Fabio Ciceri

Quantitative muscle strength assessment in duchenne muscular dystrophy: longitudinal study and correlation with functional measures

BackgroundThe aim of this study was to perform a longitudinal assessment using Quantitative Muscle Testing (QMT) in a cohort of ambulant boys affected by Duchenne muscular dystrophy (DMD) and to correlate the results of QMT with functional measures. This study is to date the most thorough long-term evaluation of QMT in a cohort of DMD patients correlated with other measures, such as the North Star Ambulatory Assessment (NSAA) or thee 6-min walk test (6MWT).MethodsThis is a single centre, prospective, non-randomised, study assessing QMT using the Kin Com® 125 machine in a study cohort of 28 ambulant DMD boys, aged 5 to 12 years. This cohort was assessed longitudinally over a 12 months period of time with 3 monthly assessments for QMT and with assessment of functional abilities, using the NSAA and the 6MWT at baseline and at 12 months only. QMT was also used in a control group of 13 healthy age-matched boys examined at baseline and at 12 months.ResultsThere was an increase in QMT over 12 months in boys below the age of 7.5 years while in boys above the age of 7.5 years, QMT showed a significant decrease. All the average one-year changes were significantly different than those experienced by healthy controls. We also found a good correlation between quantitative tests and the other measures that was more obvious in the stronger children.ConclusionOur longitudinal data using QMT in a cohort of DMD patients suggest that this could be used as an additional tool to monitor changes, providing additional information on segmental strength.

Autologous Islet Transplantation in Patients Requiring Pancreatectomy: A Broader Spectrum of Indications Beyond Chronic Pancreatitis

Islet autotransplantation (IAT) is usually performed in patients undergoing pancreatic surgery for chronic pancreatitis. In the present series, IAT was offered also to patients undergoing pancreatic surgery for both nonmalignant and malignant diseases, having either completion pancreatectomy as treatment for severe pancreatic fistulas (n = 21) or extensive distal pancreatectomy for neoplasms of the pancreatic neck (n = 19) or pancreatoduodenectomy because of the high risk of pancreatic fistula (n = 32). Fifty‐eight of 72 patients who were eligible to this broader spectrum of indication actually received IAT. There was no evidence of a higher‐than‐expected rate of major complications for pancreatectomy. Forty‐five patients receiving IAT were still alive at the time of the last scheduled follow‐up (1375 ± 365 days). Eighteen (95%) of 19 and 11 (28%) of 39 patients reached insulin independence after partial or total pancreatectomy, respectively. The metabolic results were dependent on the transplanted islet mass. Thirty‐one of 58 patients had malignant diseases of the pancreas or periampullary region, and only three patients developed ex novo liver metastases after IAT (median follow‐up 914 ± 382 days). Our data demonstrate the feasibility, efficacy, and safety of IAT for a broader spectrum of clinical indications beyond chronic pancreatitis.

Transplant-Associated Thrombotic Microangiopathy (TA-TMA) and Consensus Based Diagnostic and Therapeutic Recommendations: Which TA-TMA Patients to Treat and When?

Background: Transplant-associated thrombotic microangiopathy (TA-TMA) is considered one of the most severe complications after hematopoietic stem cell transplantation. Unfortunately, controversial approaches on TA-TMA diagnostic criteria contribute to a delay in both diagnosis and treatment. Recommendations for TA-TMA based in the past on case reports or retrospective studies lack a reasonable level of evidence. One of the most promising drugs for TA-TMA likely induced by endothelium damage is Defibrotide, a polydisperse oligonucleotide. Auto-antibody depleting or complement blocking therapy has also emerged as new strategy to decrease TA-TMA-associated morbidity and mortality. Methods: A joint study group of experts on TA-TMA met during the 2013 ASH Meeting (New Orleans, USA) and the 2014 EBMT Meeting (Milan, Italy) with the aim of proposing a reliable treatment for this complication. Common diagnostic criteria for TA-TMA have been discussed and are described in the review. Factors influencing the outcome of TA-TMA are also addressed. Results: The panel agreed that an endothelial damage pathway is involved in the pathogenesis of TA-TMA. With emerging data, an updated version of TA-TMA diagnostic criteria is suggested. High or standard risk patients have been defined according to TA-TMA risk factors and a comprehensive therapeutic strategy for TA-TMA patients has been designed for a possible multicentre study. Conclusions: The panel focused primarily on high level of awareness about an early TA-TMA diagnosis and treatment before a TA-TMA-induced multi-organ failure. An important consensus was obtained to investigate whether Defibrotide or Eculizumab can improve the outcome of TA-TMA in a multicentre study.

Mechanism of thymic renewal after infusion of suicide gene-modified donor T cells after hematopoietic stem cell transplantation (HSCT) in adult patients.

6526 Background: In haploidentical HSCT, the infusion of donor T cells genetically modified to express the Herpes Simplex Virus Thymidine kinase (HSV-Tk) suicide gene allows GvHD control, while rapidly providing effective and polyclonal T cell repertoire against pathogens and underlying tumors (Ciceri, Bonini, Lancet Oncol 2009). METHODS In phase I/II trial, 28 pts with hematologic tumors received purified HSV-Tk transduced cells after T cell depleted HSCT and 22/28 had rapid and stable T cell immune reconstitution (IR). Though HSV-Tk+ cell infusions are needed to achieve these effects, HSV-Tk+ cells represent the minority of lymphocytes circulating in treated pts. Therefore, we hypothesized an indirect role of HSV-Tk+ cells in prompting T cell development from graft progenitors by a thymus-dependent pathway. RESULTS Treated pts showed early recovery of naïve T cells, mostly negative for the HSV-Tk transgene. Newly reconstituted CD4+ naïve T cells were almost entirely comprised by CD31+ recent thymic emigrants. Accordingly, CT scans showed increased thymic volume and single joint T cell Receptor Excision Circles counts rose following HSV-Tk cell add backs. Comparison with a cohort of pts subject to T-cell replete HSCT further suggested a unique direct role of HSV-Tk+ cells in promoting thymopoiesis. Once HSV-Tkneg T cells appeared, full immune competence against infections was obtained, and was not compromised in those pts in whom the suicide gene was activated to control GvHD. Notably, serum IL-7 markedly rose after Tk cell add backs, suggesting that the genetically manipulated T cells may mediate the release of this stromal cytokine, in turn supporting the generation and maturation of T cells. Notably, in absence of HSV-Tk cell engraftment, neither increase in IL-7 levels nor appearance of HSV-Tkneg T cells were noted. CONCLUSIONS The infusion of suicide gene-modified T cells induces IL-7 release, boosts the function of adult thymus and prompts recovery of a polyclonal, fully competent, T cell repertoire. A phase III trial (TK008) with HSV-Tk+ cells in haploidentical HSCT for leukemia, already ongoing in Italy, is expanding in EU.