Impact of anesthesia choice in cutaneous melanoma surgery.

Invasive cutaneous melanoma is the most lethal skin cancer, but fortunately, the vast majority can be surgically treated with wide local excision, and sometimes additionally with sentinel or index lymph node biopsy for prognostication. Melanomas are particularly immunogenic malignancies, and preclinical studies have demonstrated that use of volatile anesthetics and opioids, unlike local agents, can suppress the immune system during the perioperative period. Immunosuppression has implications for creating a potentially favorable microenvironment for the survival and propagation of residual melanoma cells or micro-metastases, which could lead to disease relapse, both in the local tumor bed and distally. Results from observational clinical studies are mixed, but the literature would suggest that patients are at risk of decreased melanoma-specific survival after undergoing general anesthesia compared to regional anesthesia and spinal blocks. With the safety of close observation now established rather than automatic completion or total lymph node dissection for patients with either a positive sentinel lymph node biopsy or significant clinical response to neoadjuvant immunotherapy after index node sampling, the indications for definitive surgery with local or regional anesthesia have increased tremendously in recent years. Therefore, cutaneous melanoma patients might benefit from avoidance of general anesthesia and other perioperative drugs that suppress cell-mediated immunity if the option to circumvent systemic anesthesia agents is feasible.

Immunotherapy in malignant peritoneal mesothelioma (Review).

Over the last decade, there has been a movement in cancer treatment away from cytotoxic therapies toward strategies that enhance the immune system against cancer. Immune checkpoint inhibitors (ICIs) have been incorporated into the treatment regimens for patients with various solid tumors. Mesothelioma trials revealed encouraging efficacy; however, patients with peritoneal mesothelioma are usually excluded, slowing the progress of improving the treatment of this aggressive cancer and compelling oncologist to rely on retrospective studies despite their flaws and limitations. Currently, there is no consensus on the role of ICIs in the treatment of malignant peritoneal mesothelioma (MPeM). The present review discusses data from clinical studies that examined immunotherapy in MPeM and evaluates what is known about the relevance of the tumor microenvironment and clinically validated biomarkers for ICIs efficacy. Furthermore, a proposed strategy for utilizing immunotherapy in treating MPeM is discussed.

Manipulating adrenergic stress receptor signalling to enhance immunosuppression and prolong survival of vascularized composite tissue transplants.

BACKGROUND: Vascularized composite tissue allotransplantation (VCA) to replace limbs or faces damaged beyond repair is now possible. The resulting clear benefit to quality of life is a compelling reason to attempt this complex procedure. Unfortunately, the high doses of immunosuppressive drugs required to protect this type of allograft result in significant morbidity and mortality giving rise to ethical concerns about performing this surgery in patients with non-life-threatening conditions. Here we tested whether we could suppress anti-graft immune activity by using a safe ß2 -adrenergic receptor (AR) agonist, terbutaline, to mimic the natural immune suppression generated by nervous system-induced signalling through AR. METHODS: A heterotopic hind limb transplantation model was used with C57BL/6 (H-2b) as recipients and BALB/c (H-2d) mice as donors. To test the modulation of the immune response, graft survival was investigated after daily intraperitoneal injection of ß2 -AR agonist with and without tacrolimus. Analyses of immune compositions and quantification of pro-inflammatory cytokines were performed to gauge functional immunomodulation. The contributions to allograft survival of ß2 -AR signalling in donor and recipient tissue were investigated with ß2 -AR-/- strains. RESULTS: Treatment with the ß2 -AR agonist delayed VCA rejection, even with a subtherapeutic dose of tacrolimus. ß2 -AR agonist decreased T-cell infiltration into the transplanted grafts and decreased memory T-cell populations in recipient's circulation. In addition, decreased levels of inflammatory cytokines (IFN-γ, IL-6, TNF-α, CXCL-1/10 and CCL3/4/5/7) were detected following ß2 -AR agonist treatment, and there was a decreased expression of ICAM-1 and vascular cell adhesion molecule-1 in donor stromal cells. CONCLUSIONS: ß2 -AR agonist can be used safely to mimic the natural suppression of immune responses, which occurs during adrenergic stress-signalling and thereby can be used in combination regimens to reduce the dose needed of toxic immunosuppressive drugs such as tacrolimus. This strategy can be further evaluated for feasibility in the clinic.

Tertiary Lymphoid Structures as Mediators of Immunotherapy Response.

Since its first application in the treatment of cancer during the 1800s, immunotherapy has more recently become the leading edge of novel treatment strategies. Even though the efficacy of these agents can at times be predicted by more traditional metrics and biomarkers, often patient responses are variable. TLS are distinct immunologic structures that have been identified on pathologic review of various malignancies and are emerging as important determinants of patient outcome. Their presence, location, composition, and maturity are critically important in a host's response to malignancy. Because of their unique immunogenic niche, they are also prime candidates, not only to predict and measure the efficacy of immunotherapy agents, but also to be potentially inducible gatekeepers to increase therapeutic efficacy. Herein, we review the mechanistic underpinnings of TLS formation, the data on its relationship to various malignancies, and the emerging evidence for the role of TLS in immunotherapy function.

Recombinant human Hsp110-gp100 chaperone complex vaccine is nontoxic and induces response in advanced stage melanoma patients.

Heat shock proteins (hsp) are intracellular chaperones that possess extracellular immunostimulatory properties when complexed with antigens. A recombinant Hsp110-gp100 chaperone complex vaccine showed an antitumor response and prolonged survival in murine melanoma. A phase Ib dose-escalation study of a recombinant human Hsp110-gp100 vaccine in advanced-stage melanoma patients was performed to evaluate toxicity, immunostimulatory potential and clinical response. Patients with pretreated, unresectable stage IIIB/C/IV melanoma received the chaperone complex vaccine in a dose-escalation protocol; three vaccinations over a 43-day-period. Tumor response, clinical toxicity and immune response were measured. Ten patients (eight female, median age 70 years) were enrolled and two patients had grade 1 adverse events; minor skin rash, hyperhidrosis and fever (no grade 2 or higher adverse events). Median progression-free survival was longer for lower vaccine doses as compared to the maximum dose of 180 mcg (4.5 vs. 2.9 months; P = 0.018). The lowest dose patients (30 and 60 mcg) had clinical tumor responses (one partial response, one stable disease). CD8+ T cell interferon-γ responses to gp100 were greater in the clinically responding patients. A pattern of B cell responses to vaccination was not observed. Regulatory T cell populations and co-stimulatory molecules including cytotoxic T-lymphocyte-associated protein 4 and PD-1 appeared to differ in responders versus nonresponders. A fully recombinant human Hsp110-gp100 chaperone complex vaccine had minimal toxicity, measurable tumor responses at lower doses and produced peripheral CD8+ T cell activation in patients with advanced, pretreated melanoma. Combination with currently available immunotherapies may augment clinical responses.

Managing Metastatic Melanoma in 2022: A Clinical Review.

Cutaneous melanoma remains the most lethal of the primary cutaneous neoplasms, and although the incidence of primary melanoma continues to rise, the mortality from metastatic disease remains unchanged, in part through advances in treatment. Major developments in immunomodulatory and targeted therapies have provided robust improvements in response and survival trends that have transformed the clinical management of patients with metastatic melanoma. Additional advances in immunologic and cancer cell biology have contributed to further optimization in (1) risk stratification, (2) prognostication, (3) treatment, (4) toxicity management, and (5) surveillance approaches for patients with an advanced melanoma diagnosis. In this review, we provide a comprehensive overview of the historical and future advances regarding the translational and clinical implications of advanced melanoma and share multidisciplinary recommendations to aid clinicians in the navigation of current treatment approaches for a variety of patient cohorts.

Restrictive Intraoperative Fluid Rate is Associated with Improved Outcomes in Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

BACKGROUND: Management of patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CS/HIPEC) has historically favored liberal fluid administration owing to lengthy duration of surgery and hyperthermia. This practice has been challenged in recent years with studies demonstrating improved outcomes with restrictive fluid administration. METHODS: Patients who underwent CS/HIPEC between March 2010 and September 2018 were included for analysis. Patients who received an above-median fluid rate (high-IVF) versus below-median fluid rate (low-IVF) were compared, and multivariate analyses were performed for length of stay, 90-day unplanned readmissions, and major complications. RESULTS: The 167 patients had a mean age of 56.7 ± 11.4 years and body mass index of 29.5 ± 6.9 kg/m2. The median rate of total intraoperative crystalloid and colloid was 7.4 mL/kg/h. The low-IVF group had less blood loss (183 vs. 330 mL, p = 0.002), were less likely to need intraoperative vasopressor drip (2.4% vs. 11.9%, p = 0.018), and experienced fewer cardiac complications (2.4% vs. 10.7%, p = 0.031), pneumonias (0% vs. 6.0%, p = 0.024), and Clavien-Dindo grade 3-5 complications (14.5% vs. 33.3%, p = 0.004). Multivariate analyses identified bowel resection (HR 4.65, p = 0.0008) as a risk factor for 90-day unplanned readmission, while bowel resection, intraoperative fluid rate, and estimated blood loss were associated with increased length of stay. CONCLUSION: Higher intraoperative fluid intake was associated with multiple postoperative complications and increased length of stay, and represents a potentially avoidable risk factor for morbidity in CS/HIPEC.

Barriers to Referral for Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy Identified Using a Tailoring Grid Methodology: Interviews with Stakeholders in New York State.

INTRODUCTION: Cytoreduction and hyperthermic intraperitoneal chemotherapy (CS/HIPEC) has variable uptake, with referrals reliant on other physicians. To characterize barriers to referral for CS/HIPEC, we created a pragmatic "tailoring grid", incorporating the concepts of Pathman's 4 As of awareness, agreement, adoption, and adherence and barriers acting at the individual, practice group, and organization level. METHODS AND MATERIALS: We invited surgeons and medical oncologists from Western New York State who potentially refer patients for CS/HIPEC to participate in tailoring grid interviews. RESULTS: Interviews of 10 surgeons and 10 medical oncologists were completed. The participants were positioned in the Pathman 4 A's with respect to referrals for CS/HIPEC as follows: (1) A 19 aware (1 not aware); (2) A 3 in agreement (17 not in agreement); (3) A 9 adopters; and (4) A 6 adherent. Among the 9 participants who had referred at least one patient for CS/HIPEC (adopters/adherent), only 2 were in agreement with the appropriateness of CS/HIPEC. Barriers to awareness of included lack of interaction with colleagues and knowledge of indications. Barriers to agreement included lack of high quality of evidence supporting CS/HIPEC such as well-designed RCTs. Barriers to adoption included lack of communication with CS/HIPEC surgeons; lack of inclusion of the procedure into algorithms and defined morbidity/mortality rates. Barriers to adherence included lack of inclusion into guidelines by major societies; perceptions that the procedure is resource-intensive; lack of defined quality measures. CONCLUSIONS: The tailoring grid efficiently identified barriers to awareness, agreement, adoption and adherence for routine referral for CS/HIPEC. Barriers to increased referrals included lack of high-quality evidence supporting CS/HIPEC. Barriers more easily addressed included communication between referring and CS/HIPEC surgeons, and outcomes at the individual patient and hospital level.

Neoadjuvant Pembrolizumab and High-Dose IFNα-2b in Resectable Regionally Advanced Melanoma.

PURPOSE: Neoadjuvant immunotherapy may improve the clinical outcome of regionally advanced operable melanoma and allows for rapid clinical and pathologic assessment of response. We examined neoadjuvant pembrolizumab and high-dose IFNα-2b (HDI) therapy in patients with resectable advanced melanoma. PATIENTS AND METHODS: Patients with resectable stage III/IV melanoma were treated with concurrent pembrolizumab 200 mg i.v. every 3 weeks and HDI 20 MU/m2/day i.v., 5 days per week for 4 weeks, then 10 MU/m2/day subcutaneously 3 days per week for 2 weeks. Definitive surgery followed, as did adjuvant combination immunotherapy, completing a year of treatment. Primary endpoint was safety of the combination. Secondary endpoints included overall response rate (ORR), pathologic complete response (pCR), recurrence-free survival (RFS), and overall survival (OS). Blood samples for correlative studies were collected throughout. Tumor tissue was assessed by IHC and flow cytometry at baseline and at surgery. RESULTS: A total of 31 patients were enrolled, and 30 were evaluable. At data cutoff (October 2, 2019), median follow-up for OS was 37.87 months (range, 33.2-43.47). Median OS and RFS were not reached. Radiographic ORR was 73.3% [95% confidence interval (CI): 55.5-85.8], with a 43% (95% CI: 27.3-60.1) pCR rate. None of the patients with a pCR have had a recurrence. HDI and pembrolizumab were discontinued in 73% and 43% of patients, respectively. Correlative analyses suggested that intratumoral PD-1/PD-L1 interaction and HLA-DR expression are associated with pCR (P = 0.002 and P = 0.008, respectively). CONCLUSIONS: Neoadjuvant concurrent HDI and pembrolizumab demonstrated promising clinical activity despite high rates of treatment discontinuation. pCR is a prognostic indicator.See related commentary by Menzies et al., p. 4133.

A pilot trial of intravital microscopy in the study of the tumor vasculature of patients with peritoneal carcinomatosis.

Aberrancies in the tumor microvasculature limit the systemic delivery of anticancer agents, which impedes tumor response. Using human intravital microscopy (HIVM), we hypothesized that HIVM would be feasible in patients with peritoneal carcinomatosis (PC). During cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for PC, HIVM was performed in both tumor and non-tumor areas. The primary outcome was HIVM feasibility to measure vessel characteristics. We secondarily evaluated associations between HIVM vessel characteristics and oncologic outcomes (RECIST response to neoadjuvant therapy and disease-specific survival). Thirty patients with PC were enrolled. Nineteen patients (63.3%) received neoadjuvant therapy. HIVM was feasible in all patients. Compared to non-tumor (control) areas, PC areas had a lower density of functional vessels, higher proportion of non-functional vessels, smaller lumenal diameters, and lower blood flow velocity. Qualitative differences in these vessel characteristics were observed among patients who had partial response, stable disease, or progressive disease after receiving neoadjuvant therapy. However, no statistically significant relationships were found between HIVM vessel characteristics and oncologic outcomes. These novel findings comprise the first-in-human, real-time evidence of the microscopic differences between normal and tumor-associated vessels and form the basis for our larger, ongoing clinical trial appropriately powered to determine the clinical utility of HIVM (NCT03823144).

Dynamic control of tumor vasculature improves antitumor responses in a regional model of melanoma.

Despite advances in therapy for melanoma, heterogeneous responses with limited durability represent a major gap in treatment outcomes. The purpose of this study was to determine whether alteration in tumor blood flow could augment drug delivery and improve antitumor responses in a regional model of melanoma. This approach to altering tumor blood flow was termed "dynamic control." Dynamic control of tumor vessels in C57BL/6 mice bearing B16 melanoma was performed using volume expansion (saline bolus) followed by phenylephrine. Intravital microscopy (IVM) was used to observe changes directly in real time. Our approach restored blood flow in non-functional tumor vessels. It also resulted in increased chemotherapy (melphalan) activity, as measured by formation of DNA adducts. The combination of dynamic control and melphalan resulted in superior outcomes compared to melphalan alone (median time to event 40.0 vs 25.0 days, respectively, p = 0.041). Moreover, 25% (3/12) of the mice treated with the combination approach showed complete tumor response. Importantly, dynamic control plus melphalan did not result in increased adverse events. In summary, we showed that dynamic control was feasible, directly observable, and augmented antitumor responses in a regional model of melanoma. Early clinical trials to determine the translational feasibility of dynamic control are ongoing.

A Translational Hepatic Artery Infusion (HAI) Model for Hepatocellular Carcinoma in Woodchucks.

BACKGROUND: Woodchucks (Marmota monax) are a well-accepted animal model for the investigation of spontaneous hepatocellular carcinoma (HCC). As HCC tumors obtain nutrient blood supply exclusively from the hepatic artery, hepatic artery infusion (HAI) has been applied to HCC. However, there is a scarcity of experimental animal models to standardize drug regimens and examine novel agents. The purpose of this study was to establish an HAI model in woodchucks. MATERIALS AND METHODS: HAI ports were placed in the gastroduodenal artery (GDA) of 11 woodchucks. The ports were infused with either a vehicle (dextrose 5% in water) or an experimental drug, CBL0137, once a week for 3 wk. Technical success rates, anatomical variation, morbidity and mortality, and tumor responses between groups were analyzed. RESULTS: The GDA access was feasible and reproducible in all woodchucks (11/11). The average operation time was 95 ± 20 min with no increase in the levels of liver enzymes detected from either infusate. The most common morbidity of CBL0137 therapy was anorexia after surgery. One woodchuck died due to hemorrhage at the gallbladder removal site from hepatic coagulopathy. Significantly higher CBL0137 concentrations were measured in the liver compared with blood after each HAI. Tumor growth was suppressed after multiple CBL0137 HAI treatments which corresponded to greater T cell infiltration and increased tumor cell apoptosis. CONCLUSIONS: HAI via GDA was a feasible and reproducible approach with low morbidity and mortality in woodchucks. The described techniques serve as a reliable platform for the identification and characterization of therapeutics for HCC.

Outcomes After Adjuvant Hyperthermic Intraperitoneal Chemotherapy for High-Risk Primary Appendiceal Neoplasms After Complete Resection.

INTRODUCTION: Appendiceal neoplasms are uncommon tumors. Optimal treatment for patients with perforation or high-grade pathology after initial resection is unknown. This study evaluated patients with increased risk for peritoneal dissemination after primary resection, but no evidence of peritoneal disease, who underwent adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: This multi-institutional cohort study evaluated 56 patients with high-risk (HR) appendiceal neoplasms with a peritoneal carcinomatosis index of 0 who underwent HIPEC. The patients were divided into two groups: perforated low-grade appendiceal (LGA) carcinoma and HR neoplasms, which included perforated high-grade appendiceal carcinoma, positive margins after initial resection, minimal macroscopic peritoneal disease that was previously resected or completely responded to systemic chemotherapy prior to HIPEC, goblet cell carcinoma, and adenocarcinoma with signet ring cell features. Overall survival (OS) and recurrence-free survival (RFS) were estimated by Kaplan-Meier analysis. RESULTS: Thirty-eight percent of patients had perforated LGA and 68% had HR features. Five-year OS probability was 82.1% for the entire cohort, and 100% and 70.1% for patients with perforated LGA and HR features, respectively (p = 0.024). Five-year RFS probability was 79.3% for the entire cohort, and 90.0% and 72.4% for patients with perforated LGA and HR features, respectively (p = 0.025). Eight patients recurred after HIPEC and their OS was significantly worse (p < 0.001). CONCLUSION: While adjuvant HIPEC is both safe and feasible, there appears to be little benefit over close surveillance when outcomes are compared with historical and prospective studies, especially for perforated LGA carcinoma.

Surgical Management of Primary Cutaneous Melanoma.

Primary cutaneous melanomas are potentially curative with surgical excision alone. Surgical management is based on several factors determined from the initial biopsy, including primary tumor thickness, histologic features including ulceration, and anatomic location. Cosmesis, although important, should be a secondary consideration as oncologic principles take precedence. Pathology has evolved to synoptic reporting with key variables to assist in staging and risk stratification.

Intravital microscopy in the study of the tumor microenvironment: from bench to human application.

Intravital microscopy (IVM) is a dynamic imaging modality that allows for the real time observation of biologic processes in vivo, including angiogenesis and immune cell interactions. In the setting of preclinical cancer models, IVM has facilitated an understanding of the tumor associated vasculature and the role of effector immune cells in the tumor microenvironment. Novel approaches to apply IVM to human malignancies have thus far focused on cancer diagnosis and tumor vessel characterization, but have the potential to provide advances in the field of personalized medicine by identifying individual patients who may respond to systemically delivered chemotherapeutic drugs or immunotherapeutic agents. In this review, we highlight the role that IVM has had in investigating tumor vasculature and the tumor microenvironment in preclinical studies and discuss its current and future applications to directly observe human tumors.

Improved Cuff Technique and Intraoperative Detection of Vascular Complications for Hind Limb Transplantation in Mice.

BACKGROUND: Vascularized composite tissue allotransplantation (VCA) from a cadaveric donor has now become a clinical reality and the treatment modality of choice for patients with devastating injuries, deformities, and complex tissue defects. However, many VCA patients experience severe toxicities due to the strong immunosuppression required secondary to high antigenicity of the grafts. To improve immunosuppressive protocols for VCA, feasible and reliable preclinical models are necessary. The purpose of this study was to introduce new techniques to an established preclinical VCA model to accelerate future investigations. METHODS: C57BL/6 (H-2b) and BALB/c (H-2d) mice were used to perform VCA as recipients and donors, respectively. Surgery time, success rate, associated complications, and mortality were analyzed. Blood flow in grafts was interrogated with laser speckle image (LSI). RESULTS: A nonsuture cuff technique was used with the abdominal aorta for end-to-end anastomosis. The cuff technique demonstrated efficiency for donor surgery (52 ± 10 minutes for donor vs. 45 ± 8 minutes for recipient surgery). Successful revascularization was achieved in 27 (90%) of 30 transplants. The majority of surgical complications occurred within 48 hours including artery occlusion, venous occlusion, cerebral stroke, and minor bleeding without mortality. LSI was useful in detecting intraoperative vascular complications with display patterns predictive of complication type. CONCLUSIONS: The described techniques may facilitate a more efficient heterotopic hind limb transplantation mouse model of VCA.

Novel mouse models of hepatic artery infusion.

BACKGROUND: The liver has unique anatomy in that most blood flow to normal hepatocytes is derived from the portal venous system, whereas liver tumors obtain their nutrient blood supply exclusively from the hepatic artery. The focused arterial delivery of anticancer agents to liver tumors has been performed for decades; however, preclinical models to standardize drug regimens and examine novel agents have been lacking. The purpose of this study was to establish preclinical hepatic artery infusion (HAI) models in a mouse and to evaluate the safety and delivery capability of the models. MATERIAL AND METHODS: C57BL/6 and BALB/c mice were used to develop models of HAI via the hepatic artery (HA), superior pancreaticoduodenal artery (SPDA), or lienogastric artery (LGA). Success rates, distribution of perfusion, and associated morbidity and mortality were analyzed between groups. RESULTS: All three models were feasible and reproducible in mice, and there was no statistical difference on body weight change between models. The HA model had a 13.3% mortality from acute liver failure, and the SPDA model demonstrated duodenal and pancreatic toxicity. SPDA and LGA routes had the highest success rates (96.7% and 91.4%, respectively) with low mortality, better drug delivery, and preserved physiologic liver function compared with the HA model. CONCLUSIONS: The optimal route of HAI was mouse breed specific; SPDA access in BALB/c mice, and the LGA access in C57BL/6 mice. The described techniques serve as a reproducible platform for the identification and characterization of therapeutics for diverse metastatic liver tumors.

Current Delivery of Hyperthermic Intraperitoneal Chemotherapy with Cytoreductive Surgery (CS/HIPEC) and Perioperative Practices: An International Survey of High-Volume Surgeons.

BACKGROUND: Cytoreductive surgery and heated intraperitoneal chemotherapy (CS/HIPEC) is performed for selected indications at a limited number of specialized centers worldwide. Currently there is no standardized approach to the perioperative care process. We sought to capture current practices in the perioperative management of patients who undergo CS/HIPEC at high-volume centers. METHODS: Surgeon members of the American Society of Peritoneal Surface Malignancies working at high-volume CS/HIPEC centers (>10 cases/year) were invited to complete an online survey. The survey included questions relating to preoperative preparation of patients, intraoperative practices, and postoperative care. RESULTS: Ninety-seven surgeons from five continents completed the survey (response rate 55%). The majority (80%) practiced in academic environments. Most respondents (68%) indicated that a formal preoperative preparatory pathway for CS/HIPEC surgery existed at their centers, but few (26%) had used enhanced recovery protocols in this group of patients. Whereas the intraoperative technical practices of the CS/HIPEC procedure were relatively consistent across respondents, there was little agreement on pre- and postoperative care practices, including use of mechanical bowel preparation, nutritional supplementation, methods of perioperative analgesia, timing of physical therapy and ambulation, nasogastric tube and Foley removal, intravenous fluids, blood transfusion parameters, and postoperative use of deep-vein thrombosis prophylaxis and antibiotics. CONCLUSIONS: Perioperative care practices for CS/HIPEC are widely variable nationally and internationally. Standardization of such practices offers an opportunity to incorporate evidence-based interventions and may enhance patient outcomes and improve care standards across all centers that offer this procedure.