Fucoidan enhances the anti-tumor effect of anti-PD-1 immunotherapy by regulating gut microbiota.

Currently, the clinical efficacy of anti-PD-1/PD-L1 monotherapy strategies against breast cancer is limited, and low response rates need to be improved. Gut microbiota plays a crucial role in the sensitization process of immunotherapy. As a natural dietary supplement, fucoidan has been reported to have immunomodulatory effects, while some studies have found that oral fucoidan may act as a potential prebiotic to modulate the gut microbiota. Therefore, this study investigated whether fucoidan could enhance the effects of anti-PD-1 monoclonal antibody antitumor immunotherapy by modulating gut microbiota and its metabolites. We found that the anti-tumor effect of the combination treatment was significantly enhanced, while fucoidan significantly improved the composition of the gut microbiota by increasing the number of potentially beneficial bacteria, such as Bifidobacterium, Faecalibaculum and Lactobacillus. Interference with the gut microbiota by antibiotics revealed impaired antitumor efficacy, confirming the necessity of gut microbiota in the antitumor effects of fucoidan in vivo. Metabolomics further revealed that fucoidan may have reversed the metabolic disturbances induced by the breast cancer model through tryptophan metabolism and glycerophospholipid metabolism pathways, with the most significant increase in the content of short-chain fatty acids, especially acetic and butyric acids. These modulations improved the function of effector T cells and suppressed Treg cell production. Thus, our findings suggest that fucoidan combined with the anti-PD-1 monoclonal antibody may be a novel strategy to sensitize breast cancer patients to anti-PD-1 monoclonal antibody immunotherapy. Meanwhile, the gut microbiota might serve as a new biomarker to predict the anti-PD-1 monoclonal antibody response to breast cancer immunotherapy.

Chidamide with PEL regimen (prednisone, etoposide, lenalidomide) for elderly or frail patients with relapsed/refractory diffuse large B-Cell lymphoma -results of a single center, retrospective cohort in China.

Treatment for relapsed/refractory Diffuse Large B-Cell Lymphoma (R/R DLBCL) is evolving rapidly due to the emergence of novel drugs, of which histone deacetylase inhibitors (HDACis) are an important example. This study showed efficacy in patients with R/R DLBCL after failure of conventional therapies. We conducted a single-center, retrospective study of 34 frail or elderly R/R DLBCL patients who had been treated off-label with chidamide-containing regimens from 2018 to 2020. X2 or Fisher test were used to compare response rate and Kaplan-Meier method was used to perform the survival analyses which compared with log-rank test between different groups. The test standard was p < 0.05. In total, 34 patients with R/R DLBCL received CPEL+/-R for at least 1 cycle were included. Most of them were refractory patients (n = 28,82.4%). The interim objective response rate (ORR) was 73.5% (32.4% complete remission [CR]), and the ultimate ORR was 50.0% (35.3% CR). After a median follow-up of 13.1 months, the median progression-free survival (PFS) was 10.5 months (95%CI 6.4-14.6) and the median overall survival (OS) was 19.3 months (95%CI 11.8-26.9). The 1 year expected PFS and OS rate was 43.0% and 73.7%, respectively. The most common grade 3/4 hematologic adverse events (AEs) were neutropenia (n = 11,32.3%) and anemia (n = 4, 11.8%) 0.23.5% (8/34) of all patients experienced grade 3/4 nonhematologic AEs. No treatment-related deaths were observed. The study showed chidamide-included regimen could be an option for R/R DLBCL patients ineligible for intensive chemotherapies. Current data showed favorable efficiency and moderate safety profile. Further study is warranted for better illustration of efficacy and usage in combination therapies.

Prognostic value of circulating tumor DNA in lymphoma: a meta-analysis.

Circulating tumor DNA (ctDNA) can be used to evaluate the prognosis of lymphoma. However, there is no uniform consensus about the mechanistic role that ctDNA plays in the prognosis of lymphoma. This meta-analysis explores the prognostic value of ctDNA in lymphoma, especially in diffuse large B cell lymphoma (DLBCL). All relevant reports published as of May 14, 2020, were retrieved by searching electronic databases in Pubmed, Embase and Cochrane Library. The prognostic value of ctDNA was evaluated using meta-analysis. Revman 5.3 software was used for prognostic data extraction and analysis. Eight studies, including a total of 767 lymphoma patients, were enrolled in this meta-analysis. Five out of eight studies investigated the association between ctDNA levels and progression-free survival (PFS) in 501 lymphoma patients, indicating that high levels of ctDNA were significantly associated with poor PFS (HR 2.24, 95%CI: 1.63-3.08, P < 0.00001). We conducted a subgroup analysis of 379 patients with DLBCL across three of the studies and came to the same conclusion (HR 2.01, 95%CI: 1.42-2.85, P < 0.0001). Two studies with a total of 192 lymphoma patients described the association between ctDNA levels and event-free survival (EFS), showing that high levels of ctDNA were also associated with adverse EFS (HR 4.53, 95%CI: 1.79-11.47, P = 0.001). The remaining two studies analyzed the potential clinical value of ctDNA for predicting the overall survival time (OS) of DLBCL patients, demonstrating that high levels of ctDNA correlated with inferior OS (HR 3.09, 95%CI: 1.50-6.35, P = 0.002). Our meta-analysis showed that high levels of ctDNA were associated with poor prognosis in patients with lymphoma, especially DLBCL.

Lymphocyte-Activation Gene-3 Expression and Prognostic Value in Neoadjuvant-Treated Triple-Negative Breast Cancer.

PURPOSE: In this study, we aimed to evaluate lymphocyte-activation gene-3 (LAG-3) expression and its prognostic value in neoadjuvant-treated triple-negative breast cancer (TNBC). METHODS: LAG-3, programmed death-1 (PD-1), programmed death ligand-1 (PD-L1), and CD8+ tumor-infiltrating lymphocyte (TILs) levels were examined using immunohistochemistry in 148 preand 114 post-neoadjuvant chemotherapy (NACT) specimens of human TNBC tissue. Correlations between expression levels and clinicopathological features were analyzed. Prognostic values for combined detection in TNBC following NACT were evaluated. RESULTS: In pre-NACT specimens, LAG-3 expression showed a significant association with pathological complete response (pCR, p=0.038) and was correlated with PD-1 (p<0.001) and PD-L1 (p=0.008). In post-NACT specimens, high expression of LAG-3 showed significant effects on nodal status (p=0.023) and PD-1 (p<0.001). The expression of immune markers on TILs significantly increased following NACT. Multivariate analysis indicated that only nodal status (odds ratio [OR], 0.226; 95% confidence interval [CI], 0.079-0.644; p=0.005) and high quantities of CD8+TILs (OR, 3.186; 95% CI, 1.314-7.721; p=0.010) are independent predictors of pCR. Nodal status (hazard ratio [HR], 2.666; 95% CI, 1.271-5.594; p=0.010), CD8+TILs (HR, 0.313; 95% CI, 0.139-0.705; p=0.005), and the LAG-3-high/PD-L1-high group (HR, 2.829; 95% CI, 1.050-7.623; p=0.040) provided prognostic values for patients with TNBC following NACT. CONCLUSION: CD8+TILs were sensitive predictive markers in response to NACT. High expression of LAG-3 in residual tissues, especially in combination with PD-L1, was associated with poor prognosis.

Tumor LDH-A expression and serum LDH status are two metabolic predictors for triple negative breast cancer brain metastasis.

There are limited therapeutic methods for triple negative breast cancer in the clinic, which is easy to progress into the brain to form metastatic lesions and evolve into the terminal stage. Because both the primary cancer and the brain metastasis have high glycolysis, we hypothesize that lactate dehydrogenase (LDH), which catalyzes the final step of glycolysis, may be a predictor, as well as a treatment target, for breast cancer brain metastasis. Therefore, the expression of LDH-A was detected on 119 triple negative breast cancer tissues with immunohistochemistry, and the serum LDH levels were also measured. Our results showed that the LDH-A expression inside the tumor was significantly higher than the matched normal tissues. Tumor LDH-A expression, serum LDH status, and the slope of serum LDH status were closely associated with triple negative breast cancer brain metastasis and brain metastasis free survival. This study indicates that tumor LDH and serum LDH status are two predictors for triple negative breast cancer brain metastasis.

The Relationship Between Tamoxifen-associated Nonalcoholic Fatty Liver Disease and the Prognosis of Patients With Early-stage Breast Cancer.

PURPOSE: To investigate the relationship between tamoxifen-associated nonalcoholic fatty liver disease (NAFLD) and survival outcomes in patients with breast cancer. METHODS: Patients with early-stage invasive breast cancer after curative resection from January 2009 to June 2011 were selected. A total of 646 patients who were treated with tamoxifen were included. Patients diagnosed with NAFLD on ultrasonography were classified into the NAFLD and non-NAFLD groups. RESULTS: The NAFLD group included 221 patients, and the non-NAFLD group included 425 patients. Patients in the NAFLD group had significantly higher body mass index than those in the non-NAFLD group (P < .001). Disease-free survival was significantly longer in the non-NAFLD group than the NAFLD group (P = .006). However, there were no significant statistical differences between these 2 groups on overall survival (P = .387). With regard to body mass index, total cholesterol, triglyceride, low-density lipoprotein cholesterol, alanine aminotransferase, and high-density lipoprotein cholesterol, the optimal cutoff points were 21.06, 4.28, 1.22, 3.13, 27.50 and 1.29, respectively, which can be identified as risk factors for distinguishing patients who developed NAFLD from those who did not (P < .05). Moreover, a risk score ≥ 3 indicated a high risk of development of NAFLD (odds ratio, 3.03; 95% confidence interval, 1.11-8.28; P = .037). CONCLUSION: NAFLD development had a negative effect on survival outcomes of patients with breast cancer. The risk score created ≥ 3 had a high-level risk of developing NAFLD, and it might be used for physicians to evaluate each patient and give instructive advice for further treatment.

Altered glycometabolism affects both clinical features and prognosis of triple-negative and neoadjuvant chemotherapy-treated breast cancer.

Glycometabolism is a distinctive aspect of energy metabolism in breast cancer, and key glycometabolism enzymes/pathways (glycolysis, hexosamine biosynthetic pathway, and pentose phosphate pathway) may directly or indirectly affect the clinical features. In this study, we analyzed the particular correlation between the altered glycometabolism and clinical features of breast cancer to instruct research and clinical treatment. Tissue microarrays containing 189 hollow needle aspiration samples and 295 triple-negative breast cancer tissues were used to test the expression of M2 isoform of pyruvate kinase (PKM2), glutamine-fructose-6-phosphate transaminase 1 (GFPT1), glucose-6-phosphate dehydrogenase (G6PD), and p53 by immunohistochemistry and the intensity of these glycometabolism-related protein was evaluated. Chi-square test, Kaplan-Meier estimates, and Cox proportional hazards model were used to analyze the relationship between the expression of these factors and major clinical features. PKM2, GFPT1, and G6PD affect the pathologic complete response rate of neoadjuvant chemotherapy patients in different ways; pyruvate kinase muscle isozyme 2 (PKM2) and G6PD are closely associated with the molecular subtypes, whereas GFPT1 is correlated with cancer size. All these three factors as well as p53 have impacts on the progression-free survival and overall survival of triple-negative breast cancer patients. Cancer size shows significant association with PKM2 and GFPT1 expression, while the pN stage and grade are associated with PKM2 and G6PD expression. Our study support that clinical characteristics are reflections of specific glycometabolism pathways, so their relationships may shed light on the orientation of research or clinical treatment. The expression of PKM2, GFPT1, and G6PD are hazardous factors for prognosis: high expression of these proteins predict worse progression-free survival and overall survival in triple-negative breast cancer, as well as worse pathologic complete response rate in neoadjuvant chemotherapy breast cancer. However, p53 appears as a protective factor only in the patients receiving neoadjuvant chemotherapy. All the four proteins, PKM2, GFPT1, G6PD and p53, are prognostic markers of breast cancer. The correlation among them suggests that there may be crosstalk of the four proteins in breast cancer.

The Expression of CD9 and PIK3CD is Associated with Prognosis of Follicular Lymphoma.

BACKGROUND: Follicular lymphoma (FL) frequently develops drug-resistance and transforms into more aggressive subtypes over time. It is urgent to find prognostic biomarkers and disclose signaling pathways that have potential to be drug targets. In this study, we investigated the association of FL prognosis with the expression of 2 proteins: PIK3CD, a PI3K pathway component, and CD9, a tetraspanin family member. METHOD: The expression of PIK3CD and CD9 were examined on 76 FL tumor tissues and 15 normal tissues with Immunohistochemistry. Chi-square test, Cox proportional hazards model, and Kaplan-Meier estimates were used to analyze the relationships of CD9 and PIK3CD expression and major clinicopathological features. RESULT: PIK3CD expression was significantly higher, whereas CD9 expression was significantly lower in the 76 FL specimens than normal tissues. Concomitantly, low CD9 or high PIK3CD expression is associated with high degrees of Ann Arbor stages. In agreement with this, PIK3CD is an unfavorable and CD9 is a favorable factor for progression-free survival (PFS). Interestingly, PIK3CD expression is negatively correlated with CD9 expression, and the PIK3CD-high/CD9-low was significantly associated with short PFS when the 2 factors were combined together. Lastly, CD9 expression was significant higher in patients with bone marrow infiltration (BMI) than those without BMI. CONCLUSION: Both CD9 and PIK3CD are prognostic markers of FL. The negative correlation between CD9 and PIK3CD expression suggests that there may be crosstalks of the 2 proteins in FL.

Identification of proteins responsible for adriamycin resistance in breast cancer cells using proteomics analysis.

Chemoresistance is a poor prognostic factor in breast cancer and is a major obstacle to the successful treatment of patients receiving chemotherapy. However, the precise mechanism of resistance remains unclear. In this study, a pair of breast cancer cell lines, MCF-7 and its adriamycin-resistant counterpart MCF-7/ADR was used to examine resistance-dependent cellular responses and to identify potential therapeutic targets. We applied nanoflow liquid chromatography (nLC) and tandem mass tags (TmT) quantitative mass spectrometry to distinguish the differentially expressed proteins (DEPs) between the two cell lines. Bioinformatics analyses were used to identify functionally active proteins and networks. 80 DEPs were identified with either up- or down-regulation. Basing on the human protein-protein interactions (PPI), we have retrieved the associated functional interaction networks for the DEPs and analyzed the biological functions. Six different signaling pathways and most of the DEPs strongly linked to chemoresistance, invasion, metastasis development, proliferation, and apoptosis. The identified proteins in biological networks served to resistant drug and to select critical candidates for validation analyses by western blot. The glucose-6-phosphate dehydrogenase (G6PD), gamma-glutamyl cyclotransferase (GGCT), isocitrate dehydrogenase 1 (NADP+,soluble)(IDH1), isocitrate dehydrogenase 2 (NADP+,mitochondrial) (IDH2) and glutathione S-transferase pi 1(GSTP1), five of the critical components of GSH pathway, contribute to chemoresistance.