Evaluation of Pathway to Diagnosis of Pediatric Brain Tumors in Tamil Nadu, India.

PURPOSE: Delayed diagnosis and poor awareness are significant barriers to the early intervention of pediatric brain tumors. This multicenter observational study aimed to evaluate the baseline routes and time to diagnosis for pediatric brain tumors in Tamil Nadu (TN), with the goal of promoting early diagnosis and timely referrals in the future. METHODS: A standard proforma was used to retrospectively collect information on demographics, diagnosis, referral pathways, and symptoms of incident pediatric brain tumor cases between January 2018 and October 2020 across eight tertiary hospitals in TN. Dates of symptom onset, first presentation of health care, and diagnosis were used to calculate total diagnostic interval (TDI), patient interval (PI), and diagnostic interval (DI). RESULTS: A total of 144 cases (mean age, 6.64 years; range, 0-15.1 years) were included in the analysis. Among those, 94% (135/144) were from city/district areas, 40% (55/144) were self-referred, and 90% (129/144) had one to three health care professional visits before diagnosis. Median TDI, PI, and DI were 3.5 (IQR, 1-9.3), 0.6 (IQR, 0.1-4.6), and 0.6 (IQR, 0-3.3) weeks, respectively. Low-grade gliomas had the longest median TDI (6.6 weeks), followed by medulloblastomas (4.6 weeks) and high-grade gliomas (3.3 weeks). Average number of symptoms recorded was 1.7 at symptom onset and 1.9 at diagnosis. CONCLUSION: Although there are some similarities with data from the United Kingdom, many low-grade and optic pathway tumors were unaccounted for in our study. DIs were relatively short, which suggests that infrastructure may not be a problem in this cohort. Increased training and establishment of proper cancer registries, combined with proper referral pathways, could enhance early diagnosis for these children.

Challenges in long-term control of hypercalcaemia with denosumab after haematopoietic stem cell transplantation for TNFRSF11A osteoclast-poor autosomal recessive osteopetrosis.

Autosomal recessive osteopetrosis (ARO) is rare, involving increased bone density due to defective osteoclast differentiation or function, with several genetic subtypes. CASE: This child with compound heterozygous novel loss-of-function TNFRSF11A pathogenic variants causing osteoclast-poor ARO underwent haematopoietic stem cell transplantation (HSCT) aged 3.1 years and experienced episodic severe hypercalcaemia over 2.5 years. She initially presented aged 8 months with craniosynostosis and visual impairment and underwent surgery; no increased bone density evident on skull imaging nor variants in genes associated with craniosynostosis identified. She was subsequently referred for investigation of poor linear growth and low alkaline phosphatase. Clinical abnormalities included asymmetric pectus carinatum, thickened anterior tibia and wrists, and markedly delayed dentition. Skeletal survey revealed generalised osteosclerosis with undertubulation. MANAGEMENT: She received haploidentical HSCT aged 3.1 years and developed hypercalcaemia (adjusted calcium 4.09mmol/L = 16.4mg/dL) Day 18 post-HSCT, unresponsive to hyperhydration and diuretics. Denosumab achieved normocalcaemia, which required 0.6mg/kg every 6 weeks long-term. The ensuing 2.75 years feature full donor engraftment, good HSCT graft function, skeletal remodelling with 2.5 years recurrent severe hypercalcaemia and nine fragility long bone fractures. CONCLUSION: This case illustrates challenges of bone and calcium management in ultrarare TNFRSF11A-related OP-ARO. Craniosynostosis was an early feature, evident pre-sclerosis in osteopetrosis. Following HSCT, restoration of osteoclast activity in the context of elevated bone mass produced severe and prolonged (2.5 years) hypercalcaemia. Denosumab was effective medium-term, but required concurrent long duration (11 months) zoledronic acid to manage recurrent hypercalcaemia. Fragility fractures brought appreciable additional morbidity in the post-HSCT phase.

Mesenchymal stromal cells for acute graft-versus-host disease: response at 1 week predicts probability of survival.

Mesenchymal stromal cells (MSCs) have been successfully used for the treatment of steroid-resistant graft-versus-host-disease (GvHD). However, the lack of early predictors of clinical responses impacts on the time at which to add further treatment and consequently the design of informative clinical trials. Here, we present the UK experience of one of the largest cohorts of GvHD patients undergoing MSC infusions so far reported. We show that clinical responses assessed as early as 1 week after MSC infusion predict patients' overall survival. In our cohort, cell dose, patients' age and type of organ involvement are crucial factors associated with clinical responses.

Incidence of Adenovirus Infection in Hematopoietic Stem Cell Transplantation Recipients: Findings from the AdVance Study.

Adenovirus (AdV) is an increasingly recognized threat to recipients of allogeneic hematopoietic stem cell transplantation (allo-HCT), particularly when infection is prolonged and unresolved. AdVance is the first multinational, multicenter study to evaluate the incidence of AdV infection in both pediatric and adult allo-HCT recipients across European transplantation centers. Medical records for patients undergoing first allo-HCT between January 2013 and September 2015 at 50 participating centers were reviewed. The cumulative incidence of AdV infection (in any sample using any assay) during the 6 months after allo-HCT was 32% (95% confidence interval [CI], 30.9% to 33.4%) among pediatric allo-HCT recipients (n = 1736) and 6% (95% CI, 4.7% to 6.4%) among adult allo-HCT recipients (n = 2540). The incidence of AdV viremia ≥1000copies/mL (a common threshold for initiation of preemptive treatment) was 14% (95% CI, 13.0% to 14.8%) in pediatric recipients and 1.5% (95% CI, 1.1% to 2.0%) in adult recipients. Baseline risk factors for developing AdV viremia ≥1000copies/mL included younger age, use of T cell depletion, and donor type other than matched related. Baseline demographic factors were broadly comparable across patients of all ages and identified by multivariate analyses. Notably, the incidence of AdV infection decreased stepwise with increasing age; younger adults (age 18 to 34 years) had a similar incidence as older pediatric patients (<18 years). This study provides a contemporary multicenter understanding of the incidence and risk factors for AdV infection following allo-HCT. Our findings may help optimize infection screening and intervention criteria, particularly for younger at-risk adults.

High transplant-related mortality associated with haematopoietic stem cell transplantation for paediatric therapy-related acute myeloid leukaemia (t-AML). A study on behalf of the United Kingdom Paediatric Blood and Bone Marrow Transplant Group.

Paediatric therapy-related acute myeloid leukaemia (t-AML) is rare and the outcome is poor. While allogeneic haematopoietic stem cell transplantation (HSCT) is generally the accepted modality of treatment, data regarding salvage chemotherapy, remission induction, conditioning regimens, transplant-related mortality and outcome is scarce. Between 2000 and2016, 36 children with t-AML were treated in seven UK paediatric HSCT centres. The most common salvage protocol for remission induction was FLAG with or without idarubicin and 28 patients were in complete morphological remission prior to BMT. Only 12 patients survived (33%). Transplant-related mortality (TRM) was the leading cause of death.

Brincidofovir is highly efficacious in controlling adenoviremia in pediatric recipients of hematopoietic cell transplant.

Cidofovir is preemptively used for controlling adenoviremia and preventing disseminated viral disease in hematopoietic cell transplant (HCT) recipients but does not lead to resolution of viremia without T-cell immune-reconstitution. The lipid-conjugated prodrug of cidofovir, brincidofovir, has improved oral bioavailability and achieves higher intracellular concentrations of active drug. We present retrospective multicenter data comparing the kinetics of viremia and toxicities following preemptive treatment with and brincidofovir in children and adolescents diagnosed with HCT-related adenoviremia. Forty-one episodes (18 = brincidofovir; 23 = cidofovir) of antiviral therapy were observed in 27 patients. The 2 groups had comparable immune-reconstitution and viral burden. Major (≥2 log-reduction in 2 weeks; n = 13) and minor (≥1 to ≤2 log-reduction in 2 weeks; n = 2) virological responses were observed in 15 (83%) brincidofovir episodes compared to only 2 (9%) major virological responses with cidofovir (P < .0001). Brincidofovir mediated major responses in 9 of 11 cidofovir-unresponsive patients and resulted in complete responses (CR) despite significant lymphopenia (Brincidofovir vs cidofovir; CR = 13 (80%) vs 8 (35%); median lymphocyte count = 320/µl vs 910/µl; P < .05). One patient experienced abdominal cramps and diarrhea necessitating interruption of brincidofovir and none developed nephrotoxicity with brincidofovir. Thus, brincidofovir is well-tolerated and highly efficacious in controlling adenoviremia during the lymphopenic phase of HCT.

Survival and long-term outcomes in children with hepatoblastoma treated with continuous infusion of cisplatin and doxorubicin.

Despite high survival rates, many survivors of hepatoblastoma develop late effects including ototoxicity and cardiomyopathy. With the goal of minimizing long-term toxicities, our institution treated hepatoblastoma with continuous infusion of doxorubicin and cisplatinum (PLADO), rather than short infusion or bolus dosing as used in other treatment protocols. This retrospective cohort study includes consecutive patients diagnosed between 1985 and 2007. Patients were scheduled for treatment with 6 cycles of continuous infusion of PLADO with resection after the third or fourth cycle. Audiograms and echocardiograms were obtained at baseline, after every 2 chemotherapy cycles and yearly after the completion of therapy. Fifty-five patients were treated (34 localized; 21 metastatic). Fifty-one patients received at least 1 cycle of PLADO. Median follow-up was 7.0 years (range, 0.11 to 17.8 y). Event-free and overall survival for these 51 patients were 72.2% (standard error 6.3%) and 75.6% (standard error 6.2%) respectively. Of the 38 survivors treated with cisplatin who had an audiogram during follow-up, 4 (11%) demonstrated severe (Brock grade 3/4) and 13 (34%) mild (Brock grade 1/2) hearing loss. At a median of 10.0 years (range, 5.0 to 13.0 y) after therapy, 2 of 41 (5%) patients who were still alive had evidence of cardiac dysfunction. Overall, continuous infusion of PLADO therapy resulted in survival rates consistent with those observed in intergroup studies, but rates of chronic cardiac and ototoxicity did not differ sufficiently from those observed after shorter infusion of PLADO therapy to warrant the use of continuous infusions.

A rare case of peripheral T-cell lymphoma in 1-year-old child.

Peripheral T-cell lymphoma (PTCL) represents approximately 12% of lymphoid neoplasms. They are even rarer in children and represent only 1% of Non-Hodgkin's lymphoma in this age group. We report a case of PTCL in a 1-year-old female child for its rarity.

Splenic hamartoma in a child in the era of PET-CT.

We present a case of a healthy 7-year-old female with an incidental finding of a growing splenic lesion, diagnosed as a splenic hamartoma after splenectomy. This case highlights the diagnostic challenge of splenic lesions and that the role of positron emission tomography/computerized tomography (PET/CT) in defining splenic lesions in the pediatric population remains to be defined.

Improved outcome from invasive adenovirus infection in pediatric patients after hemopoietic stem cell transplantation using intensive clinical surveillance and early intervention.

Adenovirus is a common cause of morbidity and mortality after hemopoietic stem cell transplantation in children. Recently the incidence, risk factors, and outcome of such infections have been better defined using improved virologic detection methods, in particular polymerase chain reaction. We have introduced intensive virologic surveillance for adenovirus in our institution including at least weekly polymerase chain reaction testing of blood and stool samples. We report on 71 prospectively monitored transplants, including 40 from unrelated donors. In total, there were 8 cases of invasive adenovirus infection, 3 of whom died. Mortality was less than in previous studies as cases were managed with antiviral chemotherapy and reduction of immune suppression. In fatal cases, there was concurrent difficult graft versus host disease making withdrawal of immune suppression therapy impossible. We describe 2 cases of graft failure in association with adenovirus viremia and its treatment that were successfully managed with further donor cell infusion.