Comparison of genomic profiling of circulating tumor DNA in pancreaticobiliary malignancies in plasma and bile.

BACKGROUND: Obtaining sufficient pancreaticobiliary tumor tissue for genomic profiling has limitations. Liquid biopsies using plasma do not provide sufficient sensitivity. Thus, this study aimed to determine the effectiveness of liquid biopsy between bile and plasma for identifying oncogenic and drug-matched mutations. METHODS: This study created a panel of 60 significantly mutated genes specific to pancreaticobiliary cancer (PBCA) and used it for genomic analysis of 212 deoxyribonucleic acid (DNA) samples (87 bile supernatant, 87 bile precipitate, and 38 plasma) from 87 patients with PBCA. The quantity of extracted DNA from bile and plasma was compared, as were genomic profiles of 38 pairs of bile and plasma from 38 patients with PBCA. Finally, we investigated 87 bile and 38 plasma for the ability to detect druggable mutations. RESULTS: The amount of DNA was significantly lower in plasma than in bile (p < .001). Oncogenic mutations were identified in 21 of 38 (55%) patients in bile and nine (24%) in plasma samples (p = .005). Bile was significantly more sensitive than plasma in identifying druggable mutations (p = .032). The authors detected 23 drug-matched mutations in combined bile and plasma, including five ERBB2, four ATM, three BRAF, three BRCA2, three NF1, two PIK3CA, one BRCA1, one IDH1, and one PALB2. CONCLUSIONS: Liquid biopsy using bile may be useful in searching for therapeutic agents, and using the obtained genomic information may improve the prognoses of patients with PBCA. PLAIN LANGUAGE SUMMARY: Genomic profiling of formalin-fixed paraffin-embedded tissues may provide actionable targets for molecular and immuno-oncological treatment. However, most pancreaticobiliary malignancies are unresectable and formalin-fixed paraffin-embedded tissues cannot be obtained. Although comprehensive genomic profiling tests using plasma have been used in recent years, the utility of those using bile is not clear. Our study revealed that bile identified more drug-matched mutations than plasma in advanced pancreaticobiliary cancer patients. Bile may help widen the patient population benefiting from targeted drugs.

Palliation of malignant gastric outlet obstruction with simultaneous endoscopic insertion of afferent and efferent jejunal limb enteral stents in patients with recurrent malignancy.

BACKGROUND: Patients with prior pancreaticobiliary or distal gastric cancer treated surgically may have local anastomotic recurrence with obstruction of the afferent and efferent jejunal limbs. This report describes the efficacy and safety of simultaneous endoscopic insertion of self-expanding metal stents into the afferent and efferent jejunal limbs in patients with gastric outlet obstruction (GOO) of post-surgical anatomy for palliation of recurrent malignancy. METHODS: Patients were identified from an endoscopic database at a specialized cancer center between September 2007 and March 2014. Technical success was defined as single-session insertion of afferent and efferent jejunal limb enteral stents. Clinical success was defined as immediate symptom relief and ability to advance diet. A durable response was defined as symptom relief of at least 60 days or until hospice placement or death. RESULTS: Twenty-three patients were identified who underwent insertion of two 22-mm-diameter uncovered duodenal stents. Stent length varied from 60 to 120 mm. Stents were placed under endoscopic and fluoroscopic guidance. Three patients required balloon dilation to facilitate stent insertion. Average procedure time was 58.8 min (range 28-120). Technical success was achieved in 23/24 (96%) patients. Clinical success was achieved in 19/23 (83%) patients. Following initial stent insertion and prior to subsequent re-intervention, 11/19 (58%) patients had a durable response with a median duration of 70 days (range 4-315). Eight (42%) patients underwent subsequent re-intervention at a median of 22 days (range 11-315). Five patients had stent revision and were able to tolerate oral intake. Two patients had percutaneous endoscopic gastrostomy/jejunostomy insertion. One patient required surgical diversion for persistent obstruction. Complications included stent migration and post-stent insertion bacteremia due to food bolus obstruction. CONCLUSIONS: Recurrent malignant GOO in patients with post-surgical anatomy treated with simultaneous endoscopic enteral stenting of afferent and efferent jejunal limbs has a high rate of technical and clinical success and low rate of complications and provides effective palliation.

Association between Cholecystectomy and the Incidence of Pancreaticobiliary Cancer after Endoscopic Choledocholithiasis Management.

(1) Background: Previous studies have raised concerns about a potential increase in pancreaticobiliary cancer risk after cholecystectomy, but few studies have focused on patients who undergo cholecystectomy after receiving endoscopic retrograde cholangiopancreatography (ERCP) for choledocholithiasis. This study aims to clarify cancer risks in these patients, who usually require cholecystectomy, to reduce recurrent biliary events. (2) Methods: We conducted a nationwide cohort study linked to the National Health Insurance Research Database, the Cancer Registry Database, and the Death Registry Records to evaluate the risk of pancreaticobiliary cancers. All patients who underwent first-time therapeutic ERCP for choledocholithiasis from 2011 to 2017 in Taiwan were included. We collected the data of 13,413 patients who received cholecystectomy after endoscopic retrograde cholangiopancreatography and used propensity score matching to obtain the data of 13,330 patients in both the cholecystectomy and non-cholecystectomy groups with similar age, gender, and known pancreaticobiliary cancer risk factors. Pancreaticobiliary cancer incidences were further compared. (3) Results: In the cholecystectomy group, 60 patients had cholangiocarcinoma, 61 patients had pancreatic cancer, and 15 patients had ampullary cancer. In the non-cholecystectomy group, 168 cases had cholangiocarcinoma, 101 patients had pancreatic cancer, and 49 patients had ampullary cancer. The incidence rates of cholangiocarcinoma, pancreatic cancer, and ampullary cancer were 1.19, 1.21, and 0.3 per 1000 person-years in the cholecystectomy group, all significantly lower than 3.52 (p < 0.0001), 2.11 (p = 0.0007), and 1.02 (p < 0.0001) per 1000 person-years, respectively, in the non-cholecystectomy group. (4) Conclusions: In patients receiving ERCP for choledocholithiasis, cholecystectomy is associated with a significantly lower risk of developing pancreaticobiliary cancer.

Detection of actionable mutations in archived cytological bile specimens.

BACKGROUND/PURPOSE: There are limitations in obtaining sufficient pancreaticobiliary tumor tissue for genomic profiling of tumors. Herein, we investigated whether archived cytological specimen (ACS) is suitable for genomic profiling to identify oncogenic and drug-matched mutations. METHODS: We constructed a pancreaticobiliary cancer panel for targeted sequencing covering 60 significantly mutated genes (280 220 bp). Eighty DNA samples (19 formalin-fixed paraffin-embedded [FFPE] tissues and 61 ACS) from 44 patients with pancreaticobiliary disease were analyzed. We compared genomic profiles of 19 FFPE and 29 ACS from 19 patients with malignancies (Validation Cohort). We tested 32 ACS from 25 patients (15 malignant and 10 benign) for the ability to discriminate between malignant and benign disorders (Testing Cohort). We explored whether actionable and drug-matched mutations (Validation and Testing Cohorts) could be identified from ACS. RESULTS: Oncogenic mutations observed in ACS were identical to those identified in FFPE specimens (76% consistency). Genomic profiling using only ACS discriminated between malignant and benign disorders with 93% accuracy, 91% sensitivity, and 100% specificity. Actionable and drug-matched mutations were identified in 74% and 32% of ACS, respectively, and in 79% and 21% in FFPE samples, respectively. CONCLUSION: Archived cytological specimen may be used to discriminate malignancy and to detect drug-matched mutations in patients with advanced pancreaticobiliary cancer.

Postoperative arginine-enriched immune modulating nutrition: Long-term survival results from a randomised clinical trial in patients with oesophagogastric and pancreaticobiliary cancer.

BACKGROUND & AIMS: Immune modulating nutrition (IMN) has been shown to reduce postoperative infectious complications and length of stay in patients with gastrointestinal cancer. Two studies of IMN in patients undergoing surgery for head and neck cancer also suggested that this treatment might improve long-term survival and progression-free survival. In the present study, we analysed follow-up data from our previous randomised controlled trial of IMN, in patients undergoing surgery for oesophagogastric and pancreaticobiliary cancer, in order to evaluate the long-term impact on survival of postoperative IMN versus an isocaloric, isonitrogenous control feed. METHODS: This study included patients undergoing surgery for cancers of the pancreas, oesophagus and stomach, who had been randomised in a double-blind manner to receive postoperative jejunostomy feeding with IMN (Stresson, Nutricia Ltd.) or an isonitrogenous, isocaloric feed (Nutrison High Protein, Nutricia) for 10-15 days. The primary outcome was long-term overall survival. RESULTS: There was complete follow-up for all 108 patients, with 54 patients randomised to each group. There were no statistically significant differences between groups by demographics [(age, p = 0.63), sex (p = 0.49) or site of cancer (p = 0.25)]. 30-day mortality was 11.1% in both groups. Mortality in the intervention group was 13%, 31.5%, 70.4%, 85.2%, 88.9%, and 96.3% at 90 days, and 1, 5, 10, 15 and 20 years respectively. Corresponding mortality in the control group was 14.8%, 35.2%, 68.6%, 79.6%, 85.2% and 98.1% (p > 0.05 for all comparisons). CONCLUSION: Early postoperative feeding with arginine-enriched IMN had no impact on long-term survival in patients undergoing surgery for oesophagogastric and pancreaticobiliary cancer.

Dysbiosis of the duodenal microbiota as a diagnostic marker for pancreaticobiliary cancer.

BACKGROUND: Pancreaticobiliary cancer (PB Ca) is a lethal disease, and a useful diagnostic marker is urgently needed. A correlation between the human microbiota and malignant gastrointestinal diseases was recently reported. AIM: To investigate the efficacy of the duodenal microbiota for diagnosing PB Ca. METHODS: We recruited 22 patients with benign pancreaticobiliary diseases (benign group) and 12 patients with PB Ca (malignant group). The duodenal microbiota of each patient was analyzed by the 16S rDNA terminal restriction fragment length polymorphism method. Patient characteristics, tumor markers, and relative abundances of the duodenal microbiota were compared between the benign and malignant groups. RESULTS: Cancer antigen 19-9 (CA19-9), Bifidobacterium, Clostridium cluster XVIII, and Prevotella levels differed significantly between the benign and malignant groups. Clostridium cluster XVIII had the greatest area under the receiver operating characteristic curve (AUC) among the four factors with respect to diagnosing PB Ca (cutoff value: 3.038%; sensitivity: 58.3%; specificity: 95.2%; AUC: 0.81). The combination of Clostridium cluster XVIII (cutoff value: 3.038%) and CA19-9 Levels (cutoff value: 18.8 U/mL) showed 91.7% sensitivity and 71.4% specificity for diagnosing PB Ca. CONCLUSION: The duodenal microbiota may be useful for PB Ca screening.

Scope of Artificial Intelligence in Gastrointestinal Oncology.

Gastrointestinal cancers are among the leading causes of death worldwide, with over 2.8 million deaths annually. Over the last few decades, advancements in artificial intelligence technologies have led to their application in medicine. The use of artificial intelligence in endoscopic procedures is a significant breakthrough in modern medicine. Currently, the diagnosis of various gastrointestinal cancer relies on the manual interpretation of radiographic images by radiologists and various endoscopic images by endoscopists. This can lead to diagnostic variabilities as it requires concentration and clinical experience in the field. Artificial intelligence using machine or deep learning algorithms can provide automatic and accurate image analysis and thus assist in diagnosis. In the field of gastroenterology, the application of artificial intelligence can be vast from diagnosis, predicting tumor histology, polyp characterization, metastatic potential, prognosis, and treatment response. It can also provide accurate prediction models to determine the need for intervention with computer-aided diagnosis. The number of research studies on artificial intelligence in gastrointestinal cancer has been increasing rapidly over the last decade due to immense interest in the field. This review aims to review the impact, limitations, and future potentials of artificial intelligence in screening, diagnosis, tumor staging, treatment modalities, and prediction models for the prognosis of various gastrointestinal cancers.

Utility of Endoscopic Ultrasound-Guided Fine Needle Aspiration in the Diagnosis of Local Recurrence of Pancreaticobiliary Cancer after Surgical Resection.

Background/Aims: Endoscopic ultrasound (EUS)-guided fine needle aspiration (FNA; EUS-FNA) allows for diagnostic tissue specimens from various regions to be analyzed. However, diagnosing recurrent pancreaticobiliary cancer after surgery is sometimes difficult. We evaluated the efficacy of EUS-FNA in the diagnosis of local recurrence of pancreaticobiliary cancer and analyzed the factors associated with falsenegative results. Methods: Fifty-one consecutive patients who underwent EUS-FNA due to suspected recurrence of pancreaticobiliary cancer after surgery in an academic center were retrospectively analyzed. The criteria for EUS-FNA were a resected margin or remnant pancreas mass, round swollen lymph node (≥10 mm in diameter), and soft-tissue enhancement around a major artery. Patients with suspected liver metastasis or malignant ascites were excluded. Results: Thirty-nine of the 51 patients had pancreatic cancer; the remaining 12 had biliary cancer. The target sites for EUS-FNA were the soft tissue around a major artery (n=22, 43%), the resected margin or remnant pancreas (n=12, 24%), and the lymph nodes (n=17, 33%). The median size of the suspected recurrent lesions was 15 mm (range, 8 to 40 mm). The overall sensitivity, specificity and accuracy of EUS-FNA for the diagnosis of recurrence was 84% (32/38), 100% (13/13), and 88% (45/51), respectively. FNA of the soft tissue around major arteries (odds ratio, 8.23; 95% confidence interval, 1.2 to 166.7; p=0.033) was significantly associated with a falsenegative diagnosis in the multivariate analysis. Conclusions: EUS-FNA is useful for diagnosing recurrent cancer, even after pancreaticobiliary surgery. The diagnoses of recurrence at soft-tissue sites should be interpreted with caution.

An unusual case of primary acinar cell carcinoma of the liver and its treatment.

Acinar cell carcinoma (ACC) is an epithelial neoplasm characterized by morphological features similar to acinar cells found in exocrine glands. Most cases of hepatic ACC reveal evidence of pancreatic exocrine enzyme production and are considered to be metastatic from the pancreas. However, a small number of hepatic ACC cases have been reported in which the tumor is believed to have originated in the liver rather than being a metastatic lesion. In this report we present a case of primary ACC of the liver. A 59-year-old female with no significant past medical history presented with the chief complaint of abdominal pain. A computed tomography (CT) scan of the abdomen showed innumerable mass lesions throughout the liver, initially concerning for metastatic disease. Histopathologic morphology was most consistent with that of ACC, possibly of pancreatic origin. However, the CA 19-9 level was not elevated and no pancreatic lesions were detected on the CT scan. Similar to a previously reported case, the diagnosis of primary ACC of the liver was made based on: acinar cells seen on histology, findings on immunohistochemical staining, radiographic images of liver masses, and the absence of extrahepatic lesions. Previous case reports of primary ACC have differing hypotheses regarding this rare finding. One hypothesis suggests an ectopic origin of acinar cells within the liver. An alternative hypothesis proposes that hepatic and pancreatic cells are ontogenetically derived from a common progenitor cell, which is thought to result in hepatic cells differentiating into acinar cells. The patient was treated with gemcitabine and paclitaxel every 2 weeks for 8 months and then transitioned to every 3 weeks for better tolerance. The patient's symptoms significantly improved within the first 6 weeks of treatment. At the time of the preparation of this report, it has been 17 months since initiation of therapy, and follow-up imaging continues to demonstrate a dramatic decrease in both size and number of hepatic nodules. ACC's are rare tumors that are usually found in glandular tissues. Primary ACC of the liver is extremely rare with only a few cases having been reported. This article adds to the limited literature available on primary hepatic ACC.

Quality of life, coping, and psychological and physical symptoms after surgery for non-metastatic digestive tract cancer.

OBJECTIVE: The aim of this study was to investigate the impact of curative surgery for non-metastatic digestive tract cancers on quality of life (QoL), psychological status, and coping strategies. METHODS: A prospective, transversal, multicenter study was conducted in 404 patients: 361 with colorectal, 44 with gastroesophageal, and 35 with pancreaticobiliary cancer six months after surgery. Participants completed questionnaires evaluating QoL, including functioning (EORTC-QLC-C30), coping strategies (Mini-MAC), and psychological distress (BSI-18). RESULTS: The effects of surgery had a strong impact on functional domains, global QoL, and symptoms, especially in pancreaticobiliary and gastroesophageal cancer. Patients with pancreaticobiliary and gastroesophageal cancer had lower functional scale scores than those with colorectal cancer. Fatigue, appetite loss, diarrhea, depression, and psychological distress were the most common symptoms after surgery. Subjects with pancreaticobiliary cancer reported more fatigue, pain, insomnia, depression, somatization and psychological distress, whereas individuals with gastroesophageal cancer exhibited more fatigue, nausea/vomiting, diarrhea, depression, psychological distress, and helplessness than those with colorectal cancer. Only participants with colorectal cancer displayed improved QoL six months post-surgery, albeit their psychological state had worsened. CONCLUSION: Surgeons should discuss expectations regarding symptoms and QoL with patients prior to surgery to minimize physical and psychological impact.

Surgeon-Led Imaging Review for Patients with Periampullary Disease: An Important Aspect of the Preoperative Consultation.

Background: The perceived benefit of utilizing patients' own imaging studies as a preoperative educational tool has not been studied. Methods: Pancreaticobiliary surgeons reviewed key findings of imaging studies with patients to educate about their diagnosis and inform treatment recommendations. Patient surveys were administered pre- and postvisit by an independent researcher to assess the impact of this practice. Results: Only 55% of patients stated that it was important to see their imaging studies before the consultation. However, after the visit, 90% of patients understood their disease process better, and 86% of patients had a clearer understanding of their planned operation having seen their imaging studies. This represents significant improvement in patients' understanding of their medical condition (p < 0.05). Conclusion: Reviewing imaging findings with patients is an underappreciated aspect of the surgical consultation. It is a powerful educational tool that takes little time, improves patient understanding, and enhances patient experience.

Eligibility Criteria Specific to Pancreaticoduodenectomy for Octogenarians: Single-center Opinion.

BACKGROUND/AIM: Pancreaticoduodenectomy (PD) treatment outcomes in elderly patients have been reported to be acceptable, but the eligibility criteria are not clear. To elucidate the importance of PD in octogenarians in particular, we set five eligibility criteria for elderly patients based on preoperative cardiac and pulmonary function, nutritional status, daily activity status, and psychological independence status for the first time and evaluated prospectively whether the validity of patient selection was adaptable. PATIENTS AND METHODS: The study population consisted of 222 patients with pancreaticobiliary cancer aged over 70 years. The patients were divided into two groups: 192 patients as septuagenarians and 30 as octogenarians. Postoperative morbidity and long-term outcome were compared between the two groups, and prognostic factors relating to survival time were identified. RESULTS: Octogenarians had a significantly higher frequency of two or more comorbidities (p<0.0001). The difference in the mortality rates between the two groups was not significant, being 3.3% and 4.2%, respectively. No difference between the two groups was found in overall survival rate, including deaths due to other diseases, for any type of pancreaticobiliary cancer. Independent prognostic factors relating to survival duration were intraoperative blood loss (p=0.0004) and duration of surgery (p=0.0093). CONCLUSION: These five eligibility criteria for PD in elderly patients are also satisfactorily applicable to octogenarian patients. These criteria may be helpful when uncertainties arise regarding the selection of PD.

Surgical Outcomes of Non-small Cell Lung Cancer in Patients with a History of Pancreaticobiliary Cancer.

AIM: To determine the efficacy of surgery for non-small cell lung cancer in patients who had previously undergone surgery for pancreaticobiliary cancer. PATIENTS AND METHODS: Seven patients who underwent pulmonary resection for primary lung cancer after curative surgery for pancreaticobiliary cancer at our Institution from 2006 to 2016 were retrospectively evaluated. RESULTS: Five patients had metachronous and two patients had synchronous cancer of pancreaticobiliary and lung origin. The median time between surgeries for the two cancers was 35 months. All patients underwent complete resection of both cancers. The 5-year survival was 68.6% after pulmonary resection. Two patients had recurrence after lung surgery, with a mean recurrence-free interval of 6.5 months. CONCLUSION: Surgery should be considered for lung cancer in patients who have undergone curative surgery for pancreaticobiliary cancer.

Malignant mediastinal lymphadenopathy detected by endoscopic ultrasound and guided fine needle aspiration in patients with resectable pancreaticobiliary cancer.

BACKGROUND: Resection surgery for pancreaticobiliary malignancies carries significant morbidity and mortality. Hence, preoperative assessment to exclude unresectable disease is mandatory. CT abdomen is the primary modality for staging of pancreaticobiliary cancers. However, some patients have malignant mediastinal lymphadenopathy (MML), which may be detected on endoscopic ultrasound (EUS) but not on CT scan. METHODS: We prospectively evaluated 75 consecutive patients (median age 54 years: 44 men) with a diagnosis of resectable pancreaticobiliary cancer (carcinoma gallbladder, carcinoma pancreas, cholangiocarcinoma, or periampullary carcinoma) for the presence of MML using EUS by an experienced endosonographer. If a lymph node had one or more features suggestive of malignancy, i.e. size exceeding 1 cm, hypoechoic appearance, a round shape, and regular margins, it was subjected to EUS-FNA. RESULTS: In seven (9.3%; 95% confidence intervals: 3.8% to 18.2%) of the 75 patients, EUS revealed enlarged mediastinal lymph nodes. The location of these lymph nodes was subcarinal in three, paraesophageal in two, and paratracheal in one patient; another patient had lymph nodes at two sites, i.e. the subcarinal and aortopulmonary window. In four of these seven patients, FNA documented the presence of MML. The overall rate of pathologically proven MML was 4/75 (5.3%; 95% CI [1.4% to 13%]). CONCLUSION: EUS-FNA diagnosed MML in 5.3% of patients with pancreaticobiliary cancer. It may be useful to consider EUS assessment in patients with otherwise resectable pancreaticobiliary malignancy.