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Background: Anti-PD-1 antibody combined with antiangiogenic drugs have demonstrated antitumor activity in advanced triple negative breast cancer (TNBC). Anlotinib, an oral multi-targeted tyrosine kinase inhibitor (TKI), has synergistic effect with anti-PD-1 antibody. Preclinical studies showed that metronomic chemotherapy inhibited angiogenesis and enhanced immunotherapy efficacy in TNBC via modulation of tumor immune microenvironment. We hereby conducted a single-arm, multicenter, phase II trial to investigate the efficacy and safety of sintilimab (anti-PD-1 antibody) in combination with anlotinib plus metronomic chemotherapy as a potential novel therapeutic strategy in advanced TNBC and explore potential biomarkers. Methods: Forty-three cases were planning to be included in this trial. The eligible patients who had received no more than two lines of chemotherapy for metastatic disease were enrolled and received sintilimab (200 mg iv q3w) in combination with anlotinib (12 mg po d1-14 q3w) plus capecitabine (500 mg po, tid) or vinorelbine (40 mg po, tiw) until disease progression or intolerable toxicity. The primary endpoint is objective response rate (ORR) and secondary endpoints are disease control rate (DCR), progression free survival (PFS), and overall survival (OS). The safety profile has also been assessed. Blood samples collected at different time points of the baseline, first and second cycle post-treatment, and disease progression were used for next-generation sequencing of ctDNA containing 654 tumor-related genes. Results: As of July 2022, a total of 32 patients were enrolled, and 29 patients were evaluable for efficacy. 2 patients (6.9%) achieved complete response (CR). 6 patients (20.7%) achieved partial response (PR). The ORR is 27.6% (8/29) and DCR is 79.3% (23/29). The median PFS was not reached. The most common grade 1 or 2 adverse events (AEs) include elevated thyroid stimulating hormone (37.0%, 10/27), hand-foot syndrome (18.5%, 5/27), elevated aspartate aminotransferase (14.8%, 4/27), elevated bilirubin (11.1%, 3/27) and hypertension (11.1%, 3/27). Grade 3 AEs include elevated bilirubin (3.7%, 1/27) and hypertension (3.7%, 1/27). No grade 4 or 5 AEs occurred. By analyzing ctDNA mutations of blood samples in 10 patients at baseline, we found that genes with high mutation frequency were HLA-DRB5 (8/10, 80%), TP53 (7/10, 70%), HLA-DRB1 (5/10, 50%) and PIK3CA (4/10, 40%). Among these 10 patients, 2, 3 and 5 patients achieved PR, SD and PD, respectively. The number of gene mutations in patients with PD was higher than that in patients with PR or SD at baseline. This indicate that mutations in ctDNA may be associated with poor efficacy in advanced TNBC. But this still needs further verification. Dynamic analysis of gene mutations at different time points showed that the amplification of HLA-DRB5 or the elimination of KMT2D, RELN and TP53 occurred in patients with PR and SD, but not in patients with PD. Conclusions: Sintilimab in combination with anlotinib plus metronomic chemotherapy has shown favorable efficacy and acceptable safety profile in patients with advanced TNBC. The clinical significance of ctDNA dynamic monitoring needs further validation. Clinical trial information: ChiCTR2100044725 Citation Format: Huihui Li, Qiaorui Tan, Shujuan Sun, Dongdong Zhou, Bo Yu, Mu Su, Baojiang Li, Shu Fang, Ling Qiang, Guohua Ren, Bing Bu, Sha Yin, Xiaochu Man, Pengfei Qiu, Xinzhao Wang, Chao Li, Fangli Cao, Qian Shao, Dali Han, Lihua Song, Bingjie Fan, Baoxuan Zhang, Liang Xu, Xianguang Zhao, Yuqian Liao, Xuemei Xie, Lanping Liu. Efficacy and safety of sintilimab in combination with anlotinib plus metronomic chemotherapy in advanced triple negative breast cancer (SPACE): preliminary results of a single-arm, multicenter phase II trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT1-05-02.

Background. RACK1 is known to be involved in tumor progression, and its prognostic value on many kinds of tumors has been identified. However, there are limited studies about the functional role of RACK1 in esophageal squamous cell carcinoma (ESCC). Patients and methods. RACK1 expression was examined in 100 ESCC tissue samples using immunohistochemistry staining. RACK1 was knocked-down in ESCC cell lines by shRNA. The effects on cell proliferation, invasion and migration were examined in ESCC cell lines and nude mouse model. Vimentin and E-cadherin were introduced to further study the association between RACK1 and EMT. Results. RACK1 expression was significantly associated with the tumor length (P = 0.012), diameter

Background: Cerebral Salt Wasting Syndrome (CSWS) refers to the process of intracranial lesions, sodium salt loss by hypothalamus-renal pathway and caused clinical manifestations syndrome of high urinary sodium, hyponatremia, hypovolemia. The clinical manifestations and laboratory are similar to syndrome of inappropriate antidiuretic hormone secretion (SIADH). It is easy to be misdiagnosed. Case description and management: In this paper, the clinical data of one case of cerebral salt wasting syndrome was diagnosed. By given fluid and sodium replacement, the condition can improve quickly. Through analyzing and reviewing related literature, the understand of diagnosis and treatment of cerebral salt wasting syndrome can be improved. Conclusions: The main clinical manifestations of cerebral salt wasting syndrome are hyponatremia, high urine sodium, diuresis, hypovolemia. Cerebral salt wasting syndrome in children has very high risks and we should improve the understanding. Early diagnosis and prompt treatment are very important.

gamma-aminobutyric acid type B (GABA(B)) receptor is an allosteric complex made of two subunits, GABA(B1) and GABA(B2). GABA(B2) plays a major role in the coupling to G protein whereas GABA(B1) binds GABA. It has been shown that GABA(B) receptor activates ERK(1/2) in neurons of the central nervous system, but the molecular mechanisms underlying this event are poorly characterized. Here, we demonstrate that activation of GABA(B) receptor by either GABA or the selective agonist baclofen induces ERK(1/2) phosphorylation in cultured cerebellar granule neurons. We also show that CGP7930, a positive allosteric regulator specific of GABA(B2), alone can induce the phosphorylation of ERK(1/2). PTX, a G(i/o) inhibitor, abolishes both baclofen and CGP7930-mediated-ERK(1/2) phosphorylation. Moreover, both baclofen and CGP7930 induce ERK-dependent CREB phosphorylation. Furthermore, by using LY294002, a PI-3 kinase inhibitor, and a C-term of GRK-2 that has been reported to sequester Gbetagamma subunits, we demonstrate the role of Gbetagamma in GABA(B) receptor-mediated-ERK(1/2) phosphorylation. In conclusion, the activation of GABA(B) receptor leads to ERK(1/2) phosphorylation via the coupling of GABA(B2) to G(i/o) and by releasing Gbetagamma subunits which in turn induce the activation of CREB. These findings suggest a role of GABA(B) receptor in long-term change in the central nervous system.

Background: Smoking is well-known as a risk factor for esophageal squamous cell carcinoma. However, little is known about the effect of this factor on survival. Methods: Esophageal cancer patients who underwent esophagectomy without any preoperative therapy were retrospectively reviewed. Patients’ postoperative overall and disease-free survivals were compared between 2 groups (non-heavy smokers and heavy smokers). Results: A total of 109 cases were evaluated in this study. The 5-year OS rate of the non-heavy smokers was 53.2% and 32.3% for the heavy group. The 5-year DFS rate of the non-heavy smokers was 51.1% and 27.4% for the heavy group. Kaplan-Meier survival analysis revealed that heavy smokers had significantly poorer OS (P=0.018) and DFS (P=0.009) than non-heavy smokers. In multivariate analysis, smoking was found to be an independent prognostic factor for OS (P=0.003; HR: 2.186; 95% CI: 1.309-3.650) and DFS (P=0.001; HR: 2.471; 95% CI: 1.467-4.163). Conclusion: Smoking was associated with survival among patients with ESCC, and it was recognized as an independent factor in both OS and DFS.

Background Socioeconomic status (SES) has been focused on as a key determinant of the incidence of cancer, cancer stage at diagnosis as well as treatment choices in western countries. However, to the authors’ knowledge, little work has been done concerning the relationship of SES and esophageal cancer in China. Methods Patients diagnosed with primary esophageal cancer from January to December 2007 in Qilu hospital were included. Socioeconomic status was determined by a questionnaire including religion, years of schooling and high education, place of residence, occupation, annual household income, and insurance. Results A total of 238 cases were collected in this study. Linear-by-linear association testing revealed that health-care delay was significantly associated with SES (P = 0.009). Multivariable logistic regression analysis revealed that increased health-care delay (>2 months) was more frequently observed in patients with lower SES (OR 2.271; 95% CI 1.069–4.853). Patients diagnosed at TNM I and II were more frequently in higher SES groups (P = 0.017). The association test was statistically significant for undergoing surgical resection only (P = 0.015) and chemotherapy (P = 0.015). Multivariable logistic regression analysis revealed that surgical resection only was less performed in higher SES group compared with lower SES group (OR 0.372; 95% CI 0.188–0.734). For chemotherapy, higher SES patients had a three-fold higher likelihood compared with lower SES group (OR 3.042; 95% CI 1.335–6.928). Conclusion Socioeconomic status was found to be associated with health-care delay, tumor stage and treatment modalities in esophageal cancer. Electronic supplementary material The online version of this article (doi:10.1186/s12967-015-0579-9) contains supplementary material, which is available to authorized users.

Table S3. Multivariable logistic regression analysis of between SES and health-care delay.

Table S6. Linear-by linear association between TNM stage and treatment modalities.

Table S5. Multivariable logistic regression analysis of between SES and treatment modalities.

Table S2. Linear-by linear association between SES and health-care delay/tumor stage /treatment.

Table S4. Multivariable logistic regression analysis of between SES and tumor stage.

Table S1. Patient characteristics.

Objective: Cancer-associated fibroblasts (CAFs; α-SMA positivity), as a representative of the tumor microenvironment, play an important role in influencing the proliferation, invasion and metastasis of cancer cells. The objective is to investigate the prognostic value of CAFs density in esophageal squamous cell carcinoma (ESCC) after surgery. Method: A total of 95 patients who underwent esophagectomy for ESCC in 2007 were included in this study. These specimens were immunostained with α-smooth muscle actin (α-SMA) antibodies to quantify CAFs. Antibodies D2-40 and CD34 were used to evaluate the lymphatic vessel density (LVD) and microvessel density (MVD) of the lesions. The Cox proportional hazards model was used to determine the hazard ratio of CAFs density on 3-year overall survival and 3-year disease-free survival. The correlation between CAFs density and lymphatic vessel density (LVD) or microvessel density (MVD) were analyzed. Results: 3-year overall survival rate in the CAF-poor group (63%) was significantly better than those in the CAF-rich group (42%) (P < 0.01). In the Cox univariate and multivariate analysis of 3-year overall survival, the hazard ratio (HR) of CAFs density was 1.870 (95% CI 1.033-3.385; P = 0.039) and 2.196 (95% CI 1.150-4.193; P = 0.017), respectively. CAFs density was proved to be an independent prognostic factor for 3-year overall survival. CAFs density correlated significantly with increased LVD and MVD in ESCC. Conclusion: CAFs density may be a marker for predicting prognosis and guiding therapeutic management of ESCC.

Platelets play a role in tumor angiogenesis and growth and are the main transporters of several angiogenesis regulators. Here, we aimed to determine the levels of angiogenesis regulators and epithelial-mesenchymal transition factors sequestered by circulating platelets in breast cancer patients and age-matched healthy controls. Platelet pellets (PP) and platelet-poor plasma (PPP) were collected by routine protocols. Vascular endothelial growth factor (VEGF), platelet-derived growth factor BB (PDGF-BB), thrombospondin-1 (TSP-1), platelet factor 4 (PF4), and transforming growth factor-β1 (TGF-β1) were measured by enzyme-linked immunosorbent assay. Angiogenesis-associated expression of VEGF (2.1 pg/106platelets versus 0.9 pg/106platelets,P < 0.001), PF4 (21.2 ng/106platelets versus 10.2 ng/106platelets,P < 0.001), PDGF-BB (42.9 pg/106platelets versus 19.1 pg/106platelets,P < 0.001), and TGF-β1 (15.3 ng/106platelets versus 4.3 ng/106platelets,P < 0.001) differed in the PP samples of cancer and control subjects. In addition, protein concentrations were associated with clinical characteristics(P<0.05). Circulating platelets in breast cancer sequester higher levels of PF4, VEGF, PDGF-BB, and TGF-β1, suggesting a possible target for early diagnosis. VEGF, PDGF, and TGF-β1 concentrations in platelets may be associated with prognosis.

SIRT1 is the homologue of sir2 in mammals, which is a nicotinamide adenine dinucleotide (NAD(+)) dependent histone deacetylase. SIRT1 is involved in many physiological processes, such as metabolism, senescence, inflammatory response, neuroprotection, and tumorigenesis by acetylating histones and multiple transcription factors. However, the exact role of SIRT1 in tumor is still under controversial. Immunohistochemistry and Western blot were performed to investigate the expressions and subcellular localizations of SIRT1 and Phospho-SIRT1 in colorectal cancer tissues and adjacent normal tissues. The relationship between SIRT1 or Phospho-SIRT1 and clinicopathological characteristics was also analyzed. Real-Time PCR was performed to investigate the transcriptional level of SIRT1 mRNA in colorectal cancer tissues and adjacent normal tissues. SIRT1 and Phospho-SIRT1 were both localized in the nucleus. The expressions of SIRT1 and Phospho-SIRT1 were higher in colorectal cancer tissues than normal tissues. SIRT1 expression in cancer tissues was associated with patient age, TNM stage and mutant P53 loss. Phospho-SIRT1 expression in cancer tissues was associated with Ki67. SIRT1 and Phospho-SIRT1 were highly correlated in cancer tissues and normal tissues. The ratios of Phospho-SIRT1 and SIRT1 expression in cancer tissues were higher than normal tissues. SIRT1 mRNA level was no significant difference in cancer tissues and normal tissues. SIRT1 have a dual character in colorectal cancer, and Phospho-SIRT1 may determine the role of SIRT1 in colorectal cancer formation.

To investigate the effect of interleukin-17A (IL-17A) antibodies on radiation-induced lung injuries in mice.The thorax of 135 mice were divided into Sham (n = 30), radiation control (RC, n = 35), treatment (n = 35, IL-17A-neutralizing antibody, 4 μg/mouse, IV, 4 days per month for 4 months) and placebo group (n = 35) before a single dose irradiation (15 Gy) to the thorax. Inflammation and collagen contents in the lung tissues were examined, and the concentration of IL-17A, TGF-β1, and IL-6 in bronchoalveolar lavage fluid (BALF) were measured. In another 50 animals, 180-day survival rate following the irradiation and treatment was calculated by Kaplan-Meier method.Sixteen weeks after the irradiation and treatment, there was significant inflammatory cell infiltration and interstitial collagen depositions in the radiation control and placebo groups, whereas these changes were relatively mild in the treatment group. The percentage of grade II and III alveolitis in the treatment group (16%, P.05) was lower than in the RC (72%) or placebo group (64%). The mean Aschcroft fibrosis scores were 2.8 (treatment group), 5.2 (RC), and 4.8 (placebo group), respectively. The scores of treatment group was lower than that of RC (P.001) or placebo group (P.001). The IL-17A, TGF-β, and IL-6 concentrations in the treatment group were lower than in the RC and placebo group (P.01) following the irradiation. The 180-day mortality rate in the treatment group was lower than in the RC group 16.7% versus 75.0%, P.05).IL-17A antibody treatment alleviates radiation-induced pneumonitis and subsequent fibrosis, and improvise postirradiation survival.

Purpose. Human papillomavirus (HPV) as a risk factor for esophageal squamous cell carcinoma (ESCC) has previously been studied, but importance of HPV status in ESCC for prognosis is less clear.Methods. A total of 105 specimens with ESCC were tested by in situ hybridization for HPV 16/18 and immunohistochemistry for p16 expression. The 5-year overall survival (OS) and progression-free survival were calculated in relation to these markers and the Cox proportional hazards model was used to determine the hazard ratio (HR) of variables in univariate and multivariate analysis.Results. HPV was detected in 27.6% (29) of the 105 patients with ESCC, and all positive cases were HPV-16. Twenty-five (86.2%) of the 29 HPV-positive tumors were stained positive for p16. HPV infected patients had better 5-year rates of OS (65.9% versus 43.4% among patients with HPV-negative tumors;P= 0.002 by the log-rank test) and had a 63% reduction in the risk of death (adjusted HR = 0.37, 95% CI = 0.16 to 0.82, andP= 0.01).Conclusions. HPV infection may be one of many factors contributing to the development of ESCC and tumor HPV status is an independent prognostic factor for survival among patients with ESCC.

Background and objective Despite great progress in treatment, the prognosis for patients with esophageal squamous cell carcinoma (ESCC) remains poor, highlighting the importance of early detection. Although upper endoscopy can be used for the screening of esophagus, it has limited sensitivity for early stage disease. Thus, development of new diagnosis approach to improve diagnostic capabilities for early detection of ESCC is an important need. The aim of this study was to assess the feasibility of using cathepsin B (CB) as a novel imaging target for the detection of human ESCC by near-infrared optical imaging in nude mice. Methods Initially, we examined specimens from normal human esophageal tissue, intraepithelial neoplasia lesions, tumor in situ, ESCC and two cell lines including one human ESCC cell line (Eca-109) and one normal human esophageal epithelial cell line (HET-1A) for CB expression by immunohistochemistry and western blot, respectively. Next, the ability of a novel CB activatable near-infrared fluorescence (NIRF) probe detecting CB activity presented in Eca-109 cells was confirmed by immunocytochemistry. We also performed in vivo imaging of tumor bearing mice injected with the CB probe and ex vivo imaging of resected tumor xenografts and visceral organs using a living imaging system. Finally, the sources of fluorescence signals in tumor tissue and CB expression in visceral organs were identified by histology. Results CB was absent in normal human esophageal mucosa, but it was overexpressed in ESCC and its precursor lesions. The novel probe for CB activity specifically detected ESCC xenografts in vivo and in vitro. Conclusions CB was highly upregulated in human ESCC and its precursor lesions. The elevated CB expression in ESCC allowed in vivo and in vitro detection of ESCC xenografts in nude mice. Our results support the usefulness of CB activity as a potential imaging target for the detection of human ESCC.