Sirolimus in solid organ transplantation: current therapies and new frontiers

Sirolimus (SRL) is a mammalian target of rapamycin inhibitor, which provides an immunosuppressive effect by inhibiting cell cycle progression. The encouraging results of combined SRL-cyclosporine therapy paved the way to further immunosuppressant combinations. Although SRL is relatively non-nephrotoxic when administered as monotherapy, it pharmacodynamically enhances the toxicity of calcineurin inhibitors. Other side effects may include hyperlipidemia and myelosuppression and less commonly wound healing impairment, proteinuria, edema and pneumonitis. Surprisingly, SRL also showed encouraging properties as an antiatherogenic and antineoplastic, opening a large spectrum of new potential applications. Whether SRL can be used safely over the long term with low doses of calcineurin inhibitors requires further study. The use of SRL as a corticosteroid-sparing agent also remains to be proven in controlled trials.     

Experimental Stimulation of Bone Healing with Teriparatide: Histomorphometric and Microhardness Analysis in a Mouse Model of Closed Fracture

Fracture consolidation is a crucial goal to achieve as early as possible, but pharmacological stimulation has been neglected so far. Teriparatide has been considered for this purpose for its anabolic properties. We set up a murine model of closed tibial fracture on which different doses of teriparatide were tested. Closed fracture treatment avoids any bias introduced by surgical manipulations. Teriparatide’s effect on callus formation was monitored during the first 4 weeks from fracture. Callus evolution was determined by histomorphometric and microhardness assessment. Daily administration of 40 μg/kg of teriparatide accelerated callus mineralization from day 9 onward without significant increase of sizes, and at day 15 the microhardness properties of treated callus were similar to those of bone tissue. Teriparatide considerably improved callus consolidation in the very early phases of bone healing.     

Abdominal obesity modifies the risk of hypertriglyceridemia for all-cause and cardiovascular mortality in hemodialysis patients

Hypertriglyceridemia is the most prevalent lipid alteration in end-stage renal disease, and we studied the relationship between serum triglycerides and all-cause and cardiovascular death in these patients. Since abdominal fat modifies the effect of lipids on atherosclerosis, we analyzed the interaction between serum lipids and waist circumference (WC) as a metric of abdominal obesity. In a cohort of 537 hemodialysis patients, 182 died, 113 from cardiovascular causes, over an average follow-up of 29 months. In Cox models that included traditional and nontraditional risk factors, there were significant strong interactions between triglycerides and WC to both all-cause and cardiovascular death. A fixed (50 mg/dl) excess in triglycerides was associated with a progressive lower risk of all-cause and cardiovascular mortality in patients with threshold WC <95 cm but with a progressive increased risk in those above this threshold. A significant interaction between cholesterol and WC with all-cause and cardiovascular death emerged only in models excluding the triglycerides-WC interaction. Neither high-density lipoprotein (HDL) nor non-HDL cholesterol or their interaction terms with WC were associated with study outcomes. Thus, the predictive value of triglycerides and cholesterol for survival and atherosclerotic complications in hemodialysis patients is critically dependent on WC. Hence, intervention studies in end-stage renal disease should specifically target patients with abdominal obesity and hyperlipidemia.     

Pregnancy under everolimus-based immunosuppression

The ability to give birth to a live child is one of the best success of kidney transplantation. While there are an increasing number of pregnancies reported in kidney transplant recipients treated with cyclosporine or tacrolimus, there is little evidence of pregnancy among kidney transplant recipients exposed to sirolimus or everolimus. We present the first successful delivery in an organ transplant recipient exposed to everolimus during the whole gestation. The absence of congenital anomalies in the child as well as the recipient's successful renal outcome are promising, although pregnancy in renal transplant recipients exposed to everolimus should be considered at higher risk.     

Endoscope-assisted microsurgical transoral approach to the anterior craniovertebral junction compressive pathologies

At the present time, an update to the classical microsurgical transoral decompression is strongly provided by the most recent literature dealing with the introduction of the endoscopy in spine surgery. In this paper, we present our experience on the endoscope-assisted microsurgical transoral approach to anterior craniovertebral junction (CVJ) compressive pathology. We analysed seven patients (3 paediatrics and 4 adults ranging from 6 to 78 years) operated on for CVJ decompressive procedures using an open access, microsurgical technique, neuronavigation and endoscopy. All techniques mentioned were simultaneously employed. Among the endoscopic routes described in the literature, we have preferred the transoral using 30° endoscopes. In all the cases endoscopy allowed a radical decompression compared to the microsurgical technique alone, as confirmed intraoperatively with contrast medium fluoroscopy. In conclusion, endoscopy represents a useful complement to the standard microsurgical approach to the anterior CVJ; it provides information for a better decompression with no need for soft palate splitting, hard palate resection, or extended maxillotomy. Moreover, intraoperative fluoroscopy helps to recognize residual compression. Virtually, in normal anatomic conditions, no surgical limitations exist for endoscopically assisted transoral approach, compared with the pure endonasal and transcervical endoscopic approaches. In our opinion, the endoscope deserves a role as “support” to the standard transoral microsurgical approach since 30° angulated endoscopy significantly increases the surgical area exposed at the level of the anterior CVJ.     

Cystic peritoneal mesothelioma: report of a case

Benign multicystic peritoneal mesothelioma (BMPM) is a rare disease with good short-term prognosis and rare malignant transformation. However, its biological significance remains unexplained. A neoplastic origin is considered by many authors to require a surgical excision, based on the high recurrence and progressive growth rate of the tumors. However, alternative or integrative treatment options have also been proposed. A 45-year-old woman presented to our unit with a history of occasional discomfort and pain in the left hip. On physical examination, we noticed a tough-elastic, fixed mass located in the iliac fossa. Computed tomography scan detected a mass with multiseptated cystic-like areas. Due to the similarity of these findings to a primitive sarcomatous tumor of the retroperitoneum, an arteriographic study was also performed. The patient underwent en bloc resection of the mass, including a segment of the sigmoid colon. The final pathologic diagnosis was cystic mesothelioma. Further studies are needed to better understand the etiology and pathogenesis of this rare disease, and to define a more tailored treatment plan.     

Mesoangioblasts from facioscapulohumeral muscular dystrophy display in vivo a variable myogenic ability predictable by their in vitro behavior

Facioscapulohumeral muscular dystrophy (FSHD) is the third most frequent inherited myopathy. We previously demonstrated that mesoangioblasts can be efficiently isolated from FSHD muscles, although their differentiation ability into skeletal muscle was variably impaired. This correlates with overall disease severity and degree of histopathologic abnormalities, since mesoangioblasts from morphologically normal muscles did not show any myogenic differentiation block. The aim of our present study was to verify whether mesoangioblasts from differentially affected FSHD muscles reproduce in vivo the same differentiation ability shown in vitro by studying their capability to form new muscle fibers during muscle regeneration of experimentally damaged muscles. We show that a diverse ability of FSHD mesoangioblasts to engraft and differentiate into skeletal muscle of SCID mice is strictly related to the characteristics of the muscle of origin, closely replicating in vivo what was previously observed in vitro. Moreover, we demonstrate that mesoangioblasts obtained from severely affected muscles scarcely integrate into muscle fibers, remaining mainly localized in the connective tissue. This suggests a defective migration in response to chemoattractants released by damaged fibers, as indicated by cell migration assays in response to HMGB1 and very low levels of RAGE expression, along with a decreased ability to fuse or to appropriately trigger the myogenic program. Our study indicates that FSHD mesoangioblasts from unaffected muscles can be used as selective treatment to halt muscle degeneration in severely affected muscles, and suggests that pharmacological and molecular interventions aimed to ameliorate homing and engraftment of transplanted autologous mesoangioblasts may open the way to cell therapy for FSHD patients, without requiring immunosuppression or genetic correction in vitro.