Increased risk of subsequent neoplasm after hematopoietic stem cell transplantation in 5-year survivors of childhood acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) survivors are at risk for developing subsequent neoplasms, but there is limited information on long-term risks and risk factors for both subsequent malignant neoplasms (SMNs) and subsequent non-malignant neoplasms (SNMNs). We analyzed long-term risk and risk factors for SMNs and SNMNs among 3291 5-year ALL survivors from the Dutch Childhood Cancer Survivor Study-LATER cohort (1963-2014). We calculated standardized incidence ratios (SIRs) and cumulative incidences and used multivariable Cox proportional hazard regression analyses for analyzing risk factors. A total of 97 survivors developed SMNs and 266 SNMNs. The 30-year cumulative incidence was 4.1% (95%CI: 3.5-5.3) for SMNs and 10.4%(95%CI: 8.9-12.1) for SNMNs. Risk of SMNs was elevated compared to the general population (SIR: 2.6, 95%CI: 2.1-3.1). Survivors treated with hematopoietic stem cell transplantation (HSCT) with total body irradiation (TBI) (HR:4.2, 95%CI: 2.3-7.9), and without TBI (HR:4.0,95%CI: 1.2-13.7) showed increased SMN risk versus non-transplanted survivors. Cranial radiotherapy (CRT) was also a risk factor for SMNs (HR:2.1, 95%CI: 1.4-4.0). In conclusion, childhood ALL survivors have an increased SMN risk, especially after HSCT and CRT. A key finding is that even HSCT-treated survivors without TBI treatment showed an increased SMN risk, possibly due to accompanied chemotherapy treatment. This emphasizes the need for careful follow-up of HSCT and/or CRT-treated survivors.

Neuroblastoma survivors at risk for developing subsequent neoplasms: A systematic review.

Neuroblastoma survivors have an increased risk of unfavorable long-term health outcomes, of which developing subsequent neoplasms is one of the most serious. We aimed to provide an overview of the current knowledge on the risk of subsequent neoplasms in neuroblastoma survivors. We conducted a systematic literature search in Medline/Pubmed (01-01-1945-13-01-2022) to identify studies that reported on ≥ 100 neuroblastoma survivors and assessed subsequent neoplasms as an outcome. We identified 410 potentially eligible articles, of which we eventually included 13 reports. All articles described retrospective cohorts with sizes varying from 145 to 5,987 neuroblastoma survivors. Within these cohorts 0.7% - 17.2% of the survivors developed a subsequent neoplasm. A wide variety of types of subsequent malignant and non-malignant neoplasms were observed, of which thyroid carcinoma and acute myeloid leukemia were most frequently reported. The risk of developing a subsequent neoplasm was 2.8 to 10.4 times higher in neuroblastoma survivors than in the general population. Although no statistically significant risk factors for subsequent neoplasms were observed in multivariable analyses, high-risk group survivors, women and those treated with radiotherapy seemed to have a higher risk. In conclusion, the studies in this systematic review consistently show that neuroblastoma survivors are at elevated risk of developing subsequent neoplasms. Future research should further explore risk factors for subsequent neoplasms in neuroblastoma survivors, so future treatment protocols and follow-up care can be improved.

Damage in the Thalamocortical Tracts is Associated With Subsequent Thalamus Atrophy in Early Multiple Sclerosis.

Background: In early multiple sclerosis (MS), thalamus atrophy and decreased integrity of the thalamocortical white matter (WM) tracts have been observed. Objective: To investigate the temporal association between thalamus volume and WM damage in the thalamocortical tract in subjects with early MS. Methods: At two time points, 72 subjects with early MS underwent T1, FLAIR and diffusion tensor imaging. Thalamocortical tracts were identified with probabilistic tractography using left and right thalamus as seed regions. Regression analysis was performed to identify predictors of annual percentage change in both thalamus volumes and integrity of the connected tracts. Results: Significant atrophy was seen in left and right thalamus (p < 0.001) over the follow-up period (13.7 ± 4.8 months), whereas fractional anisotropy (FA) and mean diffusivity (MD) changes of the left and right thalamus tracts were not significant, although large inter-subject variability was seen. Annual percentage change in left thalamus volume was significantly predicted by baseline FA of the left thalamus tracts F (1.71) = 4.284, p = 0.042; while no such relation was found for the right thalamus. Annual percentage change in FA or MD of the thalamus tracts was not predicted by thalamus volume or any of the demographic parameters. Conclusion: Over a short follow-up time, thalamus atrophy could be predicted by decreased integrity of the thalamic tracts, but changes in the integrity of the thalamic tracts could not be predicted by thalamus volume. This is the first study showing directionality in the association between thalamus atrophy and connected WM tract damage. These results need to be verified over longer follow-up periods.

Metachromatic leukodystrophy and transplantation: remyelination, no cross-correction.

OBJECTIVE: In metachromatic leukodystrophy, a lysosomal storage disorder due to decreased arylsulfatase A activity, hematopoietic stem cell transplantation may stop brain demyelination and allow remyelination, thereby halting white matter degeneration. This is the first study to define the effects and therapeutic mechanisms of hematopoietic stem cell transplantation on brain tissue of transplanted metachromatic leukodystrophy patients. METHODS: Autopsy brain tissue was obtained from eight (two transplanted and six nontransplanted) metachromatic leukodystrophy patients, and two age-matched controls. We examined the presence of donor cells by immunohistochemistry and microscopy. In addition, we assessed myelin content, oligodendrocyte numbers, and macrophage phenotypes. An unpaired t-test, linear regression or the nonparametric Mann-Whitney U-test was performed to evaluate differences between the transplanted, nontransplanted, and control group. RESULTS: In brain tissue of transplanted patients, we found metabolically competent donor macrophages expressing arylsulfatase A distributed throughout the entire white matter. Compared to nontransplanted patients, these macrophages preferentially expressed markers of alternatively activated, anti-inflammatory cells that may support oligodendrocyte survival and differentiation. Additionally, transplanted patients showed higher numbers of oligodendrocytes and evidence for remyelination. Contrary to the current hypothesis on therapeutic mechanism of hematopoietic cell transplantation in metachromatic leukodystrophy, we detected no enzymatic cross-correction to resident astrocytes and oligodendrocytes. INTERPRETATION: In conclusion, donor macrophages are able to digest accumulated sulfatides and may play a neuroprotective role for resident oligodendrocytes, thereby enabling remyelination, albeit without evidence of cross-correction of oligo- and astroglia. These results emphasize the importance of immunomodulation in addition to the metabolic correction, which might be exploited for improved outcomes.