Plasma-based protein biomarkers can predict the risk of acute graft-versus-host disease and non-relapse mortality in patients undergoing allogeneic hematopoietic stem cell transplantation.

Predictive biomarkers for acute graft-versus-host disease (aGVHD) is currently lacking. In this study, we employed an unbiased proteome profiling method to prospectively collected plasma samples from allogeneic hematopoietic stem cell transplantation (alloHSCT) recipients to identify protein biomarkers that predict the risk of aGVHD and non-relapse mortality (NRM). In the discovery set, including five aGVHD patients and five controls, we identified seven candidate proteins. Patients with high levels of these proteins tended to exhibit a higher risk of aGVHD and NRM compared to patients with low levels in post-engraftment plasma samples from an independent validation set (n = 89). Tissue inhibitor of metalloproteinase 1, plastin-2, and regenerating islet-derived protein 3-α were selected as the most-predictive biomarkers via an exhaustive variable screening algorithm and were collectively used to develop a biomarker panel score ranging from 0 to 3. The biomarker panel score correlated significantly with aGVHD and NRM risk in univariable and multivariable Cox models. Furthermore, using the biomarker panel score in conjunction with clinical predictors significantly improved the discriminatory performance of the Cox model in predicting aGVHD and NRM risk. Our findings suggest that plasma-derived protein biomarkers can be used to predict aGVHD and NRM before the onset of clinical manifestations.

Oncogenic effects of germline variants in lysosomal storage disease genes.

PURPOSE: Clinical and experimental evidence has suggested pathobiological crosstalk between lysosomal storage diseases (LSDs) and cancer. We aimed to elucidate the association between germline variants in LSD genes and cancer. METHODS: We performed aggregate rare variant association analysis of potentially pathogenic variants (PPVs) in 42 LSD genes and >30 histological types of cancer using genome sequencing data from 2567 cancer patients (Pan-Cancer cohort) and 2504 healthy individuals (1000 Genomes cohort) and exome sequencing data from 53,105 individuals without cancer (ExAC cohort). RESULTS: PPVs were significantly enriched in the Pan-Cancer cohort compared with the 1000 Genomes cohort (PPV prevalence, 20.7% vs. 13.5%; P = 8.7 × 10-12). Cancer risk was higher in individuals with a greater number of PPVs (P = 7.3 × 10-12). Population structure-adjusted optimal sequence kernel association test (SKAT-O) revealed 37 significantly associated cancer type-LSD gene pairs. These results were supported by the consistent tendency toward enrichment of PPVs in cancer patients compared with the ExAC cohort. Cancer developed earlier in PPV carriers than in wild-type patients. Analysis of tumor transcriptomic data from the pancreatic adenocarcinoma cohort revealed 508 genes differentially expressed according to PPV carrier status, which were highly enriched in the core signaling pathways of pancreatic cancer. CONCLUSION: Carriers of PPVs in LSD genes are at increased risk of cancer.

Achieving the laser intensity of 5.5×1022 W/cm2 with a wavefront-corrected multi-PW laser.

The generation of ultrahigh intensity laser pulses was investigated by tightly focusing a wavefront-corrected multi-petawatt Ti:sapphire laser. For the wavefront correction of the PW laser, two stages of deformable mirrors were employed. The multi-PW laser beam was tightly focused by an f/1.6 off-axis parabolic mirror and the focal spot profile was measured. After the wavefront correction, the Strehl ratio was about 0.4, and the spot size in full width at half maximum was 1.5×1.8 µm2, close to the diffraction-limited value. The measured peak intensity was 5.5×1022 W/cm2, achieving the highest laser intensity ever reached.

Prognostic Impact of DNA Repair Protein Expression in Non-Small Cell Lung Cancers Treated with Platinum-Based Chemotherapy and Subsequent Curative Lung Resection.

OBJECTIVE: Multimodal treatments that include preoperative platinum-based chemotherapy are fundamental to the treatment of advanced non-small cell lung cancer (NSCLC). This study aimed to investigate the predictive value of DNA repair protein expression in surgically resected NSCLCs in terms of prognosis and responses to platinum-containing chemotherapy. METHODS: This retrospective study included 136 patients with NSCLC who were treated with preoperative platinum-based chemotherapy, followed by curative lung resection. ATM, RAD51, LKB1, H2AX, and SIRT1 expression levels were analyzed in resected tumor specimens via immunostaining and were used to classify patients and compare survival and responses to chemotherapy. RESULTS: SIRT1 expression correlated significantly with improved responses to platinum-based chemotherapy (odds ratio, 2.28; p = 0.024), progression-free survival (hazard ratio [HR], 0.74; p = 0.036), overall survival (HR, 0.63; p = 0.006), and tumor-bearing survival (HR, 0.62; p = 0.014). After adjusting for clinical variables, the HR of SIRT1 expression remained significant for overall survival (HR, 0.59; p = 0.039) but not for progression-free survival (HR, 0.74; p = 0.183). No prognostic stratification was observed for the other 4 markers. CONCLUSION: Patients with SIRT1-expressing NSCLC had superior responses to chemotherapy and longer survival durations than those with SIRT1-negative cancer.

Screening of non-steroidal anti-inflammatory drugs for inhibitory effects on the activities of six UDP-glucuronosyltransferases (UGT1A1, 1A3, 1A4, 1A6, 1A9 and 2B7) using LC-MS/MS.

Non-steroidal anti-inflammatory drugs (NSAIDs) are used widely to relieve pain and to decrease inflammation. Several clinical studies have reported that NSAIDs inhibit uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes. Therefore, the study evaluated the inhibitory potential of 15 NSAIDs on the activities of six UGT isoforms (i.e. UGT1A1, 1A3, 1A4, 1A6, 1A9 and 2B7) in human liver microsomes (HLMs). Among the 15 NSAIDs tested here, mefenamic acid and diclofenac inhibited all UGTs tested in this study. Piroxicam and niflumic acid inhibited UGT1A9 activity (IC50 = 73.8 µm and 0.38 µm, respectively) and naproxen selectively inhibited UGT2B7 activity (IC50 = 53.1 µm), whereas it did not inhibit the other UGTs tested (IC50 > 200 µm). Diflunisal inhibited the UGT1A1 (IC50 = 33.0 µm) and UGT1A9 (IC50 = 19.4 µm). Acetaminophen, fenoprofen, ibuprofen, ketoprofen, meloxicam, phenylbutazone, salicylic acid and sulindac showed negligible inhibitory effects on the six UGTs (IC50 > 100 µm). These results suggest that some NSAIDs have the potential to inhibit UGTs in vitro.

A lipidomic platform establishment for structural identification of skin ceramides with non-hydroxyacyl chains.

The stratum corneum (SC) is the outermost layer of skin that functions as a barrier and protects against environmental influences and transepidermal water loss. Its unique morphology consists of keratin-enriched corneocytes embedded in a distinctive mixture of lipids containing mainly ceramides, free fatty acids, and cholesterol. Ceramides are sphingolipids consisting of sphingoid bases, which are linked to fatty acids by an amide bond. Typical sphingoid bases in the skin are composed of dihydrosphingosine (dS), sphingosine (S), phytosphingosine (P), and 6-hydroxysphingosine (H), and the fatty acid acyl chains are composed of non-hydroxy fatty acid (N), α-hydroxy fatty acid (A), ω-hydroxy fatty acid (O), and esterified ω-hydroxy fatty acid (E). The 16 ceramide classes include several combinations of sphingoid bases and fatty acid acyl chains. Among them, N-type ceramides are the most abundant in the SC. Mass spectrometry (MS)/MS analysis of N-type ceramides using chip-based direct infusion nanoelectrospray-ion trap mass spectrometry generated the characteristic fragmentation pattern of both acyl and sphingoid units, which could be applied to structural identification of ceramides. Based on the MS/MS fragmentation patterns of N-type ceramides, comprehensive fragmentation schemes were proposed. In addition, mass fragmentation patterns, which are specific to the sphingoid backbone of N-type ceramides, were found in higher m/z regions of tandem mass spectra. These characteristic and general fragmentation patterns were used to identify N-type ceramides in human SC. Based on established MS/MS fragmentation patterns of N-type ceramides, 52 ceramides (including different classes of NS, NdS, NP, and NH) were identified in human SC. The MS/MS fragmentation patterns of N-type ceramides were characterized by interpreting their product ion scan mass spectra. This information may be used to identify N-type ceramides in the SC of human, rat, and mouse skin.

A Phase II Study to Evaluate the Efficacy of Bortezomib in Combination with Thalidomide in Treatment-Naïve Waldenstrom Macroglobulinemia Patients.

PURPOSE: Despite the recent success of Bruton's tyrosine kinase (BTK) inhibitors for the treatment of Waldenstrom macroglobulinemia (WM), their indefinite treatment duration ultimately tantamount to substantial financial and emotional burden. On the other hand, fixed duration of proteasome inhibitors (PI) have shown rapid and reasonable response in WM treatment. Despite the well-known synergism between PI and immunomodulatory drugs (IMiD), there is no trials evaluating such combination in WM. MATERIALS AND METHODS: Based on above, we designed this phase II study to investigate the efficacy and safety of 6 cycles of 28-day bortezomib-thalidomide-dexamethasone (VTD) regimen for treatment-naïve WM. RESULTS: A total of 15 patients were enrolled: major response rate was 64.3%, and overall response rate was 78.6%. During the median follow-up of 41 months, median progression-free survival (PFS) was 13 months and overall survival 40 months. For responders, median duration of response was 13 months and median PFS 19 months. The most common adverse event (AE) of any grade was constipation (57.1%). The most common grade ≥ 3 AE was anemia (21.4%). CONCLUSION: All in all, we hereby provide proof-of-concept that PI + IMiD may be an attractive backbone for fixed duration treatment. It should be noted that granting the same level of access to newer drugs globally is virtually impossible. Thus efforts to develop regimens using readily available drugs to yield similar or adequate treatment outcomes should not be disregarded. In this sense, we believe our study holds its place for its novelty and eloquently addresses achieving the daunting societal quest of health equity.

Adjuvant Pembrolizumab in Patients with Stage IIIA/N2 Non-Small Cell Lung Cancer Completely Resected after Neoadjuvant Concurrent Chemoradiation: A Prospective, Open-Label, Single-Arm, Phase 2 Trial.

Purpose: Optimal treatment for stage IIIA/N2 non-small cell lung cancer (NSCLC) is controversial. We aimed to assess the efficacy and safety of adjuvant pembrolizumab for stage IIIA/N2 NSCLC completely resected after neoadjuvant concurrent chemoradiation therapy (CCRT). Materials and Methods: In this open-label, single-center, single-arm phase 2 trial, patients with stage IIIA/N2 NSCLC received adjuvant pembrolizumab for up to two years after complete resection following neoadjuvant CCRT. The primary endpoint was disease-free survival (DFS). Secondary endpoints included overall survival (OS) and safety. As an exploratory biomarker analysis, we evaluated the proliferative response of blood CD39+PD-1+CD8+ T cells using fold changes in the percentage of proliferating Ki-67+ cells from days 1 to 7 of cycle 1 (Ki-67D7/D1). Results: Between October 2017 and October 2018, 37 patients were enrolled. Twelve (32%) and three (8%) patients harbored EGFR and ALK alterations, respectively. Of 34 patients with programmed cell death ligand 1 assessment, 21 (62%), 9 (26%), and 4 (12%) had a tumor proportion score of <1%, 1-50%, and ≥50%, respectively. The median follow-up was 71 months. The median DFS was 22.4 months in the overall population, with a five-year DFS rate of 29%. The OS rate was 86% at two years and 76% at five years. Patients with tumor recurrence within six months had a significantly lower Ki-67D7/D1 among CD39+PD-1+CD8+ T cells than those without (p=0.036). No new safety signals were identified. Conclusion: Adjuvant pembrolizumab may offer durable disease control in a subset of stage IIIA/N2 NSCLC patients after neoadjuvant CCRT and surgery.

CYP2J2 and CYP2C19 are the major enzymes responsible for metabolism of albendazole and fenbendazole in human liver microsomes and recombinant P450 assay systems.

Albendazole and fenbendazole are broad-spectrum anthelmintics that undergo extensive metabolism to form hydroxyl and sulfoxide metabolites. Although CYP3A and flavin-containing monooxygenase have been implicated in sulfoxide metabolite formation, the enzymes responsible for hydroxyl metabolite formation have not been identified. In this study, we used human liver microsomes and recombinant cytochrome P450s (P450s) to characterize the enzymes involved in the formation of hydroxyalbendazole and hydroxyfenbendazole from albendazole and fenbendazole, respectively. Of the 10 recombinant P450s, CYP2J2 and/or CYP2C19 was the predominant enzyme catalyzing the hydroxylation of albendazole and fenbendazole. Albendazole hydroxylation to hydroxyalbendazole is primarily mediated by CYP2J2 (0.34 µl/min/pmol P450, which is a rate 3.9- and 8.1-fold higher than the rates for CYP2C19 and CYP2E1, respectively), whereas CYP2C19 and CYP2J2 contributed to the formation of hydroxyfenbendazole from fenbendazole (2.68 and 1.94 µl/min/pmol P450 for CYP2C19 and CYP2J2, respectively, which are rates 11.7- and 8.4-fold higher than the rate for CYP2D6). Correlation analysis between the known P450 enzyme activities and the rate of hydroxyalbendazole and hydroxyfenbendazole formation in samples from 14 human liver microsomes showed that albendazole hydroxylation correlates with CYP2J2 activity and fenbendazole hydroxylation correlates with CYP2C19 and CYP2J2 activities. These findings were supported by a P450 isoform-selective inhibition study in human liver microsomes. In conclusion, our data for the first time suggest that albendazole hydroxylation is primarily catalyzed by CYP2J2, whereas fenbendazole hydroxylation is preferentially catalyzed by CYP2C19 and CYP2J2. The present data will be useful in understanding the pharmacokinetics and drug interactions of albendazole and fenbendazole in vivo.

In vitro metabolism of obovatol and its effect on cytochrome P450 enzyme activities in human liver microsomes.

Obovatol, a major constituent of the leaves of Magnolia obovata Thunb, is known to inhibit nuclear factor-κB activity and arachidonic acid-induced platelet aggregation. This study was performed to identify the metabolites of obovatol in human liver microsomes. Human liver microsomes incubated with obovatol in the presence of NADPH and/or UDPGA resulted in the formation of six metabolites, M1-M6. M1 and M2 were identified as hydroxyobovatol, on the basis of liquid chromatography/tandem mass spectrometric (LC-MS/MS) analysis. M1, M2 and obovatol were further metabolized to their glucuronide conjugates, obovatol-glucuronide (M3), obovatol-diglucuronide (M4) and hydroxyobovatol-glucuronide (M5 and M6). The inhibitory potency of obovatol on eight major human P450s was also investigated in human liver microsomes. In these experiments, obovatol strongly inhibited CYP2C19-mediated S-mephenytoin hydroxylase activity with an IC(50) value of 0.8 µM, which could have implications for drug-drug interactions.

Real World Experience of Second-Line Treatment Strategies after Palbociclib and Letrozole: Overall Survival in Metastatic Hormone Receptor-Positive Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer.

BACKGROUND: We analyzed real-world practice of second-line treatment in hormone receptor (HR)+ human epidermal growth factor receptor-2 (HER2)- metastatic breast cancer (MBC) following the first-line CDK4/6 inhibitor with letrozole. In addition, we evaluated the relationship between second-line treatment strategies and survival outcome. METHODS: Using the clinical data warehouse, clinical information including MBC diagnosis, treatment and survival outcomes were collected. RESULTS: In total, 305 patients were treated with the first-line palbociclib plus letrozole, and we evaluated 166 patients who were treated with second-line treatment. Of the 166 patients, 28.5% were treated with capecitabine (C), followed by exemestane with everolimus (EE) (27.3%) or cytotoxic chemotherapy other than capecitabine (T) (18.8%) and fulvestrant-based treatment or endocrine monotherapy (F) (12.7%). Eighteen patients (10.9%) were enrolled in clinical trials (CT). With regard to treatment strategies, and the median progression-free survival of second-line treatment in a metastatic setting (PFS2) was 7.4 months with C, 5.2 months with EE, 4.8 months with T, 3.6 months with F, and 3.6 months with CT (p = 0.066). In patients with visceral organ disease progression, C (31.3%) or T(31.3%) was the most common second-line treatment followed by EE (21.9%). Most of the 47 patients with bone metastasis alone were treated with EE (38.2%), followed by C (23.4%) and F (21.3%) (p = 0.008). The median overall survival of second-line treatment in a metastatic setting (OS2) was 42.3 months with C, 35.7 months with F, 30.7 months with EE, and 23.1 months with T. The median OS2 for those in CT was not reached (p = 0.064). ER driven BC, disease progression site and PFS2 were associated with OS and OS2 in HR+HER2- MBC (ps < 0.05). CONCLUSIONS: We suggested the second line treatment strategy was important to improve prognosis in patients with HR+/HER2- MBC, especially given the recent standardization of first-line treatment and the many available second-line options.

The Association Between Institutional Case Volume of Hematopoietic Stem Cell Transplantation and Mortality.

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is a complex, high-risk procedure with significant morbidity and mortality. The positive impact of higher institutional case volume on survival has been reported in various high-risk procedures. The association between annual institutional HSCT case volume and mortality was analyzed using the National Health Insurance Service database. METHODS: Data on 16,213 HSCTs performed in 46 Korean centers between 2007 and 2018 were extracted. Centers were divided into low- or high-volume centers using an average of 25 annual cases as the cut-off. Adjusted odds ratios (OR) for 1-year mortality after allogeneic and autologous HSCT were estimated using multivariable logistic regression. RESULTS: For allogeneic HSCT, low-volume centers (≤25 cases/y) were associated with higher 1-year mortality (adjusted OR 1.17, 95% CI 1.04-1.31, P = .008). However, low-volume centers did not show higher 1-year mortality (adjusted OR 1.03, 95% CI 0.89-1.19, P = .709) for autologous HSCT. Long-term mortality after HSCT was significantly worse in low-volume centers (adjusted hazard ratio [HR] 1.17, 95% CI, 1.09-1.25, P < .001 and adjusted HR 1.09, 95% CI, 1.01-1.17, P = .024, allogeneic and autologous HSCT, respectively) compared with high-volume centers. CONCLUSION: Our data suggest that higher institutional HSCT case volume seems to be associated with better short- and long-term survival.

Comprehensive Clinical Characterization of Decade-Long Survivors of Metastatic Breast Cancer.

BACKGROUND: Elucidating the clinical features of metastatic breast cancer (MBC) patients with an exceptionally favorable prognosis may offer insights to improve the survival of more typical patients. METHODS: We collected comprehensive real-world data on clinicopathologic characteristics, treatments, and outcomes of 110 consecutive MBC patients who survived for over ten years from the clinical data warehouse of Samsung Medical Center. RESULTS: The cohort included 54 hormone receptor (HR)-positive/HER2-negative (HR+/HER2-), 21 HR+/HER2+, 16 HR-/HER2+, and 14 triple-negative breast cancer (TNBC) patients. The median age at MBC diagnosis was 48.5 years. Approximately 70% of patients initially had a single-organ metastasis. The most common site of metastasis was the lung (46.4%), followed by distant lymph nodes (37.3%). During a median follow-up of 14.6 years, the median duration of systemic therapy was 11, 8.4, 7.3, and 0.8 years in the HR+/HER2-, HR+/HER2+, HR-/HER2+, and TNBC subgroups, respectively. Seven HER2+ and ten TNBC patients received systemic treatment for less than two years and remained treatment-free for most of the follow-up period, suggesting a potential chance of cure. The TNBC subtype (p < 0.001) and local treatment with curative intent within 1 year of MBC diagnosis (p = 0.002) were significantly associated with long-term treatment-free survival. The survival of HER2+ MBC and TNBC patients, but not that of HR+/HER2- patients, plateaued approximately 13 years after MBC diagnosis. CONCLUSIONS: A small subset of patients with HER2+ MBC and metastatic TNBC may be curable with multimodality therapy. Prospective studies integrating clinical and genomic data may identify unique clinicogenomic features of MBC patients who can achieve durable disease control without prolonged chemotherapy.

Outcome of Extracorporeal Ventricular Assist Device for Cardiogenic Shock as a Bridge to Transplantation.

BACKGROUND: The extracorporeal ventricular assist device (e-VAD) system is designed for left ventricular support using a permanent life support console. This study aimed to determine the impact of temporary e-VAD implantation bridging on posttransplant outcomes. METHODS: We reviewed the clinical records of 6 patients with the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile 1, awaiting heart transplantation, who were provided with temporary e-VAD from 2018 to 2019. The circuit comprised a single centrifugal pump without an oxygenator. The e-VAD inflow cannula was inserted into the apex of the left ventricle, and the outflow cannula was positioned in the ascending aorta. The median follow-up duration was 8.4±6.9 months. RESULTS: After e-VAD implantation, lactate dehydrogenase levels significantly decreased, and Sequential Organ Failure Assessment scores significantly improved. Bedside rehabilitation was possible in 5 patients. After a mean e-VAD support duration of 14.5±17.3 days, all patients were successfully bridged to transplantation. After transplantation, 5 patients survived for at least 6 months. CONCLUSION: e-VAD may reverse end-organ dysfunction and improve outcomes in INTERMACS I heart transplant patients.

Venous thromboembolism in relapsed or refractory multiple myeloma patients treated with lenalidomide plus dexamethasone.

Lenalidomide plus dexamethasone (LD) is currently the mainstay of treatment for both untreated and relapsed or refractory multiple myeloma (RRMM). Although lenalidomide-associated venous thromboembolism (VTE) is a major clinical concern, its incidence and prognostic impact have not been delineated. In this nationwide retrospective cohort study, we aimed to determine the cumulative incidence of VTE and its prognostic value using two consecutive cohorts of LD-treated RRMM patients: the KMM151 cohort (N = 542) and the HIRA cohort (N = 1559). Data were collected from medical records for the KMM151 cohort and healthcare insurance claims database for the HIRA cohort. Throughout the study period, 24 patients (4.4%) in the KMM151 cohort and 80 patients (5.1%) in the HIRA cohort developed VTE. The cumulative incidence reached a plateau approximately 2 years after LD initiation. The 2-year incidence was 4.9% in the KMM151 cohort and 8% in the HIRA cohort. Higher starting dose of lenalidomide, previous history of VTE, and older age were associated significantly with an increased VTE risk. Early-onset VTE was associated significantly with poor survival. In conclusion, VTE occurred in 5-8% of RRMM patients treated with LD over 2 years, and early-onset VTE was a strong indicator of poor prognosis.

Effect of Platinum-Based Chemotherapy on PD-L1 Expression on Tumor Cells in Non-small Cell Lung Cancer.

PURPOSE: Programmed death-1 (PD-1)/PD-1 ligand (PD-L1) axis blockades have revolutionized the treatment of advanced non-small cell lung cancer (NSCLC). We assessed the effect of platinum-based chemotherapy on tumor PD-L1 expression and its clinical implications. MATERIALS AND METHODS: We used immunohistochemistry to retrospectively evaluate the percentage of tumor cells with membranous PD-L1 staining (tumor proportion score) in paired tumor specimens obtained before and after platinum-based neoadjuvant chemotherapy (NACT) in 86 patients with NSCLC. We analyzed the correlation between the change in PD-L1 tumor proportion score and clinicopathologic characteristics, response to NACT, and survival. RESULTS: The PD-L1 tumor proportion score increased in a significant proportion of patients with NSCLC after platinum-based NACT (Wilcoxon signed-rank test, p=0.002). That pattern was consistent across clinically defined subgroups except for patients with partial response to NACT. Tumors from 26 patients (30.2%) were PD-L1‒negative before NACT but PD-L1-positive after NACT, whereas the reverse pattern occurred in six patients (7%) (McNemar's test, p < 0.001). Increase in PD-L1 tumor proportion score was significantly associated with lack of response to NACT (Fisher exact test, p=0.015). There was a tendency, albeit not statistically significant, for patients with an increase in PD-L1 tumor proportion score to have shorter survival. CONCLUSION: Tumor PD-L1 expression increased after platinum-based NACT in a significant proportion of patients with NSCLC. Increase in tumor PD-L1 expression may predict poor clinical outcome.

Body Cavity-Based Lymphoma in a Country with Low Human Immunodeficiency Virus Prevalence: A Series of 17 Cases from the Consortium for Improving Survival of Lymphoma.

PURPOSE: Primary effusion lymphoma (PEL) is a type of body cavity-based lymphoma (BCBL). Most patients with PEL are severely immunocompromised and seropositive for human immunodeficiency virus (HIV). We investigated the distinctive clinicopathologic characteristics of BCBL in a country with low HIV burden. MATERIALS AND METHODS: We retrospectively collected data on the clinicopathologic characteristics, treatments, and outcomes of 17 consecutive patients with BCBL at nine institutions in Korea. RESULTS: Latency-associated nuclear antigen 1 (LANA1) immunostaining indicated that six patients had PEL, six patients had human herpesvirus 8 (HHV8)-unrelated BCBL, and five patients had HHV8-unknown BCBL. The patients with PEL exhibited no evidence of immunodeficiency except for one who was HIV positive. One (20%) and four (80%) patients with PEL and six (100%) and zero (0%) patients with HHV8-unrelated BCBL were positive for CD20 and CD30 expression, respectively. The two patients with PEL (one HIV-positive and one HIV-negative patient) with the lowest proliferation activity as assessed by the Ki-67 labeling index survived for > 1 and > 4 years without chemotherapy, respectively, in contrast to the PEL cases in the literature, which mostly showed a high proliferation index and poor survival. CONCLUSION: PEL mostly occurred in ostensibly immunocompetent individuals and had a favorable outcome in Korea. A watchful waiting approach may be applicable for managing HIV-seronegative patients with PEL with a low Ki-67 labeling index. A possible trend was detected among LANA1, CD20, and CD30 expression in BCBL.

In-plane direct current probing for spin orbit torque-driven effective fields in perpendicularly magnetized heavy metal/ferromagnet/oxide frames.

Electrical manipulation of magnetization states has been the subject of intense focus as it is a long-standing goal in the emerging field of spintronics. In particular, torque generated by an in-plane current with a strong spin-orbit interaction shows promise for control of the adjacent ferromagnetic state in heavy-metal/ferromagnet/oxide frames. Thus, the ability to unlock precise spin orbit torque-driven effective fields represents one of the key approaches in this work. Here, we address an in-plane direct current measurement approach as a generic alternative tool to identify spin orbit torque-driven effective fields in a full polar angle range without adopting the commonly used harmonic analyses. Our experimental results exhibited a strongly polar angular dependency of the spin orbit torque-driven effective fields observed from Ta or W/CoFeM/MgO frames.

A phase 4 study of nilotinib in Korean patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: ENESTKorea.

Although nilotinib has improved efficacy compared to imatinib, suboptimal response and intolerable adverse events (AEs) limit its effectiveness in many patients with chronic myeloid leukemia in chronic phase (CML-CP). We investigated the 2-year efficacy and safety of nilotinib and their relationships with plasma nilotinib concentrations (PNCs). In this open-label, multi-institutional phase 4 study, 110 Philadelphia chromosome-positive CML-CP patients were treated with nilotinib at a starting dose of 300 mg twice daily. Molecular responses (MRs) and AEs were monitored for up to 24 months. The 24-month cumulative MR4.5 rate was evaluated as the primary endpoint. Plasma samples were collected from 94 patients to determine PNCs, and the per-patient mean was used to categorize them into four mean PNC (MPNC) groups. Cumulative MR rates and safety were compared between groups. With a median follow-up of 22.2 months, the 24-month cumulative MR4.5 rate was 56.2% (95% confidence interval, 44.0%-8.3%), and the median time to MR4.5 was 23.3 months. There were no significant differences in the cumulative rates of major molecular response, MR4 , and MR4.5 between MPNC groups. One patient died due to acute viral hepatitis, and two developed hematological or cytogenetic relapse, while no progression to accelerated or blast phase was observed. Safety results were consistent with previous studies with no new safety signal identified. Across the MPNC groups, there was no significant linear trend in the frequency of AEs. Nilotinib is highly effective for the treatment of CML-CP with manageable AEs. The measurement of PNC has no predictive value for patient outcomes and is thus not found to be clinically useful. This study is registered with clinicaltrials.gov, Number NCT03332511.