Primary hemophagocytic lymphohistiocytosis, a rare genetic immune disorder characterized by hyperinflammation, manifests in infancy and is associated with high mortality. In a study involving 34 ...children, an antibody to interferon-γ (emapalumab) produced responses in 65%; it served as a bridge to marrow transplantation in 70% of those who had received previous treatment.
Background Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening disease affecting mostly children but also adults and characterized by hyperinflammatory features. A subset of patients, ...referred to as having familial hemophagocytic lymphohistiocytosis (FHL), have various underlying genetic abnormalities, the frequencies of which have not been systematically determined previously. Objective This work aims to further our understanding of the pathogenic bases of this rare condition based on an analysis of our 25 years of experience. Methods From our registry, we have analyzed a total of 500 unselected patients with HLH. Results Biallelic pathogenic mutations defining FHL were found in 171 (34%) patients; the proportion of FHL was much higher (64%) in patients given a diagnosis during the first year of life. Taken together, mutations of the genes PRF1 (FHL2) and UNC13D (FHL3) accounted for 70% of cases of FHL. Overall, a genetic diagnosis was possible in more than 90% of our patients with FHL. Perforin expression and the extent of degranulation have been more useful for diagnosing FHL than hemophagocytosis and the cytotoxicity assay. Of 281 (56%) patients classified as having “sporadic” HLH, 43 had monoallelic mutations in one of the FHL-defining genes. Given this gene dosage effect, FHL is not strictly recessive. Conclusion We suggest that the clinical syndrome HLH generally results from the combined effects of an exogenous trigger and genetic predisposition. Within this combination, different weights of exogenous and genetic factors account for the wide disease spectrum that ranges from HLH secondary to severe infection to FHL.
A rapid test for detecting total immunoglobulins directed towards the nucleocapsid protein (N) of severe acute syndrome coronavirus 2 (SARS CoV-2) was developed, based on a multi-target lateral flow ...immunoassay comprising two test lines. Both test lines bound to several classes of immunoglobulins (G, M, and A). Specific anti-SARS immunoglobulins were revealed by a colorimetric probe formed by N and gold nanoparticles. Targeting the total antibodies response to infection enabled achieving 100% diagnostic specificity (95.75–100, C.I. 95%, n = 85 healthy and with other infections individuals) and 94.6% sensitivity (84.9–98.9, C.I. 95%, n = 62 SARS CoV-2 infected subjects) as early as 7 days post confirmation of positivity. Agreeing results with a reference serological ELISA were achieved, except for the earlier detection capability of the rapid test. Follow up of the three seroconverting patients endorsed the hypothesis of the random rise of the different immunoglobulins and strengthened the ‘total antibodies’ approach for the trustworthy detection of serological response to SARS CoV-2 infection.
Display omitted A rapid test based on the lateral flow immunoassay technology was established to detect the total serological response to the SARS CoV-2 infection.
•A sensitive and specific lateral flow immunoassay for detecting antibodies to Covid-19.•Broad-specific agents to capture total immunoglobulins enabled increasing the sensitivity.•Two test lines were combined to guarantee no false positive results.•Diagnosis based on the multi-target LFIA can complement molecular assays.
Patients given allogeneic hematopoietic stem cell transplantation (alloHSCT) present an increased incidence of long-term toxicities that can be attributed to the preparative regimen. We ...retrospectively analyzed in a population of 670 children receiving allo-HSCT for acute leukemia the occurrence of different late effects in function of the choice made between total body irradiation (TBI) and busulfan, as part of the preparative regimen. In univariable analysis, we found that patients treated with TBI developed cataract in 24% of the cases compared with 4% in patients treated with BU (p = 0.0001) and that the incidence of secondary malignant neoplasia (SMN) was higher in patients treated with TBI (18%) as compared with those prepared to the allograft with a Bu-based regimen (0%) (p = 0.019). Conditioning regimen did not show a statistically significant correlation with the occurrence of all the other investigated late effects. In multivariable analysis, TBI remained associated with the occurrence of cataracts (Relative Risk: 0.33 p = 0.012) and secondary malignancies (Relative Risk 3.96 × 10e-6 p < 0.001); however, other variables, as GvHD and disease type, were also correlated with these long-term sequels, indicating that in our study population the preparative regimen is not the only factor influencing the incidence of these complications.
Letermovir (LMV) is licensed for prophylaxis of CMV infection in allogeneic hematopoietic cell transplant adult CMV-seropositive patients. Due to its favorable safety profile, LMV brings potential ...for use in other clinical situations, outside the approved indication. The objective of the study was to analyze the efficacy and safety of the use of LMV in off-label indications in EBMT centers. A total of 49 patients were reported including 44 adults and 5 children. LMV was administered for: secondary prophylaxis (37 adults, 3 children), primary prophylaxis (2 children), pre-emptive treatment (5 adults), and therapy of CMV disease (2 adults; pneumonia, colitis). Cyclosporine was concomitantly used in 26 patients. Overall, LMV was used for a median 112 days (range: 10-473). Cumulative incidence of breakthrough infections during secondary prophylaxis was 10.1% (95% CI = 3.1-21.9). Prophylactic treatment with LMV resulted in 94.9% (95% CI = 81.0-98.7), and 81.9% (95% CI = 65.7-90.9) probability of, respectively, 60 and 120-day survival without CMV infection in patients receiving secondary prophylaxis. During therapy of CMV infection/disease, probability of 60 and 120-day overall survival was 100% and 71.4% (95% CI = 25.8-92.0), respectively. No breakthrough infection occurred in children on LMV prophylaxis. Adverse events were reported in 15/49 (30.4%) patients: the most common being nausea/vomiting (22.4%). In conclusion, the efficacy of the use of LMV as secondary prophylaxis was high, and the preliminary experience with the use of LMV for the treatment of patients with refractory CMV infection/disease was positive. Our data showed that higher dose or prolonged therapy did not result in increased rate of adverse events.
Summary Background Results of previous study showed promising but short-lived activity of sorafenib in the treatment of patients with unresectable advanced and metastatic osteosarcoma. This treatment ...failure has been attributed to the mTOR pathway and might therefore be overcome with the addition of mTOR inhibitors. We aimed to investigate the activity of sorafenib in combination with everolimus in patients with inoperable high-grade osteosarcoma progressing after standard treatment. Methods We did this non-randomised phase 2 trial in three Italian Sarcoma Group centres. We enrolled adults (≥18 years) with relapsed or unresectable osteosarcoma progressing after standard treatment (methotrexate, cisplatin, and doxorubicin, with or without ifosfamide). Patients received 800 mg sorafenib plus 5 mg everolimus once a day until disease progression or unacceptable toxic effects. The primary endpoint was 6 month progression-free survival (PFS). All analyses were intention-to-treat. This trial is registered with ClinicalTrials.gov , number NCT01804374. Findings We enrolled 38 patients between June 16, 2011, and June 4, 2013. 17 (45%; 95% CI 28–61) of 38 patients were progression free at 6 months. Toxic effects led to dose reductions, or short interruptions, or both in 25 (66%) of 38 patients and permanent discontinuation for two (5%) patients. The most common grade 3–4 adverse events were lymphopenia and hypophosphataemia each in six (16%) patients, hand and foot syndrome in five (13%), thrombocytopenia in four (11%), and fatigue, oral mucositis, diarrhoea, and anaemia each in two (5%). One patient (3%) had a grade 3 pneumothorax that required trans-thoracic drainage, and that recurred at the time of disease progression. This was reported as a serious adverse event related to the study drugs in both instances. No other serious adverse events were reported during the trial. There were no treatment-related deaths. Interpretation Although the combination of sorafenib and everolimus showed activity as a further-line treatment for patients with advanced or unresectable osteosarcoma, it did not attain the prespecified target of 6 month PFS of 50% or greater. Funding Italian Sarcoma Group.
The neurotrophic tropomyosin receptor kinase (
) genes (
,
, and
) code for three transmembrane high-affinity tyrosine-kinase receptors for nerve growth factors (TRK-A, TRK-B, and TRK-C) which are ...mainly involved in nervous system development. Loss of function alterations in these genes can lead to nervous system development problems; conversely, activating alterations harbor oncogenic potential, promoting cell proliferation/survival and tumorigenesis. Chromosomal rearrangements are the most clinically relevant alterations of pathological
activation, leading to constitutionally active chimeric receptors.
fusions have been detected with extremely variable frequencies in many pediatric and adult cancer types, including central nervous system (CNS) tumors. These alterations can be detected by different laboratory assays (e.g., immunohistochemistry, FISH, sequencing), but each of these approaches has specific advantages and limitations which must be taken into account for an appropriate use in diagnostics or research. Moreover, therapeutic targeting of this molecular marker recently showed extreme efficacy. Considering the overall lack of effective treatments for brain neoplasms, it is expected that detection of
fusions will soon become a mainstay in the diagnostic assessment of CNS tumors, and thus in-depth knowledge regarding this topic is warranted.
We compared two chemotherapy regimens that included methotrexate (MTX), cisplatin (CDP), and doxorubicin (ADM) with or without ifosfamide (IFO) in patients with nonmetastatic osteosarcoma of the ...extremity.
Patients age ≤ 40 years randomly received regimens with the same cumulative doses of drugs (ADM 420 mg/m(2), MTX 120 g/m(2), CDP 600 mg/m(2), and IFO 30 g/m(2)) but with different durations (arm A, 44 weeks; arm B, 34 weeks). IFO was given postoperatively when pathologic response to MTX-CDP-ADM was poor (arm A) or given in the primary phase of chemotherapy with MTX-CDP-ADM (arm B). End points of the study included pathologic response to preoperative chemotherapy, toxicity, and survival. Given the feasibility of accrual, the statistical plan only permitted detection of a 15% difference in 5-year overall survival (OS).
From April 2001 to December 2006, 246 patients were enrolled. Two hundred thirty patients (94%) underwent limb salvage surgery (arm A, 92%; arm B, 96%; P = .5). Chemotherapy-induced necrosis was good in 45% of patients (48% in arm A, 42% in arm B; P = .3). Four patients died of treatment-related toxicity (arm A, n = 1; arm B, n = 3). A significantly higher incidence of hematologic toxicity was reported in arm B. With a median follow-up of 66 months (range, 1 to 104 months), 5-year OS and event-free survival (EFS) rates were not significantly different between arm A and arm B, with OS being 73% (95% CI, 65% to 81%) in arm A and 74% (95% CI, 66% to 82%) in arm B and EFS being 64% (95% CI, 56% to 73%) in arm A and 55% (95% CI, 46% to 64%) in arm B.
IFO added to MTX, CDP, and ADM from the preoperative phase does not improve the good responder rate and increases hematologic toxicity. IFO should only be considered in patients who have a poor histologic response to MTX, CDP, and ADM.
Cytokine-induced killer (CIK) cells are a very promising cell population raising growing interest in the field of cellular antitumor therapy. The aim of our study was to validate the most ...advantageous expansion method for this advanced therapy medicinal product (ATMP) and to translate it from preclinical field to good manufacturing practices (GMP). GMP ensures that ATMP are consistently produced and controlled to the quality standards required to their intended use. For this reason, the use of the xenogenic sera tended to be minimized by GMP for their high variability and the associated risk of transmitting infectious agents.
We decided to replace Fetal Bovine Serum (FBS), largely used as medium supplement for CIKs expansion, with other culture media. Firstly, Human Serum (HS) and Human Pool Plasma (HPP) were tested as medium supplements giving not compliant results to acceptance criteria, established for CIKs, probably for the great batch to batch variability. Consequently, we decided to test three different serum free expansion media: X-VIVO 15, (largely used by other groups) and Tex Macs and Cell Genix GMP SCGM: two GMP manufactured media. We performed a validation consisting in three run-sand even if the small number of experiments didn't permit us to obtained statistical results we demonstrated that both X-VIVO 15 and Tex Macs fulfilled the quality standards in terms of cellular growth, viability and identity while Cell Genix GMP SCGM resulted not compliant as it caused some technical problems such as high mortality.
In conclusion, these preclinical validation data lay the bases for a GMP-compliant process to improve the CIKs expansion method.
The 2021 World Health Organization Classification of Tumors of the Central Nervous System, Fifth Edition (WHO-CNS5), has strengthened the concept of tumor grade as a combination of histologic ...features and molecular alterations. The WHO-CNS5 tumor type "Diffuse midline glioma, H3K27-altered," classified within the family of "Pediatric-type diffuse high-grade gliomas," incarnates an ideally perfect integrated diagnosis in which location, histology, and genetics clearly define a specific tumor entity. It tries to evenly characterize a group of neoplasms that occur primarily in children and midline structures and that have a dismal prognosis. Such a well-defined pathological categorization has strongly influenced the pediatric oncology community, leading to the uniform treatment of most cases of H3K27-altered diffuse midline gliomas (DMG), based on the simplification that the mutation overrides the histological, radiological, and clinical characteristics of such tumors. Indeed, multiple studies have described pediatric H3K27-altered DMG as incurable tumors. However, in biology and clinical practice, exceptions are frequent and complexity is the rule. First of all, H3K27 mutations have also been found in non-diffuse gliomas. On the other hand, a minority of DMGs are H3K27 wild-type but have a similarly poor prognosis. Furthermore, adult-type tumors may rarely occur in children, and differences in prognosis have emerged between adult and pediatric H3K27-altered DMGs. As well, tumor location can determine differences in the outcome: patients with thalamic and spinal DMG have significantly better survival. Finally, other concomitant molecular alterations in H3K27 gliomas have been shown to influence prognosis. So, when such additional mutations are found, which one should we focus on in order to make the correct clinical decision? Our review of the current literature on pediatric diffuse midline H3K27-altered DMG tries to address such questions. Indeed, H3K27 status has become a fundamental supplement to the histological grading of pediatric gliomas; however, it might not be sufficient alone to exhaustively define the complex biological behavior of DMG in children and might not represent an indication for a unique treatment strategy across all patients, irrespective of age, additional molecular alterations, and tumor location.
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