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IMPORTANCE: The use of neoadjuvant therapy (NAT) in resectable pancreatic ductal adenocarcinoma (PDAC) remains controversial. A favorable pathologic response (complete or marked tumor regression) to NAT is associated with better outcomes in patients with resected PDAC. The role of NAT for early systemic control compared with immediate surgical resection for PDAC is under investigation. In the era of precision medicine, biomarkers for patient selection and prediction of therapy response are crucial. OBJECTIVE: To evaluate the use of assessment for protein expression on fine-needle aspiration (FNA) biopsy specimens in predicting pathologic response to NAT in treatment-naive patients. DESIGN, SETTING, AND PARTICIPANTS: This was a single-institution prognostic study from a high-volume center for pancreatic cancer. All specimens were obtained between January 1, 2009, and December 31, 2018, with a median (SE) follow-up of 20.2 (1.4) months. Analysis of the data was performed from October 1, 2019, to April 30, 2021. Targeted RNA sequencing of frozen FNA biopsy specimens from a discovery cohort of 23 patients was performed to identify genes with aberrant expression that was associated with patients’ pathologic response to NAT. Immunohistochemical staining was performed on an additional 80 FNA biopsy specimens to assess expression of matrix metalloproteinase 7 (MMP-7) and its association with pathologic response. Receiver operating characteristic curves for prediction of favorable pathologic response were determined. RESULTS: In the discovery cohort (12 [52.1%] male; 3 [13.0%] Black and 20 [86.9%] White), RNA sequencing showed that lower MMP-7 expression was associated with favorable pathologic response (College of American Pathologists system scores of 0 [complete response] and 1 [marked response]). In the validation cohort (40 [50.0%] female; 9 [11.3%] Black and 71 [88.7%] White), patients with negative MMP-7 expression were significantly more likely to have a favorable pathologic response (odds ratio, 21.25; 95% CI, 6.19-72.95; P = .001). Receiver operating characteristic curves for prediction of favorable pathologic response from multivariable Cox proportional hazards regression modeling showed that MMP-7 expression increased the area under the curve from 0.726 to 0.906 (P

Pancreatic cancer is the fourth leading cause of cancer-related death with a 10% 5-year overall survival rate (OS). Radiation therapy (RT) in addition to dose escalation improves the outcome by significantly increasing the OS at 2 and 3 years but is hindered by the toxicity of the duodenum. Our group showed that the insertion of hydrogel spacer reduces duodenal toxicity, but the complex anatomy and the demanding procedure make the benefits highly uncertain. Here, we investigated the feasibility of augmenting the workflow with intraoperative feedback to reduce the adverse effects of the uncertainties.We simulated three scenarios of the virtual spacer for four cadavers with two types of gross tumor volume (GTV) (small and large); first, the ideal injection; second, the nonideal injection that incorporates common spacer placement uncertainties; and third, the corrective injection that uses the simulation result from nonideal injection and is designed to compensate for the effect of uncertainties. We considered two common uncertainties: (1) "Narrowing" is defined as the injection of smaller spacer volume than planned. (2) "Missing part" is defined as failure to inject spacer in the ascending section of the duodenum. A total of 32 stereotactic body radiation therapy (SBRT) plans (33 Gy in 5 fractions) were designed, for four cadavers, two GTV sizes, and two types of uncertainties. The preinjection scenario for each case was compared with three scenarios of virtual spacer placement from the dosimetric and geometric points of view.We found that the overlapping PTV space with the duodenum is an informative quantity for determining the effective location of the spacer. The ideal spacer distribution reduced the duodenal V33Gy for small and large GTV to less than 0.3 and 0.1cc, from an average of 3.3cc, and 1.2cc for the preinjection scenario. However, spacer placement uncertainties reduced the efficacy of the spacer in sparing the duodenum (duodenal V33Gy: 1.3 and 0.4cc). The separation between duodenum and GTV decreased by an average of 5.3 and 4.6 mm. The corrective feedback can effectively bring back the expected benefits from the ideal location of the spacer (averaged V33Gy of 0.4 and 0.1cc).An informative feedback metric was introduced and used to mitigate the effect of spacer placement uncertainties and maximize the benefits of the EUS-guided procedure.

There has been a growing interest in developing endoscopic ultrasound (EUS)-guided interventions for pancreatic cancer, some of which have become standard of care. There are two main factors that drive these advancements to facilitate treatment of patients with pancreatic cancer, ranging from direct locoregional therapy to palliation of symptoms related to inoperable pancreatic cancer. Firstly, an upper EUS has the capability to access the entire pancreas-lesions in the pancreatic head and uncinate process can be accessed from the duodenum, and lesions in the pancreatic body and tail can be accessed from the stomach. Secondly, there has been a robust development of devices that allow through-the-needle interventions, such as placement of fiducial markers, brachytherapy, intratumoral injection, gastroenterostomy creation, and ablation. While these techniques are rapidly emerging, data from a multicenter randomized controlled trial for some procedures are awaited prior to their adoption in clinical settings.

Background & Aims The tumor microbiome of patients with pancreas ductal adenocarcinoma (PDAC) includes bacteria normally present in the upper gastrointestinal tract. If the predominant source of intratumoral bacteria in patients with PDAC is retrograde migration from the duodenum, duodenal fluid could be a representative biospecimen for determining microbiome profiles of patients with PDAC or at risk of developing PDAC. Methods We performed a case-control study comparing bacterial and fungal (16S and 18S rRNA) profiles of secretin-stimulated duodenal fluid collections from 308 patients undergoing duodenal endoscopy including 134 normal pancreas control subjects, 98 patients with pancreatic cyst(s) and 74 patients with PDAC. Results Alterations in duodenal fluid microbiomes with diminished alpha diversity were significantly associated with age >70 and proton pump inhibitor use. Patients with PDAC had significantly decreased duodenal microbial alpha diversity compared with age-matched control subjects with normal pancreata and those with pancreatic cyst(s). There was evidence of enrichment of Bifidobacterium genera in the duodenal fluid of patients with PDAC compared with control subjects and those with pancreatic cyst(s). There were also enrichment of duodenal fluid Fusobacteria and Rothia bacteria among patients with PDAC with short-term survival. Duodenal fluid microbiome profiles were not significantly different between control subjects and patients with pancreatic cyst(s). Conclusion Patients with PDAC have alterations in their duodenal fluid microbiome profiles compared with patients with pancreatic cysts and those with normal pancreata. ClinicalTrials.gov , Number: NCT02000089

BACKGROUND AND AIMS Endoscopic ablation can eradicate neoplastic Barrett's esophagus (BE) without visible lesions. Cryoballoon ablation (CBA) is an established but relatively newer ablative technique that can eliminate BE but data on the durability of its treatment effects are lacking. We assessed the durability of CBA treatment for neoplastic BE. METHODS We performed a single-center cohort study of consecutive BE patients with confirmed low-grade dysplasia (LGD), high-grade dysplasia (HGD) or intramucosal cancer (ImCA) treated with CBA to eradicate all BE. We excluded patients with prior ablative therapy. Visible lesions were removed with endoscopic mucosal resection (EMR) prior to CBA. Outcomes included complete eradication of dysplasia (CE-D) and complete eradication of intestinal metaplasia (CE-IM) at 1 year, durability at 2 and 3 years after initial ablation, cumulative recurrence rate of dysplasia and IM, and rate of neoplastic progression. RESULTS 59 patients (55.9% with HGD; 20.3% with prior EMR) were tracked for a median of 54.3 months. CE-D and CE-IM at 1 year were 94.6% (53/56) and 75% (42/56), respectively. Allowing for retreatment, rates of maintained CE-D and CE-IM for those who have achieved CE-D or CE-IM were 100% (53/53) and 98% (47/48) at 2 years; 100% (45/45) and 98% (40/41), at 3 years, respectively. Cumulative recurrence rate was 1.9% (1/53) for dysplasia and 14.6% (7/48) for IM (not allowing for retreatment). There was no neoplastic progression. CONCLUSION In treatment-naive patients with dysplastic BE, CBA is a durable endoscopic eradication therapy but endoscopic surveillance after eradication is still warranted.

Chemical exposure accidents pose a risk of serious injury and property damage if the diagnosis or response is not properly performed after the initial discovery. Due to lack of research on the dynamically changing environment and detection of chemical substances considering symptoms, real-time knowledge services are required, such as rapid diagnosis of chemicals exposed at the accident site and the following early response. In this study, we propose an AI-based analysis system, Symptom-based Expert for Advanced Response to Chemical Hazards (SEARCH), for chemical substance diagnosis from exposure symptoms actively collected for real-time response and mitigation to hazardous material accidents. Knowledge is collected from chemical database such as WISER, PubChem etc., and integrated for the analytics of chemical exposure accidents and contact symptoms. We design and construct ontology and knowledge graph (KG) for 1001 major chemical substances. The built KG is verified using KG embedding models and the performance of each model is compared. The proposed system identifies the substance candidates through KG query and reasoning considering the exposure conditions. Using the symptom KG, the system SEARCH can provide the means to analyze real-time data from the field and transform it into insights and actions related to emergency response.

Purpose: The measurement of mutations in pancreatic juice samples collected from the duodenum during endoscopic ultrasound (EUS) may improve the diagnostic evaluation of patients undergoing pancreatic surveillance. Our aim was to evaluate the accuracy of using pancreatic juice mutation concentrations to predict the presence and histologic grade of neoplasia in the pancreas.Experimental Design: Digital next-generation sequencing (NGS) of pancreatic juice DNA using a targeted 12-gene panel was performed on 67 patients undergoing pancreatic evaluation during EUS, including patients with pancreatic ductal adenocarcinoma, patients who subsequently underwent pancreatic resection for precursor lesions, patients undergoing surveillance for their familial/inherited susceptibility to pancreatic cancer, and normal pancreas disease controls.Results: Patients with pancreatic cancer or high-grade dysplasia as their highest grade lesion had significantly higher pancreatic juice mutation concentrations than all other subjects (mean/SD digital NGS score; 46.6 ± 69.7 vs. 6.2 ± 11.6, P = 0.02). Pancreatic juice mutation concentrations distinguished patients with pancreatic cancer or high-grade dysplasia in their resection specimen from all other subjects with 72.2% sensitivity and 89.4% specificity [area under the curve (AUC) = 0.872]. Mutant TP53/SMAD4 concentrations could distinguish patients with pancreatic cancer or high-grade dysplasia in their resection specimen from all other subjects with 61.1% sensitivity and 95.7% specificity (AUC = 0.819). Among 31 high-risk individuals under surveillance, 2 of the 3 individuals with most abnormal pancreatic juice mutation profiles also had the most abnormalities on pancreatic imaging.Conclusions: Pancreatic juice mutation analysis using digital NGS has potential diagnostic utility in the evaluation of patients undergoing pancreatic surveillance. Clin Cancer Res; 24(12); 2963–74. ©2018 AACR.See related commentary by Lipner and Yeh, p. 2713

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Inactivation of the tumor suppressor genes tumor protein p53 ( TP53 ) and cyclin-dependent kinase inhibitor 2A ( CDKN2A ) occurs early during gastroesophageal junction (GEJ) tumorigenesis. However, because of a paucity of GEJ-specific disease models, cancer-promoting consequences of TP53 and CDKN2A inactivation at the GEJ have not been characterized. Here, we report the development of a wild-type primary human GEJ organoid model and a CRISPR-edited transformed GEJ organoid model. CRISPR-Cas9–mediated TP53 and CDKN2A knockout ( TP53/CDKN2A KO ) in GEJ organoids induced morphologic dysplasia and proneoplastic features in vitro and tumor formation in vivo. Lipidomic profiling identified several platelet-activating factors (PTAFs) among the most up-regulated lipids in CRISPR-edited organoids. PTAF/PTAF receptor (PTAFR) abrogation by siRNA knockdown or a pharmacologic inhibitor (WEB2086) reduced proliferation and other proneoplastic features of TP53/CDKN2A KO GEJ organoids in vitro and tumor formation in vivo. In addition, murine xenografts of Eso26, an established human esophageal adenocarcinoma cell line, were suppressed by WEB2086. Mechanistically, TP53/CDKN2A dual inactivation disrupted both the transcriptome and the DNA methylome, likely mediated by key transcription factors, particularly forkhead box M1 (FOXM1). FOXM1 activated PTAFR transcription by binding to the PTAFR promoter, further amplifying the PTAF-PTAFR pathway. Together, these studies established a robust model system for investigating early GEJ neoplastic events, identified crucial metabolic and epigenomic changes occurring during GEJ model tumorigenesis, and revealed a potential cancer therapeutic strategy. This work provides insights into proneoplastic mechanisms associated with TP53/CDKN2A inactivation in early GEJ neoplasia, which may facilitate early diagnosis and prevention of GEJ neoplasms.

Inactivation of the tumor suppressor genes tumor protein p53 (TP53) and cyclin-dependent kinase inhibitor 2A (CDKN2A) occurs early during gastroesophageal junction (GEJ) tumorigenesis. However, because of a paucity of GEJ-specific disease models, cancer-promoting consequences of TP53 and CDKN2A inactivation at the GEJ have not been characterized. Here, we report the development of a wild-type primary human GEJ organoid model and a CRISPR-edited transformed GEJ organoid model. CRISPR-Cas9–mediated TP53 and CDKN2A knockout (TP53/CDKN2A(KO)) in GEJ organoids induced morphologic dysplasia and proneoplastic features in vitro and tumor formation in vivo. Lipidomic profiling identified several platelet-activating factors (PTAFs) among the most up-regulated lipids in CRISPR-edited organoids. PTAF/PTAF receptor (PTAFR) abrogation by siRNA knockdown or a pharmacologic inhibitor (WEB2086) reduced proliferation and other proneoplastic features of TP53/CDKN2A(KO) GEJ organoids in vitro and tumor formation in vivo. In addition, murine xenografts of Eso26, an established human esophageal adenocarcinoma cell line, were suppressed by WEB2086. Mechanistically, TP53/CDKN2A dual inactivation disrupted both the transcriptome and the DNA methylome, likely mediated by key transcription factors, particularly forkhead box M1 (FOXM1). FOXM1 activated PTAFR transcription by binding to the PTAFR promoter, further amplifying the PTAF-PTAFR pathway. Together, these studies established a robust model system for investigating early GEJ neoplastic events, identified crucial metabolic and epigenomic changes occurring during GEJ model tumorigenesis, and revealed a potential cancer therapeutic strategy. This work provides insights into proneoplastic mechanisms associated with TP53/CDKN2A inactivation in early GEJ neoplasia, which may facilitate early diagnosis and prevention of GEJ neoplasms.

Grignard reagents featuring carbanion characteristics are mostly unreactive toward alkyl halides and require a catalyst for the coupling reaction. With the need to prepare

Recent research on genomic profiling of pancreatic ductal adenocarcinoma (PDAC) has identified many potentially actionable alterations. However, the feasibility of using genomic profiling to guide routine clinical decision making for PDAC patients remains unclear. We retrospectively reviewed PDAC patients between October 2013 and December 2017, who underwent treatment at the Johns Hopkins Hospital and had clinical tumor next-generation sequencing (NGS) through commercial resources. Ninety-two patients with 93 tumors tested were included. Forty-eight (52%) patients had potentially curative surgeries. The median time from the tissue available to the NGS testing ordered was 229 days (interquartile range 62–415). A total of three (3%) patients had matched targeted therapies based on genomic profiling results. Genomic profiling guided personalized treatment for PDAC patients is feasible, but the percentage of patients who receive targeted therapy is low. The main challenges are ordering NGS testing early in the clinical course of the disease and the limited evidence of using a targeted approach in these patients. A real-time department level genomic testing ordering system in combination with an evidence-based flagging system for potentially actionable alterations could help address these shortcomings.

PURPOSE Genetic alterations in many components of the homologous recombination, DNA damage response, and repair (HR-DDR) pathway are involved in the hereditary cancer syndromes, including familial pancreatic cancer. HR-DDR genes beyond BRCA1, BRCA2, ATM, and PALB2 may also mutate and confer the HR-DDR deficiency in pancreatic ductal adenocarcinoma (PDAC). METHODS We conducted a study to examine the genetic alterations using a companion diagnostic 15-gene HR-DDR panel in PDACs. HR-DDR gene mutations were identified and characterized by whole-exome sequencing and whole-genome sequencing. Different HR-DDR gene mutations are associated with variable homologous recombination deficiency (HRD) scores. RESULTS Eight of 50 PDACs with at least one HR-DDR gene mutation were identified. One tumor with BRCA2 mutations is associated with a high HRD score. However, another tumor with a CHEK2 mutation is associated with a zero HRD score. Notably, four of eight PDACs in this study harbor a RAD51B gene mutation. All four RAD51B gene mutations were germline mutations. However, currently, RAD51B is not the gene panel for germline tests. CONCLUSION The finding in this study thus supports including RAD51B in the germline test of HR-DDR pathway genes.

PURPOSE To report pancreas surveillance outcomes of high-risk individuals within the multicenter Cancer of Pancreas Screening-5 (CAPS5) study and to update outcomes of patients enrolled in prior CAPS studies. METHODS Individuals recommended for pancreas surveillance were prospectively enrolled into one of eight CAPS5 study centers between 2014 and 2021. The primary end point was the stage distribution of pancreatic ductal adenocarcinoma (PDAC) detected (stage I v higher-stage). Overall survival was determined using the Kaplan-Meier method. RESULTS Of 1,461 high-risk individuals enrolled into CAPS5, 48.5% had a pathogenic variant in a PDAC-susceptibility gene. Ten patients were diagnosed with PDAC, one of whom was diagnosed with metastatic PDAC 4 years after dropping out of surveillance. Of the remaining nine, seven (77.8%) had a stage I PDAC (by surgical pathology) detected during surveillance; one had stage II, and one had stage III disease. Seven of these nine patients with PDAC were alive after a median follow-up of 2.6 years. Eight additional patients underwent surgical resection for worrisome lesions; three had high-grade and five had low-grade dysplasia in their resected specimens. In the entire CAPS cohort (CAPS1-5 studies, 1,731 patients), 26 PDAC cases have been diagnosed, 19 within surveillance, 57.9% of whom had stage I and 5.2% had stage IV disease. By contrast, six of the seven PDACs (85.7%) detected outside surveillance were stage IV. Five-year survival to date of the patients with a screen-detected PDAC is 73.3%, and median overall survival is 9.8 years, compared with 1.5 years for patients diagnosed with PDAC outside surveillance (hazard ratio [95% CI]; 0.13 [0.03 to 0.50], P = .003). CONCLUSION Most pancreatic cancers diagnosed within the CAPS high-risk cohort in the recent years have had stage I disease with long-term survival.

Inactivation of the tumor suppressor genes TP53 and CDKN2A occurs early during gastroesophageal junction (GEJ) tumorigenesis. However, due to a paucity of GEJ-specific disease models, cancer-promoting consequences of TP53 and CDKN2A inactivation at the GEJ have been incompletely characterized. Here we report the development of the first wild-type primary human GEJ organoid model, as well as a CRISPR-edited transformed GEJ organoid model. CRISPR/Cas9 engineering to inactivate TP53 and CDKN2A (TP53/CDKN2AKO) in GEJ organoids induced morphologic dysplasia as well as pro-neoplastic features in vitro and tumor formation in vivo. Notably, lipidomic profiling identified several Platelet-Activating Factors (PTAFs) among the most upregulated lipids in CRISPR-edited organoids; and importantly, PTAF/PTAFR abrogation by siRNA knockdown or a pharmacologic inhibitor (WEB2086) significantly blocked proliferation and other pro-neoplastic features of TP53/CDKN2AKO GEJ organoids in vitro and tumor formation in vivo. In addition, murine xenografts derived from Eso26, an established esophageal adenocarcinoma (EAC) cell line, were suppressed by WEB2086. Mechanistically, TP53/CDKN2A dual inactivation disrupted both the transcriptome and the DNA methylome, likely mediated by key transcription factors, particularly Forkhead Box M1 (FOXM1). Importantly, FOXM1 activated PTAFR transcription by binding to the PTAFR promoter, further amplifying the PTAF-PTAFR pathway. In summary, we established a robust model system for investigating early GEJ neoplastic events, identified crucial metabolic and epigenomic changes occurring during GEJ model tumorigenesis, and discovered a potential cancer-therapeutic strategy, while providing insights into pro-neoplastic mechanisms associated with TP53/CDKN2A inactivation in early GEJ neoplasia.One Sentence SummaryNovel tumorigenic FOXM1-PTAFR-PTAF axis revealed by multi-omic profiling in TP53/CDKN2A-double knockout human gastroesophageal junction organoid model.Graphic Abstract

PURPOSE: We assessed the feasibility and safety of placing a radiopaque hydrogel in the pancreaticoduodenal groove via endoscopic ultrasound guidance in patients with borderline resectable/locally advanced pancreatic cancer (BR/LAPC). METHODS AND MATERIALS: Hydrogel injections were done at time of fiducial placement to form blebs in the pancreaticoduodenal groove. Patients subsequently underwent simulation computed tomography (sim-CT) followed by hypofractionated stereotactic body radiotherapy (SBRT; 33 Gy in 5 fractions). Four to 8 weeks after SBRT, patients underwent CT re-evaluation for surgical candidacy and assessment of hydrogel location and size. Hydrogel placement was considered successful if identified in the pancreaticoduodenal groove on sim-CT scan. Stability was evaluated using equivalence testing analyses, with a null hypothesis of the presence of a ≥20% mean percentage change in volume and ≥change in the median and mean interbleb surface distance with a P value

Introduction Ablation of Barrett's esophagus (BE) is the preferred approach for the treatment of neoplasia without visible lesions. Limited data on cryoballoon ablation (CBA) suggest its potential clinical utility. We evaluated the safety and efficacy of CBA in a multicenter study of patients with neoplastic BE. Methods In a prospective clinical trial, 11 academic and community centers recruited consecutive patients with BE of 1-6 cm length and low-grade dysplasia, high-grade dysplasia (HGD), or intramucosal adenocarcinoma (ImCA) confirmed by central pathology. Patients with symptomatic pre-existing strictures or visible BE lesions had dilation or endoscopic mucosal resection (EMR), respectively, before enrollment. A nitrous oxide cryoballoon focal ablation system was used to treat all visible columnar mucosa in up to 5 sessions. Study end points included complete eradication of all dysplasia (CE-D) and intestinal metaplasia (CE-IM) at 1 year. Results One hundred twenty patients with BE with ImCA (20%), HGD (56%), or low-grade dysplasia (23%) were enrolled. In the intention-to-treat analysis, the CE-D and CE-IM rates were 76% and 72%, respectively. In the per-protocol analysis (94 patients), the CE-D and CE-IM rates were 97% and 91%, respectively. Postablation pain was mild and short lived. Fifteen subjects (12.5%) developed strictures requiring dilation. One patient (0.8%) with HGD progressed to ImCA, which was successfully treated with EMR. Another patient (0.8%) developed gastrointestinal bleeding associated with clopidogrel use. One patient (0.8%) had buried BE with HGD in 1 biopsy, not confirmed by subsequent EMR. Discussion In patients with neoplastic BE, CBA was safe and effective. Head-to-head comparisons between CBA and other ablation modalities are warranted (clinicaltrials.gov registration NCT02514525).

PURPOSE: To examine the safety and efficacy of bariatric arterial embolization (BAE) with X-ray-visible embolic microspheres (XEMs) and an anti-reflux catheter in swine. MATERIAL AND METHODS: BAE with selective infusion of XEMs (n = 6) or saline (n = 4, control) into the gastric fundal arteries was performed under X-ray guidance. Weight and plasma hormone levels were measured at baseline and weekly for four weeks after embolization. Cone beam CT (CBCT) images were acquired immediately after embolization and weekly for four weeks. Hormone-expressing cells in the stomach were assessed by immunohistochemical staining. RESULTS: BAE pigs lost weight at one week after embolization followed by significantly impaired weight gain relative to controls (14.3% vs 20.9% at 4 weeks, P = 0.03). Plasma ghrelin levels were significantly lower in embolized animals than those in controls (1221.6 vs 1706.2 at 4 weeks, P < 0.01). XEMs were visible on X-ray and CBCT during embolization and their radiopacity persisted over four weeks (165.5 HU at week-1 vs. 158.5 HU at week-4, P = 0.9). Superficial mucosal ulcerations were noted in 1 of 6 BAE animals. Ghrelin-expressing cell counts were significantly lower in the gastric fundus (17.7 vs 36.8, P < 0.00001) and antrum (24.2 vs 46.3, P < 0.0001) than those in controls. Gastrin-expressing cell counts were markedly reduced in BAE pigs relative to controls (98.5 vs 127.0, P < 0.02). Trichrome staining demonstrated significantly more fibrosis in BAE animals compared with controls (13.8% vs 8.7%, P < 0.0001). CONCLUSION: XEMs enabled direct visualization of the embolic material during and after embolization. BAE with XEMs and anti-reflux microcatheters was safe and effective.

PurposePancreatic cancer is the fourth leading cause of cancer-related death, with a very low 5-year overall survival rate (OS). Radiation therapy (RT) together with dose escalation significantly increases the OS at 2 and 3 years. However, dose escalation is very limited due to the proximity of the duodenum. Hydrogel spacers are an effective way to reduce duodenal toxicity, but the complexity of the anatomy and the procedure makes the success and effectiveness of the spacer procedure highly uncertain. To provide a preoperative simulation of hydrogel spacers, we presented a patient-specific spacer simulator algorithm and used it to create a decision support system (DSS) to provide a preoperative optimal spacer location to maximize the spacer benefits.Materials and MethodsOur study was divided into three phases. In the validation phase, we evaluated the patient-specific spacer simulator algorithm (FEMOSSA) for the duodenal spacer using the dice similarity coefficient (DSC), overlap volume histogram (OVH), and radial nearest neighbor distance (RNND). For the simulation phase, we simulated four virtual spacer scenarios based on the location of the spacer in para-duodenal space. Next, stereotactic body radiation therapy (SBRT) plans were designed and dosimetrically analyzed. Finally, in the prediction phase, using the result of the simulation phase, we created a Bayesian DSS to predict the optimal spacer location and biological effective dose (BED).ResultsA realistic simulation of the spacer was achieved, reflected in a statistically significant increase in average target and duodenal DSC for the simulated spacer. Moreover, the small difference in average mean and 5th-percentile RNNDs (0.5 and 2.1 mm) and OVH thresholds (average of less than 0.75 mm) showed that the simulation attained similar separation as the real spacer. We found a spacer-location-independent decrease in duodenal V20Gy, a highly spacer-location-dependent change in V33Gy, and a strong correlation between L1cc and V33Gy. Finally, the Bayesian DSS predicted the change in BED with a root mean squared error of 3.6 Gys.ConclusionsA duodenal spacer simulator platform was developed and used to systematically study the dosimetric effect of spacer location. Further, L1cc is an informative anatomical feedback to guide the DSS to indicate the spacer efficacy, optimum location, and expected improvement.

Quality metrics and standardization has become critical as the Affordable Care Act mandates that the Center for Medicare and Medicaid Services change reimbursement from volume to a value-based system. While the most commonly used quality indicators are related to that of colonoscopy, quality metrics for other procedures and endoscopy units have been developed mainly by the American College of Gastroenterology and the American Society of Gastrointestinal Endoscopy. Data to show that these quality metrics, especially in the field of advanced endoscopy as well as in the era of COVID-19 pandemic, can improve patient outcomes, are anticipated.

BACKGROUND: Bariatric embolization is a new endovascular procedure to treat patients with obesity. However, the safety and efficacy of bariatric embolization are unknown. PURPOSE: To evaluate the safety and efficacy of bariatric embolization in severely obese adults at up to 12 months after the procedure. MATERIALS AND METHODS: For this prospective study (NCT0216512 on ClinicalTrials.gov), 20 participants (16 women) aged 27–68 years (mean ± standard deviation, 44 years ± 11) with mean body mass index of 45 ± 4.1 were enrolled at two institutions from June 2014 to February 2018. Transarterial embolization of the gastric fundus was performed using 300- to 500-µm embolic microspheres. Primary end points were 30-day adverse events and weight loss at up to 12 months. Secondary end points at up to 12 months included technical feasibility, health-related quality of life (Short Form-36 Health Survey ([SF-36]), impact of weight on quality of life (IWQOL-Lite), and hunger or appetite using a visual assessment scale. Analysis of outcomes was performed by using one-sample t tests and other exploratory statistics. RESULTS: Bariatric embolization was performed successfully for all participants with no major adverse events. Eight participants had a total of 11 minor adverse events. Mean excess weight loss was 8.2% (95% confidence interval [CI]: 6.3%, 10%; P < .001) at 1 month, 11.5% (95% CI: 8.7%, 14%; P < .001) at 3 months, 12.8% (95% CI: 8.3%, 17%; P < .001) at 6 months, and 11.5% (95% CI: 6.8%, 16%; P < .001) at 12 months. From baseline to 12 months, mean SF-36 scores increased (mental component summary, from 46 ± 11 to 50 ± 10, P = .44; physical component summary, from 46 ± 8.0 to 50 ± 9.3, P = .15) and mean IWQOL-Lite scores increased from 57 ± 18 to 77 ± 18 (P < .001). Hunger or appetite decreased for 4 weeks after embolization and increased thereafter, without reaching pre-embolization levels. CONCLUSION: Bariatric embolization is well tolerated in severely obese adults, inducing appetite suppression and weight loss for up to 12 months. Published under a CC BY-NC-ND 4.0 license. Online supplemental material is available for this article.

Overlapping of Alzheimer's disease and Parkinson's disease is associated with the formation of hetero-oligomers derived from amyloid-beta and alpha-synuclein. However, the structural identity of the hetero-oligomer has yet to be elucidated, particularly at high resolution. Here, with atomic force microscopy, the surface structure of hetero-oligomer was examined with four AFM tips tethering one of the selected antibodies recognizing N-terminus or C-terminus of each peptide. All aggregates were found to be hetero-oligomers, and probability of recognizing the termini is higher than that for the homo-oligomers, suggesting that the termini of the former have a greater tendency to be located at the surface or the termini have more freedom to be recognized, probably through loose packing. The methodology in this study provides us with a new approach to elucidate the structure of such aggregates at the single-molecule level, allowing the exploration of other intrinsically disordered proteins frequently found in nature.

Stereotactic body radiation therapy (SBRT) is an important treatment option for pancreatic cancer, which is known to be one of the malignancies with the worst prognosis. However, the high radiation doses delivered during SBRT may cause damage to adjacent radiosensitive organs. To minimize such damage, fiducial markers are used for localization during SBRT for pancreatic cancer. The development of endoscopic ultrasound (EUS) has enabled fiducial markers to be inserted into the pancreas using an EUS fine-needle aspiration (FNA) needle, unlike in the past when percutaneous placement was generally performed. For successful EUS-guided fiducial marker placement, it is necessary for the fiducial markers to be loaded within the EUS-FNA needles to have a low probability of complications and a low migration risk, and to be stably observed in SBRT imaging. A systematic review has shown that the technical success rate of EUS-guided fiducial marker placement is 96.27%, whereas the fiducial marker migration and adverse event rates are 4.33% and 4.85%, respectively. Nonetheless, standardized techniques for fiducial marker placement and the characteristics of optimal fiducial markers have not yet been established. This review will introduce the characteristics (e.g., materials and shapes) of fiducial markers used in fiducial marker placement for pancreatic cancer and will discuss conventional techniques along with their success rates, difficulties, and adverse events.

Along with the increase in the production, distribution, and consumption of chemicals, the risk of chemical accidents is increasing, and damage by chemicals exposure accidents can be greatly expanded if initial response is inappropriate. Since early determination of chemical substances in the event of a leakage accident is essential for minimizing accidental loss, this study proposes an AI-based system that supports chemical determination by field personnel based on exposure symptoms, in addition to detection using sensors, and provides predictive information on symptoms that may be lacking for new chemicals. In order to analyze and document the symptoms expressed when contacting chemical substances, the knowledge of domestic and foreign symptoms is established as a knowledge base using a knowledge graph. Afterwards, the symptom-based chemical estimation knowledge service is completed by estimating exposed chemicals through reasoning methods such as SPARQL and providing response information that can be immediately taken on site. In order to expand the knowledge of new chemicals, machine learning is used to predict useful symptom information from molecular structure information of chemicals, so that pre-emptive risk management for new materials could be carried out using the proposed system.

Huntington’s disease (HD) is a severe inherited neurological disorder caused by a CAG repeat expansion in the huntingtin gene (HTT), leading to the accumulation of mutant huntingtin with polyglutamine repeats. Despite its severity, there is no cure for this debilitating disease. HTT lowering strategies, including antisense oligonucleotides (ASO) showed promising results very recently. Attempts to develop stem cell-based therapeutics have shown efficacy in preclinical HD models. Using an HD patient’s autologous cells, which have genetic defects, may hamper therapeutic efficacy due to mutant HTT. Pretreating these cells to reduce mutant HTT expression and transcription may improve the transplanted cells’ therapeutic efficacy. To investigate this, we targeted the SUPT4H1 gene that selectively supports the transcription of long trinucleotide repeats. Transplanting SUPT4H1-edited HD-induced pluripotent stem cell-derived neural precursor cells (iPSC-NPCs) into the YAC128 HD transgenic mouse model improved motor function compared to unedited HD iPSC-NPCs. Immunohistochemical analysis revealed reduced mutant HTT expression without compensating wild-type HTT expression. Further, SUPT4H1 editing increased neuronal and decreased reactive astrocyte differentiation in HD iPSC-NPCs compared to the unedited HD iPSC-NPCs. This suggests that ex vivo editing of SUPT4H1 can reduce mutant HTT expression and provide a therapeutic gene editing strategy for autologous stem cell transplantation in HD.

Endoscopic therapy (ET) has been used to treat nonampullary duodenal neuroendocrine tumors (NAD-NETs) ≤10 mm in size, but data on long-term outcomes are limited. In addition, management of 11- to 19-mm NAD-NETs is not well defined because of variable estimates of risk of metastasis. We aimed to determine the prevalence and risk factors of metastasis of NAD-NETs ≤19 mm and evaluate the long-term survival of patients after ET as compared with radical surgery.The Surveillance Epidemiology and End Result database was used to identify 1243 patients with T1-2 histologically confirmed NAD-NETs ≤19 mm in size. Cancer-specific survival (CSS) and overall survival (OS) were calculated.Overall, 4.8% of cases had metastasis at the time of diagnosis, with lower prevalence in ≤10-mm lesions (3.1%) versus 11- to 19-mm lesions (11.7%, P .001). The risk factors for metastases included invasion to the muscularis propria (odds ratio, 25.95; 95% confidence interval, 9.01-76.70), age 65 years (odds ratio, 1.93), submucosal involvement (odds ratio, 3.1), and 11 to 19 mm in size (vs ≤10 mm). In patients with well- to moderately differentiated T1-2N0M0 NAD-NETs ≤19 mm confined to the mucosa/submucosa who underwent ET or surgery, the 5-year CSS was 100%. The 5-year OS was similar between the ≤10-mm and 11- to 19-mm groups (86.6% vs 91.0%, P = .31) and the ET and surgery groups (87.4% vs 87.5%, P = .823).In NAD-NETs, invasion to the muscularis propria is the strongest risk factor for metastasis. In the absence of metastasis, in lesions with well/moderate differentiation and without muscle invasion, ET is adequate for NAD-NETs ≤10 mm and is a viable option for 11- to 19-mm lesions.

Purpose of review Dose escalation radiation therapy such as those delivered by stereotactic body radiation therapy (SBRT) has shown to improve local disease control in multiple types of malignancies. This requires fiducial placement to improve accuracy of treatment and avoid adverse events to adjacent radiosensitive organs during respiration phases. The purpose of this review is to provide updates of recent high-quality articles related to endoscopic ultrasonography (EUS)-guided fiducial placement for gastrointestinal malignancies, particularly in pancreatic cancer, which is expected to be the second leading cause of cancer-related deaths in the USA within this decade. Recent findings A recent systematic review and meta-analysis has shown that EUS-guided fiducial placement for gastrointestinal malignancies has excellent technical success and safety profile. Comparative studies of most commercially available fiducial types via a 22-gauge needle system showed that a 0.035 mm diameter and 10 mm long gold fiducial with coiled configuration, hollow core and external helical design might be favoured due to its most balanced performance of visibility, artifact and migration. Summary A fine balance of performance characteristics of fiducials should be discussed with radiation oncologists to select a suitable and preferred type of fiducials. The comparative studies of other newly developed platinum fiducials and liquid fiducial are pending.

321 Background: The phase III CheckMate 577 study resulted in adjuvant nivolumab becoming a new standard of care for patients with completely resected E/GEJ cancer with residual pathologic disease post neoadjuvant chemoradiotherapy. We evaluated if neoadjuvant nivolumab (N) or nivolumab/relatlimab (N/R) combined with chemoradiotherapy (CRT) can further improve patient outcomes. Methods: Patients with stage II/III E/GEJ carcinoma eligible for curative resection were treated with standard of care regimen of carboplatin (AUC2), paclitaxel (50mg/m2), RT 41.1Gy in 23 fractions and an Ivor-Lewis esophagectomy (E/MIE) 6-10 weeks after last CRT/IO dose. Patients on arm A (n=16) received 2 cycles of induction N (240mg q2 wks) plus three additional cycles of N on week 1, 3 and 5 of CRT. After safety and feasibility evaluation of arm A, patients on arm B (n=16) received N (240mg q 2 wks) plus R (80mg q 2 wks) following the same schedule. The primary endpoints of the study were safety and feasibility. Secondary endpoints include pCR, MPR (

Background Larger caliber lumen-apposing stents (LAMSs) have been increasingly used in the management of pancreatic fluid collections, specifically when solid debris is present; however, their advantages over smaller caliber plastic stents in the management of pancreatic pseudocysts are unclear. The aim of this study was to investigate the safety and efficacy of LAMS specifically in the management of pancreatic pseudocysts compared with double-pigtail plastic stents (DPPSs). Methods We performed a multicenter, international, retrospective study between January 2012 and August 2016. A total of 205 patients with a diagnosis of pancreatic pseudocysts were included, 80 patients received LAMSs and 125 received DPPSs. Measured outcomes included clinical success, technical success, adverse events, stent dysfunction, pancreatic pseudocyst recurrence, and need for surgery. Results Technical success was similar between the LAMS and the DPPS groups (97.5 % vs. 99.2 %; P = 0.32). Clinical success was higher for LAMSs than for DPPSs (96.3 % vs. 87.2 %; P = 0.03). While the need for surgery was similar between the two groups (1.3 % vs. 4.9 %, respectively; P = 0.17), the use of percutaneous drainage was significantly lower in the LAMS group (1.3 % vs. 8.8 %; P = 0.03). At 6-month follow-up, the recurrence rate was similar between the groups (6.7 % vs 18.8 %, respectively; P = 0.12). The rate of adverse events was significantly higher in the DPPS group (7.5 % vs. 17.6 %; P = 0.04). There was no difference in post-procedure mean length of hospital stay (6.3 days [standard deviation 27.9] vs. 3.7 days [5.7]; P = 0.31). Conclusion When compared to DPPSs, LAMSs are a safe, feasible, and effective modality for the treatment of pancreatic pseudocysts and are associated with a higher rate of clinical success, shorter procedure time, less need for percutaneous interventions, and a lower overall rate of adverse events.