Isoliquiritigenin inhibits NLRP3 inflammasome activation with CAPS mutations by suppressing caspase-1 activation and mutated NLRP3 aggregation.

The nucleotide-binding oligomerization domain leucine-rich repeat and pyrin domain containing 3 (NLRP3) inflammasome contributes to the development of inflammatory diseases. Cryopyrin-associated periodic syndrome (CAPS) is an autoinflammatory disease caused by NLRP3 gene mutations that results in excessive IL-1ß production. We previously identified isoliquiritigenin (ILG), a component of Glycyrrhiza uralensis extracts, as a potent inhibitor of the NLRP3 inflammasome. Here, we aimed to investigate whether ILG inhibits the activation of NLRP3 inflammasome caused by NLRP3 gene mutations. We demonstrated that ILG significantly inhibited NLRP3 inflammasome-mediated lactate dehydrogenase (LDH) release and IL-1ß production in two CAPS model THP-1 cell lines, NLRP3-D303N and NLRP3-L353P, in a dose-dependent manner. Interestingly, the NLRP3 inhibitor MCC950 inhibited LDH release and IL-1ß production in NLRP3-D303N cells, but not in NLRP3-L353P cells. Western blotting and caspase-1 activity assays showed that ILG, as well as caspase inhibitors, including Z-VAD and YVAD, suppressed caspase-1 activation. Notably, ILG prevented cryo-sensitive foci formation of NLRP3 without affecting the levels of intracellular Ca2+. We concluded that ILG effectively prevents the constitutive activation of the inflammasome associated with NLRP3 gene mutations by inhibiting the aggregation of cryo-sensitive mutated NLRP3.

First complete remission favours haploidentical haematopoietic stem cell transplantation with post-transplant cyclophosphamide over cord blood transplantation in acute lymphoblastic leukaemia.

To assess the benefits of HLA-haploidentical haematopoietic stem cell transplantation using post-transplant cyclophosphamide (PTCy-haplo) relative to those of umbilical cord blood (UCB) transplantation in acute lymphoblastic leukaemia (ALL), we analysed 1999 patients (PTCy-haplo, 330; UCB, 1669), using the nationwide Japanese registry. PTCy-haplo was associated with a significantly higher relapse rate, but lower non-relapse mortality, which results in overall survival and disease-free survival, comparable to those of UCB. Among patients in CR1, PTCy-haplo showed a significantly higher survival than UCB regardless of the CD34+ cell dose. Our findings provide valuable insights into the donor selection algorithm in allogeneic HSCT for adult patients with ALL.

Secondary central nervous system involvement in patients with diffuse large B-cell lymphoma treated with rituximab combined CHOP therapy - a supplementary analysis of JCOG0601.

Secondary central nervous system involvement (sCNSi) in diffuse large B-cell lymphoma (DLBCL) is fatal. However, its features in patients with sCNSi who are categorized as lower risk by international prognostic index (IPI) or CNS-IPI are not yet fully understood. In the present analysis, we evaluated DLBCL patients who developed sCNSi at their first progression and who participated in JCOG0601, most of whom were lower risk by IPI. Of 409 patients, 21 (5.1%) developed sCNSi during a median follow-up of 4.9 years. Five-year cumulative incidence of sCNSi were 5.1%; and 4.0%, 5.3%, and 11.5% at low, intermediate, and high risk of CNS-IPI, respectively. The most common locations of extranodal lesions at the time of registration in patients with sCNSi were the stomach (n = 4), paranasal cavity (n = 3), and bone marrow (n = 2). In univariable analysis, paranasal cavity lesion was a high-risk factor for sCNSi (subdistribution hazard ratio, 4.34 [95% confidence interval 1.28-14.73]). Median overall survival after sCNSi was 1.3 years, with a 2-year overall survival rate of 39.3%. The incidence of sCNSi in DLBCL patients at lower risk of CNS-IPI was low, as previously reported, but paranasal cavity lesion might indicate high risk for organ involvement. CLINICAL TRIAL REGISTRATION: JCOG0601 was registered in the UMIN Clinical Trials Registry (UMIN000000929, date of registration; December 04, 2007) and the Japan Registry of Clinical Trials (jRCTs031180139, date of registration; February 20, 2019).

Long-term follow-up after R-High CHOP/CHASER/LEED with Auto-PBSCT in untreated mantle cell lymphoma-Final analysis of JCOG0406.

Progression-free survival after R-High CHOP/CHASER/LEED with auto-PBSCT in untreated mantle cell lymphoma in JCOG0406 study. A continuous pattern of relapse was observed.

Comparison of transplant outcomes between haploidentical transplantation and single cord blood transplantation in non-remission acute myeloid leukaemia: A nationwide retrospective study.

Allogeneic haematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for some patients with acute myeloid leukaemia (AML) who are refractory to chemotherapy. Cord blood transplantation (CBT) is a reasonable option in such cases because of its rapid availability. Recently, a growing number of human leucocyte antigen (HLA)-haploidentical related donor HSCTs (haplo-HSCTs) have been performed, although its effectiveness remains undetermined. Using the Japanese nationwide transplantation registry data, we identified 2438 patients aged ≥16 years who received CBT or haplo-HSCT as their first transplant for non-remission AML between January 2008 and December 2018. After 2:1 propensity score matching, 918 patients in the CBT group and 459 patients in the haplo-HSCT group were selected. In this matched cohort, no significant difference in overall survival (OS) was observed between the CBT and haplo-HSCT groups (hazard ratio [HR] of haplo-HSCT to CBT 1.02, 95% confidence interval [CI] 0.89-1.16). Similarly, no significant difference in the cumulative incidence of relapse (HR 1.09, 95% CI 0.93-1.28) or non-relapse mortality (HR 0.94, 95% CI 0.76-1.18). Subgroup analysis showed that CBT was significantly associated with preferable OS in patients receiving myeloablative conditioning. Our data showed comparable outcomes between haplo-HSCT and CBT recipients with non-remission AML.

Improved survival after single-unit cord blood transplantation using fludarabine and melphalan-based reduced-intensity conditioning for malignant lymphoma: impact of melphalan dose and graft-versus-host disease prophylaxis with mycophenolate mofetil.

We evaluated 413 adult patients with lymphoma who underwent unrelated cord blood transplantation (UCBT) with fludarabine and melphalan (FM)-based reduced-intensity conditioning between 2002 and 2017 to investigate longitudinal changes in outcomes and the optimal melphalan dose and graft-versus-host disease (GVHD) prophylaxis regimen. Outcomes were compared between FM80/100 (melphalan dose: 80 or 100 mg/m2) and FM140 (melphalan dose: 140 mg/m2), as well as between calcineurin inhibitor (CNI) plus methotrexate (MTX), CNI plus mycophenolate mofetil (MMF), and CNI alone. The 3-year overall survival (OS) and non-relapse mortality (NRM) rates improved over time (OS: 27% in 2000s vs. 42% in 2010s, p < 0.001; NRM: 43% in 2000s vs. 26% in 2010s, p < 0.001). Multivariable analysis showed that in the 2000s, melphalan dose and GVHD prophylaxis regimen did not affect any outcomes. In the 2010s, FM80/100 (vs. FM140) related to better OS (hazard ratio [HR] 0.62, p = 0.01) and NRM (HR 0.52, p = 0.016). MTX + CNI and CNI alone (vs. CNI + MMF) related to worse OS (CNI + MTX, HR 2.01, p < 0.001; CNI alone, HR 2.65, p < 0.001) and relapse/progression (CNI + MTX, HR 2.40, p < 0.001; CNI alone, HR 2.13, p = 0.023). In recent years, the use of FM80/100 and CNI + MMF significantly reduced the risk of NRM and relapse/progression, respectively, and resulted in better OS after UCBT for lymphoma.

Stabilizers for Osmium Isotopes in Microwave-Irradiated Acid Digestion and Inductively Coupled Plasma Mass Spectrometry Analysis.

Osmium is defined in the international council for harmonization (ICH-Q3D) guidelines as an element whose concentration can be determined by validated methods including microwave-assisted nitric acid digestion and inductively coupled plasma mass spectrometry. However, microwave digestion using nitric acid is known to result in osmium recoveries higher than the theoretical values in spiked tests because of the formation of highly volatile osmium tetroxide in an oxidation reaction. To stabilize osmium, the addition of thiourea as a complexing agent has been tested and proved its utility. It remains unclear whether other compounds can prevent the over-recovery of osmium. In this study, we investigated four compounds, thiourea, ascorbic acid, sodium sulfite, and potassium metabisulfite, that could reduce the overestimation of osmium isotopes. The minimum amounts of thiourea, ascorbic acid, sodium sulfite, and potassium metabisulfite required to stabilize 10 ng/mL osmium in blank matrix were 1.0, 1.0, 2.5, and 2.5 g/L, respectively. The relative standard deviations obtained from 12 analyses for each stabilization solution were less than 3.3% in thiourea, 12.7% in ascorbic acid, 9.0% in sodium sulfite, and 10.6% in potassium metabisulfite. The stabilization solutions were investigated in a digested tablet matrix and were found to be effective. The impact of adding stabilization solutions on the determination of all ICH-Q3D element concentrations was also evaluated. As stabilization solutions had a small or significant impact on the determination of some elements, it was concluded that osmium determination should be conducted independently.

Single response assessment of transplant-ineligible multiple myeloma: a supplementary analysis of JCOG1105 (JCOG1105S1).

BACKGROUND: The International Myeloma Working Group response criteria require two consecutive assessments of paraprotein levels. We conducted an exploratory analysis to evaluate whether a single response assessment could be a substitute for the International Myeloma Working Group criteria using data from JCOG1105, a randomized phase II study on melphalan, prednisolone and bortezomib. METHODS: Of 91 patients with transplant-ineligible newly diagnosed multiple myeloma, 79 patients were included. We calculated the kappa coefficient to evaluate the degree of agreement between the International Myeloma Working Group criteria and the single response assessment. RESULTS: Based on the International Myeloma Working Group criteria, 11 (13.9%), 20 (25.3%), 36 (45.6%) and 12 (15.2%) patients had stringent complete response/complete response, very good partial response, partial response and stable disease, respectively. Based on the single response assessment, 17 (21.5%), 19 (24.1%), 35 (44.3%) and 8 (10.1%) patients had stringent complete response/complete response, very good partial response, partial response and stable disease, respectively. The kappa coefficient was 0.76 (95% confidence interval, 0.65-0.88), demonstrating good agreement. The single response assessment was not inferior to the International Myeloma Working Group criteria in the median progression-free survival (3.8 and 2.9 years) in stringent complete response/complete response patients, suggesting that the single response assessment was not an overestimation. CONCLUSIONS: The single response assessment could be a substitute for the current International Myeloma Working Group criteria for transplant-ineligible newly diagnosed multiple myeloma.

Consecutive single-institution case series of primary central nervous system lymphoma treated by R-MPV or high-dose methotrexate monotherapy.

OBJECTIVE: The optimal regimen for use of high dose-methotrexate-based chemotherapy in primary central nervous system lymphoma is still under debate. We conducted a retrospective study to evaluate the treatment outcome of a combination immunochemotherapy consisting of rituximab, methotrexate, procarbazine and vincristine followed by with or without whole brain radiotherapy and consolidation cytarabine, in comparison with high dose-methotrexate monotherapy followed by full dose whole brain radiotherapy. METHODS: Newly diagnosed primary central nervous system lymphoma patients treated with either rituximab, methotrexate, procarbazine and vincristine or high dose-methotrexate in Kyorin University Hospital were identified, and the response rates and survival were compared. Toxicities, post-treatment transition of Mini-Mental State Examination, Karnofsky performance status score, Fazekas scale and prognostic factors were analysed in the rituximab, methotrexate, procarbazine and vincristine group. RESULTS: Ninety-five patients treated with rituximab, methotrexate, procarbazine and vincristine (n = 39) or high dose-methotrexate (n = 56) were analysed. The complete response/complete response unconfirmed rate was significantly higher in the rituximab, methotrexate, procarbazine and vincristine group (74.4 vs. 15.4%, P < 0.001). Accordingly, both median progression-free survival and overall survival were significantly longer in the rituximab, methotrexate, procarbazine and vincristine group (median progression-free survival: unreached vs. 14.75 months, P < 0.001) (median overall survival: unreached vs. 63.15 months, P = 0.005). Although the rate of grade 3/4 hematologic toxicities was high both during rituximab, methotrexate, procarbazine and vincristine and consolidation cytarabine, the rate of grade 3/4 infections was low, and no treatment related deaths were observed. Deterioration in Karnofsky performance status or Mini-Mental State Examination was rare, except on disease recurrence. Although whole brain radiotherapy was associated with Fazekas scale deterioration, its association with Karnofsky performance status or Mini-Mental State Examination deterioration was not significant. CONCLUSIONS: Rituximab, methotrexate, procarbazine and vincristine was apparently promising in comparison with high dose-methotrexate monotherapy with manageable toxicity in this retrospective study, and further investigation is warranted.

R-High-CHOP/CHASER/LEED with autologous stem cell transplantation in newly diagnosed mantle cell lymphoma: JCOG0406 STUDY.

Although induction immunochemotherapy including high-dose cytarabine and rituximab followed by high-dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) is recommended for younger patients (≤65 years old) with untreated mantle cell lymphoma (MCL), no standard induction and HDC regimen has been established. We conducted a phase II study of induction immunochemotherapy of R-High-CHOP/CHASER followed by HDC of LEED with ASCT in younger patients with untreated advanced MCL. Eligibility criteria included untreated MCL, stage II bulky to IV, and age 20-65 years. Patients received 1 cycle of R-High-CHOP followed by 3 cycles of CHASER every 3 weeks. Peripheral blood stem cells (PBSC) were harvested during CHASER. LEED with ASCT was delivered to patients who responded to R-High-CHOP/CHASER. Primary endpoint was 2-year progression-free survival (PFS). From June 2008 to June 2012, 45 patients (median age 59 years; range 38-65 years) were enrolled. PBSC were successfully harvested from 36 of 43 patients. Thirty-five patients completed ASCT. Two-year PFS was 77% (80% CI 68-84), which met the primary endpoint. Five-year PFS and overall survival were 52% (95% CI 34-68%) and 71% (95% CI 51-84%), respectively. Overall response and complete response rates after induction immunochemotherapy were 96% and 82%, respectively. The most common grade 4 toxicities were hematological. In younger patients with untreated MCL, R-High-CHOP/CHASER/LEED with ASCT showed high efficacy and acceptable toxicity, and it can now be considered a standard treatment option.

Haploidentical transplantation with post-transplant cyclophosphamide versus single cord blood transplantation in adults with relapsed/refractory non-Hodgkin lymphoma.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for relapsed or refractory non-Hodgkin lymphoma (R/R NHL). Allo-HSCT using post-transplant cyclophosphamide (PTCY-haplo) and umbilical cord blood transplantation (uCBT) are important donor options in the absence of matched related siblings. However, the data comparing these two donor sources in R/R NHL are limited. Using the Japanese nationwide transplantation registry data, we identified 857 patients with R/R NHL, including 169 patients who received PTCY-haplo and 688 who received uCBT for their first allo-HSCT between January 2013 and December 2021; 514 patients (60%) had B-cell lymphoma. More PTCY-haplo recipients received allo-HSCT using a reduced-intensity conditioning regimen in recent years. The 3-year overall survival (OS), progression-free survival (PFS), and graft-versus-host disease (GVHD)-free/relapse-free survival (GRFS) rates in the PTCY-haplo and uCBT groups were 44% versus 39% (P = 0.326), 34% versus 33% (P = 0.660), and 19% versus 23% (P = 0.910), respectively; the adjusted hazard ratios for OS, PFS, and GRFS were 0.89 (95% confidence interval: 0.69-1.15, P = 0.373), 0.98 (0.78-1.22, P = 0.852), and 0.92 (0.83-1.21, P = 0.920), respectively. The PTCY-haplo group showed faster neutrophil and platelet engraftment and a lower incidence of grade III-IV acute GVHD. Thus, PTCY-haplo and uCBT could serve as alternative donor sources in patients with R/R NHL.

Cladribine combined with rituximab (R-2-CdA) therapy is an effective salvage therapy in relapsed or refractory indolent B-cell non-Hodgkin lymphoma.

Although cladribine has been reported to be an active purine analog against indolent B-cell non-Hodgkin lymphoma (B-NHL), there are few reports of combination use of cladribine and rituximab. This multicenter phase II study evaluated the efficacy and toxicity of cladribine with rituximab (R-2-CdA) therapy in relapsed or refractory indolent B-NHL. Twenty patients with the median age of 58.5 yrs (range, 42-72) were enrolled and received R-2-CdA therapy from April 2005 to July 2007. The median number of prior regimens was 2 (range, 1-3), and fifteen patients (75%) were previously treated with rituximab-containing regimens. Disease histology included follicular lymphoma in 16 patients, MALT lymphoma in two patients, nodal marginal B-cell lymphoma in one patient, and lymphoplasmacytic lymphoma in one patient. The overall response rate (ORR) was 90%, with a complete response rate (CRR) of 70%. Estimated median progression-free survival (PFS) time was 22.4 months (95%CI, 10.9-32.6 months) at a median follow-up time of 27 months (range, 12-43). Two-year PFS and 2-yr overall survival (OS) were 52.6% (95%CI, 31.0-73.2%) and 89.5% (95%CI, 66.1-97.3%), respectively. Grade 3 or grade 4 toxicities were neutropenia in 74% and thrombocytopenia in 11%. R-2-CdA therapy was demonstrated to have a high activity with durable PFS and acceptable toxicity in relapsed or refractory indolent B-NHL mostly pretreated with rituximab-containing therapy. Although a large-scale trial is needed for confirmation, R-2-CdA therapy could be a good salvage therapy option in relapsed or refractory indolent B-NHL.

A penetrating atherosclerotic ulcer rapidly growing into a saccular aortic aneurysm during treatment of leukaemia: a case report.

BACKGROUND: The clinical course of penetrating atherosclerotic ulcers is variable and can be complicated with intramural haematomas, dissection, pseudoaneurysms, or aortic rupture. Because it can lead to life-threatening conditions, it needs to be managed carefully. CASE SUMMARY: A 68-year-old woman, who was treated for acute myeloid leukaemia (subtype: M0-FAB) approximately 1 year before presentation, visited the hospital with complaints of a headache and lumbar pain. After hospitalization, investigations revealed miliary tuberculosis. On the same day, she developed a Stanford type A acute aortic dissection (AAD) with cardiac tamponade; during the course of the previous leukaemia treatment, a small ulcerative lesion at the distal aortic arch grew into a small saccular aortic aneurysm (SAA) that expanded rapidly and finally developed into a Stanford type A AAD. However, the relationship between the SAA and aortic dissection could not be confirmed. DISCUSSION: The chronological changes in the atherosclerotic lesion at the distal aortic arch could be clearly observed because computed tomography scans were repeatedly obtained until just before the onset of AAD. The rapid progression of atherosclerotic lesions in the unique context of leukaemia treatment and miliary tuberculosis was considered to be a pathological characteristic, and the mechanism underlying this process was investigated. Clinicians should be aware of the aortic complications that may progress under special circumstances, such as anthracycline use or immunodeficiency. Careful observation is mandatory for patients with aortic disease.

Cutaneous adverse events induced by azacitidine in myelodysplastic syndrome patients: Case reports and a lesson from published work review.

Subcutaneous injection of azacitidine (AZA) is an important treatment option for myelodysplastic syndrome (MDS), which improves overall survival. In hematology, the incidence of AZA-induced cutaneous adverse events (AE) has been known to be relatively high, which has not been well recognized by dermatologists. Discontinuation of AZA can result in the deterioration of MDS disease activity. Therefore, on dermatological consultation, precise evaluation of AE severity and careful consideration is required for post-AE medication management. To enhance our understanding of AZA-induced cutaneous AE, we report four cases with two representative cutaneous AE subtypes and summarize the clinicopathological phenotypes and courses of the cases in the published work. Case 1, a 71-year-old man, developed neutrophilic dermatosis involving the dermis and subcutaneous tissue. The other three cases, a 75-year-old man, a 78-year-old woman and a 68-year-old man, presented injection-site erythema associated with flare-up reaction. Discontinuation of AZA was necessary for case 1 alone. The published work review delineated three major subtypes of AZA-induced cutaneous AE: systemic cutaneous reaction, neutrophilic dermatosis type and erythematous type injection-site reaction. Histologically, the first two subtypes are mostly characterized by neutrophil infiltration, while the third subtype presents lymphocytic cell infiltration. Neither AZA discontinuation nor intensive interventions were required for the erythematous type injection-site reaction, while AZA termination or systemic treatments, represented by corticosteroid administration, were preferentially conducted for the systemic cutaneous reaction or the neutrophilic dermatosis type injection-site reaction subgroup. These observations support the necessity of subtype-dependent treatment strategies for the management of AZA-induced cutaneous AE.

Primary diffuse large B-cell lymphoma of the frontal sinus: A case report and literature review.

Diffuse large B-cell lymphoma arising as a primary tumor in the frontal sinus is very rare. Moreover, it is often difficult to diagnose frontal sinus lesions. A 67-year-old Japanese man initially presented with diplopia and a swollen left upper eyelid. Diffusion-weighted magnetic resonance imaging suggested a malignant lymphoma of the frontal sinus, and subsequent extensive examination revealed diffuse large B-cell lymphoma of the frontal sinus with left orbital invasion. Six courses of combined immunodirected chemotherapy were administered. The patient is tumor-free owing to the accurate diagnosis of lymphoma at an early stage.

Hepatosplenic γδ T Cell Lymphoma Involving the Brain.

BACKGROUND: Brain involvement of hepatosplenic T cell lymphoma (HSTL) has not been reported so far. CASE DESCRIPTION: We observed an extremely rare case of HSTL, which is a rare and aggressive variant of peripheral T cell lymphoma, generally showing predominant infiltration to the liver, spleen, and bone marrow and involving the brain. A 41-year-old Japanese woman presented with dysarthria and numbness of the right hand. Radiologic examination revealed a single 3-cm mass in the left frontal cortex, which was totally removed. Pathologic examination of the specimen demonstrated T cell lymphoma with a γδ cytotoxic T cell phenotype. Multiplex polymerase chain reaction analyses confirmed monoclonality of T cell receptor γ. Systemic examination revealed infiltration of atypical T lymphoid cells of the same phenotype in bone marrow and the presence of hepatosplenomegaly. We diagnosed HSTL involving the brain. The patient was treated with several courses of intensive chemotherapy, but it failed to achieve remission. She died of sepsis 4 months after the surgery. CONCLUSIONS: HSTL can involve the brain. A diagnosis of HSTL involving the brain needs careful systemic evaluation. Timely and precise diagnosis that considers the systemic condition is important for appropriate treatment and better outcome.

Retention Behavior of Inorganic Anions in Hydrophilic Interaction Chromatography.

The retention behavior of inorganic anions was studied in hydrophilic interaction chromatography (HILIC). In this study, five kinds of HILIC stationary phases (amino, imidazole, amide, pyridine and zwitterionic) were investigated. It was found that only amino and imidazole columns exhibited the separation of inorganic anions under HILIC conditions. The retention mechanism was further investigated under both columns. A reversed elution order of inorganic anions was observed under the HILIC condition compared with those observed under the ion-exchange chromatography mode (IEC). The effect of salt species and their concentration in the eluent were investigated under constant acetonitrile (ACN) content. Sodium chloride and sodium perchlorate were chosen as the salt, and the salt (sodium perchlorate) concentration was varied from 10 to 40 mM to confirm the effect of the electrostatic interaction. The slope values of the plots of the log retention factor (k) versus the log eluent concentration were calculated to be between -0.43 and -0.45 for the amino column, while those obtained on the imidazole column were between -0.68 and -0.73. Various concentrations of ACN were also examined with 20 mM sodium perchlorate, and the typical HILIC retention behavior was observed on both amino and imidazole columns. Due to the obtained results, it is considered that the separation of inorganic anions under the HILIC condition was achieved by both electrostatic interaction and partition.