Stereotactic body radiotherapy with or without selective dismutase mimetic in pancreatic adenocarcinoma: an adaptive, randomised, double-blind, placebo-controlled, phase 1b/2 trial.

BACKGROUND: Stereotactic body radiotherapy (SBRT) has the potential to ablate localised pancreatic ductal adenocarcinoma. Selective dismutase mimetics sensitise tumours while reducing normal tissue toxicity. This trial was designed to establish the efficacy and toxicity afforded by the selective dismutase mimetic avasopasem manganese when combined with ablative SBRT for localised pancreatic ductal adenocarcinoma. METHODS: In this adaptive, randomised, double-blind, placebo-controlled, phase 1b/2 trial, patients aged 18 years or older with borderline resectable or locally advanced pancreatic cancer who had received at least 3 months of chemotherapy and had an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled at six academic sites in the USA. Eligible patients were randomly assigned (1:1), with block randomisation (block sizes of 6-12) with a maximum of 24 patients per group, to receive daily avasopasem (90 mg) or placebo intravenously directly before (ie, within 180 min) SBRT (50, 55, or 60 Gy in five fractions, adaptively assigned in real time by Bayesian estimates of 90-day safety and efficacy). Patients and physicians were masked to treatment group allocation, but not to SBRT dose. The primary objective was to find the optimal dose of SBRT with avasopasem or placebo as determined by the late onset EffTox method. All analyses were done on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, NCT03340974, and is complete. FINDINGS: Between Jan 25, 2018, and April 29, 2020, 47 patients were screened, of whom 42 were enrolled (median age was 71 years [IQR 63-75], 23 [55%] were male, 19 [45%] were female, 37 [88%] were White, three [7%] were Black, and one [2%] each were unknown or other races) and randomly assigned to avasopasem (n=24) or placebo (n=18); the placebo group was terminated early after failing to meet prespecified efficacy parameters. At data cutoff (June 28, 2021), the avasopasem group satisfied boundaries for both efficacy and toxicity. Late onset EffTox efficacy response was observed in 16 (89%) of 18 patients at 50 Gy and six (100%) of six patients at 55 Gy in the avasopasem group, and was observed in three (50%) of six patients at 50 Gy and nine (75%) of 12 patients at 55 Gy in the placebo group, and the Bayesian model recommended 50 Gy or 55 Gy in five fractions with avasopasem for further study. Serious adverse events of any cause were reported in three (17%) of 18 patients in the placebo group and six (25%) of 24 in the avasopasem group. In the placebo group, grade 3 adverse events within 90 days of SBRT were abdominal pain, acute cholangitis, pyrexia, increased blood lactic acid, and increased lipase (one [6%] each); no grade 4 events occurred. In the avasopasem group, grade 3-4 adverse events within 90 days of SBRT were acute kidney injury, increased blood alkaline phosphatase, haematoma, colitis, gastric obstruction, lung infection, abdominal abscess, post-surgical atrial fibrillation, and pneumonia leading to respiratory failure (one [4%] each).There were no treatment-related deaths but one late death in the avasopasem group due to sepsis in the setting of duodenal obstruction after off-study treatment was reported as potentially related to SBRT. INTERPRETATION: SBRT that uses 50 or 55 Gy in five fractions can be considered for patients with localised pancreatic ductal adenocarcinoma. The addition of avasopasem might further enhance disease outcomes. A larger phase 2 trial (GRECO-2, NCT04698915) is underway to validate these results. FUNDING: Galera Therapeutics.

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.

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.

Devices and techniques for flexible endoscopic management of Zenker's diverticulum (with videos).

BACKGROUND AND AIMS: Zenker's diverticulum (ZD) has traditionally been treated with open surgery or rigid endoscopy. With the advances in endoscopy, alternative flexible endoscopic treatments have been developed. METHODS: This document reviews current endoscopic techniques and devices used to treat ZD. RESULTS: The endoscopic techniques may be categorized as the traditional flexible endoscopic septal division and the more recent submucosal tunneling endoscopic septum division, also known as peroral endoscopic myotomy for ZD. This document also addresses clinical outcomes, safety, and financial considerations. CONCLUSIONS: Flexible endoscopic approaches treat symptomatic ZD with results that are favorable compared with traditional open surgical or rigid endoscopic alternatives.

Diagnostic value of digital droplet polymerase chain reaction and digital multiplexed detection of single-nucleotide variants in pancreatic cytology specimens collected by EUS-guided FNA.

BACKGROUND AND AIMS: EUS-guided FNA is recommended as a first-line procedure for the histopathologic diagnosis of pancreatic cancer. Molecular analysis of EUS-FNA samples might be used as an auxiliary tool to strengthen the diagnosis. The current study aimed to evaluate the diagnostic performances of K-ras testing using droplet digital polymerase chain reaction (ddPCR) and a novel single-nucleotide variant (SNV) assay performed on pancreatic EUS-FNA samples. METHODS: EUS-FNA specimens from 31 patients with pancreatic masses (22 pancreatic ductal adenocarcinomas, 7 chronic pancreatitis, and 2 pancreatic neuroendocrine tumors) were included in the study. K-ras testing was initially performed by ddPCR. In addition, mutational status was evaluated using an SNV assay by NanoString technology, using digital enumeration of unique barcoded probes to detect 97 SNVs from 24 genes of clinical significance. RESULTS: The overall specificity and sensitivity of cytologic examination were 100% and 63%, respectively. K-ras mutation testing was performed using ddPCR, and the sensitivity increased to 87% with specificity 90%. The SNV assay detected at least 1 variant in 90% of pancreatic ductal adenocarcinoma samples; the test was able to detect 2 K-ras codon 61 mutations in 2 cases of pancreatic ductal adenocarcinoma, which were missed by ddPCR. The overall diagnostic accuracy of the cytologic examination alone was 74%, and it increased to 91% when the results of both molecular tests were considered for the cases with negative and inconclusive results. CONCLUSIONS: The current study illustrated that integration of K-ras analysis with cytologic evaluation, especially in inconclusive cases, can enhance the diagnostic accuracy of EUS-FNA for pancreatic lesions.

Enhanced EUS imaging (with videos).

BACKGROUND AND AIMS: EUS remains a primary diagnostic tool for the evaluation of pancreaticobiliary disease. Although EUS combined with FNA or biopsy sampling is highly sensitive for the diagnosis of neoplasia within the pancreaticobiliary tract, limitations exist in specific clinical settings such as chronic pancreatitis. Enhanced EUS imaging technologies aim to aid in the detection and diagnosis of lesions that are commonly evaluated with EUS. METHODS: We reviewed technologies and methods for enhanced imaging during EUS and applications of these methods. Available data regarding efficacy, safety, and financial considerations are summarized. RESULTS: Enhanced EUS imaging methods include elastography and contrast-enhanced EUS (CE-EUS). Both technologies have been best studied in the setting of pancreatic mass lesions. Robust data indicate that neither technology has adequate specificity to serve as a stand-alone test for pancreatic malignancy. However, there may be a role for improving the targeting of sampling and in the evaluation of peritumoral lymph nodes, inflammatory pancreatic masses, and masses with nondiagnostic FNA or fine-needle biopsy sampling. Further, novel applications of these technologies have been reported in the evaluation of liver fibrosis, pancreatic cysts, and angiogenesis within neoplastic lesions. CONCLUSIONS: Elastography and CE-EUS may improve the real-time evaluation of intra- and extraluminal lesions as an adjunct to standard B-mode and Doppler imaging. They are not a replacement for EUS-guided tissue sampling but provide adjunctive diagnostic information in specific clinical situations. The optimal clinical use of these technologies continues to be a focus of ongoing research.

Validity of Endoscopic Ultrasound Findings of Chronic Pancreatitis: Evaluation from the Viewpoint of Disease Risk Factors.

BACKGROUND: The diagnosis of chronic pancreatitis (CP) using endoscopic ultrasound (EUS) criteria, referred to as the Rosemont classification (RC), has been widely performed. However, the validity of the RC, which was based on expert opinion, is still controversial. If EUS findings are associated with CP, then they should be associated with risk factors for CP. In this study, to verify the appropriateness of the RC and each EUS finding, we performed a retrospective analysis from the viewpoint of risk factors for CP. SUMMARY: Three hundred and forty-four patients were enrolled in this study. Clinical background characteristics that associate with CP were alcohol intake, smoking, history of acute pancreatitis (AP), and age. The correlation between EUS criteria for CP and clinical background was investigated. All EUS findings except the presence of cysts showed significant correlations with one or 2 of the 3 following factors: ethanol (EtOH) intake, smoking status, and history of AP. Results of the univariate and multivariate analyses showed that 3 factors (EtOH intake, smoking, and history of AP) other than age were positively correlated with the RC. Moreover, the risk of progression from normal to consistent CP to indeterminate and suggestive CP was found to increase with increasing EtOH intake. Key Messages: The RC and each EUS finding was validated from the viewpoint of risk factors for CP.

MLH1-rheMac hereditary nonpolyposis colorectal cancer syndrome in rhesus macaques.

Over the past two decades, 33 cases of colonic adenocarcinomas have been diagnosed in rhesus macaques (Macaca mulatta) at the nonhuman primate colony of the Keeling Center for Comparative Medicine and Research at The University of Texas MD Anderson Cancer Center. The distinctive feature in these cases, based on PET/computed tomography (CT) imaging, was the presence of two or three tumor lesions in different locations, including proximal to the ileocecal juncture, proximal to the hepatic flexure, and/or in the sigmoid colon. These colon carcinoma lesions selectively accumulated [18F]fluorodeoxyglucose ([18F]FDG) and [18F]fluoroacetate ([18F]FACE) at high levels, reflecting elevated carbohydrate and fatty acid metabolism in these tumors. In contrast, the accumulation of [18F]fluorothymidine ([18F]FLT) was less significant, reflecting slow proliferative activity in these tumors. The diagnoses of colon carcinomas were confirmed by endoscopy. The expression of MLH1, MSH2, and MSH6 proteins and the degree of microsatellite instability (MSI) was assessed in colon carcinomas. The loss of MLH1 protein expression was observed in all tumors and was associated with a deletion mutation in the MLH1 promoter region and/or multiple single-nucleotide polymorphism (SNP) mutations in the MLH1 gene. All tumors exhibited various degrees of MSI. The pedigree analysis of this rhesus macaque population revealed several clusters of affected animals related to each other over several generations, suggesting an autosomal dominant transmission of susceptibility for colon cancer. The newly discovered hereditary nonpolyposis colorectal cancer syndrome in rhesus macaques, termed MLH1-rheMac, may serve as a model for development of novel approaches to diagnosis and therapy of Lynch syndrome in humans.

EUS-guided hydrogel microparticle injection in a cadaveric model.

BACKGROUND AND AIMS: A potential method to reduce gastrointestinal toxicity during radiation therapy in pancreatic head cancer is to create a physical space between the head of the pancreas (HOP) and the duodenum. To date, there have been early reports on the feasibility of endoscopic ultrasound (EUS)-guided hydrogel injection into the interface between the HOP and the duodenum to increase the peri-pancreatic space for radiotherapy. We aimed to evaluate the technical feasibility of EUS-guided hydrogel injection for the creation of space at the peri-pancreatic interface in a cadaveric model. METHODS: Baseline abdominal computerized tomography (CT) was performed on three unfixed cadaveric specimens. The hydrogel was injected transduodenally into the interface between the HOP and duodenum using linear-array EUS and a 19G needle for fine needle aspiration (FNA). This procedure was repeated along the length of the HOP. CT imaging and gross dissection were performed after the procedure to confirm the localization of the hydrogel and to measure the distance between the HOP and the duodenum. RESULTS: All cadavers underwent successful EUS-guided injection of the hydrogel. Cadavers 1, 2, and 3 were injected with 9.5, 27, and 10 cc of hydrogel, respectively; along the HOP, the formation of the peri-pancreatic space was a maximum size of 11.77, 13.20, and 12.89 mm, respectively. The hydrogel injections were clearly visualized as hyperechoic bullae during EUS and on post-procedure CT images without any artifacts in all cases. CONCLUSIONS: We demonstrated that EUS-guided delivery of hydrogel is feasible, and that it increases the peri-pancreatic space in a cadaveric model. The polyethylene glycol (PEG) hydrogel was clearly visible on EUS and CT, without significant artifacts. This may lead to new treatment approaches for pancreatic carcinomas.

Total Lesion Glycolysis Assessment Identifies a Patient Fraction With a High Cure Rate Among Esophageal Adenocarcinoma Patients Treated With Definitive Chemoradiation.

OBJECTIVE: We aimed to determine whether tumor metabolism could be prognostic of cure in L-EAC patients who receive definitive chemoradiation. SUMMARY BACKGROUND DATA: Patients with inoperable localized esophageal adenocarcinoma (L-EAC) often receive definitive chemoradiation; however, biomarkers and/or imaging variables to prognosticate cure are missing. METHODS: Two hundred sixty-six patients with L-EAC who had chemoradiation but not surgery were analyzed from the prospectively maintained EAC databases in the Department of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center (Texas, USA) between March 2002 and April 2015. Maximum standardized uptake value (SUVmax) and total lesion glycolysis (TLG) from the positron emission tomography data were evaluated. RESULTS: Of 266 patients, 253 (95%) were men; the median age was 67 years (range 20-91 yrs) and 153 had poorly differentiated L-EAC. The median SUVmax was 10.3 (range 0-87) and the median TLG was 85.7 (range 0-3227). Both SUVmax and TLG were higher among those with: tumors >5 cm in length, high clinical stage, and high tumor and node categories by TNM staging (all P < 0.0001). Of 234 patients evaluable for cure, 60 (25.6%) achieved cure. In the multivariable logistic regression model, low TLG (but not low SUVmax) was associated with cure (continuous TLG value: odds ratio 0.70, 95% confidence interval (CI) 0.54-0.92). TLG was quantified into 4 quartile categorical variables; first quartile (Q1; <32), second quartile (Q2; 32.0-85.6), third quartile (Q3; 85.6-228.4), and fourth quartile (Q4; >228.4); the cure rate was only 10.3% in Q4 and 5.1% in Q3 but increased to 28.8% in Q2, and 58.6% in Q1. The cross-validation resulted in an average accuracy of prediction score of 0.81 (95% CI, 0.75-0.86). CONCLUSIONS: In this cross-validated model, 59% of patients in the 1st quartile were cured following definitive chemoradiation. Baseline TLG could be pursued as one of the tools for esophageal preservation.

Efficacy of Three-Drug Induction Chemotherapy Followed by Preoperative Chemoradiation in Patients with Localized Gastric Adenocarcinoma.

BACKGROUND: Preoperative induction chemotherapy followed by chemoradiation yields better R0 resection rates, pathologic complete response (pCR) rates and improved survival for localized gastric adenocarcinoma (GAC). We report the effect of three-drug induction chemotherapy on a large cohort of localized GAC patients. METHODS: We identified 97 patients with localized GAC who received three-drug induction chemotherapy followed by preoperative chemoradiation therapy. We assessed various endpoints (overall survival [OS], recurrence-free survival [RFS], R0 resection and pCR rate). RESULTS: The median follow-up time was 3.5 years (range; 0.4-16.7). The induction chemotherapy regimen was a fluoropyrimidine and a platinum compound (cisplatin or oxaliplatin) with a taxane (docetaxel or paclitaxel) for 95% of patients. Seventy-three (75.3%) out of 97 patients underwent planned surgery. R0 resection and pCR rae were 93.2 and 20.6%, respectively. Pathologic partial response (<50% residual carcinoma) rate was 50.7%. The median OS was 6.4 years (95% Cl 3.3-12.4) for the entire cohort and 11.1 years (95% Cl 7.1-not estimable) for patients that underwent surgery. The estimated 2- and 5-year OS rates were 72.4% (95% CI 62.1-80.3) and 54.3% (95% CI 43.2-64.1) for the entire cohort and 83.2% (95% CI 72.3--90.1) and 66% (95% CI 52.3-75.8) for patients that underwent surgery. Pathologic lesser stage (stage I/II vs. stage III/IV) (p = 0.001) and R0 resection (p = 0.02) were independently associated with longer RFS in the multivariate analysis. CONCLUSION: Our data shows that three-drug combination is feasible without providing substantial advantage compared with two-drug combination in this setting of preoperative induction chemotherapy followed by chemoradiation and surgery.

Upfront molecular profiling of pancreatic cancer patients - An idea whose time has come.

Pancreatic cancer patients have not benefited from survival improvements brought about by personalized medicine in other malignancies. Even though this is the era of precision medicine, unfortunately most clinicians in practice either do not embrace or are unaware of the concept of molecular profiling for pancreatic cancer patients. Improving the grim prognosis of this challenging disease requires a paradigm shift. To exploit all potential therapeutic options in this lethal disease, molecular profiling should be performed ideally at the moment of diagnosis to identify potentially trial-eligible tumoral mutations or support off label use of an agent approved for another indication. This perspective article aims to increase awareness of the importance of upfront molecular profiling for pancreatic cancer patients.

Techniques and devices for the endoscopic treatment of gastroparesis (with video).

BACKGROUND AND AIMS: Gastroparesis is a symptomatic chronic disorder of the stomach characterized by delayed gastric emptying in the absence of mechanical obstruction. Several endoscopic treatment modalities have been described that aim to improve gastric emptying and/or symptoms associated with gastroparesis refractory to dietary and pharmacologic management. METHODS: In this report we review devices and techniques for endoscopic treatment of gastroparesis, the evidence regarding their efficacy and safety, and the financial considerations for their use. RESULTS: Endoscopic modalities for treatment of gastroparesis can be broadly categorized into pyloric, nonpyloric, and nutritional therapies. Pyloric therapies such as botulinum toxin injection, stent placement, pyloroplasty, and pyloromyotomy specifically focus on pylorospasm as a therapeutic target. These interventions aim to reduce the pressure gradient across the pyloric sphincter, with a resultant improvement in gastric emptying. Nonpyloric therapies, such as venting gastrostomy and gastric electrical stimulation, are intended to improve symptoms. Nutritional therapies, such as feeding tube placement, aim to provide nutritional support. CONCLUSIONS: Several endoscopic interventions have shown utility in improving the quality of life and symptoms of select patients with refractory gastroparesis. Methods to identify which patients are best suited for a specific treatment are not well established. Endoscopic pyloromyotomy is a relatively recent development that may prove to be the preferred pyloric-directed intervention, although additional and longer-term outcomes are needed.

Endoscopic devices and techniques for the management of bariatric surgical adverse events (with videos).

BACKGROUND AND AIMS: As the prevalence of obesity continues to rise, increasing numbers of patients undergo bariatric surgery. Management of adverse events of bariatric surgery may be challenging and often requires a multidisciplinary approach. Endoscopic intervention is often the first line of therapy for management of these adverse events. This document reviews technologies and techniques used for endoscopic management of adverse events of bariatric surgery, organized by surgery type. METHODS: The MEDLINE database was searched through May 2018 for articles related to endoscopic management of adverse events of bariatric interventions by using relevant keywords such as adverse events related to "gastric bypass," "sleeve gastrectomy," "laparoscopic adjustable banding," and "vertical banded sleeve gastroplasty," in addition to "endoscopic treatment" and "endoscopic management," among others. Available data regarding efficacy, safety, and financial considerations are summarized. RESULTS: Common adverse events of bariatric surgery include anastomotic ulcers, luminal stenoses, fistulae/leaks, and inadequate initial weight loss or weight regain. Devices used for endoscopic management of bariatric surgical adverse events include balloon dilators (hydrostatic, pneumatic), mechanical closure devices (clips, endoscopic suturing system, endoscopic plication platform), luminal stents (covered esophageal stents, lumen-apposing metal stents, plastic stents), and thermal therapy (argon plasma coagulation, needle-knives), among others. Available data, composed mainly of case series and retrospective cohort studies, support the primary role of endoscopic management. Multiple procedures and techniques are often required to achieve clinical success, and existing management algorithms are evolving. CONCLUSIONS: Endoscopy is a less invasive alternative for management of adverse events of bariatric surgery and for revisional procedures. Endoscopic procedures are frequently performed in the context of multidisciplinary management with bariatric surgeons and interventional radiologists. Treatment algorithms and standards of practice for endoscopic management will continue to be refined as new dedicated technology and data emerge.

Devices and techniques for endoscopic treatment of residual and fibrotic colorectal polyps (with videos).

BACKGROUND AND AIMS: Residual neoplasia after macroscopically complete EMR of large colon polyps has been reported in 10% to 32% of resections. Often, residual polyps at the site of prior polypectomy are fibrotic and nonlifting, making additional resection challenging. METHODS: This document reviews devices and methods for the endoscopic treatment of fibrotic and/or residual polyps. In addition, techniques reported to reduce the incidence of residual neoplasia after endoscopic resection are discussed. RESULTS: Descriptions of technologies and available outcomes data are summarized for argon plasma coagulation ablation, snare-tip coagulation, avulsion techniques, grasp-and-snare technique, EndoRotor endoscopic resection system, endoscopic full-thickness resection device, and salvage endoscopic submucosal dissection. CONCLUSIONS: Several technologies and techniques discussed in this document may aid in the prevention and/or resection of fibrotic and nonlifting polyps.

Role of gastrointestinal endoscopy in the screening of digestive tract cancers in Europe: European Society of Gastrointestinal Endoscopy (ESGE) Position Statement.

In Europe at present, but also in 2040, 1 in 3 cancer-related deaths are expected to be caused by digestive cancers. Endoscopic technologies enable diagnosis, with relatively low invasiveness, of precancerous conditions and early cancers, thereby improving patient survival. Overall, endoscopy capacity must be adjusted to facilitate both effective screening programs and rigorous control of the quality assurance and surveillance systems required. 1 : For average-risk populations, ESGE recommends the implementation of organized population-based screening programs FOR COLORECTAL CANCER: , based on fecal immunochemical testing (FIT), targeting individuals, irrespective of gender, aged between 50 and 75 years. Depending on local factors, namely the adherence of the target population and availability of endoscopy services, primary screening by colonoscopy or sigmoidoscopy may also be recommendable. 2 : In high-risk populations, endoscopic screening FOR GASTRIC CANCER: should be considered for individuals aged more than 40 years. Its use in countries/regions with intermediate risk may be considered on the basis of local settings and availability of endoscopic resources. 3 : For esophageal and pancreatic cancer, endoscopic screening may be considered only in high-risk individuals:- FOR SQUAMOUS CELL CARCINOMA: , in those with a personal history of head/neck cancer, achalasia, or previous caustic injury; - FOR BARRETT'S ESOPHAGUS (BE)-ASSOCIATED ADENOCARCINOMA: , in those with long-standing gastroesophageal reflux disease symptoms (i. e., > 5 years) and multiple risk factors (age ≥ 50 years, white race, male sex, obesity, first-degree relative with BE or esophageal adenocarcinoma [EAC]). - FOR PANCREATIC CANCER SCREENING: , endoscopic ultrasound may be used in selected high-risk patients such as those with a strong family history and/or genetic susceptibility.

Brain metastases in patients with upper gastrointestinal cancer is associated with proximally located adenocarcinoma and lymph node metastases.

BACKGROUND: As cancer patients are surviving longer, more patients manifest brain metastases (BRMs). However, the rate of BRMs from upper gastrointestinal cancer is unclear. We therefore evaluated the frequency and prognostic effect of BRMs in this setting. METHODS: We analyzed records of 2348 patients who were treated between January 2002 and December 2016 for upper gastrointestinal cancer, including esophageal and gastroesophageal junction adenocarcinoma (EAC; proximal EAC, Siewert types I and II), esophageal squamous cell carcinoma (ESCC), and gastric adenocarcinoma (GAC; Siewert type III and stomach cancer) in our Gastrointestinal Medical Oncology Database. Frequency, risk factors, and survival after BRMs were evaluated. RESULTS: Of 2348 patients, 68 (2.9%) had BRMs upon follow-up. The BRM rates were as follows: proximal EAC, 4.8%; Siewert type I, 5.9%; Siewert type II, 2.2%; Siewert type III, 0.7%; ESCC: 1.2%; and stomach cancer, 0%. Among EAC patients, Siewert type I and lymph node metastases were independent the risk factors for BRMs in the multivariable analysis. The median overall survival (OS) in the 68 patients with BRMs was only 1.16 years (95% CI 0.78-1.61). However, OS for patients who had a solitary BRM, who had BRM but no other distant metastasis, or who underwent surgery or stereotactic radiosurgery favorable. CONCLUSION: Patients with proximally located adenocarcinoma, or with lymph node metastases are at a higher risk for BRMs and patients fare better after treatment of isolated BRM.

Endoscopic Ultrasound-Guided Treatment of Pancreatic Cancer.

PURPOSE OF REVIEW: The aim of this review is to evaluate the emerging role of endoscopic ultrasound (EUS) in the guidance of tumor-targeted therapies for patients with pancreatic cancer (PC). RECENT FINDINGS: EUS-guided ablation, brachytherapy, fiducial marker placement, and antitumor agent injection have been described to date. EUS-guided fiducial placement for SBRT in pancreatic cancer has entered the clinical practice and is performed at many centers clinically without a research protocol. EUS-guided brachytherapy and RFA have been shown to be feasible and safe procedures, and potentially offer local disease control. Other potential techniques of EUS-guided treatment of pancreatic cancer are still considered experimental, with many of them appearing to be safe and reasonably well tolerated. However, their effectiveness and exact role in oncological treatment have yet to be established. Clinical trials with many of the techniques/agents described are underway and multicentric randomized trials with prospective design are eagerly awaited.

Low metabolic activity in primary gastric adenocarcinoma is associated with resistance to chemoradiation and the presence of signet ring cells.

PURPOSES: Preoperative chemoradiation is a potential treatment option for localized gastric adenocarcinoma (GAC). Currently, the response to chemoradiation cannot be predicted. We analyzed the pretreatment maximum standardized uptake value (SUVmax) and total lesion glycolysis (TLG) on positron emission tomography/computed tomography as potential predictors of the response to chemoradiation. METHODS: We analyzed the SUVmax and TLG data from 59 GAC patients who received preoperative chemoradiation. We used logistic regression models to predict a pathologic complete response (pCR) and Kaplan-Meier curves to determine overall survival among patients with high and low SUVmax or TLG. RESULTS: Twenty-nine patients (49%) had Siewert type III adenocarcinoma and 30 (51%) had tumors located in the lower stomach. Forty-one patients had poorly differentiated GAC, and 26 had signet ring cells. The median SUVmax was 7.3 (0-28.2) and the median TLG was 56.6 (0-1881.5). Patients with signet ring cells had a low pCR rate, as well as a low SUVmax and TLG. In the multivariable logistic regression model, high SUVmax was a predictor of pCR (odds ratio = 11.1, 95% confidence interval = 2.12-50.0, p = 0.004). Overall survival was not associated with the SUVmax (log-rank p = 0.69) or TLG (log-rank p = 0.85) CONCLUSION: A high SUVmax was associated with sensitivity to chemoradiation and pCR in GAC, and signet ring cells seemed to confer resistance.

LncRNA PVT1 up-regulation is a poor prognosticator and serves as a therapeutic target in esophageal adenocarcinoma.

BACKGROUND: PVT1 has emerged as an oncogene in many tumor types. However, its role in Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) is unknown. The aim of this study was to assess the role of PVT1 in BE/EAC progression and uncover its therapeutic value against EAC. METHODS: PVT1 expression was assessed by qPCR in normal, BE, and EAC tissues and statistical analysis was performed to determine the association of PVT1 expression and EAC (stage, metastases, and survival). PVT1 antisense oligonucleotides (ASOs) were tested for their antitumor activity in vitro and in vivo. RESULTS: PVT1 expression was up-regulated in EACs compared with paired BEs, and normal esophageal tissues. High expression of PVT1 was associated with poor differentiation, lymph node metastases, and shorter survival. Effective knockdown of PVT1 in EAC cells using PVT1 ASOs resulted in decreased cell proliferation, invasion, colony formation, tumor sphere formation, and reduced proportion of ALDH1A1+ cells. Mechanistically, we discovered mutual regulation of PVT1 and YAP1 in EAC cells. Inhibition of PVT1 by PVT1 ASOs suppressed YAP1 expression through increased phosphor-LATS1and phosphor-YAP1 while knockout of YAP1 in EAC cells significantly suppressed PVT1 levels indicating a positive regulation of PVT1 by YAP1. Most importantly, we found that targeting both PVT1 and YAP1 using their specific ASOs led to better antitumor activity in vitro and in vivo. CONCLUSIONS: Our results provide strong evidence that PVT1 confers an aggressive phenotype to EAC and is a poor prognosticator. Combined targeting of PVT1 and YAP1 provided the highest therapeutic index and represents a novel therapeutic strategy.