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OBJECTIVE: To compare pancreaticoduodenectomy (PD) and total pancreatectomy (TP) with islet autotransplantation (IAT) in patients at high risk of postoperative pancreatic fistula (POPF). BACKGROUND: Criteria to predict the risk of POPF occurrence after PD are available. However, even when a high risk of POPF is predicted, TP is not currently accepted as an alternative to PD, because of its severe consequences on glycaemic control. Combining IAT with TP may mitigate such consequences. METHODS: Randomized, open-label, controlled, bicentric trial (NCT01346098). Candidates for PD at high-risk pancreatic anastomosis (ie, soft pancreas and duct diameter ≤3 mm) were randomly assigned (1:1) to undergo either PD or TP-IAT. The primary endpoint was the incidence of complications within 90 days after surgery. RESULTS: Between 2010 and 2019, 61 patients were assigned to PD (n=31) or TP-IAT (n=30). In the intention-to-treat analysis, morbidity rate was 90·3% after PD and 60% after TP-IAT ( P =0.008). According to complications' severity, PD was associated with an increased risk of grade ≥2 [odds ratio (OR)=7.64 (95% CI: 1.35-43.3), P =0.022], while the OR for grade ≥3 complications was 2.82 (95% CI: 0.86-9.24, P =0.086). After TP-IAT, the postoperative stay was shorter [median: 10.5 vs 16.0 days; P <0.001). No differences were observed in disease-free survival, site of recurrence, disease-specific survival, and overall survival. TP-IAT was associated with a higher risk of diabetes [hazard ratio=9.1 (95% CI: 3.76-21.9), P <0.0001], but most patients maintained good metabolic control and showed sustained C-peptide production over time. CONCLUSIONS: TP-IAT may become the standard treatment in candidates for PD, when a high risk of POPF is predicted.
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Trasplante de Islotes Pancreáticos , Pancreatitis Crónica , Humanos , Pancreatectomía/efectos adversos , Pancreatoyeyunostomía , Pancreaticoduodenectomía/efectos adversos , Estudios Prospectivos , Trasplante Autólogo , Pancreatitis Crónica/cirugía , Resultado del Tratamiento , Trasplante de Islotes Pancreáticos/efectos adversos , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/prevención & control , Complicaciones Posoperatorias/etiología , Fístula Pancreática/epidemiología , Fístula Pancreática/etiología , Fístula Pancreática/prevención & controlRESUMEN
The First World Consensus Conference on Pancreas Transplantation provided 49 jury deliberations regarding the impact of pancreas transplantation on the treatment of diabetic patients, and 110 experts' recommendations for the practice of pancreas transplantation. The main message from this consensus conference is that both simultaneous pancreas-kidney transplantation (SPK) and pancreas transplantation alone can improve long-term patient survival, and all types of pancreas transplantation dramatically improve the quality of life of recipients. Pancreas transplantation may also improve the course of chronic complications of diabetes, depending on their severity. Therefore, the advantages of pancreas transplantation appear to clearly surpass potential disadvantages. Pancreas after kidney transplantation increases the risk of mortality only in the early period after transplantation, but is associated with improved life expectancy thereafter. Additionally, preemptive SPK, when compared to SPK performed in patients undergoing dialysis, appears to be associated with improved outcomes. Time on dialysis has negative prognostic implications in SPK recipients. Increased long-term survival, improvement in the course of diabetic complications, and amelioration of quality of life justify preferential allocation of kidney grafts to SPK recipients. Audience discussions and live voting are available online at the following URL address: http://mediaeventi.unipi.it/category/1st-world-consensus-conference-of-pancreas-transplantation/246.
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Diabetes Mellitus Tipo 1 , Trasplante de Riñón , Trasplante de Páncreas , Supervivencia de Injerto , Humanos , Calidad de Vida , Diálisis RenalRESUMEN
Allogeneic islet transplantation is a standard of care treatment for patients with labile type 1 diabetes in many countries around the world, including Japan, the United Kingdom, Australia, much of continental Europe, and parts of Canada. The United States is now endorsing islet cell treatment for type 1 diabetes, but the FDA has chosen to consider islets as a biologic that requires licensure, making the universal implementation of the procedure in the clinic very challenging and opening the manufacture of islet grafts to private companies. The commercialization of human tissues raises significant legal and ethical issues and ironically leads to a situation where treatments developed as a result of the scientific and economic efforts of academia over several decades become exploited exclusively by for-profit entities.
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Diabetes Mellitus Tipo 1 , Trasplante de Islotes Pancreáticos , Islotes Pancreáticos , Australia , Diabetes Mellitus Tipo 1/cirugía , Europa (Continente) , Humanos , Japón , Reino Unido , Estados Unidos , United States Food and Drug AdministrationRESUMEN
Islet autotransplant is particularly attractive to prevent diabetes after extended pancreatectomy for benign or borderline/malignant pancreas disease. Between 2008 and 2018, 25 patients underwent left extended pancreatectomy (>60%) and islet autotransplant for a neoplasm located in the pancreatic neck or proximal body. Overall, disease-free and diabetes-free survivals were estimated and compared with those observed in 68 nondiabetic patients who underwent distal pancreatectomy for pancreatic neoplasms without islet autotransplant. Median follow-up was 4 years. We observed no deaths and a low morbidity (nonserious procedure-related complications in 2 of 25 patients). Patient and insulin-independent survival rates at 4 years were 100% and 96%, respectively. Glucose homeostasis remained within a nondiabetic range at all times for 19 (73%) of 25 patients. Preoperative glycemic level and insulin resistance were major predictors of diabetes development in these patients. Patients undergoing islet autotransplant had a longer diabetes-free survival than did patients without islet autotransplant (P = .04). In conclusion, islet autotransplant after extended pancreatic resection for neoplasms is a safe and successful procedure for preventing diabetes.
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Diabetes Mellitus/mortalidad , Trasplante de Islotes Pancreáticos/mortalidad , Pancreatectomía/mortalidad , Neoplasias Pancreáticas/mortalidad , Autoinjertos , Estudios de Casos y Controles , Terapia Combinada , Diabetes Mellitus/prevención & control , Estudios de Factibilidad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/terapia , Pronóstico , Factores de RiesgoRESUMEN
PURPOSE OF REVIEW: In patients with type 1 diabetes with extreme glycemic variability, the restoration of pancreas endocrine function is potentially and completely achieved with islets of Langerhans (tissue derived from whole organ) or pancreas (whole organ) transplantation. The aim of our review is to report on the latest studies and to highlight the benefits and risks of the two procedures, providing clearer, more selective, evidence-based clinical indications that also consider the impact on the degenerative complications of diabetes as a potential benefit. RECENT FINDINGS: Clinical experience in this field has been dynamic over the last three decades, and has been characterized by the development of more standardized protocols and a clearer definition of clinical outcome. On the contrary, the recommendations thus far are not well delineated and tend to overlap, and the past ADA position statement for pancreas transplant alone has also been applied to islet transplant alone, without differentiation. Both outcome-driven and non-outcome-driven criteria are considered in the conclusions, in an attempt to streamline indications for islet-alone or pancreas-alone transplantation.
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Trasplante de Islotes Pancreáticos , Trasplante de Páncreas , Glucemia , Diabetes Mellitus Tipo 1 , Humanos , PáncreasRESUMEN
Islet transplantation is considered an advanced therapy in the treatment of type-1 diabetes, with a progressive improvement of clinical results as seen in the Collaborative Islet Transplant Registry (CITR) report. It is an accepted method for the stabilization of frequent hypoglycemia, or severe glycemic lability, in patients with hypoglycemic unawareness, poor diabetic control, or a resistance to intensive insulin-based therapies. Worldwide data confirm a positive trend in this field, with the integrated management of pivotal factors: adequate islet mass, immunosuppressive protocols, additional anti-inflammatory therapy, and pre-transplant allo-immunity assessment. Insulin independence has been observed in several clinical trials with different rate, ranging 100-65% of patients; the maintenance of this condition during the follow-up progressively decreased, actually arranged on 44% 3 years after the last infusion, according to data reported from the CITR. Successful duration is progressively increasing, with ≥13 years being the longest reported insulin-free condition on record. The immediate results of functioning islet transplantation are an improvement in hypoglycemic awareness and a reduction in the glycated hemoglobin level. Furthermore, many studies have shown its influence on the chronic complications of diabetes, such as peripheral neuropathy, retinopathy, and macroangiopathy. Pre-transplant nephropathy remains an exclusion criterion as immunosuppressive therapy can exacerbate kidney-function deterioration. The problems linked to immunosuppression following islet transplantation for the treatment of type-1 diabetes need to be considered in order to achieve the correct risk/benefit ratio for each patient.
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Diabetes Mellitus Tipo 1/cirugía , Trasplante de Islotes Pancreáticos/métodos , Animales , Ensayos Clínicos como Asunto , Diabetes Mellitus Tipo 1/metabolismo , Humanos , Hipoglucemia/etiología , Trasplante de Riñón , Resultado del TratamientoRESUMEN
Percutaneous intra-portal islet transplantation (PIPIT) is a less invasive, safer, and repeatable therapeutic option for brittle type 1 diabetes, compared to surgical pancreas transplantation. Hepatic steatosis is a consequence of the islet engraftment but it is curiously present in a limited number of patients and its meaning is controversial. The aims of this study were to assess hepatic steatosis at ultrasound (US) after PIPIT investigating its relationship with graft function and its role in predicting the clinical outcome. From 1996 to 2012, 108 patients underwent PIPIT: 83 type-1 diabetic patients underwent allo-transplantation, 25 auto-transplantation. US was performed at baseline, 6, 12, and 24 months, recording steatosis prevalence, first detection, duration, and distribution. Contemporaneously, steatotic and non-steatotic patients were compared for the following parameters: infused islet mass, insulin independence rate, ß-score, C-peptide, glycated hemoglobin, exogenous insulin requirement, and fasting plasma glucose. Steatosis at US was detected in 21/108 patients, 20/83 allo-transplanted and 1/25 auto-transplanted, mostly at 6 and 12 months. Infused islet mass was significantly higher in steatotic than non-steatotic patients (IE/kg: S=10.822; NS=6138; p=0.001). Metabolically, steatotic patients had worse basal conditions, but better islet function when steatosis was first detected, after which progressive islet exhaustion, along with steatosis disappearance, was observed. Conversely, in non-steatotic patients these parameters remained stable in time. Number of re-transplantations was significantly higher in steatotic than in non-steatotic patients (1.8 vs 1.1; p=0.001). Steatosis at US seems to be related to the islet mass and local overworking activity. It precedes metabolic alterations and can predict graft dysfunction addressing to therapeutic decisions before islet exhaustion. If steatosis does not appear, no conclusion can be drawn.
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Hígado Graso/diagnóstico por imagen , Hígado Graso/etiología , Trasplante de Islotes Pancreáticos/efectos adversos , Adulto , Anciano , Diabetes Mellitus Tipo 1/terapia , Hígado Graso/epidemiología , Femenino , Humanos , Células Secretoras de Insulina/trasplante , Hígado/patología , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Pruebas de Función Pancreática , Valor Predictivo de las Pruebas , Prevalencia , Trasplante Autólogo , Resultado del Tratamiento , Ultrasonografía , Adulto JovenRESUMEN
Plasticity is a hallmark of macrophages, and in response to environmental signals these cells undergo different forms of polarized activation, the extremes of which are called classic (M1) and alternative (M2). Rapamycin (RAPA) is crucial for survival and functions of myeloid phagocytes, but its effects on macrophage polarization are not yet studied. To address this issue, human macrophages obtained from six normal blood donors were polarized to M1 or M2 in vitro by lipopolysaccharide plus interferon-γ or interleukin-4 (IL-4), respectively. The presence of RAPA (10 ng/ml) induced macrophage apoptosis in M2 but not in M1. Beyond the impact on survival in M2, RAPA reduced CXCR4, CD206 and CD209 expression and stem cell growth factor-ß, CCL18 and CCL13 release. In contrast, in M1 RAPA increased CD86 and CCR7 expression and IL-6, tumour necrosis factor-α and IL-1ß release but reduced CD206 and CD209 expression and IL-10, vascular endothelial growth factor and CCL18 release. In view of the in vitro data, we examined the in vivo effect of RAPA monotherapy (0·1 mg/kg/day) in 12 patients who were treated for at least 1 month before islet transplant. Cytokine release by Toll-like receptor 4-stimulated peripheral blood mononuclear cells showed a clear shift to an M1-like profile. Moreover, macrophage polarization 21 days after treatment showed a significant quantitative shift to M1. These results suggest a role of mammalian target of rapamycin (mTOR) into the molecular mechanisms of macrophage polarization and propose new therapeutic strategies for human M2-related diseases through mTOR inhibitor treatment.
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Inmunosupresores/farmacología , Activación de Macrófagos/efectos de los fármacos , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Sirolimus/farmacología , Adulto , Apoptosis/efectos de los fármacos , Citocinas/inmunología , Diabetes Mellitus Tipo 1/cirugía , Femenino , Citometría de Flujo , Rechazo de Injerto/prevención & control , Humanos , Trasplante de Islotes Pancreáticos/inmunología , Masculino , Persona de Mediana Edad , Serina-Treonina Quinasas TOR/inmunología , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
OBJECTIVE: To assess metabolic and oncologic outcomes of islet autotransplantation (IAT) in patients undergoing pancreatic surgery for either benign or malignant disease. BACKGROUND: IAT is performed to improve glycemic control after extended pancreatectomy, almost exclusively in patients with chronic pancreatitis. Limited experience is available for other indications or in patients with pancreatic malignancy. METHODS: In addition to chronic pancreatitis, indications for IAT were grade C pancreatic fistula (treated with completion or left pancreatectomy, as indicated); total pancreatectomy as an alternative to high-risk anastomosis during pancreaticoduodenectomy; and distal pancreatectomy for benign/borderline neoplasm of pancreatic body-neck. Malignancy was not an exclusion criterion. Metabolic and oncologic follow-up is presented. RESULTS: From November 2008 to June 2012, 41 patients were candidates to IAT (accounting for 7.5% of all pancreatic resections). Seven of 41 did not receive transplantation for inadequate islet mass (4 pts), patient instability (2 pts), or contamination of islet culture (1 pt). IAT-related complications occurred in 8 pts (23.5%): 4 bleeding, 3 portal thromboses (1 complete, 2 partial), and 1 sepsis. Median follow-up was 546 days. Fifteen of 34 patients (44%) reached insulin independence, 16 patients (47%) had partial graft function, 2 patients (6%) had primary graft nonfunction, and 1 patient (3%) had early graft loss. Seventeen IAT recipients had malignancy (pancreatic or periampullary adenocarcinoma in 14). Two of them had already liver metastases at surgery, 13 were disease-free at last follow-up, and none of 2 patients with tumor recurrence developed metastases in the transplantation site. CONCLUSIONS: Although larger data are needed to definitely exclude the risk of disease dissemination, the present study suggests that IAT indications can be extended to selected patients with neoplasm.
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Diabetes Mellitus/prevención & control , Trasplante de Islotes Pancreáticos , Pancreatectomía , Enfermedades Pancreáticas/cirugía , Complicaciones Posoperatorias/prevención & control , Adulto , Anciano , Diabetes Mellitus/etiología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Enfermedades Pancreáticas/mortalidad , Fístula Pancreática/mortalidad , Fístula Pancreática/cirugía , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/cirugía , Pancreatitis Crónica/mortalidad , Pancreatitis Crónica/cirugía , Estudios Retrospectivos , Análisis de Supervivencia , Trasplante Autólogo , Resultado del TratamientoRESUMEN
Community engagement (CE) is essential to humanitarian assistance, and the social sciences have been credited in recent epidemics and disease outbreaks as having played a crucial, supportive role. Broadening this attention to other humanitarian fields, this scoping review asks what lessons learned can be found in grey and peer-reviewed literature on the integration of the social sciences in CE for conflicts and disasters. Using an analytical framework developed through a UNICEF-led project called Social Science for Community Engagement (SS4CE) in Humanitarian Action, we identified 1093 peer reviewed publications and 315 grey literature reports of possible relevance. The results show that only a small minority-18 publications and 4 reports-tangibly comment on the relevance of social sciences, mostly only in passing and implicitly. While social science techniques are used and the importance of understanding a community's cultural, linguistic, and religious context is emphasized, further discussion on the integration of transdisciplinary and multidisciplinary social sciences is absent. Furthermore, CE is mostly seen as an instrumental ('means to an end') involvement, for example to collect data in emergency situations and receive feedback on interventions, but not as a critical and transformative intervention. We conclude that unlike the attention given to social sciences in disease outbreaks, there is a knowledge gap and an accordingly proper planning and implementation gap regarding the potentiality of social science to improve CE across all humanitarian contexts of disasters and conflicts.
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Desastres , Epidemias , Sistemas de Socorro , Altruismo , Brotes de EnfermedadesRESUMEN
BACKGROUND: Periodic surges of COVID-19 patients seeking care in the hospital environment overwhelm systems reduce the availability of resources for treatment of non-COVID-19 cases (Zheng et al. in J Hosp Infect 106:325-329, 2020). Hospital flow and resource management could be greatly enhanced by differentiating patients who are likely at risk of adverse clinical outcomes from those who could safely be discharged after evaluation and managed outside of the hospital setting (Sun et al. in J Infect Dis 223:38-46, 2021). Herein, we propose a prognostic score named PEGALUS (Predictivity of Elderly age, arterial blood Gas Analysis and Lung UltraSound) that could potentially help clinicians properly and rapidly choose the appropriate allocation of COVID-19 patients admitted to the emergency department (ED). METHODS: This observational prospective study enrolled COVID-19 patients who were admitted to the ED of IRCCS San Raffaele Hospital (HSR). RESULTS: 230 COVID-19 patients were enrolled and 30-day follow-up data was collected. Composite outcome was death or need for oro-tracheal intubation (OTI). 50 patients (21.5%) reached the outcome during the observational period. In multivariate Cox analysis, age, PO2/FiO2 ratio, pCO2, duration of symptoms, and lung ultrasound evaluation were significantly associated with the adverse outcome. We obtained a new scorecard (PEGALUS) according to the hazard ratio of the identified predictors. PEGALUS score performed well in predicting the composite outcome (AUC 0.866, 95% IC 0.812-0.921; p < 0.001). Kaplan-Meier showed that a PEGALUS score < 7 was associated with a good 30-day prognosis (survival rate 97.5%), compared to a PEGALUS score of 7-11 (survival rate 85.9%; p log-rank 0.009) and PEGALUS score > 11 (survival rate 49.3%; p log-rank < 0.001). CONCLUSIONS: PEGALUS score performed at the admission can predict adverse outcomes in patients with COVID-19. The systematic application of this score might permit a more accurate and rapid treatment allocation in this setting.
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COVID-19 , Humanos , Anciano , Estudios Prospectivos , Pronóstico , Servicio de Urgencia en Hospital , Pulmón/diagnóstico por imagenRESUMEN
Pancreatic surgery still remains burdened by high levels of morbidity and mortality with a relevant incidence of complications, even in high volume centers. This review highlights the interventional radiological management of complications after pancreatic surgery. The current literature regarding the percutaneous drainage of fluid collections due to pancreatic fistulas, percutaneous transhepatic biliary drainage due to biliary leaks and transcatheter embolization (or stent-graft) due to arterial bleeding is analyzed. Moreover, also, percutaneous intra-portal islet auto-transplantation for the prevention of pancreatogenic diabetes in case of extended pancreatic resection is also examined. Moreover, a topic not usually treated in other similar reviewsas percutaneous intra-portal islet auto-transplantation for the prevention of pancreatogenic diabetes in case of extended pancreatic resection is also one of our areas of focus. In islet auto-transplantation, the patient is simultaneously donor and recipient. Differently from islet allo-transplantation, it does not require immunosuppression, has no risk of rejection and is usually efficient with a small number of transplanted islets.
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Successful transplantation requires the prevention of allograft rejection and, in the case of transplantation to treat autoimmune disease, the suppression of autoimmune responses. The standard immunosuppressive treatment regimen given to patients with autoimmune type 1 diabetes who have received an islet transplant results in the loss of T cells. In many other situations, the immune system responds to T cell loss through cytokine-dependant homeostatic proliferation of any remaining T cells. Here we show that T cell loss after islet transplantation in patients with autoimmune type 1 diabetes was associated with both increased serum concentrations of IL-7 and IL-15 and in vivo proliferation of memory CD45RO(+) T cells, highly enriched in autoreactive glutamic acid decarboxylase 65-specific T cell clones. Immunosuppression with FK506 and rapamycin after transplantation resulted in a chronic homeostatic expansion of T cells, which acquired effector function after immunosuppression was removed. In contrast, the cytostatic drug mycophenolate mofetil efficiently blocked homeostatic T cell expansion. We propose that the increased production of cytokines that induce homeostatic expansion could contribute to recurrent autoimmunity in transplanted patients with autoimmune disease and that therapy that prevents the expansion of autoreactive T cells will improve the outcome of islet transplantation.
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Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/terapia , Interleucina-15/inmunología , Interleucina-7/inmunología , Trasplante de Islotes Pancreáticos , Subgrupos de Linfocitos T/inmunología , Linfocitos T/inmunología , Adulto , Animales , Diabetes Mellitus Tipo 1/sangre , Homeostasis , Humanos , Inmunosupresores/farmacología , Inmunosupresores/uso terapéutico , Interleucina-15/sangre , Interleucina-7/sangre , Masculino , Ratones , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/farmacología , Ácido Micofenólico/uso terapéutico , Sirolimus/farmacología , Sirolimus/uso terapéutico , Linfocitos T/efectos de los fármacos , Tacrolimus/farmacología , Tacrolimus/uso terapéuticoRESUMEN
BACKGROUND: Solid organ transplant (SOT) recipients may be at increased risk for severe disease and mortality from COVID-19 because of immunosuppression and prolonged end-stage organ disease. As a transplant center serving a diverse patient population, we report the cumulative incidence and outcomes of SARS-CoV-2 infection in our cohort of SOT recipients. METHODS: We prospectively included in this observational study SOT recipients with a functioning kidney (n = 201), pancreas ± kidney (n = 66) or islet transplant (n = 24), attending outpatient regular follow-up at the San Raffaele Hospital from February 2020 to April 2021. Antibodies to SARS-CoV-2 were tested in all patients by a luciferase immunoprecipitation system assay. RESULTS: Of the 291 SOT recipients, 30 (10.3%) tested positive for SARS-CoV-2 during the study period and prevalence was not different among different transplants. The SARS-CoV-2 antibody frequency was around 2.6-fold higher than the incidence of cases who tested positive for SARS-CoV-2 RT-PCR. As for the WHO COVID-19 severity classification, 19 (63.3%) SOT recipients were mild, nine (30%) were moderate, and two were critical and died yielding a crude mortality rate in our patient population of 6.7%. Kidney transplant (OR 12.9 (1.1-150) p = 0.041) was associated with an increased risk for moderate/critical disease, while statin therapy (OR 0.116 (0.015-0.926) p = 0.042) and pancreas/islet transplant (OR 0.077 (0.007-0.906) p = 0.041) were protective. CONCLUSIONS: The incidence of SARS-CoV-2 infection in SOT recipients may be higher than previously described. Due to the relative high crude mortality, symptomatic SOT recipients must be considered at high risk in case of SARS-CoV-2 infection.
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OBJECTIVE: Reparixin is an inhibitor of CXCR1/2 chemokine receptor shown to be an effective anti-inflammatory adjuvant in a pilot clinical trial in allotransplant recipients. RESEARCH DESIGN AND METHODS: A phase 3, multicenter, randomized, double-blind, parallel-assignment study (NCT01817959) was conducted in recipients of islet allotransplants randomized (2:1) to reparixin or placebo in addition to immunosuppression. Primary outcome was the area under the curve (AUC) for C-peptide during the mixed-meal tolerance test at day 75 ± 5 after the first and day 365 ± 14 after the last transplant. Secondary end points included insulin independence and standard measures of glycemic control. RESULTS: The intention-to-treat analysis did not show a significant difference in C-peptide AUC at both day 75 (27 on reparixin vs. 18 on placebo, P = 0.99) and day 365 (24 on reparixin vs. 15 on placebo, P = 0.71). There was no statistically significant difference between treatment groups at any time point for any secondary variable. Analysis of patient subsets showed a trend for a higher percentage of subjects retaining insulin independence for 1 year after a single islet infusion in patients receiving reparixin as compared with patients receiving placebo (26.7% vs. 0%, P = 0.09) when antithymocyte globulin was used as induction immunosuppression. CONCLUSIONS: In this first double-blind randomized trial, islet transplantation data obtained with reparixin do not support a role of CXCR1/2 inhibition in preventing islet inflammation-mediated damage.
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Diabetes Mellitus Tipo 1/terapia , Secreción de Insulina/efectos de los fármacos , Trasplante de Islotes Pancreáticos , Sulfonamidas/administración & dosificación , Adolescente , Adulto , Anciano , Terapia Combinada , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Método Doble Ciego , Esquema de Medicación , Femenino , Humanos , Inmunosupresores/administración & dosificación , Masculino , Persona de Mediana Edad , Placebos , Periodo Posoperatorio , Receptores de Interleucina-8A/antagonistas & inhibidores , Receptores de Interleucina-8B/antagonistas & inhibidores , Sulfonamidas/efectos adversos , Sulfonamidas/farmacología , Factores de Tiempo , Adulto JovenRESUMEN
BACKGROUND: Results in murine and nonhuman primate suggested that the bone marrow (BM) might be an alternative site for pancreatic islet transplantation. METHODS: We report the results of 2 clinical studies in patients with type 1 diabetes receiving an intra-BM allogeneic islet transplantation: a feasibility study in patients with hepatic contraindications for liver islet allotransplantation receiving a single intra-BM islet infusion (n = 4) and a pilot randomized trial (1:1 allocation using blocks of size 6) in which patients were randomized to receive islets into either the liver (n = 6) or BM (n = 3) to evaluate islet transplant function and survival. RESULTS: We observed no adverse events related to the intrabone injection procedure or the presence of islets in the BM. None of the recipient of an intra-BM allogeneic islet transplantation had a primary nonfunction, as shown by measurable posttransplantation C-peptide levels and histopathological evidence of insulin-producing cells or molecular markers of endocrine tissue in BM biopsy samples collected during follow-up. All patients receiving islets in the BM except 1 lost islet function during the first 4 months after infusion (2 with an early graft loss). Based on biopsies and immunomonitoring, we concluded that the islet loss was primarily caused by the recurrence of autoimmunity. CONCLUSIONS: Bone marrow is not a suitable alternative site for pancreatic islet allotransplantation in patients with type 1 diabetes.
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Médula Ósea/cirugía , Diabetes Mellitus Tipo 1/cirugía , Trasplante de Islotes Pancreáticos/métodos , Biopsia , Médula Ósea/patología , Diabetes Mellitus Tipo 1/inmunología , Humanos , Proyectos Piloto , Trasplante HomólogoRESUMEN
BACKGROUND: The immunosuppressive drug rapamycin may influence insulin sensitivity in insulin-responsive tissues. AIMS: This study aimed at evaluating the effectiveness of rapamycin pre-treatment before pancreatic islet allotransplantation (ITx) in patients with type 1 diabetes mellitus (T1DM). METHODS: Forty-one T1DM patients were studied. Thirteen patients with poor glycemic control underwent a short-term rapamycin treatment before ITx (Group 1), and they were compared to 28 patients undergoing ITx without rapamycin pre-treatment (Group 2). Outcomes were daily insulin requirement (DIR), fasting blood glucose, HbA1c, C-peptide and the SUITO index of beta-cell function. A subgroup of patients pre-treated with rapamycin before ITx underwent euglycemic hyperinsulinemic clamp with [6,6-2H2] glucose before and after ITx to evaluate insulin sensitivity. RESULTS: We found a significant reduction in DIR after rapamycin pre-treatment (- 8 ± 6 U/day, mean ± SD, p < 0.001) and 1 year after ITx. DIR reduction 1 year after ITx was greater in Group 1 as compared to Group 2 (- 37 ± 15 vs. - 19 ± 13 U/day, p = 0.005) and remained significant after adjusting for gender, age, glucose and baseline HbA1c (beta = 18.2 ± 5.9, p = 0.006). Fasting glucose and HbA1c significantly decreased 1 year after ITx in Group 1 (HbA1c: - 2.1 ± 1.4%, p = 0.002), while fasting C-peptide (+0.5 ± 0.3 nmol/l, p = 0.002) and SUITO index increased (+57.4 ± 39.7, p = 0.016), without differences between the two groups. Hepatic glucose production decreased after rapamycin pre-treatment (- 1.1 ± 1.1 mg/kg/min, p = 0.04) and after ITx (- 1.6 ± 0.6 mg/kg/min, p = 0.015), while no changes in peripheral glucose disposal were observed. CONCLUSIONS: Rapamycin pre-treatment before ITx succeeds in reducing insulin requirement, enhancing hepatic insulin sensitivity. This treatment may improve short-term ITx outcomes, possibly in selected patients with T1DM complicated by insulin resistance. CLINICAL TRIAL: Clinicaltrials.gov NCT01060605; NCT00014911.
Asunto(s)
Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/cirugía , Insulina/uso terapéutico , Trasplante de Islotes Pancreáticos , Sirolimus/administración & dosificación , Acondicionamiento Pretrasplante/métodos , Adolescente , Adulto , Anciano , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Diabetes Mellitus Tipo 1/sangre , Esquema de Medicación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
Although the life expectancy of patients with type 1 diabetes mellitus (T1DM) has improved since the introduction of insulin therapy, the acute life-threatening and long-term complications from diabetes mellitus are significant causes of both mortality and morbidity. Percutaneous intra-portal pancreatic islet transplantation (PIPIT) is a minimally invasive, repeatable procedure which allows a ß-cell replacement therapy through a liver islet engraftment, leading to insulin release and glycaemic control restoration in patients with diabetes. Allo-PIPIT, in which isolated and purified islets from cadaveric donor are used, does not require major surgery, and is potentially less expensive for the recipient. In case of long-term T1DM, islet-after-kidney (IAK) transplantation can simultaneously cure diabetes and chronic renal failure, while islet-transplant-alone (ITA) is performed in brittle, short-term T1DM, based on the infusion of an adequate islet mass and on a steroid-free immunosuppressive regimen according to the Edmonton protocol. Results of the Collaborative Islet Transplant Registry (CITR) demonstrate that allo-PIPIT reduces episodes of hypoglycemia and diabetic complications, and improves quality of life of diabetic patients. Auto-PIPIT, in which the own patient's islets are used, has been investigated as a preventive treatment for pancreatogenic diabetes in patients who undergo extensive pancreatectomy for malignant and non-malignant disease. This Review outlines the role of imaging and interventional radiology in allo- and auto-PIPIT.
RESUMEN
In recent times, the global prevalence of diabetes has increased substantially, reaching 8.3% in 2014, which corresponds to 387 million patients. Studies in Europe and USA have shown increased incidence of type 1 Diabetes (T1D) over time at a rate of 3-5% per year. Another most worrying feature of the rapid increase of diabetes is the emergence of type 2 Diabetes (T2D) in children, adolescents, and young adults. The well-known behavioral risks factors and epigenetic mechanisms recently observed require an integrated approach to prevent T2D. Diabetes significantly influences the patient' survival, quality of life, and development of organ system degeneration. Epidemiological studies have shown increased mortality in diabetic patients, especially women, which increased approximately fivefold, whereas cardiovascular mortality increased 20- to 30-fold when compared to the normal population. Diabetes is the leading cause of end-stage renal disease and vision loss in developed countries. Around 40% of T1D and T2D start on renal replacement therapy. While after 40 years of diabetes, the cumulative proportion of patients with any retinopathy and advanced retinopathy was 84.1 and 50.2%, respectively. However, the most prevalent chronic complication of diabetes is neuropathy. Distal Symmetric Polyneuropathy occurs in at least 20% of people with T1D after 20 years and in 10-15% of newly diagnosed T2D, increasing to 50% after 10 years. Cardiovascular Autonomic Neuropathy may be present in up to 60% of patients after 15 years and is an independent risk factor for cardiovascular mortality.
Asunto(s)
Complicaciones de la Diabetes/epidemiología , Diabetes Mellitus Tipo 1/epidemiología , Diabetes Mellitus Tipo 2/epidemiología , Calidad de Vida , Diabetes Mellitus Tipo 1/psicología , Diabetes Mellitus Tipo 2/psicología , Salud Global , Humanos , Incidencia , Prevalencia , Factores de RiesgoRESUMEN
BACKGROUND: To assess feasibility, safety, and metabolic outcome of islet auto transplantation (IAT) in patients undergoing completion pancreatectomy because of sepsis or bleeding after pancreatic surgery. METHODS: From November 2008 to October 2016, approximately 22 patients were candidates to salvage IAT during emergency relaparotomy because of postpancreatectomy sepsis (n = 11) or bleeding (n = 11). Feasibility, efficacy, and safety of salvage IAT were compared with those documented in a cohort of 36 patients who were candidate to simultaneous IAT during nonemergency preemptive completion pancreatectomy through the pancreaticoduodenectomy. RESULTS: The percentage of candidates that received the infusion of islets was significantly lower in salvage IAT than simultaneous IAT (59.1% vs 88.9%, P = 0.008), mainly because of a higher rate of inadequate islet preparations. Even if microbial contamination of islet preparation was significantly higher in candidates to salvage IAT than in those to simultaneous IAT (78.9% vs 20%, P < 0.001), there was no evidence of a higher rate of complications related to the procedure. Median follow-up was 5.45 ± 0.52 years. Four (36%) of 11 patients reached insulin independence, 6 patients (56%) had partial graft function, and 1 patient (9%) had primary graft nonfunction. At the last follow-up visit, median fasting C-peptide was 0.43 (0.19-0.93) ng/mL; median insulin requirement was 0.38 (0.04-0.5) U/kg per day, and median HbA1c was 6.6% (5.9%-8.1%). Overall mortality, in-hospital mortality, metabolic outcome, graft survival, and insulin-free survival after salvage IAT were not different from those documented after simultaneous IAT. CONCLUSIONS: Our data demonstrate the feasibility, efficacy, and safety of salvage IAT after relaparotomy.