Development of intravascular large B-cell lymphoma during prophylactic antibiotic treatment for anti-interferon-gamma autoantibody syndrome: A case report.

Anti-interferon (IFN)-γ autoantibody-positive syndrome is one of the acquired non-HIV cellular immunodeficiencies, caused by abnormalities in the IFN-γ/interleukin (IL)-12 pathways. It is often diagnosed alongside the onset of disseminated mycobacterium infection, and requires continuous antimycobacterial chemotherapy; however, the detailed pathological mechanisms underlying this syndrome, including its prognosis, are not known. To the best of our knowledge, this is the first reported case of intravascular large B-cell lymphoma complicated by anti-IFN-γ autoantibody syndrome, presented in an 82-year-old woman. The patient had been diagnosed with anti-IFN-γ autoantibody immunodeficiency ten years ago. She had repeated subacute fever of undetermined origin for 13 months that made us suspect infections, such as disseminated mycobacterium disease and other viral and fungal infections, despite receiving prophylactic antimycobacterial chemotherapy with rifampicin and clarithromycin. However, all the screenings performed showed no evidence of infectious diseases; thus, she was finally diagnosed with intravascular large B-cell lymphoma via a random skin biopsy. Unfortunately, the patient debilitated rapidly and died. Evidence supporting a correlation between anti-IFN-γ autoantibody syndrome and carcinogenesis is still lacking, although it is known that patients with anti-IFN-γ autoantibody syndrome are at risk of persistent viral infection-related and T-cell lineage-related carcinogenesis. This case demonstrated that patients with anti-IFN-γ autoantibody syndrome are also at risk of developing B-cell lymphoma, such as intravascular lymphoma. This emphasizes that caution should be paid to increased risk of developing malignancy during the long-term management of anti-IFN-γ autoantibody syndrome with cellular immunodeficiency.

[Isolated central nervous system relapse of Philadelphia chromosome-positive acute lymphoblastic leukemia during ponatinib maintenance therapy].

A 65-year-old man was diagnosed with Philadelphia chromosome-positive acute lymphoblastic leukemia with no initial central nervous system (CNS) involvement. Complete remission was achieved after the induction therapy. However, during consolidation therapy, he developed septic shock and pneumocystis pneumonia, leading to interruption in chemotherapy and allogeneic transplantation. Subsequently, he achieved complete molecular remission and ponatinib maintenance therapy was initiated. Two years later, he developed left leg paralysis and was diagnosed with isolated CNS relapse; however, radiation therapy improved CNS lesions and paralysis. Thus, ponatinib maintenance therapy alone is inadequate in preventing CNS relapse in patients who have not completed systemic chemotherapy for CNS relapse prevention.

[Spontaneous resolution of refractory ascites in the late phase after cord blood transplantation in acute myeloid leukemia].

Patients with refractory ascites that develops >3 months after allogenic stem cell transplantation typically have a poor prognosis. We present the case of a 61-year-old man who developed refractory massive ascites approximately 3 months after cord blood transplantation (CBT) and showed complete and spontaneous remission from ascites after 18 months. The patient complained of severe bloating and needed weekly paracentesis to manage the fluid levels. Laboratory tests indicated that the ascites was caused by liver fibrosis. After the patient underwent Keisuke-Matsusaki cell-free and concentrated ascites reinfusion therapy (KM-CART), we were able to decrease the frequency of paracentesis treatments. We planned a transjugular liver biopsy, but the patient contracted pneumocystis pneumonia before the procedure could be performed. Although the pneumonia improved, the ascites worsened again. However, weekly paracentesis spontaneously stopped the progression of ascites and eventually resolved it completely, resulting in the patient's survival.

[Bendamustine and rituximab combination therapy for recurrent indolent B-cell lymphomas: a retrospective single-institution study].

This retrospective study evaluated the outcomes of patients treated with combination of bendamustine and rituximab (BR) for recurrent indolent B-cell lymphoma from January 2011 to February 2018 in our department. The cohort included 36 males and 27 females, and majority of the patients (59%) were between 51 and 70 years of age. The disease types were follicular lymphoma (FL) and mantle-cell lymphoma in 42 (67%) and 15 (24%) patients, respectively. Median progression-free survival (PFS) was not reached in patients with FL who completed BR therapy. The analysis of patients who received BR therapy revealed that the number of CD4-positive lymphocytes remained around 200/µl even five years after the end of treatment. BR therapy was a useful treatment option for recurrent indolent B-cell lymphoma, especially in patients with FL, and completion of BR therapy appeared to be important for improved PFS. Furthermore, attention should be paid for potential infections for at least five years after BR therapy because cell-mediated immunodeficiency may become apparent after treatment.

Successful Control of Dasatinib-related Chylothorax by the Japanese Herbal Medicine "Goreisan".

Dasatinib-related chylothorax is a rare adverse event, and the mechanism underlying its occurrence is still not fully understood. We herein report the case of a 73-year-old woman with chronic myeloid leukemia (CML) who developed dasatinib-related chylothorax refractory to conventional treatments, except for steroids. To the best of our knowledge, this is the first case of dasatinib-related chylothorax which was successfully controlled by combining diuretics with the Japanese herbal medicine "Goreisan." "Goreisan" is known to inhibit aquaporin channels and regulate the water flow. Our findings showed that "Goreisan" is an effective treatment option for uncontrollable dasatinib-related chylothorax.

Increased SLAMF7high monocytes in myelofibrosis patients harboring JAK2V617F provide a therapeutic target of elotuzumab.

Monocyte-derived fibrocytes recently garnered attention because the novel pathogenesis of myelofibrosis (MF), and suppression of fibrocyte differentiation by serum amyloid P remarkably improved MF. We previously revealed that human fibrocytes highly expressed signaling lymphocytic activation molecule F7 (SLAMF7) compared with macrophages and that SLAMF7high monocytes in the peripheral blood (PB) of MF patients were significantly elevated relative to those in healthy controls (HCs). In this study, we evaluated SLAMF7high monocyte percentage in the PB of HCs, myeloproliferative neoplasm (MPN) patients with MF, and MPN patients without MF by using a cross-sectional approach. We found that MPN patients with MF who harbored JAK2V617F had a significantly elevated SLAMF7high monocyte percentage, which correlated positively with the JAK2V617F allele burden. In addition, the serum concentration of interleukin-1ra (IL-1ra) was significantly correlated with the SLAMF7high monocyte percentage and JAK2V617F allele burden. These findings suggest that both SLAMF7high monocytes and IL-1ra could be useful noninvasive markers of MF onset. Furthermore, the JAK2V617F allele burden of SLAMF7high monocytes was significantly higher than that of SLAMF7low monocytes and could be a potential target of elotuzumab (Elo), an anti-SLAMF7 antibody used for treating multiple myeloma. Elo independently inhibited differentiation of fibrocytes derived not only from HCs but also from MF patients in vitro. Elo also ameliorated MF and splenomegaly induced by romiplostim administration in humanized NOG mice. In conclusion, an increase of SLAMF7high monocytes with higher JAK2V617F allele burden was associated with the onset of MF in MPN patients harboring JAK2V617F, and Elo could be a therapeutic agent for MPN patients with MF who harbor JAK2V617F.

[VEGF secretion from Epstein-Barr virus-infected cells as a cause of severe anasarca in a patient with angioimmunoblastic T-cell lymphoma].

A 69-year-old woman presented to National Defense Medical College hospital for suspected nephrotic syndrome due to weight gain of 30 kg in 3 weeks and bilateral lower leg edema. However, her urinalysis showed microproteinuria, which excluded nephrotic syndrome. Computed tomography revealed severe systemic edema, pleural effusion, ascites, and enlarged cervical and axillary lymph nodes. Histological examination of axillary lymph node specimen showed a typical architecture of angioimmunoblastic T-cell lymphoma. One course of CHOP chemotherapy regimen was administered which improved the lymph nodes and systemic edema. The patient achieved complete remission after 6 courses of CHOP. Because serum vascular endothelial growth factor (VEGF) level was elevated before the treatment and normalized after the treatment, increased vascular permeability mediated by VEGF was hypothesized to have caused the systemic edema. In addition, VEGF secretion from Epstein-Barr virus (EBV)-infected cells was likely associated with the patient's clinical condition because B lymphocytes stained with CD20 were positive for Epstein-Barr virus-encoded small RNAs (EBERs) and VEGF.

GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes.

OBJECTIVE: A genome-wide association study (GWAS) of gout and its subtypes was performed to identify novel gout loci, including those that are subtype-specific. METHODS: Putative causal association signals from a GWAS of 945 clinically defined gout cases and 1213 controls from Japanese males were replicated with 1396 cases and 1268 controls using a custom chip of 1961 single nucleotide polymorphisms (SNPs). We also first conducted GWASs of gout subtypes. Replication with Caucasian and New Zealand Polynesian samples was done to further validate the loci identified in this study. RESULTS: In addition to the five loci we reported previously, further susceptibility loci were identified at a genome-wide significance level (p<5.0×10-8): urate transporter genes (SLC22A12 and SLC17A1) and HIST1H2BF-HIST1H4E for all gout cases, and NIPAL1 and FAM35A for the renal underexcretion gout subtype. While NIPAL1 encodes a magnesium transporter, functional analysis did not detect urate transport via NIPAL1, suggesting an indirect association with urate handling. Localisation analysis in the human kidney revealed expression of NIPAL1 and FAM35A mainly in the distal tubules, which suggests the involvement of the distal nephron in urate handling in humans. Clinically ascertained male patients with gout and controls of Caucasian and Polynesian ancestries were also genotyped, and FAM35A was associated with gout in all cases. A meta-analysis of the three populations revealed FAM35A to be associated with gout at a genome-wide level of significance (p meta =3.58×10-8). CONCLUSIONS: Our findings including novel gout risk loci provide further understanding of the molecular pathogenesis of gout and lead to a novel concept for the therapeutic target of gout/hyperuricaemia.

Common variant of PDZ domain containing 1 (PDZK1) gene is associated with gout susceptibility: A replication study and meta-analysis in Japanese population.

PDZ domain containing 1 (PDZK1) is a scaffold protein that organizes a transportsome and regulates several transporters' functions including urate and drug transporters. Therefore, PDZK1 in renal proximal tubules may affect serum uric acid levels through PDZK1-binding renal urate transporters. Two previous studies in Japanese male population reported that a PDZK1 single nucleotide polymorphism (SNP), rs12129861, was not associated with gout. In the present study, we performed a further association analysis between gout and rs12129861 in a different large-scale Japanese male population and a meta-analysis with previous Japanese population studies. We genotyped rs12129861 in 1210 gout cases and 1224 controls of a Japanese male population by TaqMan assay. As a result, we showed that rs12129861 was significantly associated with gout susceptibility (P = 0.016, odds ratio [OR] = 0.80, 95% confidence interval [CI] 0.67-0.96). The result of the meta-analysis among Japanese populations also showed a significant association (P = 0.013, OR = 0.85, 95%CI 0.75-0.97). Our findings show the significant association between gout susceptibility and common variant of PDZK1 which reportedly regulates the functions of urate transporters in the urate transportsome.

Genome-wide association study of clinically defined gout identifies multiple risk loci and its association with clinical subtypes.

OBJECTIVE: Gout, caused by hyperuricaemia, is a multifactorial disease. Although genome-wide association studies (GWASs) of gout have been reported, they included self-reported gout cases in which clinical information was insufficient. Therefore, the relationship between genetic variation and clinical subtypes of gout remains unclear. Here, we first performed a GWAS of clinically defined gout cases only. METHODS: A GWAS was conducted with 945 patients with clinically defined gout and 1213 controls in a Japanese male population, followed by replication study of 1048 clinically defined cases and 1334 controls. RESULTS: Five gout susceptibility loci were identified at the genome-wide significance level (p<5.0×10(-8)), which contained well-known urate transporter genes (ABCG2 and SLC2A9) and additional genes: rs1260326 (p=1.9×10(-12); OR=1.36) of GCKR (a gene for glucose and lipid metabolism), rs2188380 (p=1.6×10(-23); OR=1.75) of MYL2-CUX2 (genes associated with cholesterol and diabetes mellitus) and rs4073582 (p=6.4×10(-9); OR=1.66) of CNIH-2 (a gene for regulation of glutamate signalling). The latter two are identified as novel gout loci. Furthermore, among the identified single-nucleotide polymorphisms (SNPs), we demonstrated that the SNPs of ABCG2 and SLC2A9 were differentially associated with types of gout and clinical parameters underlying specific subtypes (renal underexcretion type and renal overload type). The effect of the risk allele of each SNP on clinical parameters showed significant linear relationships with the ratio of the case-control ORs for two distinct types of gout (r=0.96 [p=4.8×10(-4)] for urate clearance and r=0.96 [p=5.0×10(-4)] for urinary urate excretion). CONCLUSIONS: Our findings provide clues to better understand the pathogenesis of gout and will be useful for development of companion diagnostics.

Common missense variant of monocarboxylate transporter 9 (MCT9/SLC16A9) gene is associated with renal overload gout, but not with all gout susceptibility.

Gout is a common disease caused by hyperuricemia, which shows elevated serum uric acid (SUA) levels. From a viewpoint of urate handling in humans, gout patients can be divided into those with renal overload (ROL) gout with intestinal urate underexcretion, and those with renal underexcretion (RUE) gout. Recent genome-wide association studies (GWAS) revealed an association between SUA and a variant in human monocarboxylate transporter 9 (MCT9/SLC16A9) gene. Although the function of MCT9 remains unclear, urate is mostly excreted via intestine and kidney where MCT9 expression is observed. In this study, we investigated the relationship between a variant of MCT9 and gout in 545 patients and 1,115 healthy volunteers. A missense variant of MCT9 (K258T), rs2242206, significantly increased the risk of ROL gout (p = 0.012), with odds ratio (OR) of 1.28, although it revealed no significant association with all gout cases (p = 0.10), non-ROL gout cases (p = 0.83), and RUE gout cases (p = 0.34). In any case groups and the control group, minor allele frequencies of rs2242206 were >0.40. Therefore, rs2242206 is a common missense variant and is revealed to have an association with ROL gout, indicating that rs2242206 relates to decreased intestinal urate excretion rather than decreased renal urate excretion. Our study provides clues to better understand the pathophysiology of gout as well as the physiological roles of MCT9.

Common dysfunctional variants in ABCG2 are a major cause of early-onset gout.

Gout is a common disease which mostly occurs after middle age, but more people nowadays develop it before the age of thirty. We investigated whether common dysfunction of ABCG2, a high-capacity urate transporter which regulates serum uric acid levels, causes early-onset gout. 705 Japanese male gout cases with onset age data and 1,887 male controls were genotyped, and the ABCG2 functions which are estimated by its genotype combination were determined. The onset age was 6.5 years earlier with severe ABCG2 dysfunction than with normal ABCG2 function (P = 6.14 × 10(-3)). Patients with mild to severe ABCG2 dysfunction accounted for 88.2% of early-onset cases (twenties or younger). Severe ABCG2 dysfunction particularly increased the risk of early-onset gout (odds ratio 22.2, P = 4.66 × 10(-6)). Our finding that common dysfunction of ABCG2 is a major cause of early-onset gout will serve to improve earlier prevention and therapy for high-risk individuals.