Efficacy and safety of neoadjuvant sintilimab in combination with FLOT chemotherapy in patients with HER2-negative locally advanced gastric or gastroesophageal junction adenocarcinoma: an investigator-initiated, single-arm, open-label, phase II study.

BACKGROUND: The addition of immune checkpoint inhibitors to neoadjuvant chemotherapy in operable advanced gastric or gastroesophageal junction (G/GEJ) cancer aroused wide interest. This study was designed to assess the efficacy and safety of neoadjuvant sintilimab, a programmed cell death protein-1 (PD-1) inhibitor, in combination with fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) chemotherapy for HER2-negative locally advanced G/GEJ cancer. METHODS: Eligible patients with clinical stage cT4 and/or cN+M0 G/GEJ cancer were enroled in this phase II study. Patients received neoadjuvant sintilimab (200 mg every 3 weeks) for three cycles plus FLOT (50 mg/m 2 docetaxel, 80 mg/m 2 oxaliplatin, 200 mg/m 2 calcium levofolinate, 2600 mg/m 2 5-fluorouracil every 2 weeks) for four cycles before surgery, followed by four cycles of adjuvant FLOT with same dosages after resection. The primary endpoint was the pathological complete response (pCR) rate. RESULTS: Thirty-two patients were enroled between August 2019 and September 2021, with a median follow-up of 34.8 (95% CI, 32.8-42.9) months. Thirty-two (100%) patients received neoadjuvant therapy, and 29 underwent surgery with an R0 resection rate of 93.1%. The pCR (TRG0) was achieved in 5 (17.2%; 95% CI, 5.8-35.8%) patients, and the major pathological response was 55.2%. Twenty-three (79.3%) patients had T downstaging, 21 (72.4%) had N downstaging, and 19 (65.5%) had overall TNM downstaging. Six (20.7%) patients experienced recurrence. Patients achieving pCR showed better event-free survival (EFS), disease-free survival (DFS), and overall survival (OS) than non-pCR. The estimated 3-year EFS rate, 3-year DFS rate, and 3-year OS rate were 71.4% (95% CI, 57.2-89.2%), 78.8% (95% CI, 65.1-95.5%), and 70.9% (95% CI, 54.8-91.6%), respectively. The objective response rate and disease control rate were 84.4% (95% CI, 68.3-93.1%) and 96.9% (95% CI, 84.3-99.5%), respectively. Twenty-five (86.2%) received adjuvant therapy. The main grade ≥3 treatment-related adverse events (TRAEs) were lymphopenia (34.4%), neutropenia (28.1%), and leukopenia (15.6%). no patients died from TRAE. The LDH level exhibited a better predictive value to pathological responses than PD-L1 and MSI status. CONCLUSIONS: The study demonstrated an encouraging efficacy and manageable safety profile of neoadjuvant sintilimab plus FLOT in HER2-negative locally advanced G/GEJ cancer, which suggested a potential therapeutic option for this population.

IRF4 rearrangement may predict favorable prognosis in children and young adults with primary head and neck large B-cell lymphoma.

PURPOSE: Large B-cell lymphoma with IRF4 rearrangement (LBCL, IRF4+) has been recently recognized as a specific entity that is frequently associated with young age and favorable prognosis. However, whether the good outcome of the disease is due to IRF4+ or other factors remains obscure. We thus analyzed 100 young patients with primary head and neck LBCL to see the clinicopathologic correlates of IRF4+. METHODS: The histopathology, immunophenotype, IRF4 status of the tumors, and clinical data were reviewed. RESULTS: Twenty-one tumors were diagnosed as LBCL, IRF4+, which were more frequently associated with a follicular growth pattern, medium-sized blastoid cytology, germinal center B-cell-like, and CD5+ phenotype, compared with IRF4- ones. While most of the patients received chemotherapy with or without radiation, eight IRF4+ patients received mere surgical resection of the tumor and exhibited excellent outcome. IRF4+ cases featured a significantly higher complete remission rate, and better survivals compared with IRF4- ones. Multivariate analysis confirmed IRF4+ correlates with a better survival. CONCLUSION: Our work confirmed the unique clinicopathologic features of LBCL, IRF4+, and disclosed for the first time the independent favorable prognostic impact of IRF4+. These findings may further unravel the heterogeneity of LBCL occurring in youth, and aid in risk stratification and tailoring the therapeutic strategy.

Combining PD-1 Inhibitor Nivolumab with Radiotherapy Successfully Treated a Patient with Refractory Primary Mediastinal Large B-Cell Lymphoma: A Case Report and Literature Review.

Primary mediastinal large B-cell lymphoma (PMBCL) is relatively infrequent and generally has a good prognosis with standard immunochemotherapy. However, treatment options are limited for patients with relapsed/refractory PMBCL who are ineligible for stem cell transplantation. In this report, we treated a refractory PMBCL patient, who did not respond to salvage chemotherapy, with combined nivolumab and radiotherapy. The patient achieved a complete remission with mild adverse reactions and has survived without relapse 2 years after treatment.

L-Type Cav 1.2 Calcium Channel-α-1C Regulates Response to Rituximab in Diffuse Large B-Cell Lymphoma.

PURPOSE: One third of patients with diffuse large B-cell lymphoma (DLBCL) succumb to the disease partly due to rituximab resistance. Rituximab-induced calcium flux is an important inducer of apoptotic cell death, and we investigated the potential role of calcium channels in rituximab resistance. EXPERIMENTAL DESIGN: The distinctive expression of calcium channel members was compared between patients sensitive and resistant to rituximab, cyclophosphamide, vincristine, doxorubicin, prednisone (RCHOP) regimen. The observation was further validated through mechanistic in vitro and in vivo studies using cell lines and patient-derived xenograft mouse models. RESULTS: A significant inverse correlation was observed between CACNA1C expression and RCHOP resistance in two independent DLBCL cohorts, and CACNA1C expression was an independent prognostic factor for RCHOP resistance after adjusting for International Prognostic Index, cell-of-origin classification, and MYC/BCL2 double expression. Loss of CACNA1C expression reduced rituximab-induced apoptosis and tumor shrinkage. We further demonstrated direct interaction of CACNA1C with CD20 and its role in CD20 stabilization. Functional modulators of L-type calcium channel showed expected alteration in rituximab-induced apoptosis and tumor suppression. Furthermore, we demonstrated that CACNA1C expression was directly regulated by miR-363 whose high expression is associated with worse prognosis in DLBCL. CONCLUSIONS: We identified the role of CACNA1C in rituximab resistance, and modulating its expression or activity may alter rituximab sensitivity in DLBCL.

Association between 12p13 SNP rs11833579 and ischemic stroke in Asian population: An updated meta-analysis.

BACKGROUND: A GWAS found that the single-nucleotide polymorphism rs11833579 near the NINJ2 gene on chromosome 12p13 was associated with an increased risk of ischemic stroke in Caucasians in 2009. Several studies have been carried out to explore the association between this SNP and ischemic stroke in Asians, but published results were contradictory. In the present study, we performed a meta-analysis to further evaluate this association in the Asian population. METHODS: All relevant articles were retrieved from the databases of PubMed, EMBASE, Chinese Biomedical Literature Database, CNKI, CQVIP, and WANFANG Database from the establishment date to February 2014. Statistical analyses were performed by using Stata 11. The pooled odds ratios (ORs) with 95% confidence intervals (95% CIs) were used to assess the strength of the association. Possible publication bias was checked by funnel plots, Begg's test and Egger's test. RESULTS: Eleven studies were eligible for meta-analysis including 9358 cases and 8936 controls. Overall, there were no significant associations between rs11833579 and ischemic stroke under the allelic (OR=0.963, 95% CI: 0.850-1.092, p=0.559), dominant (OR=0.946, 95% CI: 0.778-1.150, p=0.580), recessive (OR=0.993, 95% CI: 0.914-1.078, p=0.868), and homozygote (OR=0.968, 95% CI: 0.796-1.177, p=0.744) genetic models in the Asian population. Further, we found no evidence of association of rs11833579 with large artery atherosclerosis (LAA) or small-artery occlusion (SAO) stroke in all genetic models. The results of the subgroup analysis for Chinese population and Japanese population were consistent with that of the overall study. CONCLUSIONS: Our meta-analysis shows that SNP rs11833579 is not related to ischemic stroke in the Asian population.

PTEN tumor suppressor plays less prognostic role than P53 tumor suppressor in diffuse large B-cell lymphoma.

The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and P53 tumor suppressors are among the most commonly inactivated or mutated genes in human cancers, whose pathways cross-talk and interact in a complementary mode. In order to understand their roles and relationship in diffuse large B-cell lymphoma (DLBCL), we examined their expression and evaluated their prognostic significance in 62 patients with DLBCL treated with standard chemotherapy. Results showed that PTEN protein was lost in 23 (37.1%) cases, and the loss was associated with the activation of PI3K/AKT pathway, but was not associated with patient's clinical outcome. P53 mutation protein was detected in 30 (48.4%) cases and was associated with poor survival. Results of multivariate analysis showed that P53 mutation but not PTEN loss is associated with short survival in patients with DLBCL. PTEN status has no effect on P53 mutation-associated poor survival. We conclude that PTEN may play less prognostic role than P53 and that P53 mutation protein should be considered as a predictive factor of the need for a more aggressive therapy in patients with DLBCL who express P53.