Clinical implications of CSF-ctDNA positivity in newly diagnosed diffuse large B cell lymphoma.

The clinical implications of CSF-ctDNA positivity in newly diagnosed diffuse large B cell lymphoma (ND-DLBCL) remains largely unexplored. One hundred ND-DLBCL patients were consecutively enrolled as training cohort and another 26 ND-DLBCL patients were prospectively enrolled in validation cohort. CSF-ctDNA positivity (CSF(+)) was identified in 25 patients (25.0%) in the training cohort and 7 patients (26.9%) in the validation cohort, extremely higher than CNS involvement rate detected by conventional methods. Patients with mutations of CARD11, JAK2, ID3, and PLCG2 were more predominant with CSF(+) while FAT4 mutations were negatively correlated with CSF(+). The downregulation of PI3K-AKT signaling, focal adhesion, actin cytoskeleton, and tight junction pathways were enriched in CSF(+) ND-DLBCL. Furthermore, pretreatment CSF(+) was significantly associated with poor outcomes. Three risk factors, including high CSF protein level, high plasma ctDNA burden, and involvement of high-risk sites were used to predict the risk of CSF(+) in ND-DLBCL. The sensitivity and specificity of pretreatment CSF-ctDNA to predict CNS relapse were 100% and 77.3%. Taken together, we firstly present the prevalence and the genomic and transcriptomic landscape for CSF-ctDNA(+) DLBCL and highlight the importance of CSF-ctDNA as a noninvasive biomarker in detecting and monitoring of CSF infiltration and predicting CNS relapse in DLBCL.

Cause-specific mortality in a population-level cohort of diffuse large B-cell lymphoma following chemotherapy in the early 21st century.

Diffuse large B-cell lymphoma (DLBCL) is a severe non-Hodgkin's lymphoma. Life expectancy has improved with rituximab, but cause-specific mortality data is lacking. Using the Surveillance, Epidemiology, and End Results (SEER) database to study 27,449 individuals aged 20-74 years diagnosed with primary DLBCL who received chemotherapy between 2000 and 2019, we calculated standardized mortality rate (SMR) and excess absolute risk (EAR) and examined the connection between age, sex, time after diagnosis, and cause of death. Based on 12,205 deaths, 68.7% were due to lymphoma, 20.1% non-cancer causes, and 11.2% other cancers. Non-cancer mortality rates (SMR 1.2; EAR, 21.5) increased with DLBCL compared to the general population. The leading non-cancer death causes were cardiovascular (EAR, 22.6; SMR, 1.6) and infectious (EAR, 9.0; SMR, 2.9) diseases with DLBCL. Risks for non-cancer death and solid neoplasms are highest within the first diagnosis year, then decrease. Among socioeconomic factors, being white, being married, and having a higher income were favorable factors for reducing non-cancer mortality. To improve survival, close surveillance, assessment of risk factors, and early intervention are needed.

NOTCH pathway mutation contributes to inferior prognosis in HBV-infected chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) patients with hepatitis B virus (HBV) infection have a poor prognosis, underlying mechanism remains unclear. NOTCH mutations are frequent in CLL and associated with disease progression and drug resistance. It is also reported to be associated with hepatitis infection in lymphoid malignancies. In order to investigate the relation between the NOTCH pathway and HBV-associated CLL, we studied 98 previously untreated HBV-positive CLL patients and 244 HBV-negative CLL. NOTCH mutations were more frequent in HBV-positive CLL subgroup (p = 0.033). By survival analysis, HBV infection was associated with disease progression and poor survival (p = 0.0099 for overall survival (OS) and p = 0.0446 for time-to-treatment (TTT)). Any lesions of the NOTCH pathway (NOTCH1, NOTCH2, and SPEN) aggravated prognosis. In multivariate analysis, NOTCH mutation retained an independent significance for HBV-infected patients (p = 0.016 for OS and p = 0.023 for TTT). However, HBV positive with NOTCH unmutated had no statistical difference in prognosis compared with HBV-negative patients (p = 0.1706 for OS and p = 0.2387 for TTT), which indicated that NOTCH pathway mutation contributed to inferior prognosis in HBV-infected CLL. In conclusion, a cohort of CLL patients with HBV positive displayed a worse clinical outcome and the status of the NOTCH signaling pathway might play a crucial role.

Prognostic significance of absolute monocyte count and lymphocyte to monocyte ratio in mucosa-associated lymphoid tissue (MALT) lymphoma.

To investigate the prognostic significance of peripheral blood absolute monocyte count (AMC) and lymphocyte to monocyte ratio (LMR) in mucosa-associated lymphoid tissue (MALT) lymphoma, we retrospectively analyzed 316 newly diagnosed patients with MALT lymphoma. The best cut-off value of AMC was 0.6 × 109/L and LMR was 1.8 by x-tile according to progression-free survival (PFS). Multivariate analysis showed that MALT-IPI (p < 0.001), Eastern Cooperative Oncology Group performance status (ECOG PS) (p = 0.010), and LMR (p = 0.003) have independent prognostic significance for PFS, MALT-International Prognostic Index (MALT-IPI) (p = 0.018), ß2-microglobulin (ß2-MG) (p = 0.015), and LMR (p = 0.029) predicted poor overall survival (OS). Receiver-operator characteristic (ROC) curves were used to compare the prognostic prediction capability of MALT-IPI and MALT-IPI-M (MALT-IPI combined with LMR); area under the curves (AUCs) for MALT-IPI-M were larger than that for MALT-IPI both PFS (0.682 vs 0.654) and OS (0.804 vs 0.788). Our results indicated that that low level LMR at diagnosis was associated with inferior prognosis. The new prognostic index, MALT-IPI-M, enabled the risk stratification capability for MALT lymphoma survival.

Prognostic significance of serum immunoglobulin paraprotein in mucosa-associated lymphoid tissue (MALT) lymphoma.

To assess the prognostic significance of immunoglobulin (Ig) paraproteinaemia in mucosa-associated lymphoid tissue (MALT) lymphoma, 218 patients diagnosed with MALT lymphoma were enrolled in this study. Serum Ig paraprotein was detected in 42 of 218 patients (19.3%), mostly IgM-K (15, 35.7%), followed by IgM-L and IgG-L. Advanced age (p = 0.025), poor Eastern Cooperative Oncology Group performance status (p = 0.014), bone marrow involvement (p = 0.019), B symptoms (p = 0.039), advanced disease stage (III-IV) (p < 0.0001), elevated serum ß2-microglobulin level (p < 0.0001), multiple extranodal sites of involvement (p < 0.0001), nodal involvement (p < 0.0001), systemic therapy (p < 0.0001) and higher MALT-lymphoma International Prognostic Index (MALT-IPI) scores (p = 0.001) were significantly associated with the presence of serum Ig paraprotein. Multivariate Cox regression analysis showed that Ig paraproteinaemia was an independent prognostic predictor for inferior progression-free survival (PFS) and overall survival. A new prognostic index based on MALT-IPI and Ig paraproteinaemia, as assessed using receiver operating characteristic curves and the area under the curve statistics, showed better discriminative ability than MALT-IPI in predicting PFS. In conclusion, Ig paraproteinaemia was a promising prognostic predictor for MALT lymphoma. Ig paraproteinaemia together with MALT-IPI might contribute to optimising therapeutic management in clinical practice.

A bubble bursting-mediated oral drug delivery system that enables concurrent delivery of lipophilic and hydrophilic chemotherapeutics for treating pancreatic tumors in rats.

The therapeutic outcome of pancreatic cancer remains unsatisfactory, despite many attempts to improve it. To address this challenge, an oral drug delivery system that spontaneously initiates an effervescent reaction to form gas-bubble carriers is proposed. These carriers concurrently deliver lipophilic paclitaxel (PTX) and hydrophilic gemcitabine (GEM) in the small intestine. The bursting of the bubbles promotes the intestinal absorption of the drugs. The antitumor efficacy of this proposed oral drug delivery system is evaluated in rats with experimentally created orthotopic pancreatic tumors. The combined administration of equivalent amounts of PTX and GEM via the intravenous (i.v.) route, which is clinically used for treating pancreatic cancer, serves as a control. Following oral administration, the lipophilic PTX is initially absorbed through the intestinal lymphatic system and then enters systemic circulation, whereas the hydrophilic GEM is directly taken up into the blood circulation, ultimately accumulating in the tumorous pancreatic tissues. A pharmacokinetic study reveals that the orally delivered formulation has none of the toxic side-effects that are associated with the i.v. injected formulation; changes the pharmacokinetic profiles of the drugs; and increases the bioavailability of PTX. The oral formulation has a greater impact than the i.v. formulation on tumor-specific stromal depletion, resulting in greater inhibition of tumor growth with no evidence of metastatic spread. As well as enhancing the therapeutic efficacy, this unique approach of oral chemotherapy has potential for use on outpatients, greatly improving their quality of life.