Mitochondrial DNA Fragmentation and Risk of Non-Hodgkin Lymphoma.

Importance: Research suggests that increased mitochondrial DNA copy number (mtDNAcn) is associated with increased risk of non-Hodgkin lymphoma (NHL); however, no studies to date have evaluated whether the mitochondrial DNA fraction with breaks (mtDNAfb) is associated with risk of NHL. Objective: To evaluate the association of mtDNAfb with NHL risk. Design, Setting, and Participants: This nested case-control study, which used prospectively collected samples as part of baseline enrollment (from 1985 through 1988) of 29 133 men who smoked for the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study conducted in southwest Finland, included 107 incident NHL cases and 107 controls (matched on date of birth ±5 years). Analyses were conducted from January to September 2022. Exposure: High-throughput real-time polymerase chain reaction assays quantifying mtDNAfb. Main Outcomes and Measures: Incident NHL cases were identified in the ATBC Study through April 30, 2002, using the Finnish Cancer Registry and the Register of Causes of Death. The mtDNAfb was quantified and categorized based on the median, tertile, and quartile distributions among controls. Odds ratios (ORs) and 95% CIs were estimated using conditional logistic regression models to assess the associations between categorized mtDNAfb and future risk of NHL, controlling for age, body mass index, number of cigarettes smoked per day, number of pack-years, and mtDNAcn. Results: A total of 29 133 men (median [IQR] age, 57.2 [52.6-62.5] years) participated in ATBC Study. Higher mtDNAfb was associated with an increased risk of NHL (median OR, 2.89; 95% CI, 1.40-5.93) in a dose-dependent manner (quartile 2 vs 1 OR, 1.24; 95% CI, 0.43-3.40; quartile 3 vs 1 OR, 3.58; 95% CI, 1.39-9.24; quartile 4 vs 1 OR, 3.42; 95% CI, 1.30- 8.99; P = .004 for trend). Conclusions and Relevance: This study's findings suggest that increased mtDNAfb is associated with an increased future risk of NHL. Additional studies are needed to confirm these findings, particularly among women and nonsmokers.

Drivers of Differential Time to Diagnosis in Pediatric ALL Tied to Race and Ethnicity.

Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy, with diagnosis preceded by symptoms that may include fever, weight loss, fatigue, bleeding, and bruising. Timely diagnosis and treatment of ALL may lead to improved outcomes and reduced morbidity from associated complications, including tumor lysis syndrome, hyperviscosity, and stroke. We performed a retrospective cohort analysis of 274 pediatric pre-B cell ALL and acute lymphoblastic lymphoma patients within Montefiore Health System to determine whether there were factors associated with time from symptom onset to diagnosis. The median time to diagnosis for all patients was 11.5 days (interquartile range: 7.8, 14.3). Those with Medicaid insurance (n=189) were diagnosed sooner than those with private/self-pay insurance (n=85) (median of 10 vs. 16 days; P =0.05). English and other language speakers experienced fewer median days from symptom onset to diagnosis date compared with Spanish speakers (11 vs. 7 vs. 14; P =0.05). Insurance status may impact the time to diagnosis to a greater degree in non-Hispanic patients, while the English language and female sex may represent a greater advantage to Hispanic patients. Insurance status and language preference may impact the time to diagnosis of pediatric ALL. There is a further need to confirm our findings and to study possible causes driving these disparities.

Impact of race/ethnicity and language preferences on pediatric ALL survival outcomes.

BACKGROUND: Ethnic and racial disparities have recently been observed both in treatment-related toxicities and rates of long-lasting cure in acute lymphoblastic leukemia (ALL) and acute lymphoblastic lymphoma (ALLy), the most common pediatric malignancy. Despite significant improvements in overall survival in the recent past, a large number of children die from aggressive disease. METHODS: We performed a retrospective cohort analysis of 274 pediatric ALL/ALLy patients within Montefiore Health System from 2004 to 2021 to determine differences in all-cause mortality within the Pediatric Hematologic Malignancies Cohort using Cox Proportional Hazard regression modeling, adjusted for age at diagnosis, race/ethnicity, administration of intensive chemotherapy, preferred language, maximum glucose, and hypertension. RESULTS: Among our 274 patients, 132 were Hispanic, 54 Non-Hispanic Black, and 25 Non-Hispanic White, with 25 identified as "Non-Hispanic Other," including Asian, Arabic, and Other. Hispanic patients were 78% less likely to die (HR 0.22; 95% CI 0.07, 0.73) when compared with Non-Hispanic Black individuals. Spanish speakers were 2.91 times more likely to die compared with those who spoke English (HR 2.91; 95% CI 1.08, 7.82). Among those English speakers, the diagnosis of hypertension and Hispanic ethnicity significantly impacted the risk of death, while these factors did not impact survival in Spanish speakers. High-risk cytogenetics did not impact survival. CONCLUSIONS: Hispanic children with ALL/ALLy have improved survival outcomes compared with Non-Hispanic Blacks. Additionally, Spanish language preference was strongly associated with poorer survival, a novel finding that should be validated in future studies.

Targeted proteomic scan identifies alteration of serum proteins among workers occupationally exposed to low levels of trichloroethylene.

Occupational exposure to trichloroethylene (TCE) has been associated with alterations in B-cell activation factors and an increased risk of non-Hodgkin's lymphoma (NHL). Here, we aimed to examine the biological processes influenced by TCE exposure to understand the underlying molecular mechanisms. This cross-sectional molecular epidemiology study included data of 1317 targeted proteins in the serum from 42 TCE exposed and 34 unexposed factory workers in Guangdong, China. We used multivariable linear regressions to identify proteins associated with TCE exposure and examined their exposure-response relationship across categories of TCE exposure (unexposed, low exposed: <10 ppm, high exposed: ≥10 ppm). We further examined pathway enrichment of TCE-related proteins to understand their biological response. Occupational exposure to TCE was associated with lower levels of tumor necrosis factor receptor superfamily member 17 (TNFRSF17; ß = -.08; p-value = .0003) and kynureninase (KYNU; ß = -.10, p-value = .002). These proteins also showed a significant exposure-response relation across the unexposed, low exposed, and high exposed workers (all p-trends < .001, false discovery rate [FDR] < 0.20). Pathway analysis of TCE-related proteins showed significant enrichment (FDR < 0.05) for several inflammatory and immune pathways. TCE exposure was associated with TNFRSF17, a key B-cell maturation antigen that mediates B-cell survival and KYNU, an enzyme that plays a role in T-cell mediated immune response. Given that altered immunity is an established risk factor for NHL, our findings support the biological plausibility of linking TCE exposure with NHL.

Respiratory Distress: Three Patient Cases.

As mentioned in the January 2022 Pediatrics in Review Commentary, we now present three patients who have a common chief complaint followed by 5 questions for CME credit. All three cases have discussions on presentation, the differential diagnosis, and management that collectively serve as a Review article. The common theme here is that all three patients have difficulty breathing. We hope you will enjoy this review format.

The Differential Diagnosis of Vertigo in Children: A Systematic Review of 2726 Cases.

OBJECTIVES: Vertigo is a relatively common complaint in children with 5.3% of pediatric patients complaining of this symptom. Although the causes of vertigo have been well established in adults, the diagnoses in children have not been well described. The aims of this systematic review are to discover the current information regarding etiologies of vertigo in children and to determine the most common diagnoses that present with vertigo in pediatric patients. METHODS: PubMed, Scopus, and Embase were searched using the PRISMA guidelines. The inclusion and exclusion criteria were established a priori. All results were analyzed using a Bayesian methodology for point estimation and credible interval calculation. RESULTS: From the database searches, 1419 titles were reviewed. Twenty-two studies met inclusion criteria. From these studies, a total of 2726 children aged 2 months to 19 years were reported. The top 4 diagnoses associated with childhood vertigo include vestibular migraine (23.8%; credible interval, 22.3%-25.5%), benign paroxysmal vertigo of childhood (13.7%; credible interval, 12.4%-15%), idiopathic or no identified association (11.7%; credible interval, 10.5%-12.9%), and labyrinthitis/vestibular neuronitis (8.47%, credible interval, 7.46%-9.55%) accounting for approximately 57% of cases. Less common diagnoses included Meniere disease and central nervous system tumors. CONCLUSIONS: Although the most common causes of pediatric vertigo include vestibular migraine and benign paroxysmal vertigo of childhood, the etiologies are myriad. Rates and credible intervals are provided to permit a probabilistic diagnostic approach to these children.