White muscle disease in foals: focus on selenium soil content. A case series

BACKGROUND: White muscle disease (WMD) is a nutritional myopathy caused by selenium (Se) deficiency. In most soils, Se is present in low concentrations, sometimes even below 0.2 mg/kg, a trend which is seen in many countries. Apart from total soil Se concentrations, soil conditions may be such that the bio-availability of Se is so low that it causes very low uptake in plants which can ultimately lead to deficiency problems in animals. This is the first case series to report clinical WMD in foals in areas deficient in Se, in the Netherlands. The aim of the current report is to provide an overview of the clinical history, symptoms and (clinical) pathology of 8 newborn foals living at 4 different premises and suffering from WMD together with the effectiveness of Se and vitamin E (Vit E) supplementation in the affected foals, their dams and herd members. Hands on practical information is provided to apply a correct and effective Se supplementation management in horses and which pitfalls need to be avoided for a successful approach. CASE PRESENTATION: Case features and history were mapped out for all foals. Se and Vit E status were assessed for the foals, their dams and herd members, at admission and after 3 months of Vit E/Se supplementation. Common symptoms were muscle weakness, inability to rise, lethargy and inadequate suckle reflex together with increased serum muscle enzymes and low glutathione peroxidase (GSH-Px) and low to normal serum vit E levels. Necropsy revealed necrosis of skeletal muscles consistent with nutritional myopathy. Se status of the dams and herd members correlated well with the Se status of the foals. All surviving foals (n = 6) showed normal Vit E and GSH-Px levels after supplementation, likewise, all horses tested at premises 1, 3 and 4. However, dams and herd members in premises 2 showed no normalization. Horses of that premises were diagnosed with pyrrolizidine intoxication one year prior to the study. CONCLUSIONS: Certain regions in the Netherlands are sufficiently Se deficient to predispose newborn foals to develop WMD, especially when they are being fed a diet that mainly consists of locally harvested roughage

White muscle disease in foals: focus on selenium soil content. A case series

Background: White muscle disease (WMD) is a nutritional myopathy caused by selenium (Se) deficiency. In most soils, Se is present in low concentrations, sometimes even below 0.2 mg/kg, a trend which is seen in many countries. Apart from total soil Se concentrations, soil conditions may be such that the bio-availability of Se is so low that it causes very low uptake in plants which can ultimately lead to deficiency problems in animals. This is the first case series to report clinical WMD in foals in areas deficient in Se, in the Netherlands. The aim of the current report is to provide an overview of the clinical history, symptoms and (clinical) pathology of 8 newborn foals living at 4 different premises and suffering from WMD together with the effectiveness of Se and vitamin E (Vit E) supplementation in the affected foals, their dams and herd members. Hands on practical information is provided to apply a correct and effective Se supplementation management in horses and which pitfalls need to be avoided for a successful approach. Case presentation: Case features and history were mapped out for all foals. Se and Vit E status were assessed for the foals, their dams and herd members, at admission and after 3 months of Vit E/Se supplementation. Common symptoms were muscle weakness, inability to rise, lethargy and inadequate suckle reflex together with increased serum muscle enzymes and low glutathione peroxidase (GSH-Px) and low to normal serum vit E levels. Necropsy revealed necrosis of skeletal muscles consistent with nutritional myopathy. Se status of the dams and herd members correlated well with the Se status of the foals. All surviving foals (n = 6) showed normal Vit E and GSH-Px levels after supplementation, likewise, all horses tested at premises 1, 3 and 4. However, dams and herd members in premises 2 showed no normalization . Horses of that premises were diagnosed with pyrrolizidine intoxication one year prior to the study. Conclusions: Certain regions in the Netherlands are sufficiently Se deficient to predispose newborn foals to develop WMD, especially when they are being fed a diet that mainly consists of locally harvested roughage.status: publishe

Impact of Neoadjuvant Therapy in Resected Pancreatic Ductal Adenocarcinoma of the Pancreatic Body or Tail on Surgical and Oncological Outcome: A Propensity-Score Matched Multicenter Study

Background: Several studies have suggested a survival benefit of neoadjuvant therapy (NAT) for pancreatic ductal adenocarcinoma (PDAC) in the pancreatic head. Data concerning NAT for PDAC located in pancreatic body or tail are lacking. Methods: Post hoc analysis of an international multicenter retrospective cohort of distal pancreatectomy for PDAC in 34 centers from 11 countries (2007–2015). Patients who underwent resection after NAT were matched (1:1 ratio), using propensity scores based on baseline characteristics, to patients who underwent upfront resection. Median overall survival was compared using the stratified log-rank test. Results: Among 1236 patients, 136 (11.0%) received NAT, most frequently FOLFIRINOX (25.7%). In total, 94 patients receiving NAT were matched to 94 patients undergoing upfront resection. NAT was associated with less postoperative major morbidity (Clavien–Dindo ≥ 3a, 10.6% vs. 23.4%, P = 0.020) and pancreatic fistula grade B/C (9.6% vs. 21.3%, P = 0.026). NAT did not improve overall survival [27 (95% CI 14–39) versus 31 months (95% CI 19–42), P = 0.277], as compared with upfront resection. In a sensitivity analysis of 251 patients with radiographic tumor involvement of splenic vessels, NAT (n = 37, 14.7%) was associated with prolonged overall survival [36 (95% CI 18–53) versus 20 months (95% CI 15–24), P = 0.049], as compared with upfront resection. Conclusion: In this international multicenter cohort study, NAT for resected PDAC in pancreatic body or tail was associated with less morbidity and pancreatic fistula but similar overall survival in comparison with upfront resection. Prospective studies should confirm a survival benefit of NAT in patients with PDAC and splenic vessel involvement

Pancreatic cancer and immunotherapy: A clinical overview

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with high mortality. The vast majority of patients present with unresectable, advanced stage disease, for whom standard of care chemo(radio)therapy may improve survival by several months. Immunotherapy has led to a fundamental shift in the treatment of several advanced cancers. However, its efficacy in PDAC in terms of clinical benefit is limited, possibly owing to the immunosuppressive, inaccessible tumor microenvironment. Still, various immunotherapies have demonstrated the capacity to initiate local and systemic immune responses, suggesting an immune potentiating effect. In this review, we address PDAC’s immunosuppressive tumor microenvironment and immune evasion methods and discuss a wide range of immunotherapies, including immunomodulators (i.e., immune checkpoint inhibitors, immune stimulatory agonists, cytokines and adjuvants), oncolytic viruses, adoptive cell therapies (i.e., T cells and natural killer cells) and cancer vaccines. We provide a general introduction to their working mechanism as well as evidence of their clinical efficacy and immune potentiating abilities in PDAC. The key to successful implementation of immunotherapy in this disease may rely on exploitation of synergistic effects between treatment combinations. Accordingly, future treatment approaches should aim to incorporate diverse and novel immunotherapeutic strategies coupled with cytotoxic drugs and/or local ablative treatment, targeting a wide array of tumor-induced immune escape mechanisms

Impact of Neoadjuvant Therapy in Resected Pancreatic Ductal Adenocarcinoma of the Pancreatic Body or Tail on Surgical and Oncological Outcome: A Propensity-Score Matched Multicenter Study

Background Several studies have suggested a survival benefit of neoadjuvant therapy (NAT) for pancreatic ductal adenocarcinoma (PDAC) in the pancreatic head. Data concerning NAT for PDAC located in pancreatic body or tail are lacking. Methods Post hoc analysis of an international multicenter retrospective cohort of distal pancreatectomy for PDAC in 34 centers from 11 countries (2007–2015). Patients who underwent resection after NAT were matched (1:1 ratio), using propensity scores based on baseline characteristics, to patients who underwent upfront resection. Median overall survival was compared using the stratified log-rank test. Results Among 1236 patients, 136 (11.0%) received NAT, most frequently FOLFIRINOX (25.7%). In total, 94 patients receiving NAT were matched to 94 patients undergoing upfront resection. NAT was associated with less postoperative major morbidity (Clavien–Dindo ≥ 3a, 10.6% vs. 23.4%, P = 0.020) and pancreatic fistula grade B/C (9.6% vs. 21.3%, P = 0.026). NAT did not improve overall survival [27 (95% CI 14–39) versus 31 months (95% CI 19–42), P = 0.277], as compared with upfront resection. In a sensitivity analysis of 251 patients with radiographic tumor involvement of splenic vessels, NAT (n = 37, 14.7%) was associated with prolonged overall survival [36 (95% CI 18–53) versus 20 months (95% CI 15–24), P = 0.049], as compared with upfront resection. Conclusion In this international multicenter cohort study, NAT for resected PDAC in pancreatic body or tail was associated with less morbidity and pancreatic fistula but similar overall survival in comparison with upfront resection. Prospective studies should confirm a survival benefit of NAT in patients with PDAC and splenic vessel involvement

Irreversible Electroporation and Nivolumab Combined with Intratumoral Administration of a Toll-Like Receptor Ligand, as a Means of In Vivo Vaccination for Metastatic Pancreatic Ductal Adenocarcinoma (PANFIRE-III). A Phase-I Study Protocol

Irreversible electroporation (IRE) is a novel image-guided tumor ablation technique with the ability to generate a window for the establishment of systemic antitumor immunity. IRE transiently alters the tumor’s immunosuppressive microenvironment while simultaneously generating antigen release, thereby instigating an adaptive immune response. Combining IRE with immunotherapeutic drugs, i.e., electroimmunotherapy, has synergistic potential and might induce a durable antitumor response. The primary objective of this study is to assess the safety of the combination of IRE with IMO-2125 (a toll-like receptor 9 ligand) and/or nivolumab in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). In this randomized controlled phase I clinical trial, 18 patients with mPDAC pretreated with chemotherapy will be enrolled in one of three study arms: A (control): nivolumab monotherapy; B: percutaneous IRE of the primary tumor followed by nivolumab; or C: intratumoral injection of IMO-2125 followed by percutaneous IRE of the primary tumor and nivolumab. Assessments include contrast enhanced computed tomography (ceCT), 18F-FDG and 18F-BMS-986192 (PD-L1) positron emission tomography (PET)-CT, biopsies of the primary tumor and metastases, peripheral blood samples, and quality of life and pain questionnaires. There is no curative treatment option for patients with mPDAC, and palliative chemotherapy regimens only moderately improve survival. Consequently, there is an urgent need for innovative and radically different treatment approaches. Should electroimmunotherapy establish an effective and durable anti-tumor response, it may ultimately improve PDAC’s dismal prognosis

Irreversible electroporation and nivolumab combined with intratumoral administration of a toll‐like receptor ligand, as a means of in vivo vaccination for metastatic pancreatic ductal adenocarcinoma (Panfire‐iii). a phase‐i study protocol

Irreversible electroporation (IRE) is a novel image‐guided tumor ablation technique with the ability to generate a window for the establishment of systemic antitumor immunity. IRE transiently alters the tumor’s immunosuppressive microenvironment while simultaneously generating antigen release, thereby instigating an adaptive immune response. Combining IRE with immunotherapeutic drugs, i.e., electroimmunotherapy, has synergistic potential and might induce a durable antitumor response. The primary objective of this study is to assess the safety of the combination of IRE with IMO‐2125 (a toll‐like receptor 9 ligand) and/or nivolumab in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). In this randomized controlled phase I clinical trial, 18 patients with mPDAC pretreated with chemotherapy will be enrolled in one of three study arms: A (control): nivolumab monotherapy; B: percutaneous IRE of the primary tumor followed by nivolumab; or C: intratumoral injection of IMO‐2125 followed by percutaneous IRE of the primary tumor and nivolumab. Assessments include contrast enhanced computed tomography (ceCT),18F‐FDG and18F‐BMS‐986192 (PD‐L1) positron emission tomography (PET)‐CT, biopsies of the primary tumor and metastases, peripheral blood samples, and quality of life and pain questionnaires. There is no curative treatment option for patients with mPDAC, and palliative chemotherapy regimens only moderately improve survival. Consequently, there is an urgent need for innovative and radically different treatment approaches. Should electroimmunotherapy establish an effective and durable anti‐tumor response, it may ultimately improve PDAC’s dismal prognosis

Minimally invasive versus open distal pancreatectomy for pancreatic ductal adenocarcinoma (DIPLOMA) : study protocol for a randomized controlled trial

Background: Recently, the first randomized trials comparing minimally invasive distal pancreatectomy (MIDP) with open distal pancreatectomy (ODP) for non-malignant and malignant disease showed a 2-day reduction in time to functional recovery after MIDP. However, for pancreatic ductal adenocarcinoma (PDAC), concerns have been raised regarding the oncologic safety (i.e., radical resection, lymph node retrieval, and survival) of MIDP, as compared to ODP. Therefore, a randomized controlled trial comparing MIDP and ODP in PDAC regarding oncological safety is warranted. We hypothesize that the microscopically radical resection (R0) rate is non-inferior for MIDP, as compared to ODP. Methods/design: DIPLOMA is an international randomized controlled, patient- and pathologist-blinded, non-inferiority trial performed in 38 pancreatic centers in Europe and the USA. A total of 258 patients with an indication for elective distal pancreatectomy with splenectomy because of proven or highly suspected PDAC of the pancreatic body or tail will be randomly allocated to MIDP (laparoscopic or robot-assisted) or ODP in a 1:1 ratio. The primary outcome is the microscopically radical resection margin (R0, distance tumor to pancreatic transection and posterior margin &amp;gt;= 1 mm), which is assessed using a standardized histopathology assessment protocol. The sample size is calculated with the following assumptions: 5% one-sided significance level (alpha), 80% power (1-beta), expected R0 rate in the open group of 58%, expected R0 resection rate in the minimally invasive group of 67%, and a non-inferiority margin of 7%. Secondary outcomes include time to functional recovery, operative outcomes (e.g., blood loss, operative time, and conversion to open surgery), other histopathology findings (e.g., lymph node retrieval, perineural- and lymphovascular invasion), postoperative outcomes (e.g., clinically relevant complications, hospital stay, and administration of adjuvant treatment), time and site of disease recurrence, survival, quality of life, and costs. Follow-up will be performed at the outpatient clinic after 6, 12, 18, 24, and 36 months postoperatively. Discussion: The DIPLOMA trial is designed to investigate the non-inferiority of MIDP versus ODP regarding the microscopically radical resection rate of PDAC in an international setting.Funding Agencies|Covidien AG (Medtronic, Neuhausen am Rheinfall, Switzerland) [ISR2017-10928]</p