Clinical outcomes of etoposide and cytarabine as consolidation in elderly patients with primary CNS lymphoma.

BACKGROUND: A consolidation strategy has not been established for transplant-ineligible elderly patients with primary central nervous system lymphoma (PCNSL). In this study, we aimed to retrospectively evaluate the clinical outcomes of etoposide and cytarabine (EA) as consolidation chemotherapy for transplant-ineligible patients with PCNSL following high-dose methotrexate (MTX)-based induction chemotherapy. MATERIALS AND METHODS: Between 2015 and 2021, newly diagnosed transplant-ineligible patients with PCNSL with diffuse large B-cell lymphoma were consecutively enrolled. All enrolled patients were over 60 years old and received EA consolidation after achieving a complete or partial response following induction chemotherapy. RESULTS: Of the 85 patients who achieved a complete or partial response to MTX-based induction chemotherapy, 51 received EA consolidation chemotherapy. Among the 25 (49.0%, 25/51) patients in partial remission before EA consolidation, 56% (n = 14) achieved complete remission after EA consolidation. The median overall survival and progression-free survival were 43 and 13 months, respectively. Hematological toxicities were most common, and all patients experienced grade 4 neutropenia and thrombocytopenia. Forty-eight patients experienced febrile neutropenia during consolidation chemotherapy, and 4 patients died owing to treatment-related complications. CONCLUSION: EA consolidation chemotherapy for transplant-ineligible, elderly patients with PCNSL improved response rates but showed a high relapse rate and short progression-free survival. The incidences of treatment-related mortality caused by hematologic toxicities and severe infections were very high, even after dose modification. Therefore, the use of EA consolidation should be reconsidered in elderly patients with PCNSL.

Comprehensive insights into AML relapse: genetic mutations, clonal evolution, and clinical outcomes.

INTRODUCTION: Acute myeloid leukemia (AML) is a complex hematologic malignancy characterized by uncontrolled proliferation of myeloid precursor cells within bone marrow. Despite advances in understanding of its molecular underpinnings, AML remains a therapeutic challenge due to its high relapse rate and clonal evolution. METHODS: In this retrospective study, we analyzed data from 24 AML patients diagnosed at a single institution between January 2017 and August 2023. Comprehensive genetic analyses, including chromosomal karyotyping, next-generation sequencing, and gene fusion assays, were performed on bone marrow samples obtained at initial diagnosis and relapse. Clinical data, treatment regimens, and patient outcomes were also documented. RESULTS: Mutations in core genes of FLT3, NPM1, DNMT3A, and IDH2 were frequently discovered in diagnostic sample and remained in relapse sample. FLT3-ITD, TP53, KIT, RUNX1, and WT1 mutation were acquired at relapse in one patient each. Gene fusion assays revealed stable patterns, while chromosomal karyotype analyses indicated a greater diversity of mutations in relapsed patients. Clonal evolution patterns varied, with some cases showing linear or branching evolution and others exhibiting no substantial change in core mutations between diagnosis and relapse. CONCLUSIONS: Our study integrates karyotype, gene rearrangements, and gene mutation results to provide a further understanding of AML heterogeneity and evolution. We demonstrate the clinical relevance of specific mutations and clonal evolution patterns, emphasizing the need for personalized therapies and measurable residual disease monitoring in AML management. By bridging the gap between genetics and clinical outcome, we move closer to tailored AML therapies and improved patient prognoses.

Haploidentical hematopoietic cell transplantation as a platform for natural killer cell immunotherapy.

An innovative approach is crucially needed to manage relapse after allogeneic hematopoietic cell transplantation (HCT) in patients with advanced hematological malignancies. This review explores key aspects of haploidentical HCT with post-transplant cyclophosphamide, highlighting the potential and suitability of this platform for natural killer (NK) cell immunotherapy. NK cells, known for their unique abilities to eliminate cancer cells, can also exhibit memory-like features and enhanced cytotoxicity when activated by cytokines. By discussing promising results from clinical trials, the review delves into the recent major advances: donor-derived NK cells can be expanded ex vivo in large numbers, cytokine activation may enhance NK cell persistence and efficacy in vivo, and post-HCT NK cell infusion can improve outcomes in high-risk and/or relapsed myeloid malignancies without increasing the risk of graft-versus-host disease, severe cytokine release syndrome, or neurotoxicity. Looking ahead, cytokine-activated NK cells can be synergized with immunomodulatory agents and/or genetically engineered to enhance their tumor-targeting specificity, cytotoxicity, and persistence while preventing exhaustion. The ongoing exploration of these strategies holds promising preliminary results and could be rapidly translated into clinical applications for the benefit of the patients.

A population pharmacokinetic model of methotrexate in Korean patients with haematologic malignancy.

AIMS: This study was conducted to develop a population pharmacokinetic (PK) model of methotrexate in Korean patients with haematologic malignancy, identify factors affecting methotrexate PK, and propose an optimal dosage regimen for the Korean population. METHODS: Data were retrospectively collected from 188 patients with acute leukaemia or non-Hodgkin's lymphoma who were admitted to Severance Hospital during the period from November 2005 to January 2016. Using demographic factors and laboratory results as potential covariates for PK parameters, model development was performed using NONMEM and optimal dosing regimens were developed using the final PK model. RESULTS: A two-compartment model incorporating body weight via allometry best described the data, yielding typical parameter values of 25.09 L for central volume of distribution ( V 1 ), 17.65 L for peripheral volume of distribution ( V 2 ), 12.89 L/h for clearance (CL) and 0.655 L/h for inter-compartmental clearance in a 50 kg patient. Covariate analyses showed that, at the weight of 50 kg, CL decreased by 0.11 L/h for each 1-year increase in age above 14 years old and decreased 0.8-fold when serum creatinine level doubled, indicating the importance of age-specific dose individualization in methotrexate treatment. Volume of distribution at steady state derived from PK parameters (= V 1 + V 2 ) was 0.85 L/kg, which was similar to those in the Western or Chinese populations. Optimal doses simulated from the final model successfully produced the PK measures close to the target chosen. CONCLUSIONS: The population PK model and optimal dosage regimens developed in this study can be used as a basis to achieve precision dosing in Korean patients with haematologic malignancy.

A Multicenter Analysis of Clinical Features and Long-Term Outcomes of POEMS Syndrome in Korea.

BACKGROUND: POEMS syndrome is a rare form of plasma cell dyscrasia characterized by polyneuropathy, organomegaly, endocrinopathy, monoclonal proteins, and skin changes. Owing to its low incidence, there are few reports regarding this syndrome. This multicenter study included 84 patients diagnosed with POEMS syndrome in South Korea. METHODS: We retrospectively evaluated 84 patients diagnosed with POEMS syndrome at 8 hospitals in South Korea between January 2000 and October 2022. The clinical characteristics and treatment outcomes were analyzed. RESULTS: The median patient age was 53 years (range, 26-77 years), and 63.1% of the patients were male. All patients had peripheral neuropathy, and 81 (96.4%) had monoclonal plasma cell proliferation. Plasma vascular endothelial growth factor levels were available for 32 patients with a median of 821 pg/mL (range, 26-12,900 pg/mL). Other common features included skin changes (54.2%), volume overload (71.4%), and organomegaly (72.6%). Of the 84 patients, 75 received initial treatment (local radiotherapy, 6 [8.0%]; chemotherapy, 17 [22.7%]; both chemotherapy and local radiotherapy, 9 [12.0%]), upfront autologous stem cell transplantation (ASCT), 43 (57.3%; with induction chemotherapy, n = 12, 16.0%; without induction chemotherapy, n = 31, 41.3%). The median follow-up duration was 40.7 months. The 5-year overall survival (OS) was 78%, and the 5-year progression-free survival (PFS) was 55%. Patients who underwent upfront ASCT and were diagnosed after 2014 had a longer OS and PFS. CONCLUSION: The demographics of Korean patients with POEMS syndrome were similar to those reported previously. Because of the introduction of new treatment agents and the reduced rate of transplant-related mortality related to ASCT, the treatment outcomes of Korean patients with POEMS syndrome have improved in recent years.

Utility of Plasma Microbial Cell-Free DNA Whole-Genome Sequencing for Diagnosis of Invasive Aspergillosis in Patients With Hematologic Malignancy or COVID-19.

BACKGROUND: We evaluated the clinical accuracy and utility of whole-genome sequencing (WGS) of plasma microbial cell-free DNA (cfDNA) as a novel noninvasive method in diagnosing invasive aspergillosis (IA) in patients with hematologic malignancy (HM) or coronavirus disease 2019 (COVID-19). METHODS: Adults with HM or COVID-19 and suspected IA were recruited. IA cases were retrospectively diagnosed according to EORTC/MSG definitions and ECMM/ISHAM criteria for HM and COVID-19 patients, respectively. The results of cfDNA WGS were compared with the conventional diagnosis. RESULTS: Microbial cfDNA WGS was performed 53 times from 41 participants (19 from HM, 16 from COVID-19, and 7 from the control group). In participants with HM, Aspergillus cfDNA was detected in 100% of proven IA and 91.7% of probable IA cases. In participants with COVID-19, 50.0% of probable IA were positive for Aspergillus in cfDNA WGS. Concordance between Aspergillus cfDNA detection and proven/probable IA conventional diagnosis was significantly higher in participants with HM than in those with COVID-19. IA diagnosed using EORTC/MGS definitions showed significantly high concordance between Aspergillus cfDNA detection and proven/probable IA. CONCLUSIONS: Aspergillus cfDNA detection strongly correlated with proven/probable IA diagnosed using EORTC/MSG definitions and could be used as an additional diagnostic tool for IA.

Using Single-Crystal Graphene to Form Arrays of Nanocapsules Enabling the Observation of Light Elements in Liquid Cell Transmission Electron Microscopy.

We have designed and fabricated a TEM (transmission electron microscopy) liquid cell with hundreds of graphene nanocapsules arranged in a stack of two Si3N4-x membranes. These graphene nanocapsules are formed on arrays of nanoholes patterned on the Si3N4-x membrane by focused ion beam milling, allowing for better resolution than for the conventional graphene liquid cells, which enables the observation of light elements, such as atomic structures of silicon. We suggest that multiple nanocapsules provide opportunities for consecutive imaging under the same conditions in a single liquid cell. The use of single-crystal graphene windows offers an excellent signal-to-noise ratio and high spatial resolution. The motion of silicon nanoparticles (a low atomic number (Z) material) interacting with nanobubbles was observed, and analyzed, in detail. Our approach will help advance liquid-phase TEM observations by providing a straightforward method to encapsulate liquid between monolayers of various 2-dimensional materials.

Real-world data on prognostic value of measurable residual disease assessment by fragment analysis or next-generation sequencing in multiple myeloma.

Measurable residual disease (MRD) negativity is a strong prognostic indicator in multiple myeloma (MM). However, the optimal use of MRD in daily clinical practice has been hampered by the limited feasibility of MRD testing. Therefore, we examined the clinical relevance of commercially available MRD modalities based on clonality assays by fragment analysis with IdentiClone® (n = 73 patients) and next-generation sequencing (NGS) with LymphoTrack® (n = 116 patients) in newly diagnosed patients with MM who received autologous stem cell transplantation (ASCT). MRD was assessed at the end of induction (pre-ASCT) and/or at 100 days after ASCT (post-ASCT). MRD could not predict survival when assessed by fragment analysis. However, NGS-based MRD negativity at pre- or post-ASCT was beneficial in terms of progression-free and overall survival. Moreover, NGS-based MRD negativity was independently associated with improved progression-free and overall survival, and MRD-positive patients both pre- and post-ASCT had worst outcome. Indeed, initial adverse prognostic features by high-risk cytogenetics could be mitigated upon achieving MRD negativity by NGS. We demonstrate the feasibility and clinical benefit of achieving MRD negativity by commercially available clonality-based MRD assays in MM and support incorporating NGS, but not fragment analysis, to tailor therapeutic strategies in real-world practice.

Clinical characteristics and prognostic factors of acquired haemophilia A in Korea.

INTRODUCTION: Acquired haemophilia A (AHA) treatment involves the haemostatic treatment for acute haemorrhage and immunosuppressive therapy (IST) to eradicate FVIII inhibitory antibodies. AIM: We assessed the clinical features of AHA and analysed treatment outcomes in Korea. We further identified prognostic factors affecting treatment outcomes. METHODS: Medical records of 55 patients with AHA from 18 institutions were reviewed retrospectively. Logistic and Cox regression analyses were performed to elucidate clinical factors affecting the achievement of complete remission (CR). The primary endpoint was time to CR after IST, and secondary endpoints were time to haemostasis, the achievement of CR, and overall survival (OS). RESULTS: Among the 55 patients, 50 (91%) had bleeding symptoms. Bleeding was severe in 74% of patients. Thirty-six (72%) patients received haemostatic therapy. Of the 42 patients who received IST, 23 (52%) received steroid alone, with a 52% response rate, and 10 (25%) received a combination of steroid and cyclophosphamide, with an 83% response rate. Five (16%) patients relapsed after a median duration of 220 days. There were eight deaths. In the Cox regression analysis, the FVIII inhibitor titre ≥ 20 BU/mL was the only significant prognostic factor affecting time to CR and haemostasis. No significant difference was observed in OS based on the inhibitor titre. CONCLUSION: The present study demonstrated the demographic data of AHA in Korea and showed that FVIII inhibitory antibody titre was a predictor of time to achieve CR after IST.

Serum albumin and C-reactive protein as significant predictors of non-relapse mortality in lower gastrointestinal graft-versus-host disease.

Acute graft-versus-host disease (aGVHD) of the lower gastrointestinal (GI) tract is the major cause of non-relapse mortality (NRM) in allogeneic hematopoietic stem cell transplantation (alloHSCT). This study aimed to identify variables associated with corticosteroid response and NRM in patients who developed lower GI aGVHD. We retrospectively analyzed the clinical data of patients treated at Yonsei University Severance Hospital between 2008 and 2017. Among 244 recipients of alloHSCT, 48 (19.7%) were diagnosed as lower GI aGVHD at a median of 22 days after alloHSCT. In these cases, 20 (41.6%) patients were resistant to corticosteroid therapy. Corticosteroid resistance was associated with advanced stage of lower GI aGVHD (P = 0.019), low serum albumin (P = 0.006), and elevated CRP (P = 0.030) on day 7 after corticosteroid therapy. NRM rate was significantly higher in the corticosteroid-resistant group compared with the sensitive group (HR 5.339, P = 0.003). Multivariate analysis revealed serum albumin (P = 0.046), and CRP levels (P = 0.032) were independent prognostic factors for NRM. When the patients were classified into 3 groups according to Glasgow prognostic score (GPS), the rate of corticosteroid resistance was significantly higher in the high GPS group compared with the intermediate or low GPS group (83.3 vs. 27.2 and 15.3%, respectively, P < 0.001). We demonstrated that low serum albumin and elevated CRP level on day 7 after corticosteroid therapy are objective biomarkers of corticosteroid resistance and a significant predictor for higher NRM. These simple and practical parameters could be valuable information predicting response and prognosis in lower GI aGVHD.

Upfront autologous hematopoietic stem cell transplantation for high-risk patients with double-expressor diffuse large B cell lymphoma.

Although MYC and BCL2 co-expression in diffuse large B cell lymphoma (DLBCL) is associated with inferior prognosis, it remains uncertain whether upfront autologous hematopoietic stem cell transplantation (ASCT) is beneficial in this lymphoma. This study aimed to investigate whether ASCT consolidation could have a positive role for patients with MYC and BCL2 co-expression (double-expressor lymphoma, DEL). We retrospectively evaluated 67 DLBCL patients who underwent upfront ASCT following rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy. The 5-year overall survival (OS) and progression-free survival (PFS) were 82.3% and 79.2%, respectively. There were 23 (34.3%) patients with DEL and 51 (76.1%) patients with non-germinal center B cell (GCB) subtype. The 5-year OS and PFS of patients with DEL were not different from those with non-DEL (P = 0.429 and P = 0.614, respectively). No survival difference for OS and PFS was also observed between GCB and non-GCB subtypes (P = 0.950 and P = 0.901, respectively). The OS and PFS were comparable for patients with DEL and non-DEL and both GCB and non-GCB subtypes. In conclusion, MYC and BCL2 co-expression did not have a poor prognostic impact among high-risk patients with DLBCL treated with upfront ASCT regardless of molecular classification. This preliminary study suggested that the role of consolidative ASCT is needed to be evaluated in a prospective randomized clinical trial.

The protective effect of alcohol consumption on the incidence of cardiovascular diseases: is it real? A systematic review and meta-analysis of studies conducted in community settings.

BACKGROUND: This study investigated the dose-response relationship between alcohol consumption and CVD incidence, conducting a meta-analysis of studies focusing on residents from local communities. Further, we examined whether light to moderate alcohol consumption had a protective effect on CVD incidence through a sub-group analysis. METHODS: This study conducted a meta-analysis of the relationship between alcohol consumption and CVD incidence, selecting journals published up to December 2017. The alcohol consumption level was classified into non-consumers, light (0.01-10.0 g/day), light to moderate (10.1-20.0 g/day), moderate (20.1-40.0 g/day), moderate to high (40.1-60.0 g/day), and high (> 60.0 g/day) groups. The sub-group analysis was conducted according to the number of comorbidities and age. RESULTS: Seven articles were selected in total for the meta-analysis. The mean Newcastle-Ottawa scale score was 8.14 points, suggesting studies were of high quality. There was a J-shaped dose-response relationship between alcohol consumption level and CVD incidence only in men. In general, light to moderate and moderate consumption lowered CVD incidence (Relative risk (RR) [95% confidence interval (CI)] was 0.68 [0.57-0.81] and 0.72 [0.58-0.90], respectively). In men with 3-4 comorbidities, there were no protective effects of light to moderate and moderate consumption on CVD incidence. In either groups of only men or men and women there were protective effects of light to moderate and moderate consumption on CVD incidence only in those aged between 41 and 65. DISCUSSION: We found that light to moderate and moderate alcohol consumption had a protective effect on CVD incidence, there was no protective effect either in those with at least three comorbidities or people aged 40 or younger. CONCLUSIONS: We conclude that not all local community residents experience a protective effect of light to moderate consumption on CVD incidence. As such, it is necessary to recommend a moderate amount of drinking or less for each individual.

Early Cytomegalovirus Reactivation and Expansion of CD56brightCD16dim/-DNAM1+ Natural Killer Cells Are Associated with Antileukemia Effect after Haploidentical Stem Cell Transplantation in Acute Leukemia.

Cytomegalovirus (CMV) infection is a major complication after allogeneic hematopoietic stem cell transplantation but is suggested to exert a strong antileukemia effect in part due to alterations in the composition of natural killer (NK) cells. We evaluated the impact of early CMV reactivation and changes in NK cell subset recovery on relapse rate and survival after haploidentical stem cell transplantation (haploSCT) for acute leukemia. Fifty patients with acute leukemia who received haploSCT were analyzed. Expression of T cells and specific receptors (NKG2A, NKG2D, DNAM1, and CD57) on circulating NK cells (CD56brightCD16dim/- or CD56dimCD16+ cells) was serially measured using multiparametric flow cytometry. CMV reactivation during the first 100 days was observed in 41 patients (82%) at a median of 23 days after haploSCT. The incidence of acute graft-versus-host disease (GVHD) and chronic GVHD tended to be higher in patients with CMV reactivation, although this difference was not statistically significant. Multivariate analysis showed that CMV reactivation (P = .011) and a dose of infused T cells > 3.2 × 108/kg (P = .027) were independent predictors of a reduced relapse risk and only CMV reactivation (P = .029) was an independent predictor of improved leukemia-free survival. CD56brightCD16dim/-DNAM1+NK cell counts increased from day 30 to 90 in patients with CMV reactivation but decreased after day 30 in patients without CMV reactivation. An increase in CD56brightCD16dim/-DNAM1+ NK cells was not associated with the occurrence of chronic GVHD but was associated with a reduced cumulative relapse rate (16.4% versus 58.0%, P = .019). Multivariate analysis indicates that an increase in the CD56brightCD16dim/-DNAM1+NK cell count was an independent predictor of reduced relapse risk. Our study demonstrates a significant correlation between low relapse rates and CMV reactivation as well as the recovery of CD56brightCD16dim/-DNAM1+ NK cells, providing valuable information for understanding the plausible immunologic mechanism of the graft-versus-leukemia effect.

Induction of apoptosis and differentiation by Na/H exchanger 1 modulation in acute myeloid leukemia cells.

We investigated the effect of the modulation of Na/H exchanger 1 (NHE1) on apoptosis, differentiation, and chemoresistance in acute myeloid leukemia (AML) cells to evaluate the possibility of NHE1 modulation as a novel therapeutic strategy for AML. The pHi of leukemia cell lines except KG1a was higher than that of normal bone marrow mononuclear cells (BM MNCs). Notably, in K562, cytarabine (AraC)-resistant OCI-AML2, and primary leukemia cells, pHi was significantly higher than that of normal BM MNCs. Western blotting and real-time quantitative PCR confirmed that the increased NHE1 expression was responsible for the higher pHi. Specifically, compared to CD34+CD38+ leukemia cells, the mean fluorescence intensity of NHE1 was significantly higher in CD34+CD38- leukemic stem cells. The out of range in pHi by treatment with an NHE inhibitor, the amiloride analogue 5-(N,N-hexamethylene) amiloride (HMA), or an NHE activator, phorbol 12-myristate 13-acetate (PMA), resulted in dose- and time-dependent inhibition of leukemia cell proliferation. PMA induced CD14+ differentiation of leukemia cells, whereas HMA induced cell cycle arrest at the G1 phase. HMA could induce apoptosis of leukemia cells even in AraC-resistant cells and showed an additive effect on apoptosis in AraC-sensitive cells. Our result revealed that AML cells prefer more alkalic intracellular moiety than normal BM MNCs following increased NHE1 expression and that NHE1 modulation can induce apoptosis and differentiation of AML cells. These findings imply that NHE1 is a potential target in cytotoxic or differentiation-induction treatment for AML.

Contrasting life histories contribute to divergent patterns of genetic diversity and population connectivity in freshwater sculpin fishes.

BACKGROUND: Life history characteristics are considered important factors influencing the evolutionary processes of natural populations, including the patterns of population genetic structure of a species. The sister species Cottus hangiongensis and C. koreanus are small bottom-dwelling freshwater sculpin fishes from South Korea that display marked life history divergence but are morphologically nearly indistinguishable. Cottus hangiongensis evolved an 'amphidromous' life history with a post-hatching pelagic larval phase. They spawn many small eggs in the low reaches of rivers, and hatched larvae migrate to the sea before returning to grow to maturity in the river mouth. In contrast, C. koreanus evolved a 'fluvial' landlocked type with benthic larvae. They release a smaller number of larger eggs, and the larvae undergo direct development, remaining benthic in the upstream rivers throughout their entire lives. We tested whether there were differences in patterns and levels of within-population genetic diversities and spatial population structure between the two closely related Korean sculpins using mitochondrial DNA control region sequences and seven nuclear microsatellite loci. RESULTS: The combined analyses of both marker sets revealed that C. hangiongensis harboured considerably higher levels of within-population genetic diversities (e.g. haplotype/allelic richness, heterozygosities) than C. koreanus. In contrast, the fluvial sculpin exhibited noticeably more spatial population structure than did the amphidromous sculpin, as suggested by pairwise FST statistics. The finding that C. hangiongensis individuals comprised a single random mating population across the east-flowing river basins in the Korean Peninsula, whereas C. koreanus individuals comprised genetically discrete individual populations, was further supported by an individual-based Bayesian population assignment and also factorial correspondence analyses. CONCLUSIONS: The higher genetic diversity, but lower population structure, of the amphidromous sculpin relative to the fluvial sculpin may have resulted from its greater larval dispersal and also possibly, higher fecundity accompanied by an amphidromous life history. Hence, we conclude that contrasting early life histories - including the presence or absence of the pelagic larval phase - may have led to divergent patterns of within-population genetic diversities and spatial population structure between the sister Cottus species following speciation from a common ancestor of marine sculpin.

Determinants Used to Justify the Strength of Recommendations among Korean Clinical Practice Guidelines.

BACKGROUND: A standardized systematic approach to grade evidence and the strength of recommendations is important for guideline users to minimize bias and help interpret the most suitable decisions at the point of care. The study aims to identify and classify determinants used to make judgement for the strength of recommendations among 56 Korean clinical practice guidelines (CPGs), and explore strong recommendations based on low quality of evidence. METHODS: Determinants used in the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach among 34 CPGs which have reported both strength of recommendations and level of evidence were reviewed. RESULTS: Five of 34 CPGs (14.7%) considered quality of evidence, benefits and harms, patients' values and preferences, and costs. And 24 of 34 CPGs (70.6%) considered both magnitude of effect and feasibility as additional determinants. Judgement table was not widely provided for use to translate evidence into recommendations. Eighty-two of 121 recommendations (67.8%, ranged 20.0% to 100.0%) among 11 CPGs using the same judgement scheme showed 'strong' strength of recommendations based on low or very low quality of evidence. Among 5 paradigmatic situations that justify strong recommendations based on low or very low evidence, situation classified as 'potential equivalence, one option clearly less risky or costly' was 87.8% for 82 strong recommendations. Situation classified as 'uncertain benefit, certain harm' was 4.9%. CONCLUSION: There is a need to introduce and systematize an evidence-based grading system. Using judgement table to justify the strength of recommendations and applying the 5 paradigmatic situations mentioned above is also recommended in the near future.

Clinical impact of early recovery of peripheral blood absolute lymphocyte count after frontline autologous stem cell transplantation for diffuse large B-cell lymphoma.

We conducted a retrospective study to evaluate the clinical impact of an early recovery of posttransplant absolute lymphocyte count (ALC) on the outcome of frontline autologous stem cell transplantation (ASCT) for diffuse large B-cell lymphoma (DLBCL). We reviewed 65 DLBCL patients who underwent frontline ASCT after primary chemotherapy based on cyclophosphamide, doxorubicin, vincristine, and prednisone. A receiver operating characteristic analysis was performed to determine the optimal cut point (0.4 × 109 /L) for an ALC at 15 days after ASCT (ALC-15). Both event-free survival and overall survival rates of the higher-ALC-15 group were significantly better than those of the lower-ALC-15 group (event-free survival, P = .008; overall survival, P = .013). The infused CD34+ cell count was significantly associated with the recovery of ALC-15 (>0.4 × 109 /L) after ASCT (P = .028). A multivariate analysis confirmed that a higher infused CD34+ cell dose (>5.0 × 106  cells/kg) was an independent factor affecting an early recovery of ALC after ASCT (odds ratio, 4.145; 95% confidence interval, 1.106-15.528; P = .035). In conclusion, an early recovery of ALC after ASCT can be regarded as a good prognostic marker in patients with DLBCL who have undergone frontline ASCT. We found that the infused CD34+ cell dose for ASCT was associated with the recovery of ALC.

The prognostic role of CD68 and FoxP3 expression in patients with primary central nervous system lymphoma.

The prognostic role of CD68 and FoxP3 in primary central nervous system lymphoma (PCNSL) has not been evaluated. Thus, we examined the prognostic significance of CD68 and FoxP3 expression in tumor samples of 76 newly diagnosed immunocompetent PCNSL patients. All patients were treated initially with high-dose methotrexate (HD-MTX)-based chemotherapy, and 16 (21.1%) patients received upfront autologous stem cell transplantation (ASCT) consolidation. High expression of CD68 (>55 cells/high-power field) or FoxP3 (>15 cells/high-power field) was observed in 10 patients, respectively. High CD68 expression was associated with inferior overall survival (OS) and progression-free survival (PFS) in multivariate analysis (P = 0.023 and P = 0.021, respectively). In addition, we performed subgroup analysis based on upfront ASCT. High CD68 expression was also associated with inferior OS and PFS in multivariate analysis (P = 0.013 and P < 0.001, respectively) among patients who did not receive upfront ASCT (n = 60), but not in patients who received upfront ASCT. The expression of FoxP3 was not significantly associated with survival. Therefore, we identified a prognostic significance of high CD68 expression in PCNSL, which suggests a need for further clinical trials and biological studies on the role of PCNSL tumor microenvironment.

Salvage therapy for acute chemorefractory leukemia by allogeneic stem cell transplantation: the Korean experience.

Little is known about the characteristics that make patients with acute leukemia suitable for undergoing salvage therapy by allogeneic hematopoietic stem cell transplantation (allo-HSCT). Here, we analyzed the clinical outcomes of 223 patients with acute leukemia who underwent allo-HSCT while not in complete remission (CR). The primary end points were overall survival (OS) and CR rate. CR was achieved in 79.8% of patients after allo-HSCT. Acute graft-versus-host disease (GVHD) was significantly associated with CR (P = 0.045). During a median follow-up of 30.1 months, the median OS was 6.1 months. OS was significantly longer in patients with good or standard risk cytogenetic characteristics than in those with poor risk cytogenetic characteristics (P = 0.029, P = 0.030, respectively). Patients who received allo-HSCT from a matched sibling donor had better survival than those with unrelated donors (P = 0.015). Primary chemorefractoriness was not associated with poor survival (P = 0.071). The number of chemotherapies before allo-HSCT was significantly correlated with outcome (P = 0.006). Chronic GVHD was a strong predictor of a longer OS (P = 0.025). In conclusion, survival of patients with primary chemorefractory acute leukemia is not lower when treated upfront with allo-HSCT. Hence, allo-HSCT should be actively considered in such patients. Acute and chronic GVHD is associated with better outcomes patients with acute leukemia who have undergone allo-HSCT and not achieved CR.

Genetic effects of sterol regulatory element binding proteins and fatty acid-binding protein4 on the fatty acid composition of Korean cattle (Hanwoo).

OBJECTIVE: This study identifies single-nucleotide polymorphisms (SNP) or gene combinations that affect the flavor and quality of Korean cattle (Hanwoo) by using the SNP Harvester method. METHODS: Four economic traits (oleic acid [C18:1], saturated fatty acids), monounsaturated fatty acids, and marbling score) were adjusted for environmental factors in order to focus solely on genetic effects. The SNP Harvester method was used to investigate gene combinations (two-way gene interactions) associated with these economic traits. Further, a multifactor dimensionality reduction method was used to identify superior genotypes in gene combinations. RESULTS: Table 3 to 4 show the analysis results for differences between superior genotypes and others for selected major gene combinations using the multifactor dimensionality reduction method. Environmental factors were adjusted for in order to evaluate only the genetic effect. Table 5 shows the adjustment effect by comparing the accuracy before and after correction in two-way gene interactions. CONCLUSION: The g.3977-325 T>C and (g.2988 A>G, g.3977-325 T>C) combinations of fatty acid-binding protein4 were the superior gene, and the superior genotype combinations across all economic traits were the CC genotype at g.3977-325 T>C and the AACC, GACC, GGCC genotypes of (g.2988 A>G, g.3977-325 T>C).