Ten-year survival after endoscopic stent placement as a bridge to surgery in obstructing colon cancer.

BACKGROUND AND AIMS: Self-expandable metal stents are used increasingly in the treatment of obstructing colorectal cancer (CRC). Although endoscopic colon stenting is widely accepted in palliation, disagreement exists about its role in a curative setting. This study aims to describe long-term survival data in a large patient group treated with colon stenting as a bridge to surgery for CRC. METHODS: This prospective study included 97 patients who presented in a Belgian hospital between 1998 and 2013 with obstructing, although potentially curable, CRC. All patients underwent endoscopic stenting as a bridge to surgery. Procedure-related adverse events and long-term follow-up data were retrospectively collected and compared with the CRC mortality in Belgium in the same time span. RESULTS: Overall survival in this observational cohort did not differ significantly from survival in all Belgian patients with CRC in the same period (P = .14). One-year, 5-year, and 10-year survival rates were similar in both groups (95.9% vs 79.0%; 54.7% vs 51.2%; 41.0% vs 35.6%, respectively). The technical success rate was 94.8%. Seventy-three patients did not experience any adverse event. Stent migration occurred in 9 patients, whereas micro-perforations and macro-perforations were observed in 14 patients, without influence on survival. Incidence rates of peritoneal metastases did not differ between patients with and without any type of perforation (22.2% vs 15.2%, respectively; P = .47). The type of stent influenced the overall adverse event risk, mainly driven by a significant increase in stent migration in case of Wallstent enteral (Boston Scientific Corporation, Natick, Mass). CONCLUSIONS: Colon stenting before surgery is effective and did not worsen the survival outcome in patients with obstructing CRC who were treated with curative intent, which affirms the role for stenting as a bridge to surgery.

A real-world analysis on the efficacy and tolerability of liposomal irinotecan plus 5-fluorouracil and folinic acid in metastatic pancreatic ductal adenocarcinoma in Belgium.

Background: Currently, nanoliposomal irinotecan (nal-IRI) + 5-fluorouracil/folinic acid (5-FU/LV) is the only approved second-line treatment for patients suffering from metastatic pancreatic ductal adenocarcinoma (mPDAC). However, also other chemotherapeutic regimens are used in this setting and due to the lack of clear real-world data on the efficacy of the different regimens, there is no consensus on the optimal treatment sequence for mPDAC patients. Objectives: To provide information on the safe and efficacious use of nal-IRI + 5-FU/LV in clinical practice in Belgium, which is needed for healthcare professionals to estimate the risk-benefit ratio of the intervention. Methods: Medical data of adult patients with mPDAC who were treated with nal-IRI + 5-FU/LV in one of the participating Belgian hospitals were retrospectively collected. Kaplan-Meier analysis was performed to obtain survival curves to estimate the median overall survival (OS) and progression-free survival (PFS). All other results were presented descriptively. Results: A total of 56 patients [median age at diagnosis: 69 years (range 43 years), 57.1% male] were included. Patients received a median of 5 (range 49 cycles) nal-IRI + 5-FU/LV cycles, extended over 10 weeks (range 130.8 weeks). The median start dose for nal-IRI was 70 mg/m² (range 49.24 mg/m²) and chemotherapy dose reduction and delay occurred in, respectively, 42.8% and 37.5% of the patients. The median OS was 6.8 months (95% CI: 5.6-8.4 months) with a 6-month survival rate of 57.4% and a 1-year survival rate of 27.8% in the overall study population. The median OS for patients treated with nal-IRI as second-line therapy or as later-line treatment was, respectively, 6.8 months (95% CI: 5.9-7.0 months) and 5.6 months (95% CI: 4.2-no upper limit). In the overall study population, a median PFS of 3.1 months (95% CI: 2.4-4.6 months) and a disease control rate of 48.3%, comprising 30.4% stable disease, 16.1% partial and 1.8% complete response, was observed. The median PFS for patients treated with nal-IRI as second-line therapy was 3.9 months (95% CI: 2.8-4.8 months) while this was 2.4 months (95% CI: 1.9-9.1 months) for those that received nal-IRI in a later-line treatment. In terms of safety, gastrointestinal problems occurred most (64.3% of the patients) and from all reported treatment emergent adverse events, 39.2% were grade 3 or 4. Conclusion: Nal-IRI + 5-FU/LV is a valuable, effective, and safe sequential treatment option following gemcitabine-based therapy in patients with mPDAC. Trial details: Retrospective study on the efficacy and tolerability of liposomal irinotecan (NALIRI); ClinicalTrials.gov Identifier: NCT0509506 (https://clinicaltrials.gov/ct2/show/NCT05095064?term=naliri&draw=2&rank=2).

NPY Methylated ctDNA is a Promising Biomarker for Treatment Response Monitoring in Metastatic Colorectal Cancer.

PURPOSE: Analysis of methylation markers in liquid biopsies is a promising technique for the follow-up of patients with metastatic colorectal cancer (mCRC), because they can be used in all patients, regardless of their mutational status. Therefore, we studied the value of NPY methylation analysis in circulating tumor DNA (ctDNA) for accurate response monitoring in patients with mCRC in the PANIB trial. EXPERIMENTAL DESIGN: The PANIB trial was a randomized phase II trial designed to compare FOLFOX plus panitumumab and FOLFOX plus bevacizumab in patients with RAS wild-type unresectable mCRC. The results of sequential liquid biopsies were correlated with results of imaging. RESULTS: Forty patients were included from six Belgian hospitals. Analysis of the liquid biopsies revealed that higher baseline levels of methylated ctDNA was associated with a significantly shorter overall survival [HR, 1.015; 95% confidence interval (CI), 1.005-1.025; P = 0.002]. Furthermore, 37 patients provided at least two liquid biopsies. Thirty-one of them showed a decrease in the methylation ratio after the start of therapy, which corresponded with stable disease or response on imaging at the first evaluation. When comparing the panitumumab and bevacizumab arm, significantly higher objective response and early tumor shrinkage rates were observed in the panitumumab arm (P = 0.048 and 0.015, respectively). However, due to a small study population, the trial was underpowered to detect a significant difference in survival. CONCLUSIONS: The results of this study confirm that baseline methylated ctDNA is a prognostic marker and indicate that NPY methylation is a promising marker for response monitoring in patients with mCRC.

Efficacy and Safety of Lanreotide Autogel in the Treatment of Clinical Symptoms Associated With Inoperable Malignant Intestinal Obstruction: A Prospective Phase II Study.

PURPOSE: Inoperable malignant intestinal obstruction (IMIO) is a severe complication in patients with cancer, usually gastrointestinal or gynecologic in origin. For patients with IMIO, there is a need to relieve symptoms and limit nasogastric tube (NGT) use. Previous studies have suggested the efficacy of somatostatin analogues in relieving obstruction-related symptoms, such as nausea, vomiting, and pain. The purpose of this study was to assess the efficacy of lanreotide autogel 120 mg (LAN 120 mg) in the management of symptoms resulting from IMIO in patients with advanced cancer. METHODS: This single-arm, multicenter study enrolled 52 patients mostly with advanced gastrointestinal or ovarian malignant tumors (35 patients with NGT and 17 patients without NGT). Patients received 1 deep subcutaneous injection of LAN 120 mg. Evaluations were performed on days 7, 14, and 28. The primary end point was the percentage of responding patients before or at day 7. Response was defined as ≤2 vomiting episodes per day (for patients without NGT at baseline) or no vomiting recurrence (after NGT removal) during at least 3 consecutive days at any time point between treatment and day 7. Responders at day 28 were offered a second LAN 120 mg injection and followed up until day 56. FINDINGS: The proportion of responders in the intention-to-treat population was 24 of 52 (46.2%), which was significantly greater than the reference proportion of 30% (P = 0.0055). Patients without NGT had a higher response (88.2%) than patients with NGT (25.7%) and had a steady trend for clinical improvement that led to sustainable responses. Median time to response was 9 days for the overall population, 3 days for patients without NGT, and 14 days for patients with NGT (P < 0.0001). IMPLICATIONS: Our study is the first to use long-acting LAN 120 mg in patients with IMIO and suggests an effect in controlling clinical symptoms in patients with and without NGT at baseline. The safety profile of LAN 120 mg was similar to that reported in other indications. ClinicalTrials.gov identifier: NCT02275338.

Safety evaluation of the double mutant 5-enol pyruvylshikimate-3-phosphate synthase (2mEPSPS) from maize that confers tolerance to glyphosate herbicide in transgenic plants.

Glyphosate tolerance can be conferred by decreasing the herbicide's ability to inhibit the enzyme 5-enol pyruvylshikimate-3-phosphate synthase, which is essential for the biosynthesis of aromatic amino acids in all plants, fungi, and bacteria. Glyphosate tolerance is based upon the expression of the double mutant 5-enol pyruvylshikimate-3-phosphate synthase (2mEPSPS) protein. The 2mEPSPS protein, with a lower binding affinity for glyphosate, is highly resistant to the inhibition by glyphosate and thus allows sufficient enzyme activity for the plants to grow in the presence of herbicides that contain glyphosate. Based on both a review of published literature and experimental studies, the potential safety concerns related to the transgenic 2mEPSPS protein were assessed. The safety evaluation supports that the expressed protein is innocuous. The 2mEPSPS enzyme does not possess any of the properties associated with known toxins or allergens, including a lack of amino acid sequence similarity to known toxins and allergens, a rapid degradation in simulated gastric and intestinal fluids, and no adverse effects in mice after intravenous or oral administration (at 10 or 2000 mg/kg body weight, respectively). In conclusion, there is a reasonable certainty of no harm resulting from the inclusion of the 2mEPSPS protein in human food or in animal feed.

Relative adrenal insufficiency in patients with severe acute pancreatitis.

OBJECTIVE: Inadequate cortisol levels and adrenal dysfunction may play a role in the pathophysiology of severe acute pancreatitis. This study aimed to analyse the incidence of relative adrenal insufficiency (RAI) in these patients, to identify factors associated with RAI and to describe how adrenal responsiveness affects outcome. DESIGN: Prospective observational multicenter study. PATIENTS: Twenty-five patients with severe acute pancreatitis. INTERVENTIONS: A short Synacthen test (SST) was performed within 5 days after admission to the hospital. The incidence of RAI, defined as an increment after SST of less than 9 microg/dl was the primary endpoint of the study. Serum cortisol was measured at baseline and at 30 and 60 min after administration of 250 microg adrenocorticotropic hormone. MEASUREMENTS AND RESULTS: Median baseline cortisol level was 26.6 microg/dl, and increased to 43.2 microg/dl and 48.8 microg/dl after 30 min and 60 min respectively. RAI was found in 16% of all patients and in 27% of patients with organ dysfunction. Patients with RAI were more severely ill and had higher SOFA scores from days 4 to 7 after admission. All patients with RAI developed pancreatic necrosis, and all of them needed surgical intervention. Twenty-eight-day mortality was significantly higher in patients with RAI (75% vs. 5%, p =0.007). Patients who died had a lower increment in cortisol levels after the SST than patients who survived. CONCLUSION: RAI is frequent in patients with severe acute pancreatitis and organ dysfunction. It occurs in patients with more severe pancreatitis and is associated with increased mortality.

Long-acting octreotide as secondary prevention of chemotherapy-induced diarrhea: proof of concept.

BACKGROUND: The aim of this study is to investigate the role of Octreotide LAR in secondary prevention in patients with chemotherapy-induced diarrhea. METHODS: In this study, patients experiencing CID ≥ grade 2 received 30 mg long-acting octreotide as a monthly injection and the next chemotherapy dose was administrated with a 25% dose decrease. If no CID ≥ grade 2 occurred, subsequent chemotherapy doses were increased to the initial 100% values. The primary endpoint of the study was the diarrhea control rate (< grade 2) for patients receiving the optimal dose of chemotherapy for a minimum of 2 cycles. RESULTS: Twenty-nine patients were included. Ten patients experienced no improvement or ended the study very early after the first injection of octreotide LAR. Nineteen patients had a reduction in the grade of diarrhea after the first administration of Octreotide LAR and a reduced chemotherapy dose. Seven of them (24%) did not reach the end of the study because of disease progression (6) or lost in follow-up (1). Ultimately 12 patients (41%) continued the study till the end. In ten of these twelve patients, there was a significant and persisting reduction of diarrhea while receiving full dose chemotherapy. CONCLUSION: This study suggests that monthly injections with long-acting octreotide might be used as a secondary prevention of chemotherapy-induced diarrhea. Its usefulness and optimal dosage in secondary prevention in combination with antidiarrheal agents needs further research.

Safety evaluation of the phosphinothricin acetyltransferase proteins encoded by the pat and bar sequences that confer tolerance to glufosinate-ammonium herbicide in transgenic plants.

Transgenic plant varieties, which are tolerant to glufosinate-ammonium, were developed. The herbicide tolerance is based upon the presence of either the bar or the pat gene, which encode for two homologous phosphinothricin acetyltransferases (PAT), in the plant genome. Based on both a review of published literature and experimental studies, the safety assessment reviews the first step of a two-step-approach for the evaluation of the safety of the proteins expressed in plants. It can be used to support the safety of food or feed products derived from any crop that contains and expresses these PAT proteins. The safety evaluation supports the conclusion that the genes and the donor microorganisms (Streptomyces) are innocuous. The PAT enzymes are highly specific and do not possess the characteristics associated with food toxins or allergens, i.e., they have no sequence homology with any known allergens or toxins, they have no N-glycosylation sites, they are rapidly degraded in gastric and intestinal fluids, and they are devoid of adverse effects in mice after intravenous administration at a high dose level. In conclusion, there is a reasonable certainty of no harm resulting from the inclusion of the PAT proteins in human food or in animal feed.