Surgical versus endoscopic gastroenterostomy for gastric outlet obstruction: a retrospective multicentric comparative study of technical and clinical success.

PURPOSE: Gastric outlet obstruction (GOO) is mainly due to advanced malignant disease. GOO can be treated by surgical gastroenterostomy (SGE), endoscopic enteral stenting (EES), or endoscopic ultrasound-guided gastroenterostomy (EUS-GE) to improve the quality of life. METHODS: Between 2009 and 2022, patients undergoing SGE or EUS-GE for GOO were included at three centers. Technical and clinical success rates, post-procedure adverse events (AEs), length of hospital stay (LOS), 30-day all-cause mortality, and recurrence of GOO were retrospectively analyzed and compared between SGE and EUS-GE. Predictive factors for technical and clinical failure after SGE and EUS-GE were identified. RESULTS: Of the 97 patients included, 56 (57.7%) had an EUS-GE and 41 (42.3%) had an SGE for GOO, with 62 (63.9%) GOO due to malignancy and 35 (36.1%) to benign disease. The median follow-up time was 13,4 months (range 1 days-106 months), with no difference between the two groups (p = 0.962). Technical (p = 0.133) and clinical (p = 0.229) success rates, severe morbidity (p = 0.708), 30-day all-cause mortality (p = 0.277) and GOO recurrence (p = 1) were similar. EUS-GE had shorter median procedure duration (p < 0.001), lower post-procedure ileus rate (p < 0.001), and shorter median LOS (p < 0.001) than SGE. In univariate analysis, no risk factors for technical or clinical failure in SGE were identified and abdominal pain reported before the procedure was a risk factor for technical failure in the EUS-GE group. No risk factor for clinical failure was identified for EUS-GE. In the subgroup of GOO due to benign disease, SGE was associated with better technical success (p = 0.035) with no difference in clinical success rate compared to EUS-GE (p = 1). CONCLUSION: EUS-GE provides similar long-lasting symptom relief as SGE for GOO whether for benign or malignant disease. SGE may still be indicated in centers with limited experience with EUS-GE or may be reserved for patients in whom endoscopic technique fails.

Endoscopic ultrasound-guided gastroenterostomy with lumen-apposing metal stents: a retrospective multicentric comparison of wireless and over-the-wire techniques.

BACKGROUND: Endoscopic ultrasound-guided gastroenterostomy (EUS-GE) using lumen-apposing metal stents (LAMSs) appears to be effective and safe in gastric outlet obstruction (GOO); however, the EUS-GE procedure is not standardized, with the use of assisted or direct methods still debated. The aim of this study was to compare the outcomes of EUS-GE techniques focusing on an assisted with orointestinal drain wireless endoscopic simplified technique (WEST) and the nonassisted direct technique over a guidewire (DTOG). METHOD: This was a multicenter European retrospective study involving four tertiary centers. Consecutive patients who underwent EUS-GE for GOO between August 2017 and May 2022 were included. The primary aim was to compare the technical success and adverse event (AE) rates of the different EUS-GE techniques. Clinical success was also analyzed. RESULTS: 71 patients (mean [SD] age 66.2 10 years; 42.3 % men; 80.3 % malignant etiology) were included. Technical success was higher in the WEST group (95.1 % vs. 73.3 %; estimate of relative risk from odds ratio (eRR) 3.2, 95 %CI 0.94-10.9; P = 0.01). The rate of AEs was lower in the WEST group (14.6 % vs. 46.7 %; eRR 2.3, 95 %CI 1.2-4.5; P = 0.007). Clinical success was comparable between the two groups at 1 month (97.5 % vs. 89.3 %). The median follow-up was 5 months (range 1-57). CONCLUSION: The WEST resulted in a higher technical success rate with fewer AEs, with clinical success comparable with the DTOG. Therefore, the WEST (with an orointestinal drain) should be preferred when performing EUS-GE.

Risk factors for EUS-guided radiofrequency ablation adverse events in patients with pancreatic neoplasms: a large national French study (RAFPAN study).

BACKGROUND AND AIMS: EUS-guided radiofrequency ablation (EUS-RFA) has been described as a potentially curative option for solid and cystic pancreatic neoplasms. We aimed to assess the safety and efficacy of pancreatic EUS-RFA in a large study population. METHODS: A retrospective study retrieving all consecutive patients who underwent pancreatic EUS-RFA during 2019 and 2020 in France was conducted. Indication, procedural characteristics, early and late adverse events (AEs), and clinical outcomes were recorded. Risk factors for AEs and factors related to complete tumor ablation were assessed on univariate and multivariate analyses. RESULTS: One hundred patients (54% men, 64.8 ± 17.6 years old) affected by 104 neoplasms were included. Sixty-four neoplasms were neuroendocrine neoplasms (NENs), 23 were metastases, and 10 were intraductal papillary mucinous neoplasms with mural nodules. No procedure-related mortality was observed, and 22 AEs were reported. Proximity of pancreatic neoplasms (≤1 mm) to the main pancreatic duct was the only independent risk factor for AEs (odds ratio [OR), 4.10; 95% confidence interval [CI), 1.02-15.22; P = .04). Fifty-nine patients (60.2%) achieved a complete tumor response, 31 (31.6%) a partial response, and 9 (9.2%) achieved no response. On multivariate analysis, NENs (OR, 7.95; 95% CI, 1.66-51.79; P < .001) and neoplasm size <20 mm (OR, 5.26; 95% CI, 2.17-14.29; P < .001) were independently related to complete tumor ablation. CONCLUSIONS: The results of this large study confirm an overall acceptable safety profile for pancreatic EUS-RFA. Close proximity (≤1 mm) to the main pancreatic duct represents an independent risk factor for AEs. Good clinical outcomes in terms of tumor ablation were observed, especially for small NENs.

Endoscopic ultra-sound (EUS) guided management of symptomatic pelvic collections: puncture-aspiration or drainage? Results from mono-centric retrospective experience with therapeutic algorithm.

BACKGROUND: Pelvic collections may occur after surgery or in medical diseases. EUS transmural (TM) treatment has been shown as highly effective and safe, becoming an alternative to surgery or radiology. We aimed to assess the results of EUS management of pelvic collections. METHODS: Retrospective, single-center observational study conducted between 2004 and 2018. Patients with symptomatic collections treated by EUS-TM approach were enrolled. The procedures were performed with a therapeutic EUS-scope, following two possible options: puncture-aspiration-injection of antibiotics PAIA (group 1) or EUS-drainage by plastic double pigtail stents (DPS) with an ano-cavitary drain (ACD) or lumen-apposing metal Stent (LAMS) (group 2). The main objective was to assess the clinical effectiveness based on symptoms and collection resolution. RESULTS: Seventy-three patients were included. Mean age was 42.5 years [12-87]. 30 patients in group 1 (41%) underwent PAIA and 43 in group 2 (59%) underwent DPS ± ACD in 41 patients (95%) and LAMS in 2. The collection was postoperative in 58%. The mean size was 48.9 mm [8-120], 33 +/- 17 mm in group 1, compared to 67 ± 21 mm in group 2 (p < .0001). All the procedures were technically successful. Overall clinical success was 96% (93% in group 1 (28/30), 98% (42/43) in group 2). Failures occurred in 2 post sigmoiditis abscesses and 1 ileo-colic Crohn's disease. No adverse event was reported. During the median follow-up of 7.5 years [4.4-8.9], no patient had recurrence. CONCLUSIONS: EUS-TM with either PAIA or drainage depending on the collection size is confirmed to be highly effective and safe.

Long-term outcome after EUS-guided radiofrequency ablation: Prospective results in pancreatic neuroendocrine tumors and pancreatic cystic neoplasms.

Background and study aims Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) for pancreatic neuroendocrine tumors (NETs) and intraductal pancreatic mucinous neoplasia (IPMN) with worrisome features or high-risk stigmata (WF/HRS) has been evaluated in few series with short-term outcomes. This study's primary endpoint was to assess the long-term efficacy of EUS-RFA in patients with NETs or pancreatic cystic neoplasms (PCNs) over at least 3 years. Patients and methods Twelve patients had 14 NETs with a mean 13.4-mm size (10-20) and 17 patients had a cystic tumor (16 IPMN, 1 MCA) with a 29.1-mm mean size (9-60 were included. They were treated with EUS-guided RFA, evaluated prospectively at 1 year, and followed annually for at least 3 years. Results The mean duration of follow-up was 42.9 months (36-53). Four patients died during follow-up (17-42 months) from unrelated diseases. At 1-year follow-up, and 85.7 % complete disappearance was seen in 12 patients with 14 NETs. At the end of follow-up (45.6 months), complete disappearance of tumors was seen in 85.7 % of cases. One case of late liver metastasis occurred in a patient with initial failure of EUS-RFA. At 1-year follow-up, a significant response was seen in 70.5 % of 15 patients with PCNs. At the end of the follow-up, there was a significant response in 66.6 % with no mural nodules. Two cases of distant pancreatic adenocarcinoma unrelated to IPMN occurred. Conclusions EUS-RFA results for pancreatic NETs or PCNs appear to be stable during 42 months of follow-up.

Predictive factors for early progression during induction chemotherapy and chemotherapy-free interval: analysis from PRODIGE 9 trial.

BACKGROUND: Identifying patients with metastatic colorectal cancer who will have an early disease progression during induction chemotherapy (IC) and identifying patients who may have a chemotherapy-free interval (CFI) after IC are two major challenges. METHODS: A logistic model was used to identify factors associated with early progression during IC and with short duration of the first CFI in 488 patients enrolled in the PRODIGE 9 trial. Independent factors were defined with a threshold 0.10. RESULTS: In multivariate analysis, baseline leukocytes >10 × 109/L (OR = 1.98 [1.02-3.8], p = 0.04), and stable or increasing CEA at 2 months (OR = 3.61 [1.68-7.75], p = 0.01) were independent factors associated with progression during IC. Male gender (OR = 1.725 [0.92-3.325], p = 0.09) and no tumour response at first evaluation (OR = 1.90 [0.96-3.76], p = 0.07) were significantly associated with a short CFI. The presence of BRAF V600E mutation was also associated with short CFI (OR = 4.59 [0.95; 22.3], p = 0.058). CONCLUSION: High baseline leukocyte count and the lack of CEA decrease level at first evaluation were associated with early progression, and could be in favour of early chemotherapy intensification. Male gender, no tumour response at first evaluation and BRAF mutation are associated with a short CFI, and may be considered for maintenance chemotherapy after IC. CLINICAL TRIAL NUMBER: NCT00952029.

Artificial intelligence-guided tissue analysis combined with immune infiltrate assessment predicts stage III colon cancer outcomes in PETACC08 study.

OBJECTIVE: Diagnostic tests, such as Immunoscore, predict prognosis in patients with colon cancer. However, additional prognostic markers could be detected on pathological slides using artificial intelligence tools. DESIGN: We have developed a software to detect colon tumour, healthy mucosa, stroma and immune cells on CD3 and CD8 stained slides. The lymphocyte density and surface area were quantified automatically in the tumour core (TC) and invasive margin (IM). Using a LASSO algorithm, DGMate (DiGital tuMor pArameTErs), we detected digital parameters within the tumour cells related to patient outcomes. RESULTS: Within the dataset of 1018 patients, we observed that a poorer relapse-free survival (RFS) was associated with high IM stromal area (HR 5.65; 95% CI 2.34 to 13.67; p<0.0001) and high DGMate (HR 2.72; 95% CI 1.92 to 3.85; p<0.001). Higher CD3+ TC, CD3+ IM and CD8+ TC densities were significantly associated with a longer RFS. Analysis of variance showed that CD3+ TC yielded a similar prognostic value to the classical CD3/CD8 Immunoscore (p=0.44). A combination of the IM stromal area, DGMate and CD3, designated 'DGMuneS', outperformed Immunoscore when used in estimating patients' prognosis (C-index=0.601 vs 0.578, p=0.04) and was independently associated with patient outcomes following Cox multivariate analysis. A predictive nomogram based on DGMuneS and clinical variables identified a group of patients with less than 10% relapse risk and another group with a 50% relapse risk. CONCLUSION: These findings suggest that artificial intelligence can potentially improve patient care by assisting pathologists in better defining stage III colon cancer patients' prognosis.

Fertility preservation strategies for rectal cancer in reproductive-age women.

Despite rectal cancer being unusual before 40, fertility preservation (FP) remains a major concern for these reproductive-age women. Treatment usually involves pelvic radiotherapy, neoadjuvant chemotherapy, and surgery of rectum and mesorectum resection, at high risk of impairing fertility in women with risks of premature ovarian failure and radio-induced uterus damage. To date, there is no consensus on FP strategy for rectal cancer. We shared experiences between oncofertility experts from a French research network Groupe de Recherche et d'Etude en Cryoconservation Ovarienne et Testiculaire about a case of rectal cancer in a young woman. Indications, advantages and disadvantages of different FP strategies were discussed: ovarian transposition, cryopreservation of ovarian cortex and oocyte vitrification. This case was the starting point that led to the development of a French multidisciplinary e-meeting for sharing experiences and for suggesting the best strategy when faced with a complex oncofertility case.

Quality of life and cost of strategies of two chemotherapy lines in metastatic colorectal cancer: results of the FFCD 2000-05 trial.

Objectives: This study compared the cost and quality of life (QoL) of 407 advanced colorectal cancer patients, randomly assigned to receive LV5FU2 followed by FOLFOX6 (sequential strategy) or FOLFOX6 followed by FOLFIRI (combination strategy). Methods: Costs were compared from the French health insurance perspective, until the end of the second line of treatment. Consumed resources, collected during the trial, included medicines, hospitalizations, examinations, and transportation. Valuations were made using 2009 and 2016 tariffs. QoL was assessed using the QLQ-C30 questionnaire and clinically significant variations were searched. Results: In 2009, the mean cost per patient was significantly lower for the sequential strategy compared to the combination strategy (18,061€ and 23,119€, p = 0.001). In 2016, the difference was no longer significant (16,876€ and 18,090€, p = 0.41) because oxaliplatin and irinotecan became generics. The QoL analysis (292 patients) showed that there was significantly less improvement of global health status in the sequential strategy than in the combination strategy (29% and 42%; p = 0.02) during first-line therapy. No significant differences were observed for emotional functioning (p = 0.45) and physical functioning (p = 0.07) or during second-line therapy. Conclusion: The choice to treat patients with advanced colorectal cancer using one or the other strategy cannot be based on costs or QoL.

Endoscopic ultrasound-guided radiofrequency ablation for pancreatic neuroendocrine tumors and pancreatic cystic neoplasms: a prospective multicenter study.

BACKGROUND: Pancreatic neuroendocrine tumors (NETs) and intraductal pancreatic mucinous neoplasia (IPMN) with worrisome features are surgically managed. Endoscopic ultrasound (EUS)-guided radiofrequency ablation (RFA) has recently been developed. The safety of EUS-RFA was the primary end point of this study, its efficacy the secondary end point. METHODS: This was a prospective multicenter study that was planned to include 30 patients with a 1-year follow-up with either a NET < 2 cm or a pancreatic cystic neoplasm (PCN), either a branch duct IPMN with worrisome features or a mucinous cystadenoma (MCA). EUS-RFA was performed with an 18G RFA cooling needle. RESULTS: 12 patients had 14 NETs (mean size 13.1 mm, range 10 - 20 mm); 17 patients had cystic tumors (16 IPMNs, 1 MCA; mean size 28 mm, range 9 - 60 mm). Overall three adverse events occurred (10 %), two of these in the first two patients (one pancreatitis, one small-bowel perforation). After these initial patients, modifications in the protocol resulted in a decrease in complications (3.5 %), with one patient having a pancreatic ductal stenosis. Among the 14 NETs, at 1-year follow-up 12 had completely disappeared (86 % tumor resolution), with three patients having a delayed response. Among the 17 PCNs, at 12 months, there were 11 complete disappearances and one diameter that decreased by > 50 % (significant response rate 71 %). All 12 mural nodules showed complete resolution. CONCLUSIONS: EUS-RFA of pancreatic NETs or PCNs is safe with a 10 % complication rate, which can be decreased by improved prophylaxis for the procedure.

Distinct epigenetic landscapes underlie the pathobiology of pancreatic cancer subtypes.

Recent studies have offered ample insight into genome-wide expression patterns to define pancreatic ductal adenocarcinoma (PDAC) subtypes, although there remains a lack of knowledge regarding the underlying epigenomics of PDAC. Here we perform multi-parametric integrative analyses of chromatin immunoprecipitation-sequencing (ChIP-seq) on multiple histone modifications, RNA-sequencing (RNA-seq), and DNA methylation to define epigenomic landscapes for PDAC subtypes, which can predict their relative aggressiveness and survival. Moreover, we describe the state of promoters, enhancers, super-enhancers, euchromatic, and heterochromatic regions for each subtype. Further analyses indicate that the distinct epigenomic landscapes are regulated by different membrane-to-nucleus pathways. Inactivation of a basal-specific super-enhancer associated pathway reveals the existence of plasticity between subtypes. Thus, our study provides new insight into the epigenetic landscapes associated with the heterogeneity of PDAC, thereby increasing our mechanistic understanding of this disease, as well as offering potential new markers and therapeutic targets.

Overweight is associated to a better prognosis in metastatic colorectal cancer: A pooled analysis of FFCD trials.

BACKGROUND: Previous studies showed that high and low body mass index (BMI) was associated with worse prognosis in early-stage colorectal cancer (CRC), and low BMI was associated with worse prognosis in metastatic CRC (mCRC). We aimed to assess efficacy outcomes according to BMI. PATIENTS AND METHODS: A pooled analysis of individual data from 2085 patients enrolled in eight FFCD first-line mCRC trials from 1991 to 2013 was performed. Comparisons were made according to the BMI cut-off: Obese (BMI ≥30), overweight patients (BMI ≥ 25), normal BMI patients (BMI: 18.5-24) and thin patients (BMI <18.5). Interaction tests were performed between BMI effect and sex, age and the addition of antiangiogenics to chemotherapy. RESULTS: The rate of BMI ≥25 patients was 41.5%, ranging from 37.6% (1991-1999 period) to 41.5% (2000-2006 period) and 44.8% (2007-2013 period). Comparison of overweight patients versus normal BMI range patients revealed a significant improvement of median overall survival (OS) (18.5 versus 16.3 months, HR = 0.88 [0.80-0.98] p = 0.02) and objective response rate (ORR) (42% versus 36% OR = 1.23 [1.01-1.50] p = 0.04) but a comparable median progression-free survival (PFS) (7.8 versus 7.2 months, HR = 0.96 [0.87-1.05] p = 0.35). Subgroup analyses revealed that overweight was significantly associated with better OS in men. OS and PFS were significantly shorter in thin patients. CONCLUSION: Overweight patients had a prolonged OS compared with normal weight patients with mCRC. The association of overweight with better OS was only observed in men. The pejorative prognosis of BMI <18.5 was confirmed.

Pancreatic Adenocarcinoma Therapeutic Targets Revealed by Tumor-Stroma Cross-Talk Analyses in Patient-Derived Xenografts.

Preclinical models based on patient-derived xenografts have remarkable specificity in distinguishing transformed human tumor cells from non-transformed murine stromal cells computationally. We obtained 29 pancreatic ductal adenocarcinoma (PDAC) xenografts from either resectable or non-resectable patients (surgery and endoscopic ultrasound-guided fine-needle aspirate, respectively). Extensive multiomic profiling revealed two subtypes with distinct clinical outcomes. These subtypes uncovered specific alterations in DNA methylation and transcription as well as in signaling pathways involved in tumor-stromal cross-talk. The analysis of these pathways indicates therapeutic opportunities for targeting both compartments and their interactions. In particular, we show that inhibiting NPC1L1 with Ezetimibe, a clinically available drug, might be an efficient approach for treating pancreatic cancers. These findings uncover the complex and diverse interplay between PDAC tumors and the stroma and demonstrate the pivotal role of xenografts for drug discovery and relevance to PDAC.

Gene expression profiling of patient-derived pancreatic cancer xenografts predicts sensitivity to the BET bromodomain inhibitor JQ1: implications for individualized medicine efforts.

c-MYC controls more than 15% of genes responsible for proliferation, differentiation, and cellular metabolism in pancreatic as well as other cancers making this transcription factor a prime target for treating patients. The transcriptome of 55 patient-derived xenografts show that 30% of them share an exacerbated expression profile of MYC transcriptional targets (MYC-high). This cohort is characterized by a high level of Ki67 staining, a lower differentiation state, and a shorter survival time compared to the MYC-low subgroup. To define classifier expression signature, we selected a group of 10 MYC target transcripts which expression is increased in the MYC-high group and six transcripts increased in the MYC-low group. We validated the ability of these markers panel to identify MYC-high patient-derived xenografts from both: discovery and validation cohorts as well as primary cell cultures from the same patients. We then showed that cells from MYC-high patients are more sensitive to JQ1 treatment compared to MYC-low cells, in monolayer, 3D cultured spheroids and in vivo xenografted tumors, due to cell cycle arrest followed by apoptosis. Therefore, these results provide new markers and potentially novel therapeutic modalities for distinct subgroups of pancreatic tumors and may find application to the future management of these patients within the setting of individualized medicine clinics.

Geriatric factors analyses from FFCD 2001-02 phase III study of first-line chemotherapy for elderly metastatic colorectal cancer patients.

AIM: Several predictors of metastatic colorectal cancer (mCRC) outcomes have been described. Specific geriatric characteristics could be of interest to determine prognosis. METHOD: Elderly patients (75+) with previously untreated mCRC were randomly assigned to receive infusional 5-fluorouracil-based chemotherapy, either alone (FU) or in combination with irinotecan (IRI). Geriatric evaluations were included as an optional procedure. The predictive value of geriatric parameters was determined for the objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). RESULTS: From June 2003 to May 2010, the FFCD 2001-02 randomised trial enrolled 282 patients. A baseline geriatric evaluation was done in 123 patients; 62 allocated to the FU arm and 61 to the IRI arm. The baseline Charlson index was ≤1 in 75%, Mini-Mental State Examination was ≤27/30 in 31%, Geriatric Depression Scale was >2 in 10% and Instrumental Activities of Daily Living (IADL) was impaired in 34% of the patients. Multivariate analyses revealed that no geriatric parameter was predictive for ORR or PFS. Normal IADL was independently associated with better OS. The benefit of doublet chemotherapy on PFS differed in subgroups of patients ≤80 years, with unresected primary tumour, leucocytes >11,000 mm3 and carcinoembryonic antigen >2N. There was a trend towards better OS in patients with normal IADL. CONCLUSION: The autonomy score was an independent predictor for OS. A trend toward a better efficacy of doublet chemotherapy in some subgroups of patients was reported and should be further explored.