Sabina Magalini

Botulinum toxin in the therapy of gastrointestinal motility disorders

Since 1980, botulinum toxin has been employed for the treatment of various voluntary muscle spastic disorders in the fields of neurology and ophthalmology. More recently, botulinum toxin has been proved to be effective in the therapy of dyskinetic smooth muscle disorders of the gastrointestinal tract. Achalasia and anal fissure are the gastrointestinal disorders in which botulinum toxin therapy has been most extensively investigated. Botulinum toxin is the best treatment option for achalasia in patients whose condition makes them unfit for pneumatic dilation or surgery. In anal fissure, botulinum toxin is highly effective and may become the treatment of choice. In the future, botulinum toxin application in the gastrointestinal tract will be extended to many other gastrointestinal disorders, such as non‐achalasic motor disorders of the oesophagus, dysfunction of Oddis sphincter, achalasia of the internal anal sphincter and others. This article describes the mechanism of action, rationale of employment, indications and side‐effects of botulinum toxin application in smooth muscle disorders of the gastrointestinal tract, and compares the results of different techniques of botulinum toxin therapeutic application.

Marginal donors for patients on regular waiting lists for liver transplantation

Abstractu2002 The use of marginal donors is well accepted by most centers for emergency situations, but there is debate on their use for patients on regular waiting lists. We report our experience of the l‐year survival for patients on waiting lists (n= 147, 1‐year survival = 32 %), patients transplanted from good donors (n= 60, l‐year survival = 84 %), and patients transplanted from marginal donors (n = 15, l‐year survival = 56 %). We concluded that liver transplantation from marginal donors (a) is a safe procedure (b) has a 1 ‐year survival that is significantly better than that on a waiting list (c) is ethically justified especially in countries with donor shortages, and (d) may allow transplantation of “special” high risk and poor long‐term outcome patients.

Quantification of degree of steatosis in extended criteria donor grafts with standardized histologic techniques: implications for graft survival

The gap between the availability of livers from organ donors and the increased demand has led many centers to apply strategies to reduce this deficit. Splitting of cadaveric organs for use in 2 recipients; domino transplantation; and organs from living donors, non-heart-beating donors, and extended-criteria donors (ECDs) are all currently used in orthotopic liver transplantation (OLT). Fatty changes in the donor liver are a risk factor for poor function after OLT; however, the presence of steatosis, frequently present in livers from ECDs, does not exclude the use of these organs. Since January 2000 at our institution, we observed 39 steatotic grafts that were stratified istologically as follows: low steatosis, 5% to 15%; mild steatosis, 16% to 30%; moderate steatosis, 31% to 60%; and severe steatosis (>60%). Histologic techniques can enable identification of the type of fatty change as macrovesicular and microvesicular. These alterations have different effects on primary nonfunction and primary dysfunction. Fifteen grafts, all with severe or moderate, macrovesicular changes were discarded. Twenty-four fatty grafts with low to moderate steatosis were utilized for transplant. Sections from 2 liver biopsies (1 wedge in the left lobe and 1 needle in the right lobe) were stained with hematoxylin-eosin, Masson trichrome, Gomori reticulin, and oil red O. The OLT was performed only in patients with a MELD (Model for End-Stage Liver Disease) score lower than 27. The rate of primary dysfunction was 12.5%, and of primary nonfunction 8.4%. The 6-month graft survival for all fatty livers was 80%. We encourage the careful use of grafts with low to moderate steatosis in recipients without additional risks.

Liver Transplantation for Hepatitis B Virus Patients : Long-Term Results of Three Therapeutic Approaches

The indications for liver transplantation among patients with post-hepatitis B virus (HBV)-related cirrhosis have changed over the past 35 years. We reviewed the long-term results of 47 patients treated with liver transplantation for HBV-related cirrhosis. Patients were classified into 3 groups according to the perioperative regimen. In the initial experience, no immunoprophylaxis was adopted (no-IP; n=5). From 1988-1996, an immunoprophylaxis scheme was adopted (HBIg; n=16). From 1997-2007, we adopted the combination of lamivudine and HBIg (LAM-HBIg; n=26). We calculated the prevalence of serological reinfection and patient survival at 1 to 20 years, using the 3 regimens. The recurrence rate was 75% in the group of untreated patients; 30% in the HBIg group; and 9% in the LAM-HBIg group. The overall survival was 67% at 5 years, and 64% at 10 and 20 years. The long-term survival for each of the 3 therapeutic approaches, namely, for the patients who did not receive any treatment, for the HBIg group, and for the LAM-HBIg group, were 20%, 50%, and 84%, respectively. We suggest to use the LAM-HBIg combination.

Decrease in Surgery for Clostridium difficile Infection After Starting a Program to Transplant Fecal Microbiota.

Background: Clostridium difficile infection is increasing in incidence, severity, and mortality (1). Surgery is sometimes used to manage complicated infections because it improves short-term survival (2); however, it is associated with high rates of morbidity and poor long-term survival (3). Surgery is most often used when disease recurs and cannot be controlled with antibiotics, because the risk for severe complications and mortality increases greatly during these recurrences (4). An alternative effective treatment for recurrent disease involves delivery of stool from a healthy donor directly into a patients colon. This procedure is known as fecal microbiota transplantation (FMT), and it can be done via enema or colonoscopy or indirectly into the colon through the upper gastrointestinal tract using various methods (5). Objective: To determine whether the availability of FMT in our hospital was associated with a decrease in the frequency of surgery for patients with C. difficile infection. Methods: To identify patients with C. difficile infection, we used the database in the hospitals microbiology laboratory to identify all patients with a positive result for this toxin between January 2010 and April 2015, which was 30 months before and 10 months after FMT was introduced in June 2013. We then reviewed patients medical charts to identify those who were treated with surgery or FMT. Results: We identified 901 patients with C. difficile infection. Although the total number of hospital admissions per year did not change substantially, the number of patients with this infection increased gradually over time: 54 patients were diagnosed in 2010, 116 in 2011, 200 in 2012, 212 in 2013, 268 in 2014, and 71 between January and April 2015. We identified 35 patients who had FMT: 7 (3.3%) in 2013, 16 (6.0%) in 2014, and 12 (17.0%) between January and April 2015. We also identified 18 patients who had surgery: 1 (1.9%) in 2010, 3 (2.6%) in 2011, 10 (5.0%) in 2012, 4 (1.9%) in 2013, and 0 (0%) in 2014 and between January and April 2015 (Table). Table. Baseline Demographic and Clinical Characteristics of Patients With CDI Treated With FMT or Surgery Between 2010 and 2015 Discussion: The frequency of surgery in patients with C. difficile infection decreased rapidly after our hospital began using FMT to treat those with severe disease. The frequency of surgery decreased despite increased hospital admissions of patients with this infection and the continued availability of surgery from our emergency surgery team, whose membership remained unchanged during this period. Although such observational studies as this cannot establish causality, we believe that the availability of FMT probably led to the decrease in surgery, which, if true, may predict similar experiences in other hospitals.

Enteric-Coated Mycophenolate Sodium: One-Way Conversion From Mycophenolate Mofetil and De Novo Use in Stable Liver Transplant Recipients

Enteric-coated mycophenolate sodium (EC-MPS) is a formulation of mycophenolic acid (MPA) that releases the active molecule in the intestine reducing drug-related gastrointestinal (GI) side effects. The aim of present work was to summarize the use of EC-MPS for one-way conversion from mycophenolate mofetil (MMF) due to GI side effects and for de novo administration in a stable liver transplant population. In 10 patients on MMF and low-dose calcineurin inhibitors (CNI), significant GI side effects suggested drug conversion to ameliorate subjective symptoms. In 5 patients, EC-MPS was initiated de novo together with reduction of CNI for prevention of long-term renal failure. Conversion was carried out at equivalent MMF/EC-MPS dosages. Reevaluation at 2 months after conversion showed that no episode of rejection or infection occurred, and white blood cell count, CNI levels and doses, and creatinine clearance did not vary significantly. In 70% of converted patients there was a reduction of GI symptoms, especially diarrhea. Eighty percent suspended proton pump inhibitors. The de novo-treated patients showed no significant GI side effects. In conclusion, conversion from MMF to EC-MPS demonstrated significant GI symptom relief and de novo drug administration was well tolerated.

Should retransplantation still be considered for primary non-function after liver transplantation?

Primary non-function (PNF) of a transplanted liver is a postoperative condition characterized by absence of hepatic recovery due to various insults during harvesting, preservation or revascularization. Until recently early retransplantation (RTx) has been considered the policy of choice. Results of RTx for PNF are unsatisfactory (1-year survival rates ranging from 0 to 34%). The management of PNF by medical care without RTx with a recovery rate of 80% and a 1-year actuarial survival rate of 50% is reported for a series of 33 consecutive liver transplants. The guidelines for the medical care management are given and the results are discussed.

Combined anterior and posterior open treatment in infected pancreatic necrosis

ObjectiveTo compare the results of combined anterior and posterior open treatments (lesser sac marsupialization (LSM)u2009+u2009lumbostomy, LSMu2009+u2009L) in patients with infected pancreatic necrosis (IPN) with a previous experience of isolated LSM and with data in literature.Materials and methodsThirty-four consecutive patients operated on for IPN from 1981 to 2005 were divided into two groups based on the surgical technique used: single LSM (nu2009=u200923; period A, 1981–1998) and combined LSMu2009+u2009L (nu2009=u200911; period B, 1999–2005).ResultsThe postoperative mortality rate was 38.1 (nu2009=u20098) and 9% (nu2009=u20091) during period A and B, respectively. The most important cause of death was recurrent or persistent sepsis with multiple organ failure. The overall postoperative surgical morbidity was 57 (nu2009=u200913) and 27.2% (nu2009=u20093) in the two consecutive groups.ConclusionsIPN is a challenging condition associated with high mortality mainly because of a persistence of sepsis despite surgery. A comparative analysis of many proposed operative procedures is difficult because of the heterogeneity in the reported series. Open approaches seem to be more effective in controlling local infection and systemic sepsis. Combining open anterior and posterior approaches is in our experience an appropriate surgical treatment in IPN patients.

Modeling rejection immunity

BackgroundTransplantation is often the only way to treat a number of diseases leading to organ failure. To overcome rejection towards the transplanted organ (graft), immunosuppression therapies are used, which have considerable side-effects and expose patients to opportunistic infections. The development of a model to complement the physician’s experience in specifying therapeutic regimens is therefore desirable. The present work proposes an Ordinary Differential Equations model accounting for immune cell proliferation in response to the sudden entry of graft antigens, through different activation mechanisms. The model considers the effect of a single immunosuppressive medication (e.g. cyclosporine), subject to first-order linear kinetics and acting by modifying, in a saturable concentration-dependent fashion, the proliferation coefficient. The latter has been determined experimentally. All other model parameter values have been set so as to reproduce reported state variable time-courses, and to maintain consistency with one another and with the experimentally derived proliferation coefficient.ResultsThe proposed model substantially simplifies the chain of events potentially leading to organ rejection. It is however able to simulate quantitatively the time course of graft-related antigen and competent immunoreactive cell populations, showing the long-term alternative outcomes of rejection, tolerance or tolerance at a reduced functional tissue mass. In particular, the model shows that it may be difficult to attain tolerance at full tissue mass with acceptably low doses of a single immunosuppressant, in accord with clinical experience.ConclusionsThe introduced model is mathematically consistent with known physiology and can reproduce variations in immune status and allograft survival after transplantation. The model can be adapted to represent different therapeutic schemes and may offer useful indications for the optimization of therapy protocols in the transplanted patient.