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High-dose hypofractionated radiotherapy (HRT) is an important anticancer treatment modality that activates antitumor host immune responses. However, HRT for oligometastases of colorectal cancer (CRC) has shown frustrating results in the clinic. As part of immune evasion, myeloid cells express signal regulatory protein α (SIRPα) to inhibit phagocytosis by phagocytes in the tumor microenvironment (TME). We postulated that SIRPα blockade enhances HRT by alleviating the inhibitory action of SIRPα on phagocytes. We demonstrated that SIRPα on myeloid cells was upregulated in the TME after HRT. When SIRPα blockade was administered with HRT, we observed superior antitumor responses compared with anti-SIRPα or HRT alone. When anti-SIRPα was administered to local HRT, the TME could become a tumoricidal niche that was heavily infiltrated by activated CD8+T cells, but with limited myeloid-derived suppressor cells and tumor-associated macrophages. Whereas CD8+T cells were required for the effectiveness of the anti-SIRPα + HRT combination. The triple therapy with anti-SIRPα + HRT + anti-PD-1 had superior antitumor responses compared with the combination of any two therapies and established a strong and long-lasting adaptive immunological memory. Collectively, SIRPα blockade provides a novel way to overcome HRT resistance in oligometastatic CRC patients. Our results herein provide a valuable cancer treatment strategy that has the potential to be translated into clinical practice.

Lessons Learned Background We conducted a phase Ib study of radiotherapy plus programmed cell death protein 1 (PD-1) monoclonal antibody camrelizumab as first-line treatment for locally advanced esophageal squamous cell carcinoma (ESCC). Methods We planned to enroll 20 patients with newly diagnosed locally advanced ESCC. Patients received 60 Gy radiation (2.0 Gy/fraction, 5 fractions/week), with camrelizumab (200 mg every 2 weeks) starting with radiotherapy and continuing for 32 weeks (i.e., for 16 cycles). The primary endpoints were safety and feasibility. Secondary endpoints were rates of radiologic and pathologic response, overall survival (OS), and progression-free survival (PFS). Study data were collected by the week during radiotherapy (RT), every month during the maintenance camrelizumab treatment, and every 3 months after treatment. Tumor microenvironment and peripheral blood were monitored at baseline and after 40 Gy radiation for association with efficacy. Results Twenty patients were enrolled and received treatment. One patient (patient 10) was excluded upon discovery of a second tumor in the bladder during treatment, leaving 19 patients for analysis. Toxicity was deemed tolerable. Fourteen (74%) patients had assessed objective response. At a median follow-up time of 31.0 months (95% confidence interval [CI], 27.0–35.1), median OS and PFS times were 16.7 months (95% CI, 5.9–27.9) and 11.7 months (95% CI, 0–30.3), respectively. OS and PFS rates at 24 months were 31.6% and 35.5%, respectively. Kaplan-Meier analysis revealed associations between the following factors and OS/PFS: tumor programmed cell death ligand 1 (PD-L1) expression, PD-1+CD8+, PD-1+CD4+ T cells, and PD-L1+CD4+ T cells; peripheral blood CD4+, CD8+, CD4+ regulatory T cells, and their subsets. Conclusion Radiotherapy plus camrelizumab had manageable toxicity and antitumor efficacy for locally advanced ESCC. Several biomarkers were associated with clinical benefit and deserve further study.

Purpose: To investigate the prognostic differences between small-cell lung cancer (SCLC) patients with different chemosensitivity to first line chemotherapy who developed brain metastasis as first site of progression. Methods: Patients with brain metastases (BMs) after first-line treatment of SCLC in our hospital admitted from January 2012 to October 2020 were retrospectively analyzed. According to the time interval between the completion of first-line chemotherapy and the onset of BMs (TFI), the patients were divided into chemo-sensitive group (TFI ≥ 90 days, n = 145) and chemo-resistant group (TFI ＜ 90 days, n = 97). Survival time after the onset of brain metastasis (BM-OS), which was calculated from the diagnosis of brain metastases and overall survival (OS), which was calculated from the diagnosis of small-cell lung cancer, were analyzed in this study. Survival curves were plotted using Kaplan-Meier method and differences between groups were compared using the log-rank test. The Chi-square test or Fisher’s exact test was used to compare categorical variables. Results: In total, the median BM-OS and OS were 8.4 months and 18.2 months respectively. The median BM-OS in chemo-sensitive group was 8.8 months and it was 8.0 months in the chemo-resistant group (P = 0.538); and the median OS was 22.0 months and 15.6 months, respectively (P = 0.001). In patients without extracranial progression (n = 193), the median BM-OS in chemo-sensitive and chemo-resistant group were 9.4 months and 9.7 months (P = 0.947), and the median OS were 22.7 months and 16.3 months, respectively (P = 0.017). In patients with extracranial progression (n = 49), the median BM-OS were 5.4 months and 4.2 months (P = 0.161), and the median OS were 17.6 months and 12.3 months, respectively (P = 0.002). Conclusions: After the development of brain metastasis as the first site of progression following chemotherapy in small cell lung cancer, the prognosis of chemo-sensitive patients not necessarily superior to chemo-resistant patients, especially in patients without extracranial progression.

Sequence labeling, such as part-of-speech (POS) tagging, named entity recognition (NER), text chunking, is a classic task in natural language processing. Most existing neural networks models for sequence labeling are based on recurrent neural networks. Recently, convolutional neural networks have been proposed to replace the recurrent components for sequence labeling. However, they are usually shallow compared to deep convolutional networks that achieve start-of-the-art performance in other fields. Due to the vanishing gradient problem, these models usually can not work well when simply increasing the number of layers. In this paper, we propose using deep CNN architecture in sequence labeling, which can capture a large context through stacked convolutions. To reduce the vanishing gradient problem, the proposed method incorporates gated linear units, residual connections, and dense connections. Experimental results on three sequence labeling tasks show that the proposed model can achieve competitive performance to the RNN-based state-of-the-art method while maintaining $2.41\times$ faster speed, even with up to 10 convolutional layers.

Purpose Thoracic radiotherapy (TRT) is the recommended therapeutic regimen for extensive-stage small cell lung cancer (ES-SCLC). Little is known about TRT benefits in elderly populations. The aim of this study was to evaluate TRT effects on the prognosis of elderly patients with ES-SCLC. Patients and methods This retrospective analysis reviewed the records of patients over 65 years of age with metastatic ES-SCLC treated between 2010 and 2016. Enrolled patients received standard chemotherapy regimens (etoposide plus cisplatin or carboplatin). A total of 93 eligible patients were subjected to propensity score matching, which led to 40 patients being assigned to the TRT group and 40 to the no thoracic radiotherapy (noTRT) group. The cohort of 80 patients (67 males) had the median age of 69 years (range, 65-85 years), with a median of 4 chemotherapy cycle (range, 1-8 cycles), and a median chest irradiation dose of 50 Gy (range, 30-60 Gy). We analyzed overall survival (OS), progression-free survival (PFS), and local recurrence-free survival (LRFS) as endpoints; survival rates were determined by the Kaplan-Meier method and compared across groups with log-rank tests. Multivariate prognostic analysis was performed with Cox regression modeling, and categorical variables were analyzed with Chi-square tests. Results In all patients, the 1-year OS, PFS, and LRFS rates were 38.3%, 16%, and 17.9%, respectively. The TRT group had superior survival outcomes compared to the noTRT group: their 1-year OS, PFS, and LRFS rates were 55% vs. 25% (P < 0.001), 32.1% vs. 0% (P < 0.001), and 31% vs. 2.6% (P < 0.001), respectively. TRT did not increase the incidence of adverse reactions (P = 0.431). Conclusion TRT can improve chest tumor control and survival time in elderly ES-SCLC patients. Large-scale studies to further assess the benefits of TRT are warranted.

Deleted in colorectal cancer (DCC) encodes a transmembrane dependence receptor and is frequently mutated in melanoma. The associations of DCC mutation with chromosomal instability and immunotherapeutic efficacy in melanoma are largely uncharacterised.We performed an integrated study based on biological experiments and multi-dimensional data types, including genomic, transcriptomic and clinical immune checkpoint blockade (ICB)-treated melanoma cohorts from public databases.DCC mutation was significantly correlated with the tumour mutational burden (TMB) in The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC) and ICB-treated melanoma cohorts. DCC expression levels were correlated with DNA damage response and repair (DDR) pathways responsive to irradiation (IR) in the Malme-3M and SK-MEL-2 cell lines. In the TCGA cohort, DCC-mutated samples presented more neoantigens, higher proportions of infiltrating antitumour immunocytes and lower proportions of infiltrating pro-tumour immunocytes than DCC wild-type samples. DCC-mutated samples were significantly enriched in activated immune response and DDR pathways. Furthermore, patients harbouring mutated DCC treated with ICB showed remarkable clinical benefits in terms of the response rate and overall survival.Somatic mutations in DCC are associated with improved clinical outcomes in ICB-treated melanoma patients. Once further validated, the DCC mutational status can improve patient selection for clinical practice and future study enrolment.

BackgroundAccumulated evidence for systemic inflammation response in several solid tumors prompts a possibility of prediction of patients’ prognosis in a more accessible and valuable manner. However, the prognostic value of peripheral blood inflammatory markers in limited-stage small cell lung cancer (LS-SCLC) remains unclear. Therefore, we investigated the prognostic values of pretreatment inflammatory indexes in LS-SCLC patients.MethodsWe retrospectively identified 334 patients with LS-SCLC and collected their pretreatment serum levels of neutrophil, platelet, lymphocyte, leukocyte, hemoglobin, and albumin, then neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic inflammation index (SII) were calculated. Patients were dichotomized as low-Risk or high-Risk group based on their corresponding cutoff values. Univariate and multivariate analyses were conducted with a Cox proportional hazards model. The least absolute shrinkage and selection operator (LASSO)-Cox regression analysis was performed to construct the inflammation-related prognostic scoring system named Risk for OS. Nomograms were established to provide prognostic information, allowing for more individualized prediction of survival.ResultsHigher pretreatment platelet, lymphocyte, and albumin were indicators of favorable overall survival (OS), whereas higher NLR and SII were accompanied by inferior OS. The prognosis of patients with high Risk was significantly worse than that with low Risk in both the training group and the validation group (both p < 0.001). Comparable area under the curve (AUC) values between the training group and the validation group were observed, yielding 1-, 3-, and 5-year OS rates of 67.3% vs. 69.2%, 66.8% vs. 69.5%, and 66.7% vs. 71.4%, respectively. Multivariate analyses revealed that Risk [hazard ratio (HR) = 0.551, p < 0.001] was an independent negative prognostic indicator for OS, which was further verified in the validation set. The addition of Risk to nomogram (C-index = 0.643) harbored improved predictive accuracy for OS when compared with that of clinical factors alone (C-index = 0.606); the AUC values of 1-, 3-, and 5-year OS rates were 71.7% vs. 66.4%, 73.5% vs. 66.6%, and 71.9% vs. 65.6%, respectively.ConclusionsPretreatment peripheral blood inflammatory indexes may be a noninvasive serum biomarker for poor prognosis in LS-SCLC. The addition of Risk to the nomogram model could serve as a more powerful, economical, and practical method to predict survival for patients with LS-SCLC.

IntroductionSmall cell lung cancer (SCLC) has recently been characterized as heterogeneous tumors due to consensus nomenclature for distinct molecular subtypes on the basis of differential expression of four transcription markers (ASCL1, NEUROD1, POU2F3, and YAP1). It is necessary to validate molecular subtype classification in primary SCLC tumors by immunohistochemical (IHC) staining and investigate its relevance to survival outcomes.MethodsUsing a large number of surgically resected primary SCLC tumors, we assessed the mRNA and protein levels of the four subtype markers (ASCL1, NEUROD1, POU2F3 and YAP1) in two independent cohorts, respectively. Next, molecular subtypes defined by the four subtype markers was conducted to identify the association with clinicopathologic characteristics, survival outcomes, the expression of classic neuroendocrine markers, and molecules related to tumor immune microenvironment.ResultsSamples were categorized into four subtypes based on the relative expression levels of the four subtype markers, yielding to ASCL1, NEUROD1, POU2F3 and YAP1 subtypes, respectively. The combined neuroendocrine differentiation features were more prevalent in either ASCL1 or NEUROD1 subtypes. Kaplan-Meier analyses found that patients with tumors of the YAP1 subtype and ASCL1 subtype obtained the best and worst prognosis on both mRNA and IHC levels, respectively. Based on multivariate Cox proportional-hazards regression model, molecular subtype classification determined by IHC was identified as an independent indicator for survival outcomes in primary SCLC tumors. Correlation analyses indicated that the four subtype markers in SCLC cancer cells were interacted with its tumor immune microenvironment. Specifically, tumors positive for YAP1 was associated with fewer CTLA4+ T cell infiltration, while more immune-inhibitory receptors (FoxP3,PD1, and CTLA4) and fewer immune-promoting receptor (CD8) were found in tumors positive for ASCL1.ConclusionsWe validated the new molecular subtype classification and clinical relevance on both mRNA and protein levels from primary SCLC tumors. The molecular subtypes determined by IHC could be a pre-selected effective biomarker significantly influenced on prognosis in patients with SCLC, which warrants further studies to provide better preventative and therapeutic options for distinct molecular subtypes.

Aim: Adequate lymph node evaluation is recommended in patients with malignant tumors. However, the role of negative lymph nodes (NLNs) remains unclear in breast cancer (BC), especially in patients who have received neoadjuvant chemotherapy and mastectomy. Materials & methods: A total of 435 patients were included in the analysis. On multivariate analysis, NLN count was an independent predictor of 5 year disease-free survival and 5 year overall survival. Results: Patients with NLN count

Purpose To evaluate and analyze the efficacy and prognostic factors of intensity-modulated radiotherapy in 250 patients with cervical and upper esophageal carcinoma. Patients and methods From September 2009 to September 2016, we retrospectively analyzed 250 patients with cervical and upper esophageal carcinoma treated with intensity-modulated radiotherapy (IMRT). In our study, all patients received IMRT, 54 patients with cervical esophageal carcinoma and 196 patients with upper esophageal carcinoma. Treatment response, survival status and failure modes of treatment were observed, and prognostic factors were analyzed. Results The median survival time was 22.60 months and 3-year survival rate was 42%. The median progress-free survival time was 14.52 months and 3-year progress-free survival rate was 29.3%. The median survival time and the median progress-free survival time for cervical esophageal carcinoma were 20.40 and 15.15 months, respectively. The median survival time and the median progress-free survival time for upper esophageal carcinoma were 25.80 and 14.52 months, respectively (P>0.05). The significant clinical factors associated with survival were patient age, radiotherapy dose and T stages (P

8579 Background: Concurrent chemoradiotherapy (CCRT) is the standard treatment for limited-stage small-cell lung cancer (LS-SCLC). However, LS-SCLC remains an area of high unmet medical need. Anlotinib is an antiangiogenic multi-target tyrosine kinase inhibitor. In the phase II ALTER-1202 trial, anlotinib significantly improved clinical outcomes in advanced small-cell lung cancer. We report here a phase 1 trial of anlotinib with CCRT for LS-SCLC. Methods: This is a prospective, single-arm, phase I clinical trial using a 3+3 design. Patients aged between 18 and 75 with previously untreated LS-SCLC, PS 0-1 and adequate organ function are eligible. Patients received anlotinib (12mg, qd, d1-14, q3w) and chemotherapy (etoposide, 100 mg/m2, d1-3, q3w and cisplatin, 25 mg/m2, d1-3, q3w) for cycle 1, then anlotinib [dose escalation at 3 levels (DL1-3) 8mg, 10mg and 12mg, qd, d1-14, q3w], chemotherapy (etoposide, 50 mg/m2, d1-5, q4w and cisplatin, 25 mg/m2, d1-3, q4w) and thoracic radiotherapy (60-66 Gy in 30-33 daily 2-Gy fractions starting on day 1 of cycle 2) for cycles 2–3, then anlotinib (12mg, qd, d1-14, q3w) and chemotherapy (etoposide, 100 mg/m2, d1-3, q3w and cisplatin, 25 mg/m2, d1-3, q3w) for cycles 4-6. Cycles 5-6 were given as appropriate according to the patient's physical condition. Prophylactic cranial radiation was given according to the judgment of the investigator after CCRT. The purpose of this study is to determine the maximum tolerated dose (MTD) of anlotinib when combination with CCRT. Results: Twelve patients were enrolled from May 2020 to September 2021. No DLTs were observed in DL1 (3 patients) or DL2 (3 patients). At DL3 (6 patients), 1 patient had a DLT of grade 3 pulmonary embolism. Grade 3 adverse events were white blood cell count decreased, neutrophil count decreased, lymphocyte count decreased, hypertension, albumin decreased and pulmonary embolism. One patient had grade 3 pulmonary embolism and grade 4 neutrophil count decreased in DL3 at cycle 1. One patient had grade 2 radiation pneumonitis after cycle 5 and grade 1 radiation esophagitis at cycle 3 in DL3. One patient had grade 2 radiation esophagitis at cycle 3 in DL2. The MTD was not reached. Conclusions: Combined treatment with anlotinib and CCRT for limited-stage small cell lung cancer is well tolerated and further clinical investigation is warranted. Clinical trial information: NCT04882033.

OBJECTIVES We investigated whether the combination of systemic chemotherapy (SCT) and liver-directed therapy (LDT) was superior to chemotherapy alone for patients with pancreatic adenocarcinoma and synchronous liver metastases (PACLM). METHODS We reviewed the medical records of 184 patients treated with SCT ± LDT at Tianjin Medical University Cancer Hospital from 2001 to 2015. Overall survival (OS) was the primary end-point. The role of treatment modality and other clinical factors was evaluated by univariate and Cox regression analyses. RESULTS Sixty-four (34.8%) patients in the SCT-LDT group and 120 (65.2%) patients in the SCT group were included in the analysis. Baseline clinical characteristics were similar between the groups (all P > 0.05). The median survival was 8.7 months in the SCT-LDT group and was 6.3 months in the SCT group. The 0.5-, 1-, 2- and 3-year survival rates were 67.2%, 33.4%, 13.3% and 8.9%, respectively, after SCT-LDT, and were 54.9%, 19.0%, 4.5% and 2.0%, respectively, after SCT (P = 0.01). Primary tumor size, ascites, and treatment modality (SCT + LDT vs. SCT) independently predicted survival (P

BACKGROUND: This study was conducted to identify the clinicopathological characteristics and survival outcomes of pulmonary sarcomatoid carcinoma (PSC), and to compare prognostic factors between elderly (≥65 years) and non-elderly (

Patients with locally advanced esophageal squamous cell carcinoma (ESCC) show poor survival after concurrent chemoradiotherapy. This study investigated the safety and feasibility of combining concurrent chemoradiotherapy with the anti-PD-1 antibody camrelizumab as first-line treatment for these patients. In this phase 1b study (ClinicalTrials.gov NCT03671265), patients received concurrent chemotherapy (cisplatin [25 mg/m2] plus docetaxel [25 mg/m2] for 4 weeks) and radiotherapy (2.0 Gy/fraction, total 60 Gy) with camrelizumab (200 mg every 2 weeks for 32 weeks). Primary endpoints were safety and tolerability, and health-related quality of life. Secondary endpoints were radiological and pathological response rates, overall survival (OS), and progression-free survival (PFS). Candidate biomarkers in tumor and peripheral blood were monitored at baseline and after 40 Gy radiation. Twenty patients were enrolled. The most common treatment-related grade 3 adverse events included radiation esophagitis (20%) and esophageal fistula (10%). Serious treatment-related adverse events occurred in eight (40%) patients. No treatment-related deaths were reported. Health-related quality of life did not deteriorate. Thirteen (65%) patients had an objective response after 40 Gy radiation. At a median follow-up of 23.7 months (95% CI 21.9–24.5), OS and PFS time ranged from 8.2–28.5 and 4.0–28.5 months, respectively. The 12-month and 24-month OS rate was 85.0% and 69.6%; PFS rate was 80.0% and 65.0%. Tumor PD-L1 expression and CD11c+ dendritic cells and peripheral-blood IL-27, IL-15, Eotaxin-3, and IL-22 were associated with OS. First-line concurrent chemoradiotherapy plus camrelizumab had a manageable safety profile and promising antitumour efficacy for ESCC, and deserves further study.

In previous studies, the estimated dose of radiation to immune cells (EDRIC) showed a correlation with overall survival (OS) of patients with locally advanced non-small cell lung cancer (LA-NSCLC) who received thoracic radiotherapy. However, several factors such as gross tumor volume (GTV) and lymph node (N) stage may impact EDRIC. The purpose of this study was to identify the factors influencing EDRIC and to further assess the prognostic relevance of EDRIC.We retrospectively analyzed 201 patients with LA-NSCLC who received radiotherapy between 2012 and 2017. EDRIC was calculated based on the model developed by Jin et al. Kaplan-Meier method and Cox proportional hazards regression were used to analyze the correlation of potential factors with OS, local progression-free survival (LPFS), and distant metastasis-free survival (DMFS). Spearman's rank correlation was used to assess the correlation between variables.Both GTV and N stage showed a positive correlation with EDRIC (r = 0.347, P 0.001 and r = 0.249, P 0.001, respectively). EDRIC was independently associated with DMFS (HR 1.185, P 0.001). GTV was associated with OS (HR 1.006, P 0.001), LPFS (HR 1.003, P = 0.017), and DMFS (HR 1.003, P = 0.032). While using GTV as a stratification factor in Kaplan-Meier analysis, EDRIC showed a trend of negative correlation with OS in GTV ≤ 66.6 cmEDRIC was an independent prognostic factor for metastasis and it was affected by GTV and N stage. However, the effect of EDRIC on OS was influenced by GTV.

BACKGROUND: Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR) are all markers of systemic inflammation response. The role of systemic inflammation in the development of esophageal fistula (EF) has yet to be defined. This study aimed to investigate the predictive value of hematologic measures of inflammation and to set up a predictive model. METHODS: The data of esophageal cancer (EC) patients who received chemoradiotherapy (CRT) in our institution between January, 2015 and January, 2018 were retrospectively collected. The NLR, PLR, and MLR of these enrolled patients were calculated. Univariate and multivariate analyses were performed to find the independent risk factors of EF. Moreover, a nomogram model was developed to predict the probability of fistula occurring in EC patients. RESULTS: For PLR, the optimal cut-off value was 153. Patients with PLR >153 had a higher probability of developing fistula than those with PLR ≤153 (P

Background In order to obtain a high dose conformal index of tumor and steep dose fall-off in healthy tissues for brain metastasis stereotactic radiosurgery (SRS), the aim of this study was to investigate SRS planning optimization by comparing one multiple-lesions plan (MLP) with multiple single-lesion plans (SLPs) for patients with multiple brain metastases using the Cyberknife (CK) system. Methods Fifty non-small cell lung cancer (NSCLC) patients (28 males and 22 females) with 2–4 brain metastases, inter-tumour distances less than 3 cm, were retrospectively replanned with the original prescription dose (12–32 Gy) in the original fractions (1–3). Two different clinical CK SRS plans (SLPs and MLP) were generated for the same patients with the same collimator and prescription isodose line (62–68%) by the CK Multiplan System. Both SLPs and MLP were able to achieve > 95% PTV volume covered prescription dose and met the Timmerman 2011 organs at risk (brainstem, optic nerve and pituitary) constraints. Results Compared with those in the SLPs, the maximum dose (Dmax) and mean dose (Dmean) of brainstem in the MLP were reduced 0.22–3.13% (2.62%) and 2.71–12.56% (5.57%), respectively, all P < 0.05. Meanwhile, the volumes of the whole brain minus the tumors that received a single dose equivalent of 8–16 Gy (V8Gy-V16Gy) were effectively reduced in the MLP. The treatment time parameters, the total number of beams and monitor units, of the MLP were reduced by 3.31 and 1.47% (P < 0.05), respectively. Although there were a few differences in the conformity index (CI) and homogeneity index (HI) between the two treatment plans, the differences were not statistically significant (P = 2.94 and 1.08 > 0.05). Conclusion One multiple-lesions plan for brain metastases could achieve higher precision in the target and lower doses in healthy tissue while shortening the treatment time and improving the treatment efficiency over multiple single-lesion plans.

Background: In order to obtain a high dose conformal index of tumor and steep dose fall-off in healthy tissues for brain metastasis stereotactic radiosurgery (SRS), the aim of this study was to investigate SRS planning optimization by comparing one multiple-lesions plan (MLP) with multiple single-lesion plans (SLPs) for patients with multiple brain metastases using the Cyberknife (CK) system.Methods: Fifty non-small cell lung cancer (NSCLC) patients (28 males and 22 females) with 2-4 brain metastases, inter-tumour distances less than 3 cm, were retrospectively replanned with the original prescription dose (12-32 Gy) in the original fractions (1-3). Two different clinical CK SRS plans (SLPs and MLP) were generated for the same patients with the same collimator and prescription isodose line (62-68%) by the CK Multiplan System. Both SLPs and MLP were able to achieve >95% PTV volume covered prescription dose and met the Timmerman 2011 organs at risk (brainstem, optic nerve and pituitary) constraints.Results: Compared with those in the SLPs, the maximum dose (Dmax) and mean dose (Dmean) of brainstem in the MLP were reduced 0.22-3.13% (2.62%) and 2.71-12.56% (5.57%), respectively, all P<0.05. Meanwhile, the volumes of the whole brain minus the tumors that received a single dose equivalent of 8-16 Gy (V8Gy-V16Gy) were effectively reduced in the MLP. The treatment time parameters, the total number of beams and monitor units, of the MLP were reduced by 3.31% and 1.47% (P<0.05), respectively. Although there were a few differences in the conformity index (CI) and homogeneity index (HI) between the two treatment plans, the differences were not statistically significant (P = 2.94 and 1.08>0.05).Conclusion: One multiple-lesions plan for brain metastases could achieve higher precision in the target and lower doses in healthy tissue while shortening the treatment time and improving the treatment efficiency over multiple single-lesion plans.

The aim of the present study was to explore the safety of apatinib plus S-1 in treating advanced solid tumors after failure of two or more lines of chemotherapy. A total of 33 patients with advanced cancer treated between April 2016 to March 2019 were retrospectively analyzed. Of these, 13 patients had non-small cell lung cancer (NSCLC), 13 patients had SCLC, 4 patients had esophageal cancer and 3 had cervical cancer. All patients were treated with apatinib 250 mg once daily combined with S-1 60 mg/m2 twice daily for 14 days, repeated every 3 weeks. Adverse reactions were observed until aggravation of adverse reactions beyond the tolerable range or disease progression, and the survival rate and clinical benefits were calculated. The results suggested that the incidence rate of adverse effects (grade 3-4) was 45.5% (15/33). The top three severe adverse effects were hypertension (15.2%), thrombocytopenia (12.1%) and proteinuria (9.1%). A total of 2 patients with lung squamous-cell carcinomas died of severe pulmonary hemorrhage. Other adverse reactions were tolerated in the cohort. A total of 10 patients achieved partial response and the objective response rate was 30.3%. Furthermore, 13 patients achieved stable disease and 10 patients had progressive disease, and accordingly, the disease control rate was 72.7%. In conclusion, apatinib plus S-1 for advanced solid tumor patients as palliative treatment have a certain efficacy and was relatively safe but should be used with caution in patients with squamous-cell lung carcinoma and the efficacy and safety requires further assessment.

Aim: To evaluate the prognostic role of EGFR mutations in patients with multi-site metastases from non-small-cell lung cancer (NSCLC). Patients & methods: A total of 215 advanced NSCLC patients with multi-site metastases were included. The overall survival (OS) was the primary end point. Results: EGFR tyrosine kinase inhibitors (TKIs) significantly improved the OS in patients with brain metastases (p = 0.031) and bone metastases (p = 0.048). Meanwhile, it prolonged the OS in patients with lung or adrenal metastases, but not in patients with liver metastases. However, in patients without liver metastases, EGFR TKIs significantly improved the OS (p < 0.001). Conclusion: EGFR TKIs improved the prognosis in NSCLC patients with brain, bone, lung and adrenal metastases, but not in patients with liver metastases.

Prostate cancer is the second most common cancer and the fifth cause of cancer death in males. Currently, there are no effective therapies for prostate cancer yet, and the status of treatment remains severe. In this study, we analyzed the composition of tumor-infiltrating immune cells (TIICs) in prostate cancer and paracancerous samples based on the gene expression profiles using CIBERSORT. Calculation of the TIIC subset proportions in 52 paired prostate cancer and paracancerous samples showed that their proportions were similar in intergroup and varied in intragroup. Compared with the paracancerous samples, the proportion of M0 macrophages was significantly increased in prostate cancer samples. Cox regression analysis using the TIIC subpopulations as continuous variables revealed that high plasma cell proportion was associated with poor 3-year Disease-Free Survival (DFS) in prostate cancer (hazard ratios = 1.8e-76

Background There is no consensus on the therapeutic approach to ECOG 2 patients with locally advanced non-small-cell lung cancer (LA-NSCLC), despite the sizable percentage of these patients in clinical practice. This study focused on the efficacy, toxicity and the optimal chemotherapy regimen of CCRT in ECOG 2 patients in a phase III trial. Methods Patients capable of all self-care with bed rest for less than 50% of daytime were classified as ECOG 2 subgroup. A subgroup analysis was performed for ECOG 2 patients recruited in the phase III trial receiving concurrent EP (etoposide + cisplatin)/PC (paclitaxel + carboplatin) chemotherapy with intensity-modulated radiation therapy (IMRT) or three-dimensional conformal external beam radiation therapy (3D-CRT). Results A total of 71 ECOG 2 patients were enrolled into the study. Forty-six (64.8%) patients were treated with IMRT technique. The median overall survival (OS) and progression free survival (PFS) for ECOG 2 patients were 16.4 months and 9 months, respectively. No difference was observed in treatment compliance and toxicities between ECOG 2 patients and ECOG 0–1 patients. Within the ECOG 2 group (31 in the EP arm and 40 in the PC arm), median OS and 3-year OS were 15.7 months and 37.5% for the EP arm, and 16.8 months and 7.5% for the PC arm, respectively (p = 0.243). The incidence of grade ≥ 3 radiation pneumonitis was higher in the PC arm (17.5% vs. 0.0%, p = 0.014) with 5 radiation pneumonitis related deaths, while the incidence of grade 3 esophagitis was numerically higher in the EP arm (25.8% vs. 10.0%, p = 0.078). Conclusions CCRT provided ECOG 2 patients promising outcome with acceptable toxicities. EP might be superior to PC in terms of safety profile in the setting of CCRT for ECOG 2 patients. Prospective randomized studies based on IMRT technique are warranted to validate our findings. Trial registration ClinicalTrials.gov registration number: NCT01494558. (Registered 19 December 2011).

BackgroundTo pursue high precision in tumor and steeper dose fall-off in healthy tissues of brain metastases stereotactic radiosurgery (SRS), this study investigated an opitimized planning by comparison only one multiple-lesions-plan (MLP) and multiple single-lesion-plans (SLP) in the treatment of brain metastases using Cyberknife (CK) Robotic Radiosurgery System. MethodsFifty non-small cell lung cancer (NSCLC) patients (28 males and 22 females) with 2-4 multiple brain metastases were retrospectively replanned with 12 to 32 Gy prescription dose in 1 to 3 fractions. Two different clinical SRS plans (SLP and MLP) for the same patients were generated, under the same collimator and prescription isodose line (62-68%) by CK Multiplan System. Both the SLP and MLP were able to get ＞95% PTV volume covered prescription isodose and meet the Timmerman 2011 OAR (brainstem, optic nerve and pituitary) constraints.ResultsCompared with the SLP, the maximum dose (Dmax) and mean dose (Dmean) of brainstem in the MLP decreased 0.22-3.13% (2.62%) and 2.71-12.56% (5.57%), over all P＜0.05. While the volumes of whole brain minus the tumors received a single dose equivalence of 8-16Gy (V8Gy-V16Gy) could effectively reduce in the MLP. And the treatment time parameters (the total number of beams and monitor units (MU)) of the MLP declined 3.31% and 1.47% (P＜0.05) respectively. Although there were a few differences of conformity index (CI) and homogeneity index (HI) between two treatment plans, it was no statistical significance (P = 2.94 and 1.08＞ 0.05). ConclusionOne multiple-lesions-plan for brain metastases could achieve higher precision in target and lower dose in healthy tissue, while shorten the treatment time and improve the treatment efficiency.

In this work, we explore the way to quickly adjust an existing named entity recognition (NER) system to make it capable of recognizing entity types not defined in the system. As an illustrative example, consider the case that a NER system has been built to recognize person and organization names, and now it requires to additionally recognize job titles. Such a situation is common in the industrial areas, where the entity types required to recognize vary a lot in different products and keep changing. To avoid laborious data labeling and achieve fast adaptation, we propose to adjust the existing NER system using the previously labeled data and entity lexicons of the newly introduced entity types. We formulate such a task as a partially supervised learning problem and accordingly propose an effective algorithm to solve the problem. Comprehensive experimental studies on several public NER datasets validate the effectiveness of our method.

Backgrounds: Chemoradiation therapy (CRT) is the standard care for unresectable locally advanced non-small cell lung cancer (LA-NSCLC). The optimal management of patients with epidermal growth factor receptor gene (EGFR) mutant LA-NSCLC is not determine. Methods: We retrospectively collected data from patients with unresectable stage III lung adenocarcinoma (LAC) harboring EGFR mutations from 2012 to 2018 and categorized their primary treatment as CRT (group 1), combined radiation therapy (RT) and EGFR-tyrosine kinase inhibitors (TKI) with/without chemotherapy (group 2), or EGFR-TKI alone until tumor progression (group 3). Inverse probability of multiple treatment weighting (IPTW) of propensity score was used to compare overall survival (OS) and progression free survival (PFS) between treatments and account for confounding. Findings: EGFR mutations were present in 24.1% of genotyped patients (N=516/2137). Of 440 patients with adequate information, 104, 105, and 231 patients were in groups 1-3. Upon IPTW analysis, adjusted median PFS was 12.4, 26.2 and 16.2 months (log-rank P=0.001) for groups 1-3, and median OS was 51.0, 67.4 and 49.3 months (log-rank P= 0.084), respectively. Comparing to CRT, RT+TKI with/without chemotherapy significantly improved both PFS (adjusted HR [aHR], 0.40; 95% CI, 0.29-0.54; P= 0.001) and OS (aHR, 0.61; 95% CI, 0.38-0.98; P=0.039);TKI alone prolonged PFS (aHR=0.66; 95%CI, 0.50-0.87; P=0.003) but not OS (aHR,0.90; 95% CI, 0.62-1.32; P= 0.595). Similar findings were found in doubly robust IPTW analysis and multivariable Cox regression analysis. Interpretation: First-line use of RT+TKI with/without chemotherapy was associated with the longest PFS and OS compared with CRT or TKI alone in patients with EGFR-mutant unresectable LA-NSCLC. Trial Registration: The study was registered with Clinical Trials.gov, number NCT04304638. Funding Statement: This trial was funded by the National Natural Sciences Foundation Key Program (81572971); CAMS Innovation Fund for Medical Sciences (No. 2017-I2M-1-005), and Sanming Project of Medicine in Shenzhen (No. SZSM201612063) Declaration of Interests: All authors have declared no conflicts of interest. Ethics Approval Statement: The study protocol was approved by the ethics review boards of the Cancer Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College. Each participating center obtained regulatory approval per their institutional ethics guidelines.

To evaluate the clinical outcomes of simultaneous dose reduction of elective nodal area with intensity-modulated radiotherapy (SIR-IMRT) versus conventional IMRT (C-IMRT) in patients with limited-stage small-cell lung cancer (LS-SCLC), patients with LS-SCLC who received definitive SIR-IMRT or C-IMRT were retrospectively analyzed. In SIR-IMRT group, the prescribed dose was 60Gy to the planning gross target volume (PTVG), and 54Gy to the planning target volume (PTV). In the C-IMRT group, the prescribed dose was 60Gy to the whole PTV. Radiation-related toxicities were estimated according to Common Terminology Criteria for Adverse Events (version 3.0). The primary endpoint was loco-regional recurrence-free survival (LRFS), and the secondary endpoints include overall survival (OS) and toxicities. LRFS and OS were estimated with Kaplan-Meier method. After propensity score matching, 84 patients were included in this study, with 42 patients in each group. Fifty-eight patients experienced treatment failure. Grade 3 and above radiation-induced lung toxicity developed in 2 patients in SIR-IMRT group and 5 patients in C-IMRT group, respectively. Grade 3 and above radiation-related esophagitis was observed in 3 patients and 5 patients, respectively. The 1-, 3-year LRFS rates of the SIR-IMRT group and C-IMRT group were 90.4%, 73.3% and 87.1%, 45.0%(P=0.025), respectively. Reducing the irradiation dose to the elective nodal region may reduce radiation-induced toxicities without compromising local-regional control and overall survival.

// Xue Li 1, 2, * , Lujun Zhao 1, * , Wencheng Zhang 1 , Chengwen Yang 1 , Zhen Lian 1 , Shuai Wang 1 , Ningbo Liu 1 , Qingsong Pang 1 , Ping Wang 1 and Jinming Yu 1, 2 1 Department of Radiation Oncology and Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China 2 Department of Radiation Oncology, Shandong University Affiliated Shandong Cancer Hospital and Institute, Jinan 250000, China * These authors have contributed equally to this work Correspondence to: Jinming Yu, email: sdyujinming@163.com Keywords: esophageal squamous cell carcinoma, supraclavicular nodes, celiac nodes, common hepatic nodes, radiotherapy Received: February 17, 2017 Accepted: April 17, 2017 Published: May 19, 2017 ABSTRACT The purpose of this study is to assess the prognostic value of supraclavicular nodes, left gastric nodes, celiac nodes and common hepatic nodes metastasis in esophageal squamous cell carcinoma (ESCC) treated with definitive radiotherapy. A total of 293 ESCC patients treated with radiotherapy or chemoradiotherapy entered the study. The results showed that the presence of supraclavicular nodes (χ 2 = 0.075, P = 0.785) and left gastric nodes (χ 2 = 3.603, P = 0.058) metastasis had no significant influence on survival, while celiac nodes (χ 2 = 33.775, P < 0.001) and common hepatic nodes (χ 2 = 42.350, P < 0.001) metastasis were associated with significantly shorter survival, regardless of the sites of primary tumor. Multivariate analysis showed that celiac nodes (HR: 0.457, 95% CI: 0.256-0.816; P = 0.008) and common hepatic nodes (HR: 0.241, 95% CI: 0.092-0.630; P = 0.004) metastasis were independently adverse indicator of survival in upper ESCC. While in the middle and lower ESCC, only the common hepatic nodes (middle ESCC: HR: 0.345, 95% CI: 0.161-0.738, P = 0.006; lower ESCC: HR: 0.377, 95% CI: 0.160-0.890, P = 0.026) metastasis was an independently adverse indicator of survival. In conclusion, our study demonstrated that in ESCC treated with definitive radiotherapy, both of celiac nodes and common hepatic nodes metastasis were adverse indicator of survival in upper ESCC, and common hepatic nodes metastasis were adverse indicator of survival in middle and lower ESCC. Supraclavicular nodes an left gastric nodes metastasis is not associated with patients survival in ESCC.

// Baozhong Zhang 1 , Zhiyong Yuan 1 , Lujun Zhao 1 , Qingsong Pang 1 , Ping Wang 1 1 Department of Radiotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, People’s Republic of China Correspondence to: Baozhong Zhang, email: baozhongtj@163.com Keywords: non-small cell lung cancer (NSCLC), N2, post-operative chemo-radiotherapy (POCRT), nomogram Received: December 28, 2016 Accepted: March 16, 2017 Published: March 25, 2017 ABSTRACT In this retrospective study, we developed nomograms for predicting the efficacy of post-operation radiotherapy (PORT) in IIIA-N2 non-small cell lung cancer (NSCLC) patients. In total, 334 patients received post-operational chemotherapy and were included in the analysis. Of those, 115 also received either concurrent or sequential post-operational radiotherapy (PORT). Nomograms were developed using Cox proportional hazard regression models to identify clinicopathological characteristics that predicted progression free survival (PFS) and overall survival (OS), and subgroup analyses of the effects of PORT were performed using nomogram risk scores. PFS and OS predicted using the nomogram agreed well with actual PFS and OS, and patients with high PFS/OS nomogram scores had poorer prognoses. In subgroup analyses, PORT increased survival more in patients with low PFS nomogram risk scores or high OS nomogram risk scores. Thus, our novel nomogram risk score model predicted PFS, OS, and the efficacy of PORT in IIIA-N2 NSCLC patients.

Aspect category detection is an essential task for sentiment analysis and opinion mining. However, the cost of categorical data labeling, e.g., label the review aspect information for a large number of product domains, can be inevitable but unaffordable. In this study, we propose a novel problem, cross-domain aspect category transfer and detection, which faces three challenges: various feature spaces, different data distributions, and diverse output spaces. To address these problems, we propose an innovative solution, Traceable Heterogeneous Graph Representation Learning (THGRL). Unlike prior text-based aspect detection works, THGRL explores latent domain aspect category connections via massive user behavior information on a heterogeneous graph. Moreover, an innovative latent variable "Walker Tracer" is introduced to characterize the global semantic/aspect dependencies and capture the informative vertexes on the random walk paths. By using THGRL, we project different domains' feature spaces into a common one, while allowing data distributions and output spaces stay differently. Experiment results show that the proposed method outperforms a series of state-of-the-art baseline models., Accepted as a full paper of The 28th ACM International Conference on Information and Knowledge Management (CIKM '19)

The current study was to compare the efficacy and safety between concurrent and sequential chemoradiotherapy after 3-4 cycles of induction chemotherapy for limited-stage small-cell lung cancer (LS-SCLC) with bulky tumor. From July 2012 to September 2015, a total of 68 patients with stage IIIA and IIIB SCLC who had completed 3-4 cycles of etoposide plus cisplatin/carboplatin and achieved clinical complete response (cCR) or clinical partial response (cPR) were randomized into the two groups equally. The concurrent group received radiotherapy combined with oral etoposide and cisplatin and the sequential group received sequential chemoradiotherapy. Thoracic radiotherapy was performed using intensity-modulated radiation therapy (IMRT) with 95% PTV 60Gy/30 times. After completing chemoradiotherapy, patients received prophylactic cranial irradiation. The primary endpoint was progression-free survival (PFS), and secondary endpoints included overall survival (OS) and toxicity. The median follow-up time was 63.3 months (95% confidence interval [CI], 50.8-75.8). Better PFS and OS were observed in concurrent group (median PFS, 26.0 months [95% CI, 9.0-43.0] versus 13.1 months [95%CI, 9.7-16.6], p=0.023; median OS, 35.0 months [95% CI, 25.4-44.6] versus 22.0 months [95% CI, 17.0-27.1], p=0.015). There was no significant difference in the incidence of radiation esophagitis and radiation pneumonitis between the two groups (p=0.795, p=0.525). This study demonstrated that after the completion of 3-4 cycles of chemotherapy with a remission, concurrent chemoradiotherapy with oral etoposide and cisplatin improved survival compared with sequential chemoradiotherapy in LS-SCLC with bulky tumor. ClinicalTrials.gov Identifier: NCT01745445.

Various types of target information have been considered in aspect-based sentiment analysis, such as entities and aspects. Existing research has realized the importance of targets and developed methods with the goal of precisely modeling their contexts via generating target-specific representations. However, all these methods ignore that these representations cannot be learned well due to the lack of sufficient human-annotated target-related reviews, which leads to the data sparsity challenge, a.k.a. cold-start problem here. In this paper, we focus on a more general multiple entity aspect-based sentiment analysis (ME-ABSA) task which aims at identifying the sentiment polarity of different aspects of multiple entities in their context. Faced with severe cold-start scenario, we develop a novel and extensible deep memory network framework with cold-start aware computational layers which use frequency-guided attention mechanism to accentuate on the most related targets, and then compose their representations into a complementary vector for enhancing the representations of cold-start entities and aspects. To verify the effectiveness of the framework, we instantiate it with a concrete context encoding method and then apply the model to the ME-ABSA task. Experimental results conducted on two public datasets demonstrate that the proposed approach outperforms state-of-the-art baselines on ME-ABSA task.

Character-level Chinese named entity recognition (NER) that applies long short-term memory (LSTM) to incorporate lexicons has achieved great success. However, this method fails to fully exploit GPU parallelism and candidate lexicons can conflict. In this work, we propose a faster alternative to Chinese NER: a convolutional neural network (CNN)-based method that incorporates lexicons using a rethinking mechanism. The proposed method can model all the characters and potential words that match the sentence in parallel. In addition, the rethinking mechanism can address the word conflict by feeding back the high-level features to refine the networks. Experimental results on four datasets show that the proposed method can achieve better performance than both word-level and character-level baseline methods. In addition, the proposed method performs up to 3.21 times faster than state-of-the-art methods, while realizing better performance.

''User reviews” are becoming an essential component of e-commerce. When buyers write a negative or doubting review, ideally, the sellers need to quickly give a response to minimize the potential impact. When the number of reviews is growing at a frightening speed, there is an urgent need to build a response writing assistant for customer service providers. In order to generate high-quality responses, the algorithm needs to consume and understand the information from both the original review and the target product. The classical sequence-to-sequence (Seq2Seq) methods can hardly satisfy this requirement. In this study, we propose a novel deep neural network model based on the Seq2Seq framework for the review response generation task in e-commerce platforms, which can incorporate product information by a gated multi-source attention mechanism and a copy mechanism. Moreover, we employ a reinforcement learning technique to reduce the exposure bias problem. To evaluate the proposed model, we constructed a large-scale dataset from a popular e-commerce website, which contains product information. Empirical studies on both automatic evaluation metrics and human annotations show that the proposed model can generate informative and diverse responses, significantly outperforming state-of-the-art text generation models.

Background: Brainstem glioma is a rare brain tumor with poor prognosis and difficulty for surgical resection. We sought to retrospectively analyze and evaluate the clinical efficacy of CyberKnife for brainstem gliomas. Methods: From 2006 to 2015, a total of 21 brainstem gliomas patients who received CyberKnife radiosurgery treatment enrolled in this study and 18 patients with follow up. CyberKnife image-guided radiosurgical system were applied consecutively with the median prescribed total dose of 26 Gy (14–33 Gy) at two to six fractions on days utilizing CyberKnife system, and the median biological equivalent doses of 59.8 Gy (33.6–76.56 Gy). The clinic pathlogical features, survival were analyzed to explore the efficacy of CyberKnife radiosurgery in treatment of brainstem glioma. Results: With median follow-up of 54.5 months, patients with brainstem gliomas had median overall survival of 19 months, five patients still alive. The primary endpoints of the 1- and 2-year overall survival rates were 87.5 and 52.4%, respectively. During the treatment course, six patients were observed to have pseudoprogression with mass effect on MRI. Four patients developed radiation complications. Grade 2 radiation-related toxicity were observed in three patients and one patient with grade 3. Conclusion: The efficacy of brainstem gliomas—treated with CyberKnife is efficacious with mild toxicity.

Customers ask questions and customer service staffs answer their questions, which is the basic service model via multi-turn customer service (CS) dialogues on E-commerce platforms. Existing studies fail to provide comprehensive service satisfaction analysis, namely satisfaction polarity classification (e.g., well satisfied, met and unsatisfied) and sentimental utterance identification (e.g., positive, neutral and negative). In this paper, we conduct a pilot study on the task of service satisfaction analysis (SSA) based on multi-turn CS dialogues. We propose an extensible Context-Assisted Multiple Instance Learning (CAMIL) model to predict the sentiments of all the customer utterances and then aggregate those sentiments into service satisfaction polarity. After that, we propose a novel Context Clue Matching Mechanism (CCMM) to enhance the representations of all customer utterances with their matched context clues, i.e., sentiment and reasoning clues. We construct two CS dialogue datasets from a top E-commerce platform. Extensive experimental results are presented and contrasted against a few previous models to demonstrate the efficacy of our model.

Background The role of the dose escalation strategy in brain radiotherapy for small cell lung cancer (SCLC) patients with brain metastases (BMs) has not been identified. This study aims to determine whether an additional radiation boost to whole brain radiation therapy (WBRT) has beneficial effects on overall survival (OS) compared with WBRT-alone. Methods A total of 82 SCLC patients who were found to have BMs treated with WBRT plus a radiation boost (n = 33) or WBRT-alone (n = 49) from January 2008 to December 2015 were retrospectively analyzed. All patients were limited-stage (LS) SCLC at the time of the initial diagnosis, and none of them had extracranial metastases prior to detection of BMs. The primary end point was OS. Results The median OS for all of the patients was 9.6 months and the 6-, 12- and 24-months OS rates were 69.1, 42.2 and 12.8%, respectively. At baseline, the proportion of more than 3 BMs was significantly higher in the WBRT group than in the WBRT plus boost group (p = 0.0001). WBRT plus a radiation boost was significantly associated with improved OS in these patients when compared with WBRT-alone (13.4 vs. 8.5 months; p = 0.004). Further, the survival benefit still remained significant in WBRT plus boost group among patients with 1 to 3 BMs (13.4 vs. 9.6 months; p = 0.022). Conclusion Compared with WBRT-alone, the use of WBRT plus a radiation boost may prolong survival in SCLC patients with BMs. The dose escalation strategy in brain radiotherapy for selected BMs patients with SCLC should be considered.

Baozhong Zhang, Lujun Zhao, Zhiyong Yuan, Qingsong Pang, Ping Wang Department of Radiotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, and Tianjin Lung Cancer Center, Tianjin, People’s Republic of China Objective: The use of postoperative radiotherapy (PORT) remains controversial for Stage IIIA-N2 non-small-cell lung cancer (NSCLC) patients, a possible reason is that IIIA-pN2 NSCLC diseases are a heterogeneous group with different clinicopathologic features. The aim of this research was to prove whether the mediastinal lymph nodes’ (LNs) skipping status could indicate the necessity of the PORT for the pN2 NSCLC patients.Methods: The skip metastasis was defined as pN0N2 (no N1 LN involved), and nonskip metastasis was pN1N2 (one or more N1 LNs involved). Patients were divided into two groups: LNs nonskip and LNs skip, and postoperative chemoradiotherapy (POCRT) and postoperative chemotherapy. Then, the LN nonskip and LN skip groups were further divided into subgroups: POCRT and point of care testing (POCT) for subgroup analysis.Results: There were 220 cases included in the analysis, and 43 of them received PORT. Onunivariate analysis, the median 3-year progression-free survival (PFS) was, respectively, 16 months (27.7%) for the LN skip group and 11 months (15.3%) for the LN nonskip group (P=0.001). The median 3-year overall survival (OS) was, respectively, 35 months (47.0%) for the LN skip group and 27 months (38.7%) for the LN nonskip group (P=0.025). The median 3-year local recurrence-free survival (LRFS) was, respectively, 25 months (41.0%) for the LN skip group and19 months (29.9%) for the LN nonskip group (P=0.014). The median 3-year distant metastasis-free survival (DMFS) was, respectively, 22 months (32.5%) for the LN skip group and 15 months (20.4%) for the LN nonskip group (P=0.013). The median 3-year PFS was, respectively, 17 months (25.6%) for the POCRT group and 12months (18.6%) for the POCT group (P=0.037). Although the POCRT group showed better OS, LRFS, and DMFS than the POCT group, the results showed no statistical significance. In subgroup analysis, there was no statistical significance in the Kaplan–Meier analysis between subgroups, but it showed that POCRT resulted in better PFS, OS, and DMFS in both LN skip and LN nonskip subgroups; this advantage was more obvious in the LN skip subgroup.Conclusion: The LN skip status is closely related to the survival of the IIIA-N2 NSCLC disease, and the LN skip patients may get more benefit in PFS and LRFS than the LN nonskip patients from PORT. Keywords: non-small-cell lung cancer (NSCLC), N2, postoperative chemoradiotherapy (POCRT), LN skip/nonskip, PFS, OS, DMFS

Radiotherapy is used to treat many different human tumors. Paradoxically, radiation can activate TGF-β1 signaling and induce the epithelial-mesenchymal transition (EMT), which is associated with enhanced tumor progression. This study investigated the inhibitory effects of halofuginone, a plant-derived alkaloid that has been shown to inhibit TGF-β1 signaling, on radiation-induced EMT and explored the underlying mechanisms using a Lewis lung carcinoma (LLC) xenograft model. The cells and animals were divided into five treatment groups: Normal Control (NC), Halofuginone alone (HF), Radiotherapy alone (RT), Radiotherapy combined with Halofuginone (RT+HF), and Radiotherapy combined with the TGF-β1 inhibitor SB431542 (RT+SB). Radiation induced EMT in lung cancer cells and xenografts, as evidenced by increased expression of the mesenchymal markers N-cadherin and Vimentin, and reduced expression of the epithelial markers E-cadherin and Cytokeratin. Further, radiotherapy treatment increased the migration and invasion of LLC cells. Halofuginone reversed the EMT induced by radiotherapy in vitro and in vivo, and inhibited the migration and invasion of LLC cells. In addition, TGF-β1/Smad signaling was activated by radiotherapy and the mRNA expression of Twist and Snail was elevated; this effect was reversed by halofuginone or the TGF-β1 inhibitor SB431542. Our results demonstrate that halofuginone inhibits radiation-induced EMT, and suggest that suppression of TGF-β1 signaling may be responsible for this effect.

Dong Qian,1 Jingjing Cheng,1 Xiaofeng Ding,1 Xiuli Chen,1 Xi Chen,1 Yong Guan,1 Bin Zhang,2 Jiefu Wang,3 Puchun Er,1 Minghan Qiu,1 Xianliang Zeng,1 Yihang Guo,1 Huanhuan Wang,1 Lujun Zhao,1 Dan Xie,4 Zhiyong Yuan,1 Ping Wang,1 Qingsong Pang1 1Department of Radiotherapy, 2Department of Lung Cancer, 3Department of Colorectal Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 4State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, People’s Republic of China Abstract: PinX1 plays positive and negative roles in the maintenance of telomerase and telomeres, as well as in tumorigenesis. The aim of the present study was to investigate the expression and clinical significance of PinX1 in colorectal carcinoma (CRC) and to determine the effect of PinX1 on CRC cell proliferation and apoptosis. A total of 86 CRC patients treated with radical resection and 5-fluorouracil-based adjuvant chemotherapy were enrolled in this study. The expression dynamics of PinX1 was detected by immunohistochemistry in the CRC patients and 25 normal colonic mucosa controls. PinX1 expression was significantly reduced in tumor tissues as compared to normal tissues, and the rate of PinX1 protein low/negative expression in CRC and normal tissues was 60% (52/86) and 24% (6/25), respectively (P=0.037). In addition, PinX1 downregulation was significantly associated with short overall survival (P=0.016) and disease-free survival (P=0.042) in CRC patients. Cox proportional hazards model further revealed that PinX1 expression was an independent factor in predicting overall survival and disease-free survival for CRC patients. Furthermore, we demonstrated that ectopic overexpression of PinX1 in CRC cells inhibited their proliferation, promoted apoptosis, repressed telomerase activity, and induced telomere shortening. These findings suggest that PinX1 may be a prognostic biomarker for CRC patients’ survival and that it inhibits cell proliferation and promotes apoptosis by repressing telomerase activity and inducing telomere shortening. Targeting PinX1 may therefore provide a novel therapeutic strategy for CRC patients. Keywords: colorectal carcinoma, PinX1, cell proliferation, apoptosis, telomerase, telomere, prognostic biomarker

BACKGROUND: This study aimed to determine the extent to which the survival outcomes of patients with N2-III non-small cell lung cancer (NSCLC) following surgery differ by histological subtype. METHODS: Patients with N2-III NSCLC receiving surgery between 2010 to 2016 were included using the Surveillance, Epidemiology and End Results (SEER) database. Cox proportional hazards models were used to identify risk factors associated with overall survival (OS) and non-cancer mortality. The Kaplan-Meier method with log-rank tests was used to estimate survival. Propensity score matching (PSM) was used. Statistical significance was defined as P

Background This report describes the clinical work in esophageal cancer radiation group at the Department of Radiotherapy, Tianjin Medical University Cancer Institute & Hospital (TJMUCH). Methods We retrospectively analyzed the clinical data of patients with esophageal cancer who received radiotherapy (RT) at TJMUCH during the 5-year period between 2015 and 2019, including RT procedures, RT methods, treatment types, treatment outcomes and complications, and clinical trials. Results In 2015-2019, 1,464 patients with esophageal cancer received RT at the Department of Radiotherapy, TJMUCH. Of these, 1,176 patients received definitive chemoradiotherapy (CRT), 100 received preoperative neoadjuvant CRT, 120 received postoperative adjuvant RT, 49 received post-relapse RT, and 19 received palliative RT for advanced esophageal cancer. Among the patients who received definitive CRT, the incidences of grade 2 and higher radiation esophagitis, radiation pneumonitis, and leukopenia were 19.4%, 3.6%, and 19.7%, respectively; the incidences of grade 3-4 radiation esophagitis, radiation pneumonitis, and leukopenia were 9.4%, 1.2%, and 5.4%, respectively; no grade 5 acute adverse events were observed. Esophageal fistula was the major side effect during the advanced stage of RT. In 2015-2018, 44 patients (5%, 44/846) developed esophageal fistula; of these, 34 cases occurred after RT, and 10 cases occurred during RT. The overall survival was based on the data of 544 patients with esophageal cancer who underwent definitive RT at TJMUCH between March 2010 and September 2016. The median follow-up time was 21.6 months. The median survival was 19.6 months; and the 1-, 3-, and 5-year overall survival rates were 69.4%, 37.2%, and 32.3%, respectively. In 2015-2019, approximately 201 patients participated in different prospective clinical trials. Conclusions RT is a crucial and effective treatment for esophageal cancer. Standardized treatment procedures, multidisciplinary cooperation, are the foundations for good treatment effects. Many promising ongoing clinical trials will be helpful to improve the prognosis and survival of esophageal cancer patients in the future.

Background Compelling research to explore the effectiveness of simultaneous integrated dose reduction in clinical target volume (CTV) with intensity-modulated radiotherapy (SIR-IMRT) for locally advanced esophageal squamous cell carcinoma (ESCC) are limited. This study aimed to compare the clinical efficacy and treatment-related toxicity between SIR-IMRT and conventional IMRT (C-IMRT) in the treatment of ESCC. Methods From March 2010 to September 2016, the clinical data of 257 patients with ESCC who received definitive IMRT in the Tianjin Medical University Cancer Institute and Hospital were collected and retrospectively analyzed. Among these patients, 137 patients received C-IMRT with a prescribed dose of 60 Gy in 30 fractions for planning target volume (PTV), while 120 patients received SIR-IMRT with a prescribed dose of 60 Gy in 30 fractions for the planning gross tumor volume (PGTV) and a prescribed dose of 54 Gy in 30 fractions for PTV. All of the patients received definitive IMRT with elective nodal irradiation. Locoregional control, survival, treatment toxicity and dose to organs at risk (OAR) were compared between the groups. Results Patients who received SIR-IMRT showed a similar locoregional failure rate compared to the C-IMRT group (27.5% versus 29.9%, P=0.668). The 1-, 2- and 3-year overall survival (OS) rates were 71.5%, 44.3%, 44.3% vs. 77.9%, 52.1%, 32.9% in the C-IMRT and SIR-IMRT groups, respectively (P=0.825). No significant differences were observed in PFS and LRRFS between the two groups (P=0.880 and P=0.216, respectively). The dose of lung V30 and the maximum dose of spinal cord in the C-IMRT group were significantly higher than those in the SIR-IMRT group (P=0.013, P=0.047). The incidence of acute radiation esophagitis was significantly lower in the SIR-IMRT group (P=0.046), although no statistical difference was observed in the incidence of acute severe adverse events between the two groups. Conclusions SIR-IMRT offers an effective and safe option for patients with unresectable ESCC who receive definitive RT. Further prospective and larger sample size studies are warranted to confirm our results.