Identifying immune checkpoints on dysregulated T-cells as prognostic biomarkers for multiple myeloma patients with COVID-19.

Background: Broad T cell phenotypic alterations and potential dysfunctions were prominent in COVID-19. There are few and inconclusive data about the role of immune checkpoints for T cell exhaustion/activation during SARS-CoV-2 infection in multiple myeloma (MM) patients. Methods: We tested T cell subsets and immune checkpoints in 177 MM patients with COVID-19, as well as in 32 healthy infected controls and 42 uninfected MM patients. The percentage of CD4+ and CD8+ subpopulation and immune checkpoints (PD-1, TIGIT, TIM-3, LAG-3, CTLA-4, OX40, and 4-1BB) were evaluated by flow cytometry. Results: We have found that pronounced lymphopenia and inverted CD4/CD8 ratio in severe COVID-19 patients were especially developed within the first month after infection. And T cell subset dysregulation was persistent in severe patients recovering from SARS-CoV-2 infection. Immune checkpoints on CD4+ T cells were variable and uncorrelated with the level of adaptive immunity, while the proportion of CD4+ T cells was positively correlated with humoral immune response. PD-1 and TIGIT on CD8+ T cells were significantly elevated in severe patients and sustained for more than 2 months, which was associated with impaired cellular immune function. Moreover, exhausted molecules PD-1 and TIGIT on T cells were reduced in immunotherapy patients. Conclusion: The prolonged T cell dysregulation after severe SARS-CoV-2 infection highlights the close surveillance from reinfection in MM patients even during convalescence. PD-1 and TIGIT on CD8+ T cells could be important prognostic factors to stratify prognosis in MM patients with COVID-19. Moreover, immunotherapy may downregulate the expression of exhausted checkpoints PD-1 and TIGIT, leading to T cell overactivation and severe COVID-19.

MYC translocation is a valuable marker for the development and relapse of extramedullary disease in multiple myeloma.

OBJECTIVE: To study the cytogenetic characteristics of extramedullary disease (EMD) in patients with multiple myeloma (MM) and their impact on prognosis. METHODS: Patients with newly diagnosed MM (NDMM) at Peking Union Medical College Hospital (Beijing, China) between June 2007 and December 2019 were recruited for this study. Demographic information, clinical data, fluorescence in situ hybridization (FISH) results of marrow and tissue samples, and survival outcome data were collected. RESULTS: A total of 439 patients with NDMM were divided into those without EMD (non-EMD, n = 339), those with EMD with primary paraosseous plasmacytoma (pEMD-B, n = 48), those with primary EMD with soft-tissue involvement (pEMD-S, n = 33), and those with secondary EMD (sEMD, n = 19). The incidence of EMD was 18.5% (81/439) at diagnosis and 22.8% (100/439) throughout the disease course. Comparison of FISH results showed a higher proportion of RB1 deletion (n = 20; 60.0% vs. 20.0%, p = .013) and MYC translocation (n = 12; 44.4% vs. 12.5%, p = .041) in the extramedullary tissues than in the paired bone marrow samples. At diagnosis, the percentage of MYC translocations in the sEMD group was notably higher than that in the non-EMD group (55.6% vs. 15.5%, p = .012). The median overall survival (OS) of patients with pEMD-S (32 months) and sEMD (17 months) was significantly shorter (both p = .001) than that of non-EMD patients (60 months). CONCLUSION: Soft-tissue EMD can be considered a high-risk condition, even in the era of novel agents. MYC translocation can serve as a valuable marker that correlates with extramedullary spread and relapse in patients with MM and should be considered for inclusion in routine FISH panels in clinical practice.

Myc rearrangement redefines the stratification of high-risk multiple myeloma.

BACKGROUND: Myc rearrangement (Myc-R) is a controversial factor linked to adverse outcomes in newly diagnosed multiple myeloma (NDMM). AIMS: This study aimed to evaluate the impact of Myc-R on the prognosis of NDMM patients and its role in risk stratification compared with traditional high-risk cytogenetic abnormalities (HRCAs). MATERIALS & METHODS: A total of 417 NDMM patients enrolled from May 2009 to September 2022 were included. Fluorescence in situ hybridization (FISH) was used to detect Myc-R and other Myc abnormalities (Myc-OA). Median progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier methods and log-rank tests. Multivariate Cox regression analysis was used to identify independent risk factors. RESULTS: Myc-R was identified in 13.7% of patients, while 14.6% had Myc-OA. Patients with Myc-R had significantly shorter median PFS (15.9 months) and OS (25.1 months) compared with those with Myc-OA (24.5 months PFS; 29.8 months OS) and Myc-negative (Myc-N) status (29.8 months PFS, 29.8 months OS). Myc-R was independently associated with worse PFS and OS compared to Myc-OA. Patients with Myc-R alone had inferior median PFS (15.9 months vs. 28.1 months, p = 0.032) and OS (25.1 months vs. 61.2 months, p = 0.04) compared to those with traditional single HRCA. DISCUSSION: The study suggests that traditional single HRCA may not significantly impact survival in NDMM patients. However, incorporating Myc rearrangement or traditional double/triple-hit HRCAs into the risk stratification model improves its predictive value, highlighting the importance of Myc rearrangement in risk assessment. CONCLUSION: Myc rearrangement is an independent adverse prognostic factor in NDMM. The incorporation of Myc rearrangement or multiple HRCAs into risk stratification models improves their prognostic value, providing a novel perspective on high-risk factors in NDMM.

Impaired acute-phase humoral immunity is the major factor predicting unfavorable outcomes in multiple myeloma patients with SARS-CoV-2 Omicron variants outbreak infection.

At the end of 2022, a huge tide of SARS-CoV-2 infection mainly Omicron BA.4/5 developed in China. Multiple myeloma (MM) patients suffered cancer deterioration and mortality from COVID-19, yet profound analyses of Omicron variants-induced immunity function are scarce. We presented a longitudinal study in 218 MM patients and 73 healthy controls (HCs), reporting the prognostic factors and dynamic humoral and cellular immune responses. Neutralizing antibody and interferon γ ELISpot assay of SARS-CoV-2 was tested at three time points: 2-4, 8-10, and 14-16 weeks after infections. Our data showed older age, active MM, relapsed/refractory MM (R/RMM), immunotherapy, comorbidity, and non-vaccination were risk factors associated with hospitalization. Severe humoral immunity impairment within 2-4 weeks was especially seen in patients with unvaccinated, older age, immunotherapy, R/RMM and comorbidities, while T-cell response was relatively intact. Although antibodies of Omicron variants reached positive levels in MM patients at 8-10 weeks, half lost effective antibody protection at 14-16 weeks. However, most seronegative patients (76.2% at 2-4 weeks, 83.3% at 8-10 weeks) could develop effective T-cell response. Notably, the inactivated wild-type vaccinated patients exhibited weaker humoral and cellular immunity only at 2-4 weeks, escalating to similar levels as those in HCs later. Our findings indicate impairment of humoral immunity at acute-phase after infection is the major factor correlated with hospitalization. One-month suspension of immune therapy is suggested to prevent serious infection. These results confirm the value of inactivated vaccine, but indicate the need for additional booster at 14-16 weeks after infection for high-risk MM population.

Prognostic Implications of Circulating Plasma Cell Percentage in Multiple Myeloma and Primary Plasma Cell Leukemia Defined by New Criteria.

INTRODUCTION: The definition of primary plasma cell leukemia (pPCL) has been revised from ≥20% to ≥5% circulating plasma cells (CPC). However, the precise prognosis associated with CPC remains controversial. This study aimed to investigate prognostic biomarkers for myeloma patients based on CPC presence. METHODS: A comprehensive analysis was conducted on 309 consecutive patients diagnosed with either multiple myeloma or pPCL, utilizing peripheral blood smears stained with Wright-Giemsa. RESULTS: Patients were grouped by CPC percentage: 0% (221, 71.5%), 1-4% (49, 15.9%), 5-19% (16, 5.2%), ≥20% (23, 7.4%). CPC >5% correlated with unfavorable characteristics, including anemia, renal dysfunction, and advanced International Staging System. Common cytogenetic abnormalities such as 1q21 amplification, 17p deletion, and Myc rearrangement were prevalent among CPC-positive patients. Median progression-free survival (PFS) and overall survival (OS) were shorter in patients with CPC ≥5% (29.47 vs. 10.03 months; 64.10 vs. 12.30 months). Additionally, PFS and OS were shorter in CPC-positive patients without autologous hematopoietic stem cell transplantation (ASCT) and those with response < partial remission to the first-line regimen. Furthermore, an association emerged between soft tissue-related extramedullary disease and inferior PFS, while Myc rearrangement correlated with abbreviated OS. CONCLUSION: Biological characteristics displayed greater aggressiveness in patients with positive CPC, leading to significantly shorter PFS and OS. The presence of CPC, ASCT, and overall response rate were independent prognostic factors. While no new threshold for pPCL with CPCs is proposed, Myc rearrangements and CPC positivity could serve as ultra-high-risk factors for multiple myeloma.

Pure red cell aplasia and minimal residual disease conversion associated with immune reconstitution in a patient with high-risk multiple myeloma.

A second bone marrow aspiration and biopsy showed pure red cell aplasia in this case.

Triple-q Order in Na_{2}Co_{2}TeO_{6} from Proximity to Hidden-SU(2)-Symmetric Point.

In extended Heisenberg-Kitaev-Gamma-type spin models, hidden-SU(2)-symmetric points are isolated points in parameter space that can be mapped to pure Heisenberg models via nontrivial duality transformations. Such points generically feature quantum degeneracy between conventional single-q and exotic multi-q states. We argue that recent single-crystal inelastic neutron scattering data place the honeycomb magnet Na_{2}Co_{2}TeO_{6} in proximity to such a hidden-SU(2)-symmetric point. The low-temperature order is identified as a triple-q state arising from the Néel antiferromagnet with staggered magnetization in the out-of-plane direction via a 4-sublattice duality transformation. This state naturally explains various distinctive features of the magnetic excitation spectrum, including its surprisingly high symmetry and the dispersive low-energy and flat high-energy bands. Our result demonstrates the importance of bond-dependent exchange interactions in cobaltates, and illustrates the intriguing magnetic behavior resulting from them.

Rare spontaneous extensive annular intramural esophageal dissection with endoscopic treatment: A case report.

BACKGROUND: Intramural esophageal dissection (IED) is a rare disease that should be considered in patients with chest pain, dysphagia, and hematemesis. Although it occurs most frequently in older adult women with impaired coagulation or as a sequela of endoscopy, the incidence of spontaneous IED without an obvious causative agent has risen gradually. CASE SUMMARY: This report describes a case of extensive annular IED in a 75-year-old male patient who presented with dysphagia for the past month. Esophageal barium meal radiography revealed slow passage of diluted iohexol through the esophagus after swallowing, prominent luminal dilation, obstruction of the lower segment with only a small amount of contrast medium entering the gastric cavity, and no obvious extravasation. Gastroscopy revealed smooth esophageal mucosa; several esophageal mucosal bridges and webbed mucosa were observed approximately 22 cm from the incisor. The mucosal surface was occasionally rough and uneven, and the length of the esophageal mucosal defect exceeded 10 cm. The anatomy was considered to be annular because the mucosal bridge connecting the proximal and distal tube was not attached to the surrounding myotubes. The final diagnosis was spontaneous extensive annular IED. We treated the patient successfully using endoscopic esophagotomy, which completely relieved the symptoms without complications. CONCLUSION: Spontaneous annular IED can be treated successfully by endoscopic resection of the mucosal septum between the true and false lumen.

Melatonin inhibits the endoplasmic reticulum stress­induced, C/EBP homologous protein­mediated pathway in acute pancreatitis.

Melatonin, which is mainly secreted by the pineal gland, appears to have anti­inflammatory activities. Acute pancreatitis (AP) is characterized by inflammation and acinar cell death, and is associated with a high mortality rate. It has been reported that melatonin can alleviate cerulein (Cer) or Cer + lipopolysaccharide (LPS)­induced inflammatory responses in AR42J rat pancreatic acinar cells (AR42J cells). CCAAT/enhancer binding protein homologous protein (CHOP) is a specific transcription factor involved in endoplasmic reticulum (ER) stress­induced apoptosis, and regulates ER stress responses. However, the mechanisms of the anti­inflammatory effects of melatonin' are unknown, particularly the relationship between melatonin and ER stress. Therefore, the present study aimed to investigate the anti­inflammatory activity of melatonin in AR42J cells and analyze its molecular mechanisms during ER stress. The RNA interference method was used to determine the potential role of CHOP in AR42J cells during AP. In vitro models of AP were induced by treating AR42J cells with Cer + LPS, and pre­treatment with melatonin was used to identify the potential anti­inflammatory mechanisms. The cells also underwent Cell Counting Kit­8, western blotting and reverse transcription­quantitative PCR analyses. The expression levels of ER stress­related molecules were rapidly activated in the early stage and increased over time in the AR42J AP models, with significant pancreatic inflammation and apoptosis. However, knockdown of CHOP expression significantly reduced apoptosis, the activation of NF­κB and the downstream signal pathway. Moreover, cells treated with melatonin exhibited attenuated inflammation, decreased expression levels of ER stress­associated proteins and inhibition of apoptosis. Thus, the present results suggested that melatonin may attenuate the inflammatory response by inhibiting the activation of the CHOP­mediated pathway in AR42J cells.

WT1 facilitates the self-renewal of leukemia-initiating cells through the upregulation of BCL2L2: WT1-BCL2L2 axis as a new acute myeloid leukemia therapy target.

BACKGROUND: Overexpression of Wilms' tumor-1 (WT1) transcription factor facilitates proliferation in acute myeloid leukemia (AML). However, whether WT1 is enriched in the leukemia-initiating cells (LICs) and leukemia stem cells (LSCs) and facilitates the self-renewal of LSCs remains poorly understood. METHODS: MLL-AF9-induced murine leukemia model was used to evaluate the effect of knockdown of wt1 on the self-renewal ability of LSC. RNA sequencing was performed on WT1-overexpressing cells to select WT1 targets. Apoptosis and colony formation assays were used to assess the anti-leukemic potential of a deubiquitinase inhibitor WP1130. Furthermore, NOD/SCID-IL2Rγ (NSG) AML xenotransplantation and MLL-AF9-induced murine leukemia models were used to evaluate the anti-leukemogenic potential of WP1130 in vivo. RESULTS: We found that wt1 is highly expressed in LICs and LSCs and facilitates the maintenance of leukemia in a murine MLL-AF9-induced model of AML. WT1 enhanced the self-renewal of LSC by increasing the expression of BCL2L2, a member of B cell lymphoma 2 (BCL2) family, by direct binding to its promoter region. Loss of WT1 impaired self-renewal ability in LSC and delayed the progression of leukemia. WP1130 was found to modify the WT1-BCL2L2 axis, and WP1130-induced anti-leukemic activity was mediated by ubiquitin proteasome-mediated destruction of WT1 protein. WP1130 induced apoptosis and decreased colony formation abilities of leukemia cells and prolonged the overall survival in the THP1-based xenograft NSG mouse model. WP1130 also decreased the frequency of LSC and prolonged the overall survival in MLL-AF9-induced murine leukemia model. Mechanistically, WP1130 induced the degradation of WT1 by positively affecting the ubiquitination of WT1 protein. CONCLUSIONS: Our results indicate that WT1 is required for the development of AML. WP1130 exhibits anti-leukemic activity by inhibiting the WT1-BCL2L2 axis, which may represent a new acute myeloid leukemia therapy target.

Prognostic value of hypoalbuminemia at diagnosis in de novo non-M3 acute myeloid leukemia.

The association between serum albumin level and clinical outcomes has been reported for several hematological malignancies. Our study aimed to identify the relationship between serum albumin level at the time of diagnosis and subsequent clinical outcomes in patients with newly diagnosed acute myeloid leukemias (AMLs) other than acute promyelocytic leukemias (APLs). A total of 243 patients with de novo non-M3 AML were enrolled in this study. Variables including gender, age, serum albumin, white blood cell (WBC) count, hemoglobin (Hb), platelet (PLT) count, blasts at peripheral blood (PB) and bone marrow (BM), immunophenotype and cytogenetics at diagnosis, BM response after one course of chemotherapy and hematopoietic stem cell transplantation (HSCT) treatment were studied. We found that normal albumin level (serum albumin >3.5 g/dL) was significantly associated with superior overall survival (HR = 0.375, p < .001) and leukemia-free survival (HR = 0.411, p < .001). These results demonstrate that albumin could serve as a simple, cheap, and objective prognostication factor in refinement of AML regimens.