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Abstract Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin’s lymphoma, for which cyclophosphamide, doxorubicin, vincristine, and prednisone with rituximab(R–CHOP) is one of the standard regimens. Given that R–CHOP is highly emetogenic, chemotherapy-induced nausea and vomiting (CINV) prevention is clinically important. However, there is a paucity of studies focusing on these patients. This study aimed to ascertain the effectiveness of an oral fixed-dose combination of netupitant and palonosetron (NEPA) in preventing CINV in patients with DLBCL undergoing first-line R-CHOP chemotherapy. Seventy patients were enrolled in this single-center prospective non-comparative study conducted between November 2020 and May 2023 in South Korea. NEPA was administered 1 h prior to chemotherapy initiation on day 1. The primary endpoint of the study was the complete response rate (no emesis, and no rescue medication) during the acute, delayed, and overall phases, which were assessed over a period of 120 h post-chemotherapy. The complete response rates for NEPA were 90.0% [95% CI 80.5, 95.9] for the acute phase, 85.7% [95% CI 75.3, 92.9] for the delayed phase, and 84.3% [95% CI 73.6, 91.9] for the overall phase, with no-emesis rates (acute: 97.1% [95% CI 97.1, 99.7], delayed: 95.7% [95% CI 88.0, 99.1], overall: 92.9% [95% CI 84.1, 97.6]). NEPA was well tolerated with no severe treatment-emergent adverse events. NEPA exhibited substantial efficacy in mitigating CINV in DLBCL patients undergoing R–CHOP chemotherapy, demonstrating high CR and no-emesis rates, and favorable safety profiles.

Background/Aims Optimal risk stratification based on simplified geriatric assessment to predict treatment-related toxicity and survival needs to be clarified in older patients with diffuse large B-cell lymphoma (DLBCL). Methods This multicenter prospective cohort study enrolled newly diagnosed patients with DLBCL (≥ 65 yr) between September 2015 and April 2018. A simplified geriatric assessment was performed at baseline using Activities of Daily Living (ADL), Instrumental ADL (IADL), and Charlson’s Comorbidity Index (CCI). The primary endpoint was event-free survival (EFS). Results The study included 249 patients, the median age was 74 years (range, 65–88), and 125 (50.2%) were female. In multivariable Cox analysis, ADL, IADL, CCI, and age were independent factors for EFS; an integrated geriatric score was derived and the patients stratified into three geriatric categories: fit (n = 162, 65.1%), intermediate-fit (n = 25, 10.0%), and frail (n = 62, 24.9%). The established geriatric model was significantly associated with EFS (fit vs. intermediate-fit, HR 2.61, p < 0.001; fit vs. frail, HR 4.61, p < 0.001) and outperformed each covariate alone or in combination. In 87 intermediate-fit or frail patients, the relative doxorubicin dose intensity (RDDI) ≥ 62.4% was significantly associated with worse EFS (HR, 2.15, 95% CI 1.30–3.53, p = 0.002). It was related with a higher incidence of grade ≥ 3 symptomatic non-hematologic toxicities (63.2% vs. 27.8%, p < 0.001) and earlier treatment discontinuation (34.5% vs. 8.0%, p < 0.001) in patients with RDDI ≥ 62.4% than in those with RDDI < 62.4%. Conclusions This model integrating simplified geriatric assessment can risk-stratify older patients with DLBCL and identify those who are highly vulnerable to standard dose-intensity chemoimmunotherapy.

BackgroundBone marrow (BM) involvement is an indicator of a poor prognosis in diffuse large B-cell lymphoma (DLBCL); however, few studies have evaluated the role of immunoglobulin gene rearrangement (IgR) in detecting BM involvement.MethodsWe evaluated the clinical characteristics and treatment outcomes of patients with DLBCL based on histological BM involvement or positive BM IgR using polymerase chain reaction or next-generation sequencing. We also investigated the role of consolidative upfront autologous hematopoietic stem cell transplantation (ASCT) in patients with DLBCL and BM involvement.ResultsAmong 624 patients, 123 (19.7%) with histological BM involvement and 88 (17.5%) with positive IgR in histologically negative BM had more advanced disease characteristics. Overall (OS) and progression-free (PFS) survival was better for patients with negative BM histology and negative IgR than that in patients with histological BM involvement (P = 0.050 and P < 0.001, respectively) and positive IgR with negative BM histology (P = 0.001 and P = 0.005, respectively). Survival rates did not differ among 82 (13.1%) patients who were treated with upfront ASCT and had histological BM involvement or positive IgR with negative BM histology. The survival outcomes were worse for patients who were not treated with upfront ASCT and for those with histological BM involvement or positive IgR, than for those with negative BM histology and negative IgR.ConclusionPatients diagnosed with DLBCL and BM involvement based on histology or IgR had aggressive clinical features and poor survival. Upfront ASCT mitigated poor prognosis due to BM involvement.

IntroductionDespite the current effective treatments for acute promyelocytic leukemia (APL), early mortality (EM), defined as death within 30 days of presentation, is a major hurdle to long-term survival.MethodsWe performed a multicenter retrospective study to evaluate the incidence and clinical characteristics of EM in patients with newly diagnosed APL and to develop a risk stratification model to predict EM.ResultsWe identified 313 eligible patients diagnosed between 2000 and 2021 from five academic hospitals. The median age was 50 years (range 19-94), and 250 (79.9%) patients were 24 hours of presentation (HR, 2.95). Based on these factors, patients were stratified into three categories with a significantly increasing risk of EM: 4.1% for low risk (54.3%; no risk factors; HR 1), 18.5% for intermediate risk (34.5%; 1 factor; HR 4.81), and 40.5% for high risk (11.2%; 2-3 factors; HR 13.16).DiscussionThe risk of EM is still not negligible in this era of ATRA-based therapies. Our risk model serves as a clinically useful tool to identify high-risk patients for EM who may be candidates for novel treatments and aggressive supportive strategies.

Summary: Avian brood parasites and their hosts display varied egg-puncture behaviors, exerting asymmetric co-evolutionary selection pressures on eggshells’ breaking strength. We investigated eggshell structural and textural characteristics that may improve its mechanical performance. Parasitic eggshell calcified layers showed complex ultra- and microstructural patterns. However, stronger parasitic eggshells are not due to lower textural severity (characterized by lower preferred crystallographic orientation, larger local grain misorientation and smaller Kearns factor), but rather to grain boundary (GB) microstructure characteristics within the eggshell outermost layer (palisade layer, PL). Accordingly, the thicker the PL and the more complex the GB pathways are, the tougher the parasitic eggshells will be. These characteristics, which we can identify as a “GB Engineering” driven co-evolutionary process, further improve eggshell breaking strength in those parasitic species that suffer relatively high frequencies of egg-puncturing by congeneric or hosts. Overall, plain textural patterns are not suitable predictors for comparing mechanical performance of bioceramic materials.

This study explores the therapeutic potential of targeting CXCR2 in patients afflicted with ponatinib-resistant chronic myeloid leukemia (CML). Ponatinib, a third-generation tyrosine kinase inhibitor (TKI), was initially designed for treating patients with CML harboring the T315I mutation. However, resistance or intolerance issues may lead to treatment discontinuation. Additionally, TKIs have exhibited limitations in eradicating quiescent CML stem cells. Our investigation reveals the activation of CXC chemokine receptor 2 (CXCR2) signaling in response to chemotherapeutic stress. Treatment with the CXCR2 antagonist, SB225002, effectively curtails cell proliferation and triggers apoptosis in ponatinib-resistant CML cells. SB225002 intervention also results in the accumulation of reactive oxygen species and disruption of mitochondrial function, phenomena associated with TKI chemoresistance and apoptosis. Furthermore, we demonstrate that activated CXCR2 expression induces the activity of dipeptidylpeptidase Ⅳ (DPP4/CD26), a CML leukemic stem cell marker, and concomitantly inhibits the PI3K/Akt/mTOR pathway cascades. These findings underscore the novel role of CXCR2 in the regulation of not only ponatinib-resistant CML cells, but also CML leukemic stem cells. Consequently, our study proposes that targeting CXCR2 holds promise as a viable therapeutic strategy for addressing patients with CML grappling with ponatinib resistance.

Early detection of multiple cancers through a single method could be clinically important. Here the authors report the diagnostic performance for early detection for multiple cancers using surface-enhanced Raman spectroscopy (SERS) profiles of exosomes from a single blood test and artificial intelligence in a retrospective study design.

IntroductionUpfront autologous stem cell transplantation (ASCT) has been recommended for patients who are newly diagnosed with peripheral T-cell lymphoma (PTCL), and CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), an anthracycline-based chemotherapy has been the frontline chemotherapy for PTCL. However, it is not clear whether anthracycline-based chemotherapies such as CHOP could be standard induction therapy for PTCL.MethodsWe conducted a randomized phase II study to compare CHOP with fractionated ifosfamide, carboplatin, etoposide, and dexamethasone (ICED) for patients eligible for ASCT. The primary endpoint was progression-free survival (PFS) and secondary endpoints included objective response rate, overall survival (OS), and safety profiles.ResultsPatients were randomized into either CHOP (n = 69) or ICED (n = 66), and the characteristics of both arms were not different. PTCL-not otherwise specified (NOS, n = 60) and angioimmunoblastic T-cell lymphoma (AITL, n = 53) were dominant. The objective response rate was not different between CHOP (59.4%) and ICED (56.1%), and the 3-year PFS was not different between CHOP (36.7%) and ICED (33.1%). In AITL patients, CHOP was favored over ICED whereas ICED was associated with more cytopenia and reduced dose intensity. Patients who received upfront ASCT after achieving complete response to CHOP or ICED showed 80% of 3-year OS.DiscussionIn summary, our study showed no therapeutic difference between CHOP and ICED in terms of response and PFS. Thus, CHOP might remain the reference regimen especially for AITL based on its better outcome in AITL, and upfront ASCT could be recommended as a consolidation of complete response in patients with PTCL.

Chinese cabbage is a popular leaf vegetable, and many cultivars have been developed for different regions and growing seasons. For the identification of the cultivars, many marker systems have been applied, but they usually require a large number of markers and expensive equipment. Therefore, it is necessary to develop an efficient and economical method for identifying Chinese cabbage cultivars. In this study, we aimed to develop a marker system with the minimum number of markers using simple PCR and gel electrophoresis. A total of 48 simple sequence repeats (SSRs) in a previous study were screened based on their chromosomal location and applied to 105 Chinese cabbage cultivars. The minimum number of markers was selected based on their genomic location, polymorphic information content, and allele frequency. To validate the cultivar identification capability of selected SSRs, they were applied to genetically similar cultivar pairs from a previous study. Eleven SSRs were finally selected, and they successfully identified cultivars with high genetic similarity, as well as all 105 Chinese cabbage cultivars tested. The proposed SSRs require only 11 primer sets, simple PCR, and gel electrophoresis, which need less time and resources compared to previous ones. These SSRs can be used not only in small seed companies and laboratories but also in large-scale seed companies.

To fabricate multilayer ceramic capacitors (MLCCs) that can withstand external impacts, technologies to achieve excellent adhesion and mechanical strength of the cover layer should be essentially developed. Low adhesion and strength of the cover layer can lead to delamination and cracks in the MLCC, respectively. In this study, we present a method for applying polydopamine (PDA), a mussel-inspired adhesive protein, for as robust cover layer on an MLCC. Barium titanate (BT) particles treated with PDA increase the dispersion stability of the BT/PDA slurry, preventing re-agglomeration of the particles and enhancing the adhesiveness and strength owing to the cohesive properties of PDA. Compared to the BT layer, the adhesion of the BT/PDA layer was significantly enhanced by 217%; consequently, the compression modulus of the BT/PDA cover layer increased by 29.4%. After firing, the N-doped graphitic PDA played an important role in producing an MLCC cover layer with increased hardness and toughness. Furthermore, the N-doped graphitic PDA with a hydrophobic surface forms tortuous moisture paths in the cover layer, preventing the degradation of insulation resistance of the MLCC.

IntroductionPre-emptive therapy for cytomegalovirus (CMV) reactivation has been used in allogeneic hematopoietic stem cell transplantation (allo-HSCT). It is unclear if this strategy has poorer clinical outcomes in CMV-endemic areas and if more aggressive prophylaxis is required.MethodsWe retrospectively analyzed the patterns and survival after CMV reactivation in patients undergoing pre-emptive therapy following allo-HSCT and assessed high-risk patients who could benefit from aggressive CMV prophylaxis in endemic areas.ResultsOf the 292 patients who underwent allo-HSCT, 70.5% (donor+ or recipient+) were CMV seropositive. CMV reactivation occurred in 139 patients (47.6%), with a median of 31.5 days from day 0 of allo-HSCT. The overall survival of patients with CMV reactivation who received pre-emptive therapy did not differ from those without reactivation. Of the 139 patients with CMV reactivation, 78 (56.1%) underwent ≥2 rounds of pre-emptive therapy. In multivariate analysis, the risk of CMV reactivation was higher in patients with multiple myeloma, with CMV seropositivity of the recipient and donor, administered with a higher dose of anti-thymocyte globulin (ATG), and with acute graft-versus-host disease (aGVHD) ≥ grade 2.ConclusionAlthough half of the patients with allo-HSCT were administered with pre-emptive therapy for CMV, CMV reactivation did not affect their survival, indicating the advantages of pre-emptive therapy, even in CMV-endemic areas. The cost-effectiveness of more aggressive CMV prophylaxis should be re-evaluated in patients at a high risk for CMV reactivation.

Background/Aims Relatively little data are available on how the response to the coronavirus disease 2019 (COVID-19) pandemic has affected treatment outcomes in patients receiving chemotherapy for lymphoma or multiple myeloma. We aimed to determine the effect of COVID-19 countermeasures on treatment outcomes in this patient population. Methods We retrospectively analyzed data on patients treated for lymphoma or multiple myeloma in two tertiary hospitals in Seoul. Patients were divided into two groups: group 1 included patients who received chemotherapy between September and December 2019 (the control period), and group 2 included patients who received chemotherapy between September and December 2020 (the study period). Countermeasures to COVID-19 were applied to the patients in group 2. The countermeasures implemented included mask wearing and regular handwashing at home and in hospital; COVID-19 risk assessments on all hospital visitors; and pre-emptive COVID-19 screening for all newly hospitalized patients and their resident guardians. Results No differences in treatment outcomes, including treatment response, incidence and duration of neutropenia or neutropenic fever, delays in chemotherapy, or number of deaths during chemotherapy, were observed between the g roups. None of the patients in group 2 tested positive for COVID-19, and there were no COVID-19-related deaths during the study period. Conclusions Countermeasures to COVID-19 did not affect treatment outcomes in patients receiving chemotherapy for lymphoma or multiple myeloma. Data on the effect of countermeasures to COVID-19 on treatment outcomes should continue to be analyzed to ensure that treatment outcomes are not adversely affected.

As the discussion of first-line anagrelide treatment is ongoing, we aimed to prospectively examine the efficacy and safety of anagrelide in cytoreduction therapy-naïve high risk essential thrombocythemia (ET) patients in Korea. Seventy patients from 12 centers were treated with anagrelide monotherapy for up to 8 weeks, followed up until 24 months. At week 8, 50.0% of the patients were able to achieve platelet < 600 x 109/L, and by 12 months, 55/70 (78.6%) patients stayed on anagrelide, and 40.0% patients showed platelet normalization. 14 patients required additional hydroxyurea (HU) for cytoreduction. The median daily dose of needed HU was 500mg (range 250mg – 1500mg). The efficacy was independent of the somatic mutation status. There were 4 thromboembolic events and 7 bleeding events during the follow-up period. The most common adverse events associated with anagrelide use were headache, followed by palpitation/chest discomfort, edema and generalized weakness/fatigue. 7 patients wished to discontinue anagrelide treatment due to adverse events (3 due to headache; 2 due to edema; 1 due to palpitation and 1 due to skin eruption). All in all, first-line anagrelide treatment showed a favorable response with tolerable safety profiles regardless of somatic mutation status.

Background/Aims Febrile neutropenia (FN) interferes with the proper chemotherapy dose density or intensity in non-Hodgkin’s lymphoma (NHL) patients. Chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) ± rituximab has an intermediate FN risk. Prophylactic granulocyte colony-stimulating factor (G-CSF) support is recommended for patients with other host-related risk factors. Methods We evaluated the risk factors for FN-related admission in NHL patients who have received primary G-CSF (lenograstim) prophylaxis. Results Data from 148 patients were analyzed. The incidence of neutropenic fever was 96 events (12.2%), and the median period was 3.85 days (range, 0 to 5.9); the median duration of neutropenia was 4.21 days (range, 3.3 to 5.07). Eighty-three FN-related admissions were reported. Advanced age (> 60 years), female sex, a low albumin level, and prednisone use were associated with FN-related admission in multivariable analysis (p = 0.010, p < 0.001, and p = 0.010, respectively). A comparison between diffuse large B-cell lymphoma patients treated with R-CHOP and pegylated G-CSF and those treated with R-CHOP and lenograstim did not reveal significant differences in the FN-related admission rate between the two groups, although the lenograstim-treated group had a higher incidence of severe neutropenia. Conclusions Elderly patients, female patients, and patients with low albumin levels need to be actively followed-up for FN even when primary prophylaxis with G-CSF has been used.

Abstract In clinical practice, most patients with monoclonal gammopathy of undetermined significance (MGUS) undergo long-term follow-up without disease progression. There is insufficient real-world data about how closely and whether anything other than disease progression should be monitored. Herein, we performed a nationwide study of 470 patients with MGUS with a 10-year follow-up to determine the patterns of disease progression and other comorbidities. During the follow-up period, 158 of 470 patients with MGUS (33.62%) progressed to symptomatic monoclonal gammopathies. Most of these were multiple myeloma (134/470 patients, 28.51%), and those diagnosed within 2 years after diagnosis of MGUS was high. Approximately 30–50% of patients with MGUS had hypertension, diabetes, hyperlipidemia, and osteoarthritis at the time of diagnosis, and these comorbidities were newly developed during the follow-up period in approximately 50% of the remaining patients with MGUS. Approximately 20–40% of patients with MGUS have acute or chronic kidney failure, thyroid disorders, disc disorders, peripheral neuropathy, myocardial infarction, stroke, and heart failure during the follow-up period. Altogether, when MGUS is diagnosed, close follow-up of the possibility of progression to multiple myeloma is required, especially within 2 years after diagnosis; simultaneously, various comorbidities should be considered and monitored during the follow-up of patients with MGUS. Continuous research is needed to establish appropriate follow-up guidelines.

Along the cold subduction geotherm, glaucophane remains stable down to pressure and temperature (P–T) conditions of ca. 240 km depth, whereas under the warm subduction geotherm, it dehydrates and breaks down into pyroxenes and silica between ca. 50 and 100 km depths.

Albite is one of the major constituents in the Earth’s crust. Here, the authors report that under hydrous cold subduction conditions, albite undergoes breakdown into hydrated smectite and other phases, which release alkaline fluids into the mantle wedge.

Abstract Isolation of pure extracellular vesicles (EVs), especially from blood, has been a major challenge in the field of EV research. The presence of lipoproteins and soluble proteins often hinders the isolation of high purity EVs upon utilization of conventional separation methods. To circumvent such problems, we designed a single-step dual size-exclusion chromatography (dSEC) column for effective isolation of highly pure EVs from bone marrow derived human plasma. With an aim to select appropriate column design parameters, we analyzed the physiochemical properties of the major substances in bone marrow derived plasma, which include EVs, lipoproteins, and soluble proteins. Based on these findings, we devised a novel dSEC column with two different types of porous beads sequentially stacked each other for efficient separation of EVs from other contaminants. The newly developed dSEC columns exhibited better performance in isolating highly pure EVs from AML plasma in comparison to conventional isolation methods.

Background/Aims Various preoperative screening tests, such as platelet count, prothrombin time, activated partial thromboplastin time, and bleeding time, have been widely used to evaluate the risk of bleeding during surgery. Use of platelet function analyzer (PFA)-100/200 for assessing platelet function instead of bleeding time is increasing. However, its role in predicting the perioperative risk of bleeding remains controversial. Methods Data of 703 patients who underwent surgery under general anesthesia were retrospectively analyzed. Preoperative platelet function was measured using PFA-200 system and the association with intraoperative bleeding was assessed. Additionally, other variables that could affect PFA-200 results were assessed by logistic regression analysis. Results Collagen/epinephrine (COL/EPI) test was prolonged in 199/703 (28.3%) patients (EPI group), while 99/212 (46.7%) patients showed COL/adenosine diphosphate test abnormalities. Bleeding over 300 mL during surgery occurred in 14.3% and 20.1% of patients in the normal and EPI groups, respectively (p = 0.058). In addition, red blood cell transfusion within 72 hours after surgery rate was significantly higher in the EPI group than in the normal group (31.7% vs. 23.4%, p = 0.024). In multivariate logistic analysis, prolongation closure time with COL/EPI (p = 0.068) was marginally associated with risk of bleeding during surgery. Furthermore, PFA-200 results were influenced by various factors, such as nonsteroidal anti-inflammatory drug use, blood group, hematocrit, and time of blood collection. Conclusions Preoperative PFA-200 test may be helpful in predicting the risk of perioperative bleeding. However, its results should be carefully interpreted because they are affected by several factors.

Abstract Our aim was to compare the efficacy and safety of two recently developed biosimilars of pegfilgrastim, a pegylated form of the recombinant human granulocyte‐colony stimulating factor (G‐CSF) analog filgrastim with those of the reference pegfilgrastim. We retrospectively analyzed data from patients diagnosed with diffuse large B‐cell lymphoma (DLBCL) who were treated with first‐line R‐CHOP chemotherapy and received pegylated G‐CSF for primary prophylaxis. The following pegylated G‐CSFs were analyzed in this study: reference pegfilgrastim (Neulasta®) and two of its biosimilars (tripegfilgrastim; Dulastin® and pegteograstim; Neulapeg®). In total, 296 patients were enrolled. The number of patients with at least one episode of neutropenia during R‐CHOP chemotherapy was the lowest in the reference cohort (pegfilgrastim: 127 of 193 patients, 65.8%; tripegfilgrastim: 64 of 69 patients, 92.8%; pegteograstim: 28 of 34 patients, 82.4%, P

Background/Aims The diagnosis of immune thrombocytopenia (ITP) is based on clinical manifestations and there is no gold standard. Thus, even hematologic malignancy is sometimes misdiagnosed as ITP and adequate treatment is delayed. Therefore, novel diagnostic parameters are needed to distinguish ITP from other causes of thrombocytopenia. Immature platelet fraction (IPF) has been proposed as one of new parameters. In this study, we assessed the usefulness of IPF and developed a diagnostic predictive scoring model for ITP. Methods We retrospectively studied 568 patients with thrombocytopenia. Blood samples were collected and IPF quantified using a fully-automated hematology analyzer. We also estimated other variables that could affect thrombocytopenia by logistic regression analysis. Results The median IPF was significantly higher in the ITP group than in the non-ITP group (8.7% vs. 5.1%). The optimal cut-off value of IPF for differentiating ITP was 7.0%. We evaluated other laboratory variables via logistic regression analysis. IPF, hemoglobin, lactate dehydrogenase (LDH), and ferritin were statistically significant and comprised a diagnostic predictive scoring model. Our model gave points to each of variables: 1 to high hemoglobin (> 12 g/dL), low ferritin (≤ 177 ng/mL), normal LDH (≤ upper limit of normal) and IPF ≥ 7 and < 10, 2 to IPF ≥ 10. The final score was obtained by summing the points. We defined that ITP could be predicted in patients with more than 3 points. Conclusions IPF could be a useful parameter to distinguish ITP from other causes of thrombocytopenia. We developed the predictive scoring model. This model could predict ITP with high probability.

Abstract Background We assessed the mechanism of hematopoietic stem cell (HSC) mobilization using etoposide with granulocyte-colony stimulating factor (G-CSF), and determined how this mechanism differs from that induced by cyclophosphamide with G-CSF or G-CSF alone. Methods We compared the clinical features of 173 non-Hodgkin’s lymphoma patients who underwent autologous peripheral blood stem cell transplantation (auto-PBSCT). Additionally, we performed in vitro experiments to assess the changes in human bone marrow stromal cells (hBMSCs), which support the HSCs in the bone marrow (BM) niche, following cyclophosphamide or etoposide exposure. We also performed animal studies under standardized conditions to ensure the following: exclude confounding factors, mimic the conditions in clinical practice, and identify the changes in the BM niche caused by etoposide-induced chemo-mobilization or other mobilization methods. Results Retrospective analysis of the clinical data revealed that the etoposide with G-CSF mobilization group showed the highest yield of CD34+ cells and the lowest change in white blood cell counts during mobilization. In in vitro experiments, etoposide triggered interleukin (IL)-8 secretion from the BMSCs and caused long-term BMSC toxicity. To investigate the manner in which the hBMSC-released IL-8 affects hHSCs in the BM niche, we cultured hHSCs with or without IL-8, and found that the number of total, CD34+, and CD34+/CD45- cells in IL-8-treated cells was significantly higher than the respective number in hHSCs cultured without IL-8 (p = 0.014, 0.020, and 0.039, respectively). Additionally, the relative expression of CXCR2 (an IL-8 receptor), and mTOR and c-MYC (components of IL-8-related signaling pathways) increased 1 h after IL-8 treatment. In animal studies, the etoposide with G-CSF mobilization group presented higher IL-8-related cytokine and MMP9 expression and lower SDF-1 expression in the BM, compared to the groups not treated with etoposide. Conclusion Collectively, the unique mechanism of etoposide with G-CSF-induced mobilization is associated with IL-8 secretion from the BMSCs, which is responsible for the enhanced proliferation and mobilization of HSCs in the bone marrow; this was not observed with mobilization using cyclophosphamide with G-CSF or G-CSF alone. However, the long-term toxicity of etoposide toward BMSCs emphasizes the need for the development of more efficient and safe chemo-mobilization strategies.

With 32 fungicides, it was examined the inhibitory effects on the mycelial growth of Alternaria dauci KACC42997 causing Alternaria leaf blight of carrot. Showing the results of the agar dilution method, the fungicides belonging to C2, C5, G1, E2, and E3 group were excellent in inhibiting mycelial growth. Protective fungicides belonging to M group, except for iminoctadine tris-albesilate, and pyraclostrobin belonging to C3 group were effective in inhibiting spore germination of pathogens. The fungicides included into C2 group inhibiting succinate dehydrogenase activity and the G1 group inhibiting demethylase activity showed the excellent inhibitory effect on mycelial growth but the inhibitory effect of spore germination was very low. However, fluazinam belonging to C5 group was excellent in inhibiting spore germination as well as mycelial growth. Especially, when 100 μg/ml of fluxapyroxad belonging to the C2 group was treated, 47.1% of spore formation was inhibited on the medium. In comparison of the resistance factors of 3 fungicide groups, as G, C, and E group, in populations of A. dauci isolates collected from Gumi, Pyeongchang, and Jeju, resistance factor in the population of Jeju was the lowest. However, two isolates resistant to fludioxonil belonging to E2 group were found in the isolate group of Pyeongchang, and both showed crossresistance to iprodione and procymidone.

Background/Aims Bortezomib plus melphalan-prednisone (VMP) is a standard treatment for multiple myeloma, particularly for patients who are ineligible for high-dose therapy. However, early discontinuation or treatment modification is often needed owing to adverse events. The aim of this study was to investigate the clinical outcomes of modifying the dose of melphalan-prednisone (MP) in patients receiving VMP. Methods We examined 67 patients who received a modified dose of MP, and 38 patients who received the regularly planned dose of MP. We then analyzed clinical differences between the groups. Results Although there was no difference in the proportion of discontinuation due to adverse events between dose groups, more patients in the planned-dose group experienced earlier discontinuation in general. The overall response rate (ORR) was 81.0% and complete response (CR) rate was 30.5%. After a median 15.7 months of follow-up, the median progression-free survival (PFS) and overall survival (OS) were 25.0 and 47.8 months, respectively. There was no significant difference in the ORR, CR, PFS, and OS of the two dose groups. A median of four cycles were delivered, and the median cumulative bortezomib dose was 41.6 mg/m2 . The median PFS in patients with doses ≥ 41.6 mg/m2 was longer than that in patients with doses < 41.6 mg/m2 (35.1 months vs. 9.6 months). However, when MP was < 50% of the planned dose, PFS and OS were poor. Conclusions Modifying the dose of MP might be a feasible and effective therapeutic approach for multiple myeloma patients receiving VMP treatment.

BackgroundCereblon (CRBN) is a direct target of immunomodulatory drugs (IMiDs) and is known to be sensitive and responsive to IMiD therapy. We evaluated CRBN expression in bone marrow plasma cells and analyzed whether CRBN expression was associated with multiple myeloma prognosis. Lastly, we developed a nomogram model for predicting high CRBN expression based on clinically significant blood markers.MethodsWe evaluated 143 multiple myeloma patients (internal dataset) who underwent bone marrow examinations. For evaluating the prognostic ability of the nomogram model, two external cohorts (235 patients in external dataset 1 and 156 patients in external dataset 2) were analyzed. The expression of CRBN in bone marrow aspirate samples was evaluated using immunohistochemistry. High CRBN expression was defined as the study-defined H-score ≥6.ResultsIn the high CRBN group, the median progression-free survival (PFS) and overall survival (OS) of patients receiving the IMiD-based therapy and non-IMiD therapy were 29 and 10 months for PFS, and NR (not reached) and 54 months for OS, respectively. IMiD-based therapy was significantly associated with better PFS and OS outcomes. High CRBN expression was independently predicted by female sex, high serum free-light chain (FLC) ratio, higher serum M-protein level, and higher β2-microglobulin level. Based on these results, we constructed a new nomogram model to predict high CRBN expression and the effectiveness of IMiD therapy in multiple myeloma.ConclusionThis nomogram could improve the prognostic evaluation of myeloma patients exhibiting high CRBN expression treated with IMiD therapy and might help provide personalized treatment strategies to clinicians.

Galectin-9 (Gal-9) expression can be negatively or positively associated with cancer patient prognosis, depending on the cancer type. However, the nature of this relationship remains unclear in multiple myeloma. Therefore, we evaluated the prognostic value of Gal-9 and its relationship with the expression of PD-L1 molecule, the most widely studied immune checkpoint inhibitor, in patients with newly diagnosed multiple myeloma. Gal-9 and PD-L1 levels in bone marrow aspirate samples were evaluated using immunofluorescence assays. Gal-9 positivity was defined as having ≥1% Gal-9-expressing plasma cells. PD-L1 expression was categorized as low or high based on its median value. The median OS of patients with positive and negative Gal-9 expression was 42 months and not reached, respectively. However, no significant difference was observed in OS between the two groups (P = 0.10). Patients with high PD-L1 expression had OS times of 14 and 43 months in the positive and negative Gal-9 expression groups, respectively. In the high PD-L1 expression group, patients expressing Gal-9 had significantly worse OS than those negative for it (P = 0.019). Multivariable Cox analysis confirmed that Gal-9 expression could independently predict shortened OS (hazard ratio, 1.090; 95% confidence interval, 1.015–1.171; P = 0.018) in patients with high PD-L1 expression. However, in the low PD-L1 expression group, patients with high Gal-9 expression exhibited a trend toward better OS (P = 0.816). Our results indicate that the prognostic value of Gal-9 may be related to PD-L1 expression in patients with newly diagnosed multiple myeloma.

Poliovirus receptor (PVR, CD155) is upregulated during tumor progression, and PVR expression is associated with poor prognosis in cancer patients; however, prognostic implications for PVR in multiple myeloma (MM) have not been investigated. PVR plays an immunomodulatory role by interacting with CD226, CD96, and TIGIT. TIGIT is a checkpoint inhibitory receptor that can limit adaptive and innate immunity, and it binds to PVR with the highest affinity. We used immunohistochemistry, ELISA, qPCR, and flow cytometry to investigate the role of PVR in MM. PVR was highly expressed in patients with MM, and membrane PVR expression showed a significant correlation with soluble PVR levels. PVR expression was significantly associated with the Revised-International Staging System stage, presence of extramedullary plasmacytoma and bone lesion, percentage of bone marrow plasma cells (BMPCs), and β2-microglobulin levels, suggesting a possible role in advanced stages and metastasis. Furthermore, TIGIT expression was significantly correlated with the percentage of BMPCs. Patients with high PVR expression had significantly shorter overall and progression-free survival, and PVR expression was identified as an independent prognostic factor for poor MM survival. These findings indicate that PVR expression is associated with MM stage and poor prognosis, and is a potential prognostic marker for MM.

ObjectiveThe clinical characteristics and therapeutic strategy in acute myeloid leukemia (AML) are influenced by patients' age. We evaluated the impact of age on remission induction therapy for AML.MethodsWe retrospectively analyzed 3,011 adult AML patients identified from a nationwide database between January 2007 and December 2011.ResultsThree hundred twenty-nine (10.9%) acute promyelocytic leukemia (APL) and 2,682 (89.1%) non-APL patients were analyzed. The median age was 51 years and 55% of patients were male. Six hundred twenty-three patients (21%) were at favorable risk, 1522 (51%) were at intermediate risk, and 743 (25%) were at poor risk. As the age increased, the proportion of those at favorable risk and who received induction chemotherapy decreased. After induction therapy, complete response (CR) was achieved in 81.5% (243/298) of APL and 62.4% (1,409/2,258) of non-APL patients; these rates decreased as the age increased, with an obvious decrement in those older than 60 years. The median overall survival of non-APL patients was 18.7 months, while that of APL patients was not reached, with a 75% five-year survival rate.ConclusionsAge impacts both the biology and clinical outcomes of AML patients. Further studies should confirm the role of induction remission chemotherapy by age group.

Background: Although many acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients have been treated with hypomethylating agents (HMAs) as a substitute for intensive chemotherapy in recent years, the incidence of invasive fungal infections (IFIs) and the efficacy of posaconazole as antifungal prophylaxis in these patients are not well known to date. Methods: We retrospectively analyzed 280 AML and MDS patients treated with HMAs to identify IFI incidence and posaconazole efficacy as antifungal prophylaxis in these patients. Results: The overall incidence of probable or proven IFIs was 7.9% (22/280 patients): 11.5% in the no-use group (17/148 patients) and 3.8% in the posaconazole group (5/132 patients). Most IFIs occurred during the early cycles of the HMAs (median: 3 cycles; range: 1–8 cycles), especially in patients who had neutropenia or did not respond to HMAs. Posaconazole significantly lowered IFI incidence compared with that in the no-use group in univariate and multivariate analyses. Moreover, patients who had reduced liver function at HMA initiation, were treated with decitabine therapy, and did not respond to HMA chemotherapy were independently associated with a higher IFI risk. In subgroup analysis, posaconazole appeared to be more beneficial for patients with good Eastern Cooperative Oncology Group performance score or liver function at HMA initiation. Conclusion: Thus, in AML and MDS patients receiving HMAs, IFI risk may be high during the early cycles, especially when the underlying disease is not controlled. Posaconazole could represent antifungal prophylaxis in these patients; further studies are needed for its appropriate indications.

Postoperative thromboembolism (TE) is a serious, but preventable, complication in surgical patients. Orthopedic surgery, neurosurgery, and vascular surgery are considered high risk for TE, and current guidelines recommend TE prophylaxis. However, insufficient data exist regarding TE risk in other general surgeries. This study identified the actual incidence and relative risk of postoperative TE in the real world, according to surgery type. Twenty-six surgeries between 1 December 2017 and 31 August 2019 were selected from the Health Insurance Review and Assessment Service database and analyzed for postoperative TE events. Among all patients, 2.17% had a TE event within 6 months of surgery and 0.75% had a TE event owing to anticoagulant treatment. The incidence of total TE events was the highest in total knee replacement (12.77%), hip replacement (11.46%), and spine surgery (5.98%). The incidence of TE with anticoagulant treatment was the highest in total knee replacement (7.40%), hip replacement (7.20%), and coronary artery bypass graft (CABG) surgery (3.81%). Hip replacement, total knee replacement, CABG surgery, spine surgery, and cardiac surgery except CABG surgery, showed relatively higher risks for total claimed venous TE. The relative risk of venous TE with anticoagulant treatment was the highest for hysterectomy, partial hepatectomy, hip replacement, cardiac surgery except CABG surgery, and total knee replacement. The relative risk of arterial TE was the highest for cardiac surgery, total knee replacement, and hip replacement. In the real world, the incidence of postoperative TE events from total knee replacement and those from hip replacement remain high, and some surgeries could have a relatively higher risk of TE than other surgeries. For patients undergoing these surgeries, studies to reduce the incidence of postoperative TE in clinical practice should be conducted.

Previous studies have reported the survival benefit after ruxolitinib treatment in patients with myelofibrosis (MF). However, population-based data of its efficacy are limited. We analyzed the effects of ruxolitinib in MF patients with data from the Korean National Health Insurance Database. In total, 1199 patients diagnosed with MF from January 2011 to December 2017 were identified, of which 731 were included in this study. Patients who received ruxolitinib (n = 224) were matched with those who did not receive the drug (n = 507) using the 1:1 greedy algorithm. Propensity scores were formulated using five variables: age, sex, previous history of arterial/venous thrombosis, and red blood cell (RBC) or platelet (PLT) transfusion dependence at the time of diagnosis. Cox regression analysis for overall survival (OS) revealed that ruxolitinib treatment (hazard ratio (HR), 0.67; p = 0.017) was significantly related to superior survival. In the multivariable analysis for OS, older age (HR, 1.07; p < 0.001), male sex (HR, 1.94; p = 0.021), and RBC (HR, 3.72; p < 0.001) or PLT (HR, 9.58; p = 0.001) transfusion dependence were significantly associated with poor survival, although type of MF did not significantly affect survival. Considering evidence supporting these results remains weak, further studies on the efficacy of ruxolitinib in other populations are needed.

No specific markers have been identified to detect non-small cell lung cancer (NSCLC) cell-derived exosomes circulating in the blood. Here, we report a new biomarker that distinguishes between cancer and non-cancer cell-derived exosomes. Exosomes isolated from patient plasmas at various pathological stages of NSCLC, NSCLC cell lines, and human pulmonary alveolar epithelial cells isolated using size exclusion chromatography were characterized. The GRIP and coiled-coil domain-containing 2 (GCC2) protein, involved in endosome-to-Golgi transport, was identified by proteomics analysis of NSCLC cell line-derived exosomes. GCC2 protein levels in the exosomes derived from early-stage NSCLC patients were higher than those from healthy controls. Receiver operating characteristic curve analysis revealed the diagnostic sensitivity and specificity of exosomal GCC2 to be 90% and 75%, respectively. A high area under the curve, 0.844, confirmed that GCC2 levels could effectively distinguish between the exosomes. These results demonstrate GCC2 as a promising early diagnostic biomarker for NSCLC.

This study was conducted to examine infectivity (penetration and gall and egg-mass formations) of the root-knot nematodes, Meloidogyne incognita and M. hapla, on carrots grown in soil conditions of 5 different soil textures consisting of bed-soil (b) and sand (s) mixtures (b-s mixtures) at the ratios of 10:0, 7:3, 5:5, 3:7, and 0:10. For M. incognita, the nematode penetration rates in b-s of 0:10 (100% sand) were significantly higher than in the other b-s mixtures, more greatly at 2 and 5 days after inoculation than at 10 DAI, while no significant differences in the penetration rates were mostly shown for M. hapla at the above DAI. However, for both nematodes, gall and egg-mass formations were remarkably increased in the b-s mixture of 0:10, compared to the other b-s mixtures, which is coincided with the general aspects of severe nematode infestations in sandy soils. This suggests the increased gall and egg-mass formations of M. incognita should be derived from the increased penetration rates in the sandy soil conditions, which provide a sufficient aeration due to coarse soil nature for the nematodes, leading to their mobility increased for the enhanced root penetration. For M. hapla, it is suggested that the sandy soil conditions affect positively on the healthy plant growth with little accumulation of the inhibitory materials and sufficient aeration, enhancing the nematode growth and feeding activities. All of these aspects provide information reliable for the development screening techniques efficient for the evaluation of the nematode resistance in the breeding programs.

Climate change poses a disproportionate risk to alpine ecosystems. Effective monitoring of forest phenological responses to climate change is critical for predicting and managing threats to alpine populations. Remote sensing can be used to monitor forest communities in dynamic landscapes for responses to climate change at the species level. Spatiotemporal fusion technology using remote sensing images is an effective way of detecting gradual phenological changes over time and seasonal responses to climate change. The spatial and temporal adaptive reflectance fusion model (STARFM) is a widely used data fusion algorithm for Landsat and MODIS imagery. This study aims to identify forest phenological characteristics and changes at the species–community level by fusing spatiotemporal data from Landsat and MODIS imagery. We fused 18 images from March to November for 2000, 2010, and 2019. (The resulting STARFM-fused images exhibited accuracies of RMSE = 0.0402 and R2 = 0.795. We found that the normalized difference vegetation index (NDVI) value increased with time, which suggests that increasing temperature due to climate change has affected the start of the growth season in the study region. From this study, we found that increasing temperature affects the phenology of these regions, and forest management strategies like monitoring phenology using remote sensing technique should evaluate the effects of climate change.

Carrot (Dacus carota var. sativus) is one of the top-ten most economically important vegetable crops produced worldwide, and the root-knot nematodes, Meloidogyne spp., are one of the most important pests in the carrot. In Korea, M. hapla and M. incognita are presumed to be the major root-knot nematodes distributing mostly in open carrot fields and greenhouses, respectively. In our study, currently-developed and commercial carrot cultivars and the parental lines were examined for their pathological responses to M. incognita and M. hapla 7 weeks after inoculation with about 1,000 second-stage juveniles (J2) of the nematodes. All the carrot cultivars and lines showed susceptible responses to both nematodes with the gall index (GI) of 2.4–4.4, which were always higher on the carrot plants infected with M. incognita than M. hapla. Gall sizes were remarkably larger with more serious reduction of the root growths in the plants infected with M. incognita than M. hapla, suggesting the carrot lines examined in our study were more susceptible to the former than the latter. In the infection sites of the root tissues, giant cells were more extensively formed, occupying larger stellar regions with the prominent destruction of adjacent xylem vessels by M. incognita than M. hapla. All of these results suggest M. incognita affect more seriously on the carrot plants that are grown in greenhouses, compared to M. hapla that has a major distribution in open carrot fields, which would be used for determining cropping systems based on target nematode species, their damage and pathological characteristics.

To understand the lattice preferred orientation (LPO) and deformation microstructures at the top of a subducting slab in a warm subduction zone, deformation experiments of epidote blueschist were conducted in simple shear under high pressure (0.9–1.5 GPa) and temperature (400–500 °C). At low shear strain (γ ≤ 1), the [001] axes of glaucophane were in subparallel alignment with the shear direction, and the (010) poles were subnormally aligned with the shear plane. At high shear strain (γ > 2), the [001] axes of glaucophane were in subparallel alignment with the shear direction, and the [100] axes were subnormally aligned with the shear plane. At a shear strain between 2< γ 4, the alignment of the (010) epidote poles had altered from subparallel to subnormal to the shear plane, while the [001] axes were in subparallel alignment with the shear direction. The experimental results indicate that the magnitude of shear strain and rheological contrast between component minerals plays an important role in the formation of LPOs for glaucophane and epidote.

There are limited data from prospective controlled trials regarding optimal treatment strategies in patients with primary breast diffuse large B-cell lymphoma (DLBCL). In this phase 2 study (NCT01448096), we examined the efficacy and safety of standard immunochemotherapy and central nervous system (CNS) prophylaxis using intrathecal methotrexate (IT-MTX). Thirty-three patients with newly diagnosed primary breast DLBCL received six cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and four fixed doses of IT-MTX (12 mg). The median age was 50 years (range, 29–75), and all patients were females. According to the CNS-International Prognostic Index, most patients (n = 28) were categorized as the low-risk group. Among the 33 patients, 32 completed R-CHOP, and 31 completed IT-MTX as planned. With a median follow-up of 46.1 months (interquartile range (IQR), 31.1–66.8), the 2-year progression-free and overall survival rates were 81.3% and 93.5%, respectively. Six patients experienced treatment failures, which included the CNS in four patients (two parenchyma and two leptomeninges) and breast in two patients (one ipsilateral and one contralateral). The 2-year cumulative incidence of CNS relapse was 12.5%. Although standard R-CHOP and IT-MTX without routine radiotherapy show clinically meaningful survival outcomes, this strategy may not be optimal for reducing CNS relapse and warrants further investigation.

Surveillance computed tomography (CT) is usual practice for patients with aggressive non-Hodgkin lymphoma (aNHL) in complete remission (CR). However, evidence to support this strategy is lacking. We retrospectively analyzed our institutional lymphoma registry, including patients with lymphoma consecutively enrolled from June 1995 to October 2016. Of 1,385 patients with aNHL, 664 achieved CR and were followed up with or without surveillance CT. Surveillance CT was performed for 609 patients every 3 or 6 months for the first 2 years, then every 6 or 12 months thereafter. Relapse was detected in 171 patients, of whom 152 underwent surveillance CT during follow-up. Of these 152 patients, asymptomatic relapse was detected in 67 (44%) using surveillance CT, and symptomatic relapse outside the surveillance interval was detected in the remaining 85 (56%). Detection of asymptomatic relapse using surveillance CT did not improve the overall or post-relapse survival in patients with relapsed aNHL. Surveillance CT interval (3 or 6 months) did not affect survival. No subgroups were identified that favored the use of surveillance CT to detect relapse. The results of this study suggest that routine surveillance CT in patients with aNHL to detect asymptomatic relapse might have a limited role in improving survival. CT is recommended when a relapse is clinically suspected.

In total, 170 carrot lines developed in Korea were screened for resistance to Meloidogyne incognita race 1 to select parental genetic resources useful for the development of nematode-resistant carrot cultivars. Using the gall index (GI), gall formation was examined on carrot roots inoculated with approximately 1,000 second-stage juveniles of the nematode 7 weeks after inoculation. Sixty-one carrot lines were resistant (GI ≤ 1.0), while the other 109 were susceptible (GI > 1.0) with coefficient of variance (CV) of GI for total carrot lines 0.68, indicating low-variation of GI within the lines examined. The histopathological responses of two carrot plants from resistant and susceptible lines were examined after nematode infection. In susceptible carrots, giant cells formed with no discernible necrosis around the infecting nematodes. In the resistant carrot line, however, no giant cells formed, although modified cells were observed with extensive formation of necrotic layers through their middle lamella and around the infecting nematodes. This suggested that these structural modifications were related to hypersensitive responses governed by the expression of true resistance genes. Therefore, the Korean carrot lines resistant to the nematode infection are potential genetic resources for the development of quality carrot cultivars resistant to M. incognita race 1.

Chromosomal translocations are rare in myelodysplastic syndrome (MDS) and their impact on overall survival (OS) and response to hypomethylating agents (HMA) is unknown. The prognostic impact of the revised International Prognostic Scoring System (IPSS-R) and for chromosomal translocations was assessed in 751 patients from the Korea MDS Registry. IPSS-R effectively discriminated patients according to leukaemia evolution risk and OS. We identified 40 patients (5.3%) carrying translocations, 30 (75%) of whom also fulfilled complex karyotype criteria. Translocation presence was associated with a shorter OS (median, 12.0 versus 79.7 months, P < 0.01). Multivariate analysis demonstrated that translocations (hazard ratio [HR] 1.64 [1.06-2.63]; P = 0.03) as well as age, sex, IPSS-R, and CK were independent predictors of OS. In the IPSS-R high and very high risk subgroup (n = 260), translocations remained independently associated with OS (HR 1.68 [1.06-2.69], P = 0.03) whereas HMA treatment was not associated with improved survival (median OS, 20.9 versus 21.2 months, P = 0.43). However, translocation carriers exhibited enhanced survival following HMA treatment (median 2.1 versus 12.4 months, P = 0.03). Our data suggest that chromosomal translocation is an independent predictor of adverse outcome and has an additional prognostic value in discriminating patients with MDS having higher risk IPSS-R who could benefit from HMA treatment.

Antiviral agents for the suppression of hepatitis B virus (HBV) have been used for treating chronic hepatitis B. However, the emergence of drug-resistant HBV is still a major problem for antiviral treatment. To identify and characterize the drug-resistant HBV, the construction of HBV replicon and in vitro drug susceptibility assay are essential. Here we describe the experimental methods to study drug-resistant HBV.