Genomic profiles of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are still insufficiently understood, and the genetic alterations associated with drug responses have not been studied. Here, we performed whole exome sequencing of 12 GEP-NETs from patients enrolled in a nonrandomized, open-labeled, single-center phase II study for pazopanib, and integrated our results with previously published results on pancreas (n = 12) and small intestine NETs (n = 50). The mean numbers of somatic mutations in each case varied widely from 20 to 4682. Among 12 GEP-NETs, eight showed mutations of more than one cancer-related gene, including TP53, CNBD1, RB1, APC, BCOR, BRAF, CTNNB1, EGFR, EP300, ERBB3, KDM6A, KRAS, MGA, MLL3, PTEN, RASA1, SMARCB1, SPEN, TBC1D12, and VHL. TP53 was recurrently mutated in three cases, whereas CNBD1 and RB1 mutations were identified in two cases. Three GEP-NET patients with TP53 mutations demonstrated a durable response and one small intestinal grade (G) 1 NET patient with BRAF V600E mutation showed progression after pazopanib treatment. We found BRAF V600E (G1 NET from rectum and two G3 NETs from colon) and BRAF G593S (G2 NET from pancreas) missense mutations (9.1%) in an independent cohort of 44 GEP-NETs from the rectum (n = 26), colon (n = 7), pancreas (n = 4), small intestine (n = 3), stomach (n = 3) and appendix (n = 1) by Sanger sequencing. All tumor specimens were obtained before chemotherapy. In conclusion, BRAF V600E mutation is likely to result in resistance to pazopanib but may be a potentianally actionable mutation in metastatic GEP-NETs patients.

Postcholecystectomy syndrome (PCS) is characterized by abdominal symptoms following gallbladder removal. However, there is no consensus for the definition or treatment for PCS. The purpose of this study was to define PCS among various symptoms after laparoscopic cholecystectomy, and to identify risk factors affecting PCS.

Pancreatic cancer is the eighth most common cancer and the fifth most common cause of cancer-related deaths in Korea. Despite the increasing incidence and high mortality rate of pancreatic cancer, there are no appropriate surgical practice guidelines for the current domestic medical situation. To enable standardization of management and facilitate improvements in surgical outcome, a total of 10 pancreatic surgical experts who are members of Korean Association of Hepato-Biliary-Pancreatic Surgery have developed new recommendations that integrate the most up-to-date, evidence-based research findings and expert opinions. This is an English version of the Korean Surgical Practice Guideline for Pancreatic Cancer 2022. This guideline includes 13 surgical questions and 15 statements. Due to the lack of high-level evidence, strong recommendation is almost impossible. However, we believe that this guideline will help surgeons understand the current status of evidence and suggest what to investigate further to establish more solid recommendations in the future.

Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis among common cancers. The genomic landscape of PDAC is defined by four mutational pathways: kirsten rat sarcoma virus (KRAS), cellular tumor antigen p53 (TP53), cyclin dependent kinase inhibitor 2A (CDKN2A), and SMAD family member 4 (SMAD4). However, there is a paucity of data on the molecular features associated with clinical outcomes after surgery or chemotherapy.

Pancreaticobiliary tract cancer has a poor prognosis with unmet needs in a new target treatment. Some studies have reported that an enhancement of T-cell immunity is associated with a good prognosis. The aim of this study is to investigate the immunoprofile as a prognostic marker of pancreaticobiliary tract cancers. Unresectable pancreatic ductal adenocarcinoma (PDAC, n = 80) and biliary tract cancer (BTC, n = 74) diagnosed between January 2012 and December 2018 in Samsung Medical Center were analyzed. Expression levels of CD8, FOXP3, PD-1, PD-L1, and CXCL13 in PDAC and BTC tissue samples were examined with immunohistochemical staining, which was evaluated with various clinical factors. In PDAC, higher degree of PD-L1 expression was significantly associated with shorter overall survival (OS) (p = 0.0095). On the other hand, higher infiltrations of PD-1+ immune cells (p = 0.0002) and CD8+ T cells (p = 0.0067) were associated with longer OS. In BTC, higher FOXP3+ (p = 0.0343) and CD8+ (p = 0.0028) cell infiltrations were associated with better survival. Low infiltration of CD8+ (p = 0.0148), FOXP3+ (p = 0.0208), PD-1+ (p = 0.0318) cells in PDAC, and FOXP3+ cells (p = 0.005) in BTC were considerably related to metastasis. In a combined evaluation of clinical factors and immunoprofiles, univariate analysis revealed that operation after chemotherapy (p < 0.0001), mass size (p = 0.0004), metastasis (p = 0.006), PD-L1 (p < 0.0001), PD-1 (p = 0.003) and CD8 (p = 0.0063) was significantly associated with OS in PDAC, and CD8 (p = 0.007) was statistically related to OS in BTC. In multivariate analysis, prognostic factors were operation after chemotherapy (p = 0.021) in PDAC and CD8 (p = 0.037) in BTC. Therefore, immunoprofile analysis of cells expressing CD8, FOXP3, PD-1, and PD-L1 might have prognostic values in patients with pancreaticobiliary tract cancers.

Several prediction models for evaluating the prognosis of nonmetastatic resected pancreatic ductal adenocarcinoma (PDAC) have been developed, and their performances were reported to be superior to that of the 8th edition of the American Joint Committee on Cancer (AJCC) staging system. We developed a prediction model to evaluate the prognosis of resected PDAC and externally validated it with data from a nationwide Korean database.

PIK3CA mutation is considered a good candidate for targeted therapies in cancers, especially biliary tract cancer (BTC). We evaluated the utility of cell free DNA (cfDNA) from serum by using droplet digital PCR (ddPCR) as an alternative source for PIK3CA mutation analysis. To identify matching archival tumour specimens from serum samples of advanced BTC patients, mutation detection using ddPCR with Bio-Rad's PrimePCR mutation and wild type assays were performed for PIK3CA p.E542K, p.E545K, and p.H1047R. Thirty-eight patients with metastatic BTC were enrolled. Only one (BTC 29T) sample (n = 38) was positive for PIK3CA p.E542K and another (BTC 27T) for p.H1047R mutation; none was positive for PIK3CA p.E545K. Matched serum sample (BTC 29P) was positive for PIK3CA p.E542K with 28 mutant copies detected, corresponding to 48 copies/ml of serum and an allelic prevalence of 0.3%. Another matched serum sample (BTC 27P) was positive for PIK3CA p.H1047R with 10 mutant copies detected, i.e. 18 copies/ml and an allelic frequency of 0.2%. High correlation was noted in the PIK3CA mutation status between tumour gDNA and serum cfDNA. Low-level PIK3CA mutations were detectable in the serum indicating the utility of cfDNA as a DNA source to detect cancer-derived mutations in metastatic biliary cancers.

We conducted a prospective genomic screening trial with high throughput sequencing and copy number variation (CNV) assay, and immunohistochemistry array in metastatic solid cancer patients. We used Ion AmpliSeq Cancer Hotspot Panel v2 and nCounter Copy Number Variation Assay (21 genes) to identify molecular targets for potential matched therapy. Metastatic solid tumor patients were prospectively consented for molecular profiling tests. The primary outcome for this trial was the feasibility of molecular tests and response rate (matched vs non-matched treatment). Between November 2013 and August 2014, a total of 428 metastatic solid tumor patients were enrolled on to this study. The mutational profiles were obtained for 407 (95.1%) patients. CNV 21-gene assays were successfully performed in 281 (65.7%) of 428 patients. Of the 407 patients with molecular profiling results, 342 (84.0%) patients had one or more aberrations detected. Of the 342 patients, 103 patients were matched to molecularly targeted agents in the context of clinical trials or clinical practice. The response rate was significantly higher in the genome-matched treated group for gastrointestinal/hepatobiliary/rare tumors (matched vs non-matched treatment, 42.6% vs 24.3%, P = .009) and lung cancer cohort (matched vs non-matched treatment, 61.2% vs 28.6% < P = .001) when compared with the non-matched group. In this trial, we demonstrate that genome-matched treatment based on molecular profiling result in better treatment outcome in terms of response rate.

Lymph-node (LN) metastasis is an important prognostic factor in resected pancreatic cancer. In this study, the prognostic value of American Joint Committee on Cancer (AJCC) 8th edition N stage, lymph-node ratio (LNR), and log odds of positive lymph nodes (LODDS) in resected pancreatic cancer was investigated.

Certain tumors such as pancreatic ductal adenocarcinoma (PDAC) are known to contain a variety of hydrolytic enzymes including RNases and proteases that may lead to degradation of RNA and proteins during sample processing. For such tumor tissues with RNA instability, RNAlater containing a high concentration of quaternary ammonium sulfates that denature RNA-hydrolyzing enzymes is often used to protect RNAs from hydrolysis. Although a few studies have been carried out to determine the effect of RNAlater on DNA and RNA, whether RNAlater influences the proteome and phosphoproteome is largely unknown. In this study we carried out a systematic and comprehensive analysis of the effect of RNAlater on the proteome and phosphoproteome using high-resolution mass spectrometry. PDAC tissues from three patients were individually pulverized and the tissue powders of each patient were divided into two portions, one of which was incubated in RNAlater at 4 °C for 24 h (RNAlater tissue) while the other was kept at - 80 °C (frozen tissue). Comprehensive quantitative profiling experiments on the RNAlater tissues and the frozen tissues resulted in the identification of 99,136 distinct peptides of 8803 protein groups and 17,345 phosphopeptides of 16,436 phosphosites. The data exhibited no significant quantitative changes in both proteins and phosphorylation between the RNAlater tissues and the frozen tissue. In addition, the phosphoproteome data showed heterogeneously activated pathways among the three patients that were not altered by RNAlater. These results indicate that the tissue preservation method using RNAlater can be effectively used on PDAC tissues for proteogenomic studies where preservation of intact DNA, RNA and proteins is prerequisite. Data from this study are available via ProteomeXchange with the identifier PXD010710.

Several studies report worse prognosis after left-side compared to right-side liver resection in patients with perihilar cholangiocarcinoma. In this study, we compared outcomes of left-side and right-side resections for Bismuth type III hilar cholangiocarcinoma and analyzed factors affecting survival.

The role of portal vein resection for pancreatic cancer is well established but not for pancreatic neuroendocrine neoplasms. Evidence from studies providing information on long-term outcome after venous resection in pancreatic neuroendocrine neoplasms patients is lacking.

We investigated chromosomal aberrations in patients with pancreatic ductal adenocarcinoma (PDAC) and intraductal papillary mucinous neoplasm (IPMN) by fluorescence in situ hybridization (FISH) to identify cytogenetic changes and molecular markers that may be useful for preoperative diagnosis.

Neoadjuvant treatment may provide improved survival outcomes for patients with borderline resectable pancreatic cancer (BRPC). The purpose of this study is to evaluate the clinical outcomes of neoadjuvant treatment and to identify prognostic factors.

The incidence of pancreatic adenocarcinoma (PA) approximates its prevalence, as the malignancy is almost consistently fatal within a year. Although the currently available adjuvant therapy seems to provide survival benefit, it is only moderate, and the standard regimen has not yet been established. Therefore, more biological resources to investigate the PA are needed.

Solid tumors such as pancreatic ductal adenocarcinoma (PDAC) comprise not just tumor cells but also a microenvironment with which the tumor cells constantly interact. Detailed characterization of the cellular composition of the tumor microenvironment is critical to the understanding of the disease and treatment of the patient. Single-cell transcriptomics has been used to study the cellular composition of different solid tumor types including PDAC. However, almost all of those studies used primary tumor tissues.

Cholangiocarcinoma frequently recurs even after curative resection. Expression levels of proteins such as epidermal growth factor receptor (EGFR), Snail, epithelial cadherin (E-cadherin), and interleukin-6 (IL-6) examined by immunohistochemistry have been studied as potential prognostic factors for cholangiocarcinoma. The aim of this study was to investigate significant factors affecting the prognosis of resectable cholangiocarcinoma.

Cancer stigma (CS), a self-inflicted sense of hopelessness, has been identified as a major factor affecting cancer patients' outcomes. However, few studies have investigated the CS-related outcomes in hepatobiliary and pancreatic (HBP) cancer. Thus, the aim of this study was to investigate effects of CS on quality of life (QoL) of HBP cancer.

The current guidelines on branch duct type intraductal papillary mucinous neoplasm (BD-IPMN) recommend various predictive features of malignancy as well as different treatment strategies. This study aimed to identify the risk factors for malignancy with higher level of evidence. A meta-analysis was performed on 40 literatures published between 2000 and 2019. These literatures included 6301 patients with pathologically proven IPMN. Malignancy was defined as high-grade dysplasia and invasive carcinoma. It was significantly associated with symptoms (odds ratio [OR] 1.35, confidence interval [CI] 1.01-1.79), size ≥ 3 cm (OR 1.90, CI 1.51-2.40), cystic wall thickening (OR 2.53, CI 1.50-4.27), mural nodule (OR 4.10, CI 3.38-4.97), main pancreatic duct dilatation (OR 2.98, CI 2.11-4.21), abrupt caliber change of the pancreatic duct (OR 7.41, CI 2.49-22.06), lymphadenopathy (OR 8.55, CI 3.25-22.51), elevated carbohydrate antigen 19-9 (OR 4.01, CI 2.55-6.28), and elevated carcinoembryonic antigen (OR 2.04, CI 1.60-2.61). Multilocular cysts and multiple cysts did not show a significant association with malignancy. This study examined the clinical, radiological, and biochemical features of BD-IPMN, often used as malignancy predictors according to the widely used guidelines. The results confirmed that all the features currently being used are valid.

Gallbladder cancer (GBC) is an aggressive gastrointestinal malignancy with no approved targeted therapy. Here, we analyze exomes (n = 160), transcriptomes (n = 115), and low pass whole genomes (n = 146) from 167 gallbladder cancers (GBCs) from patients in Korea, India and Chile. In addition, we also sequence samples from 39 GBC high-risk patients and detect evidence of early cancer-related genomic lesions. Among the several significantly mutated genes not previously linked to GBC are ETS domain genes ELF3 and EHF, CTNNB1, APC, NSD1, KAT8, STK11 and NFE2L2. A majority of ELF3 alterations are frame-shift mutations that result in several cancer-specific neoantigens that activate T-cells indicating that they are cancer vaccine candidates. In addition, we identify recurrent alterations in KEAP1/NFE2L2 and WNT pathway in GBC. Taken together, these define multiple targetable therapeutic interventions opportunities for GBC treatment and management.