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Transplantation Direct Jul 2024Limited information is available regarding outcomes of islet cell isolation (ICI) and transplantation (ITx) using medical assistance in dying (MAiD) donors. We aimed to...
BACKGROUND
Limited information is available regarding outcomes of islet cell isolation (ICI) and transplantation (ITx) using medical assistance in dying (MAiD) donors. We aimed to assess the feasibility and outcomes of ICI and ITx in MAiD donors.
METHODS
ICI and ITx from MAiD were compared with donation after circulatory death (DCD) type III between 2016 and 2023. Differences of isolated islet equivalents (IEQs), numeric viability and other quantitative in vitro metabolic measures were assessed.
RESULTS
Overall, 81 ICIs were available of whom 34 (42%) and 47 (58%) from MAiD and DCD-III, respectively. There were no differences of pancreas and digested tissue weight and islets viability among the 2 groups; however, cold ischemic time was longer in MAiD (11.5 versus 9.1 h; = 0.021). The IEQ ( < 0.001) and percent trapped ( < 0.001) were higher in the DCD-III; however, MAiD islets demonstrated a higher purity ( = 0.020). Overall, 15 ITx were performed of whom 3 (8.8%) and 12 (25.5%) from MAiD and DCD-III, respectively ( = 0.056). Patients had a median fasting C-peptide of 0.51 ng/mL (interquartile range, 0.30-0.76 nmol/L), with no differences between groups (MAiD = 0.52 versus DCD-III = 0.51; = 0.718). The median HbA1c was 6.2% (interquartile range, 5.7%-7%) (MAiD = 6.3% versus DCD-III = 6.1%; = 0.815) and BETA2 scores (MAiD = 7.4 versus DCD-III = 12.8; = 0.229) did not differ.
CONCLUSIONS
ICI from MAiD donor pancreas may be successfully transplanted with comparable outcomes to DCD-III and may be used for research. These results justify additional efforts to consider MAiD as another valuable source of grafts for ITx. Further multicenter studies and larger clinical experience are needed to validate our findings.
PubMed: 38911274
DOI: 10.1097/TXD.0000000000001667 -
Trials Jun 2024Disease recurrence remains one of the biggest concerns in patients after resection of pancreatic ductal adenocarcinoma (PDAC). Despite (neo)adjuvant systemic therapy,...
Recurrent disease detection after resection of pancreatic ductal adenocarcinoma using a recurrence-focused surveillance strategy (RADAR-PANC): protocol of an international randomized controlled trial according to the Trials within Cohorts design.
BACKGROUND
Disease recurrence remains one of the biggest concerns in patients after resection of pancreatic ductal adenocarcinoma (PDAC). Despite (neo)adjuvant systemic therapy, most patients experience local and/or distant PDAC recurrence within 2 years. High-level evidence regarding the benefits of recurrence-focused surveillance after PDAC resection is missing, and the impact of early detection and treatment of recurrence on survival and quality of life is unknown. In most European countries, recurrence-focused follow-up after surgery for PDAC is currently lacking. Consequently, guidelines regarding postoperative surveillance are based on expert opinion and other low-level evidence. The recent emergence of more potent local and systemic treatment options for PDAC recurrence has increased interest in early diagnosis. To determine whether early detection and treatment of recurrence can lead to improved survival and quality of life, we designed an international randomized trial.
METHODS
This randomized controlled trial is nested within an existing prospective cohort in pancreatic cancer centers in the Netherlands (Dutch Pancreatic Cancer Project; PACAP) and the United Kingdom (UK) (Pancreas Cancer: Observations of Practice and survival; PACOPS) according to the "Trials within Cohorts" (TwiCs) design. All PACAP/PACOPS participants with a macroscopically radical resection (R0-R1) of histologically confirmed PDAC, who provided informed consent for TwiCs and participation in quality of life questionnaires, are included. Participants randomized to the intervention arm are offered recurrence-focused surveillance, existing of clinical evaluation, serum cancer antigen (CA) 19-9 testing, and contrast-enhanced computed tomography (CT) of chest and abdomen every three months during the first 2 years after surgery. Participants in the control arm of the study will undergo non-standardized clinical follow-up, generally consisting of clinical follow-up with imaging and serum tumor marker testing only in case of onset of symptoms, according to local practice in the participating hospital. The primary endpoint is overall survival. Secondary endpoints include quality of life, patterns of recurrence, compliance to and costs of recurrence-focused follow-up, and the impact on recurrence-focused treatment.
DISCUSSION
The RADAR-PANC trial will be the first randomized controlled trial to generate high level evidence for the current clinical equipoise regarding the value of recurrence-focused postoperative surveillance with serial tumor marker testing and routine imaging in patients after PDAC resection. The Trials within Cohort design allows us to study the acceptability of recurrence-focused surveillance among cohort participants and increases the generalizability of findings to the general population. While it is strongly encouraged to offer all trial participants treatment at time of recurrence diagnosis, type and timing of treatment will be determined through shared decision-making. This might reduce the potential survival benefits of recurrence-focused surveillance, although insights into the impact on patients' quality of life will be obtained.
TRIAL REGISTRATION
Clinicaltrials.gov, NCT04875325 . Registered on May 6, 2021.
Topics: Humans; Carcinoma, Pancreatic Ductal; Pancreatic Neoplasms; Neoplasm Recurrence, Local; Randomized Controlled Trials as Topic; Pancreatectomy; Time Factors; Quality of Life; Prospective Studies; Multicenter Studies as Topic; Treatment Outcome; Predictive Value of Tests; Netherlands; United Kingdom; Research Design; Early Detection of Cancer
PubMed: 38902836
DOI: 10.1186/s13063-024-08223-5 -
Kidney International Reports Jun 2024
PubMed: 38899215
DOI: 10.1016/j.ekir.2024.04.009 -
International Journal of Molecular... May 2024Mesenchymal stem cells (MSCs) are known for their immunosuppressive properties. Based on the demonstrated anti-inflammatory effect of mouse MSCs from hair follicles...
Mesenchymal stem cells (MSCs) are known for their immunosuppressive properties. Based on the demonstrated anti-inflammatory effect of mouse MSCs from hair follicles (moMSCORS) in a murine wound closure model, this study evaluates their potential for preventing type 1 diabetes (T1D) in C57BL/6 mice. T1D was induced in C57BL/6 mice by repeated low doses of streptozotocin. moMSCORS were injected intravenously on weekly basis. moMSCORS reduced T1D incidence, the insulitis stage, and preserved insulin production in treated animals. moMSCORS primarily exerted immunomodulatory effects by inhibiting CD4 T cell proliferation and activation. Ex vivo analysis indicated that moMSCORS modified the cellular immune profile within pancreatic lymph nodes and pancreatic infiltrates by reducing the numbers of M1 pro-inflammatory macrophages and T helper 17 cells and upscaling the immunosuppressive T regulatory cells. The proportion of pathogenic insulin-specific CD4 T cells was down-scaled in the lymph nodes, likely via soluble factors. The moMSCORS detected in the pancreatic infiltrates of treated mice presumably exerted the observed suppressive effect on CD4 through direct contact. moMSCORS alleviated T1D symptoms in the mouse, qualifying as a candidate for therapeutic products by multiple advantages: non-invasive sampling by epilation, easy access, permanent availability, scalability, and benefits of auto-transplantation.
Topics: Animals; Diabetes Mellitus, Type 1; Hair Follicle; Mesenchymal Stem Cells; Mice; Mice, Inbred C57BL; Mesenchymal Stem Cell Transplantation; Diabetes Mellitus, Experimental; Male; CD4-Positive T-Lymphocytes; Cell Proliferation; Pancreas
PubMed: 38892159
DOI: 10.3390/ijms25115974 -
JAMA Network Open Jun 2024Preoperative chemo(radio)therapy is increasingly used in patients with localized pancreatic adenocarcinoma, leading to pathological complete response (pCR) in a small... (Observational Study)
Observational Study
IMPORTANCE
Preoperative chemo(radio)therapy is increasingly used in patients with localized pancreatic adenocarcinoma, leading to pathological complete response (pCR) in a small subset of patients. However, multicenter studies with in-depth data about pCR are lacking.
OBJECTIVE
To investigate the incidence, outcome, and risk factors of pCR after preoperative chemo(radio)therapy.
DESIGN, SETTING, AND PARTICIPANTS
This observational, international, multicenter cohort study assessed all consecutive patients with pathology-proven localized pancreatic adenocarcinoma who underwent resection after 2 or more cycles of chemotherapy (with or without radiotherapy) in 19 centers from 8 countries (January 1, 2010, to December 31, 2018). Data collection was performed from February 1, 2020, to April 30, 2022, and analyses from January 1, 2022, to December 31, 2023. Median follow-up was 19 months.
EXPOSURES
Preoperative chemotherapy (with or without radiotherapy) followed by resection.
MAIN OUTCOMES AND MEASURES
The incidence of pCR (defined as absence of vital tumor cells in the sampled pancreas specimen after resection), its association with OS from surgery, and factors associated with pCR. Factors associated with overall survival (OS) and pCR were investigated with Cox proportional hazards and logistic regression models, respectively.
RESULTS
Overall, 1758 patients (mean [SD] age, 64 [9] years; 879 [50.0%] male) were studied. The rate of pCR was 4.8% (n = 85), and pCR was associated with OS (hazard ratio, 0.46; 95% CI, 0.26-0.83). The 1-, 3-, and 5-year OS rates were 95%, 82%, and 63% in patients with pCR vs 80%, 46%, and 30% in patients without pCR, respectively (P < .001). Factors associated with pCR included preoperative multiagent chemotherapy other than (m)FOLFIRINOX ([modified] leucovorin calcium [folinic acid], fluorouracil, irinotecan hydrochloride, and oxaliplatin) (odds ratio [OR], 0.48; 95% CI, 0.26-0.87), preoperative conventional radiotherapy (OR, 2.03; 95% CI, 1.00-4.10), preoperative stereotactic body radiotherapy (OR, 8.91; 95% CI, 4.17-19.05), radiologic response (OR, 13.00; 95% CI, 7.02-24.08), and normal(ized) serum carbohydrate antigen 19-9 after preoperative therapy (OR, 3.76; 95% CI, 1.79-7.89).
CONCLUSIONS AND RELEVANCE
This international, retrospective cohort study found that pCR occurred in 4.8% of patients with resected localized pancreatic adenocarcinoma after preoperative chemo(radio)therapy. Although pCR does not reflect cure, it is associated with improved OS, with a doubled 5-year OS of 63% compared with 30% in patients without pCR. Factors associated with pCR related to preoperative chemo(radio)therapy regimens and anatomical and biological disease response features may have implications for treatment strategies that require validation in prospective studies because they may not universally apply to all patients with pancreatic adenocarcinoma.
Topics: Humans; Pancreatic Neoplasms; Male; Middle Aged; Female; Adenocarcinoma; Aged; Neoadjuvant Therapy; Antineoplastic Combined Chemotherapy Protocols; Treatment Outcome; Cohort Studies; Oxaliplatin; Pancreatectomy
PubMed: 38888920
DOI: 10.1001/jamanetworkopen.2024.17625 -
European Journal of Radiology Open Jun 2024The present study aimed to compare the computed tomography (CT) and magnetic resonance imaging (MRI) features of solid pseudopapillary neoplasms (SPNs) and pancreatic...
PURPOSE
The present study aimed to compare the computed tomography (CT) and magnetic resonance imaging (MRI) features of solid pseudopapillary neoplasms (SPNs) and pancreatic neuroendocrine neoplasms (pNENs).
METHOD
Lesion imaging features of 39 patients with SPNs and 127 patients with pNENs were retrospectively extracted from 104 CT and 91 MRI scans.
RESULTS
Compared to pNEN patients, SPN patients were significantly younger (mean age 51.8 yrs versus 32.7 yrs) and more often female (female: male ratio, 5.50:1 versus 1.19:1). Most SPNs and pNENs presented as well-defined lesions with an expansive growth pattern. SPNs more often appeared as round or ovoid lesions, compared to pNENs which showed a lobulated or irregular shape in more than half of cases (p<0.01). A surrounding capsule was detected in the majority of SPNs, but only in a minority of pNENs (<0.01). Hemorrhage occurred non-significantly more often in SPNs (p=0.09). Signal inhomogeneity in T1-fat-saturated (p<0.01) and T2-weighted imaging (p=0.046) as well as cystic degeneration (p<0.01) were more often observed in SPNs. Hyperenhancement in the arterial and portal-venous phase was more common in pNENs (p<0.01). Enlargement of locoregional lymph nodes (p<0.01) and liver metastases (p=0.03) were observed in some pNEN patients, but not in SPN patients. Multivariate logistic regression identified the presence of a capsule (p<0.01), absence of arterial hyperenhancement (p<0.01), and low patient age (p<0.01), as independent predictors for SPN.
CONCLUSIONS
The present study provides three key features for differentiating SPNs from pNENs extracted from a large patient cohort: presence of a capsule, absence of arterial hyperenhancement, and low patient age.
PubMed: 38882634
DOI: 10.1016/j.ejro.2024.100576 -
Transplantation Direct Jul 2024In islet transplantation, the use of dynamic hypothermic preservation techniques is a current challenge. This study compares the efficacy of 3 pancreas preservation...
BACKGROUND
In islet transplantation, the use of dynamic hypothermic preservation techniques is a current challenge. This study compares the efficacy of 3 pancreas preservation methods: static cold storage, hypothermic machine perfusion (HMP), and oxygenated HMP.
METHODS
A standardized human pancreas split model was employed using discarded organs from both donation after brain death (n = 15) and donation after circulatory death (DCD) (n = 9) donors. The pancreas head was preserved using static cold storage (control group), whereas the tail was preserved using the 3 different methods (study group). Data on donor characteristics, pancreas histology, isolation outcomes, and functional tests of isolated islets were collected.
RESULTS
Insulin secretory function evaluated by calculating stimulation indices and total amount of secreted insulin during high glucose stimulation (area under the curve) through dynamic perifusion experiments was similar across all paired groups from both DCD and donation after brain death donors. In our hands, islet yield (IEQ/g) from the pancreas tails used as study groups was higher than that of the pancreas heads as expected although this difference did not always reach statistical significance because of great variability probably due to suboptimal quality of organs released for research purposes. Moreover, islets from DCD organs had greater purity than controls ( ≤ 0.01) in the HMP study group. Furthermore, our investigation revealed no significant differences in pancreas histology, oxidative stress markers, and apoptosis indicators.
CONCLUSIONS
For the first time, a comparative analysis was conducted, using a split model, to assess the effects of various preservation methods on islets derived from pancreas donors. Nevertheless, no discernible variances were observed in terms of islet functionality, histological attributes, or isolation efficacy. Further investigations are needed to validate these findings for clinical application.
PubMed: 38881744
DOI: 10.1097/TXD.0000000000001654 -
Frontiers in Immunology 2024About 10-20% of pancreas allografts are still lost in the early postoperative period despite the identification of numerous detrimental risk factors that correlate with...
BACKGROUND
About 10-20% of pancreas allografts are still lost in the early postoperative period despite the identification of numerous detrimental risk factors that correlate with graft thrombosis.
METHODS
We conducted a multicenter study including 899 pancreas transplant recipients between 2000 and 2018. Early pancreas failure due to complete thrombosis, long-term pancreas, kidney and patient survivals were analyzed and adjusted to donor, recipient and perioperative variables using a multivariate cause-specific Cox model stratified to transplant centers.
RESULTS
Pancreas from donors with history of hypertension (6.7%), as well as with high body mass index (BMI), were independently associated with an increased risk of pancreas failure within the first 30 post-operative days (respectively, HR= 2.57, 95% CI from 1.35 to 4.89 and HR= 1.11, 95% CI from 1.04 to 1.19). Interaction term between hypertension and BMI was negative. Donor hypertension also impacted long-term pancreas survival (HR= 1.88, 95% CI from 1.13 to 3.12). However, when pancreas survival was calculated after the postoperative day 30, donor hypertension was no longer a significant risk factor (HR= 1.22, 95% CI from 0.47 to 3.15). A lower pancreas survival was observed in patients receiving a pancreas from a hypertensive donor without RAAS (Renin Angiotensin Aldosterone System) blockers compared to others (50% vs 14%, p < 0.001). Pancreas survival was similar among non-hypertensive donors and hypertensive ones under RAAS blockers.
CONCLUSION
Donor hypertension was a significant and independent risk factor of pancreas failure. The well-known pathogenic role of renin-angiotensin-aldosterone system seems to be involved in the genesis of this immediate graft failure.
Topics: Humans; Pancreas Transplantation; Male; Female; Hypertension; Middle Aged; Adult; Thrombosis; Tissue Donors; Angiotensin II; Risk Factors; Graft Survival; Allografts; Retrospective Studies; Graft Rejection
PubMed: 38873595
DOI: 10.3389/fimmu.2024.1359381 -
Transplantation Proceedings Jun 2024We report a case of adenovirus nephritis (ADVN) in a kidney transplant recipient (KTR) occurring within 8 days post-transplantation. The patient, a 35-year-old male,...
We report a case of adenovirus nephritis (ADVN) in a kidney transplant recipient (KTR) occurring within 8 days post-transplantation. The patient, a 35-year-old male, displayed systemic symptoms, high-grade fever, and acute kidney injury (AKI) without signs of hemorrhagic cystitis (HC). Extensive diagnostic workup revealed widespread necrotizing granulomatous inflammation in the allograft, leading to the identification of adenovirus (ADV) via histopathology and polymerase chain reaction (PCR) testing. The source of ADV transmission remained uncertain, raising questions about the potential donor-derived infection. Unlike typical ADVN cases, the patient exhibited no hematuria or urinary symptoms. The case underscores the atypical presentation of ADVN in KTRs, challenging the conventional understanding of its timeline, transmission routes, and associated clinical features. We discuss the diagnostic challenges, histological findings, and management strategies for ADVN, emphasizing the importance of considering this entity in KTRs with unexplained fever and AKI, even in the absence of classical urinary symptoms or hematuria.
PubMed: 38851958
DOI: 10.1016/j.transproceed.2024.05.018 -
Science Advances Jun 2024Clinical outcomes for total-pancreatectomy followed by intraportal islet autotransplantation (TP-IAT) to treat chronic pancreatitis (CP) are suboptimal due to pancreas...
Clinical outcomes for total-pancreatectomy followed by intraportal islet autotransplantation (TP-IAT) to treat chronic pancreatitis (CP) are suboptimal due to pancreas inflammation, oxidative stress during islet isolation, and harsh engraftment conditions in the liver's vasculature. We describe a thermoresponsive, antioxidant macromolecule poly(polyethylene glycol citrate---isopropylacrylamide) (PPCN) to protect islet redox status and function and to enable extrahepatic omentum islet engraftment. PPCN solution transitions from a liquid to a hydrogel at body temperature. Islets entrapped in PPCN and exposed to oxidative stress remain functional and support long-term euglycemia, in contrast to islets entrapped in a plasma-thrombin biologic scaffold. In the nonhuman primate (NHP) omentum, PPCN is well-tolerated and mostly resorbed without fibrosis at 3 months after implantation. In NHPs, autologous omentum islet transplantation using PPCN restores normoglycemia with minimal exogenous insulin requirements for >100 days. This preclinical study supports TP-IAT with PPCN in patients with CP and highlights antioxidant properties as a mechanism for islet function preservation.
Topics: Islets of Langerhans Transplantation; Omentum; Animals; Islets of Langerhans; Oxidative Stress; Citric Acid; Humans; Antioxidants; Pancreatitis, Chronic; Polyethylene Glycols; Male; Phase Transition
PubMed: 38848367
DOI: 10.1126/sciadv.adk3081