Case report: BTK inhibitors is effective in type II mixed cryoglobulinemia with wild-type MyD88.

This study presents two cases of type II mixed cryoglobulinemia. One case is essential, while the other is presumably associated with hepatitis B virus (HBV) infection. Both patients tested positive for monoclonal IgMκ, but negative for MyD88 mutation. They showed resistance to rituximab combined with a glucosteroid regimen, but responded positively to BTK inhibitors. These cases highlight the remarkable effectiveness of BTK inhibitors in treating refractory type II cryoglobulinemia without MyD88 mutation. The first patient achieved rapid complete remission of nephrotic syndrome within one month of starting ibrutinib, along with a significant reduction in cryoglobulin levels and abnormal clonal cells. The second patient had a rapid disappearance of rash within three days and accelerated wound healing within one week of initiating orelabrutinib, accompanied by a reduction in C-reactive protein. However, there was no reduction in cryoglobulin levels during the 12-month follow-up. These findings suggest varied mechanisms of action of BTK inhibitors in type II cryoglobulinemia through different mechanisms.

The outcome of ibrutinib-based regimens in relapsed/refractory central nervous system lymphoma and the potential impact of genomic variants.

BACKGROUND: Relapsed/refractory (r/r) central nervous system lymphoma (CNSL) exhibits aggressive behavior and poor outcomes. As an effective bruton tyrosine kinase (BTK) inhibitor, ibrutinib yields benefits in B-cell malignancies. OBJECTIVES: We aimed to explore the efficacy of ibrutinib in treating r/r CNSL patients, and whether genomic variants impact treatment outcomes. MATERIAL AND METHODS: The ibrutinib-based regimens in 12 r/r primary CNSL (PCNSL) and 2 secondary CNSL (SCNSL) patients were analyzed retrospectively. The impact of genetic variants on the effects of treatments was examined using whole-exome sequencing (WES) technology. RESULTS: In PCNSL, the overall response rate was 75%, with median overall survival (OS) not reached (NR) and progression-free survival (PFS) of 4 months. Both SCNSL patients responded to ibrutinib, with median OS NR and PFS of 0.5-1.5 months. Infections were common during ibrutinib therapy (42.86%). The PCNSL patients harboring gene mutations in PIM1, MYD88 and CD79B, and the proximal BCR and nuclear factor kappa B (NF-κB) pathways responded to ibrutinib. Patients who harbored simple genetic variants and those with a low tumor mutation burden (TMB; 2.39-5.56/Mb) responded swiftly and maintained remission for more than 10 months. A patient with a TMB of 11/Mb responded to ibrutinib but continued to experience disease progression. In contrast, patients with complex genomic features, especially extremely high TMB (58.39/Mb), responded poorly to ibrutinib. CONCLUSIONS: Our study demonstrates that ibrutinib-based therapy is effective and relatively safe for the treatment of r/r CNSL. Patients with less genomic complexity, especially with regard to TMB, might benefit more from ibrutinib regimens.

Germline genetic variations in methotrexate pathway are associated with pharmacokinetics, outcome, and toxicity in patients with primary central nervous system lymphoma.

BACKGROUND: High-dose methotrexate (HD-MTX)-based regimens are the standard treatment for patients with primary central nervous system lymphoma (PCNSL); however, MTX has extensive interpatient variability in pharmacokinetics and clinical outcomes, with genetic variation an important factor involved in the variability in drug response. METHODS: 123 PCNSL patients who received 524 courses of chemotherapy were genotyped for 42 single nucleotide polymorphisms in MTX pathway. The relationship between these polymorphisms and the pharmacokinetics, clinical outcomes, and toxicity of MTX was explored using both univariate and multivariate analyses. RESULTS: We found ABCB1 rs2032582 and GGH rs2305558 were substantially associated with the pharmacokinetics of MTX. Patients with GGH rs2305558 T and ABCB1 rs2032582 non-G allele had a higher Cmax increased by 20.5%, area under the concentration-time curve (AUC0-48h) increased by 19.6% and lower clearance decreased by 19.6%. ABCB1 rs1045642 and rs2032582 might be independent predictors of progression-free survival. Patients with ABCB1 rs1045642 non-A and rs2032582 G allele correlated with higher progression risk of the disease. Furthermore, ATIC rs3821353 was associated with MTX-induced hepatotoxicity (Grade ≥ 2). CONCLUSION: These variants may serve as biomarkers to predict the pharmacokinetics, clinical outcomes, and hepatotoxicity of MTX and contribute to personalized therapy for PCNSL patients.

The characteristics of cerebrospinal fluid anaplastic large cells in a patient with primary leptomeningeal anaplastic large cell lymphoma.

BACKGROUND: Primary central nervous system lymphomas (PCNSL) anaplastic large cell lymphoma (ALCL) are very rare non-Hodgkin's lymphomas, especially in the leptomeninges. Until now, the diagnostics and therapeutics of PCNSL-ALCL is a challenge and urgent need. A 26-y Chinese male presented altered awareness and severe headache. METHODS: A 26-y Chinese male presented altered awareness and severe headache. Brain magnetic resonance imaging (MRI) delineated no intracerebral lesions and focal leptomeningeal enhancement. Diagnosis was based on cerebrospinal fluid (CSF) examination discovering anaplastic large cells (ALCs) with positive expression for anaplastic lymphoma kinase (ALK) and CD30, and no evidence of systemic involvement. In addition, we firstly performed the single-cell RNA sequencing to identify transcriptome characteristics of CSF-ALCs. RESULTS: The case was diagnosed as a rare primary leptomeningeal anaplastic large cell lymphoma (PL-ALCL). Four cycles of systemic chemotherapy with methotrexate and intrathecal cytarabine help achieve complete remission. Compared to normal T cells, 45 genes were specifically upregulated in CSF-ALCs. CSF-ALCs enriched cell proliferation and metabolism pathway and lost features of immune identity. The heterogeneity of CSF-ALCs were manifested in the expression of cancer-testis antigens and cell-cycle signature genes. In addition, the gene regulatory networks (GRNs) revealed the activity of transcription factors EZH2 and NFYC were upregulated in the CSF-ALCs. CONCLUSION: The first analysis of single-cell transcriptome signatures of CSF-ALCs will provide clues for diagnosis and mechanism research of PL-ALCL.

Risk factors for high-dose methotrexate associated toxicities in patients with primary central nervous system lymphoma.

WHAT IS KNOWN AND OBJECTIVE: Methotrexate (MTX) is an antimetabolic antitumor drug with high individual differences and may lead to severe toxicities in a considerable number of patients. This study aimed to explore the factors influencing major adverse events in patients with primary central nervous system lymphoma treated with high-dose MTX (HD-MTX), which could be useful in clinical practice. METHODS: Fifty-four patients who received 175 courses of MTX at 3-8 g/m2 between January 2015 and December 2016 were enrolled in this study. We assessed the association between clinical characteristics, MTX pharmacokinetics, MTX delayed elimination, and adverse events, including hepatotoxicity, acute kidney injury (AKI), and myelosuppression. RESULTS AND DISCUSSION: A total of 124 adverse events occurred after MTX infusion. Using independent sample t-tests, we found that patients with myelosuppression had higher MTX area under the concentration-time curve up to 48 h after infusion (AUC0-48h ) (p = 0.001) and MTX peak concentration (Cmax ) (p = 0.002). MTX concentrations at 48 and 72 h were higher in patients with AKI than in those without (p = 0.034 and p = 0.041, respectively). Using chi-square tests, we found that AKI was correlated with MTX elimination at either 48 h or 72 h (22.1% vs. 8.2%, p = 0.010). By multivariate logistic regression model, our results showed that baseline level of ALT and WBC had a significant effect on hepatotoxicity (OR = 1.079, 95% CI 1.044-1.116, p = 6.9 × 10-6 ; OR = 0.808, 95% CI 0.711-0.917, p = 0.001, respectively). Patient's age, eGFR before MTX infusion, and co-administration of vindesine had a significant effect on AKI (OR = 0.960, 95% CI 0.935-0.986, p = 0.003; OR = 1.009, 95% CI 1.001-1.017, p = 0.034; OR = 5.463, 95% CI 1.793-16.646, p = 0.003, respectively). LDH and Co-administration of vindesine had a significant effect on myelosuppression (OR = 0.985, 95% CI 0.972-0.998, p = 0.025; OR = 3.070, 95% CI 1.032-9.133, p = 0.044). WHAT IS NEW AND CONCLUSION: Our study demonstrated that co-administration of VDS, eGFR before MTX infusion, and the baseline index of laboratory examinations including ALT, WBC, LDH may be useful biomarkers for predicting MTX-induced toxicities.

Pemetrexed Plus Lenalidomide for Relapsed/Refractory Primary Central Nervous System Lymphoma: A Prospective Single-Arm Phase II Study.

The prognosis of relapsed/refractory (R/R) primary central nervous system lymphoma (PCNSL) is dismal, and there are limited treatment options for these patients. This was a prospective single-arm phase II study of combined pemetrexed and lenalidomide for salvage treatment of R/R PCNSL. Patients with R/R PCNSL (n = 38) who had undergone two or more different therapeutic regimens and experienced disease progression or recurrence were enrolled. The primary endpoint was overall response rate (ORR). Secondary endpoints were progression-free survival (PFS) and overall survival (OS). Patients were followed up for a median of 18 (range, 1-36) months. ORR was 68.4%, with median PFS and OS of 6 and 18 months, respectively. Adverse events (AEs) included myelosuppression, fatigue, nausea, fever, infection, cardiac disease, and thrombogenesis. Commonly observed grade ≥ 3 AEs included neutropenia (5.3%), leukopenia (2.6%), thrombocytopenia (7.9%), and infection (2.6%). Elevated lactate dehydrogenase (LDH) levels (χ2 = 13.25; P = 0.0003) and bulky disease (P = 0.032; χ2 = 4.580) were associated with short PFS. Elevated serum LDH level (P = 0.011; χ2 = 6.560), abnormal lymphoma cells in the cerebrospinal fluid (CSF) [P = 0.011; χ2 = 6.445], and multiple lesions (P = 0.036; χ2 = 4.404) were significantly associated with poorer OS. Abnormal lymphoma cells in the CSF were an independent predictor of poor prognosis on multivariate analysis (P = 0.034; hazard ratio (HR) = 2.836; 95% confidence interval, 1.082-7.434). Our results indicate that pemetrexed plus lenalidomide is effective for heavily treated R/R PCNSL, with moderate toxicity. Trial registration: #ChiCTR1900028070.

A transient receptor potential channel-related model based on machine learning for evaluating tumor microenvironment and immunotherapeutic strategies in acute myeloid leukemia.

Background: Acute myeloid leukemia (AML) is an aggressive hematopoietic malignancy. Transient receptor potential (TRP) channels in AML still need to be further explored. A TRP channel-related model based on machine learning was established in this study. Methods: The data were downloaded from TCGA-LAML and Genome-Tissue Expression (GTEx). TRP-related genes (TRGs) were extracted from previous literature. With the use of Single-Sample Gene Set Enrichment Analysis (ssGSEA), TRP enrichment scores (TESs) were calculated. The limma package was used to identify differentially expressed genes (DEGs), and univariate Cox regression analysis was performed to identify prognostic DEGs. The above prognostic DEGs were analyzed by Random Survival Forest and least absolute shrinkage and selection operator (Lasso) analysis to create the TRP signature. The Kaplan-Meier and receiver operating characteristic (ROC) curves were plotted to investigate the efficiency and accuracy of prognostic prediction. Moreover, genomic mutation analysis was based on GISTIC analysis. Based on ESTIMATE, TIMER, MCPcounter, and ssGSEA, the tumor microenvironment and immunological characteristics were expressly evaluated to explore immunotherapeutic strategies. Enrichment analysis for TRP signature was based on the Kyoto Encyclopedia of Genes Genomes (KEGG), Gene Ontology (GO), over-representation analysis (ORA), and Gene Set Enrichment Analysis (GSEA). Genomics of Drug Sensitivity in Cancer (GDSC) and pRRophetic were used to carry out drug sensitivity analysis. Conclusively, SCHIP1 was randomly selected to perform in vitro cyto-functional experiments. Results: The worse clinical outcomes of patients with higher TESs were observed. There were 107 differentially expressed TRGs identified. Our data revealed 57 prognostic TRGs. Eight TRGs were obtained to establish the prognostic TRP signature, and the worse clinical outcomes of patients with higher TRP scores were found. The efficiency and accuracy of TRP signature in predicting prognosis were confirmed by ROC curves and five external validation datasets. Our data revealed that the mutation rates of DNMT3A, IDH2, MUC16, and TTN were relatively high. The level of infiltrating immune cell populations, stromal, immune, and ESTIMATE scores increased as the TRP scores increased. Nevertheless, AML patients with lower TRP scores exhibited more tumor purity. The TRP scores were found to be correlated with immunomodulators and immune checkpoints, thus revealing immune characteristics and immunotherapeutic strategies. The IC50 values of six chemotherapeutics were lower in the high TRP score (HTS) group. Finally, it was found that SCHIP1 may be the oncogenic gene. Conclusion: The results of this study will help in understanding the role of TRP and SCHIP1 in the prognosis and development of AML.

Sirtuin 2 knockdown inhibits cell proliferation and RAS/ERK signaling, and promotes cell apoptosis and cell cycle arrest in multiple myeloma.

The present study aimed to explore the regulatory role of sirtuin 2 (SIRT2) in malignant progression of multiple myeloma (MM) and the potential associated signaling pathways. In total, 30 patients with MM and 15 healthy bone marrow donors were enrolled in the current study and their bone marrow samples were collected to isolate the plasma cells. The expression levels of SIRT2 were detected in MM cell lines (KMS­28BM, U266, RPMI­8226 and NCI­H929) and normal plasma cells (collected from healthy bone marrow donors as the control) via reverse transcription­quantitative PCR (RT­qPCR) and western blot analysis. SIRT2 knockdown was established by transfecting two MM cell lines (RPMI­8226 and NCI­H929 cells) with short hairpin RNA­SIRT2 recombinant plasmid; the control group was transfected with a control recombinant plasmid. Subsequently, the effect of SIRT2 knockdown on MM cell proliferation, apoptosis, cell cycle progression and RAS/ERK signaling was investigated via Cell Counting Kit­8, flow cytometry, RT­qPCR and western blot assays, respectively. The mRNA and protein expression levels of SIRT2 were increased in U266 (P<0.001), KMS­28BM (P<0.001), RPMI­8226 (P<0.001) and NCI­H929 (P<0.001) cells compared with those in the control cells. In NCI­H929 and RPMI­8226 cells, cell proliferation was decreased 48 h (P<0.05) and 72 h (P<0.05) after SIRT2 knockdown. Furthermore, the cell apoptotic rate was elevated 48 h after SIRT2 knockdown (P<0.01). In addition, the percentage of cells at the G0/G1 phase was increased (P<0.01), whereas the percentage of cells at the S phase was reduced (P<0.01) 48 h after SIRT2 knockdown. The expression levels of HRAS and phosphorylated­ERK were also reduced 48 h after SIRT2 knockdown. In conclusion, SIRT2 was highly expressed in MM cell lines, and knockdown of SIRT2 inhibited MM cell proliferation, inactivated the RAS/ERK signaling pathway, and promoted cell apoptosis and cell cycle arrest.

Metal-Free Chemoselective Oxidation of 4-Methylquinolines into Quinoline-4-Carbaldehydes.

A convenient protocol for the synthesis of quinoline-4-carbaldehydes via chemoselective oxidation of 4-methylquinolines using hypervalent iodine(III) reagents as oxidant is described. This method highlights metal-free and mild reaction conditions, nice yield, good functional group tolerance, and high chemoselectivity.

Current and emerging therapies for primary central nervous system lymphoma.

Primary central nervous system (CNS) lymphoma (PCNSL) is a rare type of extranodal lymphoma exclusively involving the CNS at the onset, with diffuse large B-cell lymphoma (DLBCL) as the most common histological subtype. As PCNSL is a malignancy arising in an immune-privileged site, suboptimal delivery of systemic agents into tumor tissues results in poorer outcomes in PCNSL than in non-CNS DLBCLs. Commonly used regimens for PCNSL include high-dose methotrexate-based chemotherapy with rituximab for induction therapy and intensive chemotherapy followed by autologous hematopoietic stem cell transplantation or whole-brain radiotherapy for consolidation therapy. Targeted agents against the B-cell receptor signaling pathway, microenvironment immunomodulation and blood-brain barrier (BBB) permeabilization appear to be promising in treating refractory/relapsed patients. Chimeric antigen receptor-T cells (CAR-T cells) have been shown to penetrate the BBB as a potential tool to manipulate this disease entity while controlling CAR-T cell-related encephalopathy syndrome. Future approaches may stratify patients according to age, performance status, molecular biomarkers and cellular bioinformation. This review summarizes the current therapies and emerging agents in clinical development for PCNSL treatment.

Long non-coding RNA T cell factor 7 is associated with increased disease risk and poor prognosis, and promotes cell proliferation, attenuates cell apoptosis and miR-200c expression in multiple myeloma.

The aim of the present study was to investigate the association of long non-coding RNA T cell factor 7 (lncRNA TCF7) with disease risk, prognosis and its cellular function in multiple myeloma (MM). A total of 132 de novo symptomatic patients with MM and 50 controls were enrolled. Plasma cells from patients with MM and controls were separated from bone marrow samples to detect lncRNA TCF7 expression using reverse transcription-quantitative PCR. In addition, treatment responses, event-free survival (EFS) and overall survival (OS) were measured. The effects of lncRNA TCF7 on proliferation, apoptosis and microRNA-200c (miR-200c) expression were assessed by gain- and loss-of-function experiments in RPMI-8226 and U-266 cells. The results demonstrated that lncRNA TCF7 expression was upregulated in patients with MM compared with controls, and the receiver operating characteristic curve revealed that lncRNA TCF7 could distinguish patients with MM from controls with an area under the curve of 0.793 (95% CI, 0.725-0.861). In patients with MM, high lncRNA TCF7 expression was associated with higher ß2-microglobulin, more advanced International Staging System stage and increased t (14; 16) mutations. Furthermore, it was demonstrated that lncRNA TCF7 was downregulated in patients with complete response (CR) compared with patients without CR. Furthermore, high lncRNA TCF7 expression predicted worse EFS and OS. lncRNA TCF7 also promoted cell proliferation, whereas it reduced cell apoptosis and miR-200c expression in RPMI-8226 and U-266 cells. In conclusion, the present results suggested that lncRNA TCF7 may be used as a potential biomarker and as a treatment target for MM.

Association of kinesin family member 2A with increased disease risk, deteriorative clinical characteristics, and shorter survival profiles in acute myeloid leukemia

This study aimed to explore the correlation of kinesin family member 2A (KIF2A) expression with disease risk, clinical characteristics, and prognosis of acute myeloid leukemia (AML), and investigate the effect of KIF2A knockdown on AML cell activities in vitro. Bone marrow samples were collected from 176 AML patients and 40 healthy donors, and KIF2A expression was measured by real-time quantitative polymerase chain reaction. Treatment response, event-free survival (EFS), and overall survival (OS) were assessed in AML patients. In vitro, KIF2A expression in AML cell lines and CD34+ cells (from healthy donors) was measured, and the effect of KIF2A knockdown on AML cell proliferation and apoptosis in HL-60 and KG-1 cells was detected. KIF2A expression was greater in AML patients compared to healthy donors, and receiver operating characteristic curve indicated that KIF2A expression predicted increased AML risk (area under curve: 0.793 (95%CI: 0.724-0.826)). In AML patients, KIF2A expression positively correlated with white blood cells, monosomal karyotype, and high risk stratification. Furthermore, no correlation of KIF2A expression with complete remission or hematopoietic stem cell transplantation was found. Kaplan-Meier curves showed that KIF2A expression was negatively correlated with EFS and OS. In vitro experiments showed that KIF2A was overexpressed in AML cell lines (KG-1, HL-60, ME-1, and HT-93) compared to CD34+ cells, moreover, cell proliferation was reduced but apoptosis was increased by KIF2A knockdown in HL-60 and KG-1 cells. In conclusion, KIF2A showed potential to be a biomarker and treatment target in AML.

Association of kinesin family member 2A with increased disease risk, deteriorative clinical characteristics, and shorter survival profiles in acute myeloid leukemia.

This study aimed to explore the correlation of kinesin family member 2A (KIF2A) expression with disease risk, clinical characteristics, and prognosis of acute myeloid leukemia (AML), and investigate the effect of KIF2A knockdown on AML cell activities in vitro. Bone marrow samples were collected from 176 AML patients and 40 healthy donors, and KIF2A expression was measured by real-time quantitative polymerase chain reaction. Treatment response, event-free survival (EFS), and overall survival (OS) were assessed in AML patients. In vitro, KIF2A expression in AML cell lines and CD34+ cells (from healthy donors) was measured, and the effect of KIF2A knockdown on AML cell proliferation and apoptosis in HL-60 and KG-1 cells was detected. KIF2A expression was greater in AML patients compared to healthy donors, and receiver operating characteristic curve indicated that KIF2A expression predicted increased AML risk (area under curve: 0.793 (95%CI: 0.724-0.826)). In AML patients, KIF2A expression positively correlated with white blood cells, monosomal karyotype, and high risk stratification. Furthermore, no correlation of KIF2A expression with complete remission or hematopoietic stem cell transplantation was found. Kaplan-Meier curves showed that KIF2A expression was negatively correlated with EFS and OS. In vitro experiments showed that KIF2A was overexpressed in AML cell lines (KG-1, HL-60, ME-1, and HT-93) compared to CD34+ cells, moreover, cell proliferation was reduced but apoptosis was increased by KIF2A knockdown in HL-60 and KG-1 cells. In conclusion, KIF2A showed potential to be a biomarker and treatment target in AML.

Effectiveness of digital PCR for MYD88L265P detection in vitreous fluid for primary central nervous system lymphoma diagnosis.

Primary central nervous system lymphoma (PCNSL) is a rare type of primary extranodal lymphoma (PEL). MYD88L265P mutation has been observed in up to 75% of PCNSL cases, however, the validity and sensitivity of digital PCR in detecting this mutation remains to be elucidated. A total of 44 PCNSL patients, 15 diffuse large B-cell lymphoma not otherwise specified (DLBCL-NOS) patients and 13 other PEL patients were enrolled in the present study. The abilities of reverse transcription quantitative PCR (RT-qPCR) and droplet digital PCR (ddPCR) to detect the MYD88L265P mutation in cerebral spinal fluid (CSF) samples were compared. The results suggested that ddPCR showed superior mutation detection sensitivity when compared with RT-qPCR (58 vs. 15%; P<0.05). The MYD88L265P mutation was significantly associated with increased MYD88 protein overexpression in PCNSL brain tissue samples (P<0.05). Analysis of MYD88L265P mutation status in CSF and vitreous fluid samples using ddPCR may be a promising technique for minimally invasive confirmation of PCNSL diagnosis.

Curative effect of methotrexate combined with teniposide in the treatment of primary central nervous system lymphoma.

The present study aimed to investigate the curative effect of high-dose methotrexate (HD-MTX) combined with teniposide (Vm26) vs. HD-MTX alone in the treatment of primary central nervous system lymphoma (PCNSL), in order to provide data for assisting decisions associated with clinical treatment. Data from 56 patients with PCNSL admitted in Shanghai Huashan Hospital (Shanghai, China) from January 2009 to December 2014 were included into the present study. Clinical data, curative effects and prognosis of patients in these two groups were retrospectively analyzed using SPSS 20 statistical software. In the HD-MTX+Vm26 group, 12 patients (42.85%) achieved complete remission (CR) and 10 patients (35.71%) achieved partial remission (PR), while in the HD-MTX group 7 patients (25%) achieved CR and 11 patients (39.29%) achieved PR (P=0.158). The median progression-free survival (PFS) time was 22 months in the HD-MTX+Vm26 group and 12 months in the HD-MTX group (P=0.019). The median overall survival time was 57 months in the HD-MTX+Vm26 group, and 28 months in the HD-MTX group (P=0.013). Compared with HD-MTX alone, the combined treatment of HD-MTX+Vm26 had an improved curative effect in the treatment of PCNSL, effectively controlled tumor progression in patients, prolonged survival time and improved prognosis. Age was an independent prognostic factor in patients with PCNSL. Patients with an age of ≤60 years exhibited longer PFS compared with patients with an age of >60 years.

Intraocular involvement is associated with a high risk of disease relapse in primary central nervous system lymphoma.

The aim of the present study was to prospectively evaluate the recurrence and survival outcome of primary central nervous system lymphoma (PCNSL) with intraocular involvement. For this purpose, a prospective cohort of 103 pathologically confirmed patients with PCNSL was enrolled in this study. Ophthalmologic examinations were performed both at diagnosis and during follow­up. The patients with PCNSL with suspected intraocular involvement underwent vitrectomy for confirmation. Patients who presented with intraocular involvement either at diagnosis or during disease progression were allocated to the intraocular lymphoma (IOL) group. All patients with PCNSL received systemic methotrexate (MTX)­based chemotherapy with or without radiotherapy. MTX intravitreal injection combined with systemic MTX­based chemotherapy was recommended once ocular lesions were confirmed. Recurrent intraocular and central nervous system (CNS) events, progression­free survival (PFS) and overall survival (OS) outcomes were analyzed. The findings of this study revealed that 21 patients with PCNSL exhibited intraocular involvement. One patient with IOL presented with isolated ocular lymphoma at the initial diagnosis, and the others presented with ocular involvement along with CNS invasion during the course of the disease. A total of 14 patients received systemic MTX­based chemotherapy prior to the diagnosis of IOL. The recurrence rates in patients with or without intraocular involvement were 71.4 and 46.3%, respectively (P=0.04) and the relapse sites in the patients with IOL included the brain (3 patients), eyes (6 patients), and both brain and eyes (6 cases). The median PFS was 13 months in the IOL group and 19 months in the patients without intraocular involvement (non­IOL) (P=0.019). The median OS was 51 months vs. 56 months, respectively (P=0.312). There was no significant difference in the 2­year PFS and OS rates between the 2 groups (23.8% vs. 23.2%, P=0.951; and 61.9% vs. 41.4%, P=0.093, respectively). On the whole, the findings of this study suggest that patients with IOL have a high risk of relapse and a poor PFS compared to patients without IOL, but a similar OS.

Methotrexate plus idarubicin improves outcome of patients with primary central nervous system lymphoma.

Primary central nervous system lymphoma (PCNSL) is a rare form of non-Hodgkin lymphoma with poor long-term survival. This study assessed methotrexate (MTX) plus idarubicin (IDA) in treating patients of PCNSL comparing to MTX alone therapy. A total of 100 patients were retrospectively enrolled and subjected to MTX alone (n = 52) and MTX plus IDA (n = 48). The completed response (CR) rate in patients treated with MTX plus IDA was 62.50%, and overall response (OR) rate was 79.17%, which in MTX alone cohort were 42.31% and 63.46% respectively. Median progression-free survival (PFS) of patients treated with MTX plus IDA was significantly better than those treated with MTX alone (18.35 months vs.8.45months, P = 0.000). The MTX plus IDA regimen exhibited a significantly better control of PCNSL. Further studies would be needed to confirm these results.

Aleukemic extramedullary T lymphoid/myeloid bilineage hematopoietic and lymphoid malignancy with progression to bilineage leukemia at relapse: A case report.

Bilineage T lymphoid and myeloid (T/My) neoplasms are rare entities among the hematopoietic and lymphoid malignancies. The majority of patients present with leukemic symptoms in which blasts are observed in the peripheral blood (PB) or bone marrow (BM) at a percentage of >20% of nucleated cells. Only a minimal number of cases of T/My bilineage hematopoietic and lymphoid malignancy have been reported with extramedullary infiltration as the initial symptom. The origin of the neoplastic cells in T/My bilineage malignancy has been documented as the hematopoietic stem cells. The present study reports the case of a 31-year-old man with a T/My bilineage malignancy, which initially showed cervical lymph node enlargement beyond the diagnostic criteria of leukemia in the PB and in the BM. Two distinct malignant populations were detected in the cervical lymph node and pleural effusion, one of which was positive for MPO-staining, while the other was positive for cytoplasmic cluster of differentiation 3. Mutations in platelet-derived growth factor receptor α, platelet-derived growth factor receptor ß, fibroblast growth factor receptor 1 and other chromosome abnormalities were excluded. The patient obtained complete remission after conventional chemotherapy, but relapsed with bilineage leukemia within a short period of time. Lymphoid and myeloid lineages have been reported to be differentiated from multipotent progenitors asymmetrically. However, the cellular mutation stage in T/My bilineage malignancy remains unclear. The present study also reviews the origin, development and therapeutic strategies for extramedullary T/My bilineage malignancy.

Dysfunction of microRNA-32 regulates ubiquitin ligase FBXW7 in multiple myeloma disease.

Dysfunction of microRNA (miRNA) expression has been associated with tumor occurrence, progression, and development. The aim of this work was to study the dysfunction of miR-32 - an miRNA that was abnormally regulated in different tumors - in clinical tissues from patients with multiple myeloma (MM). The tumor tissues in which we assessed miR-32 expression levels were collected during our 5 years of clinical practice. Our study found an increase in miR-32 expression in MM tissues. Assessment of F-box and WD repeat domain-containing 7 (FBXW7) in MM tissues showed an inverse relation between the expression of FBXW7 and miR-32. To further investigate the relation between miR-32 and FBXW7, cells were transfected with miR-32 or anti-miR-32. In vitro studies found that cells transfected with miR-32 showed a lower expression of FBXW7 and a higher expression of cancer-related proteins, c-Jun and c-Myc. In contrast, the cells transfected with anti-miR32 showed a relatively higher expression of FBXW7, but a lower expression of c-Jun and c-Myc. This study may offer perceptive insights into developing new strategies for MM cancer detection and therapy.

Functional engineered human cardiac patches prepared from nature's platform improve heart function after acute myocardial infarction.

With the advent of induced pluripotent stem cells and directed differentiation techniques, it is now feasible to derive individual-specific cardiac cells for human heart tissue engineering. Here we report the generation of functional engineered human cardiac patches using human induced pluripotent stem cells-derived cardiac cells and decellularized natural heart ECM as scaffolds. The engineered human cardiac patches can be tailored to any desired size and shape and exhibited normal contractile and electrical physiology in vitro. Further, when patching on the infarct area, these patches improved heart function of rats with acute myocardial infarction in vivo. These engineered human cardiac patches can be of great value for normal and disease-specific heart tissue engineering, drug screening, and meet the demands for individual-specific heart tissues for personalized regenerative therapy of myocardial damages in the future.