Characterization of B cell-mediated PD-1/PD-L1 interaction in pancreatic cancer patients.

Pancreatic ductal adenocarcinoma (PDAC) is a common type of pancreatic cancer with one of the worst survival rate of all malignancies. Recent studies have identified that immunosuppressive B cells could employ the PD-1/PD-L1 pathway to suppress antitumour T cell responses; hence, we examined the expression and function of PD-L1 in B cells. We found that the PD-L1 expression was significantly enriched in tumour-infiltrating (TI) B cells than in peripheral blood (PB) B cells from the same patients. Additionally, the PB B cells from stage III and stage IV PDAC patients presented significantly higher PD-L1 than the PB B cells from healthy controls. High PD-L1 expression in PB B cells could be achieved by stimulation via CpG and less effectively via anti-BCR plus CD40L, but not by coculture with pancreatic cancer cell lines in vitro. Also, STAT1 and STAT3 inhibition significantly suppressed PD-L1 upregulation in stimulated B cells. CpG-stimulated PB B cells could inhibit the IFN-γ expression and proliferation of CD8 T cells in a PD-L1-dependent manner. Also, TI CD8 T cells incubated with whole TI B cells presented significantly lower IFN-γ expression and lower proliferation, than TI CD8 T cells incubated with PD-L1+  cell-depleted TI B cells, suggesting that PD-L1+  B cells could also suppress CD8 T cells in the tumour. Overall, this study identified that B cells could suppress CD8 T cells via PD-L1 expression, indicating a novel pathway of immuno-regulation in pancreatic cancer.

MicroRNA-191 acts as a tumor promoter by modulating the TET1-p53 pathway in intrahepatic cholangiocarcinoma.

Current treatment of intrahepatic cholangiocarcinoma (ICC) remains ineffective because knowledge of ICC carcinogenesis is unclear. Increasing evidence suggests that microRNAs (miRNAs), including miR-191, play an important role in tumorigenesis; but expression and biological functions of miR-191 in ICC remain to be established. This study investigated the functions and underlying mechanisms of miR-191 in ICC. ICC miRNA profiles were generated in five pairs of ICC and matched to normal bile duct tissues by next-generation sequencing technology; ICC miRNA profiles were verified in 18 pairs of ICC tissues and normal bile duct tissues by quantitative RT-PCR. The miR-191-associated mechanisms in ICC were investigated in vitro and in vivo, and clinical outcomes associated with miR-191 were correlated in 84 patients. Our results showed that miR-191 expression was significantly increased in ICC compared with the adjacent normal bile duct tissues (P < 0.001). Overexpression of miR-191 promoted proliferation, invasion, and migration of cholangiocarcinoma cells in vitro and in vivo. The elevated miR-191 expression reduced the expression level of ten-eleven translocation 1 (TET1)-a direct target gene of miR-191 in ICC, which catalyzes demethylation. The reduced TET1 expression level allowed the methylated CpG-rich regions at the p53 gene transcription start site stay methylated, leading to reduced p53 expression level, which compromises p53's anticancer vigor. Finally, miR-191 was found to be an independent risk factor for poor prognosis in patients with ICC (overall survival, hazard ratio = 3.742, 95% confidence interval 2.080-6.733, P < 0.001; disease-free survival, hazard ratio = 2.331, 95% confidence interval 1.346-4.037, P = 0.003). CONCLUSION: Our results suggest that overexpressed miR-191 is associated with ICC progression through the miR-191/TET1/p53 pathway. (Hepatology 2017;66:136-151).

Safety and efficacy of an olive oil-based triple-chamber bag for parenteral nutrition: a prospective, randomized, multi-center clinical trial in China.

BACKGROUND: Small studies suggest differences in efficacy and safety exist between olive oil-based (OLIVE) and soybean oil-based (SOYBEAN) parenteral nutrition regimens in hospitalized adult patients. This large, prospective, randomized (1:1), open-label, multi-center, noninferiority study compared the delivery, efficacy, and safety of OLIVE (N = 226) with SOYBEAN (N = 232) in Chinese adults (≥18 years) admitted to a surgical service for whom parenteral nutrition was required. METHODS: Treatments were administered for a minimum of 5 days up to 14 days (to achieve approximately 25 kcal/kg/day, 0.9 g/kg/day amino acids, 0.8 g/kg/day lipid). Impact of treatment on anabolic/catabolic and serum inflammatory, chemistry, and hematological markers, safety, and ease of use were assessed. The primary efficacy variable was serum prealbumin level at Day 5. RESULTS: OLIVE (n = 219) was not inferior to SOYBEAN (n = 224) based on the prealbumin least square geometric mean [LSGM] ratio [95% CI] 1.12 [1.06, 1.19]; P = 0.002), improved the anabolic/catabolic status of patients enrolled in the study, and was well tolerated compared with SOYBEAN. Improved anabolic status was supported by significantly higher levels of prealbumin at Day 5, albumin at Day 5 and IGF-1 at Day 14 in the OLIVE group, while catabolism was similar between groups. C-reactive protein, intercellular adhesion molecule-1, procalcitonin, and oxidation were similar in each group, but infections were significantly lower with OLIVE (3.6% versus 10.4%; P < 0.01). CONCLUSIONS: OLIVE provided effective nutrition, was well tolerated, was associated with fewer infections, and conferred greater ease-of-use than SOYBEAN. TRIAL REGISTRATION: NTC 01579097.

Circulating follicular helper T cells presented distinctively different responses toward bacterial antigens in primary biliary cholangitis.

Primary biliary cholangitis (PBC) is a chronic and progressive cholestatic liver disease with unknown causes. The initiation of PBC is associated with bacterial infections and abnormal immune correlates, such as the presence of self-reactive anti-mitochondrial antibodies and shifted balance of T cell subsets. In particular, the CD4+CXCR5+ follicular helper T (Tfh) cells are highly activated in PBC patients and are significantly associated with PBC severity, but the underlying reasons are unknown. In this study, we found that the circulating CD4+CXCR5+ T cells were enriched with the interferon (IFN)-γ-secreting Th1-subtype and the interleukin (IL)-17-secreting Th17-subtype, but not the IL-4-secreting Th2 subtype. We further demonstrated that a host of microbial motifs, including Pam3CSK4, poly(I:C), LPS, imiquimod, and CpG, could significantly stimulate IFN-γ, IL-17, and/or IL-21 from circulating CD4+CXCR5+ T cells in PBC patients, especially in the presence of monocytes and B cells. Whole bacterial cells of Escherichia coli, Novosphingobium aromaticivorans, and Mycobacterium gordonae, could also potently stimulate IFN-γ, IL-17, and/or IL-21 production from circulating CD4+CXCR5+ T cells. But interestingly, while the whole cell could potently stimulate circulating CD4+CXCR5+ T cells from both healthy controls and PBC patients, the cell protein lysate could only potently stimulate circulating CD4+CXCR5+ T cells from PBC patients, but not those from healthy controls, suggesting that circulating CD4+CXCR5+ T cells in PBC patients had distinctive antigen-specificity from those in healthy individuals. Together, these data demonstrated that bacterial antigen stimulation is a potential source of aberrant Tfh cell activation in PBC patients.

Folate-conjugated and pH-responsive polymeric micelles for target-cell-specific anticancer drug delivery.

In this study, we developed a folate (FA)-conjugated and pH-responsive active targeting micellar system for anti-cancer drug delivery. In this system, FA was attached to the terminal of the hydrophilic segment of poly(lactic acid)-poly(L-lysine) (PLA-PLL), and PLL was modified by a citric acid group. The FA receptor-mediated active targeting and electrostatic interaction between micelles and cell membrane due to a negative-to-positive charge reversal was combined in one micellar anti-cancer drug delivery system to enhance the tumour targeting and cellular internalisation of micelles. In vitro and in vivo anti-cancer studies demonstrated that the doxorubicin-loaded, FA-conjugated and pH-responsive polymeric micelles possess an enhanced and effective cancer efficiency. STATEMENT OF SIGNIFICANCE: Negatively charged nano-carriers prolonged anti-cancer drugs' blood circulation. However it is difficult to be internalised. Therefore, a negative-to-positive charged micelle surface could improve selectivity for tumour cells and increase uptake chance. In this study, we developed a folate (FA)-conjugated and pH-responsive active targeting micellar system for anti-cancer drug delivery. The FA receptor-mediated active targeting and electrostatic interaction between micelles and cell membrane due to a negative-to-positive charge reversal was combined in one micellar anti-cancer drug delivery system to enhance the tumour targeting and cellular internalisation of micelles. In vitro and in vivo anti-cancer studies demonstrated that the doxorubicin-loaded, FA-conjugated and pH-responsive polymeric micelles possess an enhanced and effective cancer efficiency.

Combined gemcitabine and S-1 chemotherapy for treating unresectable hilar cholangiocarcinoma: a randomized open-label clinical trial.

Although the combination of cisplatin and gemcitabine (GEM) is considered the standard first-line chemotherapy against unresectable hilar cholangiocarcinoma (HC), its efficacy is discouraging. The present randomized open-label clinical trial aimed to evaluate the efficacy and safety of the GEM plus S-1 (GEM-S-1) combination against unresectable HC. Twenty-five patients per group were randomly assigned to receive GEM, S-1 or GEM-S-1. Neutropenia (56%) and leukopenia (40%) were the most common chemotherapy-related toxicities in the GEM-S-1 group. Median overall survival (OS) in the GEM-S-1, GEM and S-1 groups was 11, 10 and 6 months, respectively. GEM plus S-1 significantly improved OS compared to S-1 monotherapy (OR=0.68; 95%CI, 0.50-0.90; P=0.008). Median progression-free survival (PFS) times in the GEM-S-1, GEM and S-1 groups were 4.90, 3.70 and 1.60 months, respectively. GEM plus S-1 significantly improved PFS compared to S-1 monotherapy (OR=0.50; 95%CI, 0.27-0.91; P=0.024). Response rates were 36%, 24% and 8% in the GEM-S-1, GEM and S-1 groups, respectively. A statistically significant difference was found in response rates between the gemcitabine-S-1 and S-1 groups (36% vs 8%, P=0.017). Patients with CA19-9<466 U/ml were more responsive to chemotherapeutic agents than those with CA19-9≥571 U/ml (88.9% vs 0%, P<0.001). We conclude that the combination of GEM plus S-1 provides a better OS, PFS and response rate than S-1 monotherapy, but it did not significantly differ from GEM monotherapy. (ChiCTR-TRC-14004733).

Follicular helper T cell exhaustion induced by PD-L1 expression in hepatocellular carcinoma results in impaired cytokine expression and B cell help, and is associated with advanced tumor stages.

Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) is one of the most common cancers in HBV-endemic regions, with irreversible progression and poor prognosis. HBV-related HCC patients lack effective antiviral/antitumor B cell antibody responses. We hypothesize that dysregulation of PD-1-expressing follicular helper T (Tfh) cell, induced by intrahepatic/intratumoral PD-L1 expression in HCC, could contribute to the defects in B cell immunity. The Tfh responses in healthy control (HC) subjects, chronic hepatitis B (HepB) patients, and HBV-related HCC patients were examined. Compared to HC and HepB individuals, HCC patients showed reduced ICOS expression, IL-10 and IL-21 secretion, and proliferation in Tfh cells. Tfh cells from stage III patients demonstrated increased impairment than those from stage I and stage II patients. Compared to Tfh cells from HC and HepB subjects, those from stage III HCC patients were significantly less effective at inducing the differentiation of naive B cells toward plasmablasts. HCC is known to upregulate hepatic PD-L1 expression, which could suppress Tfh responses. Blocking PD-1 partially rescued the Tfh functions in stage I and stage II HCC subjects but not in stage III HCC patients, while treatment with recombinant PD-L1 strongly suppressed Tfh functions in all HCC stages. Moreover, the level of IL-10 and IL-21 expression by Tfh cells was inversely correlated with the intensity of PD-L1 expression in resected tumors. Together, our results demonstrated an HCC-specific Tfh exhaustion, which might have resulted from elevated PD-1 and PD-L1 signaling.

Screening of nutritional risk and nutritional support in general surgery patients: a survey from Shanghai, China.

To determine the prevalence of nutritional risk in surgical departments and to evaluate the impact of nutritional support on clinical outcomes. The nutritional risk in different surgical diseases and the different way of nutritional support on clinical outcomes in patients at nutritional risk remain unclear. Hospitalized patients from general surgical departments were screened using the Nutritional Risk Screening (NRS) 2002 questionnaire on admission. Data were collected on nutritional risk, complications, and length of stay (LOS). Overall, 5034 patients were recruited; the overall prevalence of nutritional risk on admission were 19.2%. The highest prevalence was found among patients with gastric cancer. At-risk patients had more complications and longer LOS than nonrisk patients. Of the at-risk patients, the complication rate was significantly lower and LOS was significantly shorter in the nutritional-support group than in the no-support group (20.9 versus 30.0%, P < 0.05). Subgroup analysis showed reduced complication rates and LOS only in patients with gastric cancer, colorectal cancer, and hepato-pancreato-biliary (HPB) cancer. Significantly lower complication rates relative to nonsupported patients were found among patients who received enteral nutrition or who received support for 5 to 7 days, or daily support entailing 16 to 25 kcal/kg of nonprotein energy. Different surgical diseases have different levels of nutritional risk. The provision of nutritional support was associated with a lower complication rate and a shorter LOS for gastric, colorectal, and HPB cancer patients at nutritional risk. The improper use of nutritional support may not improve outcomes for at-risk patients.

Laparoscopic or Lichtenstein repair for recurrent inguinal hernia: a meta-analysis of randomized controlled trials.

BACKGROUND: There is no clear answer regarding the use of laparoscopic techniques versus the Lichtenstein method for the treatment of recurrent inguinal hernia. OBJECTIVE: The aim of this study was to compare the outcomes of laparoscopy versus the Lichtenstein repair by a meta-analysis of available randomized controlled trials (RCTs). METHODS: Databases, including PubMed, EMBASE, the Cochrane Library, and the Science Citation Index updated to May 2012, were searched. The main outcome measures were wound infections and haematoma, urinary retention, post-operative chronic pain and recurrence. A meta-analysis of included RCTs was performed. RESULTS: Five RCTs, comprising a total of 427 patients, were included. Although most of the analysed outcomes were similar between groups, wound infection rates and post-operative chronic pain occurred less frequently in the laparoscopic group than in the Lichtenstein group (odds ratio: 0.28, 95% CI: 0.08-0.97; P = 0.05; odds ratio: 0.33, 95% CI: 0.17-0.68; P = 0.002, respectively). CONCLUSION: The laparoscopic approach to the treatment of recurrent inguinal hernia is superior to the Lichtenstein hernioplasty in some aspects that affect patient satisfaction.

Meta-analysis of stapled hemorrhoidopexy vs LigaSure hemorrhoidectomy.

AIM: To compare outcome of stapled hemorrhoidopexy (SH) vs LigaSure hemorrhoidectomy (LH) by a meta-analysis of available randomized controlled trials (RCTs). METHODS: Databases, including PubMed, EMBASE, the Cochrane Library, and the Science Citation Index updated to December 2012, were searched. The main outcomes measured were operating time, early postoperative pain, postoperative urinary retention and bleeding, wound problems, gas or fecal incontinence, anal stenosis, length of hospital stay, residual skin tags, prolapse, and recurrence. The meta-analysis was performed using the free software Review Manager. Differences observed between the two groups were expressed as the odds ratio (OR) with 95%CI. A fixed-effects model was used to pool data when statistical heterogeneity was not present. If statistical heterogeneity was present (P < 0.05), a random-effects model was used. RESULTS: The initial search identified 10 publications. After screening, five RCTs published as full articles were included in this meta-analysis. Among the five studies, all described a comparison of the patient baseline characteristics and showed that there was no statistically significant difference between the two groups. Although most of the analyzed outcomes were similar between the two operative techniques, the operating time for SH was significantly longer than for LH (P < 0.00001; OR= -6.39, 95%CI: -7.68 - -5.10). The incidence of residual skin tags and prolapse was significantly lower in the LH group than in the SH group [2/111 (1.8%) vs 16/105 (15.2%); P = 0.0004; OR= 0.17, 95%CI: 0.06-0.45). The incidence of recurrence after the procedures was significantly lower in the LH group than in the SH group [2/173 (1.2%) vs 13/174 (7.5%); P = 0.003; OR= 0.21, 95%CI: 0.07-0.59]. CONCLUSION: Both SH and LH are probably equally valuable techniques in modern hemorrhoid surgery. However, LigaSure might have slightly favorable immediate postoperative results and technical advantages.