Immunisation in children with cancer Patel, Soonie R.; Skinner, Roderick; Bate, Jessica ...
Paediatrics and child health,
August 2023, 2023-08-00, Letnik:
33, Številka:
8
Journal Article
Recenzirano
Immunosuppression of varying degree is present in children with cancer. This can range from mild to severe. Cancer itself, particularly leukaemia and lymphoma, can cause suppression of cellular and ...humoral immune function. However, cytotoxic antineoplastic therapy is the main contributor. Immune alteration is reflected by decreases in neutrophils, lymphocytes, immunoglobulin levels, and specific antibodies against previous vaccinations and infections. Immune recovery post-treatment occurs in a differential manner, with innate immune function recovering before adaptive immune function, and with B-cell function recovering faster than T-cell function. As a result of these changes children with cancer, and particularly those who are also haematopoietic stem cell transplant (HSCT) recipients, have an acquired immune deficiency, and are at increased risk of significant morbidity and mortality from infections. It is therefore important to ensure that such children are maximally protected against vaccine-preventable diseases. This can be achieved by optimising the vaccination strategy in children during immunosuppressive cancer treatment and after completion of treatment. Vaccination should be routine practice for all children treated for cancer. The vaccination strategy should not only include the patient, but also the household members and healthcare contacts of the patient.
Allogeneic hematopoietic stem cell transplantation (HSCT) is used as a therapeutic approach for primary immunodeficiencies (PIDs). The best outcomes have been achieved with HLA-matched donors, but ...when a matched donor is not available, a haploidentical or mismatched unrelated donor (mMUD) can be useful. Various strategies are used to mitigate the risk of graft-versus-host disease (GvHD) and rejection associated with such transplants.
We sought to evaluate the outcomes of haploidentical or mMUD HSCT after depleting GvHD-causing T-cell receptor (TCR) αβ CD3+ cells from the graft.
CD3+TCRαβ+/CD19+ depleted grafts were given in conditioned (except 3) children with PIDs. Treosulfan (busulfan in 1 patient), fludarabine, thiotepa, and anti-thymocyte globulin or alemtuzumab conditioning were used in 77% of cases, and all but 4 received GvHD prophylaxis.
Twenty-five patients with 12 types of PIDs received 26 HSCTs. Three underwent transplantation for refractory GvHD that developed after the first cord transplantation. At a median follow-up of 20.8 months (range, 5 month-3.3 years), 21 of 25 patients survived and were cured of underlying immunodeficiency. Overall and event-free survival at 3 years were 83.9% and 80.4%, respectively. Cumulative incidence of grade II to IV acute GvHD was 22% ± 8.7%. No case of visceral or chronic GvHD was seen. Cumulative incidences of graft failure, cytomegalovirus, and/or adenoviral infections and transplant-related mortality at 1 year were 4.2% ± 4.1%, 58.8% ± 9.8%, and 16.1% ± 7.4%, respectively. Patients undergoing transplantation with systemic viral infections had poor survival in comparison with those with absent or resolved infections (33.3% vs 100%).
CD3+TCRαβ+ and CD19+ cell–depleted haploidentical or mMUD HSCT is a practical and viable alternative for children with a range of PIDs.
Abstract BACKGROUND Medulloblastoma (MB) is the most common malignant paediatric brain tumour, with 5-year survival rates >70%. Survivors frequently suffer a wide-range of late-effects due to their ...tumour and its treatment. Cranial radiotherapy (CRT) to the whole-brain, with posterior fossa boost (PFB), underpins treatment for non-infants, however, radiotherapeutic insult to normal brain tissue has deleterious consequences to neurocognitive and physical functioning, and causes accelerated ageing/frailty. Unfortunately, approaches to ameliorate radiotherapy-induced late-effects are lacking and a paucity of appropriate model systems hinders their development. METHODS We have developed a clinically-relevant in vivo model system that recapitulates the radiotherapy dose, delivery and late-effect profile of childhood medulloblastoma, at an equivalent developmental stage. Consistent with human regimens, age-equivalent (postnatal days 28-37) C57Bl/6J mice received targeted, CT image-guided, CRT (human-equivalent 38 Gy, n=12) or CRT with PFB (human-equivalent 49 Gy, n=12), via the small animal radiation research platform (SARRP) and were longitudinally assessed for over a year. Late-effects were compared to a sham-irradiated group (n=12). RESULTS CRT was well tolerated, independent of PFB receipt, and no mice suffered severe acute toxicity. Mice were significantly more frail following irradiation (frailty index; p=0.0002) and had reduced physical functioning; time to fall from a rotating rod and grip strength were significantly lower (rotarod; p=0.026 and grip strength; p=0.006, respectively). Neurocognitive deficits were consistent with those observed in childhood MB survivors; irradiated mice displayed significantly worse working memory (Y-maze; p=0.009) and exhibited spatial memory deficits (Barnes maze; p=0.029). Receipt of PFB did not induce a more severe late-effect profile. CONCLUSION We conclude that our in vivo model of childhood MB radiotherapy recapitulates the late-effect profile of MB survivors. Our clinically-relevant model will facilitate both the elucidation of novel/target mechanisms underpinning MB late-effects and the development of novel interventions for their amelioration.
Proline-serine-threonine phosphatase-interacting protein 1–associated myeloid-related proteinemia inflammatory (PAMI) syndrome is a novel genetic disorder, causing hypercalprotectinemia and ...hyperzincemia with inflammatory complications accompanied by cytopenia. Immunosuppressive and/or anticytokine therapy is of limited effect.
Because of cytokine production in nonhematopoietic tissues, the potential therapeutic effect of allogeneic hematopoietic stem cell transplantation (HSCT) in autoinflammatory disorders, including PAMI syndrome, has remained uncertain.
Five patients with PAMI syndrome underwent allogeneic HSCT with myeloablative (4) or reduced-intensity (1) conditioning regimens. Lack of PAMI disease control served as indication for the HSCT in 4 patients and myelodysplastic syndrome development in 1.
All 5 patients engrafted; however, 1 patient at day +13 developed hemophagocytic syndrome, followed by graft rejection at day +17. After 5.5 months, a second HSCT was performed from an alternative donor. A further patient at day +116 developed an intense inflammatory syndrome with significant serositis and severe mitral and aortic valve regurgitation, controlled with adalimumab, tacrolimus, and prednisone. No other noninfectious inflammatory episodes, or acute or chronic graft-versus-host disease, occurred in any patient. At the last follow-up (median, 2.2 years), all 5 patients have predominantly or complete donor chimerism and adequate immune recovery and are free of any PAMI symptoms.
Allogeneic HSCT seems to be an effective option to cure cytopenia and severe autoinflammation in PAMI syndrome and may be a curative option for other proline-serine-threonine phosphatase-interacting protein 1–associated inflammatory disorders with poor therapeutic control.
Renal and Hepatic Health After Childhood Cancer Ehrhardt, Matthew J; Skinner, Roderick; Castellino, Sharon M
The Pediatric clinics of North America,
12/2020, Letnik:
67, Številka:
6
Journal Article
Recenzirano
Childhood cancer survivors (CCSs) are at risk for renal and hepatic complications related to curative cancer treatments. Although acute renal and hepatic toxicities of cancer treatments are well ...described, data regarding long-term and late-occurring sequelae or their associations with acute sequelae are less robust. This article highlights the literature on the prevalence of and risk factors for late renal and hepatic toxicity in CCSs. Studies investigating these outcomes are needed to inform surveillance practices and the development of future frontline cancer treatment protocols.
CONTEXT Survivors of childhood cancer are at increased risk of premature mortality compared with the general population, but little is known about the long-term risks of specific causes of death, ...particularly beyond 25 years from diagnosis at ages when background mortality in the general population starts to increase substantially. OBJECTIVE To investigate long-term cause-specific mortality among 5-year survivors of childhood cancer in a large-scale population-based cohort. DESIGN, SETTING, AND PATIENTS British Childhood Cancer Survivor Study, a population-based cohort of 17 981 5-year survivors of childhood cancer diagnosed with cancer before age 15 years between 1940 and 1991 in Britain and followed up until the end of 2006. MAIN OUTCOME MEASURES Cause-specific standardized mortality ratios (SMRs) and absolute excess risks (AERs). RESULTS Overall, 3049 deaths were observed, which was 11 times the number expected (SMR, 10.7; 95% confidence interval CI, 10.3-11.1). The SMR declined with follow-up but was still 3-fold higher than expected (95% CI, 2.5-3.9) 45 years from diagnosis. The AER for deaths from recurrence declined from 97 extra deaths (95% CI, 92-101) per 10 000 person-years at 5 to 14 years from diagnosis, to 8 extra deaths (95% CI, 3-22) beyond 45 years from diagnosis. In contrast, during the same periods of follow-up, the AER for deaths from second primary cancers and circulatory causes increased from 8 extra deaths (95% CI, 7-10) and 2 extra deaths (95% CI, 2-3) to 58 extra deaths (95% CI, 38-90) and 29 extra deaths (95% CI, 16-56), respectively. Beyond 45 years from diagnosis, recurrence accounted for 7% of the excess number of deaths observed while second primary cancers and circulatory deaths together accounted for 77%. CONCLUSION Among a cohort of British survivors of childhood cancer, excess mortality from second primary cancers and circulatory diseases continued to occur beyond 25 years from diagnosis.
Female survivors of childhood, adolescent, and young adult (CAYA) cancer who were treated with alkylating agents and/or radiation, with potential exposure of the ovaries, have an increased risk of ...premature ovarian insufficiency (POI). Clinical practice guidelines can facilitate these survivors' access to optimal treatment of late effects that may improve health and quality of survival; however, surveillance recommendations vary among the existing long-term follow-up guidelines, which impedes the implementation of screening.
The present guideline was developed by using an evidence-based approach and summarizes harmonized POI surveillance recommendations for female survivors of CAYA cancer who were diagnosed at age < 25 years. The recommendations were formulated by an international multidisciplinary panel and graded according to the strength of the evidence and the potential benefit gained from early detection and intervention. The harmonized POI surveillance recommendations were developed by using a transparent process and are intended to facilitate care for survivors of CAYA cancer.
The harmonized set of POI surveillance recommendations is intended to be scientifically rigorous, to positively influence health outcomes, and to facilitate the care for female survivors of CAYA cancer.
Physical activity (PA) is recommended for childhood cancer survivors (CCSs). However, many CCSs have low levels of activity. This review aimed to systematically identify, appraise and synthesise ...qualitative research evidence on the barriers and facilitators to PA from the perspective of CCSs. Six databases (MEDLINE, Embase, PsycINFO, CINAHL, SPORTDiscus, and Scopus) were searched to identify qualitative data on PA gathered from CCSs diagnosed ≤18 years of age and who had completed active treatment. An inductive thematic synthesis was undertaken to identify descriptive themes relating to barriers and facilitators to PA, before mapping these onto the Theoretical Domains Framework (TDF). Methodological quality was assessed using CASP, and confidence in review findings was assessed using the GRADE-CERQual approach. Eight original studies were eligible. A total of 45 descriptive themes (29 facilitators and 16 barriers) were mapped onto nine domains of the TDF; they were most commonly mapped onto the Environmental Context and Resources (n = 13 descriptive themes) and the Social Influences (n = 13) domains. Study quality was variable and overall confidence in review findings was low. Conclusive/strong evidence for the barriers and facilitators to PA is lacking, highlighting the need for further research on the perceived influences on PA in CCSs. PROSPERO Registration: CRD42019147829.
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