Immune checkpoint expression patterns on T cell subsets in light-chain amyloidosis: VISTA, PD-1, and TIGIT as potential therapeutic targets.

Amyloid light chain (AL) amyloidosis is a rare plasma cell dyscrasia with dismal prognosis. This study aims to investigate the T-cell immune checkpoint expression patterns in systemic AL amyloidosis and its relationship with clinicobiological traits. We examined the frequencies of V-domain immunoglobulin suppressor of T cell activation+ (VISTA+), programmed cell death 1+ (PD-1+), T cell immunoglobulin and mucin-domain-containing-3+ (Tim-3+), T cell immunoreceptor with Ig and ITIM domains+ (TIGIT+) T cells in peripheral blood (PB) and bone marrow (BM) from 19 patients with newly diagnosed AL amyloidosis. Patients with AL amyloidosis had significantly higher percentages of VISTA+ and PD-1+ T cells in PB than healthy individuals (HIs), with no statistical differences in BM. The percentages of some double-positive T cells in PB were also considerably higher in AL amyloidosis than those in HIs. Additionally, the patients with renal involvement had more PD-1+ and TIGIT+ T cells than the patients without, and PD-1+CD3+%, PD-1+CD4+%, PD-1+Treg% were positively correlated with 24-hour proteinuria levels. Furthermore, the AL amyloidosis patients had higher counts of PD-1+ Treg in PB than multiple myeloma (MM) patients, while the MM patients had higher counts of TIGIT+ T cells than AL amyloidosis patients. Collectively, this is the first report of elevated proportions of VISTA+ and PD-1+ T cells in PB of AL amyloidosis patients, indicating an immunosuppressive milieu, and the increased PD-1+ and TIGIT+ T cells were associated with renal damage. VISTA, PD-1, and TIGIT may be potential targets for reversing T-cell exhaustion in AL amyloidosis.

HHV8-unrelated primary effusion lymphoma in a patient with HBV-related liver cirrhosis: A case successfully treated with rituximab and lenalidomide.

Human herpesvirus type 8 (HHV-8) unrelated primary effusion lymphoma (PEL) like lymphoma (PEL-LL) is an exceedingly rare non-Hodgkin lymphoma with no characteristic symptoms and consensus on the optimal treatment. This case report presents a 55-year-old man with prior HBV-related Child-Pugh B liver cirrhosis and developing activity-related dyspnea. A moderate amount of pleural effusion was identified without tumor masses, and cytological studies confirmed a diagnosis of PEL-LL. The patient received rituximab and lenalidomide, albeit with HBV infection, and is currently on maintenance therapy with resolving symptoms but without HBV reactivation. Hence, the R2 protocol (rituximab and lenalidomide) might be clinically effective and safe for PEL-LL patients with HBV infection and Child-Pugh B liver cirrhosis.

Different expression patterns of VISTA concurrent with PD-1, Tim-3, and TIGIT on T cell subsets in peripheral blood and bone marrow from patients with multiple myeloma.

V-type immunoglobulin domain-containing suppressor of T cell activation (VISTA) is considered as an immunosuppressive factor and potential therapeutic target for anticancer therapy. However, little is known about VISTA expression and its role in immunosuppression in multiple myeloma (MM). In this study, VISTA expression and co-expression with programmed cell death receptor-1 (PD-1), T cell immunoglobulin mucin-domain-containing-3 (Tim-3), and T cell immunoglobulin and ITIM domain (TIGIT) in CD3+, CD4+, CD8+, and regulatory T (Treg) cells were analyzed in patients with MM by multi-color fluorescent flow cytometry of peripheral blood (PB) and bone marrow (BM) samples from 36 patients with MM and compared to 36 PB samples and 10 BM samples from healthy individuals (HIs), which served as controls. The results demonstrated a significant increased percentage of VISTA co-expression with PD-1, Tim-3, and TIGIT in CD3+, CD4+, CD8+, and Treg cells in PB from MM patients compared with HIs. A similar trend for VISTA+CD8+ T cells was found in BM. Moreover, a trend of a high percentage on VISTA expression and co-expression in PB rather than BM was found. Furthermore, significant positive correlations existed for VISTA expression concurrent with PD-1, Tim-3, and TIGIT in T cell subsets and clinical indicators, including Revised International Staging System (R-ISS) staging of multiple myeloma, Eastern Cooperative Oncology Group (ECOG) score, and beta-2-microglobulin (ß2-MG). In conclusion, higher VISTA expression concurrent with PD-1, Tim-3, and TIGIT on T cells, particularly in the PB of patients with MM, may result in T cell exhaustion and dysfunction and be closely associated with disease progression and clinical indicators. Thus, VISTA may be considered a potential target for reversing T cell exhaustion and improving T cell function in MM.

Deep learning-based transcriptome model predicts survival of T-cell acute lymphoblastic leukemia.

Identifying subgroups of T-cell acute lymphoblastic leukemia (T-ALL) with poor survival will significantly influence patient treatment options and improve patient survival expectations. Current efforts to predict T-ALL survival expectations in multiple patient cohorts are lacking. A deep learning (DL)-based model was developed to determine the prognostic staging of T-ALL patients. We used transcriptome sequencing data from TARGET to build a DL-based survival model using 265 T-ALL patients. We found that patients could be divided into two subgroups (K0 and K1) with significant difference (P< 0.0001) in survival rate. The more malignant subgroup was significantly associated with some tumor-related signaling pathways, such as PI3K-Akt, cGMP-PKG and TGF-beta signaling pathway. DL-based model showed good performance in a cohort of patients from our clinical center (P = 0.0248). T-ALL patients survival was successfully predicted using a DL-based model, and we hope to apply it to clinical practice in the future.

Incidence and effect of secondary cardiac amyloidosis on outcomes of patients with t(11;14) multiple myeloma.

Background: The t(11;14)(q13;32) is a common chromosome translocation in multiple myeloma (MM), but its prognostic value remains controversial. Immunoglobulin light chain amyloidosis is commonly secondary to multiple myeloma, which can rapidly cause heart failure and high mortality. We aimed to investigate the prevalence of secondary cardiac amyloidosis in MM patients with t(11;14) and to evaluate its impact on survival outcomes. Methods: We retrospectively identified 52 MM patients with t(11;14) in our center between October 2015 and April 2022. The associations between cardiac amyloidosis and clinical and biological parameters were statistically analyzed, and the impacts of concomitant of cardiac amyloidosis on survival and prognosis of MM patients with t(11;14) were also assessed. Results: Concomitant presence of cardiac amyloidosis was observed in 15 (28.8%) of all cases. Patients with cardiac amyloidosis had significantly higher NT-proBNP (p = 0.002) and higher hs-cTnT (p < 0.001), while the patients without cardiac amyloidosis had higher percentage of bone marrow plasma cells (p = 0.027), higher incidence of hemoglobin <80 g/L (p = 0.021) and bone destruction (p < 0.001). The median overall survival (OS) for all patients was 33.4 months after a median follow-up of 23.8 months. The amyloidosis group showed a significantly shorter OS than the non-amyloidosis group (15.3 vs. 41.8 months, p < 0.001). Besides, patients harboring NT-proBNP >1,800 pg/ml (p < 0.001) or hs-cTnT ≧40 pg/ml (p = 0.001) or light chain (LC) only isotype (p = 0.033) had a significantly shorter mean OS compared with patients with lower NT-proBNP or hs-cTnT or other M-protein isotype. Univariate analyses showed that NT-proBNP >1,800 pg/ml, hs-cTnT ≧40 pg/ml, LC only isotype, and concomitant presence of cardiac amyloidosis were independently associated with shorter OS, while NT-proBNP >1,800 pg/ml still retained the prognostic value for OS in multivariate analyses. Conclusion: The t(11;14) MM patients with coexisting cardiac amyloidosis may represent a distinct clinical entity that confers a poor outcome. These findings may have important clinical and biological implications.

Increased TOX expression associates with exhausted T cells in patients with multiple myeloma.

Previous studies have shown increased aberrant expression of immune checkpoint (IC) proteins, such as programmed cell death receptor-1 (PD-1) and T cell immunoglobulin mucin-domain-containing-3 (Tim-3) on T cells from patients with multiple myeloma (MM), which result in T cell exhaustion and dysfunction. However, little is known about the mechanism regulating aberrant IC protein expression. In this study, we analyzed the expression of TOX (thymocyte selection-associated HMG BOX), a crucial transcription factor involved in T cell exhaustion, and its co-expression with PD-1, Tim-3, and CD244 in T cell subsets by multi-color fluorescent flow cytometry in peripheral blood (PB) and bone marrow (BM) samples from patients with MM. Significantly, the percentage of TOX + CD3 +/CD4 +/CD8 + T cells was increased, and similarly, higher numbers of TOX co-expression with PD-1, Tim-3, and CD244 on CD3 +/CD4 +/CD8 + T cells were found. Interestingly, the numbers of TOX +, TOX + PD-1 +, and TOX + Tim-3 + regulatory T (Treg) cells also significantly increased in both the PB and BM of MM patients. In summary, we for the first time observed increased TOX expression concurrent with PD-1, Tim-3, and CD244 on T cells, which may contribute to T cell exhaustion and impair their function in MM. Thus, TOX may be considered a potential target for reversing T cell exhaustion and improving T cell function in MM.

Left atrial remodeling and the prognostic value of feature tracking derived left atrial strain in patients with light-chain amyloidosis: a cardiovascular magnetic resonance study.

Systemic light-chain (AL) amyloidosis is characterized by the aggregation of misfolded immunoglobulin light chain, predominantly infiltrating in the heart, including left atrium (LA). LA remodeling, such as increased interatrial septal thickness and enlarged size, has been observed. However, LA strain assessed by cardiac magnetic resonance feature tracking (CMR-FT) and its prognostic role remains to be further determined. Using CMR, the current study sought to investigate the characteristic of LA remodeling and the prognostic value of LA strain in patients with AL. Eighty-seven consecutive patients who underwent CMR with histologically confirmed systemic light-chain amyloidosis were retrospectively enrolled. LA strain parameters were analyzed based on CMR-FT algorithm. Amyloid infiltration and burden loads were assessed with CMR late gadolinium enhancement (LGE) and extracellular volume (ECV). Patients were categorized according to the extent of amyloid infiltration in cardiac myocardium. The primary endpoint was defined as all-cause mortality. The prognosis value of LA strain indices was evaluated using Cox proportional hazards regression and Kaplan-Meier curves. Interatrial septal thickness (3 [2-5] vs. 4 [3-5] mm, p = 0.007) and indexed LA volume (34.6 [26.9-44.6] vs. 50.5 [36.1-58.5] ml/m2, p = 0.001) were significantly higher in patients with atrial involvement (LA-LGE). Compared with patients with low amyloid burden loads (ECV group I), those at moderate and high (ECV group II and III) show progressive impairment in LA reservoir, conduit, and booster strains and strain rates. A total of 44 patients died during a median follow-up of 12 months. In multivariate analysis, LA reservoir strain, New York Heart Association (NYHA), and ECV remained independently associated with survival. On Kaplan-Meier analyses, low LA reservoir strain (< 8.6%) increased the risk of mortality. In moderate amyloid burden loads patients, low LA reservoir strain provides additive prognosis value. Progress left atrial remodeling and dysfunction are common findings in AL cardiac amyloidosis. The CMR-FT-derived LA reservoir strain provides independent and additive prognostic value for all-cause mortality in patients with AL cardiac amyloidosis.

Primary cardiac lymphoma: the management and outcome of a single-centre cohort of 22 patients.

BACKGROUND: The incidence of primary cardiac lymphoma (PCL) is increasing, but the optimal management approach remains unclear. We assessed the clinical characteristics of a single-centre cohort with the goal of determining the optimal management approach. The treatment outcomes and prognostic factors are reported. MATERIAL AND METHODS: All PCL patients were diagnosed via biopsy guided by whole-body imaging (positron emission tomography/computed tomography [PET/CT] and/or contrast-enhanced CT]. Curative therapy involved either surgery or prephase steroids followed by definitive immunochemotherapy, depending on the histological type. The primary outcomes were overall survival (OS) and progression-free survival (PFS); the secondary outcome was the treatment response. RESULTS: Twenty-two PCL patients (14 males, 8 females; age: 59.5 ± 14.7 years [mean ± S.D.]) were histologically confirmed to have diffuse large B-cell lymphoma (DLBCL; n = 17 [77.3%]), fibrin-associated DLBCL (FA-DLBCL) (n = 4 [18.2%]) and Burkitt lymphoma (n = 1 [4.5%]). Seven patients underwent cardiotomy (three for biopsy, four with curative intent). The median and longest follow-up periods were 16.3 and 180.0 months, respectively. The 16 patients who received curative therapy (complete response [CR], n = 15 [93.8%]; partial response [PR], n = 1 [6.2%]) showed better survival than those who did not (5-year OS: 83.0 ± 11.3% vs. 0%; hazard ratio [HR]: 0.025[95% confidence interval, CI: 0.003-0.187], p < 0.001); 5-year PFS: 78.7 ± 11.0% vs. 0%, HR= 0.010[0.001-0.093], p < 0.001). The left ventricular ejection fractions (LVEF) before and after definitive treatment was 63.6 ± 2.4% and 64.6 ± 4.5%, respectively (p = 0.275, power = 0.318). Extrapericardial lesions were associated with poorer survival (5-year OS: 40.0 ± 29.7% vs. 100%, p = 0.027; 5-year PFS:40.0 ± 21.9% vs. 100%, p = 0.010). CONCLUSIONS: Whole-body imaging is essential for diagnosis and prognosis. Curative therapy provided reasonable outcomes and survival; extrapericardial lesions were associated with a poorer treatment response.

Phenotype of mesenchymal stem cells from patients with myelodyplastic syndrome maybe partly modulated by decitabine.

Mesenchymal stem cells (MSCs) derived from myelodysplastic syndromes (MDSs) have been demonstrated to accelerate the progression of MDS. However, whether the phenotype of MSCs derived from MDS (MDS-MSCs) may be reversed and serve as a potential target for the treatment of MDS remains unclear. The present study investigated the functional alternations of MDS-MSCs following in vitro decitabine-treatment. Primary MSCs were cultured from the bone marrow aspirates of 28 patients with MDS. The impact on the growth of MDS-MSCs treated with decitabine was analyzed using the MTT assay. Changes in the gene expression levels of runt related transcription factor 2 (RUNX2), Sp7 transcription factor (SP7), cyclin dependent kinase inhibitor 1A (CDKN1A) and CD274 in MDS-MSCs following treatment with decitabine were analyzed by reverse transcription-quantitative polymerase chain reaction. The effects of decitabine on apoptosis and the cell cycle were examined using flow cytometry. The effect of decitabine on the immune regulation of MDS-MSCs was tested by the co-culture of MSCs with activated T cells in vitro. The results revealed that proliferation, apoptosis and the mRNA expression levels of RUNX2 and SP7 in MDS-MSCs did not significantly change following treatment with decitabine compared with control MDS-MSCs. However, treatment with decitabine resulted in a smaller population of cells in the G1 phase and an increase in the number of cells in the G2/M phase compared with control MDS-MSCs. This change was associated with decreased expression of CDKN1A in cells treated with decitabine compared with control cells. Notably, the ability of MDS-MSCs treated with decitabine to induce the differentiation of T cells into regulatory T cells was significantly reduced compared with control MDS-MSCs. This was associated with a decreased expression of CD274 in MDS-MSCs treated with decitabine compared with control MDS-MSCs. In conclusion, the phenotype of MSCs derived from patients with MDS was partially reversed by treatment with decitabine, presenting a potential therapeutic intervention.

Premature exhaustion of mesenchymal stromal cells from myelodysplastic syndrome patients.

Myelodysplastic syndrome (MDS) predominantly occurs in aging people. Over the past decades, the cellular and molecular pathologies of MDS cells have been intensively investigated. However, how the bone marrow stromal niches are altered during MDS development remains elusive. In this study, we attempted to isolate and characterize mesenchymal stromal cells (MSCs) from 30 MDS patients. We observed that only 9/30 bone marrow aspirations from MDS patients successfully formed a monolayer in vitro, while 17/17 bone marrow aspirations from normal donors (median age 45 years, range: 22-73 years) succeeded in this process. Compared to normal MSCs, the MDS MSCs showed premature exhaustion, including reduced osteogenic differentiation ability, slower passage rate, and extremely limited passage times. These functional defects were associated with downregulation of Osterix and Runx2 genes and increased cell cycle arrest and apoptosis. However, the premature exhaustion of MDS MSCs did not correlate with patients' ages, indicating that natural aging is not the cause of dysfunction in MDS MSCs. Our result provides a strong rational to target prematurely exhausting MSCs in future MDS treatment.

[Effectiveness of CLAT Protocol for Treating Patients with Refractory Acute Myeloid Leukemia].

OBJECTIVE: To explore the clinical efficacy and toxicity of CLAT protocol (cladribine, cytarabine and topotecan) for treating patients with refractory acute myeloid leukemia (R-AML). METHODS: A total of 18 patients with R-AML (median age 37 years, range 18 to 58 years; male n = 16, female n = 2) were treated with CLAT protocol, which consisted of cladribine 5 mg/m(2)/d, i.v. on days 1-5, cytarabine 1.5 g/m(2)/d, i.v. on days 1-5, topotecan 1.25 mg/m(2)/d, i.v. on days 1-5 and G-CSF 300 µg/d subcutaneous injection on day 6 until neutrophile granulocyte recovery. RESULTS: Out of 18 patients 2 died of severe infection before the assessment. Among 16 evaluated patients, 10 (55.6%) achieved complete remission (CR), and 2 (11.1%) achieved partial remission (PR), the overall response rate was 66.7%, the rest 4 patients did not respond (NR). The median overall survival time and DFS for the CR patients was 9.5 months (95%CI: 6.7-16.64) and 9.5 months (95%CI: 6.1-16.7) respectively. The 1 year OS and DFS rates were 45% and 46.9%, respectively. All patients developed grade 4 of granulocytopenia and thrombocytopenia, the median duration was 13 (range 2 to 21) days and 12 days (range 2 to 21), respectively, all patients developed infection, 2 patients died of severe infection. The most common non-hematological side effects included nausea, vomiting, diarrhoea, rash, aminotransferase or bilirubin elevation and were grade 1 to 2. CONCLUSION: The CLAT protocol seems to have promising for the treatment of refractory AML patients, and patients well tolerated. This CLAT protocol offers an alternative treatment for R-AML patients who received severe intensive treatment, especially with anthracycline-containing chemotherapy.