Background
Experimental fertility preservation programs have been started to safeguard the future fertility of prepubertal and pubertal males requiring high‐risk gonadotoxic treatment protocols. ...However, long‐term follow‐up studies evaluating the effects on their gonadal development and function related to the testicular biopsy procedure are rather limited.
Design
This two‐center follow‐up study (between 2002 and 2020) evaluated the gonadal development and function of a cohort of 59 prepubertal and pubertal males who have been offered immature testicular tissue banking (TTB) prior to conventional high‐risk chemo‐ and/or radiotherapy (HR‐C/R) or conditioning therapy before hematopoietic stem cell transplantation (CT‐HSCT). The aim is to investigate the long‐term impact of the testicular biopsy procedure and the high‐risk gonadotoxic treatment. Testicular growth and the reproductive hormones luteinizing hormone (LH), follicle‐stimulating hormone (FSH), testosterone (T), and inhibin B (INHB) were analyzed after treatment completion, and compared between males accepting TTB and those refusing TTB (control) as well as between HR‐C/R and CT‐HSCT treatment protocols.
Results
Of the 59 prepubertal and pubertal males included, 25 were treated by HR‐C/R and 34 required CT‐HSCT. TTB was accepted for 39 males and refused for 20 males. Most patients were prepubertal at diagnosis (85%), at TTB (79%), and at treatment completion (76%), and pubertal or postpubertal at their last follow‐up visit (66%). After 5.0 (1.0–13.0) years post treatment, most patients show normal testicular volumes (83%) and normal LH (89%), FSH (87%), T (87%), and INHB (79%) serum levels. The testicular biopsy procedure did not have an effect on testicular growth, LH, FSH, T, and INHB. Significantly more small postpubertal testicular volumes (p = .0278) and low INHB serum levels (p = .0130) were recorded after CT‐HSCT, especially after myeloablative conditioning.
Conclusion
The clinical follow‐up data demonstrate no effect related to the biopsy procedure, but a substantial risk for impaired gonadal development after high‐risk gonadotoxic treatment, in particular myeloablative CT‐HSCT. Longer follow‐up studies with a larger study population are needed to confirm these preliminary findings.
Destruction of cancer cells by therapeutic antibodies occurs, at least in part, through antibody-dependent cellular cytotoxicity (ADCC), and this can be mediated by various Fc-receptor-expressing ...immune cells, including neutrophils. However, the mechanism(s) by which neutrophils kill antibody-opsonized cancer cells has not been established. Here, we demonstrate that neutrophils can exert a mode of destruction of cancer cells, which involves antibody-mediated trogocytosis by neutrophils. Intimately associated with this is an active mechanical disruption of the cancer cell plasma membrane, leading to a lytic (i.e., necrotic) type of cancer cell death. Furthermore, this mode of destruction of antibody-opsonized cancer cells by neutrophils is potentiated by CD47-SIRPα checkpoint blockade. Collectively, these findings show that neutrophil ADCC toward cancer cells occurs by a mechanism of cytotoxicity called trogoptosis, which can be further improved by targeting CD47-SIRPα interactions.
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•Neutrophils kill antibody-opsonized cancer cells by a process called trogoptosis•Cancer cell plasma membrane ingestion by neutrophils is instrumental in trogoptosis•Trogoptosis by neutrophils is further enhanced by CD47-SIRPα checkpoint inhibition
Matlung et al. identify trogoptosis as an immune cell-mediated mechanism of cytotoxicity, demonstrating that neutrophil-mediated destruction of antibody-opsonized cancer cells occurs through a specific process that is distinct from that used by other immune cells.
Juvenile-onset recurrent respiratory papillomatosis (JRRP) is a rare and debilitating childhood disease that presents with recurrent growth of papillomas in the upper airway. Two common human ...papillomaviruses (HPVs), HPV-6 and -11, are implicated in most cases, but it is still not understood why only a small proportion of children develop JRRP following exposure to these common viruses. We report 2 siblings with a syndromic form of JRRP associated with mild dermatologic abnormalities. Whole-exome sequencing of the patients revealed a private homozygous mutation in NLRP1, encoding Nucleotide-Binding Domain Leucine-Rich Repeat Family Pyrin Domain-Containing 1. We find the NLRP1 mutant allele to be gain of function (GOF) for inflammasome activation, as demonstrated by the induction of inflammasome complex oligomerization and IL-1β secretion in an overexpression system. Moreover, patient-derived keratinocytes secrete elevated levels of IL-1β at baseline. Finally, both patients displayed elevated levels of inflammasome-induced cytokines in the serum. Six NLRP1 GOF mutations have previously been described to underlie 3 allelic Mendelian diseases with differing phenotypes and modes of inheritance. Our results demonstrate that an autosomal recessive, syndromic form of JRRP can be associated with an NLRP1 GOF mutation.
IntroductionVincristine is an integral component of treatment for children with cancer. Its main dose‐limiting side effect is vincristine‐induced peripheral neuropathy (VIPN). The VINCA trial was a ...randomized controlled trial that explored the effect of 1‐hour infusion compared with push injection of vincristine on the development of VIPN in children with cancer. The short‐term outcomes (median follow‐up 9 months) showed that there was no difference in VIPN between the randomization groups. However, 1‐hour infusion was less toxic in children who also received azoles. We now report the results of the final analyses (median follow‐up 20 months), which includes treatment outcome as a secondary objective (follow‐up 3 years).MethodsVIPN was measured 1–7 times per participant using the Common Terminology Criteria for Adverse Events (CTCAE) and the pediatric‐modified total neuropathy score. Poisson mixed model and logistic generalized estimating equation analysis for repeated measures were performed.ResultsForty‐five participants per randomization group were included. There was no significant effect of 1‐hour infusion compared with push injection on VIPN. In participants receiving concurrent azoles, the total CTCAE score was significantly lower in the one‐hour group (rate ratio 0.52, 95% confidence interval 0.33–0.80, p = 0.003). Four patients in the one‐hour group and one patient in the push group relapsed. Two patients in the one‐hour group died. Conclusion1‐hour infusion of vincristine is not protective against VIPN. However, in patients receiving concurrent azoles, 1‐hour infusion may be less toxic. The difference in treatment outcome is most likely the result of differences in risk profile.
Vincristine is an integral component of treatment for children with cancer. Its main dose‐limiting side effect is vincristine‐induced peripheral neuropathy (VIPN). The VINCA trial was a randomized controlled trial that explored the effect of one‐hour infusion compared with push injection of vincristine on the development of VIPN in children with cancer. We found that in patients receiving concurrent azoles, one‐hour infusion may be less toxic.
Background
Children with acute myeloid leukemia (AML) have a 70% survival rate with treatment regimens containing high doses of cytarabine and anthracyclines and, in some, hematopoietic stem cell ...transplantation (allo‐HSCT).
Procedure
In this multicenter Dutch–Belgian protocol (DB AML‐01), 112 children with de novo AML were included. Treatment was stratified according to day 15 bone marrow response after the first induction course. Poor responders received a second course without delay while good responders awaited hematological recovery. Patients achieving CR after two induction courses continued with three consolidation courses without HSCT in CR1.
Results
The overall remission rate was 93.5%. After a median follow‐up of 4.1 years, three‐year event‐free survival (EFS) was 52.6% (95% CI, 42.9%–61.3%), three‐year cumulative incidence of relapse 39.7% (95% CI, 30.1%–49.0%), and three‐year overall survival (OS) 74.0% (95% CI, 64.8%–81.2%). Significantly more events occurred in patients with high WBC at diagnosis or FLT3‐ITD/NPM1‐WT, whereas core binding factor (CBF) leukemia had a significantly better EFS. KMT2A rearrangements and age > 10 years negatively impacted OS.
Conclusions
DB AML‐01 response‐guided therapy results in a favorable OS, particularly for children with CBF leukemia, children younger than 10 years or with initial WBC counts below 100 × 109/L. Outcome of patients with FLT3‐ITD/NPM1‐WT remains poor and warrants alternative treatment strategies.
To develop and face-validate population-level indicators for potential appropriateness of end-of-life care, for children with cancer, neurologic conditions, and genetic/congenital conditions, to be ...applied to administrative health data containing medication and treatment variables.
Modified RAND/University of California at Los Angeles appropriateness method. We identified potential indicators per illness group through systematic literature review, scoping review, and expert interviews. Three unique expert panels, a cancer (n = 19), neurology (n = 21), and genetic/congenital (n = 17) panel, participated in interviews and rated indicators in individual ratings, group discussions, and second individual ratings. Each indicator was rated on a scale from 1 to 9 for suitability. Consensus was calculated with the interpercentile range adjusted for symmetry formula. Indicators with consensus about unsuitability were removed, those with consensus about suitability were retained, and those with lack of consensus deliberated in the group discussion. Experts included pediatricians, nurses, psychologists, physiotherapists, pharmacologists, care coordinators, general practitioners, social workers from hospitals, care teams, and general practice.
Literature review and expert interviews yielded 115 potential indicators for cancer, 111 for neurologic conditions, and 99 for genetic/congenital conditions. We combined similar indicators, resulting in respectively 36, 32, and 33 indicators per group. Expert scoring approved 21 indicators for cancer, 24 for neurologic conditions, and 23 for genetic/congenital conditions.
Our indicators can be applied to administrative data to evaluate appropriateness of children's end-of-life care. Differences from adults' indicators stress the specificity of children's end-of-life care. Individual care and remaining aspects, such as family support, can be evaluated with complementary tools.
Summary
Outcomes in childhood T‐cell acute lymphoblastic leukaemia (T‐ALL) are steadily improving due to intensive therapy. Between 1989 and 2008, 599 children with newly diagnosed T‐ALL were ...enrolled in two successive European Organization for Research and Treatment of Cancer ‐ Children's Leukaemia Group trials (58881 and 58951), both based on the Berlin‐Frankfurt‐Munster protocol and without cranial irradiation. In the latter trial induction chemotherapy was intensified. The most important randomizations were Medac Escherichia coli asparaginase versus Erwinia asparaginase in trial 58881, and dexamethasone (6 mg/m2/day) versus prednisolone (60 mg/m2/day) and prolonged versus conventional asparaginase duration in trial 58951. 8‐year event‐free survival (EFS) increased from 65·1% to 74·0% in trial 58951. Improvement was most profound for patients with white blood cell (WBC) counts <100 × 109/l and “good responders” to prephase. Medac E. coli asparaginase was associated with longer EFS hazard ratio (HR) 0·54, P = 0·0015 and overall survival (HR 0·51, P = 0·0018). Induction therapy with dexamethasone did not improve EFS compared to prednisolone. Remarkably, intensification of central nervous system (CNS)‐directed therapy in trial 58951 resulted in fewer bone marrow relapses, while the incidence of CNS relapses remained low. In summary, we showed that adequate asparaginase therapy, intensified induction treatment and intensification of CNS‐directed chemotherapy can result in an improvement of outcome in T‐ALL patients with good prephase response and initial WBC counts <100 × 109/l, representing approximately 50% of T‐ALL patients.
The analysis of individuals with severe congenital neutropenia (SCN) may shed light on the delicate balance of factors controlling the differentiation, maintenance and decay of neutrophils. We ...identify 9 distinct homozygous mutations in the JAGN1 gene encoding Jagunal homolog 1 in 14 individuals with SCN. JAGN1-mutant granulocytes are characterized by ultrastructural defects, a paucity of granules, aberrant N-glycosylation of multiple proteins and increased incidence of apoptosis. JAGN1 participates in the secretory pathway and is required for granulocyte colony-stimulating factor receptor-mediated signaling. JAGN1 emerges as a factor that is necessary in the differentiation and survival of neutrophils.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Abstract
Variants in ribosomal protein (RP) genes drive Diamond-Blackfan anemia (DBA), a bone marrow failure syndrome that can also predispose individuals to cancer. Inherited and sporadic RP gene ...variants are also linked to a variety of phenotypes, including malignancy, in individuals with no anemia. Here we report an individual diagnosed with DBA carrying a variant in the 5′UTR of RPL9 (uL6). Additionally, we report two individuals from a family with multiple cancer incidences carrying a RPL9 missense variant. Analysis of cells from these individuals reveals that despite the variants both driving pre-rRNA processing defects and 80S monosome reduction, the downstream effects are remarkably different. Cells carrying the 5′UTR variant stabilize TP53 and impair the growth and differentiation of erythroid cells. In contrast, ribosomes incorporating the missense variant erroneously read through UAG and UGA stop codons of mRNAs. Metabolic profiles of cells carrying the 5′UTR variant reveal an increased metabolism of amino acids and a switch from glycolysis to gluconeogenesis while those of cells carrying the missense variant reveal a depletion of nucleotide pools. These findings indicate that variants in the same RP gene can drive similar ribosome biogenesis defects yet still have markedly different downstream consequences and clinical impacts.
Summary
Asparaginase (ASNase) is an important anti‐leukaemic drug in the treatment of childhood acute lymphoblastic leukaemia (ALL) and non‐Hodgkin lymphoma (NHL). A substantial proportion of ...patients develop hypersensitivity reactions with anti‐ASNase neutralising antibodies, resulting in allergic reactions or silent inactivation (SI), and characterised by inactivation and rapid clearance of ASNase. We report results of a prospective, real‐time therapeutic drug monitoring of pegylated Escherichia coli (PEG‐)ASNase and Erwinia ASNase in children treated for ALL and NHL in Belgium. Erwinia ASNase was given as second‐line after hypersensitivity to PEG‐ASNase. In total, 286 children were enrolled in the PEG‐ASNase cohort. Allergy was seen in 11·2% and SI in 5·2% of patients. Of the 42 patients treated with Erwinia ASNase, 7·1% experienced allergy and 2·4% SI. The median trough PEG‐ASNase activity was high in all patients without hypersensitivity. After Erwinia administration significantly more day 3 samples had activities <100 IU/l (62·5% vs. 10% at day 2 (D2)). The median D2 activity was significantly higher for intramuscular (IM; 347 IU/l) than for intravenous Erwinia administrations (159 IU/l). This prospective, multicentre study shows that monitoring of ASNase activity during treatment of children with ALL and NHL is feasible and informative. Treatment with Erwinia ASNase warrants close monitoring and optimally adherence to a 2‐day interval of IM administrations.
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