Diagnosis and management of acquired aplastic anemia in childhood. Guidelines from the Marrow Failure Study Group of the Pediatric Haemato-Oncology Italian Association (AIEOP).

Acquired aplastic anemia (AA) is a rare heterogeneous disorder characterized by pancytopenia and hypoplastic bone marrow. The incidence is 2-3 per million population per year in the Western world, but 3 times higher in East Asia. Survival in severe aplastic anemia (SAA) has improved significantly due to advances in hematopoietic stem cell transplantation (HSCT), immunosuppressive therapy, biologic agents, and supportive care. In SAA, HSCT from a matched sibling donor (MSD) is the first-line treatment. If a MSD is not available, options include immunosuppressive therapy (IST), matched unrelated donor, or haploidentical HSCT. The purpose of this guideline is to provide health care professionals with clear guidance on the diagnosis and management of pediatric patients with AA. A preliminary evidence-based document prepared by a group of pediatric hematologists of the Bone Marrow Failure Study Group of the Italian Association of Pediatric Hemato-Oncology (AIEOP) was discussed, modified and approved during a series of consensus conferences that started online during COVID 19 and continued in the following years, according to procedures previously validated by the AIEOP Board of Directors.

A Rare Case of Coexisting Breast Cancer and Refractory Acute Myeloid Leukemia.

The occurrence of acute myeloid leukemia (AML) within six months from a diagnosis of breast cancer (BC) is rarely reported in the literature, and it is associated with a poor prognosis. We report herein the case of a 40-year-old woman referred to our centre affected by BC and simultaneous AML. The patient proved refractory to first line therapy and achieved complete remission (CR) with a clofarabine-based regimen followed by allogeneic stem cell transplantation (ASCT). Both during salvage chemotherapy and after ASCT, the patient presented severe infectious complications ( acute cholecistytis and Nocardia pneumonia, respectively) treated with surgery, and currently she is alive in CR for both diseases after 29 months of follow-up. The case highlights the importance of a diagnostic assessment of any unexplained cytopenia in association with solid neoplasia under treatment, underlining the feasibility and priority of a timely treatment of the haematological neoplasm in order to achieve long-term survival.

Correction to: Structural modeling of a novel TERC variant in a patient with aplastic anemia and short telomeres.

The original version of this article contained a mistake in the affiliation of E. Bellacchio. Correct affiliation is presented here.

'Real-life' report on the management of chronic GvHD in the Gruppo Italiano Trapianto Midollo Osseo (GITMO).

Several guidelines have been published about management of chronic GvHD (cGvHD), but the clinical practice still remains demanding. The Gruppo Italiano Trapianto di Midollo Osseo (GITMO) has planned a prospective observational study on cGvHD, supported by a dedicated software, including the updated recommendations. In view of this study, two surveys have been conducted, focusing the management of cGvHD and ancillary therapy in cGvHD, to address the current 'real life' situation. The two surveys were sent to all 57 GITMO centers, performing allografting in Italy; the response rate was 57% and 66% of the interviewed centers, respectively. The first survey showed a great disparity especially regarding steroid-refractory cGvHD, although extracorporeal photo-apheresis resulted as the most indicated treatment in this setting. Another challenging issue was the strategy for tapering steroid: our survey showed a great variance, and this disagreement could be a real bias in evaluating outcomes in prospective studies. As for the second survey, the results suggest that the ancillary treatments are not standardized in many centers. All responding centers reported a strong need to standardize management of cGvHD and to participate in prospective trials. Before starting observational and/or interventional studies, a detailed knowledge of current practice should be encouraged.

Decision analysis of allogeneic hematopoietic stem cell transplantation for patients with myelodysplastic syndrome stratified according to the revised International Prognostic Scoring System.

Allogeneic hematopoietic stem cell transplantation (allo-SCT) represents the only curative treatment for patients with myelodysplastic syndrome (MDS), but involves non-negligible morbidity and mortality. Crucial questions in clinical decision-making include the definition of optimal timing of the procedure and the benefit of cytoreduction before transplant in high-risk patients. We carried out a decision analysis on 1728 MDS who received supportive care, transplantation or hypomethylating agents (HMAs). Risk assessment was based on the revised International Prognostic Scoring System (IPSS-R). We used a continuous-time multistate Markov model to describe the natural history of disease and evaluate the effect of different treatment policies on survival. Life expectancy increased when transplantation was delayed from the initial stages to intermediate IPSS-R risk (gain-of-life expectancy 5.3, 4.7 and 2.8 years for patients aged ⩽55, 60 and 65 years, respectively), and then decreased for higher risks. Modeling decision analysis on IPSS-R versus original IPSS changed transplantation policy in 29% of patients, resulting in a 2-year gain in life expectancy. In advanced stages, HMAs given before transplant is associated with a 2-year gain-of-life expectancy, especially in older patients. These results provide a preliminary evidence to maximize the effectiveness of allo-SCT in MDS.

Factors predicting outcome after allogeneic transplant in refractory acute myeloid leukemia: a retrospective analysis of Gruppo Italiano Trapianto di Midollo Osseo (GITMO).

The clinical outcome of primary refractory (PRF) AML patients is poor and only a minor proportion of patients is rescued by allogenic hematopoietic stem cell transplantation (HSCT). The identification of pre-HSCT variables may help to determine PRF AML patients who can most likely benefit from HSCT. We analyzed PRF AML patients transplanted between 1999 and 2012 from a sibling, unrelated donor or a cord blood unit. Overall, 227 patients from 26 Gruppo Italiano Trapianto di Midollo Osseo e Terapia cellulare centers were included in the analysis. At 3 years, the overall survival was 14%. By multivariate analysis, the number of chemotherapy cycles, (hazard ratio (HR): 1.87; 95% confidence interval (CI): 1.24-2.85; P=0.0028), the percentage of bone marrow or peripheral blood blasts (HR: 1.75; 95% CI: 1.16-2.64; P=0.0078), the adverse cytogenetic (HR: 1.44; 95% CI: 1.00-2.07; P=0.0508) and the age of patients (HR: 1.77; 95% CI: 1.08-2.88; P=0.0223) remained significantly associated with survival. Thus, we set up a new score predicting at 3 years after transplantation, an overall survival probability of 32% for patients with score 0 (no or 1 prognostic factor), 10% for patients with score 1 (2 prognostic factors) and 3% for patients with score 2 (3 or 4 prognostic factors).

Risk factors for outcomes after unrelated cord blood transplantation for adults with acute lymphoblastic leukemia: a report on behalf of Eurocord and the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation.

We performed a retrospective analysis on 421 adult patients who underwent unrelated cord blood transplantation (UCBT) for ALL. Median age was 32 years; 46% were in first CR (CR1), 32% in CR2 and 22% had advanced disease. Double UCBT was performed in 173 patients (41%). Myeloablative conditioning (MAC) was given to 314 patients (75%). Cumulative incidence (CI) of 60-day neutrophil recovery was 78%. CI of acute and chronic GVHD was 33 and 26%, respectively. Non-relapse mortality (NRM) at 2 years was 42%. Age⩾35 years (P<0.0001), advanced disease at UCBT (P<0.0001) and use of MAC (P<0.0001) were associated with increased NRM. Relapse incidence (RI) at 2 years was 28%; use of reduced intensity conditioning (RIC) (P=0.0002) was associated with increased RI. Two-year leukemia-free survival (LFS) was 39% for patients in CR1, 31% for CR2 and 8% for advanced disease. In multivariate analysis, factors associated with decreased LFS rate were: age ⩾35 years (P=0.034), use of MAC (P=0.032) and advanced disease (P<0.0001). These results show that UCBT is a valuable option to treat high-risk adult ALL when in remission. Strategies to decrease toxicity and relapse are needed to improve final outcomes.

Strongyloides stercoralis infection in allogeneic stem cell transplant: a case report and review of the literature.

Strongyloides stercoralis infections may be documented in low-endemicity areas, particularly in immigrants from endemic areas. The case of a patient from Bangladesh, an immigrant to Italy who developed a S. stercoralis infection after allogeneic stem cell transplant, is described, and 7 further cases are reviewed. Because of the atypical clinical presentation, the low predictive role of the eosinophil count, and the low sensitivity of the microbiological tests, diagnosis of strongyloidiasis is a challenging problem. When a case of S. stercoralis infection is suspected, previous exposure may be the only clue to guide the diagnostic approach.

Impact of HLA mismatch direction on outcomes after umbilical cord blood transplantation for hematological malignant disorders: a retrospective Eurocord-EBMT analysis.

HLA matching is a critical determinant of outcomes for patients who have undergone umbilical cord blood transplantation (UCBT). Data have been published on the importance of donor/recipient HLA mismatch direction on UCBT outcomes. HLA mismatch in the graft-versus-host (GVH) direction is defined as a donor homozygous at an HLA locus, while the recipient shares one HLA Ag with the donor. HLA mismatch in the host-versus-graft (HVG) direction is defined as a recipient homozygous with the donor sharing one HLA Ag. In our study we focused on confirming, using an independent population, whether transplantation outcomes would be different when HLA mismatch direction was considered. We analyzed 1565 patients who received a single-unit UCBT for malignant disease. Median age was 15 years and 72% of patients were transplanted for leukemia. In multivariate analysis, using the 5/6 HLA-matched population as reference, one or two HLA mismatches in the GVH or HVG direction were not associated with non-relapse related mortality and survival. On the basis of our results, there is no evidence to support a change in the current practice for cord blood unit selection.

Lyme borreliosis spirochetes and spotted fever group rickettsiae in ixodid ticks from Pianosa island, Tuscany Archipelago, Italy.

A study on tick fauna and tick-borne pathogens was undertaken in Pianosa, an island in the Tuscany Archipelago that constitutes an important stopping and nesting point for migratory birds. Ticks were removed from feral cats and a few terrestrial birds, and host-seeking ticks were collected by dragging. A total of 89 ticks were found on animals: 57 Ixodes ventalloi Gil Collado, 1936 and 32 Ixodes acuminatus Neumann, 1901. Host-seeking ticks were 354 Hyalomma spp. larvae and 18 Hyalomma spp. adults, identified as Hyalomma marginatum C.L. Koch, 1844 (n=11) and 7 Hyalomma detritum Schulze, 1919 (n=7). A sample of adult ticks was subjected to molecular analyses to look for Rickettsia spp. and Borrelia burgdorferi sensu lato (s.l.). Sequence analysis of the 5S-23S intergenic spacer region and OspA gene of B. burgdorferi s.l.-positive samples showed the presence of Borrelia spielmanii (n=3; 3.7%, 95% confidence interval [CI] 0.08-10.4) and Borrelia valaisiana (n=13; 13.6%, 95% CI 7.0-23.0) in Ixodes ticks from cats and terrestrial birds. Ixodes spp. were also infected by Rickettsia helvetica (n=19; 23.4%, 95% CI 14.7-34.2). Finally, we detected Rickettsia aeschlimannii in 3 out of 12 host-seeking Hyalomma spp. adults tested (25%, 95% CI 5.5-57.2). Our study shows the presence of several tick-borne pathogens in Pianosa. Hyalomma spp. and Ixodes ticks other than I. ricinus seem to be involved in their epidemiological cycle, and birds could contribute to the pathogen dispersal along their migration routes. This is the first finding of B. spielmanii in Italy. We hypothesize the involvement of peridomestic rodents or hedgehogs in its maintenance in Pianosa.

Atrial fibrillation (AF) and cognitive impairment in the elderly: a case-control study.

AF is able not only to increase the risk of cognitive decline due to acute cerebrovascular events, but also to reduce cardiac output, with the consequence of impaired cerebral perfusion. The aim of this study was to evaluate the association between AF, dementia and depression in patients with negative anamnesis for past strokes. Our sample included 26 patients with a diagnosis of AF (paroxystic, persistent, permanent) and 31 patients with sinus rhythm, enrolled as controls. All selected patients underwent a Multidimensional Geriatric Assessment in order to investigate cognitive and behavioral functions. Statistical analysis of results showed a greater frequency of latent cognitive impairment in patients with AF, even in the absence of memory disorders. As a matter of facts, AF patients showed Mini Mental State Examination (MMSE) scores significantly lower than those with sinus rhythm (p<0.05) and Geriatric Depression Scale (GDS) scores higher than those without AF, evidencing a greater risk of depression too (p<0.02). Results showed a statistically significant association between AF, depression and cognitive impairment in early stage. In conclusion, AF is not only associated with the risk of developing cognitive impairment, but it can also be considered as a risk factor for dementia and depression, even in the absence of medical history of past stroke.

Related cord blood banking for haematopoietic stem cell transplantation.

The aims of this single centre study were to assess the feasibility of related cord blood collecting, the appropriateness of storage and the final suitability for transplantation. Since September 1994, 63 families were enrolled in this study. Families were eligible if they were caring for a patient with a disorder treatable by haematopoietic stem cell transplantation and were experiencing a pregnancy. A total of 72 cord blood units were collected and stored for 64 patients (both siblings and parents). We focussed on human leucocyte antigen (HLA) compatibility and cell content as critical requirements to unit's suitability for transplantation. HLA-typing was carried out for 34 donor-recipient couples and most units (72%) mismatched with the related patients. About 60% of collections had a minimum cell dose considered acceptable for transplantation. Only 21% of units had both compatibility degree and cell content suitable for transplantation. When applicable, information on the compatibility degree between the foetus and the patient should be obtained during pregnancy. Appropriateness of related cord blood banking for parents should be further investigated and cost-effective guidelines policies should be provided. Finally, as banking of related cord blood units is an important resource then, this public service should be supported and enhanced.

The treatment of hypertension with telmisartan in the sphere of circadian rhythm in metabolic syndrome in the elderly.

This study compares the efficacy of telmisartan with that of valsartan and ramipril in reducing blood pressure (BP) over 24 hrs in the elderly patients with metabolic syndrome (MS). This prospective and open label study analyzed a sample of 60 patients over 65 years of age with hypertension and with MS. At the beginning the BP was monitored by a 24-hr ambulatory blood pressure monitoring (AMBP). Following this, the 60 patients were divided into 3 groups of 20, to each of which was prescribed, respectively, telmisartan, valsartan and ramipril to take for 12 weeks. The drugs were to be taken at 9.00 a.m. Later on the doses were increased. After 12 weeks of therapy, BP was monitored by a 24-hr AMBP. The use of telmisartan caused a greater reduction of the BP in the final 4-6 hours of the period between the 1st administration of the drug and the next one, these last 4-6 hours being those when cardiovascular and cerebrovascular accidents are more frequent (between 6.00 and 10.00 a.m.). Comparing to valsartan and ramipril, telmisartan results in excellent pressure control during the last 4-6 hours between the 1st administration of the drug and the next one.

Impact of therapy with alpha-lipoic acid (ALA) on the oxidative stress in the controlled NIDDM: a possible preventive way against the organ dysfunction?

There is a growing evidence that excess generation of highly reactive free radicals, largely due to hyperglycemia, causes oxidative stress, which further exacerbates the development and progression of diabetes and its complications. The purpose of this study was to evaluate the impact of ALA on lipid profile, oxidative pattern and inflammation in patients with controlled non-insulin dependent diabetes mellitus (NIDDM). ALA, 400mg/day was investigated in NIDDM patients over a period of 4 weeks using a randomized, placebo-(PLA)-controlled study with two parallel groups. The marker of oxidative stress was the concentration of reactive oxygen metabolites, evaluated using a commercially available test, called d-ROMs test, and the biological antioxidant potential (BAP); besides, the lipid profile (total cholesterol=TC, high-density lipoprotein-cholesterol = HDL-C; low-density lipoprotein-cholesterol=LDL-C, and triglycerides=TG) and the C-reactive protein (CRP), marker of inflammation were measured at the beginning and at the end of the treatment. A total of 14 patients were randomly assigned to the two groups. ALA was safe and well tolerated in the only oral daily administration. The d-ROMs test (p=0.03) and HDL-C (p=0.04) showed a significant difference between the two groups. BAP (p=0.06) tended to be higher in the treated patients, while LDL-C (p=0.07) presented a moderate decline. There were no significant differences in TC (p=0.65), TG (p=0.78) and CRP (p=0.96) between the ALA and PLA groups. ALA therapy appears to reduce significantly d-ROMs and to improve HDL-C value, especially in men with metabolic syndrome treated with oral hypoglycemic drugs. These findings will be useful in patient selection in future clinical trials with ALA in long term studies.

Is there a relationship between high C-reactive protein (CRP) levels and dementia?

Inflammation is believed to play a pivotal role in dementia, but its role is still unclear. The aim of our study was to analyze the interplay among markers of inflammation, such as fibrinogen and high CRP levels, and dementia. First, we performed a cross-sectional study comparing markers of inflammation between 99 patients affected by dementia (mean age: 83.0+/-0.6 years) and 99 controls (mean age: 83.9+/-0.7 years). Then, we analyzed the relationship between inflammation and dementia in the same population composed by 34 Alzheimer's disease (AD) patients (mean age: 83.4+/-0.8 years), 64 vascular dementia (VaD) patients (mean age: 82.7+0.8 years) and 99 controls. Patients affected by dementia had higher CRP levels than controls (2.6+/-+/-0.2 vs. 0.7 + 0.1 p < 0.001, respectively). AD patients had higher CRP levels than VaD patients (4.2 + 0.6 vs. 1.7+/-0.2, p < 0.001, respectively). Stepwise multiple logistic regression analysis showed that dementia (odds ratio=OR=4.965, 95% confidence interval=Cl=1.402-13.23, p=0.004), fibrinogen (OR=1.011, Cl=1.007-1.015, p<0.001), and age (OR=1.158, Cl=1.063-1.261, p<0.001) are independently correlated with high levels of CRP. The study suggests that inflammation may have a pathogenetic role in AD.

Endoparasites of red fox (Vulpes vulpes) in central Italy.

A parasitologic study on 129 red foxes (Vulpes vulpes) from Tuscany (central Italy) was carried out in 2004-2006. Five intestinal species were found at necropsy: Dipylidium caninum (prevalence 57.3%), Mesocestoides lineatus (45.4%), Uncinaria stenocephala (39.1%), Toxocara canis (9.1%), and Toxascaris leonina (5.4%). Other parasites not associated with the intestine included Crenosoma vulpis (14.7%), Capillaria aerophila (7.0%), Angiostrongylus vasorum (7.0%), and filarial parasites (17.8%). Coprologic tests were less sensitive and less specific in identifying parasites than direct examinations at necropsy. Trichinella larvae were not found in muscles submitted to artificial digestion. By immunologic assay, antigens of Echinococcus spp. were detected in fecal samples of 20 foxes, but results could not be confirmed by fecal examination or molecular tests.

NOLA1 gene mutations in acquired aplastic anemia.

BACKGROUND: Telomerase complex genes mutations (DKC1, TERC, TERT, and NOP10) lead to premature telomere shortening and are responsible for different forms of dyskeratosis congenita. TERC and TERT mutations were also found in patients with aplastic anemia. The aim of this work is to analyze the possible involvement of the telomerase complex gene NOLA1, in a population of Italian AA patients. PROCEDURE: DNA of 108 AA patients and 170 normal controls was amplified by PCR and analyzed by DHPLC. For each abnormal elution profile PCR products was directly sequenced using ABI prism 3100 Genetic Analyzer. RESULTS: We identified, in two patients and two control, the new c.390A > T variation, which is not reported in GenBank, and leads to p.H28L amino acidic change. Telomere analysis shows that the subjects carrying the change have a telomere length comparable to that of healthy controls thus suggesting that this variation has no effect on telomerase complex activity. CONCLUSIONS: We did not find any clear disruptive mutation in NOLA1 gene. The non-conservative variation identified in our sample has no effect on telomeres length. This result suggests that heterozygous point mutations in NOLA1 gene are not responsible for AA in our patients at least acting via telomere. However, in our experience, molecular analysis of other telomerase complex gene (TERC, TERT) is important for AA patients and family members in order to set up an adequate therapeutic or surveillance program and identify carriers or exclude them as potential bone marrow donors.