Consolidation therapy with autologous stem cell transplantation after remission of induction chemotherapy prolongs the survival of patients with peripheral T-cell lymphoma.

Background: There was little evidence of autologous stem cell transplantation (ASCT) as consolidation therapy after remission of induction for patients with Peripheral T-cell lymphoma (PTCL). In this study, we conducted a comparative analysis of real-world survival outcomes between consolidation therapy and observation in patients with PTCL. Methods: A total of 92 patients with peripheral T-cell lymphoma (PTCL) who were admitted to the Department of Hematology, Huadong Hospital Affiliated with Fudan University from January 2013 to April 2019 were divided into two groups based on whether they were treated with high-dose therapy (HDT) followed by autologous hematopoietic stem cell transplantation (ASCT): ASCT as consolidation therapy (n=30) and observation (n=62). Clinical characteristics, treatment patterns, and survival outcomes were analyzed between the two groups. Univariate and Cox multivariate regression analyses were also performed to detect prognostic factors of survival. Results: With a median follow-up time of 41 months, the median overall survival (OS) of peripheral T-cell lymphoma patients treated with ASCT was not reached; the median progression-free survival (PFS) was 77.0 months, which was much higher than that of patients without ASCT (p<0.003 for OS, p=0.015 for PFS). Subgroup analysis found that patients with high risks benefited more from ASCT. Combination with hemophagocytic lymphohistiocytosis (HLH) (p<0.001), clinical stage more than III (p=0.014), IPI score above 3 (p=0.049), and bone marrow involvement (p=0.010) were the independent prognostic factors significantly associated with worse OS and PFS. Additionally, pegylated liposomal doxorubicin (PLD)-containing chemotherapy regimen could bring a higher overall response rate (ORR) and prolong the survival of patients with PTCL who underwent ASCT. Conclusion: ASCT may improve the long-term survival of patients with PTCL as consolidation therapy after achieving complete or partial remission of induction treatment, particularly for those with high risks. The chemotherapy regimen containing pegylated liposomal doxorubicin may induce deeper remission than traditional doxorubicin in PTCL. It is crucial to identify the specific groups most likely to benefit from upfront ASCT.

Maintenance regimen of GM-CSF with rituximab and lenalidomide improves survival in high-risk B-cell lymphoma by modulating natural killer cells.

BACKGROUND: The treatment of high-risk B-cell lymphoma (BCL) remains a challenge, especially in the elderly. METHODS: A total of 83 patients (median age 65 years), who have achieved a complete response after induction therapy, were divided into two groups: R2 + GM-CSF regimen (lenalidomide, rituximab, granulocyte-macrophage colony-stimulating factor [GM-CSF]) as maintenance therapy (n = 39) and observation (n = 44). The efficacy of the R2 + GM-CSF regimen as maintenance in patient with high-risk BCL was analyzed and compared with observation. RESULTS: The number of natural killer cells in patients increased after R2 + GM-CSF regimen administration (0.131 × 109 /L vs. 0.061 × 109 /L, p = 0.0244). Patients receiving the R2 + GM-CSF regimen as maintenance therapy had longer remission (duration of response: 18.9 vs. 11.3 months, p = 0.001), and longer progression-free survival (not reached (NR) vs. 31.7 months, p = 0.037), and overall survival (OS) (NR vs. NR, p = 0.015). The R2 + GM-CSF regimen was safe and well tolerated. High international prognostic index score (p = 0.012), and high tumor burden (p = 0.005) appeared to be independent prognostic factors for worse PFS. CONCLUSIONS: The maintenance therapy of R2 + GM-CSF regimen may improve survival in high-risk BCL patients, which might be modulated by amplification of natural killer cells. The efficacy of the R2 + GM-CSF maintenance regimen has to be further validated in prospective random clinical trials.

AKR1B10 accelerates the production of proinflammatory cytokines via the NF-κB signaling pathway in colon cancer.

Aldo-keto reductase family one, member B10 (AKR1B10) has been reported to be involved in the tumorigenesis of various cancers. It has been reported that colorectal cancer is closely associated with chronic inflammation, but the underlying molecular mechanisms are still elusive. In our study, we evaluated the relationship between AKR1B10 expression and clinicopathological characteristics of colon cancer and showed that AKR1B10 expression was significantly correlated with the T stage and clinical stage of colon cancer. Knockdown of AKR1B10 significantly decreased the expression of the inflammatory cytokines IL1α and IL6 induced by lipopolysaccharide by inhibiting the NF-κB signaling pathway. Furthermore, AKR1B10 depends on its reductase activity to affect the NF-κB signaling pathway and subsequently affect the production of inflammatory cytokines. In addition, knockdown of AKR1B10 effectively reduced cell proliferation and clonogenic growth, indicating the biological role of AKR1B10 in colon cancer. Together, our findings provide important insights into a previously unrecognized role of AKR1B10 in colon cancer.

AKR1B10 negatively regulates autophagy through reducing GAPDH upon glucose starvation in colon cancer.

Autophagy is considered to be an important switch for facilitating normal to malignant cell transformation during colorectal cancer development. Consistent with other reports, we found that the membrane receptor Neuropilin1 (NRP1) is greatly upregulated in colon cancer cells that underwent autophagy upon glucose deprivation. However, the mechanism underlying NRP1 regulation of autophagy is unknown. We found that knockdown of NRP1 inhibits autophagy and largely upregulates the expression of aldo-keto reductase family 1 B10 (AKR1B10). Moreover, we demonstrated that AKR1B10 interacts with and inhibits the nuclear importation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and then subsequently represses autophagy. Interestingly, we also found that an NADPH-dependent reduction reaction could be induced when AKR1B10 interacts with GAPDH, and the reductase activity of AKR1B10 is important for its repression of autophagy. Together, our findings unravel a novel mechanism of NRP1 in regulating autophagy through AKR1B10.

Anticancer effect of LS-HB-mediated photodynamic therapy on hepatocellular carcinoma in vitro and in vivo.

Photodynamic therapy (PDT) is a relatively safe way for disease diagnosis and treatment that is based on light and photosensitizers. LS-HB is a promising photosensitizer with a light absorption peak of 660 nm. AIMS: The present study aimed to investigate the anticancer effects of LS-HB-PDT on hepatocellular carcinoma and its underlying molecular mechanism. METHODS: In the present study, the MTT assay and xenograft tumor model experiment were used to evaluate its anticancer effects as well as its dark toxicity in hepatocellular carcinoma in vitro and in vivo. Reactive oxygen species assay kit was utilized to detect the reactive oxygen species production induced by LS-HB-PDT. RESULTS: In vitro, the MTT assay results revealed that LS-HB-PDT exhibited significant cytotoxic effects both in a drug- and light dose-dependent manner. The IC50 of LS-HB-PDT on hepatocellular carcinoma cells was 2.685 µg/ml. However, no dark cytotoxicity was observed at the LS-HB concentrations of 0-50 µg/ml, and no light-induced cytotoxicity was observed at the light (660 nm) dosages of 0-40 J/cm2. Furthermore, reactive oxygen species could be induced after LS-HB-PDT in a drug- and light dose-dependent manner. In vivo experiment, the tumor inhibition ratio of tumor-bearing nude mice following LS-HB-PDT was enhanced with the drug and light dose increasing. Notably, tumors in 60.0% of mice disappeared after LS-HB-PDT (2 mg/kg; 100 J/cm2), and the tumor inhibition ratio reached 92.3%. Furthermore, the histological results revealed necrosis and thrombus in tumor tissue caused by LS-HB-PDT, which were not observed in the control, drug alone and light alone groups of mice. CONCLUSIONS: The present study indicated that LS-HB was a promising photosensitizer with excellent anticancer effects and low side effects. LS-HB-PDT induced reactive oxygen species damage in the cells directly and destroyed tumor blood vessels, thus leading to tumor tissue necrosis.

Establishment of a bead-based duplex assay for the simultaneous quantitative detection of Neuropilin-1 and Neuropilin-2 using xMAP technology and its clinical application.

BACKGROUND: Neuropilins (Nrps) are a new type of broad-spectrum tumor marker. Currently, a method for accurate simultaneous quantification of Nrps is not available. We aimed to develop a bead-based and duplexed flow cytometric assay that could be used for accurate and simultaneous quantification of Nrp1 and Nrp2 for scientific research or clinical diagnosis. METHODS: We coupled anti-human Nrp1-11# mAb and anti-human Nrp2-C3 mAb to magnetic beads 18# and 25#, respectively. Capturing antibodies and detecting antibodies were then combined to detect Nrps by a bead-based Luminex assay, which was subsequently applied to quantify Nrps in clinical serum samples. RESULTS: The results showed that the detection value of Nrps ranged from 10 to 100 000 pg/mL for Nrp1 and from 25 to 100 000 pg/mL for Nrp2. The detection sensitivity reached 10 pg/mL for Nrp1 and 24.8 pg/mL for Nrp2. Intra-assay variances ranged from 1.0% to 2.6% for Nrp1 and from 2.9% to 4.0% for Nrp2, and interassay variances ranged from 1.5% to 6.4% for Nrp1 and from 4.2% to 8.1% for Nrp2. The Nrp1 and Nrp2 recoveries were 96.6%-103.6% and 95.6%-102.3%, respectively. Irrelevant antigens had no interference in the paired-detection system, and the mean fluorescence intensity (MFI) values were stable for months. CONCLUSION: A bead-based, duplexed flow cytometric assay (xMAP® technology) was developed to detect Nrp1 and Nrp2. The assay provided rapid, high-throughput results and was much more sensitive, specific, reproducible, and stable than existing assays. In addition, this assay could be applied in early-stage cancer screening, tumor malignancy analysis, and prognosis assessment.