Efficacy and safety of sirolimus early conversion protocol in liver transplant patients with hepatocellular carcinoma: A single-arm, multicenter, prospective study.

Mammalian target of rapamycin (mTOR) inhibitor as an attractive drug target with promising antitumor effects has been widely investigated. High quality clinical trial has been conducted in liver transplant (LT) recipients in Western countries. However, the pertinent studies in Eastern world are paucity. Therefore, we designed a clinical trial to test whether sirolimus can improve recurrence-free survival (RFS) in hepatocellular carcinoma (HCC) patients beyond the Milan criteria after LT. This is an open-labeled, single-arm, prospective, multicenter, and real-world study aiming to evaluate the clinical outcomes of early switch to sirolimus-based regimens in HCC patients after LT. Patients with a histologically proven HCC and beyond the Milan criteria will be enrolled. The initial immunosuppressant regimens are center-specific for the first 4-6 weeks. The following regimens integrated sirolimus into the regimens as a combination therapy with reduced calcineurin inhibitors based on the condition of patients and centers. The study is planned for 4 years in total with a 2-year enrollment period and a 2-year follow-up. We predict that sirolimus conversion regimen will provide survival benefits for patients particular in the key indicator RFS as well as better quality of life. If the trial is conducted successfully, we will have a continued monitoring over a longer follow-up time to estimate indicator of overall survival. We hope that the outcome will provide better evidence for clinical decision-making and revising treatment guidelines based on Chinese population data. Trial register: Trial registered at http://www.chictr.org.cn: ChiCTR2100042869.

A novel technique of inserting pancreaticogastrostomy with duct-to-mucosa anastomosis can potentially reduce postoperative pancreatic fistula.

BACKGROUND: We describe our novel technique of inserting pancreaticogastrostomy (IPG) after pancreaticoduodenectomy. In our technique, the seromuscular and mucosal layers of the posterior gastric wall are separated to create a mucosal pouch. A duct-to-mucosa anastomosis is performed through a small incision in the mucosal layer. An inner suture at the seromuscular-mucosal margin incorporating the pancreatic parenchyma and an outer suture on the exterior margin of the seromuscular layer to wrap the pouch around the pancreas are placed to complete the IPG. MATERIALS AND METHODS: We examined the clinicopathological features and outcomes of 259 patients who underwent pancreaticoduodenectomy between January 2010 and April 2014. RESULTS: One hundred forty-three (55.2%) patients underwent IPG, while 116 (44.8%) had conventional pancreaticojejunostomy. Most preoperative and intraoperative parameters were comparable. Overall morbidity in the IPG group was 28.7%. The rate of grade A postoperative pancreatic fistula (POPF) was 7.0%, and the rates of grade B and C POPF were 0.7% and 0.0%, respectively. The corresponding rates of grade A, B, and C fistulae were 5.2%, 8.6%, and 5.2%, respectively. CONCLUSIONS: In selected patients, our novel technique can be performed safely and may reduce the rates of POPF.

A novel UPLC-MS/MS method for sensitive quantitation of boldine in plasma, a potential anti-inflammatory agent: application to a pharmacokinetic study in rats.

Boldine is a potential anti-inflammatory agent found in several different plants. Published bioanalytical methods using HPLC with ultraviolet and fluorescent detection lacked enough sensitivity and required tedious sample preparation procedures. Herein, we describe the development of a novel ultra-high performance LC with MS/MS for determination of boldine in plasma. Boldine in plasma was recovered by liquid-liquid extraction using 1 mL of methyl tert-butyl ether. Chromatographic separation was performed on a C18 column at 45°C, with a gradient elution consisting of acetonitrile and water containing 0.1% (v/v) formic acid at a flow rate of 0.3 mL/min. The detection was performed on an electrospray triple-quadrupole MS/MS by positive ion multiple reaction monitoring mode. Good linearity (r(2) > 0.9926) was achieved in a concentration range of 2.555-2555 ng/mL with a lower limit of quantification of 2.555 ng/mL for boldine. The intra- and inter-day precisions of the assay were 1.2-6.0 and 1.8-7.4% relative standard deviation with an accuracy of -6.0-8.0% relative error. This newly developed method was successfully applied to a single low-dose pharmacokinetic study in rats and was demonstrated to be simpler and more sensitive than the published methods, allowing boldine quantification in reduced plasma volume.

Protective effects of piperlongumine against adjuvant-induced arthritis in rats through modulating OPG/RANKL/NF-κB signaling pathway.

OBJECTIVES: We examined the antirheumatoid effects of piperlongumine (PLM) on rat adjuvant-induced arthritis (AIA) and explored the underlying mechanisms involved. METHODS: PLM (2.5, 5, and 10 mg/kg) was administered intraperitoneally to AIA rats to assess its effectiveness. Blood, thymus, spleen, ankle joint, and synovial tissue samples were gathered for subsequent analyses, like enzyme-linked immunosorbent assay, thymus/spleen index measurement, ankle joint pathological examination, immunohistochemistry assay, polymerase chain reaction, and western blot assay. Moreover, the involvement of osteoprotegerin (OPG)/receptor activators of nuclear factor κB ligand (RANKL)/nuclear factor-κB (NF-κB) signaling was investigated. KEY FINDINGS: PLM effectively relieved inflammation and joint destruction in AIA rats, as indicated by reductions in hind paw swelling, arthritis index, thymus/spleen index, ankle joint pathological damage, production of TNF-α, IL-1ß, and IL-6 in both serum and synovium, and osteoclast formation. Also, PLM treatment raised OPG production, reduced RANKL expression, and elevated the OPG/RANKL ratio in synovial tissues. Furthermore, PLM prevented IκBα degradation and phosphorylation, resulting in a reduced expression of the nuclear NF-κB p65 protein in AIA rat synovial tissues. CONCLUSIONS: PLM demonstrated strong antiarthritic effects in rats with AIA by influencing the OPG/RANKL/NF-κB signaling pathway, highlighting its potential clinical relevance in treating rheumatoid arthritis.

Gallbladder neuroendocrine carcinoma diagnosis, treatment and prognosis based on the SEER database: A literature review.

BACKGROUND: Gallbladder neuroendocrine carcinoma (GB-NEC) has a low incidence rate; therefore, its clinical characteristics, diagnosis, treatment and prognosis are not well explored. AIM: To review recent research and analyze corresponding data in the Surveillance Epidemiology and End Results (SEER) database. METHODS: Data of GB-NEC (n = 287) and gallbladder adenocarcinoma (GB-ADC) (n = 19 484) patients from 1975 to 2016 were extracted from the SEER database. Survival analysis was performed using Kaplan-Meier and Cox proportional hazards regression. P < 0.05 was considered statistically significant. We also reviewed 108 studies retrieved from PubMed and Reference Citation Analysis (https://www.referencecitationanalysis.com/). The keywords used for the search were: "(Carcinoma, Neuroendocrine) AND (Gallbladder Neoplasms)". RESULTS: The GB-NEC incidence rate was 1.6% (of all gallbladder carcinomas), male to female ratio was 1:2 and the median survival time was 7 mo. The 1-, 2-, 3- and 5-year overall survival (OS) was 36.6%, 17.8%, 13.2% and 7.3% respectively. Serum chromogranin A levels may be a specific tumor marker for the diagnosis of GB-NEC. Elevated carcinoembryonic antigen, carbohydrate antigen (CA)-19-9 and CA-125 levels were associated with poor prognosis. Age [hazard ratio (HR) = 1.027, 95% confidence interval (CI): 1.006-1.047, P = 0.01] and liver metastasis (HR = 3.055, 95% CI: 1.839-5.075, P < 0.001) are independent prognostic risk factors for OS. Patients with advanced GB-NEC treated with surgical resection combined with radiotherapy and/or chemotherapy may have a better prognosis than those treated with surgical resection alone. There was no significant difference in OS between GB-NEC and GB-ADC. CONCLUSION: The clinical manifestations and prognosis of GB-NEC are similar to GB-ADC, but the treatment is completely different. Early diagnosis and treatment are the top priorities.

Predictive Value of the TP53 p.G245S Mutation Frequency for the Short-Term Recurrence of Hepatocellular Carcinoma as Detected by Pyrophosphate Sequencing.

Aims: We explored the relationship between the mutation at the p.G245S site in TP53 and the short-term recurrence of hepatocellular carcinoma (HCC). Materials and Methods: 101 HCC patients were included in this study. The TP53 p.G245S mutation frequency spectrum was examined by direct sequencing of genomic DNA from tissue specimens of HCC patients. Univariate and multivariate Cox regression analyses were performed to evaluate the independent prognostic factors of tumor recurrence. ROC curve analysis was applied to determine the cut-off value for the p.G245S mutation frequency and to verify the predictive ability of the Cox model compared with single risk factor indices. Results: A multivariate Cox regression analysis showed that TP53 p.G245S mutation frequency (HR = 1.231, 95% CI: 1.006-1.505, p = 0.043), AFP (HR = 2.432, 95% CI: 1.297-4.561, p = 0.006), MTM (HR = 2.656, 95% CI: 0.930-7.583, p = 0.068), and PVTT (HR = 14.297, 95% CI: 3.085-66.243, p = 0.001) were independent prognostic factors for short-term recurrence. The cut-off value for the TP53 p.G245S mutation frequency (18.5%) was determined by ROC analysis. A predictive model integrating the TP53 p.G245S mutation frequency with PVTT, MTM, and AFP values appears to an excellent predictive indicator of short-term recurrence in HCC patients (AUC = 0.849, 95% CI = 0.748-0.950, p = 0.000001). Survival analysis indicated that the probability of short-term recurrence-free survival was significantly different among different TP53 p.G245S mutation frequency, MTM, PVTT, and AFP risk groups (p < 0.05). Conclusion: The mutation frequency of the p.G245S site is a novel prognostic risk factor for the short-term recurrence of HCC.

Comparison of the short-term outcomes of open and laparoscopic hepatectomy in the treatment of recurrent hepatocellular carcinoma: a single-center retrospective study.

Background: To retrospectively analyze the short-term outcomes between open hepatectomy (OH) and laparoscopic hepatectomy (LH) in the treatment of recurrent hepatocellular carcinoma (HCC). The objective is to develop the optimal surgical method for patients with recurrent liver cancer after operation. Methods: We retrospectively reviewed the data of 165 HCC patients whose cancer recurred after hepatectomy between January 2015 and March 2021 at our medical center. According to the inclusion and exclusion criteria, a total of 74 patients were eventually enrolled in this study. Results: Tumors located in S1, S7, or S8 and larger tumor diameters were more frequent in the OH group, and the difference was statistically significant. Furthermore, there were notable differences between the LH and OH groups in terms of intraoperative blood loss (140.00 vs. 348.68 mL, P<0.001), mean operation time (150.95 vs. 203.28 min, P=0.024), and mean postoperative hospital stay (6.76 vs. 11.28 days, P=0.014). There were no statistically significant differences in the remaining characteristics between the two groups. There was no significant difference in recurrence-free survival and overall survival between the two groups. Conclusions: Compared with OH, LH can significantly reduce the amount of intraoperative blood loss and shorten the operation time and postoperative hospital stay. At the same time, laparoscopic surgery may be a better surgical approach for patients with tumors of smaller diameter located in segments 2 to 6.

Is routine calcium supplementation necessary in patients undergoing total thyroidectomy plus neck dissection?

PURPOSE: Patients undergoing a total thyroidectomy plus neck dissection are at high risk of developing postoperative hypocalcemia. This study prospectively evaluated the possibility to identify factors that predict symptomatic hypocalcemia and the necessity of routine calcium supplements. METHODS: Sixty-five consecutive patients who underwent a total thyroidectomy plus neck dissection were included. Intact parathyroid hormone (iPTH), total serum calcium (sCa), serum phosphate (sPhos), and serum magnesium (sMg) levels were monitored and compared between the symptomatic hypocalcemic group ( group A) and the asymptomatic hypocalcemic group (group B). RESULTS: Asymptomatic and self-limiting hypocalcemia developed in 54 patients (81.5%; group B). Symptomatic hypocalcemia developed in 11 patients (18.5%; group A). They required calcium supplements. There were no significant differences in the iPTH and sMg levels between the two groups; the sCa level was significantly lower on postoperative days 1, 2, 3, and 5 in group A than in group B (P < 0.05); the sPhos level was significantly higher on postoperative days 2 and 3 in group A than in group B (P < 0.05). CONCLUSIONS: Symptomatic hypocalcemia develops within 3 days after surgery. An sCa level of less than 1.81 mmol/l can predict symptomatic hypocalcemia. Routine calcium supplements will not be necessary if the sCa level is higher than 1.81 mmol/l.

Mucin-producing intrahepatic biliary papillomatosis.

PURPOSE: Mucin-producing intrahepatic biliary papillomatosis (MPIBP) is an uncommon tumor. The purpose of this study was to evaluate the clinical, radiological, and histopathological characteristics of MPIBP, and its prognosis. METHODS: A retrospective analysis was conducted of 11 patients who underwent surgery for MPIBP. The clinical features and radiological, pathological, and operative findings were reviewed, and the survival rates were determined. RESULTS: Repeated episodes of fever and epigastric pain with or without jaundice were the common clinical manifestations. Radiologically, all patients showed diffuse bile duct dilatation with cystic change in intrahepatic bile duct. All patients underwent a hepatic resection with or without an extrahepatic bile duct resection. No in-hospital mortality occurred. All patients survived without any signs of recurrence (median 12 +/- 7 months); three patients, including two patients who underwent a palliative resection, had an attack of cholangitis, which was effectively treated with antibiotics. CONCLUSIONS: A diagnosis of MPIBP is usually made in patients with biliary dilatation following a radiologic study. Magnetic resonance cholangiopancreatography is more valuable than other modalities in diagnosis. Mucin-producing intrahepatic biliary papillomatosis is a premalignant disease with high malignant potential. The prognosis of MPIBP is excellent if an aggressive resection is performed. A combination of cholangioscopy and frozen sections during the operation is beneficial for a radical successful surgical resection.

Ro41-5253, a selective antagonist of retinoic acid receptor α, ameliorates chronic unpredictable mild stress-induced depressive-like behaviors in rats: Involvement of regulating HPA axis and improving hippocampal neuronal deficits.

Accumulating reports have highlighted an association between excess retinoids and depression development. Retinoic acid receptor α (RARα) is implicated in the activation of hypothalamus-pituitary-adrenal (HPA) axis and closely involved in the etiology of depression, suggesting it might be a novel target of antidepressant. This study investigated the antidepressant potential of Ro41-5253 (a selective RARα antagonist) and related mechanisms using a depression rat model imitated by social isolation and chronic unpredicted mild stress (CUMS). Sucrose preference test (SPT), open field test (OFT) and forced swimming test (FST) were applied to assess the antidepressant-like effect. HPA axis activity, RARα expression in hypothalamic paraventricular nucleus (PVN) and hypothalamus, and protein levels of brain-derived neurotrophic factor (BDNF) and synapse-related proteins (PSD95, SYP, MAP2) in hippocampus were measured, respectively. We found that Ro41-5253 treatment ameliorated the depressive-like behaviors in CUMS rats, as evidenced by increased sucrose preference in SPT, raised numbers of crossing and rearing in OFT, reduced immobility time and prolonged swimming time in FST. The HPA axis hyperactivity was attenuated by Ro41-5253 (1 mg/kg) treatment, indicated by reduced serum corticosterone level, decreased adrenal gland index, reduced corticotrophin-releasing hormone protein level in hypothalamus, and recovered hypothalamic glucocorticoid receptor protein level. In addition, Ro41-5253 (1 mg/kg) treatment downregulated RARα protein expression in hypothalamic PVN and hypothalamus, and increased the protein levels of BDNF, PSD95, SYP and MAP2 in the hippocampus. We concluded that Ro41-5253 had antidepressant-like effects on CUMS rats by downregulating HPA axis hyperactivity and improving the hippocampal neuronal deficits.

Portal vein/superior mesenteric vein resection in pancreatic cancer treatment in the elderly.

There is an increased interest in extending surgical criteria for pancreatic cancer by performing pancreaticoduodenectomy (PD) combined with portal vein (PV) or superior mesenteric vein (SMV) resection and reconstruction for borderline resectable patients. However, whether this procedure suitable for elderly patients remains unclear. Here, we studied cases of pancreatic cancer treatment in our medical center to evaluate feasibility and safety of this procedure in the elderly.Eighty-three patients 65 years of age or older who underwent PD from January 2009 to March 2014 were divided into 2 groups: PD only (Group A, 52 cases), and PD combined with PV/SMV resection and reconstruction (Group B, 31 cases). Surgical outcomes and survival rates were compared between groups. Information regarding preoperative, intraoperative and postoperative conditions, and follow-up visits were provided. The outcomes of postoperative complications and survival rates were investigated.No difference in the preoperative data was detected between 2 groups with the exception that the serum albumin level was significantly lower in Group B (P = .013), indicating more deteriorating health conditions in this group. Although intraoperative time and blood loss were higher in Group B (P < .001 and P = .048, respectively), the overall postoperative complications and survival curve showed no statistical differences between 2 groups with one exception in that there was higher incidence of intractable diarrhea in Group B (P = .034). The symptoms, however, resolved later on with conservative treatment. The median survival time for patients in this study was comparable to other reported PD treatments. There was zero postoperative mortality in both groups.PD combined with PV/SMV treatment did not lead to increased morbidity and motility in elderly patients 65 years of age and above. This procedure could provide a promising opportunity for borderline resectable elderly pancreatic cancer patients.

Total Hilar En Bloc Resection with Left Hemihepatectomy and Caudate Lobectomy: a Novel Approach for Treatment of Left-Sided Perihilar Cholangiocarcinoma (with Video).

BACKGROUND: "Hilar en bloc resection" using a no-touch technique has been advocated as a standard procedure in right-sided hepatectomies for treatment of perihilar cholangiocarcinoma (PHC). In principle, it has never been reported for left-sided tumors. The aim is to describe the procedures of total hilar en bloc resection with left hemihepatectomy and caudate lobectomy (THER-LH) for advanced PHC and discuss feasibility and clinical significance of this novel technique. METHODS: A retrospective study using a prospectively maintained database was performed to identify eight patients who had received THER-LH for advanced PHC from January 2013 to December 2015. The clinicopathological features, surgical procedures, and outcomes of these patients form the basis this study. RESULTS: The operative time was 546 ± 158 (380-870) min, and estimated blood loss was 875 ± 690 (400-2500) ml. Time of vessel resection and reconstruction was 25.6 ± 12.3 min for the portal vein and 19.1 ± 4.9 min for the hepatic artery. Time of hilum clamping was 27.3 ± 11.9 (15-41) min. Two patients had Clavien-Dindo grade II and IVa complications of bile leakage with one developing intraabdominal abscess and bleeding. There was no perioperative mortality. Histopathologic examination revealed that all of eight patients had tubular adenocarcinoma with microscopic invasion to the resected hepatic arteries and portal veins in seven patients. Negative bile duct margins were achieved in all of them. Three patients developed recurrence and died at 11, 18, and 24 months postoperatively. The remaining patients were alive at the time of last follow-up. The median survival was 24 months with one patient achieving a disease-free survival of 50 months. CONCLUSION: THER-LH is a technically demanding procedure that is safe and feasible that may have some beneficial effects on the prognosis of these patients with advanced PHC. Further studies are required to confirm the oncological superiority and survival benefits of this novel technique.

Changes of arginine vasopressin in elderly patients with acute traumatic cerebral injury.

OBJECTIVE: To investigate the changes and clinical significance of arginine vasopressin (AVP) in elderly patients with acute traumatic cerebral injury. METHODS: With radioimmunoassay, the plasma levels of AVP were measured in 32 elderly patients with acute traumatic cerebral injury, 30 traumatic patients without cerebral injury and 30 healthy elderly volunteers, respectively. RESULTS: The plasma level of AVP in patients with acute traumatic cerebral injury in the early stage (48.30 ng/L +/- 8.28 ng/L) was much higher than that of the traumatic patients without cerebral injury (25.56 ng/L +/- 4.64 ng/L, P<0.01), which was much higher than that of the healthy volunteers (5.06 ng/L +/- 4.12 ng/L, P<0.01). The level of AVP in the patients with acute traumatic cerebral injury was negatively related with GCS scores. CONCLUSIONS: AVP may play an important role in the pathophysiological process in patients with acute traumatic cerebral injury in the early stage. The severer the cerebral injury is, the higher the level of AVP is, which indicates that the level of AVP may be one of the severity indices of traumatic cerebral injury in elderly patients.