Inflammation-Mediated Regulation of MicroRNA Expression in Transplanted Pancreatic Islets

Nonspecific inflammation in the transplant microenvironment results in β-cell dysfunction and death influencing negatively graft outcome. MicroRNA (miRNA) expression and gene target regulation in transplanted islets are not yet well characterized. We evaluated the impact of inflammation on miRNA expression in transplanted rat islets. Islets exposed in vitro to proinflammatory cytokines and explanted syngeneic islet grafts were evaluated by miRNA arrays. A subset of 26 islet miRNAs was affected by inflammation both in vivo and in vitro. Induction of miRNAs was dependent on NF-κB, a pathway linked with cytokine-mediated islet cell death. RT-PCR confirmed expression of 8 miRNAs. The association between these miRNAs and mRNA target-predicting algorithms in genome-wide RNA studies of β-cell inflammation identified 238 potential miRNA gene targets. Several genes were ontologically associated with regulation of insulin signaling and secretion, diabetes, and islet physiology. One of the most activated miRNAs was miR-21. Overexpression of miR-21 in insulin-secreting MIN6 cells downregulated endogenous expression of the tumor suppressor Pdcd4 and of Pclo, a Ca2+ sensor protein involved in insulin secretion. Bioinformatics identified both as potential targets. The integrated analysis of miRNA and mRNA expression profiles revealed potential targets that may identify molecular targets for therapeutic interventions

Effect of the Purinergic Inhibitor Oxidized ATP in a Model of Islet Allograft Rejection

The lymphocytic ionotropic purinergic P2X receptors (P2X1R-P2X7R, or P2XRs) sense ATP released during cell damage-activation, thus regulating T-cell activation. We aim to define the role of P2XRs during islet allograft rejection and to establish a novel anti-P2XRs strategy to achieve long-term islet allograft function. Our data demonstrate that P2X1R and P2X7R are induced in islet allograft-infiltrating cells, that only P2X7R is increasingly expressed during alloimmune response, and that P2X1R is augmented in both allogeneic and syngeneic transplantation. In vivo short-term P2X7R targeting (using periodate-oxidized ATP [oATP]) delays islet allograft rejection, reduces the frequency of Th1/Th17 cells, and induces hyporesponsiveness toward donor antigens. oATP-treated mice displayed preserved islet grafts with reduced Th1 transcripts. P2X7R targeting and rapamycin synergized in inducing long-term islet function in 80% of transplanted mice and resulted in reshaping of the recipient immune system. In vitro P2X7R targeting using oATP reduced T-cell activation and diminished Th1/Th17 cytokine production. Peripheral blood mononuclear cells obtained from long-term islet-transplanted patients showed an increased percentage of P2X7R+CD4+ T cells compared with controls. The beneficial effects of oATP treatment revealed a role for the purinergic system in islet allograft rejection, and the targeting of P2X7R is a novel strategy to induce long-term islet allograft function

Effect of the Purinergic Inhibitor Oxidized ATP in a Model of Islet Allograft Rejection

The lymphocytic ionotropic purinergic P2X receptors (P2X1R-P2X7R, or P2XRs) sense ATP released during cell damage-activation, thus regulating T-cell activation. We aim to define the role of P2XRs during islet allograft rejection and to establish a novel anti-P2XRs strategy to achieve long-term islet allograft function. Our data demonstrate that P2X1R and P2X7R are induced in islet allograft-infiltrating cells, that only P2X7R is increasingly expressed during alloimmune response, and that P2X1R is augmented in both allogeneic and syngeneic transplantation. In vivo short-term P2X7R targeting (using periodate-oxidized ATP [oATP]) delays islet allograft rejection, reduces the frequency of Th1/Th17 cells, and induces hyporesponsiveness toward donor antigens. oATP-treated mice displayed preserved islet grafts with reduced Th1 transcripts. P2X7R targeting and rapamycin synergized in inducing long-term islet function in 80% of transplanted mice and resulted in reshaping of the recipient immune system. In vitro P2X7R targeting using oATP reduced T-cell activation and diminished Th1/Th17 cytokine production. Peripheral blood mononuclear cells obtained from long-term islet-transplanted patients showed an increased percentage of P2X7R+CD4+ T cells compared with controls. The beneficial effects of oATP treatment revealed a role for the purinergic system in islet allograft rejection, and the targeting of P2X7R is a novel strategy to induce long-term islet allograft function

Oncocytic Adrenocortical Neoplasm with Concomitant Papillary Thyroid Cancer

Adrenal oncocytoma (AO) is an extremely rare adrenocortical neoplasm and little is known about its malignant potential, secretory properties, and hereditary origin. We present the case of a benign AO with concomitant incidentally found papillary thyroid cancer (PTC) and review similar cases in the literature. Immunohistochemistry and next-generation sequencing (NGS) were performed. A 66-year-old women was incidentally found to have a large, androgen-secreting right adrenal mass. 18F-Fluorodeoxyglucose positron emission tomography showed intense uptake (SUVmax 88.7) of this mass and found a hypermetabolic right thyroid mass. Open adrenalectomy was performed for this highly suspicious adrenal mass. Histopathology revealed benign AO that was BRAFV600E negative, with low Ki-67, and no somatic mutation found on NGS. Thyroidectomy revealed invasive, BRAFV600E-positive PTC. At 6 months follow-up, androgen levels returned to normal, and no recurrence was seen on imaging. To our knowledge, this is the first report of an androgen-secreting AO with concomitant PTC. Possibly the simultaneous discovery of two independent neoplasms was observed. In conclusion, this case highlights that care should be given to exclude concomitant neoplasms. Long-term and regular imaging with biochemical follow-up is warranted, since the outcome and clinical behavior of AO remains uncertain

Influence of Surgical Technique, Performance Status, and Peritonitis Exposure on Surgical Site Infection in Acute Complicated Diverticulitis: A Matched Case-Control Study

Background: Acute generalized peritonitis secondary to complicated diverticulitis is a life-threatening condition; the standard treatment is surgery. Despite advances in peri-operative care, this condition is accompanied by a high peri-operative complication rate (22%-25%). No definitive evidence is available to recommend a preferred surgical technique in patients with Hinchey stage III/IV disease. Methods: A matched case-control study enrolling patients from four surgical units at Italian university hospital was planned to assess the most appropriate surgical treatment on the basis of patient performance status and peritonitis exposure, with the aim of minimizing the surgical site infection (SSI). A series of 1,175 patients undergoing surgery for Hinchey III/IV peritonitis in 2003-2013 were analyzed. Cases (n=145) were selected from among those patients who developed an SSI. The case:control ratio was 1:3. Cases and control groups were matched by age, gender, body mass index, and Hinchey grade. We considered three surgical techniques: T-1=Hartman's procedure; T-2=sigmoid resection, anastomosis, and ileostomy; and T-3=sigmoid resection and anastomosis. Six scoring systems were analyzed to assess performance status; subsequently, patients were divided into low, mild, and high risk (LR, MR, HR) according to the system producing the highest area under the curve. We classified peritonitis exposition as P-1=24h. Univariable and multivariable analyses were performed. Results: The Apgar scoring system defined the risk groups according to performance status. Lowest SSI risk was expected when applying T-3 in P1 (OR=0.22), P-2 (OR=0.5) for LR and in P-1 (OR=0.63) for MR; T-2 in P2 (OR=0.5) in LR and in P1 (OR=0.61) in MR; T-1 in P-3 (OR=0.56) in LR; in P-2 (OR=0.63) and P-3 (OR=0.54) in MR patients, and in each P subgroup (OR=0.93;0.97;1.01) in HR. Conclusions: Pre-operative assessment based on Apgar scoring system integrated with peritonitis exposure in complicated diverticulitis may offer a ready-to-use tool for reducing SSI-related complications and applying appropriate treatment, reducing the need for disabling ostomy

Low morbidity and high patient satisfaction after treatment of breast cancer in day surgery

NUOVE POSSIBILITA' DI TRATTAMENTO CHIRURGICO DI LESIONI BENIGNE E MALIGNE A VARIA SED

Low-grade fibromatosis-like spindle cell metaplastic carcinoma: a basal-like tumor with a favorable clinical outcome. Report of two cases

Fibromatosis-like spindle-cell metaplastic carcinoma (FLSpCC) is an atypical variant of spindle-cell carcinoma with a particular clinical behavior characterized by frequent local recurrence, very low potential for axillary lymph node metastasis, and uncommon distant metastases. Although it presents the typical immunoprofile of basal-like carcinomas, FLSpCC is associated with a favorable clinical outcome and conservative treatment is generally indicated. Because of the lack of specific clinical and radiological characteristics, the criteria for the differential diagnosis from other benign and malignant tumors are based only on histological findings and immunostaining. We report on two FLSpCC patients treated with wide local excision and mastectomy associated with axillary lymph node dissection. Although the biological behavior of this subtype of breast cancer has not been adequately evaluated, wide local excision or mastectomy with clear resection margins but no axillary dissection appears to be an adequate treatment approac