Spatial transcriptomic analysis of tumour-immune cell interactions in melanoma arising from congenital melanocytic nevus.

BACKGROUND: Studies on the interaction between tumour-infiltrating immune cells (TIICs) and tumour cells in melanoma arising from congenital melanocytic nevus (CMN) are lacking. OBJECTIVE: The aim of this study was to determine the intratumoral immune landscape of TIICs and tumour cells during invasion and metastasis. METHODS: Tissue specimens were obtained from patients with melanoma originating from CMN. Differential gene expression in melanoma cells and TIICs during invasion and metastasis was determined using spatial transcriptomics. RESULTS: As invasion depth increased, the expression of LGALS3, known to induce tumour-driven immunosuppression, increased in melanoma cells. In T cells, the expression of genes that inhibit T-cell activation increased with increasing invasion depth. In macrophages, the expression of genes related to the anti-inflammatory M2 phenotype was upregulated with increasing invasion depth. Compared to primary tumour cells, melanoma cells in metastatic lesions showed upregulated expression of genes associated with cancer immune evasion, including AXL and EPHA2, which impede T-cell recruitment, and BST2, associated with M2 polarization. Furthermore, T cells showed increased expression of genes related to immunosuppression, and macrophages exhibited increased expression of genes associated with the M2 phenotype. CONCLUSIONS: The interaction between melanomas arising from CMN and TIICs may be important for tumour progression and metastasis.

A CRISPR activation screen identifies MUC-21 as critical for resistance to NK and T cell-mediated cytotoxicity.

BACKGROUND: Immunotherapy has significantly advanced cancer treatments, but many patients do not respond to it, partly due to immunosuppressive mechanisms used by tumor cells. These cells employ immunosuppressive ligands to evade detection and elimination by the immune system. Therefore, the discovery and characterization of novel immunosuppressive ligands that facilitate immune evasion are crucial for developing more potent anti-cancer therapies. METHODS: We conducted gain-of-function screens using a CRISPRa (CRISPR activation) library that covered the entire human transmembrane sub-genome to identify surface molecules capable of hindering NK-mediated cytotoxicity. The immunosuppressive role and mechanism of MUC21 were validated using NK and T cell mediated cytotoxicity assays. Bioinformatics tools were employed to assess the clinical implications of mucin-21 (MUC21) in cancer cell immunity. RESULTS: Our genetic screens revealed that MUC21 expression on cancer cell surfaces inhibits both the cytotoxic activity of NK cells and antibody-dependent cellular cytotoxicity, but not affecting complement-dependent cytotoxicity. Additionally, MUC21 expression hinders T cell activation by impeding antigen recognition, thereby diminishing the effectiveness of the immune checkpoint inhibitor, anti-PD-L1. Moreover, MUC21 expression suppress the antitumor function of both CAR-T cells and CAR-NK cells. Mechanistically, MUC21 facilitates immune evasion by creating steric hindrance, preventing interactions between cancer and immune cells. Bioinformatics analysis revealed elevated MUC21 expression in lung cancer, which correlated with reduced infiltration and activation of cytotoxic immune cells. Intriguingly, MUC21 expression was higher in non-small cell lung cancer (NSCLC) tumors that were non-responsive to anti-PD-(L)1 treatment compared to responsive tumors. CONCLUSIONS: These findings indicate that surface MUC21 serves as a potent immunosuppressive ligand, shielding cancer cells from NK and CD8+T cell attacks. This suggests that inhibiting MUC21 could be a promising strategy to improve cancer immunotherapy.

Prognostic significance of 25-hydroxyvitamin D levels in patients with peripheral T-cell lymphoma.

Vitamin D insufficiency has been linked to unfavourable outcomes in diverse malignancies. However, the prognostic significance of vitamin D levels in peripheral T-cell lymphoma (PTCL) remains unclear. In this study, we thus aimed to assess the prognostic relevance of 25-hydroxyvitamin D [25(OH)D] levels in patients newly diagnosed with PTCL. The analysis included 144 patients with PTCL treated from March 2015 to May 2020. The median 25(OH)D level was 12.2 (1.7-48.8) ng/mL, and 59 (41%) patients had vitamin D deficiency. Patients with vitamin D deficiency demonstrated significantly worse event-free survival (EFS) and overall survival (OS). In the multivariate analysis, vitamin D was independently associated with OS, with a hazard ratio of 1.66 (95% confidence interval, 1.05-2.63, p = 0.030). These findings suggest that vitamin D deficiency significantly correlates with poor survival outcomes in patients with PTCL.

The comprehensive expression of BCL2 family genes determines the prognosis of diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is a prevalent and aggressive non-Hodgkin's lymphoma, and 40% of patients succumb to death. Despite numerous clinical trials aimed at developing treatment strategies beyond the conventional R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen, there have been no positive results thus far. Although the selective BCL2 inhibitor venetoclax has shown remarkable efficacy in chronic lymphocytic leukemia, its therapeutic effect in DLBCL was limited. We hypothesized that the limited therapeutic effect of venetoclax in DLBCL may be attributed to the complex expression and interactions of BCL2 family members, including BCL2. Therefore, we aimed to comprehensively analyze the expression patterns of BCL2 family members in DLBCL. We analyzed 157 patients with de novo DLBCL diagnosed at Asan Medical Center and Ajou University Hospital. The mRNA expression levels of BCL2 family members were quantified using the NanoString technology. BCL2 family members showed distinct heterogeneous expression patterns both intra- and inter-patient. Using unsupervised hierarchical cluster analysis, we were able to classify patients with similar BCL2 family expression pattern and select groups with clear prognostic features, C1 and C6. In the group with the best prognosis, C1, the expression of pro-apoptotic and pro-apoptotic BH3-only group gene expressions were increased, while anti-apoptotic group expression was significantly increased in both C1 and C6. Based on this, we generated the BCL2 signature score using the expression of pro-apoptotic genes BOK and BCL2L15, and anti-apoptotic gene BCL2. The BCL2 signature score 0 had the best prognosis, score 1/2 had intermediate prognosis, and score 3 had the worst prognosis (EFS, p = 0.0054; OS, p = 0.0011). Multivariate analysis, including COO and IPI, showed that increase in the BCL2 signature score was significantly associated with poor prognosis for EFS, independent of COO and IPI. The BCL2 signature score we proposed in this study provides information on BCL2 family deregulation based on the equilibrium of pro-versus anti-apoptotic BCL2 family, which can aid in the development of new treatment strategies for DLBCL in the future.

Deep Interactive Learning-based ovarian cancer segmentation of H&E-stained whole slide images to study morphological patterns of BRCA mutation.

Deep learning has been widely used to analyze digitized hematoxylin and eosin (H&E)-stained histopathology whole slide images. Automated cancer segmentation using deep learning can be used to diagnose malignancy and to find novel morphological patterns to predict molecular subtypes. To train pixel-wise cancer segmentation models, manual annotation from pathologists is generally a bottleneck due to its time-consuming nature. In this paper, we propose Deep Interactive Learning with a pretrained segmentation model from a different cancer type to reduce manual annotation time. Instead of annotating all pixels from cancer and non-cancer regions on giga-pixel whole slide images, an iterative process of annotating mislabeled regions from a segmentation model and training/finetuning the model with the additional annotation can reduce the time. Especially, employing a pretrained segmentation model can further reduce the time than starting annotation from scratch. We trained an accurate ovarian cancer segmentation model with a pretrained breast segmentation model by 3.5 hours of manual annotation which achieved intersection-over-union of 0.74, recall of 0.86, and precision of 0.84. With automatically extracted high-grade serous ovarian cancer patches, we attempted to train an additional classification deep learning model to predict BRCA mutation. The segmentation model and code have been released at https://github.com/MSKCC-Computational-Pathology/DMMN-ovary.

A New Prognostic Index for Extranodal Natural Killer/T-Cell Lymphoma:Incorporation of Serum ß-2 Microglobulin to PINK.

PURPOSE: Prognostic Index for Natural Killer Lymphoma (PINK) is the most widely accepted prognostic model for patients withextranodal natural killer/T-cell lymphoma (ENKTL) treated with non-anthracycline-based therapy. We aimed to evaluate the prognostic implications of serum ß-2 microglobulin (ß2M) in the context of PINK and proposed a new prognostic model. MATERIALS AND METHODS: A total of 138 patients who were newly diagnosed with ENKTL and treated with non-anthracycline-based chemotherapy were identified. The cut-off value of high serum ß2M was calculated by maximal-chi square methods (4.1 mg/L). A new prognostic model incorporating serum ß2M into PINK was proposed and validated in an independent validation cohort (n=88). RESULTS: The patients' median age was 53.5 years (range, 19 to 80 years). Patients with high serum ß2M levels had significantly worse overall survival (OS) and progression-free survival (PFS). In multivariate analysis, high serum ß2M was an independent adverse prognostic factor for OS. A new PINK-B (Prognostic Index for Natural Killer Lymphoma-serum ß-2 microglobulin) model stratifiedpatients into three groups with distinct OS and PFS in the training cohort (3-year OS, 84.1% [95% confidence interval, 75.1 to 94.2], 46.8% [36.1 to 60.8] and 17.6% [6.3 to 49.2] for the low-, intermediate, and high-risk groups, respectively; 3-year PFS, 70.6% [59.4 to 83.8], 35.9% [25.9 to 49.8], and 7.35% [1.1 to 46.7] for the low-, intermediate-, and high-risk groups, respectively). The PINK-B model was further validated in an independent cohort. CONCLUSION: Serum ß2M is an independent prognostic factor for ENKTL patients. The new serum ß2M-based prognostic model may be useful for identifying ultra-high-risk patients, and it can easily be adopted into daily clinical practice.

Acupuncture Inhibits Morphine Induced-Immune Suppress via Antioxidant System.

Objectives: A powerful analgesic called Morphine causes addiction behaviors and immune suppression as a potential oxidative stressor. Acupuncture showed to inhibit oxidative stress-induced hepatic damage, regulate reactive oxygen species, and attenuate morphine addiction behaviors. Therefore, we investigated the potential effects of acupuncture on morphine-induced immune suppression. Materials and Methods: Rats received morphine intravenously through implanted catheters for 3, 7, or 21 days to determine the optimal condition for morphine-induced immune suppression. Second, we examined whether intravenous (iv.) or intraperitoneal (ip.) administration produced different results. Third, the effects of acupuncture in rats who received morphine for 21 days were investigated. Spleen and submandibular lymph node (S-LN) weights and natural killer (NK) cell activity were measured, and the white pulp diameter, total and cortical spleen thicknesses, and the number of lymphoid follicles in S-LNs were examined. The number of immunoreactive cells was also measured. Results: Decreased organ weights and increased atrophic changes were observed as morphine-induced immune suppression. However, dose-dependent increased immune suppression was not observed between 5.0 mg/kg and 10.0 mg/kg of morphine. And, 3-day withdrawal did not affect. Similar histopathological findings were observed in 5.0 and 10.0 ip. rats when compared to equal dosages of iv., respectively. The morphine induced-immune suppression evidenced by spleen and left S-LN weights, splenic NK cell activities, histopathological findings, and the immunoreactive cell number were normalized by acupuncture. Conclusion: These results indicate that acupuncture inhibits morphine-induced immune suppression, maybe via antioxidative action.

Extra copy number of BCL2 is correlated with increased BCL-2 protein expression and poor survival in diffuse large B-cell lymphoma treated with chemoimmunotherapy.

The clinical significance of extra copy (EC) genotypes of BCL2, MYC, and BCL6 have not been fully elucidated. We evaluated the EC and translocation statuses of BCL2, MYC, and BCL6 in 190 diffuse large B-cell lymphoma (DLBCL) cases using fluorescence in situ hybridization. EC genotype was sub-classified according to copy number-gained tumor cell ratio (EC1, >20% but ≤50%; EC2, >50%). Only the BCL2-EC groups, not MYC-EC or BCL6-EC groups, displayed significantly increased immunoreactivity of the corresponding protein. Moreover, the BCL2-EC2 group was significantly associated with poor overall survival (OS) and progression-free survival (PFS) in a 147 R-CHOP-treated patient subset, which was also statistically significant as per the multivariate survival analysis for PFS. No significant differences in the survival of MYC, BCL6, concurrent BCL2/MYC, BCL6/MYC, BCL2/BCL6, or triple EC groups were observed. BCL2-EC may contribute to increased BCL-2 protein expression and serve as a predictor of treatment outcomes in DLBCL.

Involvement of MST1/mTORC1/STAT1 activity in the regulation of B-cell receptor signalling by chemokine receptor 2.

BACKGROUND: CCR2 is involved in maintaining immune homeostasis and regulating immune function. This study aims to elucidate the mechanism by which CCR2 regulates B-cell signalling. METHODS: In Ccr2-knockout mice, the development and differentiation of B cells, BCR proximal signals, actin movement and B-cell immune response were determined. Besides, the level of CCR2 in PBMC of SLE patients was analysed by bioinformatics. RESULTS: CCR2 deficiency reduces the proportion and number of follicular B cells, upregulates BCR proximal signalling and enhances the oxidative phosphorylation of B cells. Meanwhile, increased actin filaments aggregation and its associated early-activation events of B cells are also induced by CCR2 deficiency. The MST1/mTORC1/STAT1 axis in B cells is responsible for the regulation of actin remodelling, metabolic activities and transcriptional signalling, specific MST1, mTORC1 or STAT1 inhibitor can rescue the upregulated BCR signalling. Glomerular IgG deposition is obvious in CCR2-deficient mice, accompanied by increased anti-dsDNA IgG level. Additionally, the CCR2 expression in peripheral B cells of SLE patients is decreased than that of healthy controls. CONCLUSIONS: CCR2 can utilise MST1/mTORC1/STAT1 axis to regulate BCR signalling. The interaction between CCR2 and BCR may contribute to exploring the mechanism of autoimmune diseases.

Clinical Outcomes and Effectiveness of Heart Transplantation in Patients With Systemic Light-chain Cardiac Amyloidosis.

BACKGROUND: In systemic light-chain (AL) amyloidosis, cardiac involvement is a major determinant of survival; however, cardiac response is limited even after systemic treatment in a majority of patients, and some require heart transplantation. Additionally, limited information is available on specific indications for heart transplantation. We aimed to explore clinical outcomes of cardiac amyloidosis and its association with heart transplantation, including identifying factors favoring heart transplantation amenability. METHODS: We retrospectively analyzed data from patients diagnosed with AL amyloidosis with cardiac involvement between January 2007 and December 2020 at a tertiary referral center. RESULTS: Among 73 patients, 72 (99%) received systemic treatment, and 12 (16%) underwent heart transplantation. Characteristics at diagnosis were similar between heart transplant recipients and nonrecipients, although left ventricular ejection fraction tended to be lower in recipients (median 48% versus 57%, P = 0.085). Eight weeks after systemic treatment, 67% and 12% of patients achieved hematologic and brain natriuretic peptide responses. Overall survival was longer among heart transplantation recipients than nonrecipients, with 5-y survival rates of 61.1% (95% confidence interval, 25.5%-83.8%) versus 32.0% (95% confidence interval, 20.3%-44.4%; P = 0.022), respectively. Among the 34 with identifiable causes of death out of 51 deaths, 21 nonrecipients (62%) died of cardiac problems compared with none in the heart transplant recipients. Additionally, survival outcomes favored heart transplant recipients in most subgroups, including patients with higher Mayo 2004 European stage at diagnosis and with extracardiac involvement of amyloidosis. CONCLUSIONS: Heart transplantation can achieve long-term survival in appropriately selected patients with AL cardiac amyloidosis.

Cyclin D1 and PRAME expression in distinguishing melanoma in situ from benign melanocytic proliferation of the nail unit.

BACKGROUND: Distinguishing benign lesion from early malignancy in melanocytic lesions of the nail unit still remains a diagnostic challenge, both clinically and histopathologically. While several immunohistochemistry (IHC) stainings have been suggested to help discriminate benign subungual melanocytic proliferation (SMP) and subungual melanoma in situ (MIS), the diagnostic utility of IHC staining for cyclin D1 and PRAME has not been thoroughly investigated in melanocytic lesions of nail unit. METHODS: This retrospective study included cases of benign SMP and subungual MIS confirmed by biopsy at Asan Medical Center from January 2016 to December 2020. Cases of melanocytic activation without proliferation and melanoma where dermal invasion was identified were excluded. Cyclin D1 and PRAME expression was assessed by counting proportion of melanocytes with nuclear positivity under 200x magnification. RESULTS: A total of 14 patients with benign SMP and 13 patients with subungual MIS were included in this study. 11 patients with benign SMP (71.4%) and 5 patients with subungual MIS (38.5%) showed > 60% nuclear immunostaining for cyclin D1, respectively. While 13 patients with benign SMP (92.9%) showed totally negative staining for PRAME, 10 patients with subungual MIS (76.9%) exhibited > 50% nuclear immunostaining for PRAME. Using the cutoff of 10%, PRAME exhibited good overall discrimination between benign SMP and subungual MIS (AUC = 0.849, 95% CI = 0.659-0.957). CONCLUSIONS: This study suggests that PRAME IHC staining as a reliable discriminator in distinguishing subungual MIS from benign SMP.

Clinicopathological Factors Associated with the Prognosis and Chronicity of Lymphomatoid Papulosis: A Retrospective Cohort Study.

BACKGROUND: The clinical and pathological features of lymphomatoid papulosis (LYP) are diverse. The objective of this study is to evaluate the clinical and pathological features associated with the prognosis and clinical course of LYP. PATIENTS AND METHODS: The clinical and pathological features of LYP in a medical center database were retrospectively retrieved. RESULTS: Overall, 58 LYP patients were included in the study. The mean age at diagnosis was 39.1 years and the female-to-male ratio was 1:1.2. More than two-thirds (40/58, 69.0%) of the patients showed a chronic and recurrent disease course. A longer pre-diagnosis duration (odds ratio (OR), 1.01; 95% confidence interval (CI), 1.00-1.03) was significantly associated with secondary lymphoma development. Lower extremity involvement (OR, 10.40; 95% CI, 1.17-92.28) and the absence of eosinophils in the lesions (OR, 11.28; 95% CI, 1.01-126.24) were found to be significantly associated with the chronic and recurrent course of LYP. CONCLUSION: A longer pre-diagnosis duration is associated with secondary lymphoma, while a lower extremity involvement and the absence of lesional eosinophil infiltration are associated with the chronicity of LYP.

Significance of Single-cell Level Dual Expression of BCL2 and MYC Determined With Multiplex Immunohistochemistry in Diffuse Large B-Cell Lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is a fatal heterogenous neoplasm. Recent clinical trials have failed partly due to nebulous criteria for defining high-risk patients. Patients with double-expresser lymphoma (DEL) have a poor prognosis and are resistant to conventional treatment. However, many diagnostic and clinical controversies still surround DEL partly due to the arbitrariness of criteria for the diagnosis of DEL. In this study, we suggest a refined method for diagnosing DEL by evaluating the concurrent expression of BCL2 and MYC at the single-cell level (dual-protein-expressing lymphoma [DUEL]). For the proof of concept, a multiplex immunofluorescence assay for CD20, BCL2, and MYC was performed and quantitatively analyzed using spectral image analysis in patients. The analysis results and clinical applicability were verified by using dual-color immunohistochemistry performed on 353 independent multicenter patients who had been uniformly treated with standard therapy. DUEL showed significantly worse overall survival (OS) and event-free survival (EFS) (P=0.00011 and 0.00035, respectively). DUEL status remained an independent adverse prognostic variable with respect to the International Prognostic Index risk and the cell of origin. Moreover, the advantage of determining DUEL status by dual-color immunohistochemistry was shown by more robust classification and more homogeneous high-risk subgroup patient identification in both training (n=271) (OS: P<0.0001; EFS: P<0.0001) and validation sets (n=82) (OS: P=0.0087; EFS: P<0.0001). This concept of DUEL is more consistent with carcinogenesis and has greater practical utility, hence it may provide a better basis for both basic and clinical research for the development of new therapeutics.

Prognostic significance of serum ß2-microglobulin levels in patients with peripheral T-cell lymphoma not otherwise specified.

We aimed to investigate the prognostic value of serum ß2-microglobulin in patients with peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS). A cohort study of PTCL-NOS patients (n = 147) was conducted. An elevated serum ß2-microglobulin level was associated with the presence of previously identified predictors of a poor prognosis for PTCL-NOS. Patients with an elevated serum ß2-microglobulin level exhibited a significantly worse progression-free survival (PFS) and overall survival (OS). Multivariate analyses revealed that an elevated serum ß2-microglobulin level was independently associated with a shorter PFS and OS. A new prognostic index incorporating the serum ß2-microglobulin level allowed for the stratification of patients into three distinct risk subgroups. The index was validated to stratify patients with distinct survival outcomes in an independent cohort of PTCL-NOS (n = 89). In conclusion, serum ß2-microglobulin level is an independent prognostic factor in patients with PTCL-NOS. Our ß2-microglobulin-based prognostic index for PTCL-NOS deserves further investigation and validation.

BCL2 super-expressor diffuse large B-cell lymphoma: a distinct subgroup associated with poor prognosis.

Overexpression of the BCL2 protein has been reported as a poor prognostic factor for diffuse large B-cell lymphoma (DLBCL). However, there are currently no standardized criteria for evaluating BCL2 protein expression. We aimed to evaluate the prognostic value of BCL2 expression determined by immunohistochemistry (IHC), incorporating both the staining intensity and proportion, in patients with de novo DLBCL who received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) as first-line treatment. We defined tumors with BCL2 expression in nearly all tumor cells with a uniformly strong intensity by IHC as BCL2 super-expressor. The BCL2 super-expressors (n = 35) showed significantly worse event-free survival (EFS; HR, 1.903; 95% CI, 1.159-3.126, P = 0.011) and overall survival (OS; HR, 2.467; 95% CI, 1.474-4.127, P = 0.001) compared with the non-BCL2 super-expressors (n = 234) independent of the international prognostic index (IPI), cell of origin (COO), and double expressor status in the training set (n = 269). The adverse prognostic impact of BCL2 super-expression was confirmed in the validation set (n = 195). When the survival outcomes were evaluated in the entire cohort (n = 464), BCL2 super-expressor group was significantly associated with inferior EFS and OS regardless of IPI, COO, MYC expression, and stages. BCL2 super-expressors had genetic aberrations enriched in the NOTCH and TP53 signaling pathways. This study suggests that the BCL2 super-expressor characterizes a distinct subset of DLBCL with a poor prognosis and warrants further investigation as a target population for BCL-2 inhibitors.

Novel Discoveries in Immune Dysregulation in Inborn Errors of Immunity.

With the expansion of our knowledge on inborn errors of immunity (IEI), it gradually becomes clear that immune dysregulation plays an important part. In some cases, autoimmunity, hyperinflammation and lymphoproliferation are far more serious than infections. Thus, immune dysregulation has become significant in disease monitoring and treatment. In recent years, the wide application of whole-exome sequencing/whole-genome sequencing has tremendously promoted the discovery and further studies of new IEI. The number of discovered IEI is growing rapidly, followed by numerous studies of their pathogenesis and therapy. In this review, we focus on novel discovered primary immune dysregulation diseases, including deficiency of SLC7A7, CD122, DEF6, FERMT1, TGFB1, RIPK1, CD137, TET2 and SOCS1. We discuss their genetic mutation, symptoms and current therapeutic methods, and point out the gaps in this field.

Genetic profiles of subcutaneous panniculitis-like T-cell lymphoma and clinicopathological impact of HAVCR2 mutations.

Recent studies identified germline mutations in HAVCR2 (encoding T-cell immunoglobulin mucin 3) as a genetic factor that predisposes to subcutaneous panniculitis-like T-cell lymphoma (SPTCL). However, the differences between HAVCR2-mutated (HAVCR2MUT) and HAVCR2 wild-type (HAVCR2WT) SPTCLs remain unclear. A nationwide cohort of 53 patients with SPTCL diagnosed at 8 Korean institutions was established. Whole-exome sequencing and RNA-sequencing were performed on 8 patients in the discovery set. In the validation set, targeted gene sequencing or direct sequencing of HAVCR2 was performed. Of 49 patients with available HAVCR2 status, 25 (51.0%) were HAVCR2Y82C. HAVCR2Y82C was associated with younger age (P = .001), development of hemophagocytic lymphohistiocytosis or hemophagocytic lymphohistiocytosis-like systemic illness (P < .001), and short relapse-free survival (RFS) (P = .023). Most mutated genes in SPTCLs were involved in immune responses, epigenetic modifications, and cell signaling. Mutations in UNC13D, PIAS3, and KMT2D were more frequent in HAVCR2WT SPTCLs. At the gene expression level, HAVCR2Y82C SPTCLs were enriched in genes involved in IL6-JAK-STAT3 signaling and in tumor necrosis factor-α signaling via NF-κB. CCR4 was significantly upregulated in HAVCR2WT SPTCLs both at the messenger RNA level and at the protein level. We established a risk stratification system for SPTCL by integrating clinical and histopathological features, including age and HAVCR2 mutation status. This risk stratification system was strongly associated with RFS (P = .031). In conclusion, the HAVCR2Y82C mutation was common in Korean patients with SPTCL and was associated with unique clinicopathological and genetic features. Combining clinicopathological parameters could aid in predicting prognosis for patients with SPTCL.

SARS-CoV-2 infection causes immunodeficiency in recovered patients by downregulating CD19 expression in B cells via enhancing B-cell metabolism.

The SARS-CoV-2 infection causes severe immune disruption. However, it is unclear if disrupted immune regulation still exists and pertains in recovered COVID-19 patients. In our study, we have characterized the immune phenotype of B cells from 15 recovered COVID-19 patients, and found that healthy controls and recovered patients had similar B-cell populations before and after BCR stimulation, but the frequencies of PBC in patients were significantly increased when compared to healthy controls before stimulation. However, the percentage of unswitched memory B cells was decreased in recovered patients but not changed in healthy controls upon BCR stimulation. Interestingly, we found that CD19 expression was significantly reduced in almost all the B-cell subsets in recovered patients. Moreover, the BCR signaling and early B-cell response were disrupted upon BCR stimulation. Mechanistically, we found that the reduced CD19 expression was caused by the dysregulation of cell metabolism. In conclusion, we found that SARS-CoV-2 infection causes immunodeficiency in recovered patients by downregulating CD19 expression in B cells via enhancing B-cell metabolism, which may provide a new intervention target to cure COVID-19.

Upward trend in follicular lymphoma among the Korean population: 10-year experience at a large tertiary institution.

BACKGROUND: Follicular lymphoma (FL) is the second most common non-Hodgkin lymphoma (NHL) in Western countries. However, it is relatively rare in Asia. This study examined epidemiologic characteristics of FL in South Korea, with an emphasis on recent trends of increase in cases. METHODS: We retrospectively examined 239 cases of newly diagnosed FL at a large tertiary institution in Korea (Asan Medical Center, Seoul, Republic of Korea) between 2008 and 2017. Age-adjusted incidence rates and clinicopathological variables were analyzed, and joinpoint regression analysis was used to identify the changes. RESULTS: The age-adjusted incidence of FL significantly increased during the study period (p = .034), and the ratio of (relative incidence) patients with FL to patients with NHL increased from 4.28% to 9.35% in the same period. Over the 10-year study assessment duration, the proportion of patients with stage III/IV FL (p = .035) and expression of BCL2 (p = .022) or BCL6 (p = .039) significantly increased. From 2013-2017, the proportion of patients with highrisk Follicular Lymphoma International Prognostic Index (FLIPI) score increased (21.5% to 28.7%), whereas that of low-risk FLIPI decreased (55.4% to 38.6%), although those results were not statistically significant (p = .066). CONCLUSIONS: We found an increasing incidence of FL, with a disproportionate increase in the incidence of high-stage disease and recent changes in the clinicopathologic features of the Korean patient population.