Infections and Acute Lymphoblastic Leukemia: Is the Sum Worth More than the Parts? Evidence from Birth Characteristics.

The etiology of childhood acute lymphoblastic leukemia (ALL) has long been studied piecemeal with investigations leading to a lengthy list of putative risk factors including several with immune modulatory effects. The ubiquity of many of these factors (e.g., daycare attendance, low parity, breastfeeding, normal vaccinations) belies the rarity of ALL as an outcome. In this commentary, Pombo-de-Oliveira and colleagues show that a key feature may be the combination of particular risk factors, as the birth characteristics "cesarean section" and "birth order" when combined interact to impart higher risk of ALL than would be suggested by the additive risk of both factors. This statistical interaction would be predicted by the "delayed infection hypothesis" wherein infant immune isolation promotes developmental vulnerability to ALL upon infection exposure later in childhood. Pombo-de-Oliveira and colleagues show further that lack of breastfeeding, a postnatal factor leading to further immune isolation, induces additional risk. In sum, the data reveal a combination of factors that together could impart a healthy "trained" immune system allowing for moderated responses to later exposures with microbial and viral antigens. Such priming of the immune system avoids maladaptive immunologic consequences of delayed antigenic stimulation leading to ALL and other diseases. Further research utilizing biomarkers of specific exposures (in addition to the proxy measures used here) will be helpful to realize the full potential for immune modification for ALL prevention. See related article by Pombo-de-Oliveira et al., p. 371.

Bayesian inference for survival prediction of childhood Leukemia.

BACKGROUND: Childhood Leukemia is the most common type of cancer among children. Nearly 39% of cancer-induced childhood deaths are attributable to Leukemia. Nevertheless, early intervention has long been underdeveloped. Moreover, there are still a group of children succumbing to their cancer due to the cancer care resource disparity. Therefore, it calls for an accurate predictive approach to improve childhood Leukemia survival and mitigate these disparities. Existing survival predictions rely on a single best model, which fails to consider model uncertainties in predictions. Prediction from a single model is brittle, with model uncertainty neglected, and inaccurate prediction could lead to serious ethical and economic consequences. METHODS: To address these challenges, we develop a Bayesian survival model to predict patient-specific survivals by taking model uncertainty into account. Specifically, we first develop a survival model predict time-varying survival probabilities. Second, we place different prior distributions over various model parameters and estimate their posterior distribution with full Bayesian inference. Third, we predict the patient-specific survival probabilities changing with respect to time by considering model uncertainty induced by posterior distribution. RESULTS: Concordance index of the proposed model is 0.93. Moreover, the standardized survival probability of the censored group is higher than that of the deceased group. CONCLUSIONS: Experimental results indicate that the proposed model is robust and accurate in predicting patient-specific survivals. It can also help clinicians track the contribution of multiple clinical attributes, thereby enabling well-informed intervention and timely medical care for childhood Leukemia.

Associations between early-life and in utero infections and cytomegalovirus-positive acute lymphoblastic leukemia in children.

Childhood infections and cytomegalovirus (CMV) are associated with pediatric acute lymphoblastic leukemia (ALL). CMV dysregulates the host immune system and alters the immune response to subsequent antigenic exposures. We suspect that this immune dysregulation contributes to increased numbers of symptomatic infections in childhood allowing for expansion of pre-leukemic clones. We explored the association between childhood infections, maternal infections during pregnancy and CMV-positive ALL. Using a droplet digital PCR assay, we screened diagnostic ALL bone marrow samples from the California Childhood Leukemia Study (1995-2015) for the presence of CMV DNA identifying CMV-positive and CMV-negative cases. We performed a case-only analysis (n = 524) comparing the number and types of childhood infections and maternal infections during pregnancy between CMV-positive and CMV-negative ALL cases using logistic regression. With increasing numbers of infections in the first 12 months of life, children were more likely to classify to the highest tertile of CMV DNA in the bone marrow at diagnosis (OR: 1.04, 95% CI: 1.01-1.08). Specifically, those reporting cough or flu in the first 12 months were more likely to be CMV-positive at ALL diagnosis (OR: 2.15, 95% CI: 1.06-4.37 and OR: 2.06, 95% CI: 1.17-3.63 respectively). Furthermore, those with a history of maternal infection during pregnancy were more likely to be CMV-positive (OR: 2.12, 95% CI: 1.24-3.62). We hypothesize that children with underlying immune dysregulation develop more symptomatic infections in childhood and ultimately CMV-positive ALL; this underlying immune dysregulation may be due to early immune system alterations via CMV exposure (in utero or early infancy) proposing a potential link between CMV and ALL etiology.

Pediatric Metastatic Hepatoblastoma With an ARID1A Mutation and Rhabdoid Cells.

The small cell undifferentiated component of hepatoblastoma is an uncommon histologic component and is distinguished from small cell undifferentiated like pattern (originally called hepatoblastoma and now recognized to be malignant rhabdoid tumor) by the bi-allelic SMARCB1 mutations or copy number alterations in the latter. AT-rich interactive domain-containing protein 1A (ARID1A) is a part of the ATP-dependent switch/sucrose non-fermentable complex assembly, but mutations have not been reported as drivers of malignant rhabdoid tumor. ARID1A mutations in hepatocellular carcinoma are associated with poor prognosis but its significance in hepatoblastoma is unknown. We report a unique case of hepatoblastoma in a 19-month-old female with an unusual/atypical small cell undifferentiated component with ARID1A and beta-catenin mutations. It had an aggressive clinical course despite treatment, with metastases to the left psoas muscle, perihepatic and paratracheal lymph nodes, spinal cord, and leptomeninges. Leptomeningeal metastases resulted in diffuse cerebral edema and death. The initial diagnostic biopsy did not reveal rhabdoid cells while all metastatic foci showed cells with rhabdoid morphology in the autopsy specimens. Although this rhabdoid component resembled malignant rhabdoid tumor morphologically, molecular analyses failed to show mutations or deletions of SMARCB1.

Tracking Scan to Incision Time in Patients with Emergent Operative Traumatic Brain Injuries as a Measure for Systems-Based Practice in Neurosurgical Trainees.

BACKGROUND: Evaluation of trainee performance remains a challenge in resident education, particularly for systems-based practice (SysBP) metrics including care coordination and interdisciplinary teamwork. Time to intervention is an important modifiable outcome variable in severe traumatic brain injury (TBI) and may serve as a trackable metric for SysBP evaluation. METHODS: We retrospectively studied time from computed tomography head scan to surgical incision (CTH-INC, minutes) among neurosurgical trainees treating patients with emergently operative TBI as a proxy SysBP measure. Our institutional operative database was utilized to identify all emergent TBI cases between July 2015 and June 2020. Patients evaluated by program year (PGY)-2 residents proceeding directly to the operating room from the emergency department were included. Statistical analysis was performed using linear regression. RESULTS: One hundred sixty-six cases triaged by 14 PGY-2 neurosurgical trainees were analyzed. Median CTH-INC was 104 minutes (interquartile range, 82-136 minutes). CTH-INC improved 20.1% over the academic year (95% confidence interval, 4.3%-33.2%, P = 0.015). Between the first and second 6-month periods, the rate of CTH-INC within 90 minutes (29% vs. 46%, P = 0.04) improved. On a per-individual PGY-2 basis, median CTH-INC ranged from 83-127 minutes, 25th percentile CTH-INC ranged from 62-108 minutes, and fastest CTH-INC ranged from 45-92 minutes. CONCLUSIONS: CTH-INC is an objective and trackable proxy measure for evaluating SysBP during neurosurgical training. Use of CTH-INC or other time metrics in resident evaluations should not supersede the safe and effective delivery of patient care.

Remote arterial vasculitis as a possible complication of Phosphorus-32 Radiosynovectomy.

Patients with hemophilia suffer from repeated episodes of hemarthrosis leading to chronic inflammation and synovitis. Radiosynovectomy is an effective nonsurgical modality that can reduce inflammation, pain, and hemarthrosis in such cases. We describe an adolescent male with severe Hemophilia A, who developed arterial vasculitis and perivasculitis targeting the brachiocephalic, right common carotid, and right subclabvian arteries occurring within few days after difficult Phosphorus-32 radiosynovectomy, possibly as a complication of the procedure. Despite prophylaxis with recombinant FVIII therapy, he developed chronic synovitis and underwent radionuclide synovectomy with P-32 injection to the left ankle and right knee. Five days later, he developed pain in the lower right neck and right upper chest. Computed tomography and magnetic resonance imaging and angiography demonstrated inflammation involving the arteries of the right thoracic inlet. Geiger-Mueller meter indicated increased radioactivity not only in the left ankle and right knee but also in the right upper chest. Detection of radioisotope at the right thoracic inlet corresponding to the area of vasculitis was indicative of likely deposition of the P-32 isotope in an area exposed to maximum cardiac output and increased blood flow, leading to subclavian, carotid, and innominate arteritis with surrounding edema.

Alien limb syndrome secondary to multimodal treatment of recurrent oligodendroglioma.

We present a 41-year-old man who experienced alien limb syndrome as a complication of treatment for recurrent Grade III oligodendroglioma of the right parietal lobe. Alien limb syndrome is a rare phenomenon in which a limb performs involuntary actions and the affected individual feels a sense of estrangement towards the limb. It occurs most commonly as a result of corticobasal syndrome, though a variety of other etiologies have been reported. It is rarely associated with focal lesions, such as stroke or tumors.