Distribution and clinical impact of molecular subtypes with dark zone signature of DLBCL in a Japanese real-world study.

The distribution and clinical impact of cell-of-origin (COO) subtypes of diffuse large B-cell lymphoma (DLBCL) outside Western countries remain unknown. Recent literature also suggests that there is an additional COO subtype associated with the germinal center dark zone (DZ) that warrants wider validation to generalize clinical relevance. Here, we assembled a cohort of Japanese patients with untreated DLBCL and determined the refined COO subtypes, which include the DZ signature (DZsig), using the NanoString DLBCL90 assay. To compare the distribution and clinical characteristics of the molecular subtypes, we used a data set from the cohort of British Columbia Cancer (BCC) (n = 804). Through the 1050 patient samples on which DLBCL90 assay was successfully performed in our cohort, 35%, 45%, and 6% of patients were identified to have germinal center B-cell-like (GCB) DLBCL, activated B-cell-like (ABC) DLBCL, and DZsig-positive (DZsigpos) DLBCL, respectively, with the highest prevalence of ABC-DLBCL, differing significantly from the BCC result (P < .001). GCB-DLBCL, ABC-DLBCL, and DZsigpos-DLBCL were associated with 2-year overall survival rates of 88%, 75%, and 66%, respectively (P < .0001), with patients with DZsigpos-DLBCL having the poorest prognosis. In contrast, GCB-DLBCL without DZsig showed excellent outcomes after rituximab-containing immunochemotherapy. DZsigpos-DLBCL was associated with the significant enrichment of tumors with CD10 expression, concurrent MYC/BCL2 expression, and depletion of microenvironmental components (all, P < .05). These results provide evidence of the distinct distribution of clinically relevant molecular subtypes in Japanese DLBCL and that refined COO, as measured by the DLBCL90 assay, is a robust prognostic biomarker that is consistent across geographical areas.

A potential explanation for the global increase in tropical cyclone rapid intensification.

Tropical cyclone rapid intensification events often cause destructive hurricane landfalls because they are associated with the strongest storms and forecasts with the highest errors. Multi-decade observational datasets of tropical cyclone behavior have recently enabled documentation of upward trends in tropical cyclone rapid intensification in several basins. However, a robust anthropogenic signal in global intensification trends and the physical drivers of intensification trends have yet to be identified. To address these knowledge gaps, here we compare the observed trends in intensification and tropical cyclone environmental parameters to simulated natural variability in a high-resolution global climate model. In multiple basins and the global dataset, we detect a significant increase in intensification rates with a positive contribution from anthropogenic forcing. Furthermore, thermodynamic environments around tropical cyclones have become more favorable for intensification, and climate models show anthropogenic warming has significantly increased the probability of these changes.

Increasing typhoon impact and economic losses due to anthropogenic warming in Southeast China.

Despite a variety of studies on the tropical cyclone (TC) response to climate change, few of them have examined the projected damages of future TCs. Here we quantify the impact of anthropogenic warming on TC-induced damages in the late twenty-first century along the coasts of Southeast China based on convection-permitting TC simulations and machine-learning-based damage models. We found that if the area's 10 super typhoons between 2013 and 2019 were to occur at the end of the century under the high emissions RCP8.5 scenario, they would have on average a 12% ± 4% increase in landfall intensity, 25% ± 23% increase in precipitation, and 128% ± 70% increase in economic losses, compared to historical simulations. We also found a significant increase in the full risk profile. The estimated typhoon loss with a 50-year return period for Zhejiang, Fujian, Guangdong, and Hainan (four most typhoon-prone provinces among the seven provinces in the region) would increase by 71%, 170%, 20%, and 85%, respectively, towards the end of the century even under the lower emissions RCP4.5 pathway. Our findings imply the need to design effective local hazard mitigation measures to reduce future typhoon risks.

Description of two new species of the genus Tillicera Spinola (Coleoptera, Cleridae, Clerinae), with new synonyms, new distributional records, and an updated key.

Two species, Tillicerafortis sp. nov. and Tilliceraspinosa sp. nov., are newly described. New distributional records are presented for Tilliceracallosa Gerstmeier & Bernhard, 2010, Tillicerajavana Spinola, 1844, Tillicerapseudocleroides Gerstmeier & Bernhard, 2010, Tillicerasoror Schenkling, 1902, and Tilliceratonkinensis Gerstmeier & Bernhard, 2010. Cleruspostmaculatus Nakane, 1963 syn. nov. is synonymized with Tilliceraihlei Corporaal, 1949. The presence of sensory organs (sensilla) on the ventral surface of the antennae is discovered in Tillicera and Hemitrachys for the first time. A key to the valid species of Tillicera is provided.

Substantial global influence of anthropogenic aerosols on tropical cyclones over the past 40 years.

Over the past 40 years, anthropogenic aerosols have been substantially decreasing over Europe and the United States owing to pollution control measures, whereas they have increased in South and East Asia because of the economic and industrial growth in these regions. However, it is not yet clear how the changes in anthropogenic aerosols have altered global tropical cyclone (TC) activity. In this study, we reveal that the decreases in aerosols over Europe and the United States have contributed to significant decreases in TCs over the Southern Hemisphere as well as increases in TCs over the North Atlantic, whereas the increases in aerosols in South and East Asia have exerted substantial decreases in TCs over the western North Pacific. These results suggest that how society controls future emissions of anthropogenic aerosols will exert a substantial impact on the world's TC activity.

Angioimmunoblastic T-cell Lymphoma Presenting as a Methotrexate-associated Lymphoproliferative Disorder with Extreme Peripheral Blood Plasmacytosis.

A 74-year-old man was admitted to our hospital because of systemic lymphadenopathy, weight loss, and a fever at night that had persisted for approximately 1 month. Blood tests revealed extreme peripheral blood plasmacytosis and hypergammaglobulinemia. A lymph node biopsy showed angioimmunoblastic T-cell lymphoma (AITL). Based on the history of methotrexate (MTX) administration, the established diagnosis was MTX-associated lymphoproliferative disorder (MTX-LPD). After MTX was discontinued, the lymphadenopathy spontaneously regressed and the plasmacytosis disappeared. He had no disease progression for three years. We found that AITL as an MTX-LPD can cause plasmacytosis, and the prognosis of this disease may not be poor.

Sequential Combination of FLAM and Venetoclax plus Azacitidine to Bridge to Cord Blood Transplantation in a Patient with Primary Induction Failure Acute Myeloid Leukemia.

Venetoclax (VEN) is an oral B-cell lymphoma-2 (BCL-2) inhibitor that has been widely used to treat various hematological disorders. Recent studies have demonstrated that VEN in combination with fludarabine-enhanced high-dose cytarabine (FLA) is effective for treating relapsed or refractory acute myeloid leukemia (AML). In the combination therapy, salvage chemotherapy and VEN are basically concurrently administrated; however, further optimization may enable the treatment to apply to larger numbers of patients with various clinical backgrounds. Here, we describe a case of refractory AML treated with a sequential combination of the intensive chemotherapy (fludarabine, cytarabine, and mitoxantrone; FLAM) and VEN/AZA to bridge to an unrelated cord blood transplantation (uCBT). By continuously adding VEN/AZA after FLAM, the patient achieved morphologic leukemia free state with only minor toxicities. Blood cell counts did not recover until the time of transplantation because of the deep myelosuppression caused by the treatment sequence, but the infection risk was safely managed during this period. After engraftment, maintenance therapy with VEN/AZA was performed, and the patient has survived without disease recurrence for over 9 months after transplantation. Our case suggests that bridging therapy with VEN and AZA from the time of the last chemotherapy to allogeneic transplantation may provide an effective and tolerable treatment strategy for refractory AML. Further studies of larger numbers of cases are needed to validate the effectiveness of this treatment.

Bendamustine Plus Rituximab as Salvage Treatment for Patients with Relapsed or Refractory Low-grade B-cell Lymphoma and Mantle Cell Lymphoma: A Single-Center Retrospective Study.

Bendamustine plus rituximab (B-R) is an effective therapy for relapsed or refractory (r/r) low-grade B-cell lymphoma (LGBCL) and mantle cell lymphoma (MCL); however, clinical data from Japanese patients treated with B-R therapy are limited. We retrospectively evaluated the efficacy and safety of B-R therapy in 42 patients who received B-R therapy at our hospital for r/r LGBCL and MCL. All patients received intravenous (IV) ritux-imab 375 mg/m2 on day 1 and IV bendamustine 90 mg/m2 on days 2 and 3 every 28 days for up to 6 cycles. The common histologic subtypes were follicular lymphoma (n = 29, 70%), marginal zone lymphoma (n = 6, 14%), and MCL (n = 5, 12%). The overall response rate was 93%, with 62% complete response and complete response unconfirmed. The median progression-free survival (PFS) was 38 months (95% confidence interval [CI], 24.6 to not reached [NR]), and the median overall survival (OS) was 80 months (95% CI, 60.7 to NR). Patients receiving a cumulative dose of bendamustine ≥ 720 mg/m2 showed a significantly longer PFS and OS. Grade 3/4 adverse events (≥ 10%) included neutropenia (55%), lymphopenia (69%), and nausea (24%). B-R therapy was effective and well tolerated, and the cumulative dose of bendamustine was associated with a favorable outcome.

East Antarctic cooling induced by decadal changes in Madden-Julian oscillation during austral summer.

While West Antarctica has experienced the most significant warming in the world, a profound cooling trend in austral summer was observed over East Antarctica (30°W to 150°E, 70° to 90°S) from 1979 to 2014. Previous studies attributed these changes to high-latitude atmospheric dynamics, stratospheric ozone change, and tropical sea surface temperature anomalies. We show that up to 20 to 40% of the observed summer cooling trend in East Antarctica was forced by decadal changes of the Madden-Julian oscillation (MJO). Both observational analysis and climate model experiments indicate that the decadal changes in the MJO, characterized by less (more) atmospheric deep convection in the Indian Ocean (western Pacific) during the recent two decades, led to the net cooling trend over East Antarctica through modifying atmospheric circulations linked to poleward-propagating Rossby wave trains. This study highlights that changes in intraseasonal tropical climate patterns may result in important climate change over Antarctica.

Daratumumab therapy for relapsed or refractory multiple myeloma: a single-center retrospective study.

BACKGROUND: Significant advancements have been achieved in the quality of treatment for relapsed/refractory multiple myeloma (RRMM). Currently, daratumumab (DARA) is a highly effective drug widely used for RRMM; however, the knowledge on its efficacy and safety in Japanese patients remains limited. Accordingly, we aimed to evaluate the efficacy and safety of DARA therapy for RRMM. METHODS: We reviewed the medical records of patients who received DARA combination therapy and evaluated its efficacy and safety in our hospital. RESULTS: DARA was administered to 44 patients between October 2017 and March 2019. The median number of previous therapies was three (range 1-9). The rates of ≥ complete response and overall response were 27.3% and 61.4%, respectively. The median progression-free survival (PFS) duration was 12.3 months [95% confidence interval (CI) 5.1 to not reached (NR)] and estimated 2-year overall survival rate was 63.7% (95% CI 46.9-76.5%). In the multivariate analysis, patients with ≥ three previous lines of therapy and mass lesions showed significantly shorter PFS durations. The observed grade 3/4 adverse events (≥ 10%) included neutropenia (59.0%), thrombocytopenia (29.5%), anemia (36.4%), lymphopenia (38.6%) and febrile neutropenia (18.2%). None of the patients discontinued DARA therapy in spite of these AEs. CONCLUSION: DARA is an effective treatment option for most patients and is tolerable. However, patients with heavy treatment before DARA therapy and mass lesions are likely to show poorer outcomes. Our findings suggest the use of DARA therapy early in the course of the disease.

Carbon dioxide hydrate as a recovery tool after fatigue of the plantar flexors.

This study investigated the effects of cooling the triceps surae with carbon dioxide hydrate (CDH), which is a gas hydrate, a crystalline structure belonging to the clathrates, on the recovery from muscle fatigue. Thirty-six healthy young men were equally and randomly assigned to an ICE group, a CDH group, or a non-cooling (NON) group. All participants performed 80 maximal voluntary isometric contractions (MVCs) of the plantar flexors as a fatiguing task. MVC torque and voluntary activation were determined before, immediately after, and 20 min after the fatiguing task. Evoked torque was similarly assessed except for immediately after the task. In the ICE and CDH groups, the triceps surae was cooled for 5 min using ice and CDH, starting 5 min after the fatiguing task, respectively. The MVC torque and voluntary activation were higher in order of before >20 min after >immediately after the fatiguing task regardless of group, and those time-course changes did not differ between the groups. A decrease in the evoked torque from before to 20 min after the fatiguing task was observed in the ICE and NON groups but not in the CDH group. These results suggest that cooling muscle with CDH can facilitate recovery from peripheral muscle fatigue. This may be due to an increase in blood flow caused by carbon dioxide contained within the CDH, and indicates the potential of CDH as a recovery tool after fatiguing exercise.

Tropical cyclone motion in a changing climate.

The locally accumulated damage by tropical cyclones (TCs) can intensify substantially when these cyclones move more slowly. While some observational evidence suggests that TC motion might have slowed significantly since the mid-20th century (1), the robustness of the observed trend and its relation to anthropogenic warming have not been firmly established (2-4). Using large-ensemble simulations that directly simulate TC activity, we show that future anthropogenic warming can lead to a robust slowing of TC motion, particularly in the midlatitudes. The slowdown there is related to a poleward shift of the midlatitude westerlies, which has been projected by various climate models. Although the model's simulation of historical TC motion trends suggests that the attribution of the observed trends of TC motion to anthropogenic forcings remains uncertain, our findings suggest that 21st-century anthropogenic warming could decelerate TC motion near populated midlatitude regions in Asia and North America, potentially compounding future TC-related damages.

Detected climatic change in global distribution of tropical cyclones.

Owing to the limited length of observed tropical cyclone data and the effects of multidecadal internal variability, it has been a challenge to detect trends in tropical cyclone activity on a global scale. However, there is a distinct spatial pattern of the trends in tropical cyclone frequency of occurrence on a global scale since 1980, with substantial decreases in the southern Indian Ocean and western North Pacific and increases in the North Atlantic and central Pacific. Here, using a suite of high-resolution dynamical model experiments, we show that the observed spatial pattern of trends is very unlikely to be explained entirely by underlying multidecadal internal variability; rather, external forcing such as greenhouse gases, aerosols, and volcanic eruptions likely played an important role. This study demonstrates that a climatic change in terms of the global spatial distribution of tropical cyclones has already emerged in observations and may in part be attributable to the increase in greenhouse gas emissions.

[Diffuse large B-cell lymphoma relapsing with intravascular large B-cell lymphoma-like perivascular and intravascular lesions].

A 64-year-old woman was diagnosed with diffuse large B-cell lymphoma (DLBCL) in 2013. After eight courses of R-CHOP therapy followed by local irradiation of the remaining retroperitoneal soft tissue shadow, complete response was confirmed on 18F-2-fluoro-2-deoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT). Early in 2016, patient's serum LDH and soluble IL-2 receptor levels elevated. With suspected recurrence of DLBCL, FDG-PET/CT was performed that showed no lymphadenopathy or abnormal FDG uptake. By the end of July 2016, the patient developed fever and night sweating. Intravascular large B-cell lymphoma (IVLBCL) was suspected, and the patient underwent random skin biopsies, which revealed large atypical cells infiltrating peripheral and intravascular regions of the subcutaneous adipose tissue. Cell morphology, immunostaining, and PCR analysis of the immunoglobulin heavy chain gene suggested the recurrence of DLBCL. Despite salvage chemotherapy and autologous peripheral stem cell transplantation with high-dose chemotherapy, approximately 15 months later, DLBCL recurred and involved the lungs. The patient again received chemotherapy and achieved a second remission. Because DLBCL may recur like intravascular lymphoma, the same tests used for IVLBCL diagnosis are required in cases of suspected recurrence of DLBCL based on clinical and laboratory findings.

Author Correction: Recent increases in tropical cyclone intensification rates.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Recent increases in tropical cyclone intensification rates.

Tropical cyclones that rapidly intensify are typically associated with the highest forecast errors and cause a disproportionate amount of human and financial losses. Therefore, it is crucial to understand if, and why, there are observed upward trends in tropical cyclone intensification rates. Here, we utilize two observational datasets to calculate 24-hour wind speed changes over the period 1982-2009. We compare the observed trends to natural variability in bias-corrected, high-resolution, global coupled model experiments that accurately simulate the climatological distribution of tropical cyclone intensification. Both observed datasets show significant increases in tropical cyclone intensification rates in the Atlantic basin that are highly unusual compared to model-based estimates of internal climate variations. Our results suggest a detectable increase of Atlantic intensification rates with a positive contribution from anthropogenic forcing and reveal a need for more reliable data before detecting a robust trend at the global scale.

Author Correction: Recent increases in tropical cyclone intensification rates.

The original version of this Article contained an error in the second sentence of the first paragraph of the 'Quantile mapping' section of the Methods, which incorrectly read 'We primarily focus on results produced using an additive version of QDM26 by making use of R programming language code contained in the CRAN MBC package version 0.10-438.' The correct version states 'QDM29' in place of 'QDM26'. Also, the third sentence of the first paragraph of the 'Quantile mapping' section of the Methods originally incorrectly read 'As reported in Appendix A of Cannon et al.26 the additive version of QDM is functionally very similar to the equidistant CDF matching algorithm of Li et al.39.' The correct version states 'Cannon et al.29' in place of 'Cannon et al.26'. This has been corrected in both the PDF and HTML versions of the Article.

Transport of Azithromycin into Extravascular Space in Rats.

Recent clinical trials showed a prolonged retention of subinhibitory concentrations of unbound azithromycin in the interstitial fluid of soft tissues despite the fact that azithromycin is extensively distributed in tissues. In these clinical trials, interstitial fluid samples were obtained by using the microdialysis method, and it was established that drug concentrations represent protein-unbound drug concentrations. The present study was designed to measure total azithromycin concentrations in the interstitial fluid of the skin of rats by directly collecting interstitial fluid samples from a pore formed on the skin by a dissolving microneedle array. The total azithromycin concentrations in interstitial fluid of the skin were about 4 to 5 times higher than those in plasma throughout the experimental period, and stasis of the azithromycin concentration in interstitial fluid was observed when the concentration of azithromycin in plasma was at the lower limit of quantification. In addition, the skin/plasma concentration ratio transiently increased after dosing (from 4.3 to 83.1). Our results suggest that azithromycin was trapped inside white blood cells and/or phagocytic cells in not only blood but also interstitial fluid, resulting in a high total azithromycin concentration and the retention of its antimicrobial activity at the primary infection site. The stasis of azithromycin in interstitial fluid and skin would lead to long-lasting pharmacological effects (including those against skin infection) at concentrations exceeding the MIC.