Jia-Zhu Wu

Low T3 syndrome is a strong prognostic predictor in diffuse large B cell lymphoma.

The aim of this study was to evaluate the prognostic effect of low triiodothyronine (T3) syndrome on patients with diffuse large B cell lymphoma (DLBCL). A hundred and eighty‐eight patients with detailed thyroid hormone levels at diagnosis of DLBCL were enrolled. Low T3 syndrome was defined as a low serum free T3 (FT3) level with low or normal serum free tetraiodothyronine (FT4) and thyroid stimulating hormone levels. Multivariate Cox regression analysis was used to screen prognostic factors associated with progression‐free survival (PFS) and overall survival (OS). Receiver‐operator characteristic curves and the corresponding areas under the curve were calculated to assess the predictive accuracy of International Prognostic Index (IPI) and low T3 syndrome. Twenty‐four patients were diagnosed with low T3 syndrome, which was associated with worse PFS and OS in the rituximab era. It was an independent prognostic factor for PFS and OS, especially for those with IPI 0−2, extranodal sites ≤1 and stage III−IV. Synchronously low FT3 and FT4 had poorer survival outcome compared to only low FT3 and adding criterion of low T3 syndrome improved the prognostic capacity of IPI for predicting PFS and OS in DLBCL. Low T3 syndrome was found to be a strong prognostic predictor in DLBCL.

Phenotypic alteration of CD8+ T cells in chronic lymphocytic leukemia is associated with epigenetic reprogramming

Immunosuppression is a prevalent clinical feature in chronic lymphocytic leukemia (CLL) patients, with many patients demonstrating increased susceptibility to infections as well as increased failure of an antitumor immune response. However, much is currently not understood regarding the precise mechanisms that attribute to this immunosuppressive phenotype in CLL. To provide further clarity to this particular phenomenon, we analyzed the T-cell profile of CLL patient samples within a large cohort and observed that patients with an inverted CD4/CD8 ratio had a shorter time to first treatment as well as overall survival. These observations coincided with higher expression of the immune checkpoint receptor PD-1 in CLL patient CD8+ T cells when compared to age-matched healthy donors. Interestingly, we discovered that increased PD-1 expression in CD8+ T cells corresponds with decreased DNA methylation levels in a distal upstream locus of the PD-1 gene PDCD1. Further analysis using luciferase reporter assays suggests that the identified PDCD1 distal upstream region acts as an enhancer for PDCD1 transcription and this region becomes demethylated during activation of naïve CD8+ T cells by anti-CD3/anti-CD28 antibodies and IL2. Finally, we conducted a genome-wide DNA methylation analysis comparing CD8+ T cells from CLL patients against healthy donors and identified additional differentially methylated genes with known immune regulatory functions including CCR6 and KLRG1. Taken together, our findings reveal the occurrence of epigenetic reprogramming taking place within CLL patient CD8+ T cells and highlight the potential mechanism of how immunosuppression is accomplished in CLL.

Elevated absolute monocyte count predicts unfavorable outcomes in patients with angioimmunoblastic T-cell lymphoma

This study was aimed at investigating the prognostic significance of the absolute monocyte count (AMC) in peripheral blood in patients with newly diagnosed angioimmunoblastic T cell lymphoma (AITL). AMC was performed in 73 therapy-naive patients with AITL in 2 institutions during 2008-2015, and higher AMC was observed in those with extranodal sites >1, bone marrow involvement, high lactate dehydrogenase level, the EBV infection, no response to treatment and high IPI, PIT, PIAI score group. The best AMC cut-off level at diagnosis was 0.8 × 10(9)/L and the 3-year overall survival (OS) was 64% for patients with low AMC group (≤ 0.8 × 10(9)/L) compared to 10% in high AMC group (>0.8 × 10(9)/L) (P<0.001). Multivariate analysis showed that elevated AMC remained an adverse prognostic parameter. Our results suggest that AMC is an independent prognostic parameter for OS in patients with AITL, and AMC >0.8 × 10(9)/L can routinely be used to identify high-risk patients with unfavorable survival.

The distinct clinical features and prognosis of the CD10+MUM1+ and CD10−Bcl6−MUM1− diffuse large B-cell lymphoma

Using an immunohistochemistry (IHC) based method, diffuse large B-cell lymphoma (DLBCL) can be classified into germinal center B-cell (GCB) and non-GCB subtypes. However, the prognostic value of Hans algorithm was contradictory in the literature. Using IHC and fluorescence in situ hybridization, we analyzed the antibodies applied in Hans algorithm and other genetic factors in 601 DLBCL patients and prognostic value of Hans algorithm in 306 cases who were treated with chemoimmunotherapy. The results showed that patients with GCB subtype have better overall survival (OS) and progression-free survival (PFS) than non-GCB cases. However, to some extent, double positive (CD10+MUM1+, DP) and triple negative (CD10−Bcl6−MUM−, TN) showed different clinical characteristics and prognosis to others that were assigned to the same cell-of-origin group. The DP group showed similar OS (median OS: both not reached, P = 0.3650) and PFS (median PFS: 47.0 vs. 32.7 months, P = 0.0878) with the non-GCB group while the TN group showed similar OS (median OS: both not reached, P = 0.9278) and PFS (median PFS: both not reached, P = 0.9420) with the GCB group. In conclusion, Recognition of specific entities in Hans algorithm could help us to accurately predict outcome of the patients and choose the best clinical management for them.

Serum carbohydrate antigen 125 concentration as a superior predictor for serosal effusion at diagnosis and a prognostic factor in diffuse large B-cell lymphoma.

BACKGROUND Carbohydrate antigen 125 (CA-125) is one of the most common used tumor biomarkers in clinical practice. Previous studies showed an association of increased CA-125 levels with advanced characteristics and inferior outcome in non-Hodgkin lymphoma. OBJECTIVE To identify the clinical significance of CA-125 in diffuse large B-cell lymphoma (DLBCL). METHODS We retrospectively analyzed 181 patients with DLBCL with measured serum CA-125 concentration at diagnosis and follow-ups during the courses. Clinical significance of CA-125 was evaluated by assessing the association between CA-125 levels and clinical characteristics. RESULTS CA-125 levels on admission were positively correlated with serum lactate dehydrogenase, β2-microglobulin (β2-MG), serum ferritin (SF) and cavity effusion, while negatively correlated with serum albumen (ALB). During the courses, CA-125 levels were positively correlated with β 2-MG, SF and effusion, and negatively correlated with ALB. A better correlation between effusion and CA-125 levels was observed. Using a cut-off value > 50.39 U/ml gave a sensitivity of 73.8% and a specificity of 92.1% for the indication of effusion at diagnosis, while during the courses the sensitivity was much lower. On the prognostic role of CA-125, we found prognostic relevance on progression-free survival (PFS) but not on overall survival (OS). CONCLUSIONS Our study revealed limited usefulness of CA-125 concentration at diagnosis and follow-ups in DLBCL.

Polyclonal Antibody Targeting SOX11 Cannot Differentiate Mantle Cell Lymphoma From B-Cell Non-Hodgkin Lymphomas

OBJECTIVES To determine whether SOX11 is a diagnostic marker of mantle cell lymphoma (MCL). METHODS We analyzed SOX11 expression in 349 B-cell non-Hodgkin lymphomas (B-NHLs) via immunohistochemistry. RESULTS Nuclear staining of SOX11 was observed in 54 (93.1%) of 58 MCLs. We noticed that SOX11 protein was also expressed on the nuclei in 8 (21.6%) of 37 B-lymphoblastic lymphomas, 45 (32.6%) of 138 diffuse large B-cell lymphomas, 15 (44.1%) of 34 follicular lymphomas, 8 (30.8%) of 26 Burkitt lymphomas, 2 (10.0%) of 20 chronic lymphocytic leukemia/small cell lymphomas, and 3 (18.8%) of 16 marginal zone lymphomas. CONCLUSIONS Although the positive rate of SOX11 expression in MCL was significantly higher than other B-NHLs (P < .001), polyclonal antibody targeting SOX11 is not able to identify MCL from B-NHLs because the nuclear staining of SOX11 was widely positive in B-NHLs.

Elevated absolute NK cell counts in peripheral blood predict good prognosis in chronic lymphocytic leukemia

PurposeThe aim of this study was to investigate the prognostic significance of the absolute natural killer (NK) cell counts in peripheral blood in patients with chronic lymphocytic leukemia (CLL). MethodsA total of 273 previously untreated patients with CLL from April 2004 and October 2015 were enrolled into this retrospective study. We analysed the T cell subsets of all patients and figured out the number of NK cells. Comparisons of NK cell count as continuous parameter in different groups were described using Mann–Whitney U test and the Kruskal–Wallis test. Kaplan–Meier method was used to survival analysis, and the Cox proportional hazards models were used for the estimation of prognostic factors.ResultsNK cell counts were calculated in 273 therapy-naive CLL patients, and higher number of NK cell was observed in those with Binet stage A/B, ZAP-70 < 20%, normal serum albumin and β2-microglobulin levels. Using a NK cell count cut-off of 0.40 × 109/L, patients with lower NK cell count (< 0.40 × 109/L) had a significantly shorter overall survival (OS) than those with higher NK cell count (≥ 0.40 × 109/L) (P = 0.0014). Multivariate analysis showed that NK cell counts remained its prognostic value. However, the effect of NK cell count on time to treatment was not significant. ConclusionsOur results suggest that NK cell count is an independent prognostic marker for OS in patients with CLL and NK cell counts ≥ 0.40 × 109/L can routinely be used to identify patients with favorable survival.

The percentage of cells with 17p deletion and the size of 17p deletion subclones show prognostic significance in chronic lymphocytic leukemia without treatment indication

TP53 disruption is considered to be the most important prognostic factor in chronic lymphocytic leukemia (CLL), but not all patients with TP53 disruption have similar dismal outcomes. We evaluated the prognostic value of TP53 disruption in CLL patients without treatment indications. Data of 305 CLL patients were analyzed. 41 of them (13%) had TP53 disruption. Patients with lower percentage of cells with del(17p) had significantly better survival. Patients with mutated IGHV, β2‐microglobulin ≤3.5 mg/L, wild‐type TP53, age ≤65 years or without complex karyotype (CK) had relatively favorable outcomes in the del(17p) group. Furthermore, patients with del(17p) as a minor clone showed survival advantage compared with those with del(17p) as a major clone. These data suggest that the percentage of cells with del(17p), the size of the del(17p) subclone, CLL International Prognostic Index, and CK should be considered to build refined prognostication models for patients with TP53 disruption.

Albumin-to-Fibrinogen Ratio as an Independent Prognostic Parameter in Untreated Chronic Lymphocytic Leukemia: A Retrospective Study of 191 Cases

Purpose Chronic lymphocytic leukemia (CLL) is one of the most frequent type of B-cell chronic lymphoproliferative disorders and chronic inflammation takes part in the development of CLL. However, there has been no valid immune biomarker to predict the prognosis of untreated CLL patients. Materials and Methods In this retrospective study, we analyzed the clinical correlations and prognostic value of albumin-to-fibrinogen ratio (AFR) detected at diagnosis in 191 CLL patients. Results The cut-off value of AFR was 9.7 calculated by X-tile. Patients who were more than 65 years old were often accompanied by low level of AFR (p < 0.001). Survival analysis showed that patients with low level of AFR had shorter overall survival (OS) than patients with high level of AFR (p < 0.001). Multivariate analysis illustrated that AFR had a negative impact on OS (p=0.003) and was independent of parameters involved in CLL international prognostic index and other prognostic markers such as CD38 and ZAP-70. Conclusion These data provide a comprehensive view of AFR and shows that AFR at diagnosis is an adverse prognostic factor in untreated CLL patients.

NOTCH1 mutation and its prognostic significance in Chinese chronic lymphocytic leukemia: a retrospective study of 317 cases

The proto‐oncogene NOTCH1 is frequently mutated in around 10% of patients with chronic lymphocytic leukemia (CLL). This study analyzed NOTCH1 mutation status of 317 Chinese patients with CLL by Sanger sequencing. The frequencies of NOTCH1 mutation in the PEST (proline (P), glutamic acid (E), serine (S), threonine (T)‐rich protein sequence) domain and the 3′ untranslated regions (UTR) were 8.2% and 0.9%, with the most frequent mutation being c.7541_7542delCT and c.*371A>G, respectively. Clinical and biological associations were determined including NOTCH1 mutations with advanced stage (Binet stage, P = 0.010), unmutated immunoglobulin heavy‐chain variable region (IGHV) gene (P < 0.001) and trisomy 12 (+12) (P = 0.014). NOTCH1‐mutated patients had lower CD20 expression intensity than NOTCH1‐unmutated patients (P = 0.029). In addition, NOTCH1‐mutated patients had shorter overall survival (OS) (P = 0.002) and treatment‐free survival (TFS) (P = 0.002) than NOTCH1‐unmutated patients, especially for patients with NOTCH1 c.7541_7542delCT and/or c.*371A>G mutations. Patients with both mutated NOTCH1 and unmutated IGHV had shorter OS (P < 0.001) and TFS (P < 0.001) than those with unmutated NOTCH1 or mutated IGHV. These data provide a comprehensive view of the clinical relevance and prognostic impact of NOTCH1 mutations on Chinese patients with CLL.