Rita Nano

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; PP<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.

Common variable immunodeficiency (CVID) is the most frequent primary antibody deficiency whereby follicular helper T (Tfh) cells fail to establish productive responses with B cells in germinal centers. Here, we analyzed the frequency, phenotype, transcriptome, and function of circulating Tfh (cTfh) cells in CVID patients displaying autoimmunity as an additional phenotype. A group of patients showed a high frequency of cTfh1 cells and a prominent expression of PD‐1 and ICOS as well as a cTfh mRNA signature consistent with highly activated, but exhausted, senescent, and apoptotic cells. Plasmatic CXCL13 levels were elevated in this group and positively correlated with cTfh1 cell frequency and PD‐1 levels. Monoallelic variants in RTEL1, a telomere length‐ and DNA repair‐related gene, were identified in four patients belonging to this group. Their blood lymphocytes showed shortened telomeres, while their cTfh were more prone to apoptosis. These data point toward a novel pathogenetic mechanism in CVID, whereby alterations in DNA repair and telomere elongation might predispose to antibody deficiency. A Th1, highly activated but exhausted and apoptotic cTfh phenotype was associated with this form of CVID.

Purpose: To assess whether dysglycemia diagnosed during severe acute respiratory syndrome coronavirus 2 pneumonia may become a potential public health problem after resolution of the infection. In an adult cohort with suspected coronavirus disease 2019 (COVID-19) pneumonia, we integrated glucose data upon hospital admission with fasting blood glucose (FBG) in the year prior to COVID-19 and during postdischarge follow-up. Methods: From February 25 to May 15, 2020, 660 adults with suspected COVID-19 pneumonia were admitted to the San Raffaele Hospital (Milan, Italy). Through structured interviews/ medical record reviews, we collected demographics, clinical features, and laboratory tests upon admission and additional data during hospitalization or after discharge and in the previous year. Upon admission, we classified participants according to American Diabetes Association criteria as having (1) preexisting diabetes, (2) newly diagnosed diabetes, (3) hyperglycemia not in the diabetes range, or (4) normoglycemia. FBG prior to admission and during follow-up were classified as normal or impaired fasting glucose and fasting glucose in the diabetes range. Results: In patients with confirmed COVID (n = 589), the proportion with preexisting or newly diagnosed diabetes, hyperglycemia not in the diabetes range and normoglycemia was 19.6%, 6.7%, 43.7%, and 30.0%, respectively. Patients with dysglycemia associated to COVID-19 had increased markers of inflammation and organs’ injury and poorer clinical outcome compared to those with normoglycemia. After the infection resolved, the prevalence of dysglycemia reverted to preadmission frequency. Conclusions: COVID-19–associated dysglycemia is unlikely to become a lasting public health problem. Alarmist claims on the diabetes risk after COVID-19 pneumonia should be interpreted with caution.

Aim. The aim of the current study was to compare clinical characteristics, laboratory findings, and major outcomes of patients hospitalized for COVID-19 pneumonia with COVID-associated hyperglycaemia or pre-existing diabetes. Methods. A cohort of 176 adult patients with a diagnosis of pre-existing diabetes (n = 112) or COVID-associated hyperglycaemia (n = 55) was studied. Results. Patients with COVID-associated hyperglycaemia had lower BMI, significantly less comorbidities, and higher levels of inflammatory markers and indicators of multi-organ injury than those with pre-existing diabetes. No differences between pre-existing diabetes and COVID-associated hyperglycaemia were evident for symptoms at admission, the humoral response against SARS-CoV-2, or autoantibodies to glutamic acid decarboxylase or interferon alpha-4. COVID-associated hyperglycaemia was independently associated with the risk of adverse clinical outcome, which was defined as ICU admission or death (HR 2.11, 95% CI 1.34–3.31; p = 0.001), even after adjustment for age, sex, and other selected variables associated with COVID-19 severity. Furthermore, at the same time, we documented a negative association (HR 0.661, 95% CI 0.43–1.02; p = 0.063) between COVID-associated hyperglycaemia to swab negativization. Conclusions. Recognizing hyperglycaemia as a specific clinical entity associated with COVID-19 pneumonia is relevant for early and appropriate patient management and close monitoring for the progression of disease severity.

Extracellular vesicles (EVs) are implicated in the crosstalk between adipocytes and other metabolic organs, and an altered biological cargo has been observed in EVs from human obese adipose tissue (AT). Yet, the role of adipocyte-derived EVs in pancreatic β cells remains to be determined. Here, we explored the effects of EVs released from adipocytes isolated from both rodents and humans and human AT explants on survival and function of pancreatic β cells and human pancreatic islets. EVs from healthy 3T3-L1 adipocytes increased survival and proliferation and promoted insulin secretion in INS-1E β cells and human pancreatic islets, both those untreated or exposed to cytokines or glucolipotoxicity, whereas EVs from inflamed adipocytes caused β cell death and dysfunction. Human lean adipocyte-derived EVs produced similar beneficial effects, whereas EVs from obese AT explants were harmful for human EndoC-βH3 β cells. We observed differential expression of miRNAs in EVs from healthy and inflamed adipocytes, as well as alteration in signaling pathways and expression of β cell genes, adipokines, and cytokines in recipient β cells. These in vitro results suggest that, depending on the physiopathological state of AT, adipocyte-derived EVs may influence β cell fate and function.

To assess feasibility, safety and metabolic outcome of islet auto transplantation (IAT) in patients undergoing completion pancreatectomy because of sepsis or bleeding following pancreatic surgery. From November 2008 to October 2016, 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 to those documented in a cohort of 36 patients who were candidate to simultaneous IAT during nonemergency preemptive completion pancreatectomy through the pancreaticoduodenectomy. 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 due to 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 out of 11 patients (36%) reached insulin independence; 6 patients (56%) had partial graft function, 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 0.38 (0.04-0.5) U/kg/day and median HbA1c 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. Our data demonstrate the feasibility, efficacy, and safety of salvage IAT after relaparotomy.

Starting in 2011, the North Italy Transplant program (NITp) has based on the allocation of pancreas allografts on donor age and duration of intensive care unit (ICU) stay, but not on donor weight or BMI. We analyzed the detailed allocation protocols of all NITp pancreas donors (2011-2012; n=433). Outcome measures included donor characteristics and pancreas loss reasons during the allocation process. Twenty-three percent of the 433 pancreases offered for allocation were transplanted. Younger age, shorter ICU stay, traumatic brain death, and higher eGFR were predictors of pancreas transplant, either as vascularized organ or as islets. Among pancreas allografts offered to vascularized organ programs, 35% were indeed transplanted, and younger donor age was the only predictor of transplant. The most common reasons for pancreas withdrawal from the allocation process were donor-related factors. Among pancreas offered to islet programs, 48% were processed, but only 14.2% were indeed transplanted, with unsuccessful isolation being the most common reason for pancreas loss. Younger donor age and higher BMI were predictors of islet allograft transplant. The current allocation strategy has allowed an equal distribution of pancreas allografts between programs for either vascularized organ or islet transplant. The high rate of discarded organs remained an unresolved issue.

High levels of donor-derived high-mobility group box 1 (HMGB1) protein have been associated with poor islet graft outcome in mouse models. The aim of our work was to determine whether HMGB1 released by human islets had independent proinflammatory effects that influence engraftment in humans. Human islet preparations contained and released HMGB1 in different amounts, as determined by Western blot and ELISA (median 17 pg/ml/IEQ/24 h; min–max 0–211, n = 74). HMGB1 release directly correlated with brain death, donor hyperamilasemia, and factors related to the pancreas digestion procedure (collagenase and digestion time). HMGB1 release was significantly positively associated with the release of other cytokines/chemokines, particularly with the highly released “proinflammatory” CXCL8/IL-8, CXCL1/GRO-α, and the IFN-γ-inducible chemokines CXCL10/IP-10 and CXCL9/MIG. HMGB1 release was not modulated by Toll-like receptor 2, 3, 4, 5, and 9 agonists or by exposure to IL-1β. When evaluated after islet transplantation, pretransplant HMGB1 release was weakly associated with the activation of the coagulation cascade (evaluated as serum cross-linked fibrin products), but not with the immediate posttransplant inflammatory response. Concordantly, HMGB1 did not affect short-term human islet function. Our data show that human islet HMGB1 release is a sign of “damaged” islets, although without any independent direct role in graft failure.