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Waldenström macroglobulinemia (WM) is characterized by lymphoplasmacytic lymphoma associated with large amounts of monoclonal immunoglobulin M (IgM) protein (Owen et al., 2003). Common signs and symptoms include fatigue due to anemia, lymph node enlargement, hepatosplenomegaly, thrombocytopenia, symptoms related to high viscosity, and peripheral neuropathy, among others. Despite significant advances in WM treatment, this type of indolent lymphoma remains incurable, with a wide array of patient outcomes (Ruan et al., 2020). In recent years, chimeric antigen receptor T (CAR-T) cell therapy targeting cluster of differentiation 19 (CD19) has shown unprecedented response rates and durability in the treatment of B-cell malignancies. In this report, we describe a challenging case of WM that involved multiple extramedullary sites, relapsed, and was refractory to chemotherapy, immunotherapy, and targeted therapy. After anti-CD19 CAR-T cell therapy, the tumor burden significantly decreased and the patient's condition remained stable at the writing of this report.

Additional chromosomal abnormalities(ACAs) at diagnosis are associated with inferior prognosis in chronic myeloid leukemia. However, the prognostic significance of ACAs in adult patients with Philadelphia Chromosome Positive acute lymphoblastic leukemia (Ph + ALL) receiving TKI-targeted drugs and allogeneic hematopoietic stem cell transplantation(HSCT) is unknown. One hundred thirty-six adult patients with Ph + ALL were included in the study and retrospectively analysed, evaluating the effect of ACAs on outcomes of transplantation. ACAs are observed in 60 cases (44%). ACAs detected in more than 5% of cases were defined as major-route and encompass: +der(22), +der(9), + 8, -7 and complex karyotype. The median follow-up was 26.4 months. In the subgroup analyses of major route ACAs, three-year cumulative incidence of relapse (CIR) and progression-free survival(PFS) are statistically significant in + 8[66.7% vs.23.7%, P = 0.024; 77.8% vs. 23.7%, P = 0.0087], -7[53.8% vs. 23.7%, P = 0.035%; 61.5% vs. 32.9%, P = 0.033], and complex karyotypes[42.9% vs. 23.7%, P = 0.027; 47.6% vs. 23.7%] compared with t(9;22) sole. Additionally, the 3-year CIR for Ph + ALL with + der(22) is 44% vs. 23.7% for t(9;22) sole(P = 0.045). The 3-year overall survival (OS) in the - 7 group is 46.5%, which is statistically significant compared with the other groups(P = 0.001). In multivariate analyses, three years CIR and PFS are statistically significant in + der(22), + 8, -7 and complex karyotype compared with t(9;22) sole(P < 0.05). More importantly, Ph + ALL with - 7 was negatively associated with the rate of 3-year OS(P = 0.012). Thus, ACAs at diagnosis appear to have a significant prognostic impact on transplantation outcomes in patients with Ph + ALL., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Diabetes mellitus (DM) affects up to one-third of breast cancer (BC) patients. Patients with co-existing BC and DM (BC-DM) have worsened BC prognosis. Nevertheless, the molecular mechanisms orchestrating BC-DM prognosis remain poorly understood. tRNA-derived fragments (tRFs) have been shown to regulate cancer progression. However, the biological role of tRFs in BC-DM has not been explored., Methods: tRF levels in tumor tissues and cells were detected by tRF sequencing and qRT-PCR. The effects of tRF on BC cell malignancy were assessed under euglycemic and hyperglycemic conditions in vitro. Metabolic changes were assessed by lactate, pyruvate, and extracellular acidification rate (ECAR) assays. Diabetic animal model was used to evaluate the impacts of tRF on BC tumor growth. RNA-sequencing (RNA-seq), qRT-PCR, Western blot, polysome profiling, luciferase reporter assay, and rescue experiments were performed to explore the regulatory mechanisms of tRF in BC-DM., Results: We identified that tRF-Cys-GCA-029 was downregulated in BC-DM tissues and under hyperglycemia conditions in BC cells. Functionally, downregulation of tRF-Cys-GCA-029 promoted BC cell proliferation and migration in a glucose level-dependent manner. tRF-Cys-GCA-029 knockdown also enhanced glycolysis metabolism in BC cells, indicated by increasing lactate/pyruvate production and ECAR levels. Notably, injection of tRF-Cys-GCA-029 mimic significantly suppressed BC tumor growth in diabetic-mice. Mechanistically, tRF-Cys-GCA-029 regulated BC cell malignancy and glycolysis via interacting with PRKCG in two ways: binding to the coding sequence (CDS) of PRKCG mRNA to regulate its transcription and altering polysomal PRKCG mRNA expression to modify its translation., Conclusions: Hyperglycemia-downregulated tRF-Cys-GCA-029 enhances the malignancy and glycolysis of BC cells. tRF-Cys-GCA-029-PRKCG-glycolysis axis may be a potential therapeutic target against BC-DM., (© 2024. The Author(s).)

Introduction: Although the combination of venetoclax (VEN) and hypomethylating agents (HMAs) results in impressive efficacy in acute myeloid leukemia (AML), there is still a subset of patients who are refractory. We investigated the outcomes of AML patients with monocytic differentiation who were treated with frontline VEN/HMA., Methods: A total of 155 patients with newly diagnosed AML treated with frontline VEN/HMA were enrolled in the study. Monocyte-like AML was identified by flow cytometry with typical expression of monocytic markers, and M5 was identified according to French, American, and British category. We compared the outcomes of patients with different characteristics., Results: The rate of complete remission (CR) and CR with incomplete recovery of blood counts (CRi), progression-free survival (PFS), and overall survival (OS) in monocyte-like AML were inferior to those in nonmonocyte-like AML (CR/CRi rates, 26.7% vs. 80.0%, p < 0.001; median PFS, 2.1 vs. 8.8 months, p < 0.001; median OS, 9.2 vs. 19 months, p = 0.013). CR/CRi rate in M5 was lower than that in non-M5 (60.7% vs. 75.5%, p = 0.049). Multivariate analyses showed that monocyte-like AML was associated with lower odds of CR/CRi and higher risk of progression., Conclusion: Our study suggested that newly diagnosed AML with a monocytic immunophenotype had a poor prognosis with VEN/HMA treatment., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

There are limited studies on mutation profiling for Peripheral T-cell lymphomas (PTCL) in the Chinese population. We retrospectively analyzed the clinical and genetic landscape of 66 newly diagnosed Chinese patients. Targeted next-generation sequencing (NGS) was performed for tissues from these patients. At least one mutation was detected in 60 (90.9%) patients, with a median number of 3 (0-7) mutations, and 32 (48.5%) cases detected with more than 4 mutations. The genes with higher mutation frequencies were TET2, RHOA, DNMT3A, IDH2, TP53, STAT3, and KMT2D respectively. When mutant genes are classified by functional group, the most prevalent mutations are related to epigenetics and signal transduction. IPI ≥2, PIT ≥2, and failure to achieve partial remission (PR) were factors for inferior progression-free survival (PFS) and overall survival (OS). Multivariate analysis showed TP53 was an adverse factor for PFS (HR, 3.523; 95% CI, 1.262-9.835; p = 0.016), and KMT2D was an adverse factor for OS (HR, 10.097; 95% CI, 1.000-101.953; p = 0.048). Mutation profiling could help differentiate distinct types of PTCL and serve as a useful tool for determining treatment options and prognoses., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Comparative investigations evaluating the efficacy of pomalidomide-based (Pom-based) versus daratumumab-based (Dara-based) therapies in patients with relapsed/refractory multiple myeloma (RRMM) remain scarce, both in randomized controlled trials and real-world studies., Methods: This retrospective cohort study included 140 RRMM patients treated with Pom-based or Dara-based or a combination of pomalidomide and daratumumab (DPd) regimens in a Chinese tertiary hospital between December 2018 and July 2023., Results: The overall response rates (ORR) for Pom-based (n = 48), Dara-based (n = 68), and DPd (n = 24) groups were 57.8%, 84.6%, and 75.0%, respectively (p = 0.007). At data cutoff on August 1, 2023, the median progression-free survival (PFS) was 5.7 months (95% CI: 5.0-6.5) for the Pom-based group, 10.5 months (5.2-15.8) for the Dara-based group, and 6.7 months (4.0-9.3) for the DPd group (p = 0.056). Multivariate analysis identified treatment regimens (Dara-based vs. Pom-based, DPd vs. Pom-based) and Eastern Cooperative Oncology Group performance status (ECOG PS) as independent prognostic factors for PFS. In the subgroups of patients aged >65 years, with ECOG PS ≥2, lines of therapy ≥2, extramedullary disease or double-refractory disease (refractory to both lenalidomide and proteasome inhibitors), the superiority of Dara-based regimens over Pom-based regimens was not evident. A higher incidence of infections was observed in patients receiving Dara-based and DPd regimens (Pom-based 39.6% vs. Dara-based 64.7% vs. DPd 70.8%, p = 0.009)., Conclusions: In real-world settings, Pom-based, Dara-based, and DPd therapies exhibited favorable efficacy in patients with RRMM. Dara-based therapy yielded superior clinical response and PFS compared to Pom-based therapy., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: To explore the prognostic and therapeutic role of Epstein-Barr Virus (EBV) on peripheral T-cell lymphoma (PTCL)., Methods: Totally 262 newly diagnosed PTCL patients who were hospitalized from January 2014 to December 2022 were retrospectively enrolled. Molecular analysis included 31 eligible patients. EBV-encoded RNA (EBER) presence in tumor tissue and EBV DNA levels in patients at baseline (DNA1) and after 4 cycles of chemotherapy (DNA4) were assessed., Results: Our findings revealed that the EBER-positive cohort exhibited significant differences compared to counterparts in overall survival (OS, P = 0.047) and progression-free survival (PFS, P = 0.009). Both DNA1 and DNA4 were significantly associated with inferior OS. Multivariate analysis demonstrated that DNA4 independently affected PTCL prognosis for OS (hazard ratio = 5.1617; 95% confidence interval 1.1017-24.1831; P = 0.037). Treatment with the cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus azacytidine regimen showed a better OS compared to CHOP or CHOP plus etoposide for patients with partially positive EBER and EBER positive statuses (P = 0.192), although the improvement was not statistically significant. This study delineated the genetic paradigm of PTCL, comparing genetic differences by EBV status and found that EBER partially positive plus positive patients were more likely to have DNMT3A (P = 0.002), RHOA G17V (P = 0.023), and TET2 mutations (P = 0.032)., Conclusion: EBER, DNA1, and DNA4 emerged as sensitive markers for prognosis. CHOP plus azacytidine might present a preferable option for PTCL patients with DNA methylation due to EBV infection., (© 2024. The Author(s).)

Background: AML1/ETO fusion confers favorable prognosis in acute myeloid leukemia (AML) treated with intensive chemotherapy (IC). However, the impact of AML1/ETO fusion on the efficacy of venetoclax in the treatment of AML is unclear., Objective: The aim of this study was to evaluate the efficacy of venetoclax plus hypomethylating agents (VEN/HMAs) in patients with AML1/ETO-positive AML., Patients and Methods: Patients with newly diagnosed AML in two centers were reviewed and divided into three cohorts: AML1/ETO-positive AML treated with frontline VEN/HMA (Cohort A), AML1/ETO-negative AML treated with frontline VEN/HMA (Cohort B), or AML1/ETO-positive AML treated with frontline IC (Cohort C). The response and survival were compared between the cohorts., Results: A total of 260 patients were included in the study. Patients in Cohort A had a significantly lower overall response rate (ORR) than patients in Cohort B (40.9% vs 71.2%, p = 0.005). The median event-free survival (EFS) in Cohort A and Cohort B was 2.7 months and 7.7 months, respectively, with no significant difference. The ORR and median EFS in Cohort C were 80.8% and 14.9 months, respectively, which were significantly superior to those in Cohort A, and the advantages remained significant after propensity score matching. ORR and EFS in KIT-mutated patients with AML1/ETO-positive AML receiving VEN/HMA were much inferior to those in KIT wild-type patients (ORR 0.0% vs 81.8%, p = 0.001; EFS 1.2 months vs not reached, p < 0.001)., Conclusions: Newly diagnosed AML patients with AML1/ETO fusion had a poor response to frontline VEN/HMA treatment. When determining induction therapy for patients with AML1/ETO-positive AML, IC should be preferred over VEN/HM., (© 2024. The Author(s).)

BACKGROUND Systemic light chain (AL) amyloidosis is a disease characterized by the deposition of amyloid fibrils throughout tissues due to the production of misfolded immunoglobulin light chains by clonally expanded populations of CD38+ plasma cells. Some patients can have liver involvement, which typically presents with nonspecific symptoms. Daratumumab, a human CD38-targeting antibody, has shown efficacy in improving hematological parameters and organ function in patients with AL amyloidosis. Low-frequency daratumumab can reduce financial burden, but whether it is effective for patients with liver involvement has not been reported. CASE REPORT We present the case of a 64-year-old man admitted to our hospital with fatigue and recurrent fever. Histological analysis of a liver biopsy demonstrated AL amyloidosis. Bone marrow biopsy demonstrated the presence of abnormal plasma cells. Laboratory test results demonstrated increased levels of circulating free kappa (kappa) light chains, which were also seen on blood and urine immunofixation electrophoresis. Based on these findings, AL amyloidosis of the kappa light chain type with liver, cardiac, and renal involvement was diagnosed. The patient ultimately achieved hematological stringent complete response, liver remission, renal complete response, and cardiac very good partial response after 2 cycles of the low-frequency daratumumab, bortezomib, and dexamethasone regimen and 4 cycles of daratumumab and dexamethasone regimen chemotherapy. CONCLUSIONS The case indicates that low-frequency daratumumab treatment can have efficacy in AL amyloidosis with liver involvement.

KMT2A rearrangement ( KMT2A -r) in patients with acute myeloid leukemia (AML) is associated with poor outcomes; the prognostic factors after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remain unclear. We investigated 364 adults with AML who underwent allo-HSCT between April 2016 and May 2022, and 45 had KMT2A -r among them. Propensity score analysis with 1:1 matching and the nearest neighbor matching method identified 42 patients in KMT2A -r and non- KMT2A -r cohorts, respectively. The 2-year overall survival (OS), relapse-free survival (RFS), cumulative incidence of relapse (CIR), and non-relapsed mortality rates of patients with KMT2A -r ( n = 45) were 59.1%, 49.6%, 41.5%, and 8.9%, respectively. Using propensity score matching, the 2-year OS rate of patients with KMT2A -r ( n = 42) was lower than that of those without KMT2A -r ( n = 42; 56.1% vs 88.1%, P = 0.003). Among patients with KMT2A -r ( n = 45), the prognostic advantage was exhibited from transplantation in first complete remission (CR1) and measurable residual disease (MRD) negative, which was reflected in OS, RFS, and CIR ( P < 0.001, P < 0.001, and P = 0.002, respectively). Furthermore, patients with AF6 had poorer outcomes than those with AF9 , ELL , and other KMT2A -r subtypes ( P = 0.032, P = 0.001, and P = 0.001 for OS, RFS, and CIR, respectively). However, no differences were found in the OS, RFS, and CIR between patients with KMT2A -r with and without mutations (all P > 0.05). Univariate and multivariate analyses revealed that achieving CR1 MRD negative before HSCT was a protective factor for OS [hazard ratio (HR) = 0.242, P = 0.007], RFS (HR = 0.350, P = 0.036), and CIR (HR = 0.271, P = 0.021), while AF6 was a risk factor for RFS (HR = 2.985, P = 0.028) and CIR (HR = 4.675, P = 0.004). The prognosis of patients with KMT2A -r AML was poor, particularly those harboring AF6 -related translocation; however, it is not associated with the presence of mutations. These patients can benefit from achieving CR1 MRD negative before HSCT., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Despite concerns about an increased risk of adverse outcomes following coronavirus disease (COVID-19) in multiple myeloma patients treated with anti-CD38 Abs, the impact of COVID-19 on this group of patients is unclear. We tried to evaluate the clinical outcomes of these patients. We collected data from 1036 patients with multiple myeloma and enrolled 509 cases with COVID-19. We divided enrolled patients into daratumumab or nondaratumumab cohorts based on whether they had received daratumumab-based treatment within 6 months of COVID-19 infection. We applied a propensity score matching method to reduce the bias of baseline characteristics, and then compared the incidence of adverse outcomes between these two cohorts. A total of 117 patients were enrolled in the daratumumab cohort, and 392 patients in the nondaratumumab cohort. After propensity score matching, 204 patients were matched. The proportions of patients who developed COVID-19 pneumonia (59.8% vs. 34.3%, p < 0.001), were hospitalized (33.3% vs. 11.8%, p < 0.001) and developed severe disease (23.5% vs. 6.9%, p = 0.001) were higher in the matched daratumumab cohort. By multivariate analysis, daratumumab exposure was an independent risk factor for severe disease. An ECOG performance status >2 and history of chronic kidney disease were independent risk factors for COVID-19-related mortality among patients who received daratumumab-based therapy. This study suggested that multiple myeloma patients exposed to daratumumab were at a higher risk of adverse outcomes from COVID-19., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Recent advances in lymphoma treatment have significantly improved the survival of patients; however, the current approaches also have varying side effects. To overcome these, it is critical to implement individualized treatment according to the patient's condition. Therefore, the early identification of high-risk groups and targeted treatment are important strategies for prolonging the survival time and improving the quality of life of patients. Interim positron emission tomography-computed tomography (PET-CT) has a high prognostic value, which can reflect chemosensitivity and identify patients for whom treatment may fail under this regimen. To date, many prospective clinical studies on interim PET (iPET)‍-adapted therapy have been conducted. In this review, we focus on the treatment strategies entailed in these studies, as well as the means and timing of iPET assessment, with the aim of exploring the efficacy and existing issues regarding iPET-adapted treatment. It is expected that the improved use of PET-CT examination can facilitate treatment decision-making to identify precise treatment options.

Bortezomib (bort) is an effective therapeutic agent for patients with multiple myeloma (MM); however, most patients develop drug resistance. Autophagy, a highly conserved process that recycles cytosol or entire organelles via lysosomal activity, is essential for the survival, homeostasis, and drug resistance in MM. Growing evidence has highlighted that E3 ligase tripartite motif-containing protein 21 (TRIM21) not only interacts with multiple autophagy regulators but also participates in drug resistance in various cancers. However, to date, the direct substrates and additional roles of TRIM21 in MM remain unexplored. In this study, we demonstrated that low TRIM21 expression is a factor for relapse in MM. TRIM21 knockdown (KD) made MM cells more resistant to bort, whereas TRIM21 overexpression (OE) resulted in increased MM sensitivity to bort. Proteomic and phosphoproteomic studies of TRIM21 KD MM cells showed that bort resistance was associated with increased oxidative stress and elevated prosurvival autophagy. Our results showed that TRIM21 KD MM cell lines induced prosurvival autophagy after bort treatment, suppressing autophagy by 3-methyladenine treatment or by the short hairpin RNA of autophagy-related gene 5 (ATG5)-restored-bort sensitivity. Indeed, ATG5 expression was increased and decreased by TRIM21 KD and OE, respectively. TRIM21 affected autophagy by ubiquitinating ATG5 through K48 for proteasomal degradation. Importantly, we confirmed that TRIM21 could potentiate the antimyeloma effect of bort through in vitro and in vivo experiments. Overall, our findings define the key role of TRIM21 in MM bort resistance and provide a foundation for a novel targeted therapeutic approach., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Angio-based index of microcirculatory resistance (IMR) and fractional flow reserve (FFR) have been developed, however, the differences between baseline and hyperemic data and their effects on their computation have not yet been discussed. This study aimed to compare the diagnostic performance of a novel method for calculating IMR and FFR from coronary angiography under baseline and hyperemic conditions., Methods: We performed a retrospective study to investigate the diagnostic performance of angiography-derived IMR (AccuIMR) and FFR (AccuFFRangio) computed from the hyperemic condition (AccuIMR hyp , AccuFFRangio hyp ) and baseline condition (AccuIMR base , AccuFFRangio base ) in 101 consecutive patients with chronic coronary syndrome (CCS) who underwent measurements of IMR and FFR at a single center, using wire-based IMR and FFR as the reference standard., Results: AccuIMR hyp showed much better correlation with IMR than AccuIMR base (r=0.77 vs. 0.47, P<0.001). The diagnostic accuracy and area under the curve (AUC) for identifying significant microvascular dysfunction was higher for AccuIMR hyp than AccuIMR base [92.1% (95% CI: 85.0-96.5%) vs. 83.2% (95% CI: 74.4-89.9%), P=0.012; 0.942 (95% CI: 0.877-0.979) vs. 0.815 (95% CI: 0.726-0.886), P=0.003]. The computed AccuFFRangio showed good correlations with FFR and good diagnostic performance under both hyperemic and baseline conditions [r=0.68 vs. 0.68, P>0.99; diagnostic accuracy =95.9% (95% CI: 89.8-98.9%) vs. 94.9% (95% CI: 88.4-98.3%), P=0.728; AUC =0.989 (95% CI: 0.942-1.000) vs. 0.973 (95% CI: 0.919-0.995), P=0.381]. The net reclassification index (NRI) demonstrated that hyperemic group had improved reclassification ability compared to the baseline group in identification of IMR >25 (NRI =0.20, P<0.001) and FFR ≤0.8 (NRI =0.11, P<0.001)., Conclusions: By comparing the calculated angio-derived IMR and FFR under the baseline and hyperemic conditions, this study demonstrates that AccuIMR calculation is more accurate using the hyperemic condition, while AccuFFRangio calculation is accurate under both conditions., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-23-72/coif). JG receives grants from National Natural Science Foundation of China (No. 81900305), National Key Research and Development Program of China (No. 2018YFE0103000), Shanghai Clinical Research Center for Interventional Medicine (No. 19MC1910300), Shanghai Municipal Key Clinical Specialty (No. shslczdzk01701), and Clinical Research Plan of Shanghai Hospital Development Center (No. SHDC2020CR5009); YH and JH are employees of ArteryFlow; X Leng is a co-founder of ArteryFlow; JX receives grant from Hangzhou Leading Innovation and Entrepreneurship Team Project (No. TD2022007) and is the CEO of ArteryFlow. The other authors have no conflicts of interest to declare., (2023 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

Analytically solvable models are benchmarks in studies of phase transitions and pattern-forming bifurcations. Such models are known for phase transitions of the second kind in uniform media, but not for localized states (solitons), as integrable equations which produce solitons do not admit intrinsic transitions in them. We introduce a solvable model for symmetry-breaking phase transitions of both the first and second kinds (alias sub- and supercritical bifurcations) for solitons pinned to a combined linear-nonlinear double-well potential, represented by a symmetric pair of delta-functions. Both self-focusing and defocusing signs of the nonlinearity are considered. In the former case, exact solutions are produced for symmetric and asymmetric solitons. The solutions explicitly demonstrate a switch between the symmetry-breaking transitions of the first and second kinds (i.e., sub- and supercritical bifurcations, respectively). In the self-defocusing model, the solution demonstrates the transition of the second kind which breaks antisymmetry of the first excited state., (© 2023. Springer Nature Limited.)

Background: To assess the diagnostic accuracy of AccuIMR, a newly proposed, pressure wire-free index, in identifying coronary microvascular dysfunction (CMD) among patients with acute coronary syndrome [including ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI)] and chronic coronary syndrome (CCS)., Methods: A total of 163 consecutive patients (43 with STEMI, 59 with NSTEMI, and 61 with CCS), who underwent invasive coronary angiography (ICA) and for whom the index of microcirculatory resistance (IMR) was measured, were retrospectively enrolled at a single center. IMR measurements were made in 232 vessels. The AccuIMR based on computational fluid dynamics (CFD) was calculated from coronary angiography. The diagnostic performance of AccuIMR was assessed using wire-based IMR as a reference standard., Results: AccuIMR correlated well with IMR (overall r=0.76, P<0.001; STEMI r=0.78, P<0.001; NSTEMI r=0.78, P<0.001; CCS r=0.75, P<0.001) and had good diagnostic performance in detecting abnormal IMR [overall diagnostic accuracy, sensitivity, and specificity were 94.83% (91.14% to 97.30%), 92.11% (78.62% to 98.34%), and 95.36% (91.38% to 97.86%), respectively]. Using a cutoff value of IMR >40 U for AccuIMR in STEMI and IMR >25 U in NSTEMI and CCS, the area under the receiver operating characteristic (ROC) curve (AUC) of AccuIMR for predicting abnormal IMR value was 0.917 (0.874 to 0.949) in all patients, 1.000 (0.937 to 1.000) in patients with STEMI, 0.941 (0.867 to 0.980) in patients with NSTEMI, and 0.918 (0.841 to 0.966) in patients with CCS., Conclusions: The use of AccuIMR in the evaluation of microvascular diseases could provide valuable information and potentially increase the application of physiological assessment for microcirculation in patients with ischemic heart disease., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-22-961/coif). ZL reports grants from the National Natural Science Foundation of China (No. 82070425) and the Natural Science Foundation of Hubei Province of China (No. 2021CFA011). CL reports grants from the Chinese Cardiovascular Association-V.G. Fund (No. 2017-CCA-VG-006) and the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (No. 2020-JKCS-003). YH and JH are employees of ArteryFlow. XL is a co-founder of ArteryFlow. JX is the CEO of ArteryFlow and receives a grant from Hangzhou Leading Innovation and Entrepreneurship Team Project (No. TD2022007). The other authors have no conflicts of interest to declare., (2023 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

Background: Granulocyte colony-stimulating factor (G-CSF) plus plerixafor has been shown to improve the efficacy of peripheral blood stem cell (PBSC) mobilization, however, due to its high price, the use of plerixafor is limited in China. The purpose of this study was to assess the efficacy of residual plerixafor for second-day stem cell mobilization in multiple myeloma (MM) patients., Materials and Methods: In this single-center retrospective study, 69 MM patients received G-CSF + plerixafor to mobilize PBSCs, which were collected from 28 patients only for one day and 41 patients for two days. Some of the patients received residual plerixafor, and PBSCs were collected on the second day. The data on the characteristics, different doses of plerixafor and efficacy of PBSC mobilization were collected and analyzed., Results: After 1 or 2 apheresis procedures, 85.5% of patients collected more than 2 × 10 6 cells/kg PBSCs. There was no statistically significant difference in the success rate of CD34 + PBSC mobilization with the different doses of plerixafor on the first day, but the higher residual plerixafor dose resulted in better success rates on the second day (P＜0.001). Among the patients who collected PBSCs for two days, the level of the CD34 + cell yield of 24 patients (58.5%) changed better, which was significantly correlated with the dose of residual plerixafor on the second day (P = 0.001)., Discussion: These results suggested that the administration of residual plerixafor to mobilize stem cells on the second day is an economical, efficient and clinically feasible method., Competing Interests: Conflict of interest The author declares no competing interests., (Copyright © 2022. Published by Elsevier Ltd.)

ABSTRACTSWe explored the incidence of Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infections in 131 patients with multiple myeloma (MM), 53 of whom received daratumumab (Dara) treatments. The Dara group had more RRMM patients than the group without Dara. CMV infection was significantly more common in patients treated with Dara (16.98%) than in patients treated with regimens without Dara (2.56%). During Dara treatments, 24.53% of patients developed CMV and/or EBV infections. Patients who developed infections had significantly lower levels of albumin and lymphocytes in their peripheral blood. The median time from the first Dara infusion to infection was 27 days. We observed NK cell depletion and T cell expansion during Dara-treatment. Patients with CMV and/or EBV infections had significantly lower numbers of NK cells, total T cells, and CD8 + T cells at 1 month, and lower numbers of CD8 + T cells at 2 months after the first Dara infusion than those without infections.

Macrophages (MΦs) are an abundant component in the multiple myeloma (MM) environment and contribute to MM drug resistance. We previously showed that interleukin-32 (IL-32) is highly expressed in MM patients and induces the immunosuppressive function of MΦs. The present study was designed to explore the role of IL-32 in MΦ-mediated MM drug resistance and the underlying mechanism. Our analysis revealed that IL-32 expression was upregulated in relapsed MM patients and associated with CD206 + M2 MΦ infiltration. Subsequently, we found that the most active isoform, IL-32γ, promoted MΦs to protect MM cells from drug-induced apoptosis both in vitro and in vivo. Furthermore, by evaluating many parameters, including surface markers, cytokines, metabolic enzymes and characteristic molecules, IL-32γ was verified to induce the polarization of M2 MΦs, a function that was partly dependent on increasing the expression of colony-stimulating factor 1 (CSF1). Taken together, the results of our study indicate that IL-32γ promotes MΦ-mediated MM drug resistance and modifies MΦs toward the M2 phenotype, providing a crucial theoretical basis for targeted MΦ immunotherapy., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Graft-versus-host disease (GVHD) is a major complication after allogeneic hematopoietic stem cell transplantation., Objective: To elucidate the role of Toll-like receptor 4 (TLR4), the major receptor for bacterial lipopolysaccharide, in the development of GVHD, we constructed a GVHD model in TLR4 knockout (TLR4 -/- ) mice and monitored the cell chimerism., Methods: In this study, we used polymerase chain reaction to identify whether TLR4 knockout (TLR4 -/- ) mice were established. Before transplantation, we pretreated mice with irradiation so as to obtain an appropriate irradiation dose. Flow cytometry was applied to measure the chimerism status, the distributions of antigen-presenting cells (APCs), and T-cells in TLR4 +/+ and TLR4 -/- recipient mice., Results: The general condition of TLR4 -/- recipients was better than that of TLR4 +/+ recipients, and the TLR4 -/- recipient mice showed less severe GVHD manifestations than the TLR4 +/+ recipient mice. Most of the APCs and T-cells in the host mouse spleen were derived from donor cells, and CD4 + T-cells, including memory T-cells, were in the majority in host mice., Conclusion: In general, our data show that TLR4 deletion attenuated GVHD development, which suggests that TLR4 could be used as a novel target and therapeutic paradigm in GVHD therapies., (Copyright: © 2023 Permanyer.)

Background: Multiple myeloma is genetically heterogeneous, and chromosome abnormalities play a pivotal role in prognosis. A gain in chromosome 1q (+1q) is among the most common cytogenetic abnormalities; however, its relationship with overall survival (OS) and progression-free survival (PFS) in patients with multiple myeloma is still unclear. We aim to clarify the impact of +1q on the clinical characteristics and survival outcomes of patients treated with bortezomib-based combination regimes., Materials and Methods: We retrospectively analyzed 258 patients first diagnosed with myeloma who underwent bortezomib-based therapy at the bone marrow transplantation department of a multiple myeloma treatment center in the first affiliated hospital of Zhejiang University, China., Results: We identified 258 newly diagnosed patients with multiple myeloma in our department from July 2013 to September 2018. We observed that 127 (49.2%) of the patients acquired +1q at diagnosis, and +1q strongly correlated with the occurrence of del(13q) and IgH rearrangement ( P < 0.001). In the patients with +1q, the PFS was 22.2 months (95% CI 15.8-28.5 months), and the three-year and five-year PFS was 35.1% and 15.3%, respectively. Univariate analysis revealed that albumin, lactate dehydrogenase (LDH), and the percentage of plasma cells significantly affected PFS. Multivariate analysis showed that LDH and the percentage of plasma cells significantly affected PFS in the +1q patients. In terms of OS, the median OS for the +1q patients was 47.4 months (95% CI 34.7-59.5), while the OS of the non-+1q patients was not reached ( P = 0.048). The univariate and multivariate analyses revealed that age, platelet count, and extramedullary lesions were significant adverse factors for OS in the +1q patients. There were no statistical differences between PFS and OS when there were other chromosomal abnormalities, but there was a decreased tendency in PFS. LDH and +1q also had a synergistic adverse effect on survival., Conclusion: +1q is associated with a higher tumor burden and correlated with the occurrence of del(13q) and IgH rearrangement at diagnosis. In the era of novel agents, +1q still significantly affects PFS and OS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chen, Han, Zheng, Yang, Li, Zhang, Yang, Dong, He, He and Cai.)

Extramedullary relapse of multiple myeloma (MM) is often resistant to existing treatments, and has an extremely poor prognosis, but our understanding of extramedullary relapse is still limited. The incidence, clinical characteristics, impact on the prognosis of extramedullary relapse, and the risk factors for extramedullary relapse in NDMM patients were analyzed. Among the 471 NDMM patients, a total of 267 patients had disease relapse during follow-up, including 64 (24.0%) patients with extramedullary relapse. Extramedullary relapse was more common in patients with younger age, IgD subtype, elevated LDH, extensive osteolytic lesions, extramedullary involvement, and spleen enlargement at the time of MM diagnosis. Survival analysis showed that extramedullary relapse patients had significantly worse median OS than patients with relapse but without extramedullary involvement (30.8 months vs. 53.6 months, p = 0.012). Multivariate analysis confirmed that elevated LDH (OR = 2.09, p = 0.023), >2 osteolytic lesions (OR = 3.70, p < 0.001), extramedullary involvement (OR = 3.48, p < 0.001) and spleen enlargement (OR = 2.27, p = 0.011) at the time of MM diagnosis were independent risk factors for extramedullary relapse in NDMM patients. Each of the above four factors was assigned a value of 1 to form the extramedullary relapse prediction score, and the 3-year extramedullary relapse rates of patients in the 0−2 and 3−4 score groups were 9.0 % and 76.7 %, respectively. This study suggested that extramedullary relapse was associated with poor clinical characteristics and poor prognosis in NDMM patients. The extramedullary relapse prediction score model composed of LDH, osteolytic lesions, extramedullary involvement and spleen enlargement has a better ability to predict extramedullary relapse than the existing ISS and R-ISS stages.

Background: Bloodstream infection (BSI) is a common and serious complication that may lead to high mortality during the different phases after hematopoietic stem cell transplant (HSCT). We investigated BSI in patients undergoing HSCT to provide an appropriate clinical anti-infection experience and improve the prognosis of recipients with BSI after HSCT., Methods: A total of 105 patients with BSI after HSCT at our center from January 2015 to June 2020 were included in this retrospective study. We analyzed the clinical and microbiological data, and the risk factors for mortality at 3 months after BSI., Results: Of the 1141 HSCT recipients, 105 (9.2%) patients presented with 122 episodes of BSI, of which we isolated 85 (65.9%) gram-negative bacteria, 32 (24.8%) gram-positive bacteria and 12 (9.3%) fungi. Multidrug-resistant bacteria (MDR) were more than 70% of all pathogens and carbapenem-resistant organisms (CRO) were 25.6%. There were 55 episodes of BSI in the pre-engraftment phase and 67 episodes in the post-engraftment phase. The mortality of post-engraftment BSI was significantly higher than that of pre-engraftment (56.7% vs 32.7%, p = 0.005). Through multivariate analysis, the independent risk factors for all-cause mortality at 3 months after BSI were higher levels of procalcitonin (PCT), failure to cover appropriate antibiotics timely, and CRO BSI in pre-engraftment period or multidrug-resistant gram-negative bacteria (MDRGNB) BSI in post-engraftment period., Conclusion: Although the incidence of BSI was lower after HSCT, MDR-dominated BSI had a high mortality rate. Rapid identification of infection or pathogens' classification with various testing methods and the more sensible and timely antibiotic cover are critical to the outcome of BSI after HSCT., Competing Interests: The authors report no conflict of interest., (© 2022 Chen et al.)

Multiple myeloma (MM) is a common malignant hematological tumor in adults, which is characterized by clonal malignant proliferation of plasma cells in the bone marrow and secretion of a large number of abnormal monoclonal immunoglobulins (M protein), leading to bone destruction, hypercalcemia, anemia, and renal insufficiency (Alexandrakis et al., 2015; Yang et al., 2018). Since a large number of new drugs, represented by proteasome inhibitors and immunomodulators, have been successfully used to treat MM, treatment efficacy and survival of patients have been significantly improved. However, due to the high heterogeneity of this disease, patients have responded differently to treatments with these new drugs (Palumbo and Anderson, 2011; Wang et al., 2016; Huang et al., 2020). Growth and survival of MM cells depend on the bone marrow microenvironment, especially numerous inflammatory cytokines secreted by myeloma cells and bone marrow stromal cells, such as vascular endothelial growth factor (VEGF), interleukin (IL)‍-6, transforming growth factor-‍β (TGF‍‍-‍‍β), and IL-10. These cytokines can promote the growth of myeloma cells, induce angiogenesis, and inhibit antitumor immunity, and are often linked to patient prognosis (Kumar et al., 2017). In this era of new drugs, the prognostic values of the serum levels of these cytokines in MM need further evaluation.

Background: Multiple myeloma (MM) is a malignant proliferative disease of the blood system, characterized by the abnormal growth of clonal plasma cells in the bone marrow. The bone marrow microenvironment (BMM) is highly critical in the pathological process of MM. Many studies have shown that serum interleukin-17A (IL-17A) plays a key role in various infectious diseases, autoimmune diseases, and cancers. However, more clinical studies need to be performed to further prove the influence of serum IL-17A levels on multiple myeloma patients., Methods: Among a total of 357 participants in our institution's MM cohort, 175 were eligible for the retrospective study. Multivariate regression models adjusted by potential confounding factors, the violin plots, the generalized additive model and smooth curve fittings, receiver operating characteristic (ROC) curve, and Kaplan-Meier (K-M) curve analysis were applied to the research., Results: A total of 175 patients with newly diagnosed MM were enrolled in this study. The multivariate linear regression analysis showed that serum IL-17A level in MM patients correlated with the degree of bone lesions and fracture incidence (fully adjusted model, p bone lesion < 0.0001, p fracture < 0.0001). The violin plot showed that MM patients with higher serum IL-17A levels had more severe bone lesions and higher fracture incidence than those with lower serum IL-17A levels. A total of 171 patients were included in the study of the relationship between serum IL-17A and best overall effect (BOE). We found that serum IL-17A levels were independently related to the best inductive therapeutic efficacy (fully adjusted model, p = 0.037), and the relationship was especially obvious in the light chain group (fully adjusted model, p = 0.009) and IgA group (fully adjusted model, p = 0.0456). It could be deduced from the smooth curve that the higher the serum IL-17A level, the worse the BOE (p = 0.0163). The ROC prediction curve suggested that serum IL-17A could predict the BOE to a certain extent (area under the curve (AUC) = 0.717, p = 0.0327). A total of 148 MM patients were observed in the longitudinal study of the relationship between serum IL-17A and progression-free survival/overall survival (PFS/OS). The K-M curve analysis indicated that serum IL-17A levels in MM patients were not significantly correlated with PFS and OS. However, in the light chain subgroup, MM patients with high serum IL-17A had worse PFS (p = 0.015) and OS (p = 0.0076) compared to those with low serum IL-17A. In the IgA type subgroup, the higher IL-17A level was related to worse OS (p = 0.0061)., Conclusion: This retrospective study found that higher levels of serum IL-17A were independently correlated with higher severity of bone disease and fracture incidence in newly diagnosed MM patients. High serum IL-17A level was related to poor best overall efficacy in the light chain type. High serum IL-17A was also associated with poor PFS and OS in the light chain type and OS in the IgA type subgroup., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Dong, Zhang, Chen, He, Yan, Zheng, Han, He and Cai.)

Background: Multiple myeloma (MM) is the second most common hematologic malignancy with almost all patients eventually having relapse or refractory MM (RRMM), thus novel drugs or combination therapies are needed for improved prognosis. Chidamide and venetoclax, which target histone deacetylase and BCL2, respectively, are two promising agents for the treatment of RRMM., Results: Herein, we found that chidamide and venetoclax synergistically exert an anti-myeloma effect in vitro in human myeloma cell lines (HMCLs) with a combination index (CI) < 1. Moreover, the synergistic anti-myeloma effect of these two drugs was demonstrated in primary MM cells and MM xenograft mice. Mechanistically, co-exposure to chidamide and venetoclax led to cell cycle arrest at G0/G1 and a sharp increase in DNA double-strand breaks. In addition, the combination of chidamide and venetoclax resulted in BCL-X L downregulation and BIM upregulation, and the latter protein was proved to play a critical role in sensitizing HMCLs to co-treatment., Conclusion: In conclusion, these results proved the high therapeutic potential of venetoclax and chidamide combination in curing MM, representing a potent and alternative salvage therapy for the treatment of RRMM., (© 2022. The Author(s).)

To retrospectively identify the critical characteristics and prognostic factors of light-chain amyloidosis., Patients and Methods: Data were collected and compared from 91 patients who were diagnosed with light-chain amyloidosis at four hospitals between January 2010 and November 2018. We analyzed the clinical characteristics and performed an overall survival (OS) analysis., Results: Patients (median age, 60 years) were diagnosed with organ involvement of the kidney (91.2%), heart (56%), liver (14.3%), soft tissue (18.7%), or gastrointestinal tract (15.4%), and 68.1% of patients had more than two organs involved. Patients were most treated with bortezomib-based regimens (56%), and only one patient had autologous stem cell transplantation (auto-ASCT). The median OS was 36.33 months and was influenced by the ECOG score, renal involvement, cardiac involvement, hepatic involvement, and persistence of positive immunofixation. Patients who received bortezomib-based treatment had a trend of favorable OS compared to those who received non-bortezomib-based treatments, but the difference was not statistically significant. Although the overall number of organs involved was not related to OS, the number of organs involved in the heart, liver and kidney was related. Multivariate analysis indicated that cardiac involvement and negative hematologic response with persistence of positive immunofixation were independent prognostic factors for OS., Conclusion: Cardiac involvement and the hematologic response to treatment were independent prognostic factors for OS in light-chain amyloidosis patients., Competing Interests: Conflict of interestThe authors declare no conflict of interest., (© The Author(s) 2021.)

Multiple myeloma (MM) is an incurable plasma cell hematological malignancy. Bortezomib has become the primary drug in the treatment of patients with MM. However, its negative effects, especially peripheral neuropathy (PN), affect the patients' life quality and treatment continuity. However, there are few studies on baseline PN of MM, and little is known of the impact of baseline PN on the prognosis of MM patients. Therefore, we reviewed the clinical data of newly diagnosed MM patients in our center, explored the influencing factors of baseline PN, and evaluated PN's influence on the prognosis of MM patients undergoing induction therapy with bortezomib. According to the inclusion and exclusion criteria, 155 MM patients were eligible for the retrospective study. The multivariate regression analysis, generalized additive fitting smooth curve, the receiver operating characteristic curve (ROC) and K-M curve were conducted in this study. We found that baseline PN in patients with MM was age-related; MM patients with baseline PN have more severe bortezomib induced PN (BiPN) during the four courses of induction therapy with bortezomib as the primary regimen and worse PN outcome after induction therapy. Additionally, the progression-free survival (PFS) and overall survival (OS) of MM patients with baseline PN were worse than those of the MM patients without baseline PN., (© 2022. The Author(s).)

Objectives: This study sought to present a novel approach for computation of the index of microcirculatory resistance (IMR) and to evaluate its diagnostic performance., Background: IMR is a quantitative assessment to identify coronary microvascular dysfunction. However, its clinical use remains extremely limited. Calculation of IMR from coronary angiography images may increase the utility of coronary microvasculature assessment., Methods: 203 patients with 203 vessels were included in this study. Physiology measurements were obtained with pressure-wire in the whole cohort. The computational fluid dynamics (CFD)-based AccuIMR was computed and evaluated in a blinded fashion using wire-based IMR as the reference standard., Results: The overall diagnostic accuracy, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of AccuIMR for detecting coronary microvascular disease were 91.1% (95% CI: 86.4% to 94.7%), 89.4% (95% CI: 80.9% to 95.0%), 92.4% (95% CI: 86.0% to 96.5%), 89.4% (95% CI: 81.8% to 94.1%), and 92.2% (95% CI: 86.7% to 95.8%), respectively. The correlation coefficient equaled to 0.81 (p < 0.001) between AccuIMR and wire-based IMR with the receiver-operating curve had area under the curve of 0.924 (95% CI: 0.878 to 0.956)., Conclusions: AccuIMR is a novel pressure-wire free approach to assess coronary microvascular disease with great diagnostic performance, which can be a valid, efficient, and cost-reducing tool to provide an easier routine assessment of coronary microcirculation., Competing Interests: Conflict of Interest The authors have no conflict of interest to declare that are relevant to the content of this article., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Multiple myeloma (MM) is characterized by an accumulation of monoclonal plasma cells within the bone marrow (BM). Macrophages are an abundant component of myeloma BM microenvironment and support survival of the malignant cells and foster myeloma development and progression by suppression of the immune response. In our previous study, we found that MM patients overexpress pro-inflammatory cytokine interleukin-32 (IL-32). The present study aimed to investigate the role of IL-32 in myeloma progression and mechanisms of IL-32 on macrophages functions. We discovered that the expression of IL-32 was associated with the disease stage in myeloma patients. MM-derived exosomes containing IL-32γ promoted the expression of programmed death-ligand 1(PD-L1) by macrophages, thus promoting immune evasion. Mechanistically, myeloma-secreted IL-32γ acted via proteinase 3 (PR3) to enhance 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) dependent glycolysis and subsequent PD-L1 expression. Moreover, the PFKFB3-Janus kinase 1 (JAK1) axis might contribute to the expression of PD-L1 by macrophages. To sum up, we concluded that IL-32 was a critical mediator in myeloma progression, and targeting IL-32 signaling might be used as a potential strategy for treating myeloma., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2022 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Objective: To explore the efficacy and safety of intermittent, oral famciclovir prophylaxis for bortezomib-induced herpes zoster in multiple myeloma patients., Method: We retrospectively analyzed the incidence of bortezomib treatment-related varicella-zoster virus reactivation in 719 newly-diagnosed multiple myeloma patients receiving intermittent oral famciclovir prophylaxis, continuous oral acyclovir prophylaxis or no prophylaxis. The definition of intermittent oral famciclovir prophylaxis was oral famciclovir at a dose of 250mg twice daily for 9 days after finishing the last dose of bortezomib therapy every cycle. Age, gender, stage per the International Staging System, type of M protein, baseline of absolute lymphocyte count, absolute neutrophil count, and absolute monocyte count were analyzed to find the potential factors that could predispose to herpes zoster infections., Results: Varicella-zoster virus infection occurred in 96 patients (13.4%) during bortezomib treatment. The incidence of herpes zoster was significantly higher in the non-prophylaxis group compared with the prophylaxis group (22.9% vs 8.2% P<0.001), while the rate was similar between the intermittent oral famciclovir group and the continuous oral acyclovir group (8.4% vs 7.9% P=0.835). Hepatic and renal toxicity were observed in 12% and 2.8% of the patient respectively in the intermittent famciclovir group, which was similar in the continuous acyclovir group (18.1% and 4.2%). The prophylactic use of antiviral agents is a predictive factor for varicella-zoster virus reactivation., Conclusion: Intermittent famciclovir prophylaxis is effective and safe in preventing herpes zoster development and can markedly reduce the duration of oral medicine treatment compared with continuous acyclovir prophylaxis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zheng, Guan, Han, Yang, Zhao, Yang, Zhang, He, He, Wu, Huang and Cai.)

Multiple myeloma (MM) remains an incurable plasma cell cancer characterized by abnormal secretion of monoclonal immunoglobulins. The molecular mechanism that regulates the drug sensitivity of MM cells is being intensively studied. Here, we report an unexpected finding that the protein encoded by neural precursor cell-expressed developmentally downregulated gene 4L (NEDD4L), which is a HECT E3 ligase, binds the 19S proteasome, limiting its proteolytic function and enhancing autophagy. Suppression of NEDD4L expression reduced bortezomib (Bor) sensitivity in vitro and in vivo, mainly through autophagy inhibition mediated by low NEDD4L expression, which was rescued by an autophagy activator. Clinically, elevated expression of NEDD4L is associated with a considerably increased probability of responding to Bor, a prolonged response duration, and improved overall prognosis, supporting both the use of NEDD4L as a biomarker to identify patients most likely to benefit from Bor and the regulation of NEDD4L as a new approach in myeloma therapy., (© 2022. The Author(s).)

Background: Non-invasive fractional flow reserve (FFR) has been increasingly used in the clinical workflow to assist clinical decision-making for percutaneous coronary intervention (PCI). This clinical study evaluates the diagnostic accuracy of coronary stenosis assessed by a non-invasive FFR analysis method (termed AccuFFRangio) based on invasive coronary angiography (ICA). It is a blinded, self-controlled, retrospective, and dual-center clinical investigation study., Methods: Coronary angiography data and the related information of 320 patients with 320 vessels were collected, and AccuFFRangio was used to assess the FFR for these patients. Compared with the wire-measured FFR values, we evaluated AccuFFRangio performance by its accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV)., Results: The diagnostic accuracy, sensitivity, specificity, PPV, and NPV for AccuFFRangio in identifying hemodynamically significant coronary stenosis were 93.3%, 92.6%, 93.5%, 84.3%, and 97.1%, respectively. The direct correlation between computed AccuFFRangio and measured FFR was 0.812 (P<0.001), and the area under the receiver operating characteristic curve (AUC) value of AccuFFRangio was 0.96., Conclusions: This clinical study demonstrates the efficiency and accuracy of AccuFFRangio for clinical implementation when using invasive wire-measured FFR as a reference. Further validation is required in a large prospective multicenter study., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/qims-21-463). JJ receives research grants from National Natural Science Foundation of China (81570322) and Zhejiang Provincial Key Research and Development Plan (2020C03016). LT receives research grant from Zhejiang Provincial Key Research and Development Plan (2017C03034). CD receives research grant from Major Medical and Health Science and Technology Plan of Zhejiang Province (WKJ-ZJ-1913). XL receives research grant from National Natural Science Foundation of China (11802113). CL reeives research grants from Zhejiang Provincial Public Welfare Technology Research Project (LGF20H020012) and Scientific Research Project of Zhejiang Education Department (Y201330290). JX receives research grant from National Natural Science Foundation of China (81771242) and Stock/Stock Options of ArteryFlow Technology., (2022 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

RNA demethylase ALKBH5 takes part in the modulation of N 6 -methyladenosine (m 6 A) modification and controls various cell processes. ALKBH5-mediated m 6 A demethylation regulates gene expression by affecting multiple events in RNA metabolism, e.g., pre-mRNA processing, mRNA decay and translation. Mounting evidence shows that ALKBH5 plays critical roles in a variety of human malignancies, mostly via post-transcriptional regulation of oncogenes or tumor suppressors in an m 6 A-dependent manner. Meanwhile, increasing non-coding RNAs are recognized as functional targets of ALKBH5 in cancers. Here we reviewed up-to-date findings about the pathological roles of ALKBH5 in cancer, the molecular mechanisms by which it exerts its functions, as well as the underlying mechanism of its dysregulation. We also discussed the therapeutic implications of targeting ALKBH5 in cancer and potential ALKBH5-targeting strategies., (© 2022. The Author(s).)

Background: Domestic bendamustine has been approved for appearing on the market in China in the past two years. The report on bendamustine plus rituximab (BR) in the treatment of Chinese B-cell-associated indolent non-Hodgkin's lymphoma (iNHL) has not yet been published. This study probed into clinical efficacy of the BR regimen for B-cell-associated iNHL in China as well as the value of β 2-microglobulin ( β 2-MG) as a prognostic factor., Methods: We retrospectively analyzed clinical data of 73 B-cell-associated iNHL patients who received BR treatment in The First Affiliated Hospital, College of Medicine, Zhejiang University from January 2020 to January 2021, including clinical characteristics, therapies, therapeutic efficacy, and prognosis-related factors. Thirty-three patients (45.2%) did not receive any other treatment before the BR regimen, and other patients received CHOP, R-CHOP, and other regimens in the past. The cutoff date for follow-up was May 2021. Clinical characteristics of patients were analyzed. The clinical efficacy of the BR regimen was evaluated. Differences of β 2-MG expression before and after treatment were analyzed between the CR+PR group and the SD+PD group. Main outcomes were progression-free survival (PFS) and overall survival (OS). A multivariate Cox regression model was taken to analyze prognostic factors relative to survival rate of patients, and adverse events (AEs) during treatment., Results: The objective response rate (ORR) of B-cell-associated iNHL patients who received BR regimen as first-/multiline treatment was 79.5%, with complete response (CR) of 37.0%, partial response (PR) of 42.5%, median PFS of 12.1 months (95% confidence interval (CI): 10.9-13.2), and median OS of 15.5 months (95% CI: 14.8-16.1). Before treatment, there was no statistical significance in the β 2-MG level between the CR+PR group and the SD+PD group ( p > 0.05). After treatment, the β 2-MG level in the CR group was noticeably lower than that in the SD+PD group ( p < 0.05). The β 2-MG level in the CR+PR group decreased conspicuously after treatment ( p < 0.05). The β 2-MG level in the SD+PD group after treatment was not notably different from that before treatment ( p > 0.05). According to the median expression level of β 2-MG before treatment, patients were divided into two groups. The average PFS of the low expression group was 12.69 ± 0.77 months, which was longer than the high expression group (10.13 ± 0.74 months), but the difference between the groups was not statistically significant ( p > 0.05). Multivariate Cox regression analysis showed that B-cell-associated iNHL subtype was the independent prognostic marker most likely to affect PFS of patients ( p = 0.051). Incidence of any grade of AEs in all patients was 32.9% (24/73)., Conclusion: B-cell-associated iNHL patients who received BR regimen had favorable clinical efficacy and were tolerable to AEs. Though the β 2-MG level in this study could not be used to predict clinical outcome, a lower level before treatment seemed to be implicated in better survival outcomes of patients. Our research also unraveled that B-cell-associated iNHL subtype may be a key factor to patient's prognosis. Overall, this study offers some important insights into clinical application of the BR regimen for Chinese B-cell-associated iNHL patients., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Yujie Zhang et al.)

In this paper, we first modify the binary Darboux transformation to derive three types of soliton interaction solutions of the Davey-Stewartson I equation, namely the higher-order lumps, the localized rogue wave on a solitonic background, and the line rogue wave on a solitonic background. The uniform expressions of these solutions contain an arbitrary complex constant, which plays a key role in obtaining diverse interaction scenarios. The second-order dark-lump solution contains two hollows that undergo anomalous scattering after a head-on collision, and the minimum values of the two hollows evolve in time and reach the same asymptotic constant value 0 as t→±∞. The localized rogue wave on a solitonic background describes the occurrence of a waveform from the solitonic background, quickly evolving to a doubly localized wave, and finally retreating to the solitonic background. The line rogue wave on the solitonic background does not create an extreme wave at any instant of time, unlike the one on a constant background, which has a large amplitude at the intermediate time of evolution. For large t, the solitonic background has multiple parallel solitons possessing the same asymptotic velocities and heights. The obtained results improve our understanding of the generation mechanisms of rogue waves.

N 6 -methyladenosine (m 6 A), an internal modification in mRNA, plays a critical role in regulating gene expression. Dysregulation of m 6 A modifiers promotes oncogenesis through enzymatic functions that disrupt the balance between the deposition and removal of m 6 A modification on critical transcripts. However, the roles of mRNA m 6 A in multiple myeloma (MM) are poorly understood. The present study showed that RNA demethylase ALKBH5 was overexpressed in MM and associated with a poor prognosis in MM patients. Knocking down ALKBH5 induced apoptosis and inhibited the growth of MM cells in vitro. Xenograft models and gene set enrichment analysis with patient transcriptome datasets also supported the oncogenic role of ALKBH5 in MM. Mechanistic studies showed that ALKBH5 exerted tumorigenic effects in myeloma in an m 6 A-dependent manner, and TNF receptor-associated factor 1 (TRAF1) was a critical target of ALKBH5. Specifically, ALKBH5 regulated TRAF1 expression via decreasing m 6 A abundance in the 3'-untranslated region (3'-UTR) of TRAF1 transcripts and enhancing TRAF1 mRNA stability. As a result, ALKBH5 promoted MM cell growth and survival through TRAF1-mediated activation of NF-κB and MAPK signaling pathways. Collectively, our data demonstrated that ALKBH5 played a critical role in MM tumorigenesis and suggested that ALKBH5 could be a novel therapeutic target in MM., (© 2021. The Author(s).)

Background: Intravascular ultrasound (IVUS) provides good insight into lumen boundary and plaques; however, it is still difficult to detect functionally significant stenosis from IVUS images for the guidance of coronary percutaneous intervention (PCI). This study aimed to develop a novel method to estimate fractional flow reserve (FFR) value for determining the functional significance of coronary artery disease through the fusion of IVUS and X-ray angiographic images., Methods: We developed a novel approach to 3D vessel reconstruction by integrating IVUS with X-ray angiographic images. Based on the reconstructed geometry and the inlet flow derived from the thrombolysis in myocardial infarction (TIMI) frame count, a simplified fluid dynamics equation was established to compute the pressure drop and IVUS-derived FFR (AccuFFRivus) was subsequently obtained. To validate the feasibility and performance of this IVUS-based FFR method, we performed AccuFFRivus calculations on 32 coronary vessels with invasive FFR as the reference standard., Results: Great correlation (r=0.86, P<0.001) was observed between AccuFFRivus and FFR. The area under the receiver-operating characteristic curve (AUC) was higher for AccuFFRivus than minimal lumen area (MLA, <4 mm 2 ) and diameter stenosis rate (DS% ≥50%) [0.98 (95% CI: 0.86 to 1.0) vs. 0.78 (95% CI: 0.60 to 0.91) and 0.66 (95% CI: 0.47 to 0.82)]. Bland-Altman plot showed a mean difference value of -0.011 (limits of agreement: -0.156 to 0.134)., Conclusions: AccuFFRivus is a novel method for hybridizing IVUS and X-ray angiographic images to identify functionally significant stenosis with FFR ≤0.80. The good diagnostic performance from the initial validation study demonstrates the potential for clinical utilization of physiologically guided decision-making. Further validation is required in future studies with a large number of cases., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/qims-20-1324). The authors have no conflicts of interest to declare., (2021 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

Controlling the release of phosphorus (P) in sediments is important to prevent eutrophication and harmful algal blooms in water bodies. Here we explored the effect of mobile aerators on the control of P release from sediments in a eutrophic pond. The dissolved oxygen in the water body recovered significantly after six months of aeration, becoming 4.2-5.8 times higher than in the control. The pH and Eh values at the sediment-water interface considerably increased, while the concentration of soluble reactive phosphorus (SRP) in pore water significantly decreased, resulting in the alteration of SRP fluxes from 1.69 mg/m 2 d to -53.49 mg/m 2 d. Moreover, the inert P in sediments increased by 5.2% of the total P at the end of the study compared with the initial state, and the calcium-bound phosphorus (HCl-P) increased by 96.6%. However, although aeration reduced the concentration of SRP in the water column, the total P concentration was 2.45 times higher than that of the control, and the content of redox-sensitive P (BD-P) in the sediment also increased by 200%. Overall, although mobile aeration can maintain the microenvironment of the sediment interface and increase the inert P content in the sediment to reduce the P flux, it cannot reduce the risk of release of mobile P., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: A new method for calculating fraction flow reserve (FFR) without pressure-wire (angiography-derived FFR) based on invasive coronary angiography (ICA) images can be used to evaluate the functional problems of coronary stenosis. Objective: The aim of this study was to assess the diagnostic performance of a novel method of calculating the FFR compared to wire-based FFR using retrospectively collected data from patients with stable angina. Methods: Three hundred patients with stable angina pectoris who underwent ICA and FFR measurement were included in this study. Two ICA images with projections >25° apart at the end-diastolic frame were selected for 3D reconstruction. Then, the contrast frame count was performed in an angiographic run to calculate the flow velocity. Based on the segmented vessel, calculated velocity, and aortic pressure, AccuFFRangio distribution was calculated through the pressure drop equation. Results: Using FFR ≤ 0.8 as a reference, we evaluated AccuFFRangio performance for 300 patients with its accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Comparison of AccuFFRangio with wire-measured FFR resulted in an area under the curve (AUC) of 0.954 (per-vessel, p < 0.0001). Accuracy for AccuFFRangio was 93.7% for Pa set from measurement and 87% for Pa = 100 mmHg in this clinical study. Overall sensitivity, specificity, PPV, and NPV for per-vessel were 90, 95, 86.7, 96.3, and 57.5, 97.7, 90.2, 86.3%, respectively. Overall accuracy, sensitivity, specificity, PPV, and NPV for 2-dimensional (2D) quantitative coronary angiography (QCA) were 63.3, 42.5, 70.9, 34.7, and 77.2%, respectively. The average processing time of AccuFFRangio was 4.30 ± 1.87 min. Conclusions: AccuFFRangio computed from coronary ICA images can be an accurate and time-efficient computational tool for detecting lesion-specific ischemia of coronary artery stenosis., Competing Interests: XL is employed by ArteryFlow Technology and receives grants from National Natural Science Foundation of China (No. 11802113). JH and YX was employed by ArteryFlow Technology. JX is the CEO of ArteryFlow Technology and receives grants from National Natural Science Foundation of China (No. 81771242). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Li, Leng, He, Xia, Jiang, Pan, Dong, Sun, Hu, Wang, Xiang and Jiang.)

Background: Extramedullary (EM) lesions are common in multiple myeloma (MM) and are often related to the poor prognosis of MM but are scarcely understood., Methods: In this retrospective study, the baseline characteristics of 357 newly diagnosed patients with extramedullary multiple myeloma (EMM) and their impact on the prognosis were analyzed. All patients received first-line treatment with bortezomib-based regimen., Results: The overall incidence rate of EM was 22.4%, and the detection rate of PET/CT was significantly higher than other imaging methods (P = 0.015). The cohorts consisted of 10 cases of extramedullary extraosseous (EME) and 70 cases of extramedullary-bone related (EMB), including 53 cases with single site involvement (one case with EME) and 27 cases with multiple sites (>1 site) involvement (nine cases with EME). EMM patients had high levels of hemoglobin (Hgb, ≥10 g/dl) and serum lactate dehydrogenase (LDH, >245u/L) and are inclined to early-stage revised international staging system (R-ISS). Compared to patients without EM, those with EMM had worse progression-free survival (PFS) (P = 0.014) and overall survival (OS) (P = 0.032). In addition, patients without EM and those with a single site of EMB had similar PFS and OS, while patients with multiple sites of EMB or EME and multiple sites of EMB with EME had poor PFS and OS. Multivariate analysis confirmed that multiple sites of EMB and/or EME were independent prognostic predictors affecting PFS and OS in newly diagnosed MM patients., Conclusions: This study suggested that among patients treated with bortezomib-based regimens, multiple sites of EMB and/or EME are independent poor prognostic factors for newly diagnosed MM patients, while a single site of EMB does not affect the survival of newly diagnosed MM patients. Thus, these findings could be used as a reference for the study of EMM patients in the new drug era, but prospective clinical studies are needed to provide evidence-based data for the diagnosis and treatment of EMM., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 He, Yue, He, Zhao, Yang, Zheng, Zhang, Han, Wu, Yang, Chen and Cai.)

Introduction: We analyzed different patient subgroups to determine optimal maintenance therapy in newly diagnosed multiple myeloma (NDMM) patients., Methods: A total of 226 NDMM patients in our center were included in the study. The characteristics, survival, and adverse reactions were compared among patients who received maintenance therapy or not, and patients who received proteasome inhibitors (PIs) or immunomodulators (IMiDs) maintenance. The survival of different maintenance durations of bortezomib-based regimens was also analyzed., Results: The maintenance therapy not only upgraded more patient responses (34.3 vs 13.3%, P = 0.006), but also significantly prolonged their progression-free survival (PFS) (median PFS: 41.1 vs 10.5 months, P < 0.001) and overall survival (OS) (median OS: not reached vs 38.6 months, P < 0.001). Compared with IMiDs, the PFS (median PFS: 43.7 vs 38.5 months, P = 0.034) and OS (median OS: not reached vs 78.5 months, P = 0.041) were both enhanced by PIs maintenance. Patients younger than 65 years who received PIs had a significantly prolonged OS ( P = 0.032). Patients achieving only a partial response (PR) after induction and consolidation therapy had significantly longer PFS and OS after PIs maintenance compared to IMiDs ( P = 0.007, 0.002). High-risk patients (ISS 2-3, DS 2-3, and RISS 2-3) given PIs maintenance benefit from a prolonged PFS ( P = 0.002, 0.02, 0.06) and OS ( P = 0.059, 0.047, 0.044, respectively) compared with IMiDs therapy. OS was significantly prolonged in patients who received ≥ 12 months of bortezomib-based maintenance therapy compared to those who were treated for < 12 months ( P < 0.001), but no difference was observed in OS between patients who received 12 to 24 or ≥ 24 months of bortezomib-based maintenance therapy ( P = 0.292)., Conclusion: PIs maintenance was superior to IMiDs in overall PFS and OS. The beneficial effect was most evident in patients achieving PR after induction and consolidation therapy, and in high-risk patients. Moreover, younger patients also benefited from PIs maintenance with an increased OS. A bortezomib-based maintenance therapy duration of 12 to 24 months after induction and consolidation therapy produced satisfactory OS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Han, Jin, Zheng, He, Zhao, Li, Wu, Zheng, Wei, Zhang, Huang, He and Cai.)

Multiple double-pole bright-bright and bright-dark soliton solutions for the multicomponent nonlinear Schrödinger (MCNLS) system comprising three types of nonlinearities, namely, focusing, defocusing, and mixed (focusing-defocusing) nonlinearities, arising in different physical settings are constructed. An interesting type of energy-exchanging phenomenon during collision of these double-pole solitons is unraveled. To explore the objectives, we consider the general solutions of a set of generalized MCNLS equations and by taking the long-wavelength limit with proper parameter choices of single-pole bright-bright and bright-dark soliton pairs, the multiple double-pole bright-bright and bright-dark soliton solutions are constructed in terms of determinants. The regular double-pole bright-bright solitons exist in the focusing and focusing-defocusing MCNLS equations and undergo a particular type of energy-sharing collision for M≥2 in addition to the usual elastic collisions. A striking feature observed in the process of energy-sharing collisions is that the double-pole two-soliton possessing unequal intensities before collision indeed exactly exchange their intensities after collision. Further, the existence of double-pole bright-dark solitons in the MCNLS equations with focusing, defocusing, and mixed (focusing-defocusing) nonlinearities is analyzed by constructing explicit determinant form solutions, where the double-pole bright solitons exhibit elastic and energy-exchanging collisions while the double-pole dark solitons undergo mere elastic collision. The double-pole bright-dark solitons possess much richer localized coherent patterns than their counterpart double-pole bright-bright solitons. For particular choices of parameters, we demonstrate that the solitons would degenerate into the background, resulting in a lower number of solitons. Another important observation is the formation of doubly localized rogue waves with extreme amplitude, in the case of double-pole bright-dark four-solitons. Our results should stimulate interest in such special multipole localized structures and are expected to have ramifications in nonlinear optics.