 7.2%) and neutropenia/agranulocytosis (n = 5, 4.5%). Lesser complications permitting continued L1 treatment included transient mild leucopenia or thrombocytopenia (n = 3) and gastrointestinal problems (n = 5). There were a total of three deaths attributed to agranulocytosis. Although the complications associated with L1 treatment are significant and require close monitoring, they do not preclude effective long-term therapy in the vast majority of patients. A longer duration of therapy is required for effective response in chronically iron-overloaded patients. Further well-controlled prospective studies of L1 are required to identify factors affecting individual response to therapy.

Testing the hypothesis that selenium deficiency is a risk factor for clozapine-induced agranulocytosis in rats.

Clozapine is an effective atypical antipsychotic associated with a relatively high incidence of drug-induced agranulocytosis. It forms a reactive nitrenium ion metabolite upon oxidation by peripheral neutrophils and their precursors in the bone marrow. Although the mechanism of this idiosyncratic drug reaction is still unknown, the observation that it does not occur rapidly on rechallenge of patients with a history of clozapine-induced agranulocytosis suggests that it is not immune-mediated. Previous studies by other research groups had found that patients on clozapine had lower plasma and red blood cell levels of selenium. The reactive metabolite of clozapine reacts with glutathione, and therefore, it is likely that it also binds to selenocysteine-containing proteins, such as glutathione peroxidase, thioredoxin reductase, and protein disulfide isomerase. We set out to test the hypothesis that clozapine-induced agranulocytosis is associated with selenium deficiency with rats on a selenium-deficient diet. We studied the effects of clozapine on selenium levels and the effect of selenium deficiency on leukocyte and neutrophil counts and clozapine covalent binding. We did not observe any significant difference between clozapine-treated rats given a selenium-adequate or deficient diet. Therefore, it is unlikely that selenium deficiency is a major risk factor for clozapine-induced agranulocytosis.

A randomized, placebo-controlled, double-blind trial of the effect of combined therapy with deferoxamine and deferiprone on myocardial iron in thalassemia major using cardiovascular magnetic resonance.

BACKGROUND: Cardiac complications secondary to iron overload are the leading cause of death in beta-thalassemia major. Approximately two thirds of patients maintained on the parenteral iron chelator deferoxamine have myocardial iron loading. The oral iron chelator deferiprone has been demonstrated to remove myocardial iron, and it has been proposed that in combination with deferoxamine it may have additional effect. METHODS AND RESULTS: Myocardial iron loading was assessed with the use of myocardial T2* cardiovascular magnetic resonance in 167 patients with thalassemia major receiving standard maintenance chelation monotherapy with subcutaneous deferoxamine. Of these patients, 65 with mild to moderate myocardial iron loading (T2* 8 to 20 ms) entered the trial with continuation of subcutaneous deferoxamine and were randomized to receive additional oral placebo (deferoxamine group) or oral deferiprone 75 mg/kg per day (combined group). The primary end point was the change in myocardial T2* over 12 months. Secondary end points of endothelial function (flow-mediated dilatation of the brachial artery) and cardiac function were also measured with cardiovascular magnetic resonance. There were significant improvements in the combined treatment group compared with the deferoxamine group in myocardial T2* (ratio of change in geometric means 1.50 versus 1.24; P=0.02), absolute left ventricular ejection fraction (2.6% versus 0.6%; P=0.05), and absolute endothelial function (8.8% versus 3.3%; P=0.02). There was also a significantly greater improvement in serum ferritin in the combined group (-976 versus -233 microg/L; P<0.001). CONCLUSIONS: In comparison to the standard chelation monotherapy of deferoxamine, combination treatment with additional deferiprone reduced myocardial iron and improved the ejection fraction and endothelial function in thalassemia major patients with mild to moderate cardiac iron loading.

Combined therapy with deferoxamine and deferiprone.

Therapy with either deferiprone (DFP) or deferoxamine (DFO) is inadequate in achieving negative iron balance in many patients with thalassemia. There are mounting theoretical, experimental, and clinical evidences of increased efficacy when therapy includes both chelating agents. DFP and DFO chelate excess iron in different ways without affecting each other's metabolism. When both chelators are administered simultaneously, they interact either in an additive or synergistic manner, probably through "shuttling" iron from DFP to DFO. Iron-balance studies have shown that the use of both agents on the same day can induce negative iron balance in all patients. Long-term combined therapy with DFO with DFP results in considerable reduction of both ferritin levels and liver iron concentration as well as significant improvement in cardiac siderosis and function. This therapeutic regimen is well tolerated and safe, even though it may be related to a small increase in the incidence of agranulocytosis compared with DFP monotherapy. Apart from using both agents simultaneously, sequential administration of DFP and DFO has also shown promising results. Combining the available iron chelators offers many therapeutic options that can be tailored to each patient individually. It is an exciting advance in treating hemosiderosis in thalassemic patients.

Phase III study of fluorouracil, leucovorin, and levamisole in high-risk stage II and III colon cancer: final report of Intergroup 0089.

PURPOSE: In 1990, fluorouracil (FU) plus levamisole for 1 year became standard adjuvant treatment for patients with high-risk stages II and III colon cancer. Intergroup (INT) 0089 assessed the relative contributions of leucovorin and levamisole in such patients. PATIENTS AND METHODS: From 1988 to 1992, 3,794 patients were randomly assigned. Experimental treatment consisted of one of three chemotherapy regimens: the low-dose leucovorin plus FU (Mayo Clinic; LDLV) regimen, the high-dose leucovorin plus FU (Roswell Park; HDLV) regimen, and the low-dose leucovorin plus levamisole plus FU (LDLV plus LEV) regimen, each administered for 30 to 32 weeks. The control arm was levamisole plus FU (LEV) for 1 year. RESULTS: After a median follow-up of 10 years, of 3,561 eligible patients, 1,691 (47%) have died and 1,330 (37%) have experienced disease recurrence; 137 (10%) of those experiencing recurrence are still alive. A total of 481 patients (13%) died without evidence of recurrence, and 1,723 (48%) are alive and disease free. Although there were toxicity differences among the four arms, none was statistically superior in disease-free or overall survival. CONCLUSION: The 6- to 8-month regimens of LDLV and HDLV without levamisole used in this trial, rather than the previous standard regimen of 12 months of LEV, have become widely used. INT-0089 has long-term follow-up of the largest clinical trial of patients with high-risk colon cancer, documenting not only the durability of the treatment effects, but also the natural history of patients with high-risk colon cancer, and analyses of treatment based on age, race, and comorbid conditions such as obesity, diabetes, and second primary cancers.

Circadian rhythm of irinotecan tolerability in mice.

The toxicity of irinotecan (CPT-11), a topoisomerase-I inhibitor largely used in cancer patients, was investigated as a function of the circadian time of its administration in mice, with mortality, body weight loss, leukopenia, neutropenia, intestinal lesions, and bone marrow cell cycle phase distribution as end points. Four experiments were performed on a total of 773 male mice standardized with 12h light/12h darkness. Irinotecan was administered daily for 4 or 10 consecutive days (D1-4 and D1-10, respectively, in different experiments) at one of six circadian stages expressed in hours after light onset (HALO). The survival curves differed significantly as a function of the dosage and circadian time of drug administration by the D1-10 schedule, with 70% survival at 7 or 11 HALO and 51% at 19 or 23 HALO (p=0.039 from log rank test). CPT-11 administration at 19 or 23 HALO resulted in (1) greatest mean body weight loss at nadir; (2) most severe colic and bone marrow lesions and/or slowest recovery; and (3) deepest neutropenia nadir and/or slowest hematologic recovery. These circadian treatment time-related differences were statistically validated. The bone marrow cell cycle data revealed a four to eight-fold larger G2-M phase arrest following irinotecan administration at 19 or 23 HALO in comparison to the other times of drug administration, apparently representative of the repair of more extensive DNA damage (p < 0.001 from ANOVA) when the medication was given at these circadian times. Overall, CPT-11 was better tolerated by mice treated during the light (animals' rest) span. The results support the administration of CPT-11 to cancer patients in the second half of the night, during sleep, in order to improve drug tolerability.

Nasal NK/T-cell lymphoma with disseminated disease treated with aggressive combined therapy.

Thirty-two patients with nasal NK/T-cell lymphoma and disseminated disease (lung, skin, and bone marrow) were treated with an intensive combined therapy that consisted of three cycles of CMED (cyclophosphamide 2 g/m(2), metothrexate 200 mg/m(2), etoposide 600 mg/m(2), and dexamethasone 80 mg/m(2) with leucovorin rescue administered 24 h after) every 14 d, following high-dose radiotherapy: 55 Gy in 20 sesions to centrofacial region and three cycles more of the same chemotherapy regimen. To ameliorate the presence of severe granulocytopenia, granulocyte colony-stimulating factor, 5 microg/kg, daily for 14 d, begun on d 2 after chemotherapy, was administered. Complete response was achieved in 21 cases (65%); failure or progression was observed in 11 cases (35%). With a median follow-up of 69.1 mo, relapse has not been observed; thus, actuarial curves at 5 yr showed that event-free survival (EFS) is 100% in 21 patients and overall survival (OS) is 65%. Granulocytopenia grade IV was observed in 15% cycles, Nonhematological toxicity was mild and well tolerated. Radiotherapy was well tolerated; only mild mucositis was observed. Nasal NK/T-cell lymphoma is an rare presentation of malignant lymphoma (<1% of all cases) with a worse prognosis; less than 5% patients are alive free of disease at 1 yr. The use of intensive more specific chemotherapy and high dose of local radiotherapy, appear to be an excellent therapeutic approach with improvement in EFS and OS.

Metamizole use by Latino immigrants: a common and potentially harmful home remedy.

A 4-year-old boy presented with fever, septic arthritis, and persistent neutropenia. Bone marrow biopsy revealed no evidence of neoplasia. Additional history disclosed that the patient had been given metamizole for pain before onset of his illness. Metamizole, a nonsteroidal antiinflammatory agent, is prohibited in the United States because of the risk of agranulocytosis but is widely used in Mexico and other countries. The increasing number of Latinos in the United States and the extensive cross-border transfer of medicines raise concerns that metamizole use and associated complications may become more frequent. After identification of the index patient, additional inquiry revealed that the patient's mother was hospitalized previously for overwhelming sepsis associated with metamizole use. These cases prompted an investigation of metamizole use in an urban pediatric clinic, which revealed that 35% of Spanish-speaking Latino families had used metamizole; 25% of these families had purchased the medication in the United States. We conclude that metamizole use is common and may be underrecognized in immigrant Latino patients. Physicians in the United States, especially those who practice primary care, hematology/oncology, and infectious diseases, must be aware of the availability and use of metamizole in specific patient populations and its potential for harmful side effects.

Adjuvant postoperative 5-fluorouracil chemotherapy combined with pelvic radiation for rectal cancer: results from an Asian population.

Prospective randomized clinical trials have shown the effectiveness of combined adjuvant 5-fluorouracil-based chemotherapy and radiotherapy after surgical resection of rectal cancer. To assess toxicity of this therapy, prospective data were collected from 236 Asian rectal cancer patients treated with combined 5-fluorouracil-based chemotherapy and radiotherapy after surgery. Almost 82% of patients completed planned therapy. Grade 3 and 4 diarrhea, stomatitis, and granulocytopenia occurred in approximately 18-21% of patients. There were two treatment-related deaths from granulocytopenia and sepsis. With median follow-up of 3.5 years, median disease-free and overall survival was 75 and 88 months, respectively. In conclusion, combined adjuvant 5-fluorouracil-based chemotherapy and radiotherapy after surgical resection of rectal cancer is tolerable in Asian patients with moderate toxicity.

[An elderly case with pseudogout exacerbated by the administration of granulocyte-colony stimulating factor during drug-induced granulocytopenia].

A 82-year-old woman was admitted because of dehydration and chronic renal failure. Although her renal function was improved by hydration, granulocytopenia (granulocyte number 645/mm3) occurred. Treatment with a relatively high dose of H2 blocker for one month before admission may have caused the granulocytopenia. To prevent possible infection in the patient, we administered 75 g of granulocyte-colony stimulating factor (G-CSF) for 5 consecutive days but 4 days after commencement of administration of G-CSF, pain in both knee joints suddenly appeared. Synovial fluid aspiration revealed granulocytosis (10,400/mm3) and deposition of calcium pyrophosphate dihydrate in the knee joints. The level of G-CSF in the synovial fluid was increased in the joints (700 pg/ml), compared with the serum concentration (62 pg/ml). Furthermore, the concentrations of interleukin-6 and interleukin-8 were markedly increased in the synovial fluid. The results indicated that her pseudogout exacerbation by G-CSF was at least in part explained by the increased production of cytokines in the knee joints. Because the prevalence of pseudogout and gout is overwhelming in the elderly, the possibility of GCSF induced exacerbation of joint pain should be carefully considered in elderly patients.