Real-world experience with venetoclax-based therapy for patients with myeloid sarcoma.

BACKGROUND: The treatment of myeloid sarcoma (MS) is challenging and has not markedly improved patient prognosis. The introduction of venetoclax (VEN) has changed the treatment of MS, and venetoclax-based therapy has been described as very promising in several case reports. METHODS: In this retrospective study, we analyzed the treatment outcomes of 14 patients with MS treated with venetoclax-based therapy at The First Affiliated Hospital of Xiamen University from January 2020 to October 2023 RESULTS: The cohort consisted of 7 (50%) women and 7 (50%) men with an average age of 37.5 years. Four patients (28.6%) had isolated MS de novo, 2 (14.2%) were diagnosed synchronously with AML, and 8 (57.2%) had isolated extramedullary relapse. The most common sites for MS in our cohort were the skin and lung, followed by the spinal canal, soft tissue, bone and kidney. Five patients were affected at more than three sites. Nine patients received VEN in combination with azacytidine, and 5 patients received VEN in combination with other agents. The median number of venetoclax therapies administered was 2 cycles (range: 1-10 cycles). A response was observed in all patients included in the study, with 8 patients (57.2%) achieving a CR and 3 patients (21.4%) achieving a PR, corresponding to an ORR (including CR and PR) of 78.6%. The median follow-up time for all patients was 13 months (range 1-44 months), and the 1 year OS for all patients was 67.7%. CONCLUSIONS: Venetoclax-based therapy shows excellent efficacy and safety in MS patients in the "real world" at a single institution, and a corresponding prospective study is needed to verify this conclusion.

Lactate acid promotes PD-1+ Tregs accumulation in the bone marrow with high tumor burden of Acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) displayed poor response to programmed death-1 (PD-1) blockade therapy. Regulatory T cells (Tregs) was one of major immunosuppressive components in Tumor microenvironment and plays a vital role in the resistance of immunotherapy. Coinhibitory receptors regulate function of regulatory Tregs and are associated with resistance of PD-1 blockade. However, the coinhibitory receptors expression and differentiated status of Tregs in AML patients remain to be unclear. METHODS: Phenotypic determination of Tregs and CD8+ T cells in bone marrow of healthy donors and AML patients was performed by flow cytometry. Coculture experiments of AML and Tregs in vitro were performed and the concentrations of lactate acid (LA) in the supernatant were examined by ELISA. RESULTS: More Tregs differentiated into effector subsets in AML patients. However, PD-1 and T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) expression on Tregs were comparable in healthy donors and AML patients. Further analysis showed that PD-1+ and PD-1+TIGIT+Tregs are more abundant in the bone marrow of patients with higher leukemic load. Moreover, PD-1+ Tregs accumulation was associated with higher level of senescent CD4+ T cells and increased frequencies of exhausted CD4+ as well as CD8+ T cells. Notably, neither Tregs nor their effector subsets were decreased among patients in complete remission. PD-1 expression was significantly downregulated in Tregs after achieving complete remission. Mechanistically, both AML cell line (KG-1α) and primary AML blasts produced high concentration of LA. Blockade of LA by lactate transporter inhibitor abrogated the upregulation of PD-1 by AML cells. CONCLUSION: PD-1+ Tregs accumulation in bone marrow in higher leukemic burden setting was linked to lactate acid secreted by AML blasts and decreased after disease remission. Our findings provided a novel insight into Tregs in AML and possible mechanism for resistance of PD-1 blockade in AML.

Effect of prior lenalidomide or daratumumab exposure on hematopoietic stem cell collection and reconstitution in multiple myeloma.

BACKGROUND: The roles of Lenalidomide (Len) and Daratumumab (Dara) in multiple myeloma treatment are well-established, yet their influences on hematopoietic stem cell harvesting and reconstitution remain disputed. METHODS: We conducted a systematic database review to identify cohort studies or RCTs evaluating the effect of the use of Len or Dara on hematopoietic stem cell collection and peripheral blood count recovery in multiple myeloma patients. Effects on hematopoietic collection or reconstitution were estimated by comparing standardized mean differences (SMD) and mean differences (MD), or median differences. RESULTS: Eighteen relevant studies were identified, summarizing mobilization results. For Len, data from 13 studies were summarized, including total CD34+ cell yield, collection failure rate, and time to neutrophil and platelet engraftment. Results indicated that Len exposure led to decreased stem cell collection [SMD=-0.23, 95% CI (-0.34, -0.12)]. However, collection failure (<2×106) could be mitigated by plerixafor [OR=2.14, 95% CI (0.96, 4.77)]. For Dara, two RCTs and three cohort studies were included, showing that Dara exposure resulted in a reduction in total stem cells even with optimized plerixafor mobilization [SMD=-0.75, 95% CI (-1.26, -0.23)], and delayed platelet engraftment recovery [MD=1.20, 95% CI (0.73, 1.66)]. CONCLUSIONS: Our meta-analysis offers a comprehensive view of Len and Dara's impacts on hematopoietic stem cell collection and reconstitution in multiple myeloma. Len usage could lead to reduced stem cell collection, counteracted by plerixafor mobilization. Dara usage could result in diminished stem cell collection and delayed platelet engraftment.

Analysis of Correlation Between Coronary Heart Disease and Genetic Polymorphism Detected by Gold Magnetic Nanoparticles Chromatography.

It aimed to explore the correlation of Glu504Lys locus mutation of aldehyde dehydrogenase-2 (ALDH2) with coronary heart disease (CHD) based on gold magnetic nanoparticles (GMNPs) chromatography and amplification refractory mutation system-PCR (ARMS-PCR). 120 CHD patients admitted to the cardiovascular Department of Wenling First People's Hospital affiliated to Wenzhou Medical University from December 2020 to December 2021 were selected as Case group and 80 non-CHD patients admitted during the same period were selected as Ctrl group. The venous blood and indexes of Total Cholesterol (TC), Triglyceride (TG), Low Density Lipoprotein Cholesterol (LDL-C), High Density Lipoprotein Cholesterol (HDL-C), and Fasting Blood Glucose (FBS) were collected. The ARMS-PCR GMNPs chromatography based on ARMS-PCR and immunochromatography assay was adopted to detect gene polymorphism of ALDH2. Correlation between ALDH2 gene polymorphism and risk factors of CHD was analyzed via logistic regression. In contrast to Ctrl group, the genotypes of GG, GA, and AA in Case group were evidently different (P < 0.05), and the frequency of A allelic gene was obviously increased (P < 0.05). Under the dominant model, frequency of GA + AA genotype in Case group was remarkably higher in contrast to Ctrl group (P < 0.05). Under the recessive model, there was no obvious difference in genotype frequency between two groups. In contrast to Ctrl group, TC, LDL-C, and FBS in Case group were notably increased (P < 0.05), while HDL-C was notably decreased (P < 0.05). The distribution frequency of abnormal LDL-C, HDL-C, and FBS in Case group was notably higher in contrast to Ctrl group (P < 0.05). LDL-C and FBS had no obvious effect on the genotypes and frequency distribution of alleles in CHD patients. However, the frequency distribution of genotypes of GA and AA and A allelic gene in patients with abnormal HDL-C was notably lower in contrast to those with normal HDL-C (P < 0.05). Logistic regression analysis showed that abnormal HDC-C with A allelic gene were independent risk factors for CHD (P = 0.001, OR = 1.934). The gene polymorphism of Glu504Lys locus of ALDH2 was closely related to the pathogenesis of CHD, A allelic gene may be a susceptibility gene for CHD, and patients with abnormal HDC-C and carried A allelic gene had relatively higher incidence of CHD.

Nutrition knowledge, attitudes, and dietary practices among parents of children and adolescents in Weifang, China: A cross-sectional study.

Parent's nutrition knowledge, attitudes, and dietary practices (KAP) play imperative roles in preventing malnutrition for themselves and their children. Our study aimed to determine the status and contributing factors of nutrition KAP among parents of children and adolescents. A total of 1746 parents (mean age 39.67 ± 5.38 years, females accounting for 69.82%) of primary and junior high school students in Weifang, China, completed a self-reported KAP questionnaire in August 2021. An analysis of Pearson product-moment correlation was conducted to determine the relationship between knowledge, attitudes, and practices. Chi-square test, followed by a multivariable robust Poisson regression analysis, was performed to identify the contributing factors to parents' KAP. A 65.94% awareness rate of nutritional knowledge was observed. The correlations between nutrition knowledge and attitudes (r = 0.03, P = 0.23), knowledge and practices (r = 0.02, P = 0.34), and attitudes and practices (r = 0.16, P < 0.01) were relatively weak. After adjusting for other contributing factors, females [prevalence ratio (PR) = 1.28, 95% confidence interval (CI) = 1.13-1.45], participants with secondary education (PR = 4.64, 95% CI = 1.60-13.50), junior college education (PR = 5.87, 95% CI = 2.01-17.13) and college degree or above education (PR = 6.58, 95% CI = 2.25-19.23) acquired higher nutrition knowledge scores. Moreover, healthy diet behaviors were more commonly implemented by females than males (PR = 1.42, 95% CI = 1.14-1.76), and which needed to be improved in those with abnormal body mass indexes (BMIs) [overweight (PR = 0.86, 95% CI = 0.74-0.99) and obese (PR = 0.76, 95% CI = 0.56-0.99)]. It was necessary for nutrition KAP promotion to be emphasized in nutritional knowledge and dietary practices, as well as health behavior guidance, especially for parents with low education and elevated BMIs.

Cell Cycle-Related lncRNAs as Innovative Targets to Advance Cancer Management.

Long non-coding RNAs (lncRNAs) are non-coding RNAs (ncRNAs) longer than 200nt. They have complex biological functions and take part in multiple fundamental biological processes, such as cell proliferation, differentiation, survival and apoptosis. Recent studies suggest that lncRNAs modulate critical regulatory proteins involved in cancer cell cycle, such as cyclin, cell cycle protein-dependent kinases (CDK) and cell cycle protein-dependent kinase inhibitors (CKI) through different mechanisms. To clarify the role of lncRNAs in the regulation of cell cycle will provide new ideas for design of antitumor therapies which intervene with the cell cycle progression. In this paper, we review the recent studies about the controlling of lncRNAs on cell cycle related proteins such as cyclin, CDK and CKI in different cancers. We further outline the different mechanisms involved in this regulation and describe the emerging role of cell cycle-related lncRNAs in cancer diagnosis and therapy.

Bispecific antibodies as monotherapy or in combinations for non-hodgkin B-cell lymphoma: latest updates from the American society of hematology 2022 annual meeting.

Recent evidence suggests that bispecific antibodies (BsAbs) exhibit promising efficacy and low toxicity even in heavily treated non-Hodgkin B-cell lymphoma (B-NHL). However, the role of BsAbs in previously untreated NHL and the efficacy and safety of BsAbs used in combination remain uncertain. We summarized data published at the 64th American Society of Hematology (ASH) Annual Meeting on BsAb monotherapy or combination therapy for first-line or relapsed/refractory B-NHL. BsAb monotherapy in elderly/unfit newly diagnosed (ND) DLBCL patients achieved ORR and CR rates of 56% and 43%, respectively. In addition, BsAbs combined with chemotherapy or other novel agents raised the ORR higher than 50% without increasing the incidence of grade ≥ 3 CRS. We conclude that BsAb monotherapy or combination therapy for first-line or relapsed/refractory B-NHL has high efficacy and satisfactory safety.

Loss of CD28 expression associates with severe T-cell exhaustion in acute myeloid leukemia.

Introduction: Despite accumulated evidence in T-cell exhaustion in acute myeloid leukemia (AML), the immunotherapeutic targeting exhausted T cells such as programmed cell death protein 1 (PD-1) blockade in AML failed to achieve satisfying efficacy. Characteristics of exhausted T cells in AML remained to be explored. Methods: Phenotypic analysis of T cells in bone marrow (BM) using flow cytometry combining senescent and exhausted markers was performed in de novo AML patients and healthy donors as well as AML patients with complete remission (CR). Functional analysis of T-cell subsets was also performed in de novo AML patients using flow cytometry. Results: T cells experienced a phenotypic shift to terminal differentiation characterized by increased loss of CD28 expression and decrease of naïve T cells. Additionally, lack of CD28 expression could help define a severely exhausted subset from generally exhausted T cells (PD-1+TIGIT+). Moreover, CD28- subsets rather than CD28+ subsets predominantly contributed to the significant accumulation of PD-1+TIGIT+ T cells in AML patients. Further comparison of de novo and CR AML patients showed that T-cell exhaustion status was improved after disease remission, especially in CD28+ subsets. Notably, higher frequency of CD28-TIGIT-CD4+ T cells correlated with the presence of minimal residual disease in AML-CR group. However, the correlation between CD28- exhausted T cells and cytogenetic risk or white blood cell count was not observed, except for that CD28- exhausted CD4+ T cells correlated with lymphocyte counts. Intriguingly, larger amount of CD28-TGITI+CD8+ T cells at diagnosis was associated with poor treatment response and shorter leukemia free survival. Discussion: In summary, lack of CD28 expression defined a severely exhausted status from exhausted T cells. Accumulation of CD28- exhausted T cells was linked to occurrence of AML, and correlated to poor clinical outcome. Our data might facilitate the development of combinatory strategies to improve the efficacy of PD-1 blockade in AML.

Differences in clinical characteristics and outcomes between patients with grade 3a and grades 1-2 follicular lymphoma: a real-world multicenter study.

BACKGROUND: The difference between clinical characteristics and outcomes between follicular lymphoma grade 1-2 (FL1-2) and FL3a defined pathologically remains unclear, resulting in uncertainty how to treat FL3a. However, it may be crucial for clinicians to discriminate grade 3a and grade 1-2 for predicting prognosis and thus making treatment decisions. METHODS: We compared 1403 patients with FL1-2 and 765 patients with FL3a diagnosed between January 2000 and December 2020 from fifteen centers nationwide in China to describe differences in clinical characteristics and outcomes. RESULTS: Compared with FL1-2 patients, FL3a subgroup had a higher percentage of elderly patients (P = 0.003), and relatively more FL3a patients presented with increased levels of LDH (P < 0.0001) and higher Ki-67 indexs greater than 30% (P < 0.001). More FL3a patients were treated with CHOP ± R (P < 0.0001), and fewer were treated with the watchful-waiting approach (P < 0.0001). The results showed a higher incidence of relapse among FL3a patients, in which more patients underwent histological transformation (HT) when compared to FL1-2 (P = 0.003). 1470 (76.2%) patients of the entire cohort received R-CHOP therapy; survival analysis revealed that FL3a patients had a worse progression-free survival (PFS) rate than FL1-2 patients. Survival of FL3a patients with respect to FLIPI showed an inferior PFS in the intermediate and high-risk groups than FL1-2 patients. FL3a patients had a much worse prognosis than FL1-2 with or without progression of disease within 24 months (POD24). FL3a patients had higher likelihood of lymphoma-related death (LRD, P < 0.05), whereas the rates for non-LRD were comparable. CONCLUSION: In conclusion, this study demonstrates a marked difference in clinical features and outcomes in FL3a patients compared with FL1-2 patients. The results highlight the need for applying therapeutic approaches distinct from FL1-2 when treating FL3a patients.

Clinical characteristics and outcomes of follicular lymphoma patients with extranodal involvement: analysis of a series of 1090 cases in China.

BACKGROUND: Follicular lymphoma (FL) is the most common indolent B cell lymphoma in the world. The clinical features of extranodal involvement in FL were never extensively described. METHODS: We enrolled 1090 patients diagnosed as newly diagnosed FL at ten medical institutions in China from 2000 to 2020 and conducted this analysis and retrospectively explored clinical characteristics and outcomes of FL patients with extranodal involvement. RESULTS: 400 (36.7%) patients with newly diagnosed FL had no extranodal involvement, 388 (35.6%) patients had one site of extranodal involvement, and 302 (27.7%) had two or more sites of involvement. Patients with >1 extranodal site had significantly worse PFS (p<0.001), as well as OS (p=0.010). The most common site of extranodal involvements was bone marrow (33%), followed by spleen (27.7%) and intestine (6.7%). In patients with extranodal involvement, multivariate Cox analysis found that male patients (p=0.016), poor performance status (p=0.035), increased LDH (p<0.001) and pancreas involvement (p<0.001) was associated with poor PFS, while the latter three factors were also associated with poor OS. Compared to patients with one site of extranodal involvement, patients with >1 site involvement (p=0.012) had 2.04-fold risk to develop POD24. In addition, multivariate Cox analysis found that the usage of rituximab was not associated with better PFS (p=0.787) or OS (p=0.191). CONCLUSIONS: Our cohort is large enough to have statistical significance in FL patients with extranodal involvement. Male sex, increased LDH, poor performance status, >1 extranodal site, as well as pancreas involvement indicated useful prognostic factors in the clinical setting.

Orelabrutinib and venetoclax synergistically induce cell death in double-hit lymphoma by interfering with the crosstalk between the PI3K/AKT and p38/MAPK signaling.

PURPOSE: Double-hit lymphoma (DHL) is a rare and aggressive mature B-cell malignancy with concurrent MYC and BCL2 rearrangements. When DHL becomes relapsed or refractory, it becomes resistant to the majority of therapeutic approaches and has subpar clinical results. Therefore, innovative therapeutics for this particular patient population are urgently needed. METHODS: Orelabrutinib, a new oral BTK inhibitor, combined with the Bcl-2 inhibitor venetoclax, was used to confirm the antitumor effect of DHL. Cell counting kit-8 and Annexin V-FITC/PI assays were used to examine the interaction of this combined regimen on DHL cell lines and primary lymphoma cells. RNA sequencing, EdU incorporation assay, mitochondrial membrane potential assay, and western blotting were employed to explore the molecule mechanism for the cytotoxicity of orelabrutinib with or without venetoclax against DHL cell lines. RESULTS: In this study, orelabrutinib combined with venetoclax synergistically induced DHL cell death, as evidenced by the inhibition of cell proliferation, the induct of cell cycle arrest, and the promotion of cell apoptosis via the mitochondrial pathway. Orelabrutinib treatment alters genome-wide gene expression in DHL cells. The combined regimen decreases the expression of BTK and Mcl-1, potentially interfering with the activity and crosstalk of PI3K/AKT signaling and p38/MAPK signaling. In addition, the combination of orelabrutinib and venetoclax shows cytotoxic activity in primary B-lymphoma cells. CONCLUSION: In summary, these findings reveal a novel therapy targeting BCR signaling and the Bcl-2 family for DHL patients with a poor prognosis.

Vitamin D deficiency increases the risk of bacterial vaginosis during pregnancy: Evidence from a meta-analysis based on observational studies.

Background: Bacterial vaginosis (BV) is the most common microbiological syndrome in women of childbearing age, causing numerous adverse health issues in pregnant women. Several observational studies have discussed the association between vitamin D deficiency and the risk of BV during pregnancy, but the results were inconclusive. Therefore, this meta-analysis aimed to explore the association between vitamin D deficiency and BV risk in pregnant women. Materials and methods: We searched four databases, including PubMed, Embase, Cochrane Library, and Web of Science, from their inception to July 2022. Pooled odds ratios (OR) with corresponding 95% confidence intervals (CI) were estimated using random effects models. Additionally, we conducted subgroup analyses to identify the potential sources of between-study heterogeneity. Sensitivity analysis was performed using the method of exclusion, one study at a time. Publication bias was examined using Egger's test and funnel plot. Results: A total of 14 studies from 13 articles including 4,793 participants were eligible for this meta-analysis. The outcome showed that vitamin D deficiency may increase the risk of BV during pregnancy by 54% (OR, 1.54; 95% CI, 1.25-1.91; P < 0.001). In subgroup analyses, positive associations were also found in studies that were: conducted in black women (OR, 1.56; 95% CI, 0.98-2.48; P = 0.060), focused on the first trimester of pregnancy (OR, 2.22; 95% CI, 1.35-3.64; P = 0.002), of high quality (OR, 3.05; 95% CI, 1.26-7.41; P = 0.014), and adjusted for confounders (OR, 1.28; 95% CI, 1.06-1.55; P = 0.012). Sensitivity analysis reported that BV risk during pregnancy resulting from vitamin D deficiency increased by 157% (OR, 2.57; 95% CI, 1.50-4.42; P = 0.001) when removing the first two high-weight studies. Publication bias was observed using Egger's test (t = 3.43, P = 0.005) and a visual funnel plot. Conclusion: This meta-analysis showed that vitamin D deficiency is positively associated with the risk of BV during pregnancy. Further high-quality prospective cohort studies are needed to determine whether vitamin D intake reduces the prevalence of BV in pregnant women.

Preclinical Evaluation of the Multiple Tyrosine Kinases Inhibitor Anlotinib in Leukemia Stem Cells.

Leukemia stem cells (LSCs) constitute the critical barrier to the cure of acute myeloid leukemia (AML) due to their chemoresistance and immune evasion property. Herein, the role of anlotinib, a multiple tyrosine kinase inhibitor, in killing LSCs and regulating chemoresistance and immune evasion was explored. Anlotinib treatment induced apoptosis of LSC-like cells as well as primary AML LSCs, while sparing the normal mononuclear cells in vitro. Moreover, anlotinib could impair the regeneration capacity of LSCs in the patient-derived leukemia xenograft mouse model. Mechanistically, anlotinib inhibited phosphorylation of c-kit, JAK2/STAT3, and STAT5, and downregulated STAT3 and STAT5 expression. In addition, anlotinib downregulated the anti-apoptotic proteins Bcl-2 and Bcl-xL, and upregulated Bax, thereby enhancing the sensitivity of LSCs to idarubicin in vitro. Intriguingly, anlotinib could also partially rescue the interferon-g production of T cells cocultured with LSCs by downregulating PD-L1 expression. In conclusion, anlotinib showed anti-LSC activity and the potential to enhance the sensitivity to idarubicin and inhibit the immunosuppressive feature of LSCs via JAK2/STAT signaling pathway downregulation in the preclinical study. Our results provided a rational basis for combinatory strategies involving anlotinib and chemotherapy or immunotherapy.

Fatty Acid Synthase Mutations Predict Favorable Immune Checkpoint Inhibitor Outcome and Response in Melanoma and Non-Small Cell Lung Cancer Patients.

Fatty acid synthase (FASN) acts as the central member in fatty acid synthesis and metabolism processes, which regulate oncogenic signals and tumor immunogenicity. To date, no studies have reported the connection of FASN mutations with ICI efficacy. In this study, from 631 melanoma and 109 NSCLC patients who received ICI treatments, we retrospectively curated multiomics profiles and ICI treatment data. We also explored the potential molecular biological mechanisms behind FASN alterations. In melanoma patients, FASN mutations were observed to associate with a preferable immunotherapeutic prognosis and response rate (both p < 0.01). These connections were further corroborated by the NSCLC patients (both p < 0.01). Further analyses showed that a favorable tumor immunogenicity and immune microenvironment were involved in FASN mutations. This work confirms the clinical immunotherapy implications of FASN mutation-mediated fatty acid metabolism and provides a possible indicator for immunotherapy prognosis prediction.

Crosstalk among long non-coding RNA, tumor-associated macrophages and small extracellular vesicles in tumorigenesis and dissemination.

Long noncoding RNAs (lncRNAs), which lack protein-coding ability, can regulate cancer cell growth, proliferation, invasion, and metastasis. Tumor-associated macrophages (TAMs) are key components of the tumor microenvironment that have a significant impact on cancer progression. Small extracellular vesicles (sEV) are crucial mediators of intercellular communications. Cancer cell and macrophage-derived sEV can carry lncRNAs that influence the onset and progression of cancer. Dysregulation of lncRNAs, TAMs, and sEV is widely observed in tumors which makes them valuable targets for cancer immunotherapy. In this review, we summarize current updates on the interactions among sEV, lncRNAs, and TAMs in tumors and provide new perspectives on cancer diagnosis and treatment.

Identification of Jingmen tick virus (JMTV) in Amblyomma testudinarium from Fujian Province, southeastern China.

BACKGROUND: Jingmen tick virus (JMTV) is a newly discovered tick-borne virus that can cause disease in humans. This virus has been authenticated as being extremely widespread worldwide and as posing a significant threat to public health and safety. METHODS: We collected 35 ticks belonging to two tick species from wild boars in Nanping, Fujian Province, China. JMTV-specific genes were amplified by qRT-PCR and nested PCR to confirm the presence of this pathogen. RESULTS: More than one third of of all ticks collected (11/35) were positive for JMTV. Viral sequences were obtained from three of the JMTV-positive ticks, including the complete genomic sequence from one tick. This was the first time that JMTV was identified in the hard-bodied tick Amblyomma testudinarium. Phylogenetic analysis revealed that JMTV from Fujian Province shared > 90% identity with other isolates derived from China, but was distinct from those reported in France and Cambodia. CONCLUSIONS: JMTV is characterized by relatively low mutations and has its own local adaptive characteristics in different regions. Our findings provide molecular evidence of the presence of JMTV in an overlooked tick species from an area not unrecognized as being endemic. They also suggest that JMTV occupies a wider geographical distribution than currently believed and is a potential disease vector.

Revealing the evolution of the tumor immune microenvironment in follicular lymphoma patients progressing within 24 months using single-cell imaging mass cytometry.

BACKGROUND: Patients with follicular lymphoma (FL) who experience disease progression within 24 months (POD24) have inferior outcomes. The tumor immune microenvironment (TIME) plays a crucial role in pathogenesis and progression of follicular lymphoma (FL). However, TIME evolution during progression of disease within 24 months (POD24) is elusive. METHODS: Spatially resolved and single-cell image mass cytometry with a panel of 36 metal-tagged antibodies was used to quantitatively analyze the TIME structure in 13 paired FLs at diagnosis and POD24. RESULTS: Follicles and peri-follicular regions were well dissected in structure. Peri-follicular regions represented a barrier for immune infiltration into the follicles. More FL-cells in the peri-follicular regions suffered CD8+T cells attacks under simultaneous protection of regulatory T cells (Tregs) and/or macrophages compared with that in the follicles irrespective of POD24. During POD24, increased CD163- macrophages with PD-1 ligand upregulation and decreased CD8+T cells with upregulated LAG-3 expression around FL-cells were observed in the follicles. Spatial analyses demonstrated that FL-cells interacted more intimately with macrophages than with Tregs and less with cytotoxic T cells in both peri-follicular regions and follicles during POD24. In comparison, macrophages also cooperated more frequently with Tregs to simultaneously hijack FL-cells, creating an enhanced immunosuppressive environment in both peri-follicular and follicular regions during POD24. CONCLUSIONS: Peri-follicular regions function as a barrier by recruiting both CD8+T cells and immunosuppressive cells, protecting follicular FL-cells from immune attack at diagnosis or POD24. FL-cells reside in a more immune-compromised microenvironment and evade immune cell attacks during POD24. Novel immunotherapeutic approaches harnessing LAG-3, macrophages, and Tregs will be empowered to overcome poor outcomes in patients with FL POD24.

HSPG2 Mutation Association with Immune Checkpoint Inhibitor Outcome in Melanoma and Non-Small Cell Lung Cancer.

Immune checkpoint inhibitors (ICIs) markedly promote the survival outcome of advanced melanoma and non-small cell lung cancer (NSCLC). Clinically, favorable ICI treatment efficacy is noticed only in a smaller proportion of patients. Heparan sulfate proteoglycan 2 (HSPG2) frequently mutates in both tumors. Herein, we aim to investigate the immunotherapeutic and immunological roles of HSPG2 mutations in melanoma and NSCLC. A total of 631 melanoma samples and 109 NSCLC samples with both somatic mutational profiles and clinical immunotherapy data were curated. In addition, by using The Cancer Genome Atlas data, genomic and immunological traits behind HSPG2 mutations were elucidated. Melanoma patients with HSPG2 mutations had a markedly extended ICI outcome than other patients. An association between HSPG2 mutations and the improved outcome was further confirmed in NSCLC. In addition, an elevated ICI response rate was presented in HSPG2-mutated NSCLC patients (81.8% vs. 29.7%, p = 0.002). Subsequent analyses revealed that HSPG2-mutated patients had a favorable abundance of response immunocytes, an inferior abundance of suppression immunocytes, enhanced mutational burden, and interferon response-relevant signaling pathways. We uncovered that HSPG2 mutations were predictive of a better ICI response and associated with preferable immunogenicity, which may be considered as a genomic determinant to customize biotherapy strategies.

The role of central nervous system (CNS) prophylaxis in preventing DLBCL patients from CNS relapse: A network meta-analysis.

BACKGROUND: Secondary central nervous system (CNS) relapses are an uncommon yet devastating complication in diffuse large B cell lymphoma (DLBCL). Although several prophylaxis attempts were employed clinically in order to reduce the CNS relapse rate, the optimal management remained uncertain. METHODS: We employed conventional meta-analysis along with Network meta-analysis to investigate an optimal prophylactic strategy. The primary outcome was CNS relapse rate. RESULTS: A total of thirty-six studies comprising 5 RCTs, one clinical trial and 30 observational studies were included. Rituximab overall was superior in reducing CNS relapse rate, and the statistical significance exists (RR 0.79(0.68-0.93), p = 0.004). In rituximab era, none of intravenous, intrathecal administration or novel target agents could significantly decrease CNS relapse rate in high CNS risk patients. Intensive chemotherapy regimen containing HD-MTX with HD-Ara-C (SUCRA 93.4 %) was ranked as the first in reducing CNS relapse rate followed by no prophylaxis (SUCRA 57.5 %), HD-MTX (SUCRA 53.1 %), IT (SUCRA 34.5 %) and lenalidomide maintenance (SUCRA 11.5 %). In addition, intercalated HD-MTX had a trend of reducing CNS relapse but without statistical significance (RR 0.86(0.44-1.68), p = 0.67). However, i-HD-MTX was associated with increased grade 3-4 toxicities and prolonged inpatient stay. Early HD-MTX exposure also increased the treatment related death. CONCLUSION: Our network meta-analysis provides an overview of the relative efficacy of all available CNS prophylaxis strategies in DLBCL. In rituximab era, none of intravenous, intrathecal administration or novel target agents could significantly decrease CNS relapse rate in high CNS risk patients. Further studies with prospective, randomized clinical trials as well as with more focus on novel target agents that could spread blood-brain barriers are suggested.

Adverse events in lymphoma patients treated with phosphoinositide 3 kinase Inhibitor in clinical trials: a meta-analysis.

BACKGROUND: Malignant lymphomas are one of the most common cancers worldwide and with high biologic heterogeneity, while the phosphoinositide 3 kinase (PI3K)/mTOR pathway is crucial in maintaining cell growth and survival both in physiological and in pathological conditions (i.e., lymphoma). PI3K inhibitors have been proven to be effective in several subtypes of lymphomas. However, the high incidence of treatment-related adverse events as well as the special safety profile in PI3K inhibitors draws great attention. Thus, this meta-analysis was conducted to compare adverse events in PI3K inhibitors to conventional regimens in lymphoma patients. METHODS: Articles were retrieved from PubMed, Cochrane, and Embase to identify randomized controlled trials and phase III clinical trials that used PI3K inhibitors comparing with non-PI3K inhibitors in lymphoma patients. To achieve the appropriate results, we calculated the risk ratio and 95% confidence intervals. RESULTS: Four trials with 1399 patients that met our criteria were included. The PI3K inhibitors group significantly increased the risk of all-grade adverse events (AEs) (RR 0.95, 95% CI: 0.92-0.98) and high-grade AEs (RR 0.63, 95% CI: 0.57-0.70), compared with the non-PI3K inhibitors group. Besides, the incidence of neutropenia (RR 0.81, 95% CI: 0.74-0.90), pneumonia (RR 0.62, 95% CI: 0.46-0.83), and diarrhea (RR 0.40, 95% CI: 0.32-0.49) were significantly high in the PI3Ki group, while the incidence of anemia (RR 0.78, 95% CI: 0.50-1.20) and thrombocytopenia (RR 0.85, 95% CI: 0.51-1.42) had no statistic significant. CONCLUSION: PI3K inhibitors increased the risk of certain AEs in lymphoma patients.