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We report the first patient to develop ALL with a fusion gene of the erythropoietin receptor (EPOR) with immunoglobulin heavy chain (IgH) 22 years after a diagnosis of secondary erythrocytosis with unknown etiology. The IgH-EPOR rearrangement is known to induce increased expression of EPOR, and activates EPO-associated signal pathways by exogenous EPO stimulation, resulting in the increased proliferation and survival of IgH-EPOR-positive leukemic cells. Interestingly, this case may provide supporting the possibility that IgH-EPOR-positive ALL has a growth advantage under sustained high concentrations of EPO.

Overcoming drug resistance remains a major obstacle to curing relapsed or refractory lymphoma and obtaining a beneficial long-term prognosis for patients, despite the introduction of several salvage regimens to date. Our ultimate purpose is to establish a standard second-line salvage chemotherapy regimen for curing relapsed/refractory lymphoma. In this basic pre-clinical study, we evaluated a combination regimen consisting of 9-β-D: -arabinofuranosyl-2-fluoroadenine (F-araA) and carboplatin that targeted nucleotide excision repair (NER) of DNA in five representative leukemia lineages in vitro. Isobologram analysis demonstrated that simultaneous exposure to these two drugs produced synergistic interactions in U937 and K562 cells, in which lines showed enhanced NER activity by the measurement of UV or drug-induced DNA strand break (comet assay), or quantitation of ERCC1 mRNA (RT-PCR), a key enzyme for NER. Histone γH2AX formation was synergistically induced, but no such formation was observed after exposure to either agent alone in K562 cells. In summary, we synergistically inhibited the NER activity of leukemia cells by treating them with a combination of F-araA and carboplatin, suggesting that this combinatory regimen could be used as a novel salvage therapy for refractory or drug-resistant lymphoma.

Background. Urate underexcretion has been reported as the major cause of hyperuricemia in gouty patients. The four-component theory of urate transport in nephrons has been a valuable hypothesis for studying the mechanism of the urate underexcretion, but accurate quantitative analysis of urate transport in nephrons at different sites has not yet been carried out. To determine the amount of urate transport in nephrons more accurately, we applied mathematical calculations to urate transport in nephrons based on the four-component theory. Methods. In 20 gouty patients and 14 normal controls, 60-min urine fractions and blood samples taken at the midpoint of the urine collection period were collected before and after pyradinamide or benzbromarone administration, and urate clearance (Cua) was determined. Urate excretion (Uua) was defined as {Ccr(1-R1) + Cs} Sua(1-R2), where Ccr is creatinine clearance, R1 is the presecretory reabsorption rate, Cs (ml/min) is the secretion rate, Sua is serum urate level, and R2 is the postsecretory reabsorption rate. Results. In the gouty patients, urate glomerular filtration was significantly higher than in the normal controls, but approximately 96% of the filtered urate was reabsorbed. The urate secretion rate of gouty patients was markedly lower than that of the controls, but the amount of urate secretion was slightly and not significantly lower than that of the controls. Postsecretory reabsorption was proportional to intratubular urate concentration. Subsequent urinary excretion in gouty patients was significantly lower than that in the normal controls. Presecretory reabsorption, secretion, postsecretory reabsorption, and urinary excretion comprised 95.9%, 38.9% 38.6%, and 4.4% of urate glomerular filtration in gouty patients, and 96.2%, 52.2%, 49.6%, and 6.5% in normal controls, respectively. Conclusions. Urate secretion in the nephrons of gouty patients was significantly decreased compared with that in normal controls in terms of its rate and its proportion to urate glomerular filtration, which resulted in significant reduction of urinary urate excretion.