Chemotherapy with the use of next-generation tyrosine kinase inhibitors based on measurable residual disease has the potential to avoid hematopoietic stem cell transplantation in treatment for adults with Philadelphia chromosome-positive acute lymphoblastic leukemia.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) as postremission treatment is recommended for Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) in current guidelines. However, comparisons of later generation tyrosine kinase inhibitors (TKIs) plus chemotherapy with allo-HSCT have yielded similar outcomes. This meta-analysis was performed to evaluate allo-HSCT in first complete remission (CR1) versus chemotherapy for adult Ph+ ALL in the TKI era. METHODS: Pooled assessment of the hematologic and molecular complete response rates was performed after 3-month TKI treatment. Hazard ratios (HRs) were determined for disease-free survival (DFS) and overall survival (OS) benefit with allo-HSCT. The effect of measurable residual disease status on survival benefit was also analyzed. RESULTS: Thirty-nine retrospective and prospective single-arm cohort studies involving 5054 patients were included. Combined HRs indicated that in the general population, allo-HSCT favorably influenced DFS and OS. Achieving complete molecular remission (CMR) within 3 months after starting induction was a favorable survival prognostic factor regardless of whether the patient had undergone allo-HSCT. Among the patients with CMR, survival rates in the nontransplant subgroup were comparable with those in the transplant subgroup, with the estimated 5-year OS of 64% versus 58% and 5-year DFS of 58% versus 51%, respectively. The use of next-generation TKIs results in a higher proportion of patients achieving CMR (ponatinib 82% vs. imatinib 53%), while improving survival in nontransplant patients. CONCLUSION: Our novel findings suggest that combination chemotherapy plus TKIs leads to a comparable survival benefit as with allo-HSCT for MRD-negative (CMR) patients. This study provides novel evidence for allo-HSCT indications for Ph+ ALL in CR1 in the TKI era.

Dasatinib plus prednisone as induction and consolidation for adults with Ph-positive acute lymphoblastic leukaemia: A single-arm, multicentre, phase 2 trial.

To reducing chemotherapy-related toxicity, the chemo-free regimens become a new trend of Ph + ALL treatment. Therefore, we conducted a phase 2 trial of dasatinib plus prednisone, as induction (Course I) and early consolidation (Courses II and III) treating newly diagnosed Ph + ALL. The trial was registered at www.chictr.org.cn, ChiCTR2000038053. Forty-one patients were enrolled from 15 hospitals. The complete remission (CR) was 95% (39/41), including two elderly induction deaths. By the end of Course III, 25.6% (10/39) of patients achieved a complete molecular response. With a median follow-up of 15.4 months, 2-year disease-free survival (DFS) were 100% and 33% for patients who receiving haematopoietic stem cell transplantation (HSCT) at CR1 and receiving chemotherapy alone respectively. When censored at time of HSCT, 2-year DFS were 51% and 45% for young and elderly patients (p = 0.987). 2-year overall survival were 45%, 86% and 100% for patients without HSCT, receiving HSCT after relapse and receiving HSCT at CR1 respectively. A total of 12 patients had marrow recurrences and one had CNS relapse, with 38% occurred early (between Courses I and III). IKZF1 gene deletion was shown to be associated with relapse (p = 0.019). This chemo-free induction and early consolidation regimen was efficacious and well-tolerated in de novo Ph + ALL. Allogeneic HSCT conferred definite survival advantage after chemo-free induction.

Significance of initial, interim and end-of-therapy 18F-FDG PET/CT for predicting transformation risk in follicular lymphoma.

BACKGROUND: Histological transformation (HT) of follicular lymphoma to a more aggressive lymphoma is a serious event affecting patients' outcomes. To date, no strong clinical HT predictors present at diagnosis have yet been identified. The fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) is highlighted as a non-invasive diagnostic tool for the detection of HT, but its ability to predict HT at early stage of disease has not been clear. Therefore, this study investigated the predictive values of the pre-transformation standardized uptake value (SUVmax) for the risk of transformation in FL. METHODS: This retrospective study involved 219 patients with FL between June 2008 and October 2019 who had undergone 18F-FDG PET/CT scan. One hundred and thirty-two, 64, and 78 patients underwent PET at baseline (PETbaseline), interim (PETinterim) and end-of-induction therapy (PETend), respectively. Qualitative assessment was performed using the 5-point Deauville scale. Statistical analysis was done using Cox regression models, receiver operating characteristic (ROC) analysis, and Kaplan-Meir survival curves. RESULTS: Of the 219 patients included, 128 had low-grade FL (grade 1-2) and 91 had high-grade FL (grade 3a). HT eventually occurred in 30 patients. The median time to HT was 13.6 months. Among clinical indicators, advance pathological grade was shown as the most significant predictor of HT (HR = 4.561, 95% CI 1.604-12.965). We further assessed the relationship between PET and HT risk in FL. Univariate Cox regression determined that SUVbaseline and SUVend were significant predictors for HT, while neither SUVinterim nor qualitative assessment of Deauville score has predictive value for HT. Due to the noticeable impact of high pathological grade on the HT risk, we conducted the subgroup analysis in patients with low/high pathological grade, and found SUVbaseline could still predict HT risk in both low-grade and high-grade subgroups. Multivariate analysis adjusted by FLIPI2 score showed the SUVbaseline (HR 1.065, 95% CI 1.020-1.111) and SUVend (HR 1.261, 95% CI 1.076-1.478) remained as significant predictors independently of the FLIPI2 score. According to the cut-off determined from the ROC analysis, increased SUVbaseline with a cutoff value of 14.3 and higher SUVend with a cutoff value of 7.3 were highly predictive of a shorter time to HT. CONCLUSIONS: In follicular lymphoma, quantitative assessment used SUVmax at the pre-treatment and end-of-treatment PET/CT scan may be helpful for early screen out patients at high risk of transformation and guide treatment decisions.

Fatal hemorrhagic pneumonia in patients with hematologic diseases and Stenotrophomonas maltophilia bacteremia: a retrospective study.

BACKGROUND: Fatal hemorrhagic pneumonia is one of the most severe manifestations of Stenotrophomonas maltophilia (SM) infections. Here, we aimed to investigate the clinical characteristics of SM bacteremia and to identify the risk factors of hemorrhagic pneumonia caused by SM in patients with hematologic diseases. METHODS: The clinical records of 55 patients diagnosed with hematologic diseases and SM bacteremia were retrospectively reviewed. We compared patients' clinical characteristics and outcomes between the hemorrhagic pneumonia group and non-hemorrhagic pneumonia group. RESULTS: Twenty-seven (49.1%) patients developed hemorrhagic pneumonia. The overall mortality rate of SM bacteremia was 67.3%. Hemorrhagic pneumonia (adjusted HR 2.316, 95% CI 1.140-4.705; P = 0.020) was an independent risk factor of 30-day mortality in hematological patients with SM bacteremia. Compared with the non-hemorrhagic pneumonia group, patients in the hemorrhagic pneumonia group were older and showed clinical manifestations as higher proportions of isolated SM in sputum culture, neutropenia and elevated procalcitonin (PCT). Multivariate analysis showed that neutropenia, high levels of PCT, prior tigecycline therapy within 1 month were independent risk factors associated with hemorrhagic pneumonia. CONCLUSIONS: Neutropenia, high level of PCT and prior tigecycline therapy within 1 month were significant independent predictors of hemorrhagic pneumonia in hematologic patients with SM bacteremia. Due to no effective antibiotics to prevent hemorrhagic pneumonia, prophylaxis of SM infection and its progression to hemorrhagic pneumonia is particularly important.

A megakaryocyte morphological classification-based predictive model for steroid sensitivity in primary immune thrombocytopenia.

The first-line therapy for primary immune thrombocytopenia (ITP) is steroids, but about one-third of patients do not respond to steroids. Recent studies have shown megakaryocyte (MK) growth and development abnormalities and poorly compensated thrombopoiesis. Here, we attempted to determine the impact of MK morphological classification on steroid response. We enrolled 170 adult patients with primary ITP and divided them into steroid-sensitive ITP (109/170) and non-steroid-sensitive ITP (61/170) groups. In the univariate logistic model, female, reduced thrombocytogenic MK count (TMC), increased granular MK count to total MK count ratio (GMC/TM ratio), and elevated naked nucleus MK count to TM count ratio were significantly associated with steroid-sensitive ITP. In the multivariate logistic model, sex, reduced TMC, and increased GMC/TM ratio were independent predictors of steroid-sensitive ITP diagnosis. Based on the regression parameters, we established a predictive index with weighted risk score of 1 assigned each to sex, TMC, and GMC/TM ratio. A predictive index ≥2 points had the best area under the curve value (0.63) with 47.7% sensitivity and 78.7% specificity for predicting steroid sensitivity. These findings may help guide early treatment strategies in ITP.

Source-Free Active Domain Adaptation via Augmentation-Based Sample Query and Progressive Model Adaptation.

Active domain adaptation (ADA), which enormously improves the performance of unsupervised domain adaptation (UDA) at the expense of annotating limited target data, has attracted a surge of interest. However, in real-world applications, the source data in conventional ADA are not always accessible due to data privacy and security issues. To alleviate this dilemma, we introduce a more practical and challenging setting, dubbed as source-free ADA (SFADA), where one can select a small quota of target samples for label query to assist the model learning, but labeled source data are unavailable. Therefore, how to query the most informative target samples and mitigate the domain gap without the aid of source data are two key challenges in SFADA. To address SFADA, we propose a unified method SQAdapt via augmentation-based Sample Query and progressive model Adaptation. In specific, an active selection module (ASM) is built for target label query, which exploits data augmentation to select the most informative target samples with high predictive sensitivity and uncertainty. Then, we further introduce a classifier adaptation module (CAM) to leverage both the labeled and unlabeled target data for progressively calibrating the classifier weights. Meanwhile, the source-like target samples with low selection scores are taken as source surrogates to realize the distribution alignment in the source-free scenario by the proposed distribution alignment module (DAM). Moreover, as a general active label query method, SQAdapt can be easily integrated into other source-free UDA (SFUDA) methods, and improve their performance. Comprehensive experiments on multiple benchmarks have shown that SQAdapt can achieve superior performance and even surpass most of the ADA methods.

Domain Adaptation via Prompt Learning.

Unsupervised domain adaptation (UDA) aims to adapt models learned from a well-annotated source domain to a target domain, where only unlabeled samples are given. Current UDA approaches learn domain-invariant features by aligning source and target feature spaces through statistical discrepancy minimization or adversarial training. However, these constraints could lead to the distortion of semantic feature structures and loss of class discriminability. In this article, we introduce a novel prompt learning paradigm for UDA, named domain adaptation via prompt learning (DAPrompt). In contrast to prior works, our approach learns the underlying label distribution for target domain rather than aligning domains. The main idea is to embed domain information into prompts, a form of representation generated from natural language, which is then used to perform classification. This domain information is shared only by images from the same domain, thereby dynamically adapting the classifier according to each domain. By adopting this paradigm, we show that our model not only outperforms previous methods on several cross-domain benchmarks but also is very efficient to train and easy to implement.

Cancer cell membrane-wrapped nanoparticles for cancer immunotherapy: A review of current developments.

Background: As the forefront of nanomedicine, bionic nanotechnology has been widely used for drug delivery in order to obtain better efficacy but less toxicity for cancer treatments. With the rise of immunotherapy, the combination of nanotechnology and immunotherapy will play a greater potential of anti-tumor therapy. Due to its advantage of homologous targeting and antigen library from source cells, cancer cell membrane (CCM)-wrapped nanoparticles (CCNPs) has become an emerging topic in the field of immunotherapy. Key scientific concepts of review: CCNP strategies include targeting or modulating the tumor immune microenvironment and combination therapy with immune checkpoint inhibitors and cancer vaccines. This review summarizes the current developments in CCNPs for cancer immunotherapy and provides insight into the challenges of transferring this technology from the laboratory to the clinic as well as the potential future of this technology. Conclusion: This review described CCNPs have enormous potential in cancer immunotherapy, but there are still challenges in terms of translating their effects in vitro to the clinical setting. We believe that these challenges can be addressed in the future with a focus on individualized treatment with CCNPs as well as CCNPs combined with other effective treatments.

Distinct outcomes, ABL1 mutation profile, and transcriptome features between p190 and p210 transcripts in adult Philadelphia-positive acute lymphoblastic leukemia in the TKI era.

BACKGROUND: The differential signaling and outcome of patients with p190 or p210 transcripts of BCR-ABL1 have been systematically investigated in chronic myeloid leukemia rather than in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). METHODS: We analyzed the outcomes and ABL1 mutation profiles in 305 consecutive adult patients with Ph+ ALL treated with chemotherapy plus tyrosine kinase inhibitors. We also studied transcriptome features in two newly diagnosed patients with p190 and p210 using single-cell RNA sequencing (scRNA-seq). RESULTS: P190 and p210 were found in 199 (65%) and 106 (35%) patients, respectively. Compared to patients with p190, a higher white blood cell count (p = 0.05), platelet count (p = 0.047), BCR-ABL1 transcript level (p < 0.001), and lower bone marrow blasts (p = 0.003) were found in patients with p210. Patients with p210 had fewer types of ABL1 mutations (4 vs. 16) and a higher prevalence of T315I and E225K/V mutations (91.3% vs. 68.6%; p = 0.031). Patients with p210 had a similar complete remission rate (91.0% vs. 90.1%; p = 0.805) but a lower complete molecular remission rate at 1 month (9.9% vs. 22.0%; p = 0.031) compared with p190. Patients with p210 had lower 3-year overall survival (OS) and disease-free survival (DFS) rates than those with p190 (3-year DFS: 10.4% vs. 9.2%, p = 0.069, 3-year OS: 44.3% vs. 38.2%, p = 0.018, respectively). Multivariate analysis revealed that p210 was independently associated with worse OS [HR 1.692 (95% CI 1.009-2.838), p = 0.046]. Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) was associated with a better prognosis in patients with p210 (p < 0.0001). In addition, scRNA-seq data showed distinct molecular and cellular heterogeneity between bone marrow cells of the two transcripts. CONCLUSIONS: Ph+ ALL patients with p190 and p210 had different clinical characteristics, outcomes, ABL1 mutation profiles, and transcriptome features. Allo-HSCT could improve the outcomes of patients with p210.

The favorable prognostic value of the loss of sex chromosomes in patients with t(8;21) acute myeloid leukemia: an exploratory study.

BACKGROUND: Acute myeloid leukemia (AML) with t(8;21) is generally associated with a favorable clinical course. Loss of sex chromosome (LOS) are frequently observed in t (8;21) AML, but the prognostic value of LOS remains uncertain. METHODS: A total of 73 patients with AML with t(8;21) were studied and divided into t(8;21) with LOS group (n = 36) and t(8;21) alone group (n = 37). The patients with t(8;21) AML with ACAs other than LOS were excluded. The clinical characteristics of these two groups were compared, and the prognostic value of LOS was evaluated based on disease-free survival (DFS) and overall survival (OS). RESULTS: The clinical characteristics (except for gender) were found to have no significant difference between these two groups, and the male patients tended to account for a larger proportion in the former group (P = .001). The OS of the t(8;21) AML with LOS group was significantly longer than that of the t(8;21) AML alone group (P = .005). While not obvious, the patients with LOS seemed to have longer DFS (P = .061). The multivariable analysis also showed LOS to be an independent favorable prognostic factor of t(8;21) AML (P = .022). CONCLUSIONS: Our results suggested that LOS could be associated with a favorable prognosis in t(8;21) AML patients without other ACAs, and for this subtype of AML, longer DFS and a satisfactory and stable survival can be achieved with high-dose cytarabine (HDAC) consolidation treatment.

Treatment-Related Adverse Events of Chimeric Antigen Receptor T-Cell (CAR T) in Clinical Trials: A Systematic Review and Meta-Analysis.

Chimeric antigen receptors T (CAR-T) cell therapy of cancer is a rapidly evolving field. It has been shown to be remarkably effective in cases of hematological malignancies, and its approval by the FDA has significantly increased the enthusiasm for wide clinical usage and development of novel CAR-T therapies. However, it has also challenged physicians and investigators to recognize and deal with treatment-associated toxicities. A total of 2592 patients were included from 84 eligible studies that were systematically searched and reviewed from the databases of PubMed, de, the American Society of Hematology and the Cochrane Library. The meta-analysis and subgroup analysis by a Bayesian logistic regression model were used to evaluate the incidences of therapy-related toxicities such as cytokine release syndrome (CRS) and neurological symptoms (NS), and the differences between different targets and cancer types were analyzed. The pooled all-grade CRS rate and grade ≥ 3 CRS rate was 77% and 29%, respectively, with a significantly higher incidence in the hematologic malignancies (all-grade: 81%; grade ≥ 3: 29%) than in solid tumors (all-grade: 37%; grade ≥ 3: 19%). The pooled estimate NS rate from the individual studies were 40% for all-grade and 28% for grade ≥ 3. It was also higher in the hematologic subgroup than in the solid tumors group. The subgroup analysis by cancer type showed that higher incidences of grade ≥ 3 CRS were observed in anti-CD19 CAR-T therapy for ALL and NHL, anti-BCMA CAR-T for MM, and anti-CEA CAR-T for solid tumors, which were between 24-36%, while higher incidences of grade ≥ 3 NS were mainly observed in CD19-ALL/NHL (23-37%) and BCMA-MM (12%). Importantly, subgroup analysis on anti-CD19 CAR-T studies showed that young patients (vs. adult patients), allologous T cell origin (vs. autologous origin), gamma retrovirus vector, and higher doses of CAR-T cells were associated with high-grade CRS. On the other hand, the patients with NHL (vs ALL), administered with higher dose of CAR-T, and adult patients (vs. young patients) had an increased incidence of grade ≥ 3 NS events. This study offers a comprehensive summary of treatment-related toxicity and will guide future clinical trials and therapeutic designs investigating CAR T cell therapy.

Synchronous diagnosis and treatment of acute myeloid leukemia and chronic lymphocytic leukemia: Two case reports.

BACKGROUND: The concurrence of acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) is rare. Previous reports of such cases have focused mainly on clinical diagnosis and characteristics, so the mechanism remains unclear, and therapy options have been poorly explored. CASE SUMMARY: Here, we report two cases of synchronous AML and CLL. Flow cytometry revealed two distinct abnormal cell populations (myeloblasts and lymphoid cells) according to scatter characteristics. CD5-positive B cell lymphoma with myeloid leukemia invasion was observed on lymph node biopsy. Chemotherapy regimens indicated for both AML and CLL were used in our patients, and our patients achieved complete response after chemotherapy. Next-generation sequencing of 88 genes was performed. CONCLUSION: We conclude that early mutation and dysregulation at the hematopoietic stem cell stage and the accumulation of multiple rearrangements may cause the concurrence of CLL and AML. The treatment of infection and combination therapy aimed at the CLL component are significant in the management of patients with concurrent CLL and AML.

Survival Benefit and Efficiency of Low Dose Decitabine With CEG Regimen Compared to Decitabine Alone in the Elderly MDS - A Multicenter, Retrospective Study.

BACKGROUND: Decitabine are used in the treatment of myelodysplastic syndrome (MDS), but none trials reported overall survival improvement. METHODS: High-risk MDS and MDS transformed AML (sAML) patients (IPSS-R > 4.5, age above 60 years) in 6 medical centers of China were treated and compared a new regimen (decitabine with CEG) consisted of low dose decitabine (15 mg/m2, days 1-3), low dose etoposide (30 mg/m2, days 4,6,8,10,12), cytarabine (10 mg/m2 per day, days 4-12) and granulocyte colony-stimulating factor (G-CSF, 5ug/kg, adjusted by patients' WBC level, 12 hours prior to decitabine administration) with decitabine alone. The endpoints were death and disease progression. RESULTS: The baseline characteristics of these 2 groups were equivalent and none patients received prior chemotherapy. The treatment response rate (P= .048) and progression free survival (PFS, P = .030) all demonstrated significant improvement compared with decitabine alone. Decitabine with CEG regimen had attained a CR rate of 45.7%, a median OS of 36 (19-53) months and a median PFS of 34 (16.7-51.3) months in high-risk MDS patients, a CR rate of 40% in sAML. While decitabine alone only attained a median OS of 26 (24.5-27.5) months and a CR rate of 18.2% as well as a median progression free survival of 20 (17.6-22.4) months in MDS patients. Treatment response to CR or PR and TP53 mutation were 2 prognostic factor for OS and PFS in decitabine with CEG regimen. CONCLUSION: Decitabine with CEG regimen showed some promising advantage in elderly, high-risk MDS.

Complete response to trastuzumab and chemotherapy in recurrent urothelial bladder carcinoma with HER2 gene amplification: A case report.

BACKGROUND: Targeted treatments may greatly affect the natural history of urothelial carcinoma based on their pharmacokinetics. A phase II trial has explored the combination of cytotoxic chemotherapy with the anti-HER-2 monoclonal antibody trastuzumab in selected patients with metastatic bladder cancer, but it failed. CASE SUMMARY: Here, we report a case of recurrent urothelial bladder carcinoma (UBC) in a patient who has undergone three operations, and further illuminate its diagnosis and treatment. The diagnosis of UBC was rendered according to the pathological indices. Next-generation sequencing on formalin fixed paraffin-embedded (FFPE) tissue was also performed and suggested HER2 gene amplification in the FFPE tissue. Based on HER2 gene amplification in FFPE, the patient was treated with chemotherapy in combination with trastuzumab after his third surgery. Fortunately, the patient got a clinically complete remission to trastuzumab for 34 mo. CONCLUSION: There is not enough clinical evidence for incorporating trastuzumab in routine treatment of UBC. This case hinted that recurrent UBC patients with HER2 gene amplification may benefit from targeted trastuzumab. Further studies are needed to further investigate the status of HER2 gene and better determine trastuzumab in the management of UBC.

Prognostic significance of a normal karyotype in adult patients with BCR-ABL1-positive acute lymphoblastic leukemia in the tyrosine kinase inhibitor era.

OBJECTIVE: The occurrence of cryptic Philadelphia (Ph) chromosome translocation is rare in BCR-ABL1-positive acute lymphoblastic leukemia (BCR-ABL1+ ALL) and is of unknown significance in the tyrosine kinase inhibitor (TKI) era. METHODS: We retrospectively studied a series of adult patients receiving TKI-based therapy to evaluate the prognostic impact of the normal karyotype (NK) (n=22) in BCR-ABL1+ ALL by comparison with the isolated Ph+ karyotype (n=54). RESULTS: There were no statistically significant differences in clinical characteristics and complete remission rate between the two groups. Compared with the isolated Ph+ group, the NK/BCR-ABL1+ group had a higher relapse rate (55.0% versus 29.4%, p=0.044). Overall survival (OS) and disease-free survival (DFS) were significantly shorter in the NK/BCR-ABL1+ group than in the isolated Ph+ group [median OS: 24.5 versus 48.6 (months), p=0.013; median DFS: 11.0 (months) versus undefined, p=0.008]. The five-year OS and DFS for patients with NK/BCR-ABL1+ were 19.2% and 14.5%, respectively; those for patients with isolated Ph+ were 49.5% and 55.7%, respectively. Thirty-four (44.7%) patients underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) in this study. Among the patients who received allo-HSCT, the median OS and DFS in the NK/BCR-ABL+ group (n=9) were 35.5 and 27.5 months, respectively, while those in the isolated Ph+ group (n=25) were undefined. There was a trend of significant statistical difference in the OS between the two subgroups (p=0.066), but no significant difference in the DFS. Multivariate analysis revealed that NK was independently associated with worse OS and DFS in BCR-ABL1+ ALL patients [Hazard ratio (HR) 2.256 (95% confidence interval (CI), 1.005-5.066), p=0.049; HR 2.711 (95% CI, 1.319-5.573), p=0.007]. CONCLUSION: Our results suggest that the sub-classification of an NK could be applied in the prognostic assessments of BCR-ABL1+ ALL. In addition, allo-HSCT should be actively performed to improve prognosis in these patients.

Prognostic value of tissue-infiltrating immune cells in tumor microenvironment of follicular lymphoma: A meta-analysis.

BACKGROUND: The follicular lymphoma (FL) microenvironment is composed of follicular dendritic cells (FDCs), tumor-infiltrating CD4/CD8+ T cells (TILs), follicular regulatory T (Treg) cells, lymphoma-associated macrophages (LAMs), and immune checkpoint-related immune cells, all of which are relevant in the prognosis of FL, but their results remain controversial. Therefore, we performed this systematic review to explore the relationship between the FL microenvironment and prognosis. METHODS: Relevant studies were identified from PubMed, EMBASE and the Cochrane Library. Twenty-three trials involving 3336 patients with FL were included for analysis. RESULTS: This meta-analysis confirmed the unfavorable prognostic role of high CD21+/CD23+ FDC density in overall survival (OS) and progression-free survival (PFS). CD8+ or granzyme B+ TILs instead of CD4+ TILs are indicators for good OS. FoxP3+ Treg cells was not associated with prognosis, and even in subgroup analysis neither the number of cells nor the infiltration pattern had predictive value. A high degree of CD68+ macrophage infiltration was a negative prognostic factor for OS, but was associated with good prognosis in the rituximab-era subgroup. Although there was no correlation between PD1-positive immune cells and prognosis, subtypes with the follicular helper T (TFH) or exhausted T cell (TEX) phenotype tended to influence prognosis. The HR in the short time to transformation (TTT) analyses suggested that high CD68+ LAM numbers, diffuse pattern of FOXP3+ Treg cells and PD1+ cells, and high PD-L1 cell numbers are adverse factors leading to early transformation. CONCLUSIONS: Multiple tissue-infiltratingimmune cells in microenvironment play critical and different roles in FL prognosis.

Hypertriglyceridemia in Newly Diagnosed Acute Promyelocytic Leukemia.

The primary aim of the present retrospective study was to investigate lipid profiles and kinetics in acute promyelocytic leukemia (APL) patients. We analyzed 402 newly diagnosed APL patients and 201 non-APL patients with acute myeloid leukemia (as control). Incidence of hypertriglyceridemia in APL patients and non-APL patients was 55.82% and 28.4% (p = 0.0003). The initial levels of triglycerides, total cholesterol, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol were higher in APL patients than in control (all p < 0.0001). In APL patients, triglyceride levels were significantly increased during induction treatment with all-trans retinoic acid and arsenic. Multivariable analysis showed that age, being overweight (body mass index ≥25) and APL were independent risk factors for hypertriglyceridemia in all patients before treatment. High triglyceride levels were not significantly associated with disease-free survival or overall survival in the APL patients. In summary, in the current study triglyceride levels were significantly elevated in APL patients before treatment, and they increased during induction treatment, but there were no significant corresponding effects on survival.

Prognostic and clinicopathological significance of PD-1/PD-L1 expression in the tumor microenvironment and neoplastic cells for lymphoma.

BACKGROUND: Recently, unprecedented clinical efficacy was observed during treatment of many solid tumors because of the introduction of programmed cell death 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) immune checkpoint inhibitors. Preliminary clinical data indicates that checkpoint inhibition also represents a promising therapeutic strategy for certain lymphoid malignancies. However, PD-1/PD-L1 expression levels on neoplastic cells and in the tumor microenvironment vary among subtypes and their prognostic implications remain uncertain. MAIN BODY: Here, we review the clinicopathological significance of PD-1/PD-L1 expression in lymphomas. Increased infiltration of PD-1+ tumor-infiltrating lymphocytes (TILs) is a favorable prognostic factor in diffuse large B-cell lymphoma (DLBCL) but not in Hodgkin's lymphoma (HL). Higher numbers of PD-1+ TILs were observed in follicular lymphoma (FL) than in other subtypes of B-cell lymphoma; however, its prognostic significance remains controversial. Infiltration of PD-L1+ immune cells showed a trend toward better overall survival in nasal natural killer (NK)/T-cell lymphoma and adult T-cell leukemia/lymphoma, more likely to be classified as activated macrophages and dendritic cells in microenvironment but its biological effect is not clarified. Peripheral PD-1+ T cells could be detected in blood samples from DLBCL and chronic lymphocytic leukemia (CLL) and correlated with disease progression and poor prognosis. PD-1+ neoplastic T cells were more frequently observed in cutaneous T-cell lymphoma, including Sézary syndrome and mycosis fungoides, which may be involved in the progression of epithelial-derived T lymphoma. Studies on PD-L1 expression in neoplastic cells mostly focused on DLBCL. PD-L1+ neoplastic cells were observed only in a small subset of DLBCL, mainly associated with activated B cell (ABC) subtypes and Epstein-Barr virus (EBV) positivity; however, its prognostic role remains controversial. In either T or B lymphoma, elevated serum or plasma levels of soluble PD-L1 represent adverse prognostic factors. Notably, in clinical trials of classical HL, the frequency of 9p24.1 chromosome alterations increases the abundance of PD-1 ligand expression, appearing to predict responses to anti-PD-1/PD-L1 therapy. The cytogenetic alterations affecting chromosome 9p24.1 including the CIITA rearrangement were also frequently observed in certain specific subtypes of large B-cell lymphomas. CONCLUSIONS: The clinical roles of PD-1/PD-L1 expression vary between subtypes of lymphoma. Future studies should delineate the prognostic and predictive roles of PD-1 and PD-L1 expression.

PITX2 methylation: a novel and effective biomarker for monitoring biochemical recurrence risk of prostate cancer.

AIMS: Prostate cancer is one of the most common malignancies in men. Biochemical recurrence (BCR) and progression following curative treatment pose a significant public health challenge. Thus, it is essential to explore effective biomarkers for disease progression monitoring and risk stratification. The promoter region of the paired-like homeodomain transcription factor 2 (PITX2) gene has been found to be frequently methylated in prostate cancer. However, the prognostic role of PITX2 methylation in prostate cancer and which patients most likely to be recommended for PITX2 methylation tests to assess BCR risk remain controversial. Therefore, a systematic review was performed to explore the relationship of PITX2 methylation with the BCR risk of prostate cancer. METHODS: The PubMed, EMBASE, and Cochrane Library databases were systematically searched for eligible studies. Seven studies with a total of 2185 patients were included. Pooled hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were calculated. RESULTS: The overall HR was 2.71 (95% CI, 2.21-3.31), suggesting that PITX2 methylation has an adverse impact on BCR of prostate cancer. The pooled estimate of 5-year BCR-free survival for patients with a high methylation status was significantly lower than that for patients with a low methylation status (71% vs 90%; odds ratio [OR] = 3.50; 95% CI, 2.67-4.60, P = .000). A subgroup analysis was conducted according to detection method; the combined HRs were 2.68 (95% CI, 2.02-3.55) for quantitative methylation-specific PCR (qMSP) and 3.29 (95% CI, 2.31-4.68) for microarray EpiChip. In subgroups defined by region, Gleason score, pathological stage, surgical margin status and ethnicity, high methylation status was also associated with BCR of prostate cancer. CONCLUSIONS: As an effective biomarker, PITX2 methylation is feasible for individualized BCR risk assessment of prostate cancer following radical prostatectomy.