Outcome of primary hemophagocytic lymphohistiocytosis: a report on 143 patients from the Italian Registry.

Primary hemophagocytic lymphohistiocytosis (pHLH) is a severe, life-threatening hyperinflammatory syndrome caused by defects in genes of the granule-dependent cytotoxic pathway. Here we investigated the clinical presentation and outcome in a large cohort of 143 patients with pHLH diagnosed in the last 15 years and enrolled in the Italian registry. The median age at diagnosis was 12 months (IQR 2-81), and ninety-two patients (64%) fulfilled the HLH-2004 criteria. Out of 111 patients who received first-line combined therapy (HLH-94, HLH-2004, Euro-HIT protocols), 65 (59%) achieved complete response (CR) and 21 (19%) partial response (PR). Thereafter, 33 patients (30%) reactivated, and 92 (64%) received HSCT, 78 of whom (85%) survived and were alive at a median follow-up from diagnosis of 67 months. Thirty-six patients (25%) died before HSCT and 14 (10%) after. Overall, 93 patients (65%) were alive after a median follow-up of 30 months. Unadjusted predictors of non-response were age.

The real-life management of glucose homeostasis abnormalities in pediatric onco-hematological diseases: data from a national survey.

Glycemic abnormalities are a frequent finding in pediatric oncological patients, both during treatment and after its discontinuation. Moreover, impaired glucose tolerance (IGT), impaired fasting glycemia (IFG) and diabetes mellitus (DM) are not rarely diagnosed in non-oncological hematological diseases. To explore the current pediatric Italian approach to the diagnosis and the management of the glycemic alterations in this clinical setting and, thus, to identify and enforce current clinical needs, we submitted an online 23-items survey to all the Italian Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) centers, and surveys were descriptively analyzed. Thirty-nine AIEOP centers were involved in the study. In 2021, among 75278 children and adolescents affected by an oncological or a hematological disease, 1.2 and 0.65% developed DM, while IGT or IFG were widespread in 2.3 and 2.8%, respectively. The main causes of DM were the use of corticosteroids in patients with cancer and the iron overload in patients with thalassemia. Venous fasting plasma glycemia was the most used tool to detect glycemic abnormalities. The performance of oral glucose tolerance test (OGTT) was extremely limited, except when IFG occurred. Despite the diagnosis of DM, ∼45% of patients with cancer and 30% of patients with one hematological disease did not receive an appropriate treatment. In the other cases, insulin was the drug of first choice. Emerging technologies for diabetes care (glucose sensors and insulin pumps) are not largely used yet. The results of our study support the standardization of the care of the glycemic abnormalities during or after onco-hematologic diseases in the pediatric age. Despite the scarce data in pediatric literature, proper guidelines are needed.

Current practices for nutritional evaluation and care during the treatment of pediatric oncology patients: a survey among AIEOP centers.

Nutritional status plays a crucial role in the mortality rates of the pediatric oncology patients. However, there is a lack of systematic approaches for nutritional assessment in this population. This study aims to assess the current practice for nutritional assessment and care of pediatric cancer patients in Italy. A 25-items web-based, nation-wide questionnaire was circulated as of January 9, 2023 among physicians within the AIEOP network, composed of 49 national centers, out of which 21 routinely perform HCT. This survey examined the practices of 21 Italian pediatric oncology centers, revealing significant heterogeneity in nutritional practices. Only half of the centers routinely assessed all patients, utilizing different clinical and biochemical parameters. The use of neutropenic diets remained prevalent after chemotherapy or stem cell transplantation. CONCLUSION: This study underscores the pressing need for unified recommendations to improve nutritional care and potentially enhance outcomes for pediatric cancer patients. WHAT IS KNOWN: • The assessment and support of nutrition are gaining interest in the overall care of children with cancer. • The assessment and management of nutritional needs in pediatric cancer patients, including those undergoing hematopoietic cell transplantation, currently lack a systematic approach. WHAT IS NEW: • There is considerable variability in the nutritional assessment and support among Italian centers treating pediatric patients with cancer. • To enhance nutritional assessment and support for pediatric cancer patients, it is essential to establish shared national and international guidelines.

Quantification of horizontal force for the EXER-GENIE® resisted sprint training device.

Sport performance coaches use a range of modalities to apply a horizontal force (Fh) to athletes during resisted sprint training (RST). These modalities include parachutes, weighted vests, pulley devices, motored tethered devices, and, most notably, weighted sleds. Despite the widespread use of these devices, the resistance forces of the pulley devices have not been evaluated for reliability and accuracy. Therefore, the primary aim of this study is to quantify the Fh of a commercially available pulley device (EXER-GENIE®) and determine how resistance force is related to the load settings on the device. The secondary aim is to identify the differences in the Fh values between three EXER-GENIE® devices that use 36 m and 60 m ropes. The Fh values in the Newtons (N) of the three EXER-GENIE® devices were analyzed using a motorized winch, a lead acid battery, and an S-beam load cell. Four 10 s winch-driven trials were performed using 15 different EXER-GENIE® loads, ranging from 0.028 kg to 3.628 kg, employing two different 36 m devices and one 60 m device. The mean ± standard deviation for Fh was reported across the four trials for each load setting. All devices produced similar Fh values across lighter load settings (loads ≤0.141 kg). However, at heavier loads (loads ≥0.226 kg), the 60 m device had Fh values 50-85 N greater than those of the 36 m device. The coefficient of variation across the four trials was extremely high at light loads but sharply decreased to <10% at heavy loads. Absolute reliability was high for each device [intraclass correlation coefficient (ICC) = 0.99]. A regression analysis for Fh values and EXER-GENIE® load indicated a strong positive relationship between load and Fh values across all devices (R2 = 0.96-0.99). Caution should be exercised when using identical loads on the different-length pulley devices, as the 60 m device produced greater Fh values than the 36 m devices at load settings higher than 0.226 kg. These results can provide coaches and practitioners with a better understanding of the magnitude of resistance that is applied when prescribing EXER-GENIE® devices for higher training loads.

International Delphi-based consensus on the appropriate use and effect of Benzydamine hydrochloride in the treatment of sore throat.

BACKGROUND: Benzydamine hydrochloride is a locally-acting Non-Steroidal Anti-Inflammatory Drug (NSAID) with combined local anesthetic and analgesic properties, indicated for the symptomatic relief of pain in acute sore throat. The aim of this study was to obtain an European Consensus among pharmacists, general practitioners and pediatricians on the appropriate use of benzydamine hydrochloride in the treatment of sore throat. METHODS: The authors developed a Delphi questionnaire organized into 15 statements focused on 4 topics: the mechanism of action of benzydamine, the benzydamine treatment in an adult patient and in a pediatric patient, and the advantages of benzydamine over other topical treatments. The survey was administered to a panel of to 320 participants including general practitioners, pediatricians, and pharmacists from 6 European countries (Italy, Germany, Portugal, Romania, Russia, and Spain), who rated their level of agreement or disagreement with each statement on a 6-point Likert scale. Consensus was predefined as more than 66% of the panel agreeing/disagreeing with each statement. RESULTS: Panelists' agreement on statements was very high. Consensus was reached for all 15 statements in the Delphi survey, with more than 98% positive agreement on topic 4, suggesting a shared view among European healthcare professionals (HCPs) about the advantages of benzydamine over other topical treatments. A strong consensus (> 99%) was reached for all the statements of topic 1 regarding the mechanism of action of benzydamine, except for its anesthetic properties (79%). Strong agreement was reached for all statements in topics 2 and 3 regarding the treatment of acute sore throat symptoms in the adult and pediatric patient, except for one on the efficacy of benzydamine in preventing post-operative sore throat, for which it was 67%. CONCLUSION: Because all relevant publications on benzydamine are dated and there are no recommendations on its use for the symptomatic treatment of sore throat in European guidelines, this Delphi-based international consensus may be important in reinforcing the appropriate use and effect of benzydamine in the treatment of sore throat among health care professionals.

Management of Nutritional Needs in Pediatric Oncology: A Consensus Statement.

Malnutrition, intended as both overnutrition and undernutrition, is a common problem in children with cancer, impacting quality of life as well as survival. In addition, nutritional imbalances during childhood can significantly affect proper growth. Nevertheless, there is currently a lack of a systematic approach to this issue in the pediatric oncology population. To fill this gap, we aimed to provide practice recommendations for the uniform management of nutritional needs in children with cancer. Twenty-one clinical questions addressing evaluation and treatment of nutritional problems in children with cancer were formulated by selected members from four Italian Association of Pediatric Hematology and Oncology (AIEOP) centers and from the Survivorship Care and Nutritional Support Working Group of Alliance Against Cancer. A literature search in PubMed was performed; during two consensus meetings, all recommendations were discussed and finalized using the nominal group technique. Members representing every institution voted on each recommendation. Finally, recommendations were approved by all authors.

Brentuximab vedotin in the treatment of paediatric patients with relapsed or refractory Hodgkin's lymphoma: Results of a real-life study.

BACKGROUND: Brentuximab vedotin (BV) is an antibody drug-conjugated anti-CD30 approved for the treatment of adult classical Hodgkin's lymphoma (HL), whereas it is considered as off-label indication in paediatrics. The aim of the study was to evaluate the safety and efficacy of BV to treat patients aged less than 18 years with refractory/relapsed HL. MATERIALS AND METHODS: In this multicentre, retrospective study, 68 paediatric patients who received at least one dose of BV between November 2011 and August 2020 were enrolled. A median of nine doses of BV were administered as monotherapy (n = 31) or combined with other therapies (n = 37). BV was administrated alone as consolidation therapy after stem cell transplantation (SCT) in 12 patients, before SCT in 18 patients, whereas in 15 patients it was used before and after SCT as consolidation therapy. Median follow-up was 2.8 years (range: 0.6-8.9 years). RESULTS: The best response was observed in the 86% of patients; the overall response rate was 66%. The 3-year progression-free survival was 58%, whereas the overall survival was 75%. No statistically significant differences between patients treated with BV monotherapy or combination were highlighted. In multivariate analysis, patients with non-nodular sclerosis HL and not transplanted had an increased risk of failure. Overall, 46% of patients had grade 3-4 adverse events that led to BV discontinuation in five of them. CONCLUSION: In conclusion, our study confirms that BV was a safe and effective drug, able to induce complete remission, either as monotherapy or in association with standard therapy.

EBV-encoded microRNAs profile evaluation in pediatric liver transplant recipients.

BACKGROUND: Epstein-Barr virus (EBV) infects 90% of the world population, commonly causing self-limiting infectious mononucleosis or rarely inciting a range of malignancies. EBV microRNAs (miRNAs) were discovered by sequencing libraries of small RNAs generated from several EBV-positive cell lines. Little is known about their roles, but their high stability and easy quantification make these molecules potential biomarkers. OBJECTIVES: In this study a stem-loop MGB real-time RT-PCR has been used to detect and quantify miR-BART2-5p, miR-BART15 and miR-BART22 EBV miRNAs levels. STUDY DESIGNS: The profiles of EBV miRNAs levels were evaluated in 51 serum samples of 37 pediatric liver transplant patients subdivided in 3 study groups: EBV seronegative, EBV seropositive and PCR negative, EBV seropositive and PCR positive. RESULTS: miR-BART22 serum levels in patients with positive EBV PCR were significantly higher than those in patients with negative EBV PCR (p=0.0005). On the contrary, miR-BART2-5p and miR-BART15 did not exhibit significant difference in positive and negative EBV PCR patients (p=0.5511 and p=0.3523, respectively). CONCLUSION: This study described a method for quantitative detection of miR-BART 22, miR-BART2-5p and miR-BART15 EBV miRNAs in liver transplanted patients, and suggests the use of miR-BART22 as a potential biomarker for EBV reactivation.

Feasibility and Outcome of Haploidentical Hematopoietic Stem Cell Transplantation with Post-Transplant High-Dose Cyclophosphamide for Children and Adolescents with Hematologic Malignancies: An AIEOP-GITMO Retrospective Multicenter Study.

Post-transplant high-dose cyclophosphamide (PTCy) is a novel approach to prevent graft-versus-host disease (GVHD) and rejection in patients given haploidentical hematopoietic stem cell transplantation (HSCT). Thirty-three patients with high-risk hematologic malignancies and lacking a match-related or -unrelated donor were treated with PTCy haploidentical HSCT in 5 Italian AIEOP centers. Nineteen patients had a nonmyeloablative preparative regimen (57%), and 14 patients received a full myeloablative conditioning regimen (43%). No patients received serotherapy; GVHD prophylaxis was based on PTCy (50 mg/kg on days +3 and +4) combined with mycophenolate plus tacrolimus or cyclosporine A. Neutrophil and platelet engraftment was achieved on days +17 (range, 14 to 37) and +27 (range, 16 to 71). One patient had autologous reconstitution for anti-HLA antibodies. Acute GVHD grades II to IV and III to IV and chronic GVHD developed in 22% (95% CI, 11 to 42), 3% (95% CI, 0 to 21), and 4% (95% CI, 0 to 27) of cases, respectively. The 1-year overall survival rate was 72% (95% CI, 56 to 88), progression-free survival rate was 61% (95% CI, 43 to 80), cumulative incidence of relapse was 24% (95% CI, 13 to 44), and transplant-related mortality was 9% (95% CI, 3 to 26). The univariate analysis for risk of relapse incidence showed how 3 significant variables, mother as donor (P = .02), donor gender as female (P = .04), and patient gender as female (P = .02), were significantly associated with a lower risk of relapse. Disease progression was the main cause of death. PTCy is a safe procedure also for children and adolescents who have already received several lines of chemotherapy. Among the different diseases, a trend for better 1-year rates of overall survival was obtained for nonacute leukemia patients.

Quality of harvest and role of cell dose in unrelated bone marrow transplantation: an Italian Bone Marrow Donor Registry-Gruppo Italiano Trapianto di Midollo Osseo Study.

In this study, we investigated the factors affecting cell dose harvest and the role of cell dose on outcome. We analysed data from a cohort of 703 patients who underwent unrelated bone marrow transplantation facilitated by IBMDR in GITMO centers between 2002 and 2008. The median-infused cell doses is 3.7 × 10(8)/kg, the correlation between the nucleated cells requested from transplant centers and those harvested by collection centers was adequate. A harvested/requested cells ratio lower than 0.5 was observed only in 3% of harvests. A volume of harvested marrow higher than the median value of 1270 ml was related to a significant lower infused cell dose (χ(2): 44.4; P < 0.001). No patient- or donor-related variables significantly influenced the cell dose except for the recipient younger age (χ(2): 95.7; P < 0.001) and non-malignant diseases (χ(2): 33.8; P < 0.001). The cell dose resulted an independent predictor factor for a better outcome in patients affected by non-malignant disease (P = 0.05) while early disease malignant patients receiving a lower cell dose showed a higher risk of relapse (P = 0.05).

Langerhans cell histiocytosis: 40 years' experience.

OBJECTIVES: Our study analyzes 40 years' experience with pediatric Langerhans cell histiocytosis patients. MATERIALS AND METHODS: Between June 1968 and December 2009, 121 patients (79 males, 42 females; median age 4.13 y) were diagnosed at our center (74% monosystemic disease; 26% multisystemic), treated according to current protocols. We evaluated the response, the survival, and the neuroendocrinological sequelae. RESULTS: Overall survival (OS) for all patients was 93% at 10 years from diagnosis, event-free survival (EFS) 77%. OS for patients younger than 2 years and older than or equal to 2 years was 82% and 97% (P = 0.003); EFS 48% and 87% (P = 0.001). OS for patients diagnosed before and after April 1, 1991 was 84% and 98% (P = 0.007), EFS 66% and 85% (P = 0.03). OS for monosystemic and multisystemic disease was 100% and 71% (P < 0.001); EFS 88% and 45% (P < 0.001). OS for "risk" patients (involvement of bone marrow, spleen, liver, lungs) and "low-risk" patients was 50% and 94% (P = 0.007), EFS 37% and 54% (P = 0.06). Fourteen patients developed diabetes insipidus, 7 patients growth hormone deficiency, 2 hypothyroidism, and 1 neurodegeneration. CONCLUSIONS: Our study confirms improvement of pathogenetic knowledge and treatment over the last 20 years. Age at diagnosis older than or equal to 2 years and standardized treatment are associated with improved prognoses. Multisystemic involvement, especially with "risk" organs seem to be correlated to a worse outcome.

Intercurrent infectious diseases in post-stem cell transplant patients: paranasal sinusitis.

Improvements in treatments available for oncohematologic diseases have made it possible to treat patients at more advanced stages of the disease and thus at greater risk of fungal, bacterial, and viral infections; these may be extensive and have aggressive evolution. In particular, chemotherapy at high doses and allogenic bone marrow transplant expose patients to an increased risk of infection, especially because of the period of aplasia and the condition of immune depression subsequent to the procedure. We presented a case of a 15-year-old adolescent girl diagnosed with combined relapse of acute lymphoblastic leukemia 2 years after completion of first-line chemotherapy that, at 120 days after transplant, erosive lesions of the palatal mucosa at the left hemipalate in the area adjacent to tooth 2.7 were detected, of approximately 2 mm in size. These gave rise to an orosinus communication. Various therapeutic possibilities are examined. These cases are not frequent. Diseases and their related complications require an in-depth knowledge, on the part of the stomatologist, to recognize the early signs of involvement of the oral cavity and, on the part of the oral surgeon, to decide the most appropriate therapeutic strategy.

Extracorporeal photopheresis for steroid resistant graft versus host disease in pediatric patients: a pilot single institution report.

This study was aimed at ascertaining whether extracorporeal photopheresis (ECP) is an effective treatment for pediatric patients with steroid resistant graft versus host disease (GvHD). Fifteen patients with acute GvHD (aGvHD) and 10 patients with chronic GvHD (cGvHD) were enrolled in the study. At the start of the ECP protocol, aGvHD was staged as II (n=7), III (n=4), and IV (n=4). The response rate was 100% for aGvHD II, 75% for aGvHD III, and finally 0% for aGvHD IV (P=0.02). In multivariate analysis, the strongest predictor for ECP response was the aGvHD severity: aGvHD II 100%, aGvHD III-IV 30% [relative risk (RR) 5.071, confidence interval (CI) 95% 2.2-5.5, P=0.0016], this translates in a higher risk of transplant-related mortality for ECP nonresponders (RR 5.26, CI 95% 3.4-6.2, P=0.02). cGvHD was diagnosed as limited n=3, and extensive n=7; the response rate was 100% and 28% for limited or extensive cGvHD, respectively (P=0.03). For cGvHD the strongest predictor for ECP response was the absence of visceral organ involvement (RR 5.17, CI 95% 2-4.9, P=0.001), and the highest risk of transplant-related mortality was among patients not responding to ECP (RR 12.4, CI 95%, P=0.02). Our results suggest that ECP can rescue good-risk GvHD-patients, whereas for advanced, poor-risk GvHD patients, new therapies are required.