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Early diagnosis of vitreoretinal lymphoma (VRL) is critical for the successful treatment of this rare intraocular malignancy. However, fast and reliable diagnosis of VRL in patients presenting with intermediate or posterior non-infectious uveitis remains a challenge. A proliferation-inducing ligand (APRIL) and B-cell activating factor (BAFF) are vital factors in the pathophysiology, diagnosis, and prognosis of primary central nervous system lymphoma (PCNSL) and systemic autoimmune diseases. However, their utility as biomarkers for the diagnosis of VRL and uveitis remains unclear.In this retrospective study, we analyzed APRIL and BAFF levels in the aqueous humor (AH) of 43 eyes of 40 patients, including 23 eyes of 20 patients with VRL, eight eyes of eight patients with uveitis, and 12 eyes of 12 patients with other ocular diseases (OODs). Additionally, we measured their levels after induction of chemotherapy in five eyes of five patients with VRL.AH levels of APRIL reliably distinguished VRL from uveitis, with a specificity of 78.3% and sensitivity of 75%. BAFF also showed similar potential. Serial AH analysis of patients with VRL during chemotherapy demonstrated a corresponding decline in AH levels of APRIL and BAFF.This study extends the spectrum of valuable diagnostic biomarkers for VRL and uveitis. In patients with uveitis, the assessment of AH APRIL may help accelerate the diagnosis of VRL. Moreover, our results underline the important role of APRIL and BAFF in therapeutic monitoring of VRL.

Cerebrospinal fluid (CSF) free light chain (FLC) detection has been proposed as a tool for diagnosing primary central nervous system lymphoma (PCNSL), but there is no consensus on the appropriate reference range and its value for monitoring chemotherapy efficacy has not been investigated in Chinese PCNSL patients. We assessed the application potential of CSF FLC ratios for diagnosing PCNSL and monitoring associated treatment efficacy.Kappa (κ) and lambda (λ) FLC were measured by nephelometry in CSF samples of patients with PCNSL (n = 45), other neurological diseases (n = 30), and normal controls (n = 60). Results of κ/λ FLC ratios (FLCr) were correlated with patients' diagnoses and receiver operating characteristic analysis was used to determine accuracy. In PCNSL patients, FLCr analysis was compared between PCNSL before and after treatment.κ FLC and FLCr concentrations in PCNSL were significantly higher than in patients without PCNSL (P 0.05). The optimal cut-off for FLCr was 0.35, with diagnostic sensitivity and specificity of 78% and 72%, respectively. FLCr concentrations decreased after chemotherapy.CSF FLC is a novel biomarker for diagnosis and chemotherapy efficacy monitoring in PCNSL.

Marginal zone lymphoma (MZL) is an uncommon subtype of non-Hodgkin lymphoma (NHL). Combination of rituximab and cladribine (R-2CdA) is a potential option for indolent NHL (iNHL) and mantle cell lymphoma (MCL) patients. The goal of this multicenter retrospective study was to assess the efficacy and safety of R-2CdA in MZL to support consensus-reaching in first-line therapy in advanced-stage patients. We searched electronic medical records databases of eight centers in China. Between November 2014 and December 2019, 183 symptomatic advanced MZL patients (42 treated with R-2CdA and 141 with rituximab plus cyclophosphamide, adriamycin, vincristine, and prednisone [R-CHOP]) were identified. After propensity score matching (PSM) (1:1) to adjust for clinical characteristics, 39 patients from each treatment arm were selected. The overall response rate (ORR) (84.6% vs. 94.9%, P = 0.263) and complete response rate (59.0% vs. 66.7%, P = 0.487) were comparable between two protocols. Neither progression-free survival (PFS), including the 5-year PFS (67.7% vs. 56.1%, P = 0.352), nor overall survival was improved by R-2CdA versus R-CHOP. However, R-2CdA was more tolerable than R-CHOP in MZL patients regarding grade 3/4 hematological adverse events (odds ratio [OR] 0.565, 95% confidence interval [CI] neutropenic fever (OR 0.795, 95% CI 0.678-0.932), and infections (OR 0.800, 95% CI 0.640-1.000). Overall, our study demonstrated that R-2CdA is potentially as effective as but safer than R-CHOP in advanced MZL.

Predicting the clinical outcomes of primary diffuse large B-cell lymphoma of the central nervous system (PCNS-DLBCL) to methotrexate-based combination immunochemotherapy treatment in advance and therefore administering the tailored treatment to the individual is consistent with the principle of predictive, preventive, and personalized medicine (PPPM/3PM). The red blood cell distribution width (RDW) has been reported to be associated with the clinical outcomes of multiple cancer. However, its prognostic role in PCNS-DLBCL is yet to be evaluated. Therefore, we aimed to effectively stratify PCNS-DLBCL patients with different prognosis in advance and early identify the patients who were appropriate to methotrexate-based combination immunochemotherapy based on the pretreatment level of RDW and a clinical prognostic model.A prospective-retrospective, multi-cohort study was conducted from 2010 to 2020. We evaluated RDW in 179 patients (retrospective discovery cohorts of Huashan Center and Renji Center and prospective validation cohort of Cancer Center) with PCNS-DLBCL treated with methotrexate-based combination immunochemotherapy. A generalized additive model with locally estimated scatterplot smoothing was used to identify the relationship between pretreatment RDW levels and clinical outcomes. The high vs low risk of RDW combined with MSKCC score was determined by a minimalThe pretreatment RDW showed a U-shaped relationship with the risk of overall survival (OS,Based on the pretreatment RDW and MSKCC scores, a novel predictive tool was established to stratify PCNS-DLBCL patients with different prognosis effectively. The predictive model developed accordingly is promising to judge the response of PCNS-DLBCL to methotrexate-based combination immunochemotherapy treatment. Thus, hematologists and oncologists could tailor and adjust therapeutic modalities by monitoring RDW in a prospective rather than the reactive manner, which could save medical expenditures and is a key concept in 3PM. In brief, RDW combined with MSKCC model could serve as an important tool for predicting the response to different treatment and the clinical outcomes for PCNS-DLBCL, which could conform with the principles of predictive, preventive, and personalized medicine.The online version contains supplementary material available at 10.1007/s13167-022-00290-5.

Supplementary Data from Retinoblastoma Tumor Suppressor Gene Expression Determines the Response to Sequential Flavopiridol and Doxorubicin Treatment in Small-Cell Lung Carcinoma

BackgroundPrimary central nervous system lymphoma (PCNSL) is a highly aggressive non-Hodgkin’s B-cell lymphoma which normally treated by high-dose methotrexate (HD-MTX)-based chemotherapy. However, such treatment cannot always guarantee a good prognosis (GP) outcome while suffering several side effects. Thus, biomarkers or biomarker-based models that can predict PCNSL patient prognosis would be beneficial.MethodsWe first collected 48 patients with PCNSL and applied HPLC-MS/MS-based metabolomic analysis on such retrospective PCNSL patient samples. We then selected the highly dysregulated metabolites to build a logical regression model that can distinguish the survival time length by a scoring standard. Finally, we validated the logical regression model on a 33-patient prospective PCNSL cohort.ResultsSix metabolic features were selected from the cerebrospinal fluid (CSF) that can form a logical regression model to distinguish the patients with relatively GP (Z score ≤0.06) from the discovery cohort. We applied the metabolic marker-based model to a prospective recruited PCNSL patient cohort for further validation, and the model preformed nicely on such a validation cohort (AUC = 0.745).ConclusionsWe developed a logical regression model based on metabolic markers in CSF that can effectively predict PCNSL patient prognosis before the HD-MTX-based chemotherapy treatments.

Purpose An effective salvage regimen for the reinduction of remission is lacking for refractory or recurrent primary central nervous system lymphoma (r/r PCNSL). This study aimed to evaluate the efficacy and safety of high-dose cytarabine plus temozolomide in treating r/r PCNSL and to explore the associated prognostic factors. Methods A single-center retrospective cohort study was conducted to assess the efficacy and safety of high-dose cytarabine and temozolomide (AT) in r/r PCNSL patients. KIR and HLA genotyping was performed on peripheral blood samples from each patient. Results Thirty PCNSL patients receiving an AT regimen (cytarabine 3 g/m2 for 2 days combined with temozolomide 150 mg/m2 for 5 days) in our institution were analyzed. The median age was 65 years (range 25–79 years). A total of 43.4% of patients (13/30) achieved an overall response within a median follow-up of 16 months (95% confidence interval [CI]: 11–23 months). The median PFS and OS of the cohort were 1.75 months (95% CI: 1–4 months) and 19.5 months (95% CI: 11 months to not calculable), respectively. Patients harboring KIR3DL1/HLA-B genotypes predicting low affinity had a higher response rate (p = 0.042) and longer median PFS (3 months) than those with KIR3DL1/HLA-B genotypes predicting high affinity (1 month) (p = 0.0047). Cox regression analysis indicated that KIR/HLA-B genotypes were independently associated with PFS (p = 0.043). However, KIR/HLA-B genotypes had no impact on the OS of the cohort. The toxicity of AT treatment was mild and manageable. Conclusion The AT regimen was well tolerated, and patients with specific KIR-HLA genotypes may benefit from this regimen. Trial registration number: ChiCTR2100054482 Date of registration: 2021-12-18 Registration status: prospective registration

Purpose High-dose methotrexate (HD-MTX)-based chemotherapy regimen is the first-line treatment of primary central nervous system lymphoma (PCNSL). At present, doses of MTX in the range of 3.5-8 g/m2 are frequently used. However, the optimal dose of methotrexate for PCNSL remains controversial. The purpose of this real-world study was to compare the efficacy and toxicity of HD-MTX in patients with untreated PCNSL. Methods Immunocompetent adults with newly diagnosed PCNSL between January 2015 and December 2018 were investigated and followed up to June 2019. All patients' initial treatments were based on HD-MTX chemotherapy regimens. Results A total of 73 patients were reviewed. For patients who received HD-MTX at 8 g/m2 vs.3.5 g/m2, the complete response (CR) rates were 68.29% vs 43.75% (p = 0.03), and the median PFS times were 17.7 months vs 9.05 months (HR=0.455, 95% CI 0.239-0.865, p=0.016). There was no significant difference in OS between the two groups. Serious adverse effects were uncommon and clinically manageable. Conclusion There is a correlation of treatment response and clinical outcomes between the dosage of MTX in initial induction therapy in newly diagnosed PCNSL. MTX dose of 8 g/m2 provided a higher CR rate and PFS benefits with acceptable adverse effects.

Vitreoretinal lymphoma (VRL) can commonly masquerade as chronic idiopathic uveitis due to its nonspecific clinical presentation. Thus, its early diagnosis is difficult. In this study, new logistic regression models were used to classify VRL and uveitis. Additionally, the diagnostic performance of interleukin (IL)-10, the IL-10/IL-6, and the Interleukin Score for IntraOcular Lymphoma Diagnosis (ISOLD) are evaluated.Sixty-nine aqueous humors (AH) (46 VRL, 23 uveitis) and 65 vitreous humors (VH) (49 VRL, 16 uveitis) were collected from a single-center retrospective cohort. Logistic regression models were conducted based on IL-6 and IL-10. The cut-off values, area under the receiver operating characteristic curve (ROC) curve (AUC), sensitivity and specificity of IL-10, the IL-10/IL-6, the ISOLD, and the models were calculated from the ROC. Furthermore, Spearman's rank correlation analysis was performed to determine cytokine levels in VH and AH.We redefined the cut-off values of IL-10, the IL-10/IL-6, the ISOLD, and the logistic regression models. In AH, the AUC values of IL-10, ISOLD, IL10/IL6, and the model were 0.91, 0.953, 0.952, and 0.967. In VH, they were 0.93, 0.95, 0.954, and 0.954, respectively. IL-6 (r = 0.7844) and IL-10 (r = 0.8506) in AH and VH showed a strong correlation.IL-6 and IL-10 levels were introduced into new logistic regression models. The diagnostic efficacy of the models improved compared to the indicators mentioned above among Chinese patients. Additionally, the models could predict the probability of VRL more accurately. A strong correlation of cytokine levels showed the great potential of AH as prioritized auxiliary diagnostic for VRL.

Currently, risk stratification and prognosis stratification of primary central nervous system lymphoma (PCNSL) is predominantly based on the Memorial Sloan-Kettering Cancer Center (MSKCC) model, but the prognostic value is controversial. Recently, the systemic immune-inflammation index (SII) has been considered as an important prognostic factor in PCNSL. 174 newly diagnosed PCNSL patients treated with methotrexate-based combination immunochemotherapy were analyzed in two retrospective discovery cohorts (n=128) and one prospective validation cohort (n=46) to determine whether the SII-MSKCC model could better predict the clinical outcomes. Generalized additive model, Kaplan–Meier curve, and Cox analysis were performed. The scores of SII-MSKCC model were: 890>SII>450, score=0; SII＜450, score=1; SII>890, score=2; Age≦50, score=0; age >50 + KPS≧70, score=1; age >50 + KPS≦70, score=2. Here, we report the results of discovery cohort that SII-MSKCC model provided higher prognostic performance compared with the MSKCC model. We further validate the prognosis value of the SII-MSKCC model with an external dataset from an independent prospective cohort, which confirmed its robustness. In multivariable analysis, the SII-MSKCC model remained significantly independently associated with clinical outcomes. Thus, SII-MSKCC model could be used across centers to better predict prognosis in PCNSL.

Background Diffuse large B‐cell lymphoma (DLBCL) patients refractory to rituximab‐based immunochemotherapy have a dismal prognosis. However, the definition of refractory DLBCL remains inconsistent and no large cohort study data is available from Asian countries. To validate the definition and outcomes of refractory DLBCL in China, we conducted a multicenter, retrospective cohort study. Methods The REtrospective AnaLysis of Treatment REspoNse of refractory DLBCL (REAL‐TREND) study was performed using real‐world data from 8 centers in China. DLBCL patients with curative intent were included in the REAL‐TREND dataset. Overall survival (OS) was estimated using the Kaplan‐Meier method and compared by the log‐rank test. Due to heterogeneity in response rates among different centers, the response rates of refractory patients were pooled using random‐effect models. Multivariate survival analysis was performed using the Cox regression model. Results A total of 2778 DLBCL patients diagnosed between January, 2010 and December, 2015 were enrolled to this study. After validating previous definitions, the SCHOLAR‐1 study was most suitable to define refractory DLBCL. The estimated 5‐year cumulative incidence of refractory patients was 20% (95% confidence Interval [CI] = 18%‐22%). After the determination of refractory disease, overall response rate and complete remission rate were 30% (95% CI = 22%‐38%) and 9% (95% CI = 4%‐15%), respectively. Patients with either no response to immunochemotherapy or relapse within 12 months after stem‐cell transplantation had inferior survival with a median OS of 5.9 months (95% CI = 5.5‐7.1 months) and 2‐year OS rate of 16% (95% CI = 12%‐20%). International prognostic index score 4‐5 (hazard ratio [HR] = 2.22; 95% CI = 1.47‐3.35), central nervous system relapse (HR = 1.43; 95% CI = 1.04‐1.97), and best response status (HR = 2.68; 95% CI = 1.42‐5.03 for partial remission. HR = 5.97, 95% CI = 3.21‐11.11 for stable disease/progressive disease) were independent unfavorable prognostic factors. Conclusions This is the first large‐scale Asian cohort study focusing on outcomes of refractory DLBCL. The definition of the SCHOLAR‐1 study identifies patients with homogenously inferior survival, thus is appropriate to select refractory DLBCL. Due to poor clinical outcomes in the rituximab era, patients with refractory DLBCL may be potential candidates for novel treatment modalities.

Purpose An effective salvage regimen for re-induction of remission is lacking for refractory or recurrent primary central nervous system lymphoma (r/r PCNSL). This study aimed to evaluate the efficacy and safety of high dose cytarabine plus temozolomide in treating r/r PCNSL and explore the prognostic factors Methods A single-center retrospective cohort study was conducted to access the efficacy and safety of high dose cytarabine and temozolomide (AT) in r/r PCNSL patients. KIR and HLA genotyping were performed from peripheral blood sample of each patient. Results Thirty PCNSL patients receiving AT regimen (cytarabine 3g/m2 for 2 days combined with temozolomide 150mg/m2 for 5 days) in our institution were analyzed. The median age was 65 years (range 25–79 years). 43.4% of patients (13/30) achieved overall response with a median follow up of 16 months (95% confidence interval [CI]:11–23 months). The median PFS and OS of the cohort were 1.75 months (95% CI:1–4 months) and 19.5 months (95%CI:11 months to not calculable), respectively. Patients harboring KIR3DL1/HLA-B genotypes predicting low affinity had a higher response rate (p = 0.042) and longer median PFS (3 months) than those with KIR3DL1/HLA-B genotypes predicting high affinity (1 month) (p = 0.0047). Cox regression analysis indicated that KIR/HLA-B genotypes were independently associated with the PFS (p = 0.042). But it had no impact on the OS of the cohort. Toxicity of AT treatment was mild and manageable. Conclusion AT regimen was well tolerated and patients with specific KIR-HLA genotypes may benefit from it.

High-dose methotrexate (HD-MTX)-based chemotherapy regimen is the first-line option for primary central nervous system lymphoma (PCNSL). This prospective cohort study aimed to evaluate the efficacy and adverse effects of HD-MTX plus idarubicin (IDA) in patients with newly diagnosed immunocompetent PCNSL.We recruited newly diagnosed PCNSL patients from January 2017 to August 2020. Patients were assigned into two groups: HD-MTX monotherapy and HD-MTX plus IDA (HD-MTX/IDA). In the HD-MTX monotherapy group, patients were treated with MTX 8 g/mWe recruited 61 PCNSL patients, including 36 in the HD-MTX and 25 in the HD-MTX/IDA group. The CR rate was 68% in the HD-MTX/IDA group and 72.22% of patients in the HD-MTX monotherapy group (p = 0.7221), while the overall response rate was 72% vs. 77.78% (p = 0.6063). Median PFS in HD-MTX/IDA group and HD-MTX monotherapy group were 15.6 months and 18.5 months, respectively (p = 0.6374). Median OS was not reached in both groups. There were no significant differences in adverse effects between the two groups.The combination of IDA with HD-MTX showed no obvious therapeutic advantage over HD-MTX monotherapy in newly diagnosed patients with PCNSL. HD-MTX dose of 8 g/m

Purpose The pathological diagnosis of primary central nervous system lymphoma (PCNSL) by stereotactic brain biopsy and craniotomy is not often applicable due to the high cost and associated complications. In recent years, some biomarkers in cerebrospinal fluid (CSF), including interleukin 10 (IL-10), microRNAs, CXC chemokine ligand 13 (CXCL13), have been reported to be associated with PCNSL. However, this conclusion was controversial. Therefore, this study was to test whether Th17 cell-related cytokines could be used to distinguish PCNSL from other brain tumors. Patients and methods Th17 cell-related cytokines in CSF were measured in 108 patients with intracranial tumors, which included 66 PCNSL patients and 42 patients with other types of brain tumors. A receiver-operating characteristic (ROC) curve was utilized to analyze the diagnostic value of the cytokines based on the area under the curve (AUC). Results The CSF IL-10 level and IL-10/IL-6 ratios were significantly higher in PCNSL than in the other brain tumors (58.2 pg/mL VS 1.5 pg/mL, p=0.001; 24.3 VS 0.6, p=0.001). When the cutoff level of IL-10 was set at 8.3 pg/mL, its sensitivity and specificity for diagnosing PCNSL were 59.0% and 98%, respectively. The CSF IL-10 levels over 5pg/mL (+LR 12.3) were of significant value for the diagnosis of PCNSL. These parameters are highly valuable in PCNSL diagnosis, but their sensitivity is less valuable. The sensitivity of IL-4 and IL-17A, the ratio of mature lymphocytes and the monocytes/macrophages ratio in CSF were relatively high. In combination, the sensitivity increased by 15% and the specificity remained above 85%. The best combination was IL-10 and IL-17A, whose sensitivity was 70% and specificity was 96%. Conclusion The CSF level of IL-10 is a useful diagnostic biomarker in patients with PCNSL. The CSF levels of IL-4, IL-17A, mature lymphocytes and monocytes/macrophages can be used to increase the diagnostic value of CSF IL-10 level and IL-10/IL-6 ratio.

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

Xianjin Zhou,1– 3 Sha Tian,3 Xian Zhou,3 Huimin Shi,3 Yi Li,3 Jianjiang Xiao,3 Kun Chen,4 Bobin Chen,5 Gezhi Xu,1,2 Qingping Wang3 1Eye Institute, Eye and ENT Hospital, College of Medicine, Fudan University, Shanghai, People’s Republic of China; 2Shanghai Key Laboratory of Visual Impairment and Restoration, Science and Technology Commission of Shanghai Municipality, Shanghai, People’s Republic of China; 3Department of Ophthalmology, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China; 4Department of Laboratory Medicine, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China; 5Department of Hematology, Huashan Hospital, Fudan University, Shanghai, People’s Republic of ChinaCorrespondence: Qingping Wang, Department of Ophthalmology, Huashan Hospital, Fudan University, No. 12 Middle Urumqi Road, Shanghai, 200040, People’s Republic of China, Email wangqingping71@163.com Gezhi Xu, Department of Ophthalmology, Eye & ENT Hospital, Fudan University, No. 83 Fenyang Road, Shanghai, 200031, People’s Republic of China, Email drxugezhi@163.comPurpose: To describe the characteristic manifestations of vitreoretinal lymphoma (VRL) with optical coherence tomography (OCT) and monitor their outcomes after treatmEnt.Patients and Methods: Patients with primary central nervous system lymphoma (PCNSL) and intraocular involvement were assigned to the VRL group. OCT manifestations were analyzed and changes in abnormalities were recorded after intravitreal methotrexate injections. OCT manifestations of PCNSL patients without intraocular involvement were analyzed as well (non-VRL group).Results: There were 48 eyes with high-quality OCT records in the VRL group, of which 19 had abnormal manifestations. The most frequent abnormality was outer retina (OR) fuzzy borders (14 of 19, 73.7%). Other abnormalities included: focal subretinal deposits (8 of 19, 42.1%), hyperreflective subretinal dots (2 of 19, 10.5%), pigment epithelium detachment (PED) (5 of 19, 26.3%), preretinal deposits (5 of 19, 26.3%), epiretinal membrane (3 of 19, 15.8%), cystoid macular edema (3 of 19, 15.8%), subretinal fluid (3 of 19, 15.8%), outer retina atrophy (2 of 19, 10.5%), unilateral optic papilledema (2 of 19, 10.5%), retinal thickening (1 of 19, 5.3%), and subretinal fibrosis (1 of 19, 5.3%). Nine eyes with retinal abnormalities were receiving regular intravitreal methotrexate. The retinal structure of seven eyes (only outer retina involved) returned to almost normal on OCT images. The remaining two eyes (with severe retinal vasculitis) showed little improvement after treatment.Conclusion: OCT is helpful for the diagnosis of PCNSL with intraocular involvement and long-term follow-up of the disease.Summary Statement: The characteristic manifestations of vitreoretinal lymphoma (VRL) with optical coherence tomography (OCT) were described and their outcomes after treatment were monitored. These findings suggested that OCT is helpful for the diagnosis of PCNSL with intraocular involvement and long-term follow-up of the disease.Keywords: intravitreal injection, methotrexate, optical coherence tomography, primary central nervous system lymphoma, vitreoretinal lymphoma

Objective: Several population pharmacokinetic (popPK) models have been developed to determine the sources of methotrexate (MTX) PK variability. It remains unknown if these published models are precise enough for use or if a new model needs to be built. The aims of this study were to 1) assess the predictability of published models and 2) analyze the potential risk factors for delayed MTX elimination.Methods: A total of 1458 MTX plasma concentrations, including 377 courses (1–17 per patient), were collected from 77 patients who were receiving high-dose MTX for the treatment of primary central nervous system lymphoma in Huashan Hospital. PopPK analysis was performed using the NONMEM® software package. Previously published popPK models were selected and rebuilt. A new popPK model was then constructed to screen potential covariates using a stepwise approach. The covariates were included based on the combination of theoretical mechanisms and data properties. Goodness-of-fit plots, bootstrap, and prediction- and simulation-based diagnostics were used to determine the stability and predictive performance of both the published and newly built models. Monte Carlo simulations were conducted to qualify the influence of risk factors on the incidence of delayed elimination.Results: Among the eight evaluated published models, none presented acceptable values of bias or inaccuracy. A two-compartment model was employed in the newly built model to describe the PK of MTX. The estimated mean clearance (CL/F) was 4.91 L h−1 (relative standard error: 3.7%). Creatinine clearance, albumin, and age were identified as covariates of MTX CL/F. The median and median absolute prediction errors of the final model were -10.2 and 36.4%, respectively. Results of goodness-of-fit plots, bootstrap, and prediction-corrected visual predictive checks indicated the high predictability of the final model.Conclusions: Current published models are not sufficiently reliable for cross-center use. The elderly patients and those with renal dysfunction, hypoalbuminemia are at higher risk of delayed elimination.

Natural killer/T cell lymphoma (NKTCL) is a highly aggressive subtype of non-Hodgkin lymphoma. Gemcitabine, oxaliplatin, and L-asparaginase (GELOX) is one of the first-line chemotherapy regimens of NKTCL. Yet, the prognosis of NKTCL is poor. Icaritin is an herb-derived monomer from icariin with antitumor effects. We found that icaritin induced proliferation inhibition and apoptosis of NKTCL both

Objective: Acute myeloid leukemia (AML) is a clonal malignant hematological neoplasm with a poor prognosis and high heterogeneity. Many studies have been conducted on the diagnosis and treatment of AML, but the immune microenvironmental mechanisms underlying AML disease progression have not been fully elucidated. The aim of this study was to find the potential genes in tumor microenvironmental mechanisms underlying the initiation and progression of AML through relevant biological informatics analysis, and investigate the potential influence of the gene in tumor microenvironment (TME).Methods: AML samples of genes were retrieved from The Cancer Genome Atlas (TCGA) databases. The number of tumor-infiltrating immune cells (TIC) as well as immune and stromal components in AML cases was calculated using the ESTIMATE and CIBERSORT algorithms. Two methods, COX regression analysis and protein-protein interaction (PPI) network, were applied to obtain related genes, and the intersection of related genes was taken to obtain differentially expressed genes (DEGs). Gene Set Enrichment Analysis (GSEA) was used for explore the biological signaling pathway. CIBERSORT analysis for the proportion of TICs was performed to reveal that TICs which are related of the target gene.Results: Cross-tabulation analysis of univariate COX regression analysis and PPI network known the β2 integrin factor (ITGB2) as a major predictor of AML prognosis. High expression of ITGB2 was correlated with low survival of AML patients. GSEA revealed that the higher the ITGB2 gene expression, the more active the immune-related activity. CIBERSORT analysis of the TICs ratio revealed that 9 kinds of TICs were negatively correlated with the expression of ITGB2, including CD4 memory resting T cells, CD8 T cells, naive B cells, resting NK cells, Plasma cells, follicular helper T cells, resting Mast cells, Eosinophils and activated mast cells. Only monocytes were positively correlated with ITGB2 expression. These results provided further evidence that ITGB2 levels may determine the prognosis of AML patients by modulating the immune status of TME, which provides an additional suggestion for the treatment of AML.

Background Cutaneous leishmaniasis (CL) remains an important neglected tropical disease in Costa Rica, which has one of the largest burdens of this disease in Latin America. Methods We identified district-level hotspots of CL from 2006 to 2017 and conducted temporal analysis to identify where hotspots were increasing across the country. Results Clear patterns of CL risk were detected, with persistent hotspots located in the Caribbean region, where risk was also found to be increasing over time in some areas. Conclusions We identify spatiotemporal hotspots, which may be used in support of the leishmaniasis plan of action for the Americas.

Jingjing Ma,1,* Qing Li,1,* Jie Shao,1 Yan Ma,2 Zhiguang Lin,2 Hui Kang,1 Bobin Chen2 1Department of Hematology, Huashan Hospital North, Fudan University, Shanghai 201907, People’s Republic of China; 2Department of Hematology, Huashan Hospital, Fudan University, Shanghai 200040, People’s Republic of China*These authors contributed equally to this workCorrespondence: Bobin ChenDepartment of Hematology, Huashan Hospital, Fudan University, Shanghai 200040, People’s Republic of ChinaTel +86-21-52889999Email bbchen@fudan.edu.cnPurpose: The aim of this study was to identify the risk factors for central nervous system (CNS) involvement in systemic diffuse large B-cell lymphoma (DLBCL) patients and to explore prognostic for DLBCL patients with CNS involvement (relapse or progression).Patients and methods: This was a retrospective cohort study in our hospital. Data were collected from all DLBCL patients diagnosed in our institutes from January 2013 to June 2018. Clinical information was collected from medical records.Results: The participants included 138 patients with DLBCL. Among them, 38 patients were diagnosed as CNS lymphoma, including 15 patients exhibited CNS involvement while DLBCL was pathologically confirmed, and 23 patients developed CNS lymphoma during or after initial chemotherapy. The median disease-free interval to CNS involvement was 13 months. Multivariate analysis identified elevated serum lactate dehydrogenase (LDH) level [hazard ratio (HR)=4.035; 95% confidence interval (95% CI): 1.147–14.195] was an independent predictor of CNS involvement. The median progression-free survival (PFS) and overall survival (OS) time of DLBCL patients with CNS involved were 12.5 months and 22 months, respectively. Multivariate prognostic analysis showed that eastern cooperative oncology group (ECOG) score>2(P=0.018; HR=7.333; 95% CI: 1.424–42.002), elevated serum LDH level (P=0.046; HR=6.510; 95% CI: 1.035–40.949), deep lesion (P=0.005; HR=10.957; 95% CI: 2.050–58.569), and CNS with systemic involvement (P=0.023; HR=2.730; 95% CI: 1.151–6.479) were independent poor prognostic factors for the patients. The cases with lymphocyte absolute count >0.75×109/L (HR=0.047; 95% CI: 0.003–0.732) had better prognosis. The OS of DLBCL patients with secondary CNS lymphoma was inferior to DLBCL patients without CNS involvement. There was no significant difference between the patients with CNS and extra-CNS involvement. There was no significant difference between the patients with CNS involvement and stage III-IV DLBCL cases without CNS lymphoma.Conclusion: In conclusion, elevated serum LDH was independent high-risk factor for secondary CNS lymphoma. For DLBCL patients with CNS involvement, ECOG score>2, elevated serum LDH level, deep lesion, lymphocyte absolute count ≤0.75×109/L and CNS with systemic involvement retained a significant association with outcome.Keywords: diffuse large B-cell lymphoma, central nervous system involvement, risk factors, prognostic

To investigate the possible role of functional single nucleotide polymorphism (SNP) in circadian genes as prognostic markers of primary central nervous system lymphoma (PCNSL). We conducted a prospective study using data from Huashan Hospital 2006–2015 and followed up 91 PCNSL patients until June 30, 2016. The survival of patients with different prognostic factors was compared by log-rank test. Univariate and multivariate analyses were performed by Cox regression. During a long-term follow-up (6–110 months), overall survival (OS) was 32 months (95% CI, 13.3–91.1) and progression-free survival (PFS) was 23 months (95% CI, 9.0–41.0) for the entire cohort. Age (P = 0.046, P = 0.001) and performance status (PS) score (P = 0.013, P = 0.003) showed differences in OS and PFS. ABCB1 rs1045642 variant showed significant difference in PFS between patients with CC genotype and those with CT/TT genotypes (P = 0.020). In multivariate analysis, age (HR = 2.3; 95% CI, 1.2–4.2, P = 0.008), PS (HR = 2.4; 95% CI, 1.3–4.4, P = 0.007), and ABCB1 rs1045642 (HR = 1.9; 95% CI, 1.0–3.3, P = 0.036) were the independent risk factors for PFS. In our results, the most important prognostic factors associated with higher risk of progression were ABCB1 rs1045642 CC genotype, PS > 2, and older age.

Background Vitreoretinal lymphoma (VRL) is a subtype of central lymphoma, which at present is hard to diagnose. The gold standard of VRL diagnosis is vitreous cytology, but the vitreous specimen needs to be obtained by the invasive surgery of vitrectomy. Aqueous humor is easier to obtain, has better stability, and has a lower operating risk than vitreous specimens. Methods We studied the diagnostic value of interleukin 10 (IL-10), IL-10/ IL-6 ratio and interleukin score for intraocular lymphoma diagnosis (ISOLD) in both vitreous and aqueous humor for vitreoretinal lymphoma, to determine if aqueous humor could be used to assist in the diagnosis of vitreoretinal lymphoma (VRL) by detecting IL-6 and IL-10. Results The area under ROC curve (AUC) of vitreous fluid IL-10, IL-10/IL-6 ratio and ISOLD at the diagnosis of VRL diagnosis were 93.5%, 93.6% and 93.8%, respectively. The AUC of the aqueous humor IL-10, IL-10/IL-6 and ISOLD for VRL diagnosis were 83.8%, 72.8% and 85.9%, respectively. Conclusions Aqueous humor can thus replace vitreous humor as a potential sample type for the diagnosis of intraocular lymphoma.

Background Intravitreal methotrexate has been proven to be an effective treatment method for vitreoretinal lymphoma. However, keratopathy occurs as the major side effect during treatment in most cases. The purpose of this study is to describe the characteristics of primary central nervous system lymphoma (PCNSL) with intraocular involvement and to attempt to reduce the incidence of keratopathy caused by intravitreal methotrexate. Methods The medical records of 22 PCNSL patients with intraocular involvement (33 eyes) were reviewed. Patients were divided into two groups. Group A (22 eyes) received the induction-consolidation-maintenance regimen, which consisted of intravitreal methotrexate injection at a dosage of 400 μg/0.1 ml twice a week for the first four weeks, weekly for the following eight weeks, and then monthly for the last nine months. Patients with a poor systemic condition were assigned to Group B (8 eyes), who were started on the treatment protocol described above and switched directly to monthly injection (9 months) when ocular remission was achieved. Results Blurred vision (31%) and floaters (25%) were common presenting symptoms. Vitritis was the most common clinical sign and was present in 29 eyes (90%) on B-ultrasound examination. Diagnosis was made by 25G-pars plana vitrectomy, and most diagnoses were diffuse large B-cell lymphoma. Ocular remission was achieved after 8.2 (SD = 4.6) injections of methotrexate. The mean VA (visual acuity) was improved from LogMAR 0.65 to 0.3 (P = 0.002). Keratopathy was observed in 21 eyes (66%) after an average of 8.2 (SD = 2.3) injections. With a reduced injection frequency, the incidence of keratopathy was lowered from 86.4% (Group A) to 25.0% (Group B) without ocular recurrence during follow-up. Conclusions Intravitreal methotrexate is a safe, effective and flexible treatment for PCNSL patients with intraocular involvement. Keratopathy is the most common adverse effect and can be controlled by reducing the injection frequency.

POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) is a paraneoplastic syndrome driven by plasma cell dyscrasias. We report a patient with novel initial manifestation of polyneuropathy, which was considered due to Sjögren’s syndrome but with poor response to methylprednisolone (120 mg/d) and intravenous immunoglobulin (IVIg). Further investigation by imaging tests and following biopsy eventually confirmed the diagnosis of POEMS syndrome secondary to solitary plasmocytoma. To our knowledge, this is the first reported case of POEMS syndrome with Sjögren’s syndrome occurring in the absence of a peripheral monoclonal gammopathy, highlighting the diagnostic challenges posed by this disease and reviewing the diagnostic role of (18) F-FDG PET/CT in POEMS syndrome.

BACKGROUND/PURPOSE: There is currently no standard effective treatment for patients with relapsed/refractory primary central nervous system lymphoma (PCNSL). The prognosis is poor, so more studies are needed. Pemetrexed is similar to methotrexate in structure and can cross the blood-brain barrier. Compared with methotrexate, it has more targets and fewer side effects. Lenalidomide is a second generation immunomodulator with multiple functions, such as regulating immunity, anti-tumor and tumor microenvironment. A prospective observational study was conducted to explore the efficacy and safety of pemetrexed combined with lenalidomide in the treatment of relapsed/refractory primary central nervous system lymphoma. METHODS: This is a prospective observational study, we collected patients who had undergone whole brain radiotherapy and two or more chemotherapy regimens between January 2018 and December 2019 but still experienced disease progression or recurrence. each patient was treated with pemetrexed at a dose of 900mg/m2 and lenalidomide 25mg over 3 weeks as salvage chemotherapy, and one cycle consists of 4 weeks. Folic acid, vitamin B12 and dexamethasone were used to induce toxicities to pemetrexed given before chemotherapy. Oral aspirin was used to prevent thrombosis caused by lenalidomide. Adverse events were recorded in each patient during inpatients, outpatient or telephone follow-up. RESULTS: A total of 38 patients with recurrent/refractory PCNSL were enrolled in our study, including 26 males and 12 females with a median age of 57 (range from 33 to 73) years old. After treatment, the overall response rate was 68.4%(Table 1). The median progression free survival (PFS) time was 6 months and median overall survival (OS) time was 14 months (Figure1, Figure2). The adverse events mainly included fatigue, gastrointestinal reaction, myelosuppression, thrombocytopenia, fever and infection. After long-term or short-term chemotherapy, the patients had different degrees of myelosuppression symptoms presented as leukopenia (six cases in grade 1 and one case in grade 3), neutropenia (six cases in grade 1 and two cases in grade 3), anemia (6 cases in grade 1), thrombocytopenia (1 case in grade 2 and 3 cases in grade 3). Nausea and vomiting, as the common gastrointestinal reaction, appeared in two (grade 1) and one (grade 2) cases, respectively. One patient died of severe pneumonia infection. Three cases developed grade 1 cardiac disorder, including asymptomatic sinus bradycardia and asymptomatic ventricular premature beat, respectively. In addition, other reactions including fatigue (four cases in grade 1 and one case in grade 2), fever (four cases). All patients had no abnormal liver function, kidney function, constipation and leukoencephalopathy (Table 2). CONCLUSION: This study has been the first prospective clinical study of pemetrexed combined with lenalidomide in the treatment of patients with relapsed/refractory PCNSL in international. The results indicate that chemotherapy with pemetrexed combined with lenalidomide may be an effective therapy for the treatment of relapsed/refractory PCNSL with modest toxicity. KEYWORDS: Primary central nervous system lymphoma; Relapse/refractory; Pemetrexed combined with lenalidomide; Efficacy; Safety Disclosures No relevant conflicts of interest to declare.