Manuela Tumino

A Prospective Study on the Predictive Value of Plasma BK Virus-DNA Load for Hemorrhagic Cystitis in Pediatric Patients After Stem Cell Transplantation

BACKGROUND In hematopoietic stem cell transplantation (HSCT), late hemorrhagic cystitis (HC) has been associated with BK virus (BKV) infection. We assessed the value of plasma BKV load in predicting HC. METHODS Plasma and urine BKV-DNA load were assessed prospectively in 107 pediatric patients. RESULTS Twenty patients developed grade II and III HC, with 100-day cumulative incidence of 18.8%. At diagnosis of HC, the median load of BKV DNA was 2.3 × 10(3) copies/mL. A plasma BKV-DNA load of 10(3) copies/mL had a sensitivity of 100% and a specificity of 86% with a negative predictive value (NPV) of 100% and a positive predictive value (PPV) of 39% for HC. A urine BKV-DNA load of >10(7) copies/mL had a sensitivity of 86% and a specificity of 60% with a NPV of 98% and a PPV of 14% for HC. A BKV load of 10(3) copies/mL on plasma was significantly associated with HC in multivariate analysis (hazard ratio [HR], 6.1; P = .0006). Patients with HC had a significantly higher risk of mortality than patients who did not have HC (HR, 2.6; P = .018). CONCLUSIONS The above values were used to monitor plasma BKV-DNA load, and they provided a better prediction of patients at risk of HC than urine BKV-DNA load.

Annexin 2A sustains glioblastoma cell dissemination and proliferation

Glioblastoma (GBM) is the most devastating tumor of the brain, characterized by an almost inevitable tendency to recur after intensive treatments and a fatal prognosis. Indeed, despite recent technical improvements in GBM surgery, the complete eradication of cancer cell disseminated outside the tumor mass still remains a crucial issue for glioma patients management. In this context, Annexin 2A (ANXA2) is a phospholipid-binding protein expressed in a variety of cell types, whose expression has been recently associated with cell dissemination and metastasis in many cancer types, thus making ANXA2 an attractive putative regulator of cell invasion also in GBM. Here we show that ANXA2 is over-expressed in GBM and positively correlates with tumor aggressiveness and patient survival. In particular, we associate the expression of ANXA2 to a mesenchymal and metastatic phenotype of GBM tumors. Moreover, we functionally characterized the effects exerted by ANXA2 inhibition in primary GBM cultures, demonstrating its ability to sustain cell migration, matrix invasion, cytoskeletal remodeling and proliferation. Finally, we were able to generate an ANXA2-dependent gene signature with a significant prognostic potential in different cohorts of solid tumor patients, including GBM. In conclusion, we demonstrate that ANXA2 acts at multiple levels in determining the disseminating and aggressive behaviour of GBM cells, thus proving its potential as a possible target and strong prognostic factor in the future management of GBM patients.

Focal nodular hyperplasia of the liver: an emerging complication of hematopoietic SCT in children

Hepatic focal nodular hyperplasia (FNH) is a nonmalignant condition rarely affecting children previously treated for cancer, especially those who received hematopoietic SCT (HSCT). Some aspects of its pathogenesis still remain unclear and a strong association with specific risk factors has not yet been identified. We report here a single institutions case series of 17 patients who underwent HSCT and were diagnosed with FNH, analyzing retrospectively their clinical features and the radiological appearance of their hepatic lesions. We aimed to compare the diagnostic accuracy of ultrasound (US) and magnetic resonance imaging (MRI) and to explore the role of transient elastography (FibroScan) to evaluate the degree of hepatic fibrosis in FNH patients. Our analysis showed an association of FNH with age at transplant ⩽12 years (hazard ratio (HR) 9.10); chronic GVHD (HR 2.99); hormone-replacement therapy (HR 4.02) and abdominal radiotherapy (HR 4.37). MRI proved to be a more accurate diagnostic tool compared with US. Nine out of 12 patients who underwent FibroScan showed hepatic fibrosis. Our study points out that FNH is an emerging complication of HSCT, which requires a lifelong surveillance to follow its course in cancer patients.

Interleukin‐22 in the diagnosis of active chronic graft‐versus‐host disease in paediatric patients

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Psychopathological Aspects in Childhood Hematopoietic Stem Cell Transplantation (HSCT): The Perception of Parents and Adolescents

Background: Data about psychosocial sequelae of childhood Hematopoietic Stem Cell Transplantation (HSCT) are limited and the association with a specific donor type or other medical factors is largely unknown (Chang et al., 2012). The aim of the present study was to compare the psychological aspects of pediatric HSCT survivors with healthy peers. A secondary aim was to detect whether parents and children differed in the perception of mental health status. The influence of medical factors on psychological status was also examined. Method: Thirty seven HSCT survivors (23 males) with a mean age of 14.4 years (SD = 3.03; range 8.16–18.33) were recruited. Twenty-six patients underwent an allogenic HSCT (matched unrelated donor, n = 20; matched sibling donor, n = 6) and 11 patients received an autologous HSCT. The children psychological aspects were assessed using the Youth Self Report (YSR) (Achenbach and Rescorla, 2001) and compared to a group of matched healthy peers. At the same time, parents were requested to complete the Child Behavior Checklist 6–18 (Achenbach and Rescorla, 2001). Medical and socio-demographic data were also collected. Results: HSCT survivors reported significantly higher levels of somatic complains (t27 = 3.14; p = 0.004; mean = 3.1) when compared to healthy peers (mean = 1.5). The parent CBCL scores on “child total competence” exceeded the normative clinical cutoff in 48.6% cases. Inter-rater agreement between parent and patient reports was present only in three scales: total competence score (K = 0.06, p = 0.002), somatic complaints (K = 0.21, p = 0.003) and attention problems (k = 0.13; p = 0.02). According to Ancova models, internalizing problems were more frequent in HSCT from family donors (F2 = 3.13; p = 0.06) or in the presence of acute complications (F1 = 11.95; p = 0.003). Conclusion: In contrast to the perception of parents, pediatric HSCT survivors reported good psychological health. However, they complained about more somatic problems as compared with healthy peers. Medical aspects such as donor source and the presence of acute complications should be taken into consideration for the psychological approach in order to improve pediatric HSCT survivor care.

TCRαβ CD19 depletion in allogeneic haematopoietic stem cell transplantation performed for Hurler syndrome

TCRαβ CD19 depletion in allogeneic haematopoietic stem cell transplantation performed for Hurler syndrome

Haploidentical stem cell transplantation cures autoimmune hepatitis and cerebrovascular disease in a patient with sickle cell disease

Sickle Cell Disease (SCD) may lead to several acute and chronic complications and the end-organ damage may be aggravated by co-existing conditions. [1] Among SCD patients, autoimmune disorders, such as autoimmune hepatitis (AIH) or systemic lupus erythematosus, are not infrequent and are difficult to treat due to the high risk of adverse events associated with steroids or other immunosuppressive treatments. [2–4] Hematopoietic Stem Cell Transplantation (HSCT) is the most consolidated curative therapy for patients with SCD, but benefits and risks in both the short and long term must be carefully considered, taking into consideration disease variability and the recent appearance of new drugs. Despite the progressive broadening of indications for HSCT, [5] the majority of pediatric haematologists still offers it only to patients with a severe phenotype: cerebrovascular disease, recurrent vasoocclusive crises (VOC) or acute chest syndrome not responsive to Hydroxycarbamide, or sickle nephropathy. [6, 7] HSCT is also an option for the management of severe autoimmune disorders such as multiple sclerosis, systemic sclerosis and rheumatoid arthritis, but it has not been previously reported for autoimmune hepatitis. [8] We report a patient with SCD and AIH, both cured after HSCT. Our patient was diagnosed with HbSS SCD at the age of 4 years when she was hospitalized for severe haemolytic anaemia. At the age of 7 years, Trans-Cranial Doppler (TCD) showed a velocity >200 cm/s in both the middle cerebral arteries and the basilar artery with a normal brain magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA). The patient began a regular blood transfusion program for stroke prevention, which was changed to monthly red cell exchange transfusions (ECA) at the age of 8 years when adequate venous lines could be placed. At the age of 11 years, severe stenosis of the carotid syphon and middle cerebral arteries and moderate stenosis of the anterior cerebral arteries seen on MRA (Fig. 1a) prompted ECA to be scheduled every three weeks to maintain HbS under 30%. At the age of 13 years, MRI/ MRA showed a minimal reduction of arterial stenosis with a concomitant normalization of TCD, which was confirmed two years later. No clinical or subclinical stroke occurred. At the age of 13 years the patient was hospitalised for cholestatic jaundice (total bilirubin 277.1 μmol/L, conjugated bilirubin 171.2 μmol/L) and elevation of liver enzymes (AST 1188 U/L, ALT 74 U/L and GGT 188 U/L). Liver infection, liver sequestration and disorders of the biliary tree were excluded by appropriate investigations including magnetic resonance cholangio-pancreatography. Anti-nuclear and anti-smooth muscle antibodies resulted positive at a titer of 1:320 and >1:80 respectively, and hypergammaglobulinemia was noticed (IgG 25 g/L). The diagnosis of type I AIH was confirmed by liver histology, which showed portal and peri-portal fibrosis, portal inflammatory infiltrates (mostly constituted of lymphocytes and plasma cells) and focal areas of necrosis (Fig. 2). Treatment with prednisolone was initiated with prompt normalization of liver enzymes and resolution of cholestasis, and one month later azathioprine was added after having excluded TPMT variants. Steroid treatment was Raffaella Colombatti and Laura Sainati contributed equally to the work.

Unrelated donor vs HLA-haploidentical alpha/beta T-cell and B-cell depleted HSCT in children with acute leukemia

Traditionally, hematopoietic stem cell transplantation (HSCT) from both HLA-matched related and unrelated donors (UD) has been used for treating children with acute leukemia (AL) in need of an allograft. Recently, HLA-haploidentical HSCT after αβ T-cell/B-cell depletion (αβhaplo-HSCT) was shown to be effective in single-center studies. Here, we report the first multicenter retrospective analysis of 127 matched UD (MUD), 118 mismatched UD (MMUD), and 98 αβhaplo-HSCT recipients, transplanted between 2010 and 2015, in 13 Italian centers. All these AL children were transplanted in morphological remission after a myeloablative conditioning regimen. Graft failure occurred in 2% each of UD-HSCT and αβhaplo-HSCT groups. In MUD vs MMUD-HSCT recipients, the cumulative incidence of grade II to IV and grade III to IV acute graft-versus-host disease (GVHD) was 35% vs 44% and 6% vs 18%, respectively, compared with 16% and 0% in αβhaplo-HSCT recipients (P < .001). Children treated with αβhaplo-HSCT also had a significantly lower incidence of overall and extensive chronic GVHD (P < .01). Eight (6%) MUD, 32 (28%) MMUD, and 9 (9%) αβhaplo-HSCT patients died of transplant-related complications. With a median follow-up of 3.3 years, the 5-year probability of leukemia-free survival in the 3 groups was 67%, 55%, and 62%, respectively. In the 3 groups, chronic GVHD-free/relapse-free (GRFS) probability of survival was 61%, 34%, and 58%, respectively (P < .001). When compared with patients given MMUD-HSCT, αβhaplo-HSCT recipients had a lower cumulative incidence of nonrelapse mortality and a better GRFS (P < .001). These data indicate that αβhaplo-HSCT is a suitable therapeutic option for children with AL in need of transplantation, especially when an allele-matched UD is not available.

Risk Factors and Outcomes Related to Pediatric Intensive Care Unit Admission after Hematopoietic Stem Cell Transplantation: A Single-Center Experience

To describe incidence, causes, and outcomes related to pediatric intensive care unit (PICU) admission for patients undergoing hematopoietic stem cell transplantation (HSCT), we investigated the risk factors predisposing to PICU admission and prognostic factors in terms of patient survival. From October 1998 to April 2015, 496 children and young adults (0 to 23 years) underwent transplantation in the HSCT unit. Among them, 70 (14.1%) were admitted to PICU. The 3-year cumulative incidence of PICU admission was 14.3%. The main causes of PICU admission were respiratory failure (36%), multiple organ failure (16%), and septic shock (13%). The overall 90-day cumulative probability of survival after PICU admission was 34.3% (95% confidence interval, 24.8% to 47.4%). In multivariate analysis, risk factors predisposing to PICU admission were allogeneic HSCT (versus autologous HSCT, P = .030) and second or third HSCT (P = .018). Characteristics significantly associated with mortality were mismatched HSCT (P = .011), relapse of underlying disease before PICU admission (P < .001), acute respiratory distress syndrome at admission (P = .012), hepatic failure at admission (P = .021), and need for invasive ventilation during PICU course (P < .001). Our data indicate which patients have a high risk for PICU admission after HSCT and for dismal outcomes after PICU stay. These findings may provide support for the clinical decision-making process on the opportunity of PICU admission for severely compromised patients after HSCT.