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With few options available for the effective treatment of multidrug-resistant bacteria, photodynamic therapy (PDT) has emerged as a promising therapeutic strategy that does not promote the development of antibiotic resistance. Unfortunately, the beneficial bactericidal effect of PDT is oftentimes accompanied by the uncontrollable production of reactive oxygen species. To overcome this issue, a pore-forming toxin (PFT)-responsive biomimetic nanobubble is designed, which is constructed by co-encapsulating a perfluorocarbon nanoemulsion and a photosensitizer within the red blood cell membrane. It is shown that PFTs derived from three pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), group A Streptococcus (GAS), and Listeria monocytogenes (LM), can be effectively absorbed by the nanobubble. Upon toxin absorption, the formation of pores on the nanobubble surface allows the accelerated release of oxygen dissolved inside the nanoemulsion along with the photosensitizer, thus resulting in enhanced PDT and bactericidal efficacy. In three skin infection models, treatment with the nanobubbles results in significantly decreased lesion formation and reduced inflammation. In addition to oxygen, the platform can be used to deliver nitric oxide in a bacterial toxin-dependent manner. Overall, biomimetic nanobubbles may work as a broad gas delivery system that is capable of responding to a variety of PFT-based stimuli for precision PDT.

Purpose: Clonal architecture is fundamental for the understanding of cancer biology and therapy; however, multiregional sampling in advanced-stage cancers is not always applicable. This prospective clinical trial was to investigate whether paired tissue and circulating tumor DNA (ctDNA) could describe the clonal architecture of advanced non–small cell lung cancer (NSCLC) and its association with clinical outcome (NCT03059641). Patients and Methods: Paired tumor and plasma ctDNA samples were sequenced by target-capture deep sequencing of 1,021 genes. Clonal dominance analysis was performed on the basis of PyClone. Results: Overall, 300 treatment-naïve patients with stage IIIB–IV NSCLC were recruited from 14 centers. Of the 94 patients with available ctDNA data for EGFR clonal architecture analysis, 72 (76.6%) showed EGFR as the dominant clone. The median progression-free survival was longer for these patients than for the 22 patients whose EGFR was nondominant clone [11 vs. 10 months; HR, 0.46; 95% confidence interval (CI), 0.24–0.88; P = 0.02]. The difference was more significant if both tissue and ctDNA defined EGFR as dominant clone (n = 43) versus those not (n = 8; 11 vs. 6 months; HR, 0.13; 95% CI, 0.04–0.50; P = 0.003). Moreover, multivariate Cox proportional HR analysis demonstrated EGFR clonal architecture as an independent prognostic indicator of the efficacy of EGFR-tyrosine kinase inhibitors (TKIs). Conclusions: Paired tissue and ctDNA could be analyzed for clonal architecture in advanced cancer. EGFR mutations do not always make up a dominant clone in advanced NSCLC, which was associated with the efficacy of EGFR-TKIs in NSCLC.

Background: Cancer is a leading cause of death worldwide. Extensive research over decades has led to the development of therapies that inhibit oncogenic signaling pathways. The mammalian target of rapamycin (mTOR) signaling pathway plays an important role in the development of many cancers. Several mTOR inhibitors are approved for the treatment of cancers. However, the anticancer efficacies of mTOR inhibitor monotherapy are still limited. Methods: Western blot was used to detect the expression of indicated molecules. Thioredoxin reductase (TrxR) activity in cells was determined by the endpoint insulin reduction assay. Immunofluorescence staining was used to analyze precise location and expression of target proteins. Nude mice were used for xenograft tumor models. Results: We identified a synergistic lethal interaction of mTOR and TrxR inhibitors and elucidated the underlying molecular mechanisms of this synergism. We demonstrated that mTOR and TrxR inhibitors cooperated to induce cell death by triggering oxidative stress, which led to activation of autophagy, endoplasmic reticulum (ER) stress and c-Jun N-terminal Kinase (JNK) signaling pathway in cancer cells. Remarkably, we found that auranofin (AF) combined with everolimus significantly suppressed tumor growth in HCT116 and SGC-7901 xenograft models with no significant signs of toxicity. Conclusion: Our findings identify a promising therapeutic combination for cancer and has important implications for developing mTOR inhibitor-based combination treatments.

An accurate and reliable target volume delineation is critical for the safe and successful radiotherapy. The purpose of this study is to develop new 2D and 3D automatic segmentation models based on RefineNet for clinical target volume (CTV) and organs at risk (OARs) for postoperative cervical cancer based on computed tomography (CT) images.A 2D RefineNet and 3D RefineNetPlus3D were adapted and built to automatically segment CTVs and OARs on a total of 44 222 CT slices of 313 patients with stage I-III cervical cancer. Fully convolutional networks (FCNs), U-Net, context encoder network (CE-Net), UNet3D, and ResUNet3D were also trained and tested with randomly divided training and validation sets, respectively. The performances of these automatic segmentation models were evaluated by Dice similarity coefficient (DSC), Jaccard similarity coefficient, and average symmetric surface distance when comparing them with manual segmentations with the test data.The DSC for RefineNet, FCN, U-Net, CE-Net, UNet3D, ResUNet3D, and RefineNet3D were 0.82, 0.80, 0.82, 0.81, 0.80, 0.81, and 0.82 with a mean contouring time of 3.2, 3.4, 8.2, 3.9, 9.8, 11.4, and 6.4 s, respectively. The generated RefineNetPlus3D demonstrated a good performance in the automatic segmentation of bladder, small intestine, rectum, right and left femoral heads with a DSC of 0.97, 0.95, 091, 0.98, and 0.98, respectively, with a mean computation time of 6.6 s.The newly adapted RefineNet and developed RefineNetPlus3D were promising automatic segmentation models with accurate and clinically acceptable CTV and OARs for cervical cancer patients in postoperative radiotherapy.

Multi‐isocenter volumetric modulated arc therapy (VMAT) is recommended for craniospinal irradiation (CSI) to smooth the dose distribution in the junction regions relying solely on inverse optimization. However, few studies have measured the dosimetric impact of setup errors on this multi‐isocenter VMAT in the junction areas. The purpose of this study is to evaluate the impact of positional errors during VMAT CSI with two‐dimension (2D) and three‐dimension (3D) dosimetric measurements. A total of 20 patients treated by three‐isocenter VMAT CSI were retrospectively reviewed and analyzed. A 3D diode array ArcCHECK and radiochromic film EBT3 were applied to measure the percentage gamma passing rates (%GPs) and dose distributions in the junction areas between the cranial/upper‐spinal and the upper/lower‐spinal fields with intentionally introduced setup errors of ± 1 mm, ±2 mm, ±3 mm, ±5 mm, and ± 8 mm, respectively. The length and volume of planning target volume (PTV) for these CSI patients ranged from 50.14 to 80.8 cm, and 1572.3 to 2114.5 cm3, respectively. The %GPs for ±3 mm, ±5 mm, and ±8 mm positional errors were around 95%, 90%, and 85%, respectively, in the junction areas. The dosimetric verification results with EBT3 films indicated that cold and hot areas were observed with the increase of introduced setup errors. In conclusion, the dosimetric verification with intentionally introduced setup errors demonstrated that positional errors within 3 mm have a little impact for VMAT CSI, although setup errors should be minimized. Relying on the inverse optimization of VMAT to smooth the dose distribution in the junction areas is feasible for CSI.

BackgroundTo report the long-term outcomes of a phase III trial designed to test two hypotheses: (1) elective nodal irradiation (ENI) is superior to conventional field irradiation (CFI), and (2) chemoradiotherapy plus erlotinib is superior to chemoradiotherapy in locally advanced oesophageal squamous cell cancer (ESCC).MethodsPatients with locally advanced ESCC were randomly assigned (1:1:1:1 ratio) to one of the four groups: A: radiotherapy adoption of ENI with two cycles of concurrent TP chemotherapy (paclitaxel and cisplatin) plus erlotinib; B: radiotherapy adoption of ENI with two cycles of concurrent TP; C: radiotherapy adoption of CFI with two cycles of concurrent TP plus erlotinib and D: radiotherapy adoption of CFI with two cycles of concurrent TP. A total of 60 Gy of radiation doses was delivered over 30 fractions. We explored the impact of epidermal growth factor receptor (EGFR) expression on the efficacy of erlotinib plus chemoradiotherapy.ResultsA total of 352 patients (88 assigned to each treatment group) were enrolled. The 5-year survival rates were 44.9%, 34.8%, 33.8% and 19.6% in groups A, B, C and D, respectively (P = 0.013). ENI significantly improved OS compared with standard CFI (median, 38.5 vs 22.6 months; HR, 0.74;P = 0.018). The addition of erlotinib significantly improved OS (median, 39.4 vs 27.4 months; HR, 0.75;P = 0.025). Patients with overexpressing EGFR treated with erlotinib had a better OS and PFS than those without erlotinib.ConclusionsConcurrent chemoradiotherapy with ENI and/or erlotinib improved long-term survival in locally advanced ESCC.Clinical trial registrationTrial registration: NCT00686114.

Objective To research and assess automatic volumetric modulated arc therapy (VMAT) planning methods for patients with intraocular cancer. Methods The mdaccAutoPlan system was added to the Pinnacle3 treatment planning system as a plug‐in. Automatic VMAT plans were generated for 10 patients diagnosed with intraocular cancer, and evaluated according to standard dose‐volume histogram parameters. Results The planning target volume of enrolled patients ranges from 14.24 to 50.69 cm3. Both planning methods lead to acceptable planning target volume target coverage with a V95 of 97.9 ± 1.4% and 96.4 ± 1.5% for manual and automatic plans (P = 0.03), respectively. Automatic planning lowered the dose delivered to the ipsilateral lens and optical nerves, but increased the dose to the brainstem compared with manual planning. Automatic planning significantly prolonged VMAT planning time (3.25 ± 0.53 h vs. 1.02 ± 0.69 h, P

Purpose To evaluate the predictive value of blood lymphocyte, monocyte to lymphocyte ratio (MLR), and neutrophil to lymphocyte ratio (NLR) for radiation pneumonia (RP) in patients with thoracic tumors receiving radiotherapy. Patients and Methods The clinical data of 65 patients with thoracic tumor (esophageal cancer, lung cancer) treated by radiotherapy in our hospital were retrospectively analyzed. Patients were divided into the RP group and the non-RP group according to the Common Terminology Criteria for Adverse Events (CTCAE 5.0). Data on blood cell counts, including lymphocytes, monocytes, and neutrophils, were collected before (0 weeks) and after 1, 2, and 4 weeks of radiotherapy. Results Of the 65 patients enrolled, 27 developed radiation pneumonia and 38 did not. Patients' clinical factors, including age, TNM stage, tumor type, underlying lung disease, and history of smoking, had no correlation with RP. ANOVA of repeated measurement data showed that the changes of MLR in the group with RP during radiotherapy were significantly different from those in the non-RP group (P

It is of high clinical importance to identify the primary lesion and its pathological types for patients with brain metastases (BM). The purpose of this study is to investigate the feasibility and accuracy of differentiating the primary adenocarcinoma (AD) and squamous cell carcinoma (SCC) of non-small-cell lung cancer (NSCLC) for patients with BM based on radiomics from brain contrast-enhanced computer tomography (CECT) images. A total of 144 BM patients (94 male, 50 female) were enrolled in this study with 102 with primary lung AD and 42 with SCC, respectively. Radiomics features from manually contoured tumors were extracted using python. Mann–Whitney U test and the least absolute shrinkage and selection operator (LASSO) logistic regression were applied to select relative radiomics features. Binary logistic regression and support vector machines (SVM) were applied to build models with radiomics features alone and with radiomics features plus age and sex. Fourteen features were selected from a total of 105 radiomics features for the final model building. The area under the curves (AUCs) and accuracy of SVM and binary logistic regression models were 0.765 vs. 0.769, 0.795 vs.0.828, and 0.716 vs. 0.726, 0.768 vs. 0.758, respectively, for models with radiomics features alone and models with radiomics features plus sex and age. Brain CECT radiomics are promising in differentiating primary AD and SCC to achieve optimal therapeutic management in patients with BM from NSCLC. • It is of high clinical importance to identify the primary lesion and its pathological types for patients with brain metastases (BM) to define the prognosis and treatment. • Few studies had investigated the feasibility and accuracy of differentiating the pathological subtypes of primary non-small-cell lung cancer between adenocarcinoma (AD) and squamous cell carcinoma (SCC) for patients with BM based on radiomics from brain contrast-enhanced CT (CECT) images, although CECT images are often the initial imaging modality to screen for metastases and are recommended on equal footing with MRI for the detection of cerebral metastases. • Brain CECT radiomics are promising in differentiating primary AD and SCC to achieve optimal therapeutic management in patients with BM from NSCLC with a highest area under the curve (AUC) of 0.828 and an accuracy of 0.758, respectively.

Cancer immunotherapy has become a well-established treatment option for some cancers; however, its use is hampered by its cardiovascular adverse effects. Immune checkpoint inhibitors (ICIs)-related cardiac toxicity took place in kinds of different forms, such as myocarditis, acute coronary syndrome, and pericardial disease, with high mortality rates. This study aimed to investigate the roles of programmed death-1 (PD-1) inhibitor, one of widespread used ICIs, in the development of murine cardiac injury. PD-1 inhibitor is known to transduce immunoregulatory signals that modulate macrophages polarization to attack tumor cells. Hence, this study explored whether the cardiovascular adverse effects of PD-1 inhibitor were related to macrophage polarization. MicroRNA-34a (miR-34a), which appears to regulate the polarization of cultured macrophages to induce inflammation, is examined in cardiac injury and macrophage polarization induced by the PD-1 inhibitor. As a target of miR-34a, Krüppel-like factor 4 (KLF4) acted as an anti-inflammation effector to take cardiac protective effect. Further, it investigated whether modulating the miR-34a/KLF4-signaling pathway could influence macrophage polarization. The PD-1 inhibitor markedly induced M1 phenotype macrophage polarization with impaired cardiac function, whereas miR-34a inhibitor transfection treatment reversed M1 polarization and cardiac injury in vivo. In vitro, PD-1 inhibitor-induced M1 polarization was accompanied by an increase in the expression of miR-34a but a decrease in the expression of KLF4. TargetScan and luciferase assay showed that miR-34a targeted the KLF4 3′-untranslated region. Either miR-34a inhibition or KLF4 overexpression could abolish M1 polarization induced by the PD-1 inhibitor. The findings strongly suggested that the PD-1 inhibitor exerted its effect in promoting M1 polarization and cardiac injury by modulating the miR-34a/KLF4-signaling pathway and inducing myocardial inflammation. These findings might help us to understand the pathogenesis of cardiac injury during immunotherapy, and provide new targets in ameliorating cardiac injury in patients with cancer receiving PD-1 inhibitor treatment.

The clinical application of doxorubicin (Dox) is limited due to its undesirable cardiotoxicity side effects. Cellular senescence plays an important role in Dox-induced cardiotoxicity. Exosomes derived from stem cells showed a therapeutic effect in Dox-induced cardiomyopathy (DIC). Hypoxia-preconditioned exosomes (exosomeHypoxia) display pro-metabolism and pro-survival abilities. Several long-noncoding RNAs/microRNAs act as competing endogenous RNAs (ceRNAs) modulating DIC. No study investigated whether exosomeHypoxia could attenuate DIC through modulating ceRNAs. Treatment of the human adipose–derived mesenchymal stem cells with hypoxia induced lncRNA-MALAT1 accumulation in the secreted exosomes. In addition, the lncRNA-MALAT1 was identified as an exosomal transfer RNA to repress miR-92a-3p expression. Silencing the lncRNA-MALAT1 in MSCs or miR-92a-3p overexpression in cardiomyocytes significantly impaired the rejuvenation induced by exosomeHypoxia. TargetScan and luciferase assay showed that miR-92a-3p targeted the ATG4a 3' untranslated region. Silencing ATG4a blocked the anti-senescent effect of exosomeHypoxia. This study identified the lncRNA-MALAT1 that functioned as ceRNA binding to miR-92a-3p, leading to ATG4a activation, thus improving mitochondrial metabolism. LncRNA-MALAT1/miR-92a-3p/ATG4a partially mediates the cardioprotective roles of exosomeHypoxia in Dox-induced cardiac damage. ExosomeHypoxia may serve as a potential therapeutic target against DIC.

Pancreatic cancer is one of the world's leading causes of cancer-related death. Activation of STAT3 has been reported as a major contributor in pancreatic cancer tumorigenesis and chemoresistance. However, treatment of advanced pancreatic cancer patients with STAT3 inhibitors often meets drug resistance and heterogeneous response. We found that EGFR activation is a main cause for resistance to STAT3 inhibitors in pancreatic cancer cells, regardless of KRAS mutation status. Mechanistically, inhibition of STAT3 promotes STAT1- and STAT4-mediated TGF-α expression, leading to activation of the EGFR pathway. Combined treatment of pancreatic cancer cells with EGFR and STAT3 inhibitors persistently blocks EGFR and STAT3 signaling, and exerts synergistic antitumor activity both in vitro and in vivo, with or without KRAS mutation. Our results indicate that reciprocal cross-talk between STAT3 and EGFR pathways is a key molecular mechanism leading to resistance in pancreatic cancer cells. Furthermore, the study shows that combined inhibition of both EGFR and STAT3 might overcome drug resistance encountered during treatment with single agent alone. This study suggests an improved therapeutic strategy, through combined treatment with STAT3 and EGFR inhibitors, for pancreatic cancer patients.

To investigate the feasibility and accuracy of radiomics models based on contrast-enhanced CT (CECT) in the prediction of perineural invasion (PNI), so as to stratify high-risk recurrence and improve the management of patients with gastric cancer (GC) preoperatively.Total of 154 GC patients underwent D2 lymph node dissection with pathologically confirmed GC and preoperative CECT from an open-label, investigator-sponsored trial (NCT01711242) were enrolled. Radiomics features were extracted from contoured images and selected using Mann-Whitney U test and the least absolute shrinkage and selection operator (LASSO) after inter-class correlation coefficient (ICC) analysis. Models based on radiomics features (R), clinical factors (C) and combined parameters (R + C) were built and evaluated using Support Vector Machine (SVM) and logistic regression to predict the PNI for patients with GC preoperatively.Total of 11 radiomics features were selected for final analysis, along with two clinical factors. The area under curve (AUC) of models based on R, C, and R + C with logistic regression and SVM were 0.77 vs. 0.83, 0.71 vs.0.70, 0.86 vs. 0.90, and 0.73 vs.0.80, 0.62 vs. 0.64, 0.77 vs. 0.82 in the training and testing cohorts, respectively. SVM(R + C) achieved a best AUC of 0.82(0.69-0.94) in the test cohorts with a sensitivity, specificity and accuracy of 0.63, 0.91, and 0.77, respectively.The performance of these models indicates that radiomics features alone or combined with clinical factors provide a feasible way to classify patients preoperatively and improve the management of patients with GC.

Globally, colorectal cancer (CRC) is one of the leading causes of cancer-related deaths. Oxaliplatin based treatments are frequently used as chemotherapeutic methods for CRC, however, associated side effects and drug resistance often limit their clinical application. Dihydroartemisinin (DHA) induces apoptosis in various cancer cells by increasing reactive oxygen species (ROS) production. However, the direct target of DHA and underlying molecular mechanisms in oxaliplatin-mediated anti-tumor activities against CRC are unclear.We used 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT), flow cytometry, and colony formation assays to investigate cell phenotype alterations and ROS generation. We also used quantitative Real-Time PCR (qRT-PCR) and western blotting to measure relative gene and protein expression. Finally, an in vivo mouse xenograft model was used to assess the anti-tumor activity of oxaliplatin and DHA alone, and combinations.DHA synergistically enhanced the anti-tumor activity of oxaliplatin in colon cancer cells by regulating ROS-mediated ER stress, signal transducer and activator of transcription 3 (STAT3), C-Jun-amino-terminal kinase (JNK), and p38 signaling pathways. Mechanistically, DHA increased ROS levels by inhibiting peroxiredoxin 2 (PRDX2) expression, and PRDX2 knockdown sensitized DHA-mediated cell growth inhibition and ROS production in CRC cells. A mouse xenograft model showed strong anti-tumor effects from combination treatments when compared with single agents.We demonstrated an improved therapeutic strategy for CRC patients by combining DHA and oxaliplatin treatments.

Purpose Apatinib is effective and safe for several advanced or metastatic cancers, but its therapeutic value in cervical cancer is still unknown. The aim of the study was to assess the therapeutic value of apatinib in patients with chemo-refractory advanced cervical cancer. Patients and methods This was a retrospective study of patients with advanced cervical cancer treated with apatinib between April 2015 and December 2018 at the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. Patients had to have failed at least 2 lines of chemotherapy prior to receiving apatinib. The clinical tumor response was evaluated after 4 weeks of apatinib treatment, and then every 8 weeks (two cycles). Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and adverse events were evaluated. Results Twenty-five patients were included in this study. The median PFS was 5.8 months (95% CI, 4.65-6.95), and the median OS was 12.2 months (95% CI, 8.99-15.41). ORR was 48% and DCR was 96%. Complete response was not observed. The most common adverse events in this study (all grades) were hand-foot syndrome (48%), hypertension (20%), and mouth mucositis (20%). Conclusion Apatinib monotherapy showed good therapeutic value with tolerable adverse events for patients with chemo-refractory advanced cervical cancer.

Acquired radioresistance is one of the main obstacles for the anti‐tumour efficacy of radiotherapy in oesophageal cancer (EC). Recent studies have proposed microRNAs (miRNAs) as important participators in the development of radioresistance in various cancers. Here, we investigated the role of miR‐1275 in acquired radioresistance and epithelial‐mesenchymal transition (EMT) in EC. Firstly, a radioresistant cell line KYSE‐150R was established, with an interesting discovery was observed that miR‐1275 was down‐regulated in KYSE‐150R cells compared to the parental cells. Functionally, miR‐1275 inhibition elevated radioresistance in KYSE‐150 cells via promoting EMT, whereas enforced expression of miR‐1275 increased radiosensitivity in KYSE‐150R cells by inhibiting EMT. Mechanically, we demonstrated that miR‐1275 directly targeted WNT1 and therefore inactivated Wnt/β‐catenin signalling pathway in EC cells. Furthermore, WNT1 depletion countervailed the promoting effect of miR‐1275 suppression on KYSE‐150 cell radioresistance through hampering EMT, whereas WNT1 overexpression rescued miR‐1275 up‐regulation‐impaired EMT to reduce the sensitivity of KYSE‐150R cells to radiation. Collectively, our findings suggested that miR‐1275 suppressed EMT to encourage radiosensitivity in EC cells via targeting WNT1‐activated Wnt/β‐catenin signalling, providing a new therapeutic outlet for overcoming radioresistance of patients with EC.

Background Controversial conclusions had been reported in studies trying to confirm the impact of heart dose on overall survival (OS) reported in RTOG 0167 for non-small cell lung cancer (NSCLC) patients who underwent radiotherapy (RT). The purpose of this study is to investigate the association of lung and heart dosimetric parameters with OS in NSCLC patients treated by volumetric modulated arc therapy (VMAT). Methods Inoperable NSCLC patients treated by VMAT from March 2012 to December 2015 were retrospectively reviewed. OS and progression-free survival (PFS) were estimated with the Kaplan-Meier method. Univariate and multivariate analyses were conducted with Cox proportional hazards model. Multivariate model building was conducted using stepwise regression for variables with p-value smaller than 0.2 in the univariate analysis. Results There were 130 NSCLC patients enrolled in this study with a median age of 63 years (range from 34 to 82 y). The median prescription dose for these patients was 56 Gy (range 40-70 Gy) with a mean heart and lung dose of 14.8±8.5 Gy and 13.6±4.4 Gy, respectively. The rates of patients with above grade III radiation pneumonitis (RP) and fibrosis were 8.5% and 8.5%, respectively. The 2-year PFS and OS of these patients were 15.2% and 39.8%, with a median PFS and OS of 7.2 and 18.8 months, respectively. RP was correlated with OS (p=0.048) and lung V20 was associated with PFS (p=0.04) according to the univariate analysis. Multivariate analysis demonstrated that RP (HR 1.39, 95%CI 1.010-1.909, p=0.043) and heart V15 (HR 1.02, 95%CI 1.006-1.025 p=0.002) were progression factors of OS, and no factor was associated with PFS. Conclusions RP and heart V15 were associated with OS for patients with stage III NSCLC who underwent VMAT. Heart and lung dosimetric parameters were highly correlated with each other, sparing of heart and lung should be considered equally during the treatment planning.

The value of adjuvant therapy for esophageal squamous cell carcinoma (ESCC) has been controversial, at least partially due to the lack of efficient criteria for selecting suitable patients. This study aimed to explore the existence of parameters related to lymph node (LN) status that can predict the value of adjuvant therapy in ESCC. The study included 298 patients with ESCC who had undergone radical esophagectomy with lymphadenectomy. Adjuvant therapy was defined as reception of adjuvant chemotherapy, radiotherapy, or chemoradiotherapy. For the study, LN ratio (LNR), total number of resected LNs (TLNs), and pN stage were selected for Cox regression analyses, including their correlations and prognostic values for survival. Log-rank tests were used to compare the survival rates of the patients with and without adjuvant therapy stratified by pN stage, TLNs, LNR, or their combinations. The independent prognostic factors for survival were TLNs, LNR, and pN stage. Whereas pN stage was significantly related to TLNs and LNR, TLNs were not correlated with LNR. The survival rates between the patients with and those without adjuvant therapy stratified by pN stage, TLNs, or LNR did not differ significantly. We used the median values of TLNs and LNR to group the patients into four groups. The patients in the group with fewer TLNs and higher LNR who had undergone adjuvant therapy showed a significantly better survival than those without adjuvant therapy (p = 0.030). In contrast to TLNs, LNR, and pN stage as single factors, the combination of TLNs and LNR can predict the value of adjuvant therapy.

Purpose: To investigate the radiological features on magnetic resonance imaging (MRI) of brain metastases (BM) from ALK-rearranged non-small cell lung cancer (NSCLC). Patients and Methods: We retrospectively evaluated data from 40 eligible patients with ALK-rearranged NSCLC. Radiographic features of metastatic brain tumors, including the number, size, location, and peritumoral brain edema size (PBES), were delineated using MRI. Results: 13 patients had metachronous BM (MBM), having developed BM at least 6 months after diagnosis with NSCLC. The remaining patients were categorized as having synchronous BM (SBM). Compared with patients in the SBM group, patients in the MBM group were found to have more favorable values for radiological features including BM number, BM size, and PBES. Ten (76.9%) of the 13 patients with MBM had ≤3 lesions and were asymptomatic, and none had developed a diffuse BM pattern, supporting the adoption of stereotactic radiosurgery (SRS) in the majority of these patients and against the administration of prophylactic cranial irradiation (PCI). Conversely, among the 27 patients with SBM, 15 (55.6%) patients had >3 lesions and 12 (44.4%) patients were symptomatic, highlighting the necessity of rapidly administrating brain radiotherapy, either as SRS or whole brain radiotherapy (WBRT). Importantly, only two patients (5.0%) had metastases in the hippocampus and peri-hippocampus region, and both were in the SBM group, indicating the feasibility of hippocampal avoidance WBRT in ALK-rearranged NSCLC. Conclusions: Both WBRT and SRS are appropriate for the treatment of BM in patients with ALK-rearranged NSCLC. The incidence of BM in the hippocampus and peri-hippocampus region is low in our radiological data. Nearly 80% of patients with metachronous BM have oligo-metastatic lesions, indicating that SRS is the preferred therapy while PCI is not indicated.

Background: Published data on the effects and toxicities of volumetric modulated arc therapy (VMAT) in the management of inoperable lung cancer are scarce. Materials and methods: The clinical outcomes and pulmonary toxicities of 134 patients with consecutive inoperable lung cancer who underwent VMAT from March 2011 to September 2016 were retrospectively reviewed. The dosimetric and characteristic factors associated with acute radiation pneumonitis (RP) and pulmonary fibrosis were evaluated with univariate and multivariate analysis. Results: The average prescription doses to these 134 patients were 57.07±6.27 Gy (range 52-64 Gy). The overall median follow-up time was 18.6 months (range, 2-45 mo), with a median follow-up time for the surviving patients of 20 months (range, 7-45 mo). The 2-year progression-free survival (PFS) and overall survival (OS) for all patients were 18.2% and 38.4%, with a median PFS and OS of 7.6 months and 18.6 months, respectively. The percent of patients with grade III/higher RP and pulmonary fibrosis were 10.5% and 9.0%, respectively. V13 (p=0.02) and age (p=0.02) were independently associated with acute RP according to multivariate analysis. The constraints for lung dosimetric metrics V10,V13,V20 and V30 were approximately 49%,41%,26% and 17% in VMAT treatment of lung cancer to limit the RP rate < 10%. Conclusion: VMAT can be delivered safely with acceptable acute and late toxicities for lung cancer patients. Lung dosimetric metrics were valuable in predicting acute RP. A lung V13 constraint of 40% was helpful to limit the RP rate < 10% in VMAT treatment of lung cancer patients.

e16181 Background: The effect of checkpoint inhibitor therapy on HBV infection is uncertain. TIS, an anti-PD-1 antibody, was clinically active and well tolerated in pts with previously treated advanced HCC in the Phase 2 RATIONALE-208 study (NCT03419897). Objective response rate by independent committee review (IRC) in pts with a history of HBV infection was consistent with the overall population (12.5% vs 13.3%, respectively). We explored whether TIS treatment was associated with increased HBV DNA and the clinical significance of HBV DNA elevations. Methods: Pts with ≥ 1 prior systemic therapy for advanced HCC received TIS 200 mg IV Q3W. Pts with inactive, chronic, or active HBV were eligible if HBV DNA levels were < 500 IU/mL at screening (pts with detectable hepatitis B surface antigen [HBsAg] or detectable HBV DNA were required to be managed per treatment guidelines). HBV DNA testing was conducted every 4 cycles if HBV DNA was detectable at screening, or when clinically indicated. Results: Among 249 enrolled pts, 128 had a history of HBV infection. Of these pts, 114 were HBsAg positive at baseline (BL), 36 had detectable HBV DNA at BL, and 32 had detectable HBV DNA and HBsAg at BL. Clinically significant increases in HBV DNA levels from BL were reported in 7 pts, with no pattern relative to the time of TIS initiation (Table). All 7 pts were HBsAg positive at BL and had been receiving antiviral treatment for ≥ 3 months before the first dose of TIS. Six out of the 7 pts had increases in alanine transaminase (ALT) from BL during the study (Table), 4 of whom had ≥ 3-fold increases in ALT which were observed concurrently or soon after HBV DNA increases. IRC-assessed best overall response (BOR) was partial response (PR) for 1 pt with increased HBV DNA and progressive disease for the remaining 6. HBV-related treatment-emergent adverse events (TEAEs) were reported in 6 of the 7 pts (2 pts had a Grade 3 TEAE of hepatitis B; 2 pts had a Grade 2 TEAE of HBV reactivation; 2 pts had a TEAE of increased HBV DNA, with one Grade 1 and one Grade 3 event). All HBV-related TEAEs were non-serious and did not result in discontinuation of TIS. Conclusions: Clinically significant increases in HBV DNA from BL were reported in a small number of pts, which does not suggest that TIS is associated with increased HBV DNA. Tumor responses in these pts were consistent with the overall population and HBV-related TEAEs were manageable and did not require discontinuation of TIS, demonstrating that HBV DNA increases did not impact treatment. The effects of TIS in pts with HBV infection will be further investigated in an ongoing Phase 3 trial (NCT03412773). Clinical trial information: NCT03419897. [Table: see text]

Medical physicists are a tiny part of the medical staff group. Medical physics activities are categorized into administrative, clinical services, education, quality assurance (QA), and radiation safety. Medical physicists in radiation oncology departments perform the acceptance and commissioning of new equipment, dosimetry services, treatment planning, patient chart review, patient-specific QA, etc. Due to their professional characteristics, medical physicists cannot go to the front line in the battle of COVID-19. The outbreak of the pandemic in late 2019 is a global disaster and its great impact in Asia-Pacific has been unmasked in economic and health crises. COVID-19 can create devastating social, economic, and political crises that will leave deep scars. Asia-Pacific’s governments and societies should seize the historic opportunity to strengthen public health systems, make online education safer and more accessible, address poverty and social exclusion, tackle violence against children, and create greener, more sustainable economies.

Prognostic parameters and models were believed to be helpful in improving the treatment outcome for patients with brain metastasis (BM). The purpose of this study was to investigate the feasibility of computer tomography (CT) radiomics based nomogram to predict the survival of patients with BM from non-small cell lung cancer (NSCLC) treated with whole brain radiotherapy (WBRT). A total of 195 patients with BM from NSCLC who underwent WBRT from January 2012 to December 2016 were retrospectively reviewed. Radiomics features were extracted and selected from pretherapeutic CT images with least absolute shrinkage and selection operator (LASSO) regression. A nomogram was developed and evaluated by integrating radiomics features and clinical factors to predict the survival of individual patient. Five radiomics features were screened out from 105 radiomics features according to the LASSO Cox regression. According to the optimal cutoff value of radiomics score (Rad-score), patients were stratified into low-risk (Rad-score −0.14) groups. Multivariable analysis indicated that sex, karnofsky performance score (KPS) and Rad-score were independent predictors for overall survival (OS). The concordance index (C-index) of the nomogram in the training cohort and validation cohort was 0.726 and 0.660, respectively. An area under curve (AUC) of 0.786 and 0.788 was achieved for the short-term and long-term survival prediction, respectively. In conclusion, the nomogram based on radiomics features from CT images and clinical factors was feasible to predict the OS of BM patients from NSCLC who underwent WBRT.

Background: Lung cancer is the leading cause of cancer-associated mortality worldwide, and in China. Central nervous system (CNS) metastasis is a prevalent and serious complication. The most common treatment for BM is still radiation therapy (RT). An increasing number of drugs have been shown to have intracranial activity or to sensitize tumours to radiotherapy.Methods: Our study aims to demonstrate the clinical efficacy of apatinib combined with radiotherapy vs. radiotherapy alone in the treatment of patients with advanced multiline failure for non-small-cell lung cancer with brain metastasis (BM). Eligible patients were divided into two groups: Apatinib + RT group and RT group. In the apatinib + RT group. Intracranial PFS and OS were analysed using the Kaplan-Meier method. Differences between groups were compared by the log-rank test.Results: The median intracranial PFS for the RT group and Apatinib+RT group was 5.83 months and 11.81 months (p=0.034). The median OS for the RT group and Apatinib+RT group was 9.02 months and 13.62 months (p=0.311). The Apatinib+RT group had a better intracranial PFS, but there were no significant differences between the two arms in OS. The Apatinib+RT group had significantly reduced symptoms caused by BM, mainly headache and vomiting. Most patients tolerated the side effects well. Conclusion: RT combined with apatinib could help to control intracranial metastases. The Apatinib+RT group had significantly reduced symptoms caused by BM, the safety of the two treatments was similar.

Identifying the host factors influencing the COVID-19 outcome is critical to overcome the global pandemic. The associations between immune phenotypes and the risk of COVID-19 are still poorly understood. We sought to systematically evaluate the causal impact of multiple immune cell traits on COVID-19 susceptibility and its severity using two-sample Mendelian randomization (MR). Genetic variants associated with each immune phenotypes at P < 5×10-8 from genome-wide association studies (GWAS). The GWAS statistics of COVID-19 is from COVID-19 Host Genetics Initiative. Susceptibility and severity were defined as COVID-19 positive and hospitalization versus population controls, respectively. Inverse-variance weighted (IVW) method was used as the main MR analysis, and comprehensive sensitivity analyses were conducted for estimating the robustness. The MR estimates showed that genetically predicted high expression of BAFF-R on B cell was strongly associated with a lower risk of COVID-19 severity. In addition, BAFF-R expression on B cell subsets showed consistent causal relationship with COVID-19 severity, such as its expression on transitional B cell and naive-mature B cell. Evidence from all sensitivity analyses further supported these associations. In MR analysis for COVID-19 susceptibility, we observed a highly consistent protective role of BAFF-R expression, although the P value was not significant. Moreover, in multivariable MR analyses, adjusting for the effects of other B cell biomarkers displayed similar MR findings. This study provides genetic evidence that the genetically high expression of BAFF-R on B cells decreases the risk of COVID-19 severity.

Our recent study demonstrated that the QKI-5 regulated miRNA, miR-196b-5p, and it functions as an onco-microRNA in non-small cell lung cancer (NSCLC) by directly targeting GATA6 and TSPAN12. However, the role of miR-196b-5p in NSCLC progression and metastasis still remains unclear. We found that miR-196b-5p promotes lung cancer cell proliferation and colony formation by directly targeting tumor suppressor, FAS. The expression of FAS was significantly downregulated in NSCLC tissue samples and was negatively correlated with the miR-196b-5p expression. Knocking down FAS activates NFkB signaling and subsequent IL6 secretion, resulting in phosphorylation of signal transducer and activator of transcription 3 (STAT3) to promote lung cancer cell growth. Our findings indicated that miR-196b-5p might exhibit novel oncogenic function by FAS-mediated STAT3 activation in NSCLC, and suggested that targeting the miR-196b-5p/FAS/NFkB/IL6/STAT3 pathway might be a promising therapeutic strategy in treating NSCLC.

Background: The prognostic significance of the lymph node (LN) classification for small bowel neuroendocrine tumors (SBNETs) remains unknown. The aim of the present study was to evaluate and compare the prognostic assessment of different LN staging systems.Methods: Patients with SBNETs were identified from the Surveillance, Epidemiology, and End Results (SEER) database. The X-tile program was used to determine the cutoff value of the resected lymph nodes (RLNs), negative lymph nodes (NLNs), lymph node ratio (LNR), and the log odds of positive lymph nodes (LODDS). Survival analyses were performed using Kaplan–Meier curves with log-rank test. Logistic regression analysis was used to evaluate the differences between different periods. Univariate and multivariate Cox proportional hazards models were used to assess the prognostic value of different LN staging systems on cause-specific survival (CSS). The relative discriminative abilities of the different LN staging systems were assessed using the Akaike information criterion (AIC) and the Harrell consistency index (HCI).Result: A total of 3,680 patients were diagnosed with SBNETs between 1988 and 2014 from the SEER database. A significant difference over time (1988–1999 vs. 2000–2014) was seen in age (P

Colorectal cancer (CRC) is the third most common cancer and leading cause of cancer related deaths worldwide. Despite recent advancements in surgical and molecular targeted therapies that improved the therapeutic efficacy in CRC, the 5 years survival rate of CRC patients still remains frustratingly poor. Accumulated evidences indicate that microRNAs (miRNAs) play a crucial role in the progression and metastasis of CRC. Dysregulated miRNAs are closely associated with cancerous phenotypes (e.g. enhanced proliferative and invasive ability, evasion of apoptosis, cell cycle aberration, and promotion of angiogenesis) by regulating their target genes. In this review, we provide an updated overview of tumor suppressive and oncogenic miRNAs, circulatory miRNAs, and the possible causes of dysregulated miRNAs in CRC. In addition, we discuss the important functions of miRNAs in drug resistance of CRC.

It is of high clinical importance to identify the primary lesion and its pathological types for patients with brain metastases (BM). The purpose of this study is to investigate the feasibility and accuracy of differentiating the primary adenocarcinoma (AD) and squamous cell carcinoma (SCC) of non-small-cell lung cancer (NSCLC) for patients with BM based on radiomics from brain contrast-enhanced computer tomography (CECT) images.A total of 144 BM patients (94 male, 50 female) were enrolled in this study with 102 with primary lung AD and 42 with SCC, respectively. Radiomics features from manually contoured tumors were extracted using python. Mann-Whitney U test and the least absolute shrinkage and selection operator (LASSO) logistic regression were applied to select relative radiomics features. Binary logistic regression and support vector machines (SVM) were applied to build models with radiomics features alone and with radiomics features plus age and sex.Fourteen features were selected from a total of 105 radiomics features for the final model building. The area under the curves (AUCs) and accuracy of SVM and binary logistic regression models were 0.765 vs. 0.769, 0.795 vs.0.828, and 0.716 vs. 0.726, 0.768 vs. 0.758, respectively, for models with radiomics features alone and models with radiomics features plus sex and age.Brain CECT radiomics are promising in differentiating primary AD and SCC to achieve optimal therapeutic management in patients with BM from NSCLC.• It is of high clinical importance to identify the primary lesion and its pathological types for patients with brain metastases (BM) to define the prognosis and treatment. • Few studies had investigated the feasibility and accuracy of differentiating the pathological subtypes of primary non-small-cell lung cancer between adenocarcinoma (AD) and squamous cell carcinoma (SCC) for patients with BM based on radiomics from brain contrast-enhanced CT (CECT) images, although CECT images are often the initial imaging modality to screen for metastases and are recommended on equal footing with MRI for the detection of cerebral metastases. • Brain CECT radiomics are promising in differentiating primary AD and SCC to achieve optimal therapeutic management in patients with BM from NSCLC with a highest area under the curve (AUC) of 0.828 and an accuracy of 0.758, respectively.

Radiation therapy is an effective method in the management of esophageal cancer. MicroRNAs (miRNAs) have been reported to play an important role in tumorigenesis. However, the roles of specific miRNAs in radioresistant esophageal cancer remain to be investigated. In present study, the relative expression level of miR-20b-5p and miR-125a-5p were evaluated by quantitative Real-time polymerase chain reaction. Cell counting Kit-8 assay, wound-healing assay, transwell assay were used to assess cell proliferation, cell migration and cell invasion. TUNEL and Annexin V-FITC assays were applied to evaluate cell apoptosis. Dual-luciferase reporter gene assay was conducted to identify direct targets of miRNAs. The protein expression level was assessed by Western blot. The results indicated that miR-20b-5p was increased in radioresistant KYSE-150R cells compared with KYSE-150 cells, whereas miR-125a-5p was downregulated. MiR-20b-5p upregulation promoted cell proliferation, migration, invasion, and the EMT process, and decreased apoptosis by negatively regulating PTEN. MiR-125a-5p inhibited cell proliferation, migration, invasion, the EMT process and it induced apoptosis by negatively regulating IL6R. These data indicate that miR-20b-5p and miR-125a-5p promote tumorigenesis in radioresistant KYSE-150R cells and have the potential to be used as novel therapeutic targets for the treatment of esophageal cancer.

Background: Although EGFR mutations in lung cancer are identified most often as trunk mutations in the early stage, cancer evolution often follows a branched trajectory. Whether EGFR would always be the dominant clone in the advanced stage is unknown. Methods: This prospective multicenter clinical trial recruited treatment naive patients with stage IIIB-IV non–small cell lung cancer from 14 centers in China. Paired tumor and plasma ctDNA samples were sequenced by target-capture deep sequencing of 1021 genes. Clonal dominance analysis was performed on the basis of PyClone. Findings: Overall, 300 patients were recruited and 132 patients treated with first line targeted therapy were followed. The median follow-up time was 10 months (IQR 6–13). Of the 94 patients with available ctDNA data for EGFR clonal architecture analysis, 72 (76.6%) showed EGFR as the dominant clone. The mPFS was longer for these patients than for the 22 patients who had EGFR non-dominant clone (11 months vs 10 months, hazard ratio [HR] 0.46, 95% CI 0.24–0.88, p = 0.02). The difference was more significant if patients who were defined as having EGFR dominant clone by both tumor tissue and plasma (n = 43) versus those not (n = 8) (11 vs 6 months, HR = 0.13, 95% CI 0.04–0.50, p = 0.003). Moreover, multivariate cox proportional hazard ratio analysis demonstrated EGFR clonal architecture as an independent prognostic indicator of the efficacy of EGFR-tyrosine kinase inhibitors. Interpretation: In advanced NSCLC,EGFR mutations do not always make up a dominant clone. Clonal architecture of EGFR in the pretreatment ctDNA is associated with the efficacy of EGFR-TKIs in NSCLC. Trial Registration: The trial has been registered with the number NCT03059641. Funding Statement: Geneplus-Beijing Co. Ltd. Declaration of Interests: RC, PL, LC and XY were employees of Geneplus-Beijing Co. Ltd. All other authors declare no conflict of interests. Ethics Approval Statement: This study was performed under a protocol (KS1707) approved by the Institutional Review Board of Shanghai Chest hospital (Shanghai, China).

Background The development of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) has dramatically improved the prognosis of patients with EGFR-mutant non-small-cell lung cancer (NSCLC). The purpose of this study is to investigate the clinical outcome with or without EGFR-TKI resistance before WBRT and the sequence between EGFT-TKIs and whole brain radiotherapy (WBRT) of EGFR-mutant NSCLC patients who developed multiple brain metastases (BMs). Patients and methods Three hundred forty-four EGFR-mutant NSCLC patients with multiple BMs were reviewed. Enrolled patients were divided into TKI-naïve group and TKI-resistant group. The intracranial progression-free survival (PFS) and overall survival (OS) were analyzed via the Kaplan-Meier method. Results For patients with multiple BMs treated by WBRT, the median intracranial PFS and OS were longer in the TKI-naïve group than those in the TKI-resistant group, but there were no statistically significant between two groups (Intracranial PFS: 7.7 vs. 5.4 months, p = 0.052; OS: 11.2 vs. 9.2 months, p = 0.106). For patients with Lung-molGPA 0–2, no significant differences in median intracranial PFS (6.2 vs. 5.2 months, p = 0.123) and OS (7.8 vs. 6.7 months, p = 0.514) between TKI-naïve and TKI-resistant groups. For patients with Lung-molGPA 2.5–4, intracranial PFS: 12.8 vs. 10.1 months; OS: 23.3 vs. 15.3 months. Conclusions Our study found that there were no difference in intracranial PFS and OS in all patients between the two groups of TKI-naïve and TKI-resistant. But for patients in subgroup of Lung-molGPA 2.5–4, there were a better intracranial PFS and OS in TKI-naïve group.

The aim of this study was to investigate the feasibility and sensitivity of using individual volume-based 3D gamma indices for composite dose-volume histogram (DVH)-based intensity-modulated radiation therapy (IMRT) quality assurance (QA). Composite IMRT QA for 15 cervical cancer patients was performed with ArcCHECK. The percentage dosimetric errors (%DEs) of DVH metrics when comparing treatment planning system and QA-reconstructed dose distribution, percentage gamma passing rates (%GPs) with different criteria for individual volumes and global gamma indices were evaluated, as well as their correlations. Receiver operating characteristic (ROC) curves were applied in order to study the sensitivities of the global and individual volume gamma indices. Most %DEs of the DVH metrics were within 3%. The γPTV and γrectum were

The human epidermal growth factor receptor (EGFR) family has been widely studied in cancer, however, the prognostic role of EGFR family expression in lymph node-negative esophageal squamous cell carcinoma (ESCC) patients have not been invalidated. This study was designed to determine the prognostic value of EGFR family expression in a population of lymph node-negative ESCC patients treated with curative resection. EGFR family protein expression was examined by immunohistochemical analysis of tissue microarrays of 94 patients with lymph node-negative ESCC after radical esophagectomy with three-field lymphadenectomy. Survival differences were compared using Kaplan–Meier analysis. Cox regression analyses were performed to determine the prognostic factors for overall survival and disease-free survival (DFS). ErbB4 expression was found to be an independent prognostic factor for DFS in patients without lymph node metastasis; increased ErbB4 expression was associated with decreased DFS. Additionally, patients with high ErbB4 expression tended to have worse overall survival. EGFR, ErbB2 and ErbB3 expression were not significantly associated with survival in lymph node-negative ESCC patients. Increased ErbB4 immunohistochemical expression was associated with poor prognosis in lymph node-negative ESCC patients.

Purpose: To investigate the feasibility of partial arc volumetric modulated arc therapy (VMAT) in lung cancer stereotactic body radiotherapy (SBRT), as well the volumetric and dosimetric effects of different internal target volume (ITV) definitions with 4D CT. Methods: Fourteen patients with primary and metastatic lung cancer underwent SBRT were enrolled. Full and partial arc VMAT plans were generated with four different ITVs: ITVall, ITVMIP, ITVAIP and ITV2phases, representing ITVs generated from all 10 respiratory phases, maximum intensity projection (MIP), average intensity projection (AIP), and 2 extreme respiratory phases. Volumetric and dosimetric differences, as well as MU and delivery time were investigated. Results: Partial arc VMAT irradiated more dose at 2 cm away from planning target volume (PTV) (P = 0.002), however, it achieved better protection on mean lung dose , lung V5, spinal cord, heart and esophagus compared with full arc VMAT. The average MU and delivery time of partial arc VMAT were 240 and 1.6 min less than those of full arc VMAT. There were no significant differences on target coverage and organ at risks (OARs) sparing among four ITVs. The average percent volume differences of ITVMIP, ITVAIP and ITV2phases to ITVall were 8.6%, 13.4%, and 25.2%, respectively. Conclusions: Although partial arc VMAT delivered more dose 2 cm out of PTV, it decreases the dose to lung, spinal cord, and esophagus, as well decreased the total MU and delivery time compared with full arc VMAT without sacrificing target coverage. Partial arc VMAT was feasible and more efficient for lung SBRT.

BackgroundTislelizumab, an anti-PD-1 monoclonal antibody, demonstrated clinical activity and was well-tolerated in patients with previously treated advanced hepatocellular carcinoma (HCC) in the Phase 2 RATIONALE-208 study (NCT03419897). We explored whether baseline neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) or their post-treatment change correlated with clinical efficacy of tislelizumab treatment.MethodsEligible patients (>18 years) who had received ≥1 prior line of systemic therapy for advanced HCC were administered open-label tislelizumab (200 mg) intravenously every 3 weeks until no further clinical benefit was observed. NLR and PLR were assessed using peripheral blood samples collected at baseline, Cycle 2 Day 1 (C2D1), C3D1, and C4D1. Survival analysis (progression free survival [PFS] and overall survival [OS]) was conducted by Kaplan-Meier method and survival rate at risk was compared by log rank test. Logistic regression was used to analyze association of post-treatment change of NLR or PLR with objective response rate (ORR). In the baseline analysis, median NLR or PLR in this study was used as a cut-off. All statistical analysis results are post-hoc exploratory and thereby p values are descriptive.ResultsOverall, 249 patients were enrolled, of which 249, 234, 203, and 186 patients had evaluable NLR and PLR data at baseline, C2D1, C3D1, and C4D1, respectively. Analysis of NLR at baseline, using median NLR (3.2) as cut-off, demonstrated higher OS (p=0.0024) and PFS (p=0.071) in NLR-low versus NLR-high groups (median OS [mOS]:17.4 versus 9.9 months; median PFS [mPFS]: 2.8 versus 1.5 months). Analysis of PLR at baseline, using median PLR (141.4) as cut-off, showed higher OS (p=0.0085) and PFS (pAbstract 362 Table 1Post-treatment decreases in NLR or PLR were associated with response to tislelizumab monotherapyAbstract 362 Figure 1Post-treatment decreases in NLR or PLR were associated with improved OS following tislelizumab monotherapyConclusionsIn patients with previously treated advanced HCC that received tislelizumab monotherapy, lower baseline NLR or PLR was associated with longer OS and PFS, and post-treatment decreases of NLR or PLR were associated with higher ORR and longer OS. These observations support NLR and PLR as potential prognostic biomarkers in patients with advanced HCC treated with tislelizumab and will be further investigated in an on-going Phase 3 study (NCT03412773).AcknowledgementsThis study is sponsored by BeiGene Ltd. Medical writing support for the development of this abstract, under direction of the authors, was provided by Claire White, PhD, and Kirsty Millar, MSc, of Ashfield MedComms, an Ashfield Health company, and was funded by BeiGene Ltd.Trial RegistrationNCT03419897Ethics ApprovalThis study was conducted according to the ethical principles of the Declaration of Helsinki, Good Clinical Practice guidelines, the principles of informed consent and the requirements of the public registration of clinical trials. Written informed consent was obtained from each patient prior to screening. The protocol was approved by the institutional ethics committee and was monitored by the investigators and study sponsor.

Objective Because of the short potential doubling time of esophageal cancer, there is a theoretical benefit to using an accelerated radiation treatment schedule. This study evaluates outcomes and treatment-related mortality and morbidity of patients treated with neoadjuvant hyperfractionated accelerated chemoradiation for resectable esophageal cancer. Methods and materials Outcomes from 250 consecutive patients with resectable esophageal cancer treated with preoperative hyperfractionated accelerated chemoradiotherapy (45 Gy in 30 twice-daily fractions over 3 weeks) followed by planned transhiatal esophagectomy were analyzed. Grade 3 or greater treatment related toxicity, surgical complications, and treatment-related mortality were determined. Additionally, available surgical specimens were graded for pathological response to chemoradiation. Overall survival (OS) and locoregional control were calculated using the Kaplan-Meier method. The log rank test was used to determine statistical significance. Results Median follow-up was 59 months for surviving patients; 87% of patients had adenocarcinoma and 13% had squamous cell carcinoma. Eleven percent of patients did not have surgery because of the development of metastases, declining performance status, or refusal. Twenty-seven patients were found to have unresectable and/or metastatic disease at the time of surgery. Overall, 10 of 223 operated patients died within 3 months, resulting in a perioperative mortality rate of 4%. Median OS was 28.4 months (95% confidence interval, 22.3-35.6 months) for all patients and 35.1 months (95% confidence interval, 27.4-47 months) for patients who underwent esophagectomy. There were 32 isolated locoregional failures with a 3-year locoregional control rate of 83%. Of 129 patients who had independent pathology review, 29% had complete response to treatment. This group had a median OS of 98.9 months and 3-year OS of 74%. Conclusion Neoadjuvant twice-daily chemoradiation for esophageal cancer is a safe and effective alternative to daily fractionation with low treatment-related mortality and long-term outcomes similar to standard fractionation courses.

// Hanbin Chen 1, * , Yangyang Li 2, * , Yin Long 3 , Erjiang Tang 3 , Rongrong Wang 2 , Kate Huang 2, * , Congying Xie 1, * and Guorong Chen 2, * 1 Department of Radiotherapy and Chemotherapy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China 2 Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China 3 Center for Translational Medicine, Yangpu Hospital, Tongji University School of Medicine, Yangpu, Shanghai, China * These authors have contributed equally to this work Correspondence to: Kate Huang, email: handyman2002@163.com Congying Xie, email: wzxiecongying@163.com Guorong Chen, email: chengr1978@aliyun.com Key words: p16 protein, p53 protein, mucosal melanoma, prognosis of mucosal melanoma Received: April 07, 2017 Accepted: May 10, 2017 Published: June 05, 2017 ABSTRACT Primary mucosal melanoma (MM) is a rare, and aggressive, neoplasm with a poor prognosis. To date, few prognostic markers of MM have been well-defined. The aim of this study is to clarify the prognostic value of p53 and p16 proteins in predicting the clinical outcome of Chinese patients with MM. A total of 59 MM samples were contained from biopsy specimens, and, expressions of p53 and p16 proteins were assessed by immunohistochemistry. Cox regression analysis was performed to investigate the association of these proteins with the overall survival of MM patients. Increased p16 expression was significantly associated with reduced survival at three years (P=0.039). Increased p53 expression correlates with reduced one-year (P=0.025), and, two-year survival (P=0.037). Increased p53 and p16 protein expression may be helpful prognostic indicators for the management of these patients.

The present study determined the role and mechanism of miR-138 in non-small cell lung cancer (NSCLC). In total, 45 freshly resected clinical NSCLC tissues were collected. The expression of miR-138 in tissues and cell lines were determined by real-time quantitative PCR. miR-138 mimics were transfected into A549 and Calu-3 cells in vitro, and then the effects of miR-138 on lung cancer cell proliferation, cell cycle, invasion and metastasis were investigated by CCK-8 assay, Transwell and flow cytometry, respectively. The protein expression of the potential target gene Sirt1 in lung cancer cells were determined by western blot analysis. Dual-Luciferase reporter assay was performed to further confirm whether Sirt1 was the target gene of miR-138. The expression of miR-138 was significantly lower in lung cancer tissues and was negatively correlated to the differentiation degree and lymph node metastasis of lung cancer. In vitro experiment results showed that miR-138 inhibited lung cancer cell proliferation, invasion and migration. It was verified that miR-138 could downregulate Sirt1 protein expression, inhibit epithelial-mesenchymal transition (EMT), decrease the activity of AMPK signaling pathway and elevate mTOR phosphorylation level. Dual-Luciferase reporter assay demonstrated that miR-138 could directly regulate Sirt1. Downregulation of Sirt1 alone can also cause the same molecular and biological function changes. Western blot analysis and confocal microscopy results indicated that overexpression of miR-138 or interference of Sirt1 expression could inhibit lung cancer cell autophagy activity possibly through AMPK-mTOR signaling pathway. miR-138 plays a tumor suppressor function in lung cancer. It may inhibit the proliferation, invasion and migration of lung cancer through downregulation of Sirt1 expression and activation of cell autophagy. The downregulation of miR-138 is closely related to the development of lung cancer.

Although gamma analysis is still a widely accepted quantitative tool to analyze and report patient‐specific QA for intensity‐modulated radiotherapy (IMRT) and volumetric‐modulated arc therapy (VMAT), the correlation between the 2D percentage gamma passing rate (%GP), and the clinical dosimetric difference for IMRT and VMAT has been questioned. The purpose of this study was to investigate the feasibility of individual volume‐based 3D gamma indices for pretreatment VMAT QA. Percentage dosimetric errors (%DE) of dose‐volume histogram metrics (includes target volumes and organ at risks) between the treatment planning system and QA‐reconstructed dose distribution, %GPs for individual volume and global gamma indices, as well their correlations and sensitivities were investigated for one‐ and two‐arc VMAT plans. The %GPs of individual volumes had a higher percent of correlation with individual 15 %DE metrics compared with global %GPs. For two‐arc VMAT at 2%/2 mm, 3%/3 mm, and 4%/4 mm criteria, individual volume %GPs were correlated with 9, 12, and 9 out of 15 %DE metrics, while global %GPs were correlated with only 2 out of 15 %DE metrics, respectively. For one‐arc VMAT at 2%/2 mm, 3%/3 mm, and 4%/4 mm criteria, individual volume %GPs were correlated with 18, 16, and 13 out of 23 %DE metrics, and global %GPs were correlated with 19, 12, and 1 out 23 %DE metrics, respectively. The area under curves (AUC) of individual volume %GPs were higher than those of global %GPs for two‐arc VMAT plans, but with mixed results for one‐arc VMAT plans. In a conclusion, the idea of individual volume %GP was created and investigated to better serve for VMAT QA and individual volume‐based %GP had a higher percent of correlation with DVH 15 %DE metrics compared with global %GP for both one‐ and two‐arc VMAT plans.

Background: Although superior clinical benefits of first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in the treatment of advanced non-small-cell lung cancer (NSCLC) had been reported with different sensitivity, the sensitivity of second-line TKIs in NSCLC patients with different EFGR mutations was unknown. The purpose of this study is to investigate the clinical outcome of second-line EGFR-TKIs in the treatment of NSCLC patients according to different EGFR genotypes. Methods: The treatment outcomes of 166 NSCLC patients with different EGFR mutations treated by second-line TKIs were retrospectively reviewed. The efficacy was evaluated with Pearson chi-square or Fisher's exact tests, Log-rank test and Cox proportional hazards model. Results: The disease control rate (DCR) and objective response rate (ORR) of enrolled NSCLC patients were 77.7% and 11.4%, respectively. The exon 19 deletion group had a significantly longer median progression-free survival (PFS) (6.7 vs. 4.5 months, P=0.002) and overall survival (OS) (13.7 vs. 11.7 months, P=0.02) compared with the exon 19 L858R mutation group for NSCLC patients, as well for patients with brain metastasis [PFS: (6.7 vs. 3.9 months, p

Background: The rates of locoregional and distant recurrence for esophageal squamous cell carcinoma (ESCC) patients underwent radical esophagectomy remain high. The purpose of this study is to explore an optimal postoperative therapeutic modality by investigating the efficacy of various adjuvant therapies in the treatment of ESCC. Methods: We retrospectively reviewed 408 ESCC patients underwent thoracic esophagectomy and 3-field lymph node dissection from 2010 to 2015. Patients were classified into surgery alone (Group S), adjuvant chemotherapy (Group CT) and postoperative chemotherapy plus radiotherapy (Group CRT), respectively. Univariate and multivariate Cox regression analyses were used to analyze prognostic factors and survival. Results: The overall survival (OS) and disease-free survival (DFS) were similar among groups. Postoperative CT and CRT both were beneficial for patients with positive lymph nodes, particularly for those with 3 or more lymph nodes involvement and metastasis in the middle thoracic segment compared with surgery alone. The 3-year OS and DFS for patients with 3 or more lymph nodes involvement were 30.8%, 53.7%, 50.5% and 19.9%, 41.6%, 34.0% for Group S, CT, and CRT, respectively (p=0.04; p=0.004, respectively). There was no notable difference in OS and DFS between the adjuvant Group CT and CRT (p=0.42; p=0.49, respectively). Postoperative CRT significantly reduced the rates of distant metastasis and overall recurrence for patients with positive lymph nodes (p=0.042; p=0.01, respectively). Number of metastatic lymph nodes, extent of resection, and AJCC stage were independent predictors of survival. Grade 1-2 myelosuppression was experienced significantly more frequently by patients in Group CRT than those in Group CT (P=0.03). Late toxicities were rare and manageable overall. Conclusions: Postoperative CT and CRT both were associated with better survival for patients with positive lymph nodes, particularly for those with 3 or more lymph nodes involvement and metastasis in the middle thoracic segment. Postoperative CRT was significantly more effective at reducing the rates of distant metastasis and overall recurrence for patients with positive lymph nodes.

Pancreatic cancer is one of the world's leading causes of cancer-related death. Activation of STAT3 has been reported as a major contributor in pancreatic cancer tumorigenesis and chemoresistance. However, treatment of advanced pancreatic cancer patients with STAT3 inhibitors often meets drug resistance and heterogeneous response. We found that EGFR activation is a main cause for resistance to STAT3 inhibitors in pancreatic cancer cells, regardless of KRAS mutation status. Mechanistically, inhibition of STAT3 promotes STAT1- and STAT4-mediated TGF-α expression, leading to activation of the EGFR pathway. Combined treatment of pancreatic cancer cells with EGFR and STAT3 inhibitors persistently blocks EGFR and STAT3 signaling, and exerts synergistic antitumor activity both in vitro and in vivo, with or without KRAS mutation. Our results indicate that reciprocal cross-talk between STAT3 and EGFR pathways is a key molecular mechanism leading to resistance in pancreatic cancer cells. Furthermore, the study shows that combined inhibition of both EGFR and STAT3 might overcome drug resistance encountered during treatment with single agent alone. This study suggests an improved therapeutic strategy, through combined treatment with STAT3 and EGFR inhibitors, for pancreatic cancer patients.

Purpose Apatinib is effective and safe for several advanced or metastatic cancers, but its therapeutic value in cervical cancer is still unknown. The aim of the study was to assess the therapeutic value of apatinib in patients with chemo-refractory advanced cervical cancer. Patients and methods This was a retrospective study of patients with advanced cervical cancer treated with apatinib between April 2015 and December 2018 at the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. Patients had to have failed at least 2 lines of chemotherapy prior to receiving apatinib. The clinical tumor response was evaluated after 4 weeks of apatinib treatment, and then every 8 weeks (two cycles). Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and adverse events were evaluated. Results Twenty-five patients were included in this study. The median PFS was 5.8 months (95% CI, 4.65–6.95), and the median OS was 12.2 months (95% CI, 8.99–15.41). ORR was 48% and DCR was 96%. Complete response was not observed. The most common adverse events in this study (all grades) were hand-foot syndrome (48%), hypertension (20%), and mouth mucositis (20%). Conclusion Apatinib monotherapy showed good therapeutic value with tolerable adverse events for patients with chemo-refractory advanced cervical cancer.