Silencing mutated β-catenin inhibits cell proliferation and stimulates apoptosis in the adrenocortical cancer cell line H295R

Adrenocortical carcinoma (ACC) is a rare and highly aggressive endocrine neoplasm, with limited therapeutic options. Activating β-catenin somatic mutations are found in ACC and have been associated with a poor clinical outcome. In fact, activation of the Wnt/β-catenin signaling pathway seems to play a major role in ACC aggressiveness, and might, thus, represent a promising therapeutic target. Similar to patient tumor specimen the H295 cell line derived from an ACC harbors a natural activating β-catenin mutation. We herein assess the in vitro and in vivo effect of β-catenin inactivation using a doxycyclin (dox) inducible shRNA plasmid in H295R adrenocortical cancer cells line (clone named shβ). Following dox treatment a profound reduction in β-catenin expression was detectable in shβ clones in comparison to control clones (Ctr). Accordingly, we observed a decrease in Wnt/βcatenin-dependent luciferase reporter activity as well as a decreased expression of AXIN2 representing an endogenous β-catenin target gene. Concomitantly, β-catenin silencing resulted in a decreased cell proliferation, cell cycle alterations with cell accumulation in the G1 phase and increased apoptosis in vitro. In vivo, on established tumor xenografts in athymic nude mice, 9 days of β-catenin silencing resulted in a significant reduction of CTNNB1 and AXIN2 expression. Moreover, continous β-catenin silencing, starting 3 days after tumor cell inoculation, was associated with a complete absence of tumor growth in the shβ group while tumors were present in all animals of the control group. In summary, these experiments provide evidences that Wnt/β-catenin pathway inhibition in ACC is a promising therapeutic target

Study Protocol of the ESAP Study: Endoscopic Papillectomy vs. Surgical Ampullectomy vs. Pancreaticoduodenectomy for Ampullary Neoplasm—A Pancreas2000/EPC Study

Background: Lesions of the Ampulla of Vater are a rare condition and represent <10% of peri-ampullary neoplasms. Nevertheless, ampullary adenomas have the potential for malignant transformation to ampullary carcinomas by an adenoma-to-carcinoma sequence. Thus, adequate patient selection and complete resection (R0) of non-invasive ampullary lesions either by endoscopic papillectomy (EP), surgical ampullectomy (SA), or pancreaticoduodenectomy (PD) is essential. Although PD was traditionally performed, recent studies reported considerable efficacy and fewer complications following EP and SA. Since consistent comparative data are lacking, the Endoscopic Papillectomy vs. Surgical Ampullectomy vs. Pancreaticoduodectomy (ESAP) study will provide evidence for a therapeutic standard and post procedure morbidity in ampullary lesions. Methods: International multicenter retrospective study. Adult patients (>18 years of age) who underwent SA or PD for ampullary neoplasm between 2004 and 2018 or EP between 2007 and 2018 will be evaluated. Main inclusion criteria are ampullary lesions strictly located to the ampulla. This includes adenoma, adenocarcinoma (T1 and T2), neuroendocrine tumors, gastrointestinal stroma tumors and other rare conditions. Exclusion criteria are peri-ampullary lesions, e.g., from the duodenal wall or the head of the pancreas, and interventions for tumor stages higher than T2. The main objective of this study is to analyze rates of complete resection (R0), recurrence and necessity for complementary interventions following EP, SA, and PD. Treatment-quality for each procedure will be defined by morbidity, mortality and complication rates and will be compared between EP, SA, and PD. Secondary objectives include outcome for patients with incomplete resection or initially understated tumors, lesions of the minor papilla, hereditary syndromes, neuroendocrine tumors, mesenchymal lesions, and other rare conditions. Additionally, we will analyze therapy by argon plasma coagulation and radiofrequency ablation. Furthermore, outcome in curative and palliative interventions can be distinguished. Conclusion: The ESAP study will provide evidence for therapeutic algorithms and data for the implementation of guidelines in the treatment of different types of ampullary tumors, including recurrent, or incomplete resected lesions

Systematic Review with Meta-Analysis: Endoscopic and Surgical Resection for Ampullary Lesions

Ampullary lesions (ALs) can be treated by endoscopic (EA) or surgical ampullectomy (SA) or pancreaticoduodenectomy (PD). However, EA carries significant risk of incomplete resection while surgical interventions can lead to substantial morbidity. We performed a systematic review and meta-analysis for R0, adverse-events (AEs) and recurrence between EA, SA and PD. Electronic databases were searched from 1990 to 2018. Outcomes were calculated as pooled means using fixed and random-effects models and the Freeman-Tukey-Double-Arcsine-Proportion-model. We identified 59 independent studies. The pooled R0 rate was 76.6% (71.8–81.4%, I2 = 91.38%) for EA, 96.4% (93.6–99.2%, I2 = 37.8%) for SA and 98.9% (98.0–99.7%, I2 = 0%) for PD. AEs were 24.7% (19.8–29.6%, I2 = 86.4%), 28.3% (19.0–37.7%, I2 = 76.8%) and 44.7% (37.9–51.4%, I2 = 0%), respectively. Recurrences were registered in 13.0% (10.2–15.6%, I2 = 91.3%), 9.4% (4.8–14%, I2 = 57.3%) and 14.2% (9.5–18.9%, I2 = 0%). Differences between proportions were significant in R0 for EA compared to SA (p = 0.007) and PD (p = 0.022). AEs were statistically different only between EA and PD (p = 0.049) and recurrence showed no significance for EA/SA or EA/PD. Our data indicate an increased rate of complete resection in surgical interventions accompanied with a higher risk of complications. However, studies showed various sources of bias, limited quality of data and a significant heterogeneity, particularly in EA studies

Five days of postoperative antimicrobial therapy decreases infectious complications following pancreaticoduodenectomy in patients at risk for bile contamination

AbstractObjectivesPancreaticoduodenectomy (PD) is associated with high morbidity, in part as a result of infectious complications increased by preoperative bile contamination. The aim of the present study was to assess the effect on the incidence of infectious complications of short‐term antimicrobial therapy (AMT) in high‐risk patients.MethodsPatients with a high risk for positive intraoperative bile culture (i.e. those with ampulloma or pancreatic adenocarcinoma with preoperative endoscopic procedures) (high‐risk group, n = 99) were compared with low‐risk patients (i.e. those with pancreatic adenocarcinoma without preoperative endoscopic procedures) (low‐risk group, n = 76). The high‐risk group received a 5‐day course of perioperative AMT secondarily adapted to the bile antibiogram. The low‐risk group received only the usual antimicrobial prophylaxis.ResultsPositive bile cultures were significantly more frequent in high‐risk patients (81% versus 12%; P < 0.001). The overall rate of infectious complications was lower in the high‐risk group (29% versus 46%; P = 0.018). The statistically significant decrease in the rate of infectious complications reflected reduced rates of urinary tract infections, pulmonary infections and septicaemia. Rates of wound infection (3% versus 5%; P = 0.639) and intra‐abdominal abscess (7% versus 7%; P = 0.886) were similar in the high‐ and low‐risk groups, as was the need for curative AMT.ConclusionsThis exploratory study suggests that a postoperative short course of AMT in patients at high risk for biliary contamination reduces the overall rate of infectious complications after PD. The adaptation of perioperative antimicrobial policy to the patient's risk for bile contamination seems promising and should be further evaluated

Prognostic Role of Examined and Positive Lymph Nodes after Distal Pancreatectomy for Non-Functioning Neuroendocrine Neoplasms

Background: The most appropriate nodal staging system for non-functioning pancreatic neuroendocrine tumours (NF-PanNETs) remains unclear. Despite some evidence is available for pancreaticoduodenectomy, the adequate nodal staging is still unknown for distal pancreatectomy (DP). The aim of the present study was to evaluate the prognostic impact of the number of positive lymph nodes (PLNs) after DP for NF-PanNETs and to define the minimal number of lymph nodes to be harvested for an appropriate nodal staging. Methods: Data were retrospectively collected from patients who underwent DP with curative intent (R0-R1) for sporadic well-differentiated NF-PanNETs in 4 European high-volume centres. NF-PanNETs with nodal involvement (N+) were subclassified into N1 (1–3 PLNs) and N2 (4 or more PLNs). Univariate and multivariate analyses of disease-free survival (DFS) were performed. Results: Of 271 patients in the study, 62 (23%) had nodal involvement (N+). A higher probability of N+ was associated with the following factors: grading, resection margin status, perineural and microvascular invasion, and the number of examined lymph nodes. Three-year DFS rate for N0, N1, and N2 patients was 92, 72, and 50%, respectively (p &#x3c; 0.001). At multivariate analysis, independent predictors of DFS were grading, T stage, presence of necrosis, and nodal status. For patients with ≥12 examined/resected lymph nodes, the N status remained a significant predictor of disease recurrence (p &#x3c; 0.001), while it failed to predict recurrence in patients with &#x3c;12 lymph nodes examined/resected (p = 0.116). Conclusions: A minimal number of 12 nodes should be harvested in case of DP for NF-PanNET for an appropriate nodal staging. The number of positive lymph nodes is an independent predictor of DFS after DP for NF-PanNET, and the N0/N1/N2 nodal classification seems to be more relevant than the current N0/N+ staging

Efficacy and safety of filgotinib in methotrexate-naive patients with rheumatoid arthritis with poor prognostic factors: post hoc analysis of FINCH 3

OBJECTIVE: This analysis evaluated efficacy and safety of filgotinib, a Janus-associated kinase 1-preferential inhibitor, in methotrexate (MTX)-naive patients with rheumatoid arthritis (RA) with multiple poor prognostic factors (PPFs). METHODS: This was a post hoc analysis of the phase III, randomised, double-blind, active-controlled, FINCH 3 study (clinicaltrials.gov NCT02886728). Patients received once-daily oral filgotinib 200 or 100 mg plus once-weekly oral MTX ≤20 mg (FIL200 + MTX and FIL100 + MTX), filgotinib 200 mg monotherapy (FIL200), or oral MTX monotherapy (MTX-mono) for up to 52 weeks. PPFs investigated were seropositivity for rheumatoid factor or anticyclic citrullinated peptide antibodies, high-sensitivity C reactive protein (CRP) ≥4 mg/L, Disease Activity Score in 28 joints with CRP (DAS28(CRP)) >5.1, and presence of erosions. Filgotinib efficacy and safety in patients with all four PPFs at baseline were explored versus MTX-mono within this subgroup and compared informally with the overall population. RESULTS: Of 1249 patients in FINCH 3, 510 (40.8%) had all PPFs. Efficacy of FIL200 + MTX among these patients was comparable to the overall population, with higher rates of 20%/50%/70% improvement from baseline by American College of Rheumatology criteria, DAS28(CRP) <2.6, and remission; greater improvement in physical function and pain; and better inhibition of structural damage relative to MTX-mono. FIL100 + MTX and FIL200 were not consistently more efficacious versus MTX-mono. Safety of filgotinib in patients with PPFs was comparable to the overall population; no new safety signals were observed. CONCLUSION: FIL200 + MTX efficacy and safety in patients with multiple PPFs were similar to the overall population