Combined targeted therapy and immunotherapy for cancer treatment.

Although targeted therapies and immunotherapies have been effective against several malignancies, the respective monotherapies are limited by low and/or short-term responses. Specific inhibitors of oncogenic signaling pathways and tumor-associated angiogenesis can activate the anti-tumor immune responses by increasing tumor antigen presentation or intratumor T cell infiltration. Additional insights into the effects and mechanisms of targeted therapies on the induction of anti-tumor immunity will facilitate development of rational and effective combination strategies that synergize rapid tumor regression and durable response. In this review, we have summarized the recent combinations of targeted therapies and immunotherapies, along with the associated clinical challenges.

Prediction of postoperative pancreatic fistula using a nomogram based on the updated definition.

PURPOSE: The International Study Group on Pancreatic Fistula's definition of postoperative pancreatic fistula (POPF) has recently been updated. This study aimed to identify risk factors for POPF in patients having pancreaticoduodenectomy (PD) and to generate a nomogram to predict POPF. METHODS: Data on 298 patients who underwent PD from March 2012 to October 2017 was retrospectively reviewed and POPF statuses were redefined. A nomogram was constructed using data from 220 patients and validated using the remaining 78 patients. Independent risk factors for POPF were identified using univariate and multivariate analyses. A predictive nomogram was established based on the independent risk factors and was compared with existing models. RESULTS: Texture of the pancreas, size of the main pancreatic duct, portal vein invasion, and definitive pathology were the identified risk factors. The nomogram had a C-index of 0.793 and was internally validated. The nomogram performed better (C-index of 0.816) than the other most cited models (C-indexes of 0.728 and 0.735) in the validation cohort. In addition, the nomogram can assign patients into low- (less than 10%), intermediate- (10% to 30%), and high-risk (equal or higher than 30%) groups to facilitate personalized management. CONCLUSION: The nomogram accurately predicted POPF in patients having PD.

Development of a Novel Multiparametric MRI Radiomic Nomogram for Preoperative Evaluation of Early Recurrence in Resectable Pancreatic Cancer.

BACKGROUND: In pancreatic cancer, methods to predict early recurrence (ER) and identify patients at increased risk of relapse are urgently required. PURPOSE: To develop a radiomic nomogram based on MR radiomics to stratify patients preoperatively and potentially improve clinical practice. STUDY TYPE: Retrospective. POPULATION: We enrolled 303 patients from two medical centers. Patients with a disease-free survival ≤12 months were assigned as the ER group (n = 130). Patients from the first medical center were divided into a training cohort (n = 123) and an internal validation cohort (n = 54). Patients from the second medical center were used as the external independent validation cohort (n = 126). FIELD STRENGTH/SEQUENCE: 3.0T axial T1 -weighted (T1 -w), T2 -weighted (T2 -w), contrast-enhanced T1 -weighted (CET1 -w). ASSESSMENT: ER was confirmed via imaging studies as MRI or CT. Risk factors, including clinical stage, CA19-9, and radiomic-related features of ER were assessed. In addition, to determine the intra- and interobserver reproducibility of radiomic features extraction, the intra- and interclass correlation coefficients (ICC) were calculated. STATISTICAL TESTS: The area under the receiver-operator characteristic (ROC) curve (AUC) was used to evaluate the predictive accuracy of the radiomic signature in both the training and test groups. The results of decision curve analysis (DCA) indicated that the radiomic nomogram achieved the most net benefit. RESULTS: The AUC values of ER evaluation for the radiomics signature were 0.80 (training cohort), 0.81 (internal validation cohort), and 0.78 (external validation cohort). Multivariate logistic analysis identified the radiomic signature, CA19-9 level, and clinical stage as independent parameters of ER. A radiomic nomogram was then developed incorporating the CA19-9 level and clinical stage. The AUC values for ER risk evaluation using the radiomic nomogram were 0.87 (training cohort), 0.88 (internal validation cohort), and 0.85 (external validation cohort). DATA CONCLUSION: The radiomic nomogram can effectively evaluate ER risks in patients with resectable pancreatic cancer preoperatively, which could potentially improve treatment strategies and facilitate personalized therapy in pancreatic cancer. LEVEL OF EVIDENCE: 4 Technical Efficacy: Stage 4 J. Magn. Reson. Imaging 2020;52:231-245.

A nomogram for prediction of posthepatectomy liver failure in patients with hepatocellular carcinoma: A retrospective study.

To generate a nomogram to predict posthepatectomy liver failure (PHLF), we attempted to elucidate salient risk factors in patients with hepatocellular carcinoma (HCC).We performed a retrospective review of 665 patients with HCC who received hepatectomy in 2 academic institutions in China. Independent risk factors for PHLF were identified from putative demographic, intrinsic, biochemical, surgery-related, and volumetric data. A predictive nomogram was formulated based on relevant risk factors, and we compared this with existing models.We identified clinical signs of portal hypertension (P = .023), serum total bilirubin (P = .001), serum creatinine (P = .039), and intraoperative hemorrhage (P = .015) as being important risk factors in predicting PHLF. The nomogram had a C-index of 0.906 for the externally validated data. The nomogram displayed better predictive value than 2 of the other most cited models (C-indices of 0.641 and 0.616, respectively) in the current cohort. Additionally, we were able to patients into low- (<10%), intermediate- (10-30%), and high-risk (≥30%) groups based on the nomogram. This allows us to facilitate person-specific management.Here, we constructed a simple nomogram for prediction of PHLF in patients with HCC weighted by independent risk factors. Further prospective studies are required to confirm the predictive ability of our nomogram.

Predicting surgical site infections using a novel nomogram in patients with hepatocelluar carcinoma undergoing hepatectomy.

BACKGROUND: Surgical site infections (SSI) remain a major cause of morbidity after hepatectomy for hepatocellular carcinoma (HCC). AIM: To identify the risk factors associated with SSI, and develop a nomogram to predict SSI among patients undergoing hepatectomy. METHODS: We retrospectively reviewed the data of patients diagnosed with HCC undergoing hepatectomy at two academic institutions in China, and evaluated the occurrence of SSI. Independent risk factors for SSI were identified using univariate and multivariate analyses. Based on these independent risk factors, a nomogram was established using the data of patients in the first institution, and was validated using data from an external independent cohort from the second institution. RESULTS: The nomogram was established using data from 309 patients, whereas the validation cohort used data from 331 patients. The operation duration, serum albumin level, repeat hepatectomy, and ASA score were identified as independent risk factors. The concordance index (C-index) of the nomogram for SSI prediction in the training cohort was 0.86; this nomogram also performed well in the external validation cohort, with a C-index of 0.84. Accordingly, we stratified patients into three groups, with a distinct risk range based on the nomogram prediction, to guide clinical practice. CONCLUSION: Our novel nomogram offers good preoperative prediction for SSIs in patients undergoing hepatectomy.

The First Report of Laparoscopic Pancreaticoduodenectomy for Primary Duodenal Carcinoma in a Patient With Situs Inversus Totalis: Report of a Rare Case.

BACKGROUND: Situs inversus (SI) is a rare congenital anomaly characterized by the transposition of thoracic and abdominal viscera. Laparoscopic pancreaticoduodenectomy (LPD) is increasingly used in patients with periampullar and pancreatic carcinomas. For patients with SI, LPD can be more complicated because of reversed anatomy and possible other associated anomalies that have not been expected before surgery. CASE PRESENTATION: A female patient with SI totalis presented with inappetence, vomiting, and weight loss for 2 months. Imaging modalities and angiography revealed a mass in the periampullary region without obvious vascular abnormalities. The mass was successfully resected via LPD based on an elaborate preoperative plan. The surgical pathology report demonstrated adenocarcinoma of the duodenal papilla. The patient has been followed up for 4 months and no tumor recurrence or long-term complications were observed. CONCLUSION: LPD is technically difficult but feasible in patients with SI.

Preoperative prediction of peripancreatic vein invasion by pancreatic head cancer.

BACKGROUND: Pancreatic adenocarcinoma is often diagnosed at an advanced stage when adjacent vascular invasion is present. Accurate evaluation of presence of vascular invasion can help guide therapy. The aim of this study was to construct a nomogram for preoperative prediction of peripancreatic vein invasion in patients with pancreatic head cancer. STUDY DESIGN: Data of patients with carcinoma head of pancreas and suspected peripancreatic invasion (n = 247) who underwent pancreatic resection with venous reconstruction between January 2012 and January 2017 at four academic institutions were retrospectively analyzed. Univariate and multivariate analyses were used to identify independent risk factors for vein invasion from among demographic, biological, conditional host-related, and anatomical data. A predictive nomogram was constructed based on the identified independent risk factors. RESULTS: The nomogram was constructed using data from 181 patients while the validation cohort consisted of 66 patients. Length of tumor contact (P = 0.031), circumferential vein involvement (P = 0.048), and venous contour abnormalities (P = 0.001) were independent predictors of venous invasion. The C-index of the model in predicting venous invasion was 0.963 for the external validation cohort. Patients could be assigned into low- (< 50%), intermediate- (50-90%), and high-risk (> 90%) groups based on the nomogram to facilitate personalized management. CONCLUSIONS: Vein invasion by pancreatic head cancer is mainly associated with anatomical factors. The nomogram for prediction of vein invasion was found to be practicable.

Associating liver partition and portal vein ligation versus 2-stage hepatectomy: A meta-analysis.

BACKGROUND: The aim of this study was to conduct a meta-analysis comparing associating liver partition and portal vein ligation (ALPPS) with conventional 2-stage hepatectomy (TSH) in terms of clinical outcomes and to determine the feasibility and safety of ALPPS. METHODS: A comprehensive search strategy was adopted to search the PubMed, Embase, Cochrane Library, and China Biology Medicine disc databases for studies comparing ALPPS and TSH. The search was broadened by looking up the reference lists of the retrieved articles. A meta-analysis was performed using the statistical software RevMan (v 5.3; Cochrane Collaboration). RESULTS: A total of 7 studies involving 561 patients (ALPPS group, 136 patients; TSH group, 425 patients) were included in the present study, all of which were observational studies. Compared with TSH, ALPPS was associated with high completion rates of both stages [odds ratio (OR): 10.68, 95% confidence interval (95% CI): 3.26-34.97, P < .0001]. No significant differences were found in other outcomes such as complications of the first (OR: 4.04, 95% CI: 0.81-20.27, P = .09) and second surgical stage (OR: 1.59, 95% CI: 0.71-3.57, P = .26), liver failure (OR: 0.76, 95% CI: 0.29-1.98, P = .58) and the 90-day mortality rate (OR: 2.20, 95% CI: 1.00-4.84, P = .05). CONCLUSION: ALPPS is associated with lower noncompletion rate and had similar perioperative outcomes relative to TSH. However, only retrospective observational studies were included in this meta-analysis, which may have limited the strength of the evidence. High-quality, large-scale studies are required to further evaluate the outcomes of ALPPS.

The role of imaging in prediction of post-hepatectomy liver failure.

Post-hepatectomy liver failure (PHLF) is not only a leading cause of mortality but also a leading cause of life-threatening complications in patients undergoing liver resection. The ability to accurately detect the emergence of PHLF represents a crucially important step. Currently, PHLF can be predicted by a comprehensive evaluation of biological, clinical, and anatomical parameters. With the development of new technologies, imaging methods including elastography, diffusion-weighted magnetic resonance imaging, and gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid-enhanced MRI play a more significant role in the pre-operative prediction and assessment of PHLF. In this review, we summarize the mainstream studies, with the aim of evaluating the role of imaging and improving the clinical value of existing scoring systems for predicting PHLF.

A preoperative nomogram predicts prognosis of up front resectable patients with pancreatic head cancer and suspected venous invasion.

BACKGROUND: Pancreatic head adenocarcinoma is commonly diagnosed at an advanced stage when adjacent vascular invasion is present. This study aimed to establish a preoperative prognostic nomogram for patients who underwent attempted curative resectional surgery for pancreatic head cancer with suspected peripancreatic venous invasion. METHODS: Data on all consecutive patients were retrospectively collected from 2012 to 2016 at four academic institutions. The demographic and radiological parameters were analyzed using univariate and multivariate Cox regression analyses. The final nomogram was established using the concordance Harrell's C-indices and calibration curves from data obtained in three institutions and validated in the cohort of patients coming from the fourth institution. RESULTS: The nomogram was constructed using data from 178 patients while the validation cohort consisted of 61 patients. Age, length of tumor contact, peripancreatic venous abnormalities and lymph node staging were independent factors of overall survival. The nomogram showed good probabilities of survival on calibration curves. The C-index of the model in predicting overall survival (OS) was 0.824 for the validation cohort. CONCLUSIONS: The nomogram accurately predicted OS in patients with pancreatic head cancer with suspected peripancreatic venous invasion after attempted curative pancreatic resectional surgery.

Aspirin inhibited the metastasis of colon cancer cells by inhibiting the expression of toll-like receptor 4.

BACKGROUND: The metastasis of colorectal cancer frequently tends to liver, which is one of the three leading causes of cancer-related deaths worldwide. Growing evidence showed that aspirin could effectively inhibit liver metastasis of colorectal cancer. However, the potential mechanism has not been fully understood. METHODS: Mouse splenic vein metastasis assay was used to examine the metastatic ability of colon cancer cells in vivo. And wound healing and transwell assay were applied to detect the metastasis potential of C26 and HCT116 colon cancer cell lines in vitro. RT-PCR and western blotting were used to explore Toll-like receptor 4 (TLR4) expression in colon cancer cell lines. The functions of TLR4 in the migration of the colon cancer cell line were analyzed by infecting cells with lentivirus containing TLR4 siRNA. RESULTS: We demonstrated that lipopolysaccharides (LPS) could enhance the metastasis potential of C26 and HCT116 colon cancer cell lines. However, aspirin effectively decreased the metastasis capacity of colon cancer cells in vitro and in vivo. We found that the enhancement of LPS on the migration of colon cancer cells by inducing epithelial-mesenchymal transition (EMT) phenotype demonstrated a TLR4-dependent manner. Aspirin treatment lead to the downregulation of TLR4 on C26 cells which resulted in the decrease of C26 cells migration and EMT phenotype that induced by LPS. Additionally, the inhibitory effect from aspirin on the expression of TLR4 on C26 cells leads to the downregulation of NF-κB. CONCLUSION: The results of our study indicate that LPS origin from intestinal flora may promote the metastasis of colon cancer to liver and aspirin may inhibit the metastasis of colon cancer by inhibiting the expression of TLR4.

Modified-FOLFIRINOX in metastatic pancreatic cancer: A prospective study in Chinese population.

FOLFIRINOX chemotherapy has shown remarkable responses in patients with metastatic pancreatic cancer (MPC), and has significantly improved prognosis. However, FOLFIRINOX is currently not frequently applied in China because of its high incidence of adverse events, and there is no recognized optimization for this therapy in Chinese population. Modification of FOLFIRINOX may be better for its acceptance in China. In this study, we evaluated the efficacy and safety of modified-FOLFIRINOX in patients with MPC. A total of 62 MPC patients were treated with modified-FOLFIRINOX (no Fluorouracil bolus, 85% Oxaliplatin and 75% Irinotecan) between April 2014 and April 2017 in our institute. 40 of them were evaluated, with a response rate of 32.5% (13/40). The frequent grade 3/4 adverse events are neutropenia (29%) and alanine aminotransferase elevation (14.5%). No treatment-related death was observed. The median overall survival and median progression-free survival are 10.3 months and 7.0 months, respectively. In conclusion, modified-FOLFIRINOX had significantly improved tolerance with similar efficacy to FOLFIRINOX. These findings may provide evidence for the use of FOLFIRINOX in Chinese patients with MPC.

Krüppel-like factor 8 promotes cancer stem cell-like traits in hepatocellular carcinoma through Wnt/ß-catenin signaling.

Krüppel-like factor 8 (KLF8) is highly expressed in hepatocellular carcinoma (HCC) and contributes to tumor initiation and progression by promoting HCC cell proliferation and invasion. However, the role of KLF8 in liver cancer stem cells (LCSCs) is not known. In the current study, we investigated the role of KLF8 in LCSCs to determine if KLF8 is a novel marker of these cells. We found that KLF8 was highly expressed in primary HCC tumors, distant migrated tissues, and LCSCs. Patients with high KLF8 expression had a poor prognosis. KLF8 promoted stem cell-like features through activation of the Wnt/ß-catenin signaling pathway. Cell apoptosis was significantly increased in HCC cells with knockdown of KLF8 compared with the control cells when treated with the same doses of sorafenib or cisplatin. Taken together, our study shows that KLF8 plays a potent oncogenic role in HCC tumorigenesis by maintaining stem cell-like features through activation of the Wnt/ß-catenin signaling pathway and promoting chemoresistance. Thus, targeting KLF8 may provide an effective therapeutic approach to suppress tumorigenicity of HCC. © 2016 Wiley Periodicals, Inc.

Perioperative blood transfusion does not influence recurrence-free and overall survivals after curative resection for hepatocellular carcinoma: A Propensity Score Matching Analysis.

BACKGROUND & AIMS: Whether perioperative blood transfusions (PBTs) negatively impact oncologic outcomes after curative resection for HCC remains controversial. We aimed to identify the independent predictive factors of PBT for curative resection of hepatocellular carcinoma (HCC), and to investigate the impact of PBT on long-term recurrence and survivals after resection. METHODS: Of 1103 patients who underwent curative liver resection for HCC between 1999 and 2010, 285 (25.8%) patients received PBT. Univariable and multivariable regression analyses were used to identify independent predictive factors of PBT. Propensity scores and Cox regression analyses were used to compare the overall survival (OS) and recurrence-free survival (RFS) between patients who did and did not receive PBT. RESULTS: Multivariable regression analysis revealed that performance status, preoperative hemoglobin, cirrhosis, portal hypertension, tumor rupture, tumor size, macroscopic vascular invasion, and intraoperative blood loss were independent predictive factors of PBT for HCC resection. Propensity score matching analysis created 234 pairs of patients. Before propensity matching, PBT was significantly associated with increased risks of OS (HR: 2.455, 95% CI: 2.077-2.901, p<0.001) and RFS (HR: 2.018, 95% CI: 1.718-2.370, p<0.001) in the entire cohort. After propensity matching, PBT was not significantly associated with increased risks of OS (HR: 1.229, 95% CI: 0.988-1.527, p=0.063) and RFS (HR: 1.188, 95% CI: 0.960-1.469, p=0.113). After adjustment for other prognostic variables in the propensity matched cohort, PBT was still found not to be associated with OS and RFS after HCC resection. CONCLUSIONS: The present study identified that PBT did not influence RFS and OS after curative resection of HCC.

Reporting and methodological qualities of published surgical meta-analyses.

OBJECTIVES: To assess the overall qualities of published surgical meta-analysis and predictive factors for high qualities. STUDY DESIGN AND SETTING: All meta-analyses pertinent to surgical procedures published in year 2013 were selected from PubMed and EMBASE. The characteristics of the included meta-analyses were collected, and their reporting and methodologic qualities were assessed by the PRISMA (27 items) and AMSTAR (11 items) checklists, respectively. Independent predictive factors associated with these two qualities were evaluated by univariate and multivariate analyses. RESULTS: Hundred ninety-seven meta-analyses representing 10 surgical subspecialties were included. The mean PRISMA and AMSTAR adherences (by items) were 22.2 ± 2.4 and 7.8 ± 1.2, respectively, and a positive linear correlation was found between them with an R(2) of 0.793. Those meta-analyses conducted by the first authors having meta-analysis publication previously had significantly higher reporting and methodologic qualities than those who did not (P = 0.002 and P = 0.001). Meanwhile, there were also significant differences in these two qualities between studies published in Q1-ranked and (Q2 + Q3)-ranked journals as rated by the SCImago indicator (P < 0.001 and P < 0.001). On multivariate analyses, region of origin (non-Asia vs. Asia), publishing experience of first authors (ever vs. never), rank of publishing journals (Q1 vs. Q2 + Q3), and preregistration (presence vs. absence) were independently associated with superior reporting and methodologic qualities. CONCLUSIONS: The reporting and methodologic qualities of current surgical meta-analyses remained suboptimal, and first authors' experience and ranking of publishing journals were independently associated with both qualities. Preregistration might be an effective measure to improve the quality of meta-analyses, which deserves more attention from future study conductors.

Epidemiology and surgical management of intrahepatic cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC) is a rare hepatobiliary malignancy arising from the epithelial cells of the intrahepatic bile ducts. The increased incidence of ICC worldwide may reflect both a true increase and the earlier detection of the disease. Despite the advances in modern surgical care, the curative chance for ICC remained suboptimal: tumor-free margins are hard to achieve due to tumor locations, and technical challenges and recurrence, either local or distant, may hamper the resectability in a large number of patients. Lymph node involvement and vascular invasions are considered negative predictive factors for survival of ICC patients. This review discusses the epidemiology, risk factors and surgical management of ICCs, and mainly focuses on outcomes and factors associated with surgical treatment.

Risk factors of surgical site infection after hepatic resection.

A study of 7,388 consecutive patients after hepatic resection between 2011 and 2012 identified hepatolithiasis, cirrhosis, and intraoperative blood transfusion as the only independent risk factors of both incisional and organ/space surgical site infection (SSI). Patients with these conditions should be cared for with caution to lower SSI rates.

Elevated SHOX2 expression is associated with tumor recurrence of hepatocellular carcinoma.

BACKGROUND: SHOX2 (short stature homeobox 2) is a crucial transcriptional regulator in several genetic disorders and has been demonstrated to be an excellent biomarker in the diagnosis and evaluation of lung cancer. However, its expression pattern and prognostic value for hepatocellular carcinoma (HCC) are still unknown. METHODS: Expression of SHOX2 gene and protein in HCC tissues and cell lines were evaluated by RT-qPCR and western blot. Impact of RNAi-mediated SHOX2 silence on the proliferation and invasion ability of Huh7 cell line in vitro was determined by CCK-8 assay and matrigel invasion assay, respectively. RESULTS: Elevated expression of SHOX2 gene was significantly associated with higher incidence of tumor recurrence (n = 60, p = 0.001), absence of tumor capsule (p = 0.015), presence of tumor thrombi (p < 0.0001), and advanced TNM stage (p < 0.0001) of HCC. SHOX2 protein expression was more abundant in HCC cell lines compared with hepatic cell line (p = 0.001), which was associated with tumor recurrence (n = 40, p = 0.046). RNAi-mediated silence of SHOX2 expression significantly inhibited the proliferation (p < 0.001) and invasion (p = 0.006) of Huh7 cell line in vitro. CONCLUSIONS: Elevated SHOX2 expression was associated with HCC recurrence, probably by enhancing proliferation and invasion capability of cancer cells.