Revisiting the Malignant Masquerade at the Liver Hilum: Have We Made Progress?

BACKGROUND: Distinguishing malignant from benign causes of obstruction at the liver hilum can pose a diagnostic dilemma. This study aimed to determine factors that predict benign causes of hilar obstruction and long-term outcomes after resection. METHODS: Consecutive patients who underwent surgery for hilar obstruction at a single institution between 1997 and 2022 were retrospectively analyzed. Median follow-up was 26 months (range 0-281 months). RESULTS: Among 182 patients who underwent surgery for hilar obstruction, 25 (14%) patients were found to have benign disease. Median CA19-9 level after normalization of serum bilirubin was 80 U/mL (range 1-5779) and 21 U/mL (range 1-681) among patients with malignant and benign strictures, respectively (p = 0.001). Cross-sectional imaging features associated with malignancy were lobar atrophy, soft tissue mass/infiltration, and vascular involvement (all p < 0.05). Factors not correlated with malignancy were jaundice upon presentation, peak serum bilirubin, sex, and race. Preoperative bile duct brushing or biopsy had sensitivity and specificity rates of 82% and 55%, respectively. Among patients who underwent resection with curative intent, grade 3-4 complications occurred in 55% and 29% of patients with malignant and benign strictures, respectively (p = 0.028). Postoperative long-term complications of chronic portal hypertension and recurrent cholangitis occurred in ≥ 10% of patients with both benign and malignant disease (p = non-significant). CONCLUSIONS: Strictures at the liver hilum continue to present diagnostic and management challenges. Postoperative complications and long-term sequelae of portal hypertension and recurrent cholangitis develop in a significant number of patients after resection of both benign and malignant strictures.

Biliary Drainage in Hilar and Perihilar Cholangiocarcinoma; 25-Year Experience at a Tertiary Cancer Center.

INTRODUCTION: This study analyzes the optimal biliary stenting strategy for palliation in cholangiocarcinoma (CCA). METHODS: This is a retrospective study of patients with CCA who underwent biliary drainage from 1997-2023. A per-patient analysis of percutaneous biliary drainage (PTBD) rates, the median number of ERCPs, overall survival (OS), and a per-procedure analysis of clinical success (CS), stent-specific Adverse Events (AEs), and mean time to reintervention by stent type and laterality (unilateral(u) & bilateral(b)) is presented. RESULTS: A total of 333 patients underwent 1,050 ERCPs; 85% with plastic stents (PS). PTBD was eventually done in 23% of PS patients, 35% of whom had PS removed prior to PTBD. ERCPs with SEMS/uniSEMS use had higher CS (89%/91%) vs PS/uPS (85% both) and PS within SEMS (PS-SEMS)/uPS-SEMS (71%/74%;p=0.013/p=0.054). Compared to PS, SEMS and PS-SEMS were associated with higher stent-specific AEs (OR SEMS 4.85; 3.23-7.27; PS-SEMS 9.99; 5.33-18.71;p<0.001). Straight PS were associated with more stent-specific AEs compared to double-pigtail stents (OR 6.74; 3.95-11.45;p<0.001). More 7 Fr stents were used in cases with balloon dilation (BD, 109 vs. 88 with no BD; p<0.001). BD had 79% CS rate vs 87% without BD (p<0.001). Cases with pus on ERCP and those with BD had a shorter mean time to reintervention. On regression analyses, higher Bismuth class, PS use, and PS-SEMS use were associated with a shorter mean time to repeat ERCP. 52% of patients in the bSEMS arm died from cholangitis (p=0.005). CONCLUSION: The relatively higher clinical success of SEMS is countered by the higher stent-specific complication rate. PS can be removed and may better facilitate PTBD. Within PS types, DPTs may have fewer stent-specific AEs. Cases requiring balloon dilation and with endoscopic evidence of pus may benefit from earlier reintervention.

Contemporary advances in the endoscopic management of cholangiocarcinoma: a review of accomplished milestones and prospective opportunities.

INTRODUCTION: Cholangiocarcinoma, a primary malignancy of epithelial cells of the bile ducts, has been shown to have increasing incidence rates globally. Many of the current advances aim to improve the accuracy of differentiation between benign biliary strictures and cholangiocarcinoma, which include endoscopic techniques, devices, image processing, and the use of genomic sequencing in acquired specimens. AREAS COVERED: In this review, the authors explore the historical timeline of changes leading to modern management of cholangiocarcinoma, with special emphasis on endoscopic modalities and novel therapeutic interventions. The authors also expand on the strengths and shortcomings of endoscopic diagnostics and techniques in biliary drainage and finally discuss potential areas to focus for future research and development. EXPERT OPINION: Despite the advances in diagnosis and management of cholangiocarcinoma, there remain multiple tasks that are still awaiting to be completed. Next-generation sequencing in the diagnosis of cholangiocarcinoma needs to be further tested, validated, and easily obtainable. Other innovative diagnostic modalities, such as the use of artificial intelligence in cholangioscopy, may provide an effective complementary modality to existing techniques. A consensus on biliary drainage needs to be defined and account for longevity and patient convenience.

A decade's experience of managing suspected pancreatic adenocarcinoma at a tertiary cancer center.

Background: We present our experience and established management strategy for endoscopic ultrasonography-guided fine-needle aspiration (EUS-FNA) in diagnosing suspected pancreatic neoplasms at a tertiary referral cancer hospital. Method: Relevant data were extracted from our database for patients who underwent EUS-FNA for suspected pancreatic neoplasms at our institution between 2007 and 2016. Results: Among the 309 patients, the median age was 67 years and 56% were men. The most common presenting symptoms were abdominal pain (37%) and jaundice (29%). Concordance between radiographic diagnosis and final pathology was 89%. The mean lesion size was 34.9 mm on computed tomography and 31.5 mm on EUS. There were 197 patients (64%) with localized disease, of whom 115 (58%) had resectable lesions, 61 (31%) had borderline resectable, and 21 (11%) had unresectable lesions (mean CA 19-9 levels 1705 U/mL, 2490 U/mL, and 479 U/mL, respectively). A median of 3 FNA passes were performed to establish a pathologic diagnosis. Two patients (1%) had postprocedural adverse events. Median overall survival was 47 months in those who underwent surgery after EUS and 12 months in those who did not (P<0.001). Conclusions: A multidisciplinary approach is employed for management of suspected pancreatic neoplasm at our tertiary cancer center. A combination of cross-sectional imaging and EUS-FNA serves as a highly effective duo in establishing a tissue diagnosis and staging with a low adverse event rate. Counterintuitively, CA 19-9 is not necessarily higher with resectable lesions than with unresectable lesions, indicating the limitation of CA 19-9 as a pancreatic tumor marker.

Localized Gastroesophageal Adenocarcinoma in the Elderly: Is Age a Factor Associated with Suboptimal Treatment?

INTRODUCTION: Gastroesophageal adenocarcinoma is relatively common in elderly patients as the incidence increases with age. However, the optimal treatment approach is not well established in this group of patients. The aim of this study is to review our experience for localized gastroesophageal adenocarcinoma in patients aged ≥80 years and to assess association between patient characteristics, clinical factors, and overall survival (OS) in order to optimize the therapeutic approaches for this population. METHODS: Patients ≥80 years old treated for localized gastroesophageal adenocarcinoma were retrospectively analyzed. Survival curves were estimated using the Kaplan-Meier method. Univariate and multivariate Cox proportional hazards regression models were applied to assess the association between patient characteristics and OS. Factors that were significant in the multivariate model were included in the final reduced model. RESULTS: 127 patients ≥80 years old, were included in this study with median age of 83 years. The median follow-up time was 3.2 years, and median OS was 2.5 years (95% CI: 2.0-3.1 years). Independent prognostic factors for OS were Eastern Cooperative Oncology Group (ECOG) performance status (PS) (p = 0.003), baseline clinical stage (p = 0.01), and surgery (p = 0.001). ECOG PS, tumor location, baseline stage, tumor grade, and surgery were included in the final reduced model. CONCLUSION: Surgical treatment can improve survival in elderly patients. Therapeutic decisions should be based on the patients' general condition rather that age alone.

3D imaging analysis on an organoid-based platform guides personalized treatment in pancreatic ductal adenocarcinoma.

BACKGROUNDPancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, with unpredictable responses to chemotherapy. Approaches to assay patient tumors before treatment and identify effective treatment regimens based on tumor sensitivities are lacking. We developed an organoid-based platform (OBP) to visually quantify patient-derived organoid (PDO) responses to drug treatments and associated tumor-stroma modulation for personalized PDAC therapy.METHODSWe retrospectively quantified apoptotic responses and tumor-stroma cell proportions in PDOs via 3D immunofluorescence imaging through annexin A5, α-smooth muscle actin (α-SMA), and cytokeratin 19 (CK-19) levels. Simultaneously, an ex vivo organoid drug sensitivity assay (ODSA) was used to measure responses to standard-of-care regimens. Differences between ODSA results and patient tumor responses were assessed by exact McNemar's test.RESULTSImmunofluorescence signals, organoid growth curves, and Ki-67 levels were measured and authenticated through the OBP for up to 14 days. ODSA drug responses were not different from patient tumor responses, as reflected by CA19-9 reductions following neoadjuvant chemotherapy (P = 0.99). PDOs demonstrated unique apoptotic and tumor-stroma modulation profiles (P < 0.0001). α-SMA/CK-19 ratio levels of more than 1.0 were associated with improved outcomes (P = 0.0179) and longer parental patient survival by Kaplan-Meier analysis (P = 0.0046).CONCLUSIONHeterogenous apoptotic drug responses and tumor-stroma modulation are present in PDOs after standard-of-care chemotherapy. Ratios of α-SMA and CK-19 levels in PDOs are associated with patient survival, and the OBP could aid in the selection of personalized therapies to improve the efficacy of systemic therapy in patients with PDAC.FUNDINGNIH/National Cancer Institute grants (K08CA218690, P01 CA117969, R50 CA243707-01A1, U54CA224065), the Skip Viragh Foundation, the Bettie Willerson Driver Cancer Research Fund, and a Cancer Center Support Grant for the Flow Cytometry and Cellular Imaging Core Facility (P30CA16672).

The conundrum in endoscopic management of duodenal polyps: a tertiary cancer center experience.

BACKGROUND: Endoscopic mucosal resection of duodenal polyps (EMR) is a challenging intervention. The aim of this study was to review the patient characteristics, techniques, procedure outcomes, adverse events, and recurrence of duodenal polyps. RESEARCH DESIGN AND METHODS: Patients were included if they had pathologically confirmed non-ampullary duodenal polyps and had received EMR with at least one follow-up EGD for surveillance. Descriptive statistics were employed to report the findings. RESULTS: A total of 65 patients underwent a total of 90 EMRs for duodenal polyps. The mean age was 65.4 years, and 29 of the patients were female. Complete resection of the visible mass was achieved in 96.9% of cases. Endoscopic hemostasis was required in 18.5% of patients. Delayed bleeding occurred in 9%, and delayed perforations requiring surgical intervention occurred in 2.2% of patients with no mortality. Surgery after EMR was needed in 12.7% of cases. Eleven (16.9%) patients had recurrent duodenal adenoma on follow-up EGD. CONCLUSION: Duodenal polyps can be safely resected and have a notable recurrence rate. This is particularly true for adenomas, warranting post-resection endoscopic surveillance. The appropriate interval for post-resection surveillance of duodenal adenomas should be a focus of future study.

Artificial intelligence implementation in pancreaticobiliary endoscopy.

INTRODUCTION: Artificial intelligence has been rapidly deployed in gastroenterology and endoscopy. The acceleration of deep convolutional neural networks along with hardware development has allowed implementation of artificial intelligence algorithms into real-time endoscopy, particularly colonoscopy. However, artificial intelligence implementation in pancreaticobiliary endoscopy is nascent. AREAS COVERED: Initial studies have been conducted in endoscopic retrograde pancreatography (ERCP), endoscopic ultrasound (EUS), and digital single operator cholangioscopy (DSOC). Machine learning has been implemented in identifying significant landmarks, including the ampulla on ERCP, and the bile duct, pancreas, and portal confluence on EUS. Moreover, artificial intelligence algorithms have been deployed in differentiating pathology including pancreas cancer, autoimmune pancreatitis, pancreatic cystic lesions, and biliary strictures. EXPERT OPINION: There have been relatively few studies with limited sample sizes in developing these machine learning algorithms. Despite the early successful demonstration of artificial intelligence in pancreaticobiliary endoscopy, additional research needs to be conducted with larger data sets to improve generalizability and assessed in real-time endoscopy before clinical implementation. However, pancreaticobiliary endoscopy remains a promising avenue of artificial intelligence application with the potential to improve clinical practice and outcomes.

Preoperative biliary drainage for pancreatic cancer.

Pancreatic adenocarcinoma is currently one of the leading causes of cancer-related morbidity and mortality with dismal long term survival after diagnosis. Nearly 85% of pancreatic cancer patients present with advanced disease precluding curative surgical resection. In those who are candidates for surgery, preoperative biliary drainage (PBD) has been developed since the 1960s in order to improve surgical outcomes. While obstructive jaundice in resectable pancreatic cancer has been traditionally treated before surgical resection in all patients, data over the past decade demonstrated increased perioperative complications and morbidity with systematic PBD compared to direct surgery. With new evidence of potential adverse events, the role of routine PBD is being reassessed. Current indications for PBD include cholangitis, delayed surgery, and relief of jaundice in patients planned to receive neoadjuvant therapy (NAT). NAT is being increasingly utilized in borderline resectable as well as resectable pancreatic cancer and a higher proportion of patients with likely require PBD in the future. The evidence for endoscopic retrograde cholangiopancreatography as first line for PBD is robust with supporting data from endoscopic ultrasound assisted biliary drainage. Self-expanding metal stent was shown to be cost-effective in recent studies without increase in morbidity compared to plastic stents in this setting. In this review, we will summarize the current evidence for PBD in patients with pancreatic cancer.

Endoscopic Ultrasound for the Diagnosis and Staging of Biliary Malignancy.

Cholangiocarcinoma (CCA) is the most common neoplasm of the biliary tract. The biological behavior and prognosis of CCA vary depending on the tumor's location in the biliary tree, dictating a different diagnostic, and treatment approach. Establishing a diagnosis of CCA remains a challenge and up to 20% of biliary strictures can yield indeterminate results, despite extensive evaluation. Endoscopic ultrasound (EUS) has become an effective diagnostic tool, as it provides high-quality images of the bile duct and allows for the sampling of strictures in the same plane of view. In this chapter, we explore the utility of EUS as a diagnostic and staging tool for biliary cancers.

Adequacy evaluation and use of pancreatic adenocarcinoma specimens for next-generation sequencing acquired by endoscopic ultrasound-guided FNA and FNB.

BACKGROUND: Endoscopic ultrasound-guided tissue acquisition (EUS-TA), especially endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA), is the mainstay of tissue acquisition for the diagnosis of pancreatic ductal adenocarcinoma (PDAC). Recently, endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) using flexible biopsy needles has been used for patients with PDAC in an effort to increase diagnostic yields and biomarker testing. However, the role of EUS-TA in biomarker testing for personalized therapy or precise chemotherapy for PDAC is not well established. METHODS: PDAC cases with specimens acquired through concurrent EUS-FNA and EUS-FNB were identified retrospectively. Smears were prepared from EUS-FNA sampling, and cell blocks (CBs) were prepared from EUS-FNB sampling. Rapid onsite evaluation was conducted for all cases for diagnostic adequacy. The adequacy for biomarker testing, including next-generation sequencing (NGS) and immunohistochemistry (IHC) assays, was evaluated, and cases with smears and CBs adequate for NGS were processed for targeted NGS. RESULTS: There were 26 PDAC cases concurrently sampled by EUS-FNA and EUS-FNB. EUS-FNA smears for all 26 cases and EUS-FNB CBs for 20 cases (77%) were diagnostic for PDAC. Twenty-one smears (81%) and 11 CBs (42%) were adequate for NGS. Nine cases with both smears and CBs adequate for NGS underwent NGS, which identified clinically significant gene mutation variants, including KRAS, TP53, and SMAD4 mutations. CONCLUSIONS: Both EUS-FNA and EUS-FNB can provide optimal material for targeted NGS for PDACs. In PDAC cases subjected to concurrent EUS-FNA and EUS-FNB, EUS-FNA specimens had greater diagnostic yields and more adequate material for NGS than EUS-FNB specimens, whereas EUS-FNB was more suitable for IHC-based biomarker testing.

How much progress have we made?: a 20-year experience regarding esophageal stents for the palliation of malignant dysphagia.

Esophageal stents are widely used for the palliation of malignant esophageal obstruction. Advances in technology have made esophageal stenting technically feasible and widespread for such obstruction, but complications remain frequent. We present outcomes of a large cohort undergoing esophageal stent placement for malignant esophageal obstruction at a tertiary care cancer center. Patients who underwent placement of esophageal stents for malignancy-related esophageal obstruction between 1 January 2001 and 31 July 2020 were identified. Exclusion criteria included stents placed for benign stricture, fistulae, obstruction of proximal esophagus (proximal to 24 cm from incisors), or post-surgical indications. Patient charts were reviewed for demographics, procedure and stent characteristics, complications, and follow-up. A total of 242 patients underwent stent placement (median age: 64 years, 79.8% male). The majority, 204 (84.3%), had esophageal cancer. During the last two decades, there has been an increasing trend in the number of esophageal stents placed. Though plastic stents were previously used, these are no longer utilized. Complications are frequent and include early complications of pain in 68 (28.1%) and migration in 21 (8.7%) and delayed complications of recurrent symptoms of dysphagia in 46 (19.0%) and migration in 26 (10.7%). Over the study period, there has not been a significant improvement in the rate of complications. During follow-up, 92 (38%) patients required other enteral nutrition modalities after esophageal stent placement. No patient, treatment, or stent characteristics were significantly associated with stent complication or outcome. Esophageal stent placement is an increasingly popular method for palliation of malignant dysphagia. However, complications, particularly pain, migration, and recurrent symptoms of dysphagia are common. Almost 40% of patients may also require other methods of enteral access after esophageal stent placement. Given the high complication rates and suboptimal outcomes, removable stents should be considered as first-line in the case of poor palliative response.

Pancreatic paraganglioma diagnosed by endoscopic ultrasound-guided fine needle aspiration: A case report and review of literature.

BACKGROUND: Pancreatic paragangliomas (PPGL) are rare benign neuroendocrine neoplasms but malignancy can occur. PPGL are often misdiagnosed as pancreatic neuroendocrine tumor or pancreatic adenocarcinoma. CASE SUMMARY: We reviewed 47 case reports of PPGL published in PubMed to date. Fifteen patients (15/47) with PPGL underwent endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). Only six (6/15) were correctly diagnosed as PPGL. All patients with PPGL underwent surgical resection except three (one patient surgery was aborted because of hypertensive crisis, two patients had metastasis or involvement of major vessels). Our patient remained on close surveillance as she was asymptomatic. CONCLUSION: Accurate preoperative diagnosis of PPGL can be safely achieved by EUS-FNA with immunohistochemistry. Multidisciplinary team approach should be considered to bring the optimal results in the management of PPGL.

AGA Clinical Practice Update on Endoscopic Management of Perforations in Gastrointestinal Tract: Expert Review.

BEST PRACTICE ADVICE 1: For all procedures, especially procedures carrying an increased risk for perforation, a thorough discussion between the endoscopist and the patient (preferably together with the patient's family) should include details of the procedural techniques and risks involved. BEST PRACTICE ADVICE 2: The area of perforation should be kept clean to prevent any spillage of gastrointestinal contents into the perforation by aspirating liquids and, if necessary, changing the patient position to bring the perforation into a non-dependent location while minimizing insufflation of carbon dioxide to avoid compartment syndrome. BEST PRACTICE ADVICE 3: Use of carbon dioxide for insufflation is encouraged for all endoscopic procedures, especially any endoscopic procedure with increased risk of perforation. If available, carbon dioxide should be used for all endoscopic procedures. BEST PRACTICE ADVICE 4: All endoscopists should be aware of the procedures that carry an increased risk for perforation such as any dilation, foreign body removal, any per oral endoscopic myotomy (Zenker's, esophageal, pyloric), stricture incision, thermal coagulation for hemostasis or tumor ablation, percutaneous endoscopic gastrostomy, ampullectomy, endoscopic mucosal resection (EMR), endoscopic submucosal dissection (ESD), endoluminal stenting with self-expanding metal stent (SEMS), full-thickness endoscopic resection, endoscopic retrograde cholangiopancreatography (ERCP) in surgically altered anatomy, endoscopic ultrasound (EUS)-guided biliary and pancreatic access, EUS-guided cystogastrostomy, and endoscopic gastroenterostomy using a lumen apposing metal stent (LAMS). BEST PRACTICE ADVICE 5: Urgent surgical consultation should be highly considered in all cases with perforation even when endoscopic repair is technically successful. BEST PRACTICE ADVICE 6: For all upper gastrointestinal perforations, the patient should be considered to be admitted for observation, receive intravenous fluids, be kept nothing by mouth, receive broad-spectrum antibiotics (to cover Gram-negative and anaerobic organisms), nasogastric tube (NGT) placement (albeit some exceptions), and surgical consultation. BEST PRACTICE ADVICE 7: For upper gastrointestinal tract perforations, a water-soluble upper gastrointestinal series should be considered to confirm the absence of continuing leak at the perforation site before initiating a clear liquid diet. BEST PRACTICE ADVICE 8: Endoscopic closure of esophageal perforations should be pursued when feasible, utilizing through-the-scope clips (TTSCs) or over-the-scope clips (OTSCs) for perforations <2 cm and endoscopic suturing for perforations >2 cm, reserving esophageal stenting with SEMS for cases where primary closure is not possible. BEST PRACTICE ADVICE 9: Endoscopic closure of gastric perforations should be pursued when feasible, utilizing TTSCs or OTSCs for perforations <2 cm and endoscopic suturing or combination of TTSCs and endoloop for perforations >2 cm. BEST PRACTICE ADVICE 10: For large type 1 duodenal perforations (lateral duodenal wall tear >3 cm), being cognizant of the difficulty in closing them endoscopically, urgent surgical consultation should be made while the feasibility of endoscopic closure is assessed. BEST PRACTICE ADVICE 11: Because type 2 periampullary (retroperitoneal) perforations are subtle and can be easily missed, the endoscopist should carefully assess the gas pattern on fluoroscopy to avoid delays in treatment and request a computed tomography scan if there is a concern for such a perforation; identified perforations of this type at the time of ERCP may be closed with TTSCs if feasible and/or by placing a fully covered SEMS into the bile duct across the ampulla. BEST PRACTICE ADVICE 12: For the management of large duodenal polyps, endoscopic mucosal resection (EMR) should only be performed by experienced endoscopists and endoscopic submucosal dissection (ESD) only by experts because both EMR and ESD in the duodenum require proficiency in resection and mucosal defect closure techniques to manage immediate and/or delayed perforations (caused by the proteolytic enzymes of the pancreas). BEST PRACTICE ADVICE 13: Endoscopists should be aware that colon perforations occurring during diagnostic colonoscopy are most commonly located in the sigmoid colon due to direct trauma from forceful advancement of the colonoscope. Such tears recognized at the time of colonoscopy may be closed by TTSCs or OTSCs if the bowel preparation is good and the patient is stable. BEST PRACTICE ADVICE 14: Although colon perforation is responsive to various endoscopic tools such as TTSC, OTSC, and endoscopic suturing, perforations in the right colon, especially in the cecum, have been relegated to using only TTSCs because of inability to reach the site of the perforation with an endoscopic suturing device or OTSC if the colon is tortuous or unclean. Recently a new suture-based device for defect closure has been introduced allowing deep submucosal and intramuscular enhanced fixation through a standard gastroscope or colonoscope. BEST PRACTICE ADVICE 15: Patients with perforations who are hemodynamically unstable or who have suffered a delayed perforation with peritoneal signs or frank peritonitis should be surgically managed without any attempt at endoscopic closure. BEST PRACTICE ADVICE 16: In any adverse event including perforation, it is paramount to ensure accurate documentation, prompt discussion with the patient and family, and swift reporting to the quality officer (or equivalent) and risk management team of the institution (in major adverse events).

AGA Clinical Practice Update on the Optimal Management of the Malignant Alimentary Tract Obstruction: Expert Review.

BACKGROUND & AIMS: The purpose of this expert review is to describe the current methodologies available to manage malignant alimentary tract obstructions as well the evidence behind the various methods (including their efficacy and safety), indications, and appropriate timing of interventions. METHODS: This is not a formal systematic review but is based on a review of the literature to provide best practice advice statements. No formal rating of the quality of evidence or strength of recommendation is carried out. BEST PRACTICE ADVICE 1: For all patients with alimentary tract obstruction, the decision about specific interventions should be made in a multidisciplinary setting including oncologists, surgeons, and endoscopists and take into account the characteristics of the obstruction, patient's expectations, prognosis, expected subsequent therapies, and functional status. BEST PRACTICE ADVICE 2: For patients who present with esophageal obstruction from esophageal cancer and who are potential candidates for resection or chemoradiation, clinicians should not routinely insert a self-expanding metal stent (SEMS) without multidisciplinary review because of high rates of stent migration, higher morbidity and mortality, and potentially lower R0 (microscopically negative margins) resection rates. BEST PRACTICE ADVICE 3: For patients who present with esophageal obstruction from esophageal cancer who are potential candidates for resection and who have concerns of malnutrition, clinicians may consider the use of enteral feeding tubes (via nasogastric or percutaneous route). Clinicians should be aware of the potential risk of abdominal wall tumor seeding as well as making subsequent gastric conduit formation difficult with percutaneous endoscopic gastrostomy placement. BEST PRACTICE ADVICE 4: For patients who present with esophageal obstruction from esophageal cancer who are not candidates for resection, clinicians should consider either SEMS insertion or brachytherapy as sole therapy or in combination. Clinicians should not consider the use of laser therapy or photodynamic therapy because of the lack of evidence of better outcomes and superior alternatives. BEST PRACTICE ADVICE 5: For patients with malignant esophageal obstruction who are undergoing SEMS placement, clinicians should use a fully covered or partially covered SEMS and not an uncovered SEMS, with consideration of a stent-anchoring/fixation method. BEST PRACTICE ADVICE 6: For patients with gastric outlet obstruction who have a life expectancy greater than 2 months, have good functional status, and who are surgically fit, surgical gastrojejunostomy should be considered. BEST PRACTICE ADVICE 7: For patients with gastric outlet obstruction who are undergoing surgical gastrojejunostomy, a laparoscopic approach is favored over an open approach because of lower blood loss and shorter hospital stay. BEST PRACTICE ADVICE 8: For patients with gastric outlet obstruction who are not candidates for gastrojejunostomy (surgical or endoscopic ultrasound-guided), clinicians should consider the insertion of an enteral stent. BEST PRACTICE ADVICE 9: Enteral stents should not be used in patients with multiple luminal obstructions or severely impaired gastric motility because of the limited benefit in these scenarios. Clinicians can consider placement of a venting gastrostomy in these patients. BEST PRACTICE ADVICE 10: Depending on the experience of the endoscopist, endoscopic ultrasound-guided gastrojejunostomy is an acceptable alternative to surgical gastrojejunostomy and enteral stent placement. Clinicians should be aware that there are currently no dedicated Food and Drug Administration-approved devices for endoscopic ultrasound-guided gastrojejunostomy. BEST PRACTICE ADVICE 11: For patients with malignant colonic obstruction who are candidates for resection, insertion of SEMS is a reasonable choice as a "bridge to surgery" to allow for one-stage, elective resection. BEST PRACTICE ADVICE 12: For patients with malignant colonic obstruction who are not candidates for resection, either SEMS placement or a diverting colostomy are reasonable choices depending on the patient's goals and functional status. BEST PRACTICE ADVICE 13: SEMS is a reasonable option for patients with proximal (or right-sided) malignant obstructions, both as a "bridge to surgery" and in the palliative setting. BEST PRACTICE ADVICE 14: SEMS placement is a reasonable alternative for patients with extracolonic malignancy who are not candidates for surgery, although their placement is more technically challenging, clinical success rates are more variable, and complications (including stent migration) are more frequent.

Targeting cancer stem cells with a pan-BCL-2 inhibitor in preclinical and clinical settings in patients with gastroesophageal carcinoma.

OBJECTIVE: Gastro-oesophageal cancers (GEC) are resistant to therapy and lead to poor prognosis. The cancer stem cells (CSCs) and antiapoptotic pathways often confer therapy resistance. We sought to elucidate the antitumour action of a BCL-2 inhibitor, AT101 in GEC in vitro, in vivo and in a clinical trial. METHODS: Extensive preclinical studies in vitro and in vivo were carried out to establish the mechanism action of AT101 on targeting CSCs and antiapoptotic proteins. A pilot clinical trial in patients with GEC was completed with AT-101 added to standard chemoradiation. RESULTS: Overexpression of BCL-2 and MCL-1 was noted in gastric cancer tissues (GC). AT-101 induced apoptosis, reduced proliferation and tumour sphere formation in MCL-1/BCL-2 high GC cells. Interestingly, AT101 dramatically downregulated genes (YAP-1/Sox9) that control CSCs in GEC cell lines regardless of BCL-2/MCL-1 expression. Addition of docetaxel to AT-101 amplified its antiproliferation and induced apoptosis effects. In vivo studies confirmed the combination of AT101 and docetaxel demonstrated stronger antitumour activity accompanied with significant decrease of CSCs biomarkers (YAP1/SOX9). In a pilot clinical trial, 13 patients with oesophageal cancer (EC) received AT101 orally concurrently with chemoradiation. We observed dramatic clinical complete responses and encouraging overall survival in these patients. Clinical specimen analyses revealed that AT-101 dramatically reduced the expression of CSCs genes in treated EC specimens indicating antitumour activity of AT101 relies more on its anti-CSCs activity. CONCLUSIONS: Our preclinical and clinical data suggest that AT-101 overcomes resistance by targeting CSCs pathways suggesting a novel mechanism of action of AT101 in patients with GEC.

Frequency and Implications of Paratracheal Lymph Node Metastases in Resectable Esophageal or Gastroesophageal Junction Adenocarcinoma.

OBJECTIVE: We aimed to evaluate the frequency of paratracheal lymph nodes (LN) metastases and their prognostic influence. SUMMARY BACKGROUND DATA: Paratracheal LNs are considered regional nodes in the esophageal cancer classification, but their metastatic rate and influence on survival remain unclear. METHODS: One thousand one hundred ninety-nine patients with resectable esophageal or gastroesophageal junction adenocarcinoma (EAC) (January 2002 and December 2016) in our Gastrointestinal Medical Oncology Database were analyzed. Paratracheal LNs were defined as1R, 1L, 2R, 2L, 4R, and 4L, according to the 8th American Joint Committee on Cancer classification. RESULTS: Of 1199 patients, 73 (6.1%) had positive paratracheal LNs at diagnosis. The median overall survival (OS) of 73 patients with initial paratracheal LN involvement was 2.10 years (range 0.01-10.1, 5-yrs OS 24.2%). Of 1071 patients who were eligible for recurrence evaluation, 70 patients (6.5%) developed paratracheal LN metastases as the first recurrence. The median time to recurrence was 1.28 years (range 0.28-5.96 yrs) and the median OS following recurrence was only 0.95 year (range 0.03-7.88). OS in 35 patients who had only paratracheal LN recurrence was significantly longer than in patients who had other recurrences (median OS 2.26 vs 0.51 yrs, 5-yrs OS; 26.8% vs 0%, P < 0.0001). Higher T stage (T3/T4) was an independently risk factor for paratracheal LN recurrence (odds ratio 5.10, 95% confidence interval 1.46-17.89). We segregated patients in 3 groups based on the distance of tumor's proximal edge to esophagogastric junction (low; ≤2 cm, medium; 2.0-7.0 cm, and high; >7.0 cm). Paratracheal LN metastases were more frequent with the proximal tumors (low, 4.2%; medium, 12.0%; high, 30.3%; Cochran-Armitage Trend test, P < 0.001). CONCLUSION: Paratracheal LN metastases were associated with a shorter survival in resectable EAC patients. Alternate approaches to prolong survival of this group of patients are warranted.

Efficacy of uncovered colonic stents for extrinsic versus intrinsic malignant large bowel obstruction.

BACKGROUND: Previous studies evaluating self-expandable metal stents (SEMS) for management of malignant extrinsic colon obstruction have yielded conflicting results. We evaluated the efficacy of uncovered SEMS for extrinsic colon malignancy (ECM) versus intrinsic colon malignancy (ICM). METHODS: Retrospective review of all patients referred for colonic SEMS at a tertiary cancer center between 2007 and 2018 was performed. Primary outcome measures were technical success, clinical success, intervention rate, and overall survival. RESULTS: 138 patients with ECM and 119 patients with ICM underwent attempted stent placement. The rectum and/or sigmoid colon was the most common stricture site. Technical success was lower in the ECM group [86% vs 96% (p = .009)]. Clinical success was lower in the ECM group both at 7 days [82% vs 95% (p = .004)] and at 90 days [60% vs 86% (p < .001)]. Subsequent intervention was required more frequently [44% vs 35%; p = .23] and earlier [median 9 vs 132 days; p < .001] in the ECM group. Median overall survival in the ECM group was 92 vs 167 days. Among predictive variables analyzed, the ECM group had a higher frequency of peritoneal metastasis (87% vs 32%; p < .001), multifocal strictures with requirement for multiple stents (20% vs 6%; p = .002), sharp angulated strictures (39% vs 25%; p = .04) , and radiation therapy (21% vs 10%; p = .02). CONCLUSIONS: Colonic SEMS for ECM is associated with lower technical and clinical success with earlier intervention rates compared with ICM. Our findings can be used to better inform patients and referring providers as well as guide new stent design to enhance efficacy in this population.

Integrated genomic profiling and modelling for risk stratification in patients with advanced oesophagogastric adenocarcinoma.

OBJECTIVE: Prognosis of patients with advanced oesophagogastric adenocarcinoma (mEGAC) is poor and molecular determinants of shorter or longer overall survivors are lacking. Our objective was to identify molecular features and develop a prognostic model by profiling the genomic features of patients with mEGAC with widely varying outcomes. DESIGN: We profiled 40 untreated mEGACs (20 shorter survivors <13 months and 20 longer survivors >36 months) with whole-exome sequencing (WES) and RNA sequencing and performed an integrated analysis of exome, transcriptome, immune profile and pathological phenotypes to identify the molecular determinants, developing an integrated model for prognosis and comparison with The Cancer Genome Atlas (TCGA) cohorts. RESULTS: KMT2C alterations were exclusively observed in shorter survivors together with high level of intratumour heterogeneity and complex clonal architectures, whereas the APOBEC mutational signatures were significantly enriched in longer survivors. Notably, the loss of heterozygosity in chromosome 4 (Chr4) was associated with shorter survival and 'cold' immune phenotype characterised by decreased B, CD8, natural killer cells and interferon-gamma responses. Unsupervised transcriptomic clustering revealed a shorter survivor subtype with distinct expression features (eg, upregulated druggable targets JAK2, MAP3K13 and MECOM). An integrated model was then built based on clinical variables and the identified molecular determinants, which significantly segregated shorter and longer survivors. All the above features and the integrated model have been validated independently in multiple TCGA cohorts. CONCLUSION: This study discovered novel molecular features prognosticating overall survival in patients with mEGAC and identified potential novel targets in shorter survivors.