Abstract Background : Few studies investigate the relationship between lymphocyte recovery after definitive concurrent chemoradiotherapy (dCCRT) and prognosis in esophageal squamous cell carcinoma (ESCC). Methods : ESCC patients undergoing dCCRT with obtainable absolute lymphocyte counts (ALCs) at 6 months after dCCRT were screened from prospective trials. Population were categorized according to the development of and recovery from G4 and G1-3 ALC nadir during radiotherapy. Prognostic value of lymphocyte recovery in survival outcomes was estimated by Cox analysis. Irradiated relative volumes of the bone marrow and spleen were collected. The effective dose to immune cells (EDIC) was also calculated. Cut-offs of dose-volume parameters were determined by the receiver operating characteristic curve (ROC). Logistic analysis was used to explore predictive factors of lymphocyte recovery. Results : 232 patients were included. Among 69 patients with G4 ALC nadir during dCCRT, there were 27 patients with lymphocyte unrecovered (group A) and 42 patients with lymphocyte recovered (group B). As for patients with G1-3 ALC nadir, 67 patients were with lymphocyte unrecovered (group C) and 96 patients with lymphocyte recovered (group D). Cox multivariable analysis indicated that unrecovered lymphocyte after dCCRT was significantly correlated with worse overall survival (HR, 2.80 and 1.70) and a higher risk of local recurrence (HR, 4.11 and 1.83) whether in group A vs group B or group C vs group D. Logistic analysis displayed that bone marrow V5 (OR, 4.24 and 2.29) was an independent indicator associated with lymphocyte unrecovered from G4 or G1-3 ALC nadir during dCCRT, respectively. Conclusions : Lymphocyte unrecovered at 6 months after dCCRT could be a significant prognostic factor for worse survival outcomes whether patients suffered from G4 or G1-3 ALC nadir during dCCRT. Moreover, a larger relative volume of bone marrow irradiated by more than 5 Gy led to a higher risk of lymphocyte unrecovery.
Abstract Chemodynamic therapy (CDT) by introducing the Fenton‐/Fenton‐like reaction in an acidic and H 2 O 2 environment for toxic hydroxyl radical (•OH) generation, is a newly developed tumor‐selective therapeutic. However, tumor acidosis, characterized by extracellular acidity (pH e ≈ 6.5) and intracellular alkalinity (pH i ≈ 7.2), undoubtedly confers a large chemical barrier for effective implementation of intracellular CDT and thus limits its functional activity and therapeutic efficacy. Here, the unique amorphous iron nanoparticles (AFeNPs) loaded with carbonic anhydrase IX inhibitor (CAI) are constructed to re‐establish tumor acidosis with decreased pH i and increased pH e via inhibiting the over‐expressed CA IX in cancer cells by CAI for self‐enhanced CDT. The suppression of CA IX leads to H + accumulation in cells that could accelerate the AFeNPs‐based Fenton reaction to drastically exacerbate oxidative stress in cells and subsequently induce cell death; meanwhile, the inhibition of H + formation outside cells efficiently represses the potential of tumor invasion and metastasis owing to the insufficient acidic ions for degradation of tumor extracellular matrix. Re‐established tumor acidosis not only assists in the optimization of CDT, but also presents an opportunity for the development of new antitumor methods that are more tumor‐acidity specific.
Approximately 1-2% of patients with non‒small-cell lung cancer (NSCLC) harbor ROS1 rearrangements. Crizotinib, an oral small-molecule tyrosine kinase inhibitor (TKI) that targets anaplastic lymphoma kinase (ALK), MET, and ROS1, has shown marked antitumor activity in patients with ROS1-positive advanced NSCLC.Our objective was to analyze the efficacy and safety of crizotinib treatment in Chinese patients with advanced NSCLC with ROS1 rearrangement in real-world clinical practice.We included 35 patients with ROS1-positive NSCLC in this retrospective analysis. All received crizotinib 250 mg twice daily between March 2016 and April 2018 at the Fudan University Shanghai Cancer Center. All had histologically or cytologically confirmed locally advanced or metastatic NSCLC with ROS1 rearrangements, which were identified by fluorescence in situ hybridization, reverse transcriptase polymerase chain reaction, or next-generation sequencing. The main outcome measures were progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and adverse events.The median age of the patients was 51.0 years; 23 (65.7%) were female and 28 (80.0%) were never smokers. All were diagnosed as having adenocarcinoma; eight patients (22.9%) had brain metastases at baseline. The ORR and DCR were 71.4% and 94.3%, respectively. The estimated median PFS was 11.0 months (95% confidence interval [CI] 7.8-14.2). The estimated median OS was 41.0 months (95% CI 22.5-59.5). Elevated transaminases (54.3%), vision disorder (25.7%), elevated blood creatinine (22.9%), diarrhea (20.0%), and vomiting (20.0%) were the most commonly reported adverse effects.Crizotinib was effective and well tolerated in Chinese patients with ROS1-positive advanced NSCLC in real-world clinical practice. The progression sites and patterns, as well as treatments after first disease progression on crizotinib were diverse. Crizotinib beyond progressive disease and local therapy after failure of crizotinib treatment were feasible and effective in clinical practice.
The epidermal growth factor receptor (EGFR) signaling pathway is important in regulating biological behaviors in many malignancies. We explored whether expression and activation of EGFR and several components on its downstream pathways have prognostic significance in patients with esophageal squamous cell carcinoma (ESCC).Expression of EGFR, phosphorylated (p)-EGFR, AKT1, p-AKT1, AKT2, p-AKT2, ERK1, ERK2, p-ERK1/2, STAT3, and p-STAT3 was assessed by immunohistochemical analysis of tissue microarrays for 275 ESCC patients who had undergone complete three-field lymphadenectomy. Spearman rank correlation tests were used to determine the relationships among protein expression, and Cox regression analyses were performed to determine the prognostic factors on overall survival (OS).p-EGFR expression was correlated statistically with all of the other phosphorylated markers. Gender, N stage, and p-AKT1 expression were found to be independent prognostic factors for OS. Increased expression of p-AKT1 was associated with decreased patient survival. EGFR and p-EGFR expression was not significantly associated with patient survival.Activation of AKT1 was associated with poor prognosis in ESCC.
Overexpression of multidrug resistance 1 (MDR1) in cancer remains one of the major causes for the failure of chemotherapy. In the present study, we found that MyoD and PEA3 could activate P-glycoprotein (P-gp) expression in SGC7901 cells. Knockdown of MyoD and PEA3 attenuated MDR1 expression and increased the sensitivity of multidrug resistant cancer cells to cytotoxic drugs that were transported by P-gp in SGC7901/VCR cells. MyoD or PEA3 could bind to the E-box and PEA3 sites on the MDR1 promoter and activate its transcription. The regulation of MDR1 expression by MyoD and PEA3 may provide potential ways to overcome MDR in cancer treatment.
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