Integrating Clinical Data and Molecular Profiling of Hepato-Pancreato-Biliary Cancers: a Surgical-pathological Approach

Background and Aims: The Cancer Genome Atlas (TGCA project has recently published a flagship paper reporting that Cell-of-Origin patterns dominate the molecular classification of 10,000 tumors from 33 types of cancer including hepato-pancreatic and biliary (HPB) malignancies. The aim of the current project was to investigate the molecular landscape of HPB cancers to apply in the clinical practice the molecular classifications resulting from the TGCA analyses. Patients and Methods: Machine learning models (artificial neural network, ANN) were trained to predict the molecular subtypes and Cell-of-Origin (iCluster) of HPB cancers. A survival analysis was performed using Cox\u2019s survival models and machine learning models (Random Survival Forest, RSF) to investigate impact of the molecular subtypes and iClusters classifications on prognosis of HPB patients. Whole exome sequencing (WES) data of TGCA patients with cholangiocarcinoma (CHOL), liver hepatocellular carcinoma (LIHC), and pancreatic adenocarcinoma (PAAD) were used to develop the ANNs. Two control groups including patients with gastrointestinal cancers and other type of cancers were used to train the ANNs. WES data of patients who underwent surgery at the Ohio State University (OSU) for HPB cancers and of patients participating to the International Cancer Gene Consortium (ICGC) were used to validate the ANNs. Results: The ANNs predicting the iClusters (i.e. from iCluster1 to iCluster28) demonstrated an accuracy of 99% in training set versus 74% in the test set. The ANNs predicting the molecular subtypes demonstrated an accuracy of 99% in training set versus 81% in the test set. The survival data of 362 (34 TGCA, 17 OSU, and 311 ICGC) CHOL patients were investigated using the RSF algorithm. The model identified the most important variables as AJCC stage, TP53 pathways status, molecular subtypes, lymph node status, and iCluster. In the multivariable Cox model, AJCC stage, TP53 pathways status, molecular subtypes, and iCluster were associated with patients\u2019 survival. Compared with METH-3 patients, patients in IDH and METH-2 subgroups had almost 2.5- and 5-fold risk of death (IDH, HR 2.47, p=0.037; METH-2, HR 4.85, p<0.001). The c-index of the final model integrating clinical and molecular data resulted 0.72. A total of 598 (341 TGCA, 30 OSU, and 227 ICGC) LIHC patients were investigated using the RSF algorithm. The model identified the most important variables as AJCC stage, molecular subtypes, AJCC T stages, TP53 pathway status, and TGF-beta pathway status. In the multivariable Cox model, AJCC stage, TP53 pathways status, and molecular subtypes were associated with patients\u2019 survival. Compared with patients with other molecular subtypes, patients in i-Cluster2 had almost 2.2-fold increased risk of death (i-Cluster2, HR 2.18, p<0.001). The c-index of the final model was 0.63. The survival data of 1,022 (155 TGCA, 66 OSU, and 999 ICGC) PAAD patients were investigated using the RSF algorithm. The model identified the most important variables as age, AJCC stage, molecular subtypes, i-Cluster, TP53 pathway, MYC pathway, and Cell-cycle pathway status. In the multivariable Cox model, AJCC stage, TP53 pathways status, and molecular subtypes were associated with patients\u2019 survival. Compared with patients with KRAS_wt molecular subtypes, patients with a KRAS_mut PAAD subtype had almost 1.4-fold increased risk of death (KRAS_mut, HR 1.38, p=0.031). The c-index of the final model integrating clinical and molecular data was 0.61. Conclusion: TGCA project have reported a complex and interconnected landscape describing the molecular biology of HPB cancers. In this preliminary work, the WES of patients with HPB cancers was used to predict the molecular classifications proposed in the TGCA papers. Moreover, the molecular classifications of HPB malignancies when integrated with the clinical staging system demonstrated to improve our ability to predict the prognosis of HPB patients

Assessment of neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio and platelet count as predictors of long-term outcome after R0 resection for colorectal cancer

Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and platelet count (PC) were shown to be prognostic in several solid malignancies. We analysed 603 R0 resected patients to assess whether NLR, PLR and PC correlate with other well-known prognostic factors and survival of patients with colorectal cancer (CRC). Receiver operating characteristic (ROC) curve analysis was performed to define cut-off values for high and low ratios of these indices. Univariate and multivariate analysis were used to determine the prognostic value of NLR, PLR and PC for overall and cancer-related survival. The distribution of NLR, PLR and PC in CRC patients was compared with 5270 healthy blood donors. The distribution of NLR, PLR and PC was significantly different between CRC patients and controls (all p\u2009<\u20090.05). A significant but heterogeneous association was found between the main CRC prognostic factors and high values of NLR, PLR and PC. Survival appeared to be worse in patients with high NLR with cancers in AJCC/UICC TNM Stages I-IV; nonetheless its prognostic value was not confirmed for cancer-related survival in multivariate analysis. After stratification of patients according to AJCC/UICC TNM stages, high PC value was significantly correlated with overall and cancer-related survival in TNM stage IV patients

Role of inflammatory and immune-nutritional prognostic markers in patients undergoing surgical resection for biliary tract cancers

The relationship between immune-nutritional status and tumor growth; biological aggressiveness and survival, is still debated. Therefore, this study aimed to evaluate the prognostic performance of different inflammatory and immune-nutritional markers in patients who underwent surgery for biliary tract cancer (BTC). The prognostic role of the following inflammatory and immune-nutritional markers were investigated: Glasgow Prognostic Score (GPS), modified Glasgow Prognostic Score (mGPS), Prognostic Index (PI), Neutrophil to Lymphocyte ratio (NLR), Platelet to Lymphocyte ratio (PLR), Lymphocyte to Monocyte ratio (LMR), Prognostic Nutritional Index (PNI). A total of 282 patients undergoing surgery for BTC were included. According to Cox regression and ROC curves analysis for survival, LMR had the best prognostic performances, with hazard ratio (HR) of 1.656 (p = 0.005) and AUC of 0.652. Multivariable survival analysis identified the following independent prognostic factors: type of BTC (p = 0.002), T stage (p = 0.014), N stage (p < 0.001), histological grading (p = 0.045), and LMR (p = 0.025). Conversely, PNI was related to higher risk of severe morbidity (p < 0.001) and postoperative mortality (p = 0.005). In conclusion, LMR appears an independent prognostic factor of long-term survival, whilst PNI seems associated with worse short-term outcomes

Impact of age on short-term outcomes of liver surgery: Lessons learned in 10-years' experience in a tertiary referral hepato-pancreato-biliary center

We investigate the surgical outcomes of patients undergoing hepatectomy according to different age intervals, identify the clinical factors related to surgical outcomes, and propose clinical risk scores for severe morbidity and mortality based on the clinical factors.Eight hundred three patients undergoing liver resection were divided into 3 groups: young patients (YP), <65 years (n = 387), elderly patients (EP), from 65 to 74 years (n = 279); very-elderly patients (VEP), ≥75 years (n = 137).Severe morbidity was 10.6%, 12.2%, and 17.5% (P = .103), and mortality was 0.3%, 1.4%, and 4.4% (P = .002) in group YP, EP, and VEP, respectively. Ischemic heart disease, cirrhosis, major hepatectomy, biliary tract-associated procedure, and red blood cells (RBC) transfusion ≥3 U were related with severe morbidity. Ischemic heart disease, cirrhosis, major hepatectomy, and RBC transfusion were independent risk factors for postoperative mortality. Age did not result an independent factor related to mortality and severe morbidity. Two different scores were developed and have proved to be statistically related with severe morbidity and mortality. Moreover, in patients with score ≥2, severe morbidity increased from 24.2% in YP, to 29.3% in EP, and to 40.0% in VEP, P = .047. Likewise, mortality increased from 2.3% in YP, to 7.0% in EP, and to 22.7% in VEP, in patients with score ≥2, P = .017.Age alone should not be considered a contraindication for hepatectomy. We identified factors and proposed 2 scores that can be useful to stratify the risk of morbidity and mortality after hepatectomy. Moreover, severe morbidity and mortality increases according to the different age intervals in patients with scores ≥2

Surgery for Bismuth-Corlette Type 4 Perihilar Cholangiocarcinoma:Results from a Western Multicenter Collaborative Group

Contains fulltext : 239075.pdf (Publisher’s version ) (Open Access)BACKGROUND: Although Bismuth-Corlette (BC) type 4 perihilar cholangiocarcinoma (pCCA) is no longer considered a contraindication for curative surgery, few data are available from Western series to indicate the outcomes for these patients. This study aimed to compare the short- and long-term outcomes for patients with BC type 4 versus BC types 2 and 3 pCCA undergoing surgical resection using a multi-institutional international database. METHODS: Uni- and multivariable analyses of patients undergoing surgery at 20 Western centers for BC types 2 and 3 pCCA and BC type 4 pCCA. RESULTS: Among 1138 pCCA patients included in the study, 826 (73%) had BC type 2 or 3 disease and 312 (27%) had type 4 disease. The two groups demonstrated significant differences in terms of clinicopathologic characteristics (i.e., portal vein embolization, extended hepatectomy, and positive margin). The incidence of severe complications was 46% for the BC types 2 and 3 patients and 51% for the BC type 4 patients (p = 0.1). Moreover, the 90-day mortality was 13% for the BC types 2 and 3 patients and 12% for the BC type 4 patients (p = 0.57). Lymph-node metastasis (N1; hazard-ratio [HR], 1.62), positive margins (R1; HR, 1.36), perineural invasion (HR, 1.53), and poor grade of differentiation (HR, 1.25) were predictors of survival (all p ≤0.004), but BC type was not associated with prognosis. Among the N0 and R0 patients, the 5-year overall survival was 43% for the patients with BC types 2 and 3 pCCA and 41% for those with BC type 4 pCCA (p = 0.60). CONCLUSIONS: In this analysis of a large Western multi-institutional cohort, resection was shown to be an acceptable curative treatment option for selected patients with BC type 4 pCCA although a more technically challenging surgical approach was required

Surgery for Bismuth-Corlette Type 4 Perihilar Cholangiocarcinoma: Results from a Western Multicenter Collaborative Group

Background Although Bismuth-Corlette (BC) type 4 perihilar cholangiocarcinoma (pCCA) is no longer considered a contraindication for curative surgery, few data are available from Western series to indicate the outcomes for these patients. This study aimed to compare the short- and long-term outcomes for patients with BC type 4 versus BC types 2 and 3 pCCA undergoing surgical resection using a multi-institutional international database. Methods Uni- and multivariable analyses of patients undergoing surgery at 20 Western centers for BC types 2 and 3 pCCA and BC type 4 pCCA. Results Among 1138 pCCA patients included in the study, 826 (73%) had BC type 2 or 3 disease and 312 (27%) had type 4 disease. The two groups demonstrated significant differences in terms of clinicopathologic characteristics (i.e., portal vein embolization, extended hepatectomy, and positive margin). The incidence of severe complications was 46% for the BC types 2 and 3 patients and 51% for the BC type 4 patients (p = 0.1). Moreover, the 90-day mortality was 13% for the BC types 2 and 3 patients and 12% for the BC type 4 patients (p = 0.57). Lymph-node metastasis (N1; hazard-ratio [HR], 1.62), positive margins (R1; HR, 1.36), perineural invasion (HR, 1.53), and poor grade of differentiation (HR, 1.25) were predictors of survival (all p ≤0.004), but BC type was not associated with prognosis. Among the N0 and R0 patients, the 5-year overall survival was 43% for the patients with BC types 2 and 3 pCCA and 41% for those with BC type 4 pCCA (p = 0.60). Conclusions In this analysis of a large Western multi-institutional cohort, resection was shown to be an acceptable curative treatment option for selected patients with BC type 4 pCCA although a more technically challenging surgical approach was required

ASO Author Reflections: Re-resection of Positive Bile Duct Margin for Hilar Cholangiocarcinoma

Author Reflections: Re-resection of Positive Bile Duct Margin for Hilar Cholangiocarcinom

Cholangiocarcinoma risk factors and the potential role of aspirin

Choi et al. are to be congratulated on their work that adds to an already abundant literature on the topic of aspirin and cancer prevention. However, the retrospective design of the study, as well as the relative lack of detailed data on dosing, duration of usage, and concomitant other medications, do not allow for definitive evidence to support routine recommendations for daily aspirin usage. In an era of individualized medicine, future, prospective trials should aim to identify those subsets of patients who might benefit the most from aspirin usage, as well as further delineate the underlying mechanism of action related to this potential chemopreventative approach

Central Pancreatectomy: from Open to Minimally Invasive

This book provides a unique and comprehensive overview of minimally invasive (MI) surgical options for the treatment of pancreatic diseases. The opening chapters present the state of the art of MI pancreatic resection according to the 2016 IHPBA Conference, offer information on the safe dissemination of MI pancreatic surgical techniques, and discuss preoperative evaluations protocols and surgical planning options. The book subsequently investigates the full range of currently available minimally invasive techniques, which includes: biliary and gastric bypass, ampullectomy, central and distal pancreatectomy, laparoscopic and robotic pancreatoduodenectomy, and robotic pancreas transplantation. Combining the acknowledged expertise of the Italian school in pancreatic surgery and the contributions of many leading international experts, the book offers a valuable guide for all surgeons who perform this complex surgery, as well as for residents and fellows-in-training