First-line camrelizumab (a PD-1 inhibitor) plus apatinib (an VEGFR-2 inhibitor) and chemotherapy for advanced gastric cancer (SPACE): a phase 1 study.

Patients with advanced gastric cancer typically face a grim prognosis. This phase 1a (dose escalation) and phase 1b (dose expansion) study investigated safety and efficacy of first-line camrelizumab plus apatinib and chemotherapy for advanced gastric or gastroesophageal junction adenocarcinoma. The primary endpoints included maximum tolerated dose (MTD) in phase 1a and objective response rate (ORR) across phase 1a and 1b. Phase 1a tested three dose regimens of camrelizumab, apatinib, oxaliplatin, and S-1. Dose regimen 1: camrelizumab 200 mg on day 1, apatinib 250 mg every other day, oxaliplatin 100 mg/m² on day 1, and S-1 40 mg twice a day on days 1-14. Dose regimen 2: same as dose regimen 1, but oxaliplatin 130 mg/m². Dose regimen 3: same as dose regimen 2, but apatinib 250 mg daily. Thirty-four patients were included (9 in phase 1a, 25 in phase 1b). No dose-limiting toxicities occurred so no MTD was identified. Dose 3 was set for the recommended phase 2 doses and administered in phase 1b. The confirmed ORR was 76.5% (95% CI 58.8-89.3). The median progression-free survival was 8.4 months (95% CI 5.9-not evaluable [NE]), and the median overall survival (OS) was not mature (11.6-NE). Ten patients underwent surgery after treatment and the multidisciplinary team evaluation. Among 24 patients without surgery, the median OS was 19.6 months (7.8-NE). Eighteen patients (52.9%) developed grade ≥ 3 treatment-emergent adverse events. Camrelizumab plus apatinib and chemotherapy showed favorable clinical outcomes and manageable safety for untreated advanced gastric cancer (ChiCTR2000034109).

Periostin deficiency reduces PD-1+ tumor-associated macrophage infiltration and enhances anti-PD-1 efficacy in colorectal cancer.

Periostin, a multifunctional extracellular protein, plays an important role in inflammatory disorders and tumorigenesis. Our previous work has demonstrated that periostin deficiency inhibits colorectal cancer (CRC) progression. Here, we aim to clarify the role of periostin in the immune microenvironment of CRC. We find that periostin deficiency significantly decreases the infiltration of programmed death receptor 1 (PD-1)+ tumor-associated macrophages (TAMs) in CRC tissues. Periostin promotes the expression of PD-1 on TAMs by integrin-ILK-nuclear factor κB (NF-κB) signaling, and PD-1+ TAMs produce interleukin-6 (IL-6) and interferon γ (IFN-γ) to induce the expression of PD-L1 on colorectal tumor cells. Moreover, combined inhibition of periostin and PD-1 significantly suppresses CRC progression compared with the inhibition of periostin or PD-1 alone. In summary, our results suggest that periostin deficiency reduces the infiltration of PD-1+ TAMs and enhances the efficacy of anti-PD-1 treatment in CRC.

Impact of the COVID-19 Pandemic on the Perceived Physical and Mental Health and Healthy Lifestyle Behaviors of People With Disabilities: A Quantitative Analysis of the International Community Survey.

OBJECTIVE: This study aims to determine the perceived impact of the coronavirus pandemic on physical and mental health and healthy lifestyle behaviors in community-dwelling persons with disabilities, as compared with those without disabilities. DESIGN: A prospective cross-sectional study was conducted with a web-based global survey. RESULTS: Over 3 mos, 3550 responses were collected from 65 countries. The study included 2689 responses without skipped questions as full data for analysis. Most respondents were women (82.82%), and approximately half (52.81%) were between the ages of 25 and 39 yrs, followed by those between the ages of 40 and 60 yrs (38.6%). Among the participants, 52% indicated physical activity levels decreased and 20% reported eating less fruit and vegetables than before. Furthermore, 45% noted that they slept less than before. Perceived physical and mental health and changes to eating habits during the pandemic showed a significant difference in people with and without disabilities. Furthermore, perceived effects on physical health had a significant effect on the reported degree of disability. CONCLUSIONS: This study indicates that the pandemic had a larger impact on perceived physical and mental health and changes in eating habits and tobacco use among people with disabilities than people without disabilities.

The Impact of the COVID-19 Pandemic on Healthy Lifestyle Behaviors and Perceived Mental and Physical Health of People Living with Non-Communicable Diseases: An International Cross-Sectional Survey.

The huge burden and vulnerability imposed by non-communicable diseases (NCDs) during the COVID-19 pandemic highlighted how healthy lifestyle behaviors and the well-being of people living with NCDs need to be prioritized. The aim of our study is to better understand the impact of the COVID-19 pandemic on healthy lifestyle behaviors and perceived mental and physical health among adults living with NCDs, as compared to people without NCDs. We conducted a cross-sectional study using a global online survey through Qualtrics. Over four months, 3550 participants from 65 countries worldwide responded to the survey. The study included 3079 surveys with no missing data (complete survey responses) that were used for analysis. People with NCDs were more likely to report statistically significant worsening physical health (p = 0.001) and statistically insignificant worsening mental health (p = 0.354) when compared to pre-pandemic levels. They reported lower rates of smoking during the pandemic than those without NCDs, and a statistically significant (p < 0.001) relationship was found between weight gain and NCDs. Therefore, the perceived physical and mental health, including changes in body weight and tobacco consumption, of people with NCDs were significantly impacted during the pandemic. In conclusion, this study indicates that the pandemic had a significant impact on perceived physical and mental health, changes in body weight, and tobacco consumption among people with NCDs.

Low-dose apatinib combined with camrelizumab and the SOX regimen in the neoadjuvant treatment of locally advanced gastric/gastroesophageal junction adenocarcinoma (SPACE-neo): a protocol for an open-label, single-arm, clinical trial.

Background: Neoadjuvant chemotherapy with S-1 plus oxaliplatin (SOX regimen) has shown promising results in pathological response rate and survival rate in patients with locally advanced resectable gastric cancer (LAGC). We previously carried out the SPACE study to assess efficacy and safety of low-dose apatinib combined with camrelizumab and the SOX regimen as a first-line treatment of advanced gastric/gastroesophageal junction adenocarcinoma (AGC/GEJC). The preliminary results demonstrated a high objective response rate. However, the SPACE study was conducted in patients with AGC, but the efficacy of LAGC patients is not yet known. The SPACE-neo study is designed to investigate whether this combination could improve outcomes in patients with locally advanced gastric/gastroesophageal junction cancer (LAGC/GEJC) as neoadjuvant therapy. Methods: SPACE-neo is a prospective, open-label, single-arm study conducted in China at the First Affiliated Hospital of Nanjing Medical University (Jiangsu Province Hospital). Thirty-two patients with human epidermal growth factor receptor 2 (HER2)-negative or HER2-unknown LAGC/GEJC confirmed by histopathology or cytology will be recruited. Included patients shall be clinically staged as M0 and either T3 to T4 or N+ assessed by ultrasound endoscopy and thoracoabdominal-enhanced computed tomography or magnetic resonance imaging. The patients will receive three cycles of this combined regimen as a neoadjuvant treatment. Each patient will receive screening visits within 2 weeks before the first cycle and planned visits before every cycle of treatment. Key monitoring data include imaging data, pathological findings, and adverse events associated with neoadjuvant and surgical treatment. The primary endpoints are major pathological response (MPR) and safety. MPR is the proportion of patients whose residual tumor cells make up less than 10% of the primary tumor from among the total cohort. Clopper-Pearson method will be used to estimate the 95% confidence interval of MPR and safety data will be reported as descriptive statistical analysis. Discussion: The SPACE-neo trial aims to evaluate the safety and preliminary efficacy of this regimen in the neoadjuvant treatment of LAGC/GEJC. It is hoped that the study can achieve a higher pathological response rate and longer survival rate. Trial Registration: ChiCTR.gov.cn: ChiCTR2100049305.

Study on Efficacy and Safety of Low-Dose Apatinib Combined with Camrelizumab and SOX Regimen as First-Line Treatment of Locally Advanced and Unresectable Gastric/Gastroesophageal Junction Cancer: A Protocol for an Open-Label, Dose Escalation and Extension Phase Ib Clinical Trial.

BACKGROUND: The standard treatment for advanced gastric/gastroesophageal junction cancer (AGC/GEJC) is palliative chemotherapy combined with targeted therapy. The SOX regimen (S-1 plus oxaliplatin) is recommended as neoadjuvant or palliative first-line chemotherapy in Asian patients. Apatinib, an oral VEGFR tyrosine kinase inhibitor, is associated with additional survival benefit as third- or subsequent-line therapy. However, the median overall survival time of AGC/GEJC is only 8-11 months in the West and 13-17 months in East Asia/Japan, even with the application of anti-angiogenic agents. Hence, the multimodal and individual management of patients is challenging standards to improve prognosis, including the preferential use of low-dose anti-angiogenic drugs and immunotherapy, as well as the application of multi-disciplinary treatment (MDT)-directed conversion therapy. METHODS/DESIGN: This single-center study was designed to combine low-dose apatinib with camrelizumab plus the SOX regimen in diagnosed potentially resectable and initially unresectable AGC/GEJC. This a prospective, open-label, single-arm, dose escalation and extension phase Ib clinical trial, conducted in Jiangsu Province Hospital, beginning from June 2020. All patients will first receive this combined regimen (3 weeks/cycle) for at most eight cycles, then apatinib and camrelizumab in maintenance therapy until disease progression, intolerable toxicity, death, a maximum 2 years of treatment or discontinuation for any reason. Follow-up and evaluation will be carried out regularly. If surgery is allowed by MDT discussions, oral apatinib will be discontinued during the last preoperative cycle. The primary endpoints are the objective response rate and maximum tolerated dose according to the Response Evaluation Criteria In Solid Tumors (RECIST) criteria (version 1.1) and the Common Terminology Criteria for Adverse Events (CTCAE) criteria (version 5.0). DISCUSSION: This study will assess the response and side effects of AGC/GEJC patients in the use of low-dose apatinib combined with camrelizumab and the SOX regimen, and this combined therapy is expected to be a feasible and optimized first-line treatment option. In addition, this study will provide robust evidence and novel ideas for conversion therapy. TRIAL REGISTRATION: ChiCTR.gov.cn: ChiCTR2000034109.

Current Progress and Future Perspectives of Immune Checkpoint Inhibitors in Biliary Tract Cancer.

Biliary tract cancer (BTC) is an uncommon and aggressive neoplasm, with most patients presenting in an advanced stage. Systemic chemotherapy is the limited treatment available but is unsatisfactory, while targeted therapy is still awaiting validation from clinical trials. Given the potential effect of immune checkpoint inhibitors (ICIs) in the treatment of BTC, this review aims to summarize the evidence-based benefits and predictive biomarkers for using inhibitors of cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) ligand, or programmed cell death protein-1 and its ligand (PD-1 and PD-L1) as monotherapy or combined with other anti-tumor therapies, while also pointing out certain pitfalls with the use of ICIs which need to be addressed.

Hepatic Arterial Infusion Oxaliplatin Plus Oral S-1 Chemotherapy in Gastric Cancer with Unresectable Liver Metastases: A Case Series and Literature Review.

OBJECTIVE: The use of hepatic artery infusion (HAI) as a regional therapy against liver metastasis has rarely been reported in gastric cancer. This study aimed to evaluate the efficacy and safety of HAI oxaliplatin plus oral S-1 chemotherapy in first-line palliative therapy for gastric cancer with multiple liver metastases (GCLM). METHODS: We reviewed the records of five patients with GCLM who received HAI oxaliplatin (70-80 mg/m2 2 hrs d1,15) administered via a port-catheter system and S-1 with oral (35-40 mg/m2 twice daily for d1-14, 28 days for one cycle). Follow-up examination and efficacy evaluation were executed periodically. RESULTS: Until the 4th cycle response evaluation, the local effective rate and control rate were 40% and 80%, respectively; only one patient developed progression. HAI chemotherapy had a better local control against liver metastases (median progression-free survival: hepatic, 8.8 months vs. extrahepatic, 6.2 months), accompanied by less systemic toxicity, decreased tumour markers and symptomatic relief. CONCLUSION: HAI oxaliplatin plus oral S-1 chemotherapy can be considered as a new choice of first-line treatment for GCLM, which is also a good approach for controlling extrahepatic lesions with less adverse events.

Radiomic analysis using contrast-enhanced CT: predict treatment response to pulsed low dose rate radiotherapy in gastric carcinoma with abdominal cavity metastasis.

BACKGROUND: To determine the feasibility of radiomic analysis for predicting the therapeutic response of gastric carcinoma (GC) with abdominal cavity metastasis (GCACM) to pulsed low dose rate radiotherapy (PLDRT) using contrast-enhanced computed tomography (CECT) images. METHODS: Pretreatment CECT images of 43 GCACM patients were analyzed. Patients with complete response (CR) and partial response (PR) were considered responders, while stable disease (SD) and progressive disease (PD) as non-responders. A total of 1,117 image features were quantified from tumor region that segmented from arterial phase CT images. Intra-class correlation coefficient (ICC) and absolute correlation coefficient (ACC) were calculated for selecting influential feature subset. The capability of each influential feature on treatment response classification was assessed using Kruskal-Wallis test and receiver operating characteristic (ROC) analysis. Moreover, artificial neural network (ANN) and k-nearest neighbor (KNN) predictive models were constructed based on the training set (18 responders, 14 non-responders) and the testing set (6 responders, 5 non-responders) validated the reliability of the models. Comparison between the performances of the models was performed by using McNemar's test. RESULTS: The analyses showed that 6 features (1 first order-based, 1 texture-based, 1 LoG-based, and 3 wavelet-based) were significantly different between responders and non-responders (AUCs range from 0.686 to 0.728). Both two prediction models based on features extracted from CECT showed potential in predicting the treatment response with higher accuracies (ANN: 0.714, KNN: 0.749 for the training set; ANN: 0.816, KNN: 0.816 for the testing set). No statistical difference was observed between the performance of ANN and KNN (P=0.999). CONCLUSIONS: Pretreatment radiomic analysis using CECT can potentially provide important information regarding the therapeutic response to PLDRT for GCACM, improving risk stratification.

Effects of the IGF-1/PTEN/Akt/FoxO signaling pathway on male reproduction in rats subjected to water immersion and restraint stress.

The aim of the present study was to determine the effects of the insulin-like growth factor 1 (IGF-1)/phosphatase and tensin homologue deleted on chromosome 10 (PTEN)/Akt/forkhead box (FoxO) signaling pathway on male reproduction in rats subjected to water immersion and restraint stress (WRS). Sperm morphology, sperm malformation rate, and serum testosterone concentration were analyzed following WRS. In addition, the expression levels and immunolocalization of IGF­1, PTEN, Akt and FoxO proteins, as well as the rate of cell apoptosis in rat testes, were investigated. The results indicated that sperm malformation rate, serum testosterone concentration, and the number of terminal deoxynucleotidyl transferase dUTP nick end labeling­positive cells were increased in the testes after WRS. Furthermore, IGF­1 and FoxO1 proteins were predominantly localized in the sperm cytoplasm during the late stages of spermatogenesis. FoxO1 protein was also localized in Leydig cell cytoplasm. PTEN and total Akt proteins were predominantly expressed in the cytoplasm of Leydig cells and spermatogonia. PTEN protein was also detected in vascular endothelial cells. In addition, IGF­1, PTEN, Akt1, Akt2, FoxO3 and FoxO4 gene expression levels were upregulated following WRS, and peaked after 7 h of WRS. During the recovery period, the expression levels of these genes gradually returned to normal levels. The present study demonstrated that WRS induced sperm damage in the testes. In addition, the results indicated that the IGF­1/PTEN/Akt/FoxO signaling pathway may serve an anti­stress role in the testes of rats subjected to WRS.