A nomogram to predict the cumulative risk for brain metastases in patients with limited-stage small cell lung cancer without prophylactic cranial irradiation.

OBJECTIVE: Patients with small cell lung cancer (SCLC) have a high risk of developing brain metastases (BM). Prophylactic cranial irradiation (PCI) is a standard therapy for limited-stage SCLC (LS-SCLC) patients who achieved complete or partial response after thoracic chemoradiotherapy (Chemo-RT). Recent studies have indicated that a subgroup of patients with a lower risk of BM can avoid PCI, and the present study therefore tries to construct a nomogram to predict the cumulative risk of development of BM in LS-SCLC patients without PCI. METHODS: After screening of 2298 SCLC patients who were treated at the Zhejiang Cancer Hospital from December 2009 to April 2016, a total of 167 consecutive patients with LS-SCLC who received thoracic Chemo-RT without PCI were retrospectively analyzed. The paper analyzed clinical and laboratory factors that may be correlated with BM, such as response to treatment, pretreatment serum neuron-specific enolase (NSE) and lactate dehydrogenase (LDH) levels, and TNM stage. Thereafter, a nomogram was constructed to predict 3­ and 5­year intracranial progression-free survival (IPFS). RESULTS: Of 167 patients with LS-SCLC, 50 developed subsequent BM. Univariate analysis showed that pretreatment LDH (pre-LDH) ≥ 200 IU/L, an incomplete response to initial chemoradiation, and UICC stage III were positively correlated to a higher risk of BM (p < 0.05). Multivariate analysis identified pretreatment LDH level (hazard ratio [HR] 1.90, 95% confidence interval [CI] 1.08-3.34, p = 0.026), response to chemoradiation (HR 1.87, 95% CI 1.04-3.34, p = 0.035), and UICC stage (HR 6.67, 95% CI 1.03-49.15, p = 0.043) as independent predictors for the development of BM. A nomogram model was then established, and areas under the curve of 3­year and 5­year IPFS were 0.72 and 0.67, respectively. CONCLUSION: The present study has developed an innovative tool that is able to predict the individual cumulative risk for development of BM in LS-SCLC patients without PCI, which is beneficial for providing personalized risk estimates and facilitating the decision to perform PCI.

Radiation pneumonia predictive model for radiotherapy in esophageal carcinoma patients.

BACKGROUND: The machine learning models with dose factors and the deep learning models with dose distribution matrix have been used to building lung toxics models for radiotherapy and achieve promising results. However, few studies have integrated clinical features into deep learning models. This study aimed to explore the role of three-dimension dose distribution and clinical features in predicting radiation pneumonitis (RP) in esophageal cancer patients after radiotherapy and designed a new hybrid deep learning network to predict the incidence of RP. METHODS: A total of 105 esophageal cancer patients previously treated with radiotherapy were enrolled in this study. The three-dimension (3D) dose distributions within the lung were extracted from the treatment planning system, converted into 3D matrixes and used as inputs to predict RP with ResNet. In total, 15 clinical factors were normalized and converted into one-dimension (1D) matrixes. A new prediction model (HybridNet) was then built based on a hybrid deep learning network, which combined 3D ResNet18 and 1D convolution layers. Machine learning-based prediction models, which use the traditional dosiomic factors with and without the clinical factors as inputs, were also constructed and their predictive performance compared with that of HybridNet using tenfold cross validation. Accuracy and area under the receiver operator characteristic curve (AUC) were used to evaluate the model effect. DeLong test was used to compare the prediction results of the models. RESULTS: The deep learning-based model achieved superior prediction results compared with machine learning-based models. ResNet performed best in the group that only considered dose factors (accuracy, 0.78 ± 0.05; AUC, 0.82 ± 0.25), whereas HybridNet performed best in the group that considered both dose factors and clinical factors (accuracy, 0.85 ± 0.13; AUC, 0.91 ± 0.09). HybridNet had higher accuracy than that of Resnet (p = 0.009). CONCLUSION: Based on prediction results, the proposed HybridNet model could predict RP in esophageal cancer patients after radiotherapy with significantly higher accuracy, suggesting its potential as a useful tool for clinical decision-making. This study demonstrated that the information in dose distribution is worth further exploration, and combining multiple types of features contributes to predict radiotherapy response.

Analysis of the risk factors of radiation pneumonitis and the predictive ability of dosiomics in non-small-cell lung cancer.

Purpose: This prospective study investigated the incidence of radiation pneumonitis (RP) after immunotherapy followed by radiotherapy in non-small-cell lung cancer, analyzed the risk factors for RP, and explored the predictive performance of dosimetry and dosiomics. Methods & materials: Risk factors for grade ≥2 RP were calculated by using a logistic regression model. Predictive performance was compared on the basis of area under the curve values. Results: Grade ≥2 RP occurred in 16 cases (26.7%). The AUC values of V5 Gy, gray-level dependence matrix-small dependence high gray-level emphasis (GLDM-SDHGLE) and combined features were 0.685, 0.724 and 0.734, respectively. Conclusion: Smoking history, bilateral lung V5 Gy and GLDM-SDHGLE were independent risk factors for RP. Dosiomics can effectively predict RP.

Circ_0001955 promotes non-small cell lung cancer cell proliferation and invasion by regulating MiR-29a-3p/NKIRAS2 axis to activate the nuclear factor-κB pathway.

Non-small cell lung cancer (NSCLC) is one of the most common malignant tumors worldwide. Circular RNAs (circRNAs) have been widely reported to play a role in the pathogenesis of various tumors. Nevertheless, the function of circ_0001955 in NSCLC progression has not been explored yet. This study aims to explore the functions of circ_0001955 in NSCLC and investigate its regulatory molecular mechanism. First, we determined that circ_0001955 was upregulated in NSCLC cells. Subsequently, we demonstrated that knockdown of circ_0001955 restrained cell proliferation and invasion. In vivo experiments further proved the suppressive effect of circ_0001955 silence on tumor growth. Mechanism assays revealed that circ_0001955 enhanced nuclear factor-κB (NF-κB) inhibitor interacting Ras-like protein 2 (NKIRAS2) expression by sponging microRNA-29a-3p (miR-29a-3p). Upregulation of NKIRAS2 led to the deceased level of IκBß but increased levels of nuclear p65, thus activating the NF-κB signaling pathway. In conclusion, Circ_0001955 activates the NF-κB pathway to promote NSCLC cell proliferation and invasion by regulating miR-29a-3p/NKIRAS2 axis.

Immunogenic senescence sensitizes lung cancer to LUNX-targeting therapy.

The higher immunogenicity of tumors usually predicts favorable therapeutic responses. Tumor antigens dominate the immunogenic character within tumors. We investigated if there was a targetable tumor antigen during immunogenic chemotherapy within lung cancer. Chemotherapy-induced immunogenic senescence was demonstrated using a multi-marker, three-step workflow, and RNA-sequencing data. The ability of anti-lung-specific X protein (LUNX) antibody to suppress the survival of senescent lung cancer cells was evaluated in vitro and in vivo using real-time cytotoxicity analysis and xenograft mouse models, respectively. The induction of cellular senescence by immunogenic chemotherapy boosted cell-surface shuttling of LUNX and enhanced the immunogenic features of senescent tumor cells, which sensitized lung cancer cells to anti-LUNX antibody-mediated therapy and contributed to tumor suppression. The immunogenic senescence-mediated anti-tumor response was triggered by the direct action of antibody on tumor cells, strengthened by natural-killer cells through an antibody-dependent cell-mediated cytotoxicity response, and ultimately, led to tumor control. Our findings suggest that LUNX is a lung cancer targetable-immunogenic antigen. The proportion of lung cancers responding to LUNX-targeting therapy could be expanded substantially by immunogenic chemotherapy that induces senescence-associated translocation of LUNX to the plasma membrane.

Serum lactate dehydrogenase predicts brain metastasis and survival in limited-stage small cell lung cancer patients treated with thoracic radiotherapy and prophylactic cranial irradiation.

BACKGROUND: Small cell lung cancer (SCLC) is characterized by a high risk of brain metastasis and poor survival. This study aims to assess the prognostic role of lactate dehydrogenase (LDH) in limited-stage small cell lung cancer (LS-SCLC) treated with thoracic radiotherapy (TRT) and prophylactic cranial irradiation (PCI). METHODS: This study retrospectively evaluated 197 consecutive patients who underwent TRT and PCI for LS-SCLC between November 2005 and October 2017. Both pretreatment and maximal serum LDH levels (mLDH) during treatment were checked, and an increased LDH level was defined as more than 240 IU/ml. Clinical factors were tested for associations with intracranial progression-free survival (IPFS) and overall survival (OS) after PCI. The Kaplan-Meier method was used to calculate survival rates, and multivariate Cox regression analyses were carried out to identify variables associated with survival. RESULTS: Of the total patients, 28 had higher pretreatment LDH levels and mLDH levels were increased in 95 patients during treatment. In patients in the normal and elevated mLDH groups, the 1­, 2­, and 5­year IPFS rates were 96.7% vs. 90.1%, 91.7% vs. 73.8%, and 87.8% vs. 61.0% (P < 0.01), respectively. Compared to those with normal LDH levels, patients with increased mLDH levels had a higher cumulative risk of intracranial metastasis (hazard ratio [HR] 3.87; 95% confidence interval [CI] 1.73-8.63; P < 0.01) and worse overall survival (HR 2.59; 95% CI 1.67-4.04; P < 0.01). The factors LDH level at baseline or changes between pretreatment level and maximum level during treatment failed to predict brain metastases or OS with statistical significance. In the multivariate analyses, both mLDH during treatment (HR 3.53; 95% CI 1.57-7.92; P = 0.002) and patient age ≥ 60 (HR 2.46; 95% CI 1.22-4.94; P = 0.012) were independently associated with worse IPFS. Factors significantly associated with worse OS included mLDH during treatment (HR 2.45; 95% CI 1.56-3.86; P < 0.001), IIIB stage (HR 1.75; 95% CI 1.06-2.88; P = 0.029), and conventional radiotherapy applied in TRT (HR 1.66; 95% CI 1.04-2.65; P = 0.034). CONCLUSION: The mLDH level during treatment predicts brain metastasis and survival in LS-SCLC patients treated with TRT and PCI, which may provide valuable information for identifying patients with poor survival outcomes and possible candidates for treatment intensification.

3,3'-Diindolylmethane attenuates inflammation and fibrosis in radiation-induced lung injury by regulating NF-κB/TGF-ß/Smad signaling pathways.

OBJECTIVE: This study aims to investigate the protective effect of 3,3'-diindolylmethane (DIM) on the radiation-induced lung injury (RILI) model and to explore its possible mechanism. Methods: A mouse model of RILI was established by thoracic irradiation, and dexamethasone was used as a positive drug to investigate the effect of DIM on RILI mice. Lung histopathology was analyzed by HE staining and Masson staining. Then the levels of inflammatory cytokines (TGF-ß, TNF-α, IL-1ß, and IL-6), inflammatory cell counts, and activity of MPO were detected. The expression of TGFß1/Smad signaling pathway-related proteins was determined by immunohistochemistry. qPCR was used to analyze the mRNA expression levels of inflammatory factors, α­SMA and COL1A1. The expression of COX-2, NF-κB, IκBα, PI3K, and Akt proteins was assessed by Western blot. Results: Histopathological staining of lung tissues showed that DIM administration alleviated the pulmonary inflammation and fibrosis caused by RILI. Moreover, the content of inflammatory factors such as IL-1ß and IL-6, the expression of NF-κB pathway-related proteins, and the counts of inflammatory cells were inhibited in lung tissue, indicating that DIM can inhibit the NF-κB pathway to reduce inflammation. In addition, DIM could down-regulate the mRNA levels of α-SMA, COL1A1, and downregulate TGFß1, Smad3, and p-Smad2/3 in lung tissues. Conclusion: Our study confirms that DIM has the potential to treat RILI in vivo by inhibiting fibrotic and inflammatory responses in lung tissue through the TGFß/Smad and NF-κB dual pathways, respectively.

Targeting lactate dehydrogenase a improves radiotherapy efficacy in non-small cell lung cancer: from bedside to bench.

BACKGROUND: Lactate dehydrogenase A (LDHA) is overexpressed and associated with poor prognosis in many kinds of cancer. In the current study, we evaluated the prognostic value of LDHA expression in non-small cell lung cancer (NSCLC), and tested whether LDHA inhibition might improve radiotherapy efficacy in NSCLC. METHODS: LDHA expression was investigated in NSCLC patients, using online database and further verified by immunohistochemistry. The prognostic value of LDHA was evaluated using Kaplan-Meier plotter database. In vitro, two NSCLC cell lines were pretreated with oxamate, an inhibitor of LDHA, and colony formation method was performed to determine cellular radiosensitivity. Comet assay was used to detect DNA damage after irradiation. Flow cytometry was applied to test cell cycle progression and apoptosis, and monodansylcadaverine (MDC) staining was used to examine cell autophagy. RESULTS: Both mRNA and protein levels of LDHA expression were up-regulated in NSCLC tissues. High LDHA expression was a poor prognostic factor and associated with radioresistance in NSCLC patients. LDHA inhibition by oxamate remarkably increased radiosensitivity in both A549 and H1975 cancer cells, and enhanced ionizing radiation (IR)-induced apoptosis and autophagy, accompanied by cell cycle distribution alternations. Furthermore, LDHA inhibition induced reactive oxygen species (ROS) accumulation and cellular ATP depletion, which might increase DNA injury and hinder DNA repair activity. CONCLUSIONS: Our study suggests that inhibition of LDHA may be a potential strategy to improve radiotherapy efficacy in NSCLC patients, which needs to be further tested by clinical trials.

Micropapillary pattern of stage IIIA-N2 lung adenocarcinoma is a prognostic factor after adjuvant chemoradiotherapy.

Aim: This study aims to investigate the significance of a micropapillary pattern in stage IIIA-N2 lung adenocarcinoma after adjuvant chemoradiotherapy. Patients & methods: A total of 257 patients with stage IIIA-N2 lung adenocarcinoma were enrolled in this study. Patients were classified into three groups based on the proportion of micropapillary components: micropapillary negative, micropapillary minor component and micropapillary predominant component. Results: The micropapillary predominant group had the shortest median disease-free survival and overall survival times compared with the micropapillary minor component and micropapillary negative groups (median overall survival time: 54 months vs 64 months vs not reached; p = 0.004). Furthermore, the micropapillary pattern was an independent prognostic factor for disease-free survival and overall survival (p < 0.05). Conclusion: The micropapillary pattern of IIIA-N2 lung adenocarcinoma is related to worse prognosis.

HAGLROS is overexpressed and promotes non-small cell lung cancer migration and invasion.

INTRODUCTION: Non-small cell lung cancer was one of the most common and deadly cancers worldwide. Long non-coding RNAs had been implicated in multiple human cancers, including non-small cell lung cancer. In this study, we focused on a novel long non-coding RNA, HAGLROS, in non-small cell lung cancer. MATERIAL AND METHODS: In this study, we used GEPIA dataset to analyse the expression levels of HAGLROS in non-small cell lung cancer samples and normal tissues. Then, we analysed Kaplan-Meier Plotter database to reveal the association between HAGLROS expression and overall survival time in patients with non-small cell lung cancer. Moreover, we used small interfering RNA-mediated knockdown to reduce HAGLROS expression in A549 and H1299 cells. Cell Counting Kit-8 assay was used to detect the effect of HAGLROS on cell proliferation. Transwell assays were used to determine the effect of HAGLROS on cell migration and invasion. Co-expression analysis and bioinformatics analysis were conducted to predict the potential functions of HAGLROS in non-small cell lung cancer. RESULTS: We identified HAGLROS was significantly overexpressed in non-small cell lung cancer samples compared to normal tissues. Higher expression of HAGLROS was significantly associated with shorter overall survival time in patients with non-small cell lung cancer. Moreover, we found knockdown of HAGLROS in non-small cell lung cancer cells remarkably suppressed tumour proliferation, migration and invasion. By conducting bioinformatics analysis, we found HAGLROS was involved in regulating multiple cancer-related pathways, including Spliceosome, DNA replication, cell cycle, chromosome segregation and sister chromatid segregation. CONCLUSIONS: Our results for the first time demonstrated HAGLROS may serve as a target for new therapies in non-small cell lung cancer.

Elevated platelet count is a strong predictor of poor prognosis in stage I non-small cell lung cancer patients.

Stage I non-small cell lung cancer (NSCLC) show a highly variable biological behavior which cannot be accurately predicted by the current available prognostic markers. Platelet plays a significant role in cancer cell growth, progression and metastasis. This study aimed to investigate whether preoperative platelet count correlate with clinical prognosis in localized NSCLC. A retrospective clinical analysis was designed for a total of 234 stage I NSCLC patients in our hospital between October 2006 and December 2009. Pre-operative platelet count was measured. The association of platelet count with clinical pathological factors and patient outcome was evaluated. A significant correlation was detected between platelet count and tumor cell differentiation and T stage. Patients with elevated platelet count had an elevated risk of disease progression and death compared to patients with normal platelet count. The hazard ratio was 5.314 (95% confidence interval [CI] 2.750-10.269) for disease progression and 3.139 (95% CI 1.227-8.034) for death. The trend linking increasing platelet count with risk was also statistically significant for both the outcomes (p < 0.05). These finding demonstrate that preoperative platelet count is a useful predictor of high risk progression and poor prognosis in stage I NSCLC patients.

Pyroptotic T cell-derived active IL-16 has a driving function in ovarian endometriosis development.

Endometriosis, affecting 6%-10% of women, often leads to pain and infertility and its underlying inflammatory mechanisms are poorly understood. We established endometriosis models in wild-type and IL16KO mice, revealing the driver function of IL-16 in initiating endometriosis-related inflammation. Using an in vitro system, we confirmed iron overload-induced GSDME-mediated pyroptosis as a key trigger for IL-16 activation and release. In addition, our research led to the development of Z30702029, a compound inhibiting GSDME-NTD-mediated pyroptosis, which shows promise as a therapeutic intervention for endometriosis. Importantly, our findings extend beyond endometriosis, highlighting GSDME-mediated pyroptosis as a broader pathway for IL-16 release and offering insights into potential treatments for various inflammatory conditions.

Prognostic value of lymphocytes in patients with breast cancer receiving radiotherapy after breast-conserving surgery: A post hoc analysis of a phase III randomized trial.

PURPOSE: To evaluate the prognostic value of peripheral lymphocyte count (PLC) in the breast cancer patients after breast-conserving surgery (BCS) with radiotherapy (RT). METHODS AND MATERIALS: This post hoc analysis was performed using data of 628 patients from a phase III, randomized controlled trial comparing hypofractionated RT (HFRT) with conventional fractionated RT (CFRT) after BCS. PLCs were obtained before, during, and after RT until the 1-year follow-up. The optimal cut-off PLCs were determined using the maxstat package in R. Survival rates were estimated using the Kaplan-Meier method and compared with the log-rank test. RESULTS: A total of 275 (46.1 %) patients developed lymphopenia during RT, among them, 17 (2.8 %) had grade 3 lymphopenia and no one developed grade 4 lymphopenia. With a median follow-up of 110.8 months, patients with pre-RT PLCs of < 1.77 × 109/L had a significantly lower 10-year breast cancer-specific survival (BCSS) rate (P = 0.013) and overall survival (OS) rate (P = 0.026). Patients with a nadir PLC of < 1.35 × 109/L had a significantly poorer 10-year OS rate (P = 0.048). Multivariate analysis showed that a pre-RT PLC of < 1.77 × 109/L was an independent factor influencing BCSS and OS, while the effect of the nadir PLC did not remain significant. Neither PLC nor lymphopenia recovery at post-RT 1, 3, and 6 months and 1 year was associated with survival. CONCLUSIONS: Radiation-induced lymphopenia in patients with breast cancer after BCS tends to be mild. The lower pre-RT PLC predicted poorer survival.

Neoadjuvant SHR-1701 with or without chemotherapy in unresectable stage III non-small-cell lung cancer: A proof-of-concept, phase 2 trial.

We conducted a proof-of-concept, phase 2 trial to assess neoadjuvant SHR-1701 with or without chemotherapy, followed by surgery or radiotherapy, and then consolidation SHR-1701 in unresectable stage III non-small-cell lung cancer (NSCLC). In the primary cohort of patients receiving neoadjuvant combination therapy (n = 97), both primary endpoints were met, with a post-induction objective response rate of 58% (95% confidence interval [CI] 47-68) and an 18-month event-free survival (EFS) rate of 56.6% (95% CI 45.2-66.5). Overall, 27 (25%) patients underwent surgery; all achieved R0 resection. Among them, 12 (44%) major pathological responses and seven (26%) pathological complete responses were recorded. The 18-month EFS rate was 74.1% (95% CI 53.2-86.7) in surgical patients and 57.3% (43.0-69.3) in radiotherapy-treated patients. Neoadjuvant SHR-1701 with chemotherapy, followed by surgery or radiotherapy, showed promising efficacy with a tolerable safety profile in unresectable stage III NSCLC. Surgical conversion was feasible in a notable proportion of patients and associated with better survival outcomes.

The 2002 AJCC TNM classification is a better predictor of primary small cell esophageal carcinoma outcome than the VALSG staging system.

Small cell carcinoma of the esophagus (SCCE) is a rare and aggressive malignant tumor with a poor prognosis. The optimal disease staging system and treatment approaches have not yet been defined. This study aimed to evaluate the prediction of different staging systems for prognosis and treatment options of SCCE. We retrospectively accessed the clinicopathologic characteristics, treatment strategy, and prognosis of 76 patients diagnosed with primary SCCE between 2001 and 2011. The 1-, 2-, 3-, and 5-year overall survival rates were 58%, 31%, 19%, and 13%, respectively. Univariate analysis showed that the 2002 American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) classification (P = 0.002), Veterans Administration Lung Study Group (VALSG) stage (P = 0.001), predisposing factors (P < 0.001), T category (P = 0.023), and M category (P < 0.001) were prognostic factors for overall survival. Multivariate analysis showed that the 2002 AJCC TNM stage (P < 0.001) was the only independent prognostic factor for survival. The value of the area under the receiver operator characteristic (ROC) curve (AUC) of the 2002 AJCC TNM staging system was larger than that of VALSG staging system with regard to predicting overall survival (0.774 vs. 0.620). None of the single treatment regimens showed any benefit for survival by Cox regression analysis. Thus, the 2002 AJCC TMN staging system improved the prediction of SCCE prognosis; however, the optimal treatment regimen for SCCE remains unclear.

Efficacy and safety of thoracic radiotherapy for extensive stage small cell lung cancer after immunotherapy in real world.

The immunotherapy combined chemotherapy has been the standard treatment strategy for extensive-stage small lung cancer (ES-SCLC). The CREST trial reported consolidative thoracic radiotherapy (cTRT) improved overall survival (OS) for ES-SCLC with intrathoracic residual after chemotherapy. In this study, patients with ES-SCLC who received immunotherapy were assigned to receive either TRT or no TRT. TRT significantly improved progression-free survival (PFS), local recurrence-free survival (LRFS) and OS with well tolerated toxicity. Further sub-cohort analysis, TRT significantly improved LRFS in patients with oligo-metastasis and without liver metastasis.

Quality assurance in a phase III, multicenter, randomized trial of POstmastectomy radioThErapy in Node posiTive breast cancer with or without Internal mAmmary nodaL irradiation (POTENTIAL): a planning benchmark case.

PURPOSE: To report the planning benchmark case results of the POTENTIAL trial-a multicenter, randomized, phase 3 trial-to evaluate the value of internal mammary nodal (IMN) irradiation for patients with high-risk breast cancer. METHODS: All participating institutions were provided the outlines of one benchmark case, and they generated radiation therapy plans per protocol. The plans were evaluated by a quality assurance team, after which the institutions resubmitted their revised plans. The information on beams arrangement, skin flash, inhomogeneity corrections, and protocol compliance was assessed in the first and final submission. RESULTS: The plans from 26 institutions were analyzed. Some major deviations were found in the first submission. The protocol compliance rates of dose coverage for the planning target volume of chest wall, supraclavicular fossa plus axilla, and IMN region (PTVim) were all significantly improved in the final submission, which were 96.2% vs. 69.2%, 100% vs. 76.9%, and 88.4% vs. 53.8%, respectively. For OARs, the compliance rates of heart Dmean, left anterior descending coronary artery V40Gy, ipsilateral lung V5Gy, and stomach V5Gy were significantly improved. In the first and final submission, the mean values of PTVim V100% were 79.9% vs. 92.7%; the mean values of heart Dmean were 11.5 Gy vs. 9.7 Gy for hypofractionated radiation therapy and 11.5 Gy vs. 11.0 Gy for conventional fractionated radiation therapy, respectively. CONCLUSION: The major deviations were corrected and protocol compliance was significantly improved after revision, which highlighted the importance of planning benchmark case to guarantee the planning quality for multicenter trials.

Thyroid Dysfunction as a Predictive Indicator in Camrelizumab of Advanced Esophageal Squamous Cell Carcinoma.

Thyroid dysfunction (TD) induced by programmed death-1 (PD-1) or programmed cell death-ligand 1 (PD-L1) immune checkpoint inhibitors (ICIs) has been widely reported. However, the effects of ICI-induced TD on the survival of patients with esophageal squamous cell carcinoma (ESCC) have not been described. Herein, a retrospective study was conducted, which 82 patients with advanced metastatic or recurrent ESCC treated with camrelizumab were enrolled. Twenty patients (24.4%) experienced TD during camrelizumab treatment with or without chemotherapy. The median onset time of TD was 1.7 months. The incidence of TD was 35.6% in patients who previously received thoracic radiotherapy versus 10.8% in patients who did not (P =0.009). Patients with TD had significantly longer median progression-free survival (5.5 months vs 3.5 months, P =0.035) and overall survival (26.7 months vs 11.5 months, P <0.001). TD is frequently observed in ESCC patients treated with camrelizumab and especially in patients who received radiotherapy previously. ESCC patients with TD during ICIs treatment often have better prognosis.

Treatment Patterns and Outcomes of Elderly Patients With Potentially Curable Esophageal Cancer.

OBJECTIVES: The proportion of elderly patients with esophageal cancer (EC) is increasing due to prolonged life expectancy and aging process. The aim of the study is to explore the optimal treatment strategy for elderly patients (aged ≥70 years) with locally advanced EC. METHODS: Eligible patients with cT2-4aNxM0 EC were identified in the Surveillance, Epidemiology, and End Results database from 2010 to 2016. Treatment patterns were divided into six groups: surgical resection (S), chemoradiotherapy (CRT), trimodality therapy (CRT+S), radiotherapy (RT), chemotherapy (CT), or observation with no treatment (Obs). Survival between groups was compared using the log-rank test, and the Cox proportional hazards model was used to identify factors associated with overall survival (OS). RESULTS: A total of 2917 patients with potentially curable EC were identified. Of all the patients included, 6.7%, 51.8%, 18.0%, 9.4% and 3.6%received S, CRT, CRT+S, RT, and CT, respectively, whereas 10.6% underwent Obs. The 3-year OS estimates were 30.2% (95% confidence interval [CI]: 23.5-38.9%), 25.4% (95% CI: 22.8-28.3%),44.3% (95% CI: 39.3-49.9%), 11.4% (95% CI: 7.7-17.0%), 16.1% (95% CI: 9.1-28.3%), and 5.6% (95% CI: 3.2-9.8%) for S, CRT, CRT+S RT, CT, and Obs (p<0.001), respectively. Overall, patents underwent CRT+S had the longest OS, compared to other treatment patterns, and the survival difference was not significant between patients receiving CRT and S (p=0.12) in the elderly population. However, the survival benefits of trimodality therapy over CRT gradually weakened with the increase in age, and became statistically non-significant for EC patients aged ≥80 years (p=0.35). Multivariate analysis showed that treatment patterns, age, sex, tumor grade, T stage, N stage, and marital status were significantly associated with OS. CONCLUSION: Generally, the use of trimodality therapy was associated with the longest OS, the survival benefits were comparable between CRT and S alone, and CRT was superior to RT or CT alone in elderly patients with curable EC. For patients intolerable to surgery or aged ≥80 years, definitive CRT should be considered as a preferable option.

Human-Induced CD49a+ NK Cells Promote Fetal Growth.

CD49a+ natural killer (NK) cells play a critical role in promoting fetal development and maintaining immune tolerance at the maternal-fetal interface during the early stages of pregnancy. However, given their residency in human tissue, thorough studies and clinical applications are difficult to perform. It is still unclear as to how functional human CD49a+ NK cells can be induced to benefit pregnancy outcomes. In this study, we established three no-feeder cell induction systems to induce human CD49a+ NK cells from umbilical cord blood hematopoietic stem cells (HSCs), bone marrow HSCs, and peripheral blood NK cells in vitro. These induced NK cells (iNKs) from three cell induction systems display high levels of CD49a, CD9, CD39, CD151 expression, low levels of CD16 expression, and no obvious cytotoxic capability. They are phenotypically and functionally similar to decidual NK cells. Furthermore, these iNKs display a high expression of growth-promoting factors and proangiogenic factors and can promote fetal growth and improve uterine artery blood flow in a murine pregnancy model in vivo. This research demonstrates the ability of human-induced CD49a+ NK cells to promote fetal growth via three cell induction systems, which could eventually be used to treat patients experiencing adverse pregnancy outcomes.