TIGIT blockade enhances tumor response to radiotherapy via a CD103 + dendritic cell-dependent mechanism.

Blockade of the T cell immunoreceptor with the immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) can enhance innate and adaptive tumor immunity and radiotherapy (RT) can enhance anti-tumor immunity. However, our data suggest that TIGIT-mediated immune suppression may be an impediment to such goals. Herein, we report on the synergistic effects of RT combined with anti-TIGIT therapy and the mechanism of their interaction. Treatment efficacy was assessed by measuring primary and secondary tumor growth, survival, and immune memory capacity. The function of CD103 + dendritic cells (DCs) under the combined treatment was assessed in wild-type and BATF3-deficient (BATF3-/-) mice. FMS-like tyrosine kinase 3 ligand (Flt3L) was used to confirm the role of CD103 + DCs in RT combined with anti-TIGIT therapy. TIGIT was upregulated in immune cells following RT in both esophageal squamous cell carcinoma patients and mouse models. Administration of the anti-TIGIT antibody enhanced the efficacy of RT through a CD8 + T cell-dependent mechanism. It was observed that RT and the anti-TIGIT antibody synergistically enhanced the accumulation of tumor-infiltrating DCs, which activated CD8 + T cells. The efficacy of the combination therapy was negated in the BATF3-/- mouse model. CD103 + DCs were required to promote the anti-tumor effects of combination therapy. Additionally, Flt3L therapy enhanced tumor response to RT combined with TIGIT blockade. Our study demonstrated TIGIT blockade can synergistically enhance anti-tumor T cell responses to RT via CD8 + T cells (dependent on CD103 + DCs), suggesting the clinical potential of targeting the TIGIT pathway and expanding CD103 + DCs in RT.

Sarcopenia is associated with prognosis in patients with esophageal squamous cell cancer after radiotherapy or chemoradiotherapy.

BACKGROUND: This study aimed to determine the prognostic value of the sarcopenia on the progression free survival (PFS) and overall survival (OS) of esophageal squamous cell cancer (ESCC) patients who received radiotherapy (RT) or chemoradiotherapy (CRT). METHODS: Data on clinicopathological characteristics and nutritional parameters were analyzed and correlated with PFS and OS, retrospectively. Skeletal muscle, subcutaneous, visceral and total fat tissue cross-sectional areas were evaluated on CT images at the midpoint of the 3rd lumbar vertebrae. A total of 213 patients were enrolled in this study. RESULTS: Sarcopenia was significantly associated with subcutaneous fat content. The univariate analysis demonstrated that OS was superior in patients with non-sarcopenia, non-alcohol, NRI ≥ 100, albumin ≥ 40 g/L, TATI > 83.0, SATI > 27.8, VATI > 49, non-anemia, cervical and upper-thoracic ESCC, T stage 1-2, N stage 0-1 and TNM stage I-II. In the multivariate analysis, sarcopenia, albumin, N stage and TNM stage were identified as independent prognostic factors of survival. This study demonstrated that sarcopenia was related to worse PFS and OS in patients with ESCC who received RT or CRT. CONCLUSIONS: Sarcopenia is considered to be a useful predictor in patients with ESCC who received RT or CRT. This study also provided a conceptual basis for further prospective research on the application of the sarcopenia for patients receiving RT or CRT for intermediate- and advanced-stage ESCC.

Geriatric nutritional risk index as a prognostic factor in patients with hepatocellular carcinoma following transarterial chemoembolization: A retrospective study.

The geriatric nutritional risk index (GNRI) has been shown to be associated with the prognosis of cancer patients except for hepatocellular carcinoma (HCC) patients after transarterial chemoembolization (TACE). Our aim is to examine the association between the GNRI and long-term prognosis in patients with HCC who underwent TACE. Patients with HCC who underwent TACE were enrolled. The relationship between the patient characteristics and GNRI were compared, and the independent prognostic factors were investigated. Nomogram performance was assessed via the concordance index (C-index) and calibration plots. Decision curve analysis (DCA) was performed to evaluate the net benefit of the nomogram. A total of 235 patients met the inclusion criteria. Compared with the parameters of the high GNRI group, low GNRI was significantly associated with hypertension, ascites, body mass index, tumor size, anemia, Child-Turcotte-Pugh class. The univariate analysis demonstrated that overall survival (OS) was inferior when GNRI < 98, tumor size ≥ 5cm, vascular invasion, alpha-fetoprotein level ≥ 400, Barcelona clinical liver cancer stage B to C and TACE times < 3. The multivariate analysis revealed that GNRI < 98, tumor size ≥ 5cm, tumor number ≥ 2, alpha-fetoprotein level ≥ 400 and TACE times < 3 were independent predictors of a poor OS. In the validation step, OS was shown to be well calibrated (C-index = 0.724), and a satisfactory clinical utility was proven by DCA. Low GNRI score was associated with a shorter OS in patients undergoing TACE.

Use of Chemoradiotherapy as a Treatment Option for Patients with Limited-Stage Primary Small Cell Carcinoma of the Esophagus.

PURPOSE: Currently, there are no standard treatments for primary small cell carcinoma of the esophagus (PSCCE), particularly in cases of limited-stage disease. This retrospective study aimed to assess the treatment strategies and the relevant prognostic factors of limited-stage PSCCE (LS-PSCCE). PATIENTS AND METHODS: We retrospectively evaluated 129 patients with LS-PSCCE between June 2009 and December 2018. The χ2 test was performed to examine the frequencies between different groups. The Kaplan-Meier and log-rank methods were used to estimate and compare survival rates. Univariate and multivariate analyses were performed to determine the prognostic factors for overall survival (OS). RESULTS: Through a median follow-up of 23 months, the median OS of all patients was 25.0 months and the median recurrence-free survival (RFS) was 15.0 months. Univariate and multivariate analyses showed that alcohol abuse (p=0.046) and TNM stage (p<0.001) were independent prognostic factors. There was no significant difference in OS and RFS rates between the patients treated with chemoradiotherapy (CRT) and those treated with surgery and chemotherapy with or without radiotherapy (S+CT±RT) (p>0.05). Patients who received concurrent CRT had better OS and RFS than those who received sequential CRT (p<0.05). Postoperative adjuvant RT for high-risk patients can further improve the local control rate but has no significant effect on OS. CONCLUSION: LS-PSCCE patients treated with CRT had similar OS and RFS compared to those treated with S+CT±RT. This study shows that concurrent CRT confers a survival advantage for patients with LS-PSCCE compared to those with sequential CRT.

Impact of low serum hemoglobin on development of contrast-induced nephropathy (CIN) in patients with hepatocellular carcinoma (HCC) following transarterial chemoembolisation (TACE).

OBJECTIVES: To assess the association between low hemoglobin (Hb) level and development of contrast-induced nephropathy (CIN) for hepatocellular carcinoma (HCC) patients after transarterial chemoembolization (TACE). METHODS: A retrospective analysis was performed on 284 patients undergoing 503 consecutive sessions of TACE. Propensity score matching (PSM) analysis was used to reduce the influence of the difference in variables in normal and low hemoglobin groups. Risk factors of CIN were assessed by univariate and multivariate logistic regression analysis. The relation between Hb level and CIN development was analyzed by receiver operating characteristic (ROC) curve. RESULTS: CIN developed in 5.6% patients after TACE. Multivariate logistic regression analysis showed that hypertension, Hb and serum creatinine (Scr) were independent risk factors for the development of post-TACE CIN. Grouped by normal or low Hb, the incidence of CIN was 14.6% (16/110) in the low Hb group and 3.4% (4/116) in the normal Hb group after PSM. Multivariate logistic regression analysis revealed that Hb, lymphocyte count, and neutrophil to lymphocyte ratio (NLR) were independent risk factors for the development of post-TACE CIN. The optimal cut-off point at which the Hb concentration resulted in a high probability of developing CIN was 105.5 g/L in males. CONCLUSIONS: Low Hb is an independent risk factor for post-TACE CIN. Therefore, HCC patients with low Hb levels should be closely monitored before and during TACE.

Efficacy and toxicity of re-irradiation for esophageal cancer patients with locoregional recurrence: a retrospective analysis.

INTRODUCTION: There is no standard treatment for locoregional recurrent (LR) esophageal squamous cell carcinoma (ESCC) patients treated with radiotherapy (RT) previously. This retrospective study aimed to examine the efficacy and toxicity of re-irradiation (re-RT) for ESCC patients with LR. PATIENTS AND METHODS: A total of 252 patients were enrolled. Gross tumor volumes for re-RT were defined using contrast enhanced computed tomography and/or positron emission tomography/computed tomography. Overall survival (OS), after recurrence survival (ARS) and toxicities were assessed. RESULTS: Through a median follow-up of 38 months, the median OS and ARS were 39.0 and 13.0 months, respectively. The 6-, 12-, and 24-month ARS rates were 81.9%, 50.5%, and 21.8%, respectively. Multivariate analyses showed that chemotherapy, esophageal stenosis and recurrence-free interval (RFI) may be independent prognostic factors for ARS. The incidence of esophageal fistula/perforation (EP), radiation-induced pneumonitis and esophagorrhagia was 21.4%, 12.8% and 9.1%, respectively. RFI ≤ 12 months, esophageal stenosis and fat space between tumor and adjacent tissue disappeared were independent risk factors for the development of EP after re-RT. CONCLUSIONS: Re-RT was feasible for LR ESCC patients after RT initially, the complication occurred in re-RT is acceptable. Patients with RFI ≤ 12 months, esophageal stenosis and fat space between tumor and adjacent tissue disappeared should be closely observed during and after re-RT.

Evaluation of quantitative parameters of dynamic contrast-enhanced magnetic resonance imaging in qualitative diagnosis of hepatic masses.

BACKGROUND: To explore the value of parameters of multiphase dynamic contrast-enhanced magnetic resonance imaging (MDCE-MRI) in the qualitative diagnosis of hepatic masses. METHODS: Eighty patients with hepatic masses were retrospectively analyzed. All the patients underwent MDCE-MRI at 3.0 T MR before treatment. Mean enhancement time (MET), positive enhancement integral (PEI), a maximum slope of increase (MSI), and a maximum slope of decrease (MSD) were measured. RESULTS: There were significant differences between benign and malignant hepatic masses with respect to MET, PEI, and MSI values. The PEI and MSI values between hemangiomas, hepatocellular carcinomas (HCCs), cholangiocarcinomas, and metastatic tumors had significant differences. The MSD value between metastatic tumors, HCCs, and hemangiomas were significantly different. The area under the curve (AUC) values of the receiver operator characteristic curves for MET, PEI, and MSI were 0.70, 0.72, and 0.80, respectively. The specificity of MET, PEI, and MSI were all 77%, and the sensitivities of MSI was the highest, of which was 82.40%. Logistic regression analysis showed the regression equation to be P = 1/[1 + e0.008 × 1 + 0.007 × 2-6.707], and taking the Youden index maximum points as a diagnostic point was 0.2946. CONCLUSION: Some parameters of MDCE-MRI have significant roles in differentiating hepatic masses.

Effect of autophagy-associated proteins on the arecoline-induced liver injury in mice.

Arecoline can be used to treat diseases including glaucoma and tapeworm infection, however, long-term administration can cause severe adverse effects, including oral submucosal fibrosis, oral cancer, hepatic injury and liver cancer. Autophagy serves a role in these injuries. The present study established a mouse model of arecoline-induced hepatic injury and investigated the role of autophagy-associated proteins in this injury. The results indicated that the expression levels of the autophagy marker protein microtubule associated protein 1 light chain 3 B (MAP1LC3B) and autophagy-promoting protein beclin 1 were elevated in the injured hepatic cells, while the expression levels of a well-known negative regulator of autophagy, mammalian target of rapamycin (mTOR), were reduced. Following treatment of the hepatic injury with glutathione, the liver function improved and liver damage was reduced effectively. Compared with the control group, the expression levels of both MAP1LC3B and beclin 1 were significantly upregulated in the glutathione-treated mice, but the expression of mTOR was significantly downregulated. It may be concluded that in the process of protecting against arecoline-induced hepatic injury, glutathione cooperates with mTOR and beclin 1 to accelerate autophagy, maintaining stable cell morphology and cellular functions.