Therapeutic Implications of Ceritinib in Cholangiocarcinoma beyond ALK Expression and Mutation.

Cholangiocarcinoma (CCA) is a difficult-to-treat cancer, with limited therapeutic options and surgery being the only curative treatment. Standard chemotherapy involves gemcitabine-based therapies combined with cisplatin, oxaliplatin, capecitabine, or 5-FU with a dismal prognosis for most patients. Receptor tyrosine kinases (RTKs) are aberrantly expressed in CCAs encompassing potential therapeutic opportunity. Hence, 112 RTK inhibitors were screened in KKU-M213 cells, and ceritinib, an approved targeted therapy for ALK-fusion gene driven cancers, was the most potent candidate. Ceritinib's cytotoxicity in CCA was assessed using MTT and clonogenic assays, along with immunofluorescence, western blot, and qRT-PCR techniques to analyze gene expression and signaling changes. Furthermore, the drug interaction relationship between ceritinib and cisplatin was determined using a ZIP synergy score. Additionally, spheroid and xenograft models were employed to investigate the efficacy of ceritinib in vivo. Our study revealed that ceritinib effectively killed CCA cells at clinically relevant plasma concentrations, irrespective of ALK expression or mutation status. Ceritinib modulated multiple signaling pathways leading to the inhibition of the PI3K/Akt/mTOR pathway and activated both apoptosis and autophagy. Additionally, ceritinib and cisplatin synergistically reduced CCA cell viability. Our data show ceritinib as an effective treatment of CCA, which could be potentially explored in the other cancer types without ALK mutations.

Comparative outcomes of extended distal pancreatectomy and distal pancreatectomy.

PURPOSE: Patients with locally advanced pancreatic body/tail tumors, gastric cancer, or colon cancer often have contiguous organ involvement requiring extensive pancreatic resection. This study was performed to compare surgical complications and the incidence of clinically relevant postoperative pancreatic fistula (CR-POPF) between distal pancreatectomy (DP) with extended organ resection and standard DP. METHODS: In total, 128 patients who underwent DP from January 2012 to January 2021 were retrospectively reviewed. Extended DP was defined according to the International Study Group of Pancreatic Surgery definition. RESULTS: Of the 128 patients, 62 (48.4%) underwent extended DP and 66 (51.6%) underwent DP. Blood loss was greater (p < 0.001), the incidence of major complications was higher (p = 0.032), and the hospital stay was longer (p = 0.002) in the extended DP group than in the DP group. There were no differences in the incidence of CR-POPF, the readmission rate, or the need for postoperative intervention drainage. Univariate and multivariate analyses showed that extended DP was not a risk factor for CR-POPF or major complications. CONCLUSION: Extended DP can be performed with comparable CR-POPF occurrence and mortality but increased morbidity when compared with standard DP.

Timing of laparoscopic cholecystectomy after endoscopic retrograde cholangiopancreatography in cholelithiasis patients: A systematic review and meta-analysis.

There are many variations and unclear definitions of the appropriate timing of laparoscopic cholecystectomy (LC) after endoscopic retrograde cholangiopancreatography (ERCP), and there is still a lack of consistency about the appropriate timing. Inappropriate timing can be associated with serious comorbidity and can affect the patients. This meta-analysis was conducted to assess the operative outcomes and morbidity to provide a benefit to the patients based on the best timing of LC after ERCP. Randomized controlled trials (RCTs) and retrospective studies were identified from the PubMed and Scopus databases from inception to July 2021. A meta-analysis was performed to estimate the treatment effects on operative outcomes and morbidity. Four RCTs and four retrospective studies met our inclusion criteria. A meta-analysis indicated that patients who received LC after ERCP on the same day or within 72 hours had about 0.354 days shorter length of hospital stay with a shorter operative time of about 0.111-1.835 minutes and a lower risk of complications around 37%-73%. Our evidence suggests that the appropriate timing of LC after ERCP is either the same day or within 72 hours for treating cholelithiasis patients based on the severity of disease.

CP-673451, a Selective Platelet-Derived Growth Factor Receptor Tyrosine Kinase Inhibitor, Induces Apoptosis in Opisthorchis viverrini-Associated Cholangiocarcinoma via Nrf2 Suppression and Enhanced ROS.

Platelet-derived growth factors (PDGFs) and PDGF receptors (PDGFRs) play essential roles in promoting cholangiocarcinoma (CCA) cell survival by mediating paracrine crosstalk between tumor and cancer-associated fibroblasts (CAFs), indicating the potential of PDGFR as a target for CCA treatment. Clinical trials evaluating PDGFR inhibitors for CCA treatment have shown limited efficacy. Furthermore, little is known about the role of PDGF/PDGFR expression and the mechanism underlying PDGFR inhibitors in CCA related to Opisthorchis viverrini (OV). Therefore, we examined the effect of PDGFR inhibitors in OV-related CCA cells and investigated the molecular mechanism involved. We found that the PDGF and PDGFR mRNAs were overexpressed in CCA tissues compared to resection margins. Notably, PDGFR-α showed high expression in CCA cells, while PDGFR-ß was predominantly expressed in CAFs. The selective inhibitor CP-673451 induced CCA cell death by suppressing the PI3K/Akt/Nrf2 pathway, leading to a decreased expression of Nrf2-targeted antioxidant genes. Consequently, this led to an increase in ROS levels and the promotion of CCA apoptosis. CP-673451 is a promising PDGFR-targeted drug for CCA and supports the further clinical investigation of CP-673451 for CCA treatment, particularly in the context of OV-related cases.

Association of the rate of bilirubin decrease with major morbidity in patients undergoing preoperative biliary drainage before pancreaticoduodenectomy.

OBJECTIVE: The objective of this study was to examine the relationship between the rate of bilirubin decrease following preoperative biliary drainage before pancreaticoduodenectomy and postoperative morbidity. METHODS: Records of patients who underwent pancreaticoduodenectomy at the Department of Surgery in Ramathibodi Hospital between January 2008 and December 2019 were retrospectively reviewed. The patients were classified into either an adequate or inadequate drainage rate groups according to the bilirubin decrease rate. Major morbidity was defined as higher than grade II in the Clavien-Dindo classification. Risk factors for major morbidity were analyzed by logistic regression analysis. RESULTS: In total, 166 patients were included in the study. Major morbidity was observed in 36 patients (21.6%). Adequate biliary drainage rate was observed in 39 patients (23.4%). Patients who had major morbidity were less likely to have come from the adequate biliary drainage rate group than the inadequate group (38.9% vs. 61.1%). However, through multivariate logistic analysis, only body mass index, operative time, and pancreatic duct diameter were independent factors associated with major morbidity, whereas the bilirubin decrease rate was not. CONCLUSIONS: Bilirubin decrease rate following preoperative biliary drainage has no significant association with major postoperative morbidity after pancreaticoduodenectomy.

Prospective randomized controlled trial of omental roll-up technique on pancreatojejunostomy anastomosis for reducing perioperative complication in patients undergoing pancreatoduodenectomy.

BACKGROUND: Wrapping pancreatojejunal anastomosis with omentum to prevent postoperative pancreatic fistula (POPF) has only been reported in non-randomized, controlled trials. Therefore, this study aimed to conduct a randomized, controlled trial to compare outcomes between omental roll-up and non-omental roll-up in pancreatojejunal anastomosis. METHODS: This single-center, randomized, two-arm trail (Clinical Trials Register: NCT03083938) was conducted between February 2017 and February 2019. We studied 34 patients in the omental roll-up group and 34 patients in the non-omental roll-up group. The primary endpoint was the incidence of clinically relevant POPF. Thirty-day mortality and morbidity were recorded. RESULTS: Patients' demographic data were not significantly different between the two groups, except for histological diagnosis, with a significantly higher incidence of pancreatic cancer in the omental roll-up group (n = 15, 44.1%) than in the non-omental roll-up group (n = 9, 26.4%) (P = 0.042). There was one death in the non-omental roll-up group due to myocardial infarction. The incidence of POPF was not different between the omental roll-up group (n = 5, 14.7%) and non-omental roll-up group (n = 7, 20.6%) (P = 0.525). No differences were found in postoperative hemorrhage after pancreatectomy, delayed gastric emptying, and chyle leakage between the groups. CONCLUSION: This study shows that omental roll-up does not decrease the incidence of POPF after pancreatoduodenectomy.

Fluorescence cholangiography enhances surgical residents' biliary delineation skill for laparoscopic cholecystectomies.

BACKGROUND: Laparoscopic cholecystectomy (LC) is a minimally invasive procedure, often performed by surgical residents (SRs). Fluorescence cholangiography (FC) enables real-time identification of biliary anatomy. AIM: To investigate the benefit of FC for enhancing SRs' identification skills. METHODS: Prospective data was collected from January 2018 to June 2018 at our hospital. The study cohorts were the SRs (study group, n = 15) and the surgical staff (SS; control group, n = 9). Participants were assigned to watch videos of LCs with FC from five different patients who had gallbladder disease, and identify structures in the video clips (including cystic duct, common bile duct, common hepatic duct, and cystic artery), first without FC, and then with FC. RESULTS: In the without-FC phase, the overall misidentification rate by SRs (21.7%) was greater than that of the SS (11.8%; P = 0.018), However, in the FC phase, the two groups did not significantly differ in misidentification rates (23.3% vs 23.3%, P = 0.99). Paired-structure analysis of the without-FC and with-FC phases for the SR group found a significantly higher misidentification rate in the without-FC phase than the with-FC phase (21.9% vs 10.9%; P < 0.01). However, misidentification rates in the with-FC phase did not significantly differ between SRs and SS. CONCLUSION: FC enhanced identification skills of inexperienced surgeons during LC compared with conventional training. Combined with simulation-based video training, FC is a promising tool for enhancing technical and decision skills of trainees and inexperienced surgeons.

Outcomes of delayed endoscopic retrograde cholangiopancreatography in patients with acute biliary pancreatitis with cholangitis.

OBJECTIVE: The recommended treatment for acute biliary pancreatitis(ABP) with cholangitis is urgent endoscopic retrograde cholangiopancreatography(ERCP). However, tight schedules in the endoscopy room mean that urgent ERCP may not always be performed. This study aimed to compare the outcomes of early (≤72 h) and delayed(>72 h) ERCP in patients with ABP with cholangitis. METHODS: Ninety-five patients diagnosed with ABP with cholangitis who underwent ERCP between May 2012 and April 2018 were retrospectively reviewed. RESULTS: Sixty-seven patients(70.5%) were classified in the early ERCP and 28(29.5%) in the delayed ERCP groups. There was no significant difference in pancreatitis severity between the groups. Total bilirubin was higher in the early compared with the late ERCP group (5.7 ± 5.2 versus 3.5 ± 2.3 mg/dL, p = 0.03). Fewer patients in the early group had end-stage renal disease (0 versus 3, p = 0.006) and relatively fewer patients in the early group took aspirin (15(22.4%) versus 12(42.9%), p = 0.04). There were no significant differences between the early and delayed ERCP groups in terms of mortality (2(3.0%) versus 0), disease-related complications(11 (16.4%) versus 5(17.9%), p = 0.86), or ERCP-related complications(5(7.5%) versus 3(10.7%), p = 0.60). The total length of stay(LoS) was shorter in the early group(6.3 ± 4.4 versus 9.8 ± 6.1 days, p = 0.002). The rate of complete stone removal was lower in the early compared with the delayed ERCP group(32/42(76.2%) versus 18/18(100%), p = 0.02). CONCLUSION: Delayed ERCP can be performed in selected patients with ABP with cholangitis, with similar complication rates but longer LoS compared with early ERCP.

Preoperative serum albumin is associated with intra-abdominal infection following major hepatectomy.

BACKGROUND: Major hepatectomy is a complex surgical procedure with high morbidity. Intra-abdominal infection (IAI) is common following hepatectomy and affects treatment outcomes. This study was performed to investigate perioperative factors and determine whether the preoperative serum albumin level is associated with IAI following major hepatectomy. METHODS: From January 2008 to December 2018, 268 patients underwent major hepatectomy. We retrospectively analyzed demographic data and preoperative and perioperative variables. IAI was defined as organ/space surgical site infection. Risk factors for IAI were analyzed by logistic regression analysis. RESULTS: In total, 268 patients were evaluated. IAI was observed in 38 patients (14.6%). The mortality rate in the IAI group was 15.7%. Multivariate logistic analysis confirmed that the serum albumin level (odds ratio 0.91; 95% confidence interval 0.84-0.97; P = 0.03) and operative duration (odds ratio 1.50; 95% confidence interval 1.18-1.91; P < 0.01) were independent factors associated with IAI. A logistic model using the serum albumin level and operative duration to estimate the probability of IAI was analyzed. The area under the receiver operating characteristic curve for predicting IAI was 0.78. CONCLUSION: The serum albumin level and operative duration were independent factors predicting IAI following major hepatectomy.

Correlation of serum albumin and prognostic nutritional index with outcomes following pancreaticoduodenectomy.

BACKGROUND: Pancreaticoduodenectomy (PD) is a complex surgical procedure with a high morbidity rate. The serious complications are major risk factors for poor long-term surgical outcome. Studies have reported an association between early postoperative prognostic nutritional index (PNI) and prediction of severe complications after abdominal surgery. However, there have been no studies on the use of early postoperative PNI for predicting serious complications following PD. AIM: To analyze the risk factors and early postoperative PNI for predicting severe complications following PD. METHODS: We retrospectively analyzed 238 patients who underwent PD at our hospital between January 2007 and December 2017. The postoperative complications were classified according to the Dindo-Clavien classification. Grade III-V postoperative complications were classified as serious. The risk factors for serious complications were analyzed by univariate analysis and multivariate logistic regression analysis. RESULTS: Overall complications were detected in 157 of 238 patients (65.9%) who underwent PD. The grade III-V complication rate was 26.47% (63/238 patients). The mortality rate was 3.7% (9/238 patients). Multivariate logistic regression analysis revealed that preoperative serum albumin [odds ratio (OR): 0.883, 95% confidence interval (CI): 0.80-0.96; P < 0.01] and PNI on postoperative day 3 < 40.5 (OR: 2.77, 95%CI: 1.21-6.38, P < 0.05) were independent factors associated with grade III-V postoperative complications. CONCLUSION: Perioperative albumin is an important factor associated with serious complications following PD. Low early postoperative PNI (< 40.5) is a predictor for serious complications.

Platelet-to-Lymphocyte Ratio and Large Tumor Size Predict Microvascular Invasion after Resection for Hepatocellular Carcinoma

Background: Recurrence after curative resection of hepatocellular carcinoma (HCC) is associated with early death and poor prognosis. Microvascular invasion (mVI) is strongly associated with disease recurrence. Although many studies have examined the relationship between various serum inflammatory indices and post-treatment prognosis, little is known about preoperative predictors of microvascular invasion in HCC. Methods: Patients who underwent curative hepatic resection for HCC at our institute from January 2006 to December 2016 were retrospectively reviewed. The associations between mVI and various potential risk factors, including tumor size, hepatitis B and C virus infection, Child­Pugh scores, platelet-to-lymphocyte ratio, and neutrophil-to-lymphocyte ratio, were analyzed. Optimal cut-off values were determined using receiver operating characteristic curves. Results: A total of 330 HCC patients were enrolled in this study, of whom 74 (22.4%) had tumors with mVI. After univariate analysis, two parameters were significantly associated with mVI after hepatic resection: platelet-to-lymphocyte ratio ≥102 (odds ratio [OR] 2.385, p = 0.001) and tumor size ≥5 cm (OR 4.29, p < 0.001). Both variables remained significant risk factors for mVI after multivariate analysis: platelet-to-lymphocyte ratio ≥102 (OR 1.831, p = 0.034) and tumor size ≥5 cm (OR 3.791, p < 0.001). Conclusions: Large tumor size (≥5 cm) and high platelet-to-lymphocyte ratio (≥102) are independent predictive factors for mVI in HCC.

Prognostic role of alpha-fetoprotein response after hepatocellular carcinoma resection.

AIM: To investigate whether the change in pre-/post-operation serum alpha-fetoprotein (AFP) levels is a predictive factor for hepatocellular carcinoma (HCC) outcomes. METHODS: We retrospectively analyzed 334 HCC patients who underwent hepatic resection at our hospital between January 2006 and December 2016. The patients were classified into three groups according to their change in serum AFP levels: (1) the normal group, pre-AFP ≤ 20 ng/mL and post-AFP ≤ 20 ng/mL; (2) the response group, pre-AFP > 20 ng/mL and post-AFP decrease of ≥ 50% of pre-AFP; and (3) the non-response group, pre-AFP level > 20 ng/mL and post-AFP decrease of < 50% or higher than pre-AFP level, or any pre-AFP level < 20 ng/mL but post-AFP >20 ng/mL. RESULTS: Univariate and multivariate analyses revealed that multiple tumors [hazard ratio (HR): 1.646, 95%CI: 1.15-2.35, P < 0.05], microvascular invasion (mVI) (HR: 1.573, 95%CI: 1.05-2.35, P < 0.05), and the non-response group (HR: 2.425, 95% CI: 1.42-4.13, P < 0.05) were significant independent risk factors for recurrence-free survival. Similarly, multiple tumors (HR: 1.99, 95%CI: 1.12-3.52, P < 0.05), mVI (HR: 3.24, 95%CI: 1.77-5.90, P < 0.05), and the non-response group (HR: 3.62, 95%CI: 1.59-8.21, P < 0.05) were also significant independent risk factors for overall survival. The non-response group had significantly lower overall survival rates and recurrence-free survival rates than both the normal group and the response group (P < 0.05). Thus, patients with no response regarding post-surgery AFP levels were associated with poor outcomes. CONCLUSION: Serum AFP responses are significant prognostic factors for the surgical outcomes of HCC patients, suggesting post-resection AFP levels can direct the management of HCC patients.

Prognostic factors in patients with HBV-related hepatocellular carcinoma following hepatic resection.

BACKGROUND: To analyze prognostic factors following hepatic resection in patients with HBV-related hepatocellular carcinoma. METHODS: We retrospectively analyzed 217 patients with HBV-related hepatocellular carcinoma who underwent hepatic resection at our hospital between January 2006 and December 2015. Disease-free survival and overall survival rates were analyzed using the Kaplan-Meier method and the log-rank test. The association between recurrence and survival and various clinicopathological factors, including serum alpha-fetoprotein (AFP) level, platelet count, platelet-to-lymphocyte ratio, neutrophil-to-lymphocyte ratio, antiplatelet therapy, antiviral therapy, hepatitis C virus infection, and tumor-related characteristics, were assessed using univariate and multivariate logistic regression analysis. RESULTS: The 1-, 3-, and 5-year overall survival rates were 91, 84, and 79%, respectively, and the recurrence-free survival rates were 72, 51, and 44%, respectively. High post-operative AFP level (hazard ratio [HR] 1.112, 95% confidence interval [CI]: 1.02-1.21, P = 0.007), multiple tumors (HR 1.991, 95% CI: 1.11-3.56, P = 0.021), and no antiviral treatment (HR 1.823, 95% CI: 1.07-3.09, P = 0.026) were independent risk factors for recurrence. High post-operative AFP level (HR 1.222, 95% CI: 1.09-1.36, P < 0.001), multiple tumors (HR 2.715, 95% CI: 1.05-7.02, P = 0.039), and recurrence (HR 12.824, 95% CI: 1.68-97.86, P = 0.014) were independent risk factors for mortality. No other factors analyzed were associated with outcomes in this patient cohort. CONCLUSIONS: High post-operative serum alpha-fetoprotein level and multiple tumors, but not inflammatory factors, were risk factors for poor prognosis in HBV-related hepatocellular carcinoma patients after resection.

The detection of hepatocellular carcinoma (HCC) from patients' breath using canine scent detection: a proof-of-concept study.

Patients with hepatocellular carcinoma (HCC) have poor outcomes as a result of late detection of the disease. We investigated the possibility of using smell detection by dogs for detecting HCC from the breath of patients. Patients whose diagnosis of HCC was confirmed histologically or radiologically according to the American Association for the Study of Liver Diseases criteria had breaths collected using face masks and transported to the study test site. The numbering of the HCC samples was sent in a sealed envelope to blind the dog trainer during testing but allow for correct rewarding of the dog afterwards. One golden retriever was trained to detect HCC with positive feedback using known samples of HCC and healthy controls in a step-wise manner. The controls were selected from hospital staff and relatives of patients who were not involved in the study. They were questioned about the risks of their disease before selection. When the trainer was confident that the dog could recognize the HCC scent, blind testing was performed using 1 HCC : 3 healthy controls per test run. Once the dog signaled on a specimen, it was given a reward. The correct-detection rate was compared to the theoretical detection rate expected based on chance of 25% using the statistical one-sample test of proportions. Thirty-seven HCC patients were tested. The patients had a mean age of 58 years and 21/37 were male. Seventeen patients had hepatitis B and 14 patients had hepatitis C. Twenty-six patients had one HCC lesion; four patients had two lesions in the liver, whilst seven had many lesions. The number of patients in the very early, early, intermediate, advanced, and terminal stages of the Barcelona Clinic Liver Cancer classification was 5, 9, 21, 1, and 1, respectively. The dog detected correctly in 29 runs. The sensitivity for canine detection was 78% (95% CI: 62%-90%). Compared to the 25% correct indication expected based on chance, this was statistically significant (p < 0.001). CONCLUSION: This is the first study to look at the possibility of detecting HCC from breath using canine olfaction. Our results show that this is possible with an accuracy of 78% (p < 0.001 when compared to chance alone), and are thus a proof of concept. Further refinement of the process of detection will be needed before clinical application.

Risk factors for pancreatic fistula following pancreaticoduodenectomy: A retrospective study in a Thai tertiary center.

AIM: To analyze the risk factors of postoperative pancreatic fistula following pancreaticoduodenectomy in a Thai tertiary care center. METHODS: We retrospectively analyzed 179 patients who underwent pancreaticoduodenectomy at our hospital from January 2001 to December 2016. Pancreatic fistula were classified into three categories according to a definition made by an International Study Group on Pancreatic Fistula. The risk factors for pancreatic fistula were analyzed by univariate analysis and multivariate logistic regression analysis. RESULTS: Pancreatic fistula were detected in 88/179 patients (49%) who underwent pancreaticoduodenectomy. Fifty-eight pancreatic fistula (65.9%) were grade A, 22 cases (25.0%) were grade B and eight cases (9.1%) were grade C. Clinically relevant pancreatic fistula were detected in 30/179 patients (16.7%). The 30-d mortality rate was 1.67% (3/179 patients). Multivariate logistic regression analysis revealed that soft pancreatic texture (odds ratio = 3.598, 95%CI: 1.77-7.32) was the most significant risk factor for pancreatic fistula. A preoperative serum bilirubin level of > 3 mg/dL was the most significant risk factor for clinically relevant pancreatic fistula according to univariate and multivariate analysis. CONCLUSION: Soft pancreatic tissue is the most significant risk factor for postoperative pancreatic fistula. A high preoperative serum bilirubin level (> 3 mg/dL) is the most significant risk factor for clinically relevant pancreatic fistula.