A phase II randomised controlled trial of adjuvant tumour-infiltrating lymphocytes for pretreatment Epstein-Barr virus DNA-selected high-risk nasopharyngeal carcinoma patients.

PURPOSE: The safety and objective clinical responses were observed in the phase I study using adjuvant autologous tumour-infiltrating lymphocytes (TILs) following concurrent chemoradiotherapy (CCRT) in nasopharyngeal carcinoma (NPC) patients. METHODS AND MATERIALS: One hundred fifty-six patients with stage III-IVb and pretreatment Epstein-Barr virus DNA levels of ≥4000 copies/ml were randomly assigned to receive CCRT combined with TIL infusion (n = 78) or CCRT alone (n = 78). All patients received CCRT and patients assigned to the TIL group received TIL infusion within 1 week after CCRT. The primary endpoint was investigator-assessed progression-free survival (PFS) at 3 years. RESULTS: After a median follow-up of 62.3 months, no significant difference was observed in the 3-year PFS rate between the CCRT plus TIL infusion group and CCRT alone group (75.6% versus 74.4%, hazard ratios, 1.08; 95% confidence intervals, 0.62-1.89). TIL infusion was safe without grade 3 or 4 adverse events and all the high-grade adverse effects were associated with myelosuppression caused by CCRT. Exploratory analysis showed that a potential survival benefit was observed with TILs in patients with lower levels of circulating CD8+TIM3+ cells, serum IL-8 or PD-L1. The infused TIL products in patients with favourable outcomes were associated with increased transcription of interferon-γ and a series of inflammatory related genes and a lower exhausted score. CONCLUSION: The primary objective of prolonging PFS with CCRT plus TILs in high-risk NPC patients was not met. These findings may provide evidence for the design of future trials investigating the combination of TILs plus immune checkpoint inhibitors based on CCRT in high-risk NPC patients. TRIAL REGISTRATION NUMBER: NCT02421640.

T cell-intrinsic STING signaling promotes regulatory T cell induction and immunosuppression by upregulating FOXP3 transcription in cervical cancer.

BACKGROUND: Stimulator of interferon genes (STING) is an innate immune sensor of cytoplasmic double-stranded DNA originating from microorganisms and host cells. The activation of cytosolic DNA-STING pathway in tumor microenvironments is usually linked to more robust adaptive immune responses to tumors, however the intracellular function of STING in regulatory T cells is largely unknown. In the present study, we aimed to explore the contribution of intracellular STING activation to regulatory T cell induction (iTreg) in cervical cancer (CC) microenvironments. METHODS: Blood samples and tumor specimens were obtained from patients with CC. The intratumoral STING, CCL22, CD8 and forkhead box P3 (FOXP3) expression levels were measured by immunohistochemistry. T cell-specific STING conditional knockout mice (CD4-Cre/STINGflox/flox, TKO) were generated, and syngeneic TC-1 tumor model were investigated. The differentiation and molecular regulatory pathway of human and murine iTreg under different treatments were investigated by ex vivo assays, immunoblotting and quantitative PCR. Tumor-associated exosomes (T-EXO) were isolated from CC cell lines and exosomal contents were identified by ELISA and Western blot analysis. The impact of T-EXO on T cell differentiation was tested in in vitro cell culture. RESULTS: Increased STING, CCL22 level, FOXP3+ cells but decreased CD8+ cells in tumor tissues predicted poor survival. Tumor-bearing CD4-Cre-STINGflox/flox (TKO) mice displayed slower tumor growth tendencies as well as fewer FOXP3+ cells but higher CD8+ cell proportion in tumor tissues than wild-type (WT) mice. Activating of STING signaling cooperated with T cell receptor, interleukin-2 receptor and transforming growth factor-beta (TGF-ß) signals to promote CD4+CD25highFOXP3+ iTreg differentiation from both human and murine CD4+-naïve T cells from WT and IFNAR-/- mice but not TKO or IRF3-/- mice in vitro. Ectopic STING, TBK1 or IRF3 expression promoted iTreg differentiation from human CD4+-naïve T cells. T cell-intrinsic STING activation induced FOXP3 transcription through TBK1-IRF3-mediated SMAD3 and STAT5 phosphorylation independent of interferon-ß. In CC, tumor-derived exosomes activated STING signaling in tumor-infiltrated T cells by exosomal TGF-ß, cyclic GMP-AMP synthase and 2'-3'-cGAMP, leading to iTreg expansion. CONCLUSIONS: These findings highlight a novel mechanism for iTreg expansion mediated by tumor-derived exosome-activated T cell-intrinsic STING signal, and provide a rationale for developing immunotherapeutic strategies targeting STING signal in CC.

Phase I study of adjuvant immunotherapy with autologous tumor-infiltrating lymphocytes in locally advanced cervical cancer.

BACKGROUNDAdoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TILs) has achieved remarkable clinical efficacy in metastatic cancers such as melanoma and cervical cancer (CC). Here, we explored the safety, feasibility, and preliminary tumor response and performed translational investigations of adjuvant immunotherapy using infusion of autogenous TILs (auto-TILs) following concurrent chemoradiotherapy (CCRT) in patients with CC who had locally advanced disease.METHODSTwenty-seven patients with CC with stage III-IV disease were recruited in this single-center, phase I study. TILs were isolated from lesions in the uterine cervix and generated under good manufacturing practice (GMP) conditions and then infused after CCRT plus i.m. IL-2 injections.RESULTSTILs from 20 of the 27 patients were successfully expanded, with a feasibility of 74.1%. Twelve patients received TILs following CCRT. Adverse events (AEs) were primarily attributable to CCRT. Only 1 (8.3%) patient experienced severe toxicity with a grade 3 hypersensitivity reaction after TIL infusion. No autoimmune AEs, such as pneumonitis, hepatitis, or myocarditis, occurred, and there were no treatment-related mortalities. Nine of 12 patients (75.0%) attained a complete response, with a disease control duration of 9-22 months. Translational investigation showed that the transcriptomic characteristics of the infused TIL products and some immune biomarkers in the tumor microenvironment and serum of patients with CC at baseline were correlated with the clinical response.CONCLUSIONTIL-based ACT following CCRT was safe in an academic center setting, with potentially effective responses in patients with locally advanced CC. "Hot" inflammatory immune environments were beneficial to the clinical efficacy of TIL-based ACT as adjuvant therapy.TRIAL REGISTRATIONClinicalTrials.gov NCT04443296.FUNDINGNational Key R&D Program; Sci-Tech Key Program of the Guangzhou City Science Foundation; the Guangdong Province Sci-Tech International Key Program; the National Natural Science Foundation of China.

Investigation and Analysis of Influencing Factors of Moderate to Severe Pain After Uterine Artery Embolization in Patients with Cesarean Scar Pregnancy.

OBJECTIVE: To investigate the occurrence and influencing factors of moderate to severe pain in patients with cesarean scar pregnancy (CSP) after uterine artery embolization (UAE). METHODS: Ninety-eight patients with CSP who underwent UAE in gynecology department of the Fujian Medical University Union Hospital from January 2017 to December 2020 were enrolled, and the specialty data in patients were collected for pain assessment with the adoption of the numerical rating scale (NRS). RESULTS: Moderate to severe pain occurred in 36 patients after surgery, and the interquartile of time to the first onset of postoperative pain in patients was 3.04 (1.75, 7.40) hours. The number of pregnancies, number of miscarriages, human chorionic gonadotropin (HCG) before curettage, duration of medication before UAE, and hemorrhage after UAE were not significantly correlated with the occurrence of moderate to severe pain after UAE (P > 0.05). The volume of gestational sac and days of gestation were responsible for the occurrence of moderate to severe pain after UAE (P < 0.05), with the former being the main influencing factor, and these explained 8.3% of the total variance. CONCLUSION: Moderate to severe pain occurred commonly in patients with CSP undergoing UAE. In clinical care of patients with CSP who are going to undergo UAE, data concerning the volume of gestational sac and days of gestation should be considered for anticipatory pain assessment, and interventions should be implemented as early as possible to reduce the pain and improve the experience of care.

Monitored Anesthetic Care Combined with Scalp Nerve Block in Awake Craniotomy: An Effective Attempt at Enhanced Recovery After Neurosurgery.

BACKGROUND: Enhanced recovery after surgery has been attempted in neurosurgery at a greater rate. However, concern exists regarding the feasibility of using enhanced recovery after neurosurgery (ERANS). How to manage available resources to safely perform ERANS and improve clinical outcomes has been the subject of much debate and discussion. METHODS: Owing to the paucity of data available on the use of ERANS protocols, we performed the present feasibility study. We studied the outcomes of the protocols used within a tertiary referral neurosurgery center. Data from patients who had undergone awake craniotomy within an ERANS protocol were prospectively recorded in our institution from September 2017 to December 2018. We also evaluated the safety and effectiveness of the novel ERANS protocol. RESULTS: A total of 20 patients (mean age, 49.5 ± 17.8 years) were included in the present study. Intraoperative hypertension, hypotension, and bradycardia were present in 4 (20%), 1 (5%), and 1 (5%) patient, respectively. The postoperative morbidities included epilepsy in 1 (5%), pain in 3 (15%), and nausea or vomiting in 2 (10%). No significant changes had occurred in the mean arterial pressure, heart rate, blood glucose, or lactic acid level throughout the procedure. The median length of intensive care unit stay and postoperative hospital stay were 1 and 9.5 days, respectively. No 30-day readmissions or reoperations occurred during the present study. CONCLUSIONS: Applying an ERANS protocol was feasible, associated with a low incidence of complications, and acceptable intensive care unit and postoperative hospital lengths of stay. The findings from the present study might provide a new approach for the further research of ERANS.

Latest therapeutic target for gastric cancer: Anthrax toxin receptor 1.

Anthrax toxin receptor 1 (ANTXR1), also known as tumor endothelial marker 8, is a highly conserved cell surface protein overexpressed in tumor-infiltrating vessels. It was first found in vascular endothelial cells of human colorectal cancer. Although our understanding of its physiological function is limited, it has been found that ANTXR1 binds collagen and promotes migration of endothelial cells in vitro. ANTXR1 is upregulated in vessels of different tumor types in mice and humans, and is also expressed by tumor cells themselves in some tumors, such as gastric, lung, intestinal and breast cancer. Developmental angiogenesis and wound healing were not disturbed in ANTXR1 knockout mice, but compared with wild-type mice, growth of melanoma was impaired after ANTXR1 knockout, indicating that host-derived ANTXR1 can promote tumor growth on the basis of immune activity. Previous studies have shown that ANTXR1 vaccines or sublethal doses of anthrax toxin can inhibit angiogenesis, slow tumor growth and prolong survival. These studies suggest that ANTXR1 is necessary for tumor rather than physiological angiogenesis. It has been found that ANTXR1 plays an important role in tumor angiogenesisas well as in the growth and metastasis of many kinds of tumors. This article reviews the physiological function of ANTXR1 and its role in different kinds of cancer.

Surgical outcomes and survival for T4 gastric cancer extending to the transverse colon.

BACKGROUND: For the treatment of locally advanced (T4) gastric cancer, extended multi-organ resection remains controversial. This study aimed to evaluate the surgical outcomes and survival of patients with T4 gastric cancer extending to the transverse colon. METHODS: A total of 2,652 gastric cancer patients underwent surgery between December 2011 and December 2015. Data from 40 of these patients who underwent curative resection for T4 gastric cancer extending to the transverse colon were obtained. Patient characteristics, related complications, long-term survival, and prognostic factors for T4 gastric cancer were analyzed. RESULTS: Postoperative morbidity occurred in 5 (12.5%) patients. All of the patients were cured with conservative treatment. No procedure-related mortality occurred. The 1-, 3-, and 5-year overall survival (OS) rates were 75.0%, 49.2%, and 36.9%, respectively, with a median survival time of 24 months. Univariate analysis revealed tumor size (P=0.049), advanced T stage (P=0.013), and lymph node metastasis (P=0.006) to be poor prognostic factors of OS. Advanced T stage and lymph node metastasis were identified by multivariate analysis as being independent prognostic factors. Further, it was observed that lymph node metastasis grade was associated with poorer OS. CONCLUSIONS: Patients with T4 gastric cancer extending to the transverse colon might benefit from curative resection with acceptable morbidity and mortality.

Analysis of cyclin E co-expression genes reveals nuclear transcription factor Y subunit alpha is an oncogene in gastric cancer.

OBJECTIVE: To explore genes potentially co-expressed with cyclin E in gastric cancer and discover possible targets for gastric cancer treatment. METHODS: The Cancer Genome Atlas (TCGA) stomach adenocarcinoma sequencing data were used to predict genes co-expressed with cyclin E. Co-expression genes predicted by cBioPortal online analysis with Pearson correlation coefficient ≥0.4 were analyzed by gene ontology (GO) enrichment annotation using the PANTHER online platform (Ver. 7). Interactions between proteins encoded by these genes were analyzed using the STRING online platform (Ver. 10.5) and Cytoscape software (Ver. 3.5.1). Genes displaying a high degree of connection were analyzed by transcription factor enrichment prediction using FunRich software (Ver. 3). The significant transcription factor and cyclin E expression levels and their impact on gastric cancer progression were analyzed by Western blotting and Kaplan-Meier survival curve analysis. RESULTS: After filtering the co-expression gene prediction results, 78 predicted genes that included 73 protein coding genes and 5 non-coding genes with Pearson correlation coefficient ≥0.4 were selected. The expressions of the genes were considered to be correlated with cyclin E expression. Among the 78 genes co-expressed with cyclin E, 19 genes at the central of the regulatory network associated with cyclin E were discovered. Nuclear transcription factor Y subunit alpha (NF-YA) was identified as a significant transcription factor associated with cyclin E co-expressing genes. Analysis of specimen donors' clinical records revealed that high expression of NF-YA tended to be associated with increased cyclin E expression. The expression of both was associated with progression of gastric cancer. Western blotting results showed that compared with normal tissues, NF-YA and cyclin E were highly expressed in tumor tissues (P < 0.001). Survival curve analysis clearly demonstrated relatively poor overall survival of gastric cancer patients with high cyclin E or high NF-YA expression level, compared to patients with low cyclin E or NF-YA expression (P < 0.05). CONCLUSIONS: NF-YA may promote gastric cancer progression by increasing the transcription of cyclin E and other cell cycle regulatory genes. NF-YA might be a potential therapeutically useful prognostic factor for gastric cancer.

A model predicting short-term mortality in patients with advanced liver cirrhosis and concomitant infection.

Infection is a common cause of death in patients with advanced cirrhosis. We aimed to develop a predictive model in Child-Turcotte-Pugh (CTP) class C cirrhotics hospitalized with infection for optimizing treatment and improving outcomes.Clinical information was retrospectively abstracted from 244 patients at Tianjin Third Central Hospital, China (cohort 1). Factors associated with mortality were determined using logistic regression. The model for predicting 90-day mortality was then constructed by decision tree analysis. The model was further validated in 91 patients at Mayo Clinic, Rochester, MN (cohort 2) and 82 patients at Seoul St. Mary's Hospital, Korea (cohort 3). The predictive performance of the model was compared with that of the CTP, model for end-stage liver disease (MELD), MELD-Na, Chronic Liver Failure-Sequential Organ Failure Assessment, and the North American consortium for the Study of End-stage Liver Disease (NACSELD) models.The 3-month mortality was 58%, 58%, and 54% in cohort 1, 2, and 3, respectively. In cohort 1, respiratory failure, renal failure, international normalized ratio, total bilirubin, and neutrophil percentage were determinants of 3-month mortality, with odds ratios of 16.6, 3.3, 2.0, 1.1, and 1.03, respectively (P < .05). These parameters were incorporated into the decision tree model, yielding area under receiver operating characteristic (AUROC) of 0.804. The model had excellent reproducibility in the U.S. (AUROC 0.808) and Korea cohort (AUROC 0.809). The proposed model has the highest AUROC and best Youden index of 0.488 and greatest overall correctness of 75%, compared with other models evaluated.The proposed model reliably predicts survival of advanced cirrhotics with infection in both Asian and U.S.

[Bilateral ultrasound-guided supraclavicular brachial plexus block in shoulder joint release surgery for shoulder periarthritis].

OBJECTIVE: To observe the anesthetic efficacy and safety of bilateral ultrasound-guided supraclavicular brachial plexus block in patients undergoing arthrolysis for shoulder periarthritis. METHODS: Twenty-seven patients (ASA class I-II) undergoing bilateral shoulder joint release surgery and 24 ml received bilateral ultrasound-guided supraclavicular brachial plexus block anesthesia with 0.4% ropivacaine and 0.8% lidocaine. The visual analogue scale (VAS) scores for shoulder joint pain were recorded before and after anesthesia. The efficacy of axillary nerve, dorsal scapular nerve and suprascapular nerve block was evaluated, and the anesthetic effect and complications was assessed during surgery. Before and after anesthesia, the range of left and right diaphragmatic muscle movement was measured when the patient took a quiet breath and a deep breath. RESULTS: The patients showed no significant variations in MAP, HR, or SpO2after anesthesia. The VAS scores of shoulder joint pain during anteflexion, abduction, posterior extension, rotation, posterior extension and medial rotation were significantly lowered after anesthesia (P<0.05), but the left and the right diaphragm movement range showed no significant difference between quiet breath and deep breath (P>0.05). The rates of complete block of the axillary nerve and dorsal scapular nerve was 100%, and that of suprascapular nerve was 92.6%. Partial phrenic nerve block occurred in 1 case with mild local anesthetic toxicity in another. CONCLUSIONS: Bilateral ultrasound-guided supraclavicular brachial plexus block in patients has excellent analgesic effect in should joint release surgery with good safely.

Tenofovir rescue regimen following prior suboptimal response to entecavir and adefovir combination therapy in chronic hepatitis B patients exposed to multiple treatment failures.

In clinical practice, establishing a subsequent optimum treatment for chronic hepatitis B patients with a history of multiple NAs treatment failures, including a suboptimal response to a final therapy with combined ETV and ADV, is a complicated but crucial challenge. This study investigated the efficacy and safety of a tenofovir rescue regimen in these patients. A total of six eligible patients were enrolled and were switched to a tenofovir rescue regimen. At baseline, the genotypes and genotypic mutations of the reverse transcriptase and surface gene were determined by ultra-deep pyrosequencing, and further clonal analyses of the reverse transcriptase domain were performed to identify multidrug-resistant HBV strains. In addition, HBV DNA levels, serology, and biochemistry parameters were monitored at baseline and every 3 months, and abdominal ultrasonography was performed at baseline and every 6 months. All patients were confirmed to harbor LAM-related resistant HBV strains. After switching to the tenofovir rescue treatment, all patients had an undetectable level of HBV DNA within 6 months and achieved normalization of the ALT level within 9 months. These virological and biochemical responses persisted until the end of the observation period. None of the patients developed clinical deterioration or any adverse events related to the tenofovir therapy during the median 16.5-month follow-up. In conclusion, the tenofovir rescue regimen can be employed confidently as a highly effective and safe treatment choice following a suboptimal response to ETV plus ADV therapy for a subset of chronic hepatitis B patients with a history of multiple unsuccessful antiviral treatments.

[Stereological study of the placenta in patients receiving different vasopressors for hypotension during cesarean section].

OBJECTIVE: To study the effects of dopamine and phenylephrine for treatment of hypotension during cesarean section under combined spinal epidural anesthesia (CSEA) on the stereology of the placenta. METHODS: Forty puerperants undergoing cesarean section under CSEA were randomly divided into dopamine group and phenylephrine group. Ropivacaine (16 mg) was administered immediately after spinal anethesia. Blood pressure was maintained near the baseline by adjusting the drug infusion rate. Fetal blood gas, Apgar score, and placental villus microvascular stereological changes were observed during the operation. RESULTS: The microvascular density was significantly lower in dopamine group than in phenylephrine group (P<0.05). Phenylephrine group showed significantly lower umbilical artery blood pH than dopamine group (P<0.05). The Apgar score and blood pressure were comparable between the two groups (P>0.05). Compared to the baseline, both of the two groups showed significantly lowered heart rate during the operation (P<0.01). CONCLUSION: Dopamine is associated with the risk of fetal acidosis. Phenylephrine is helpful for preventing hypotension by increasing placental blood flow and improving oxygen supply to ensure maternal and fetal safety during cesarean section.

[Correlation between Pet-CO2 and PaCO2 in morbidly obese patients during anesthesia for laparoscopic gastric bypass surgery].

OBJECTIVE: To investigate the correlation between arterial partial pressure of CO2 (PaCO2) and end expiratory tidal partial pressure of CO2 (Pet-CO2) in morbidly obese patients during anesthesia for laparoscopic gastric bypass surgery. METHODS: Forty morbidly obese patients with a body mass index (BMI) between 35 and 50 kg/m(2) underwent laparoscopic gastric bypass surgery under general anesthesia. PaCO2 and Pet-CO2 were measured after intubation and before induction of pneumoperitoneum (T0), at 30 min (T1), 60 min (T2), and 120 min (T3) during pneumoperitoneum, and at 30 min (T4) and 60 min (T5) after deflation. RESULTS: At each time point of measurement, Pet-CO2 was lower than PaCO2 in all the patients. PaCO2 and Pet-CO2 were positively correlated before, during, and after pneumoperitoneum (P<0.05). At a moderate pressure of CO2 pneumoperitoneum (16 mmHg), the level of correlation between PaCO2 and Pet-CO2 at T1, T2, and T3 differed from that before and after post-pneumoperitoneum. CONCLUSIONS: PaCO2 and Pet-CO2 are closely correlated during a moderate CO2 pneumoperitoneum in morbidly obese patients undergoing laparoscopic gastric bypass surgery.

[Epidural butorphanol analgesia in elderly patients undergoing hip replacement].

OBJECTIVE: To evaluate the efficacy and safety of continuous epidural analgesia (CEA) with butorphanol in elderly patients undergoing hip replacement. METHODS: Sixty patients scheduled for selective hip replacement were randomized into group B (n=30) to receive patient-controlled epidural analgesia (PCEA) with butorphanol and group M (n=30) to receive PCEA with morphine. Their pain distribution at 5 time points, postoperative global score and the adverse effects in 48 h were observed. RESULTS: The pain distribution at the 5 time points or the global score for postoperative PCEA in 48 h showed no statistically significant difference between the two groups (P<0.05). Analgesia with butorphanol caused less adverse effects (respiratory depression, nausea and vomiting, itching and abdominal distension) than that with morphine (P<0.05). CONCLUSION: CEA with butorphanol is safe and effective for the treatment of postoperative pain in elderly patients and causes less adverse effects than morphine.