Jason R. Axt

Wilms tumor survival in Kenya

PURPOSE Survival from Wilms Tumor (WT) exceeds 90% at 5 years in developed nations, whereas at last report, 2-year event-free survival (EFS) in Kenya reached only 35%. To clarify factors linked to these poor outcomes in Kenya, we established a comprehensive web-based WT registry, comprised of patients from the four primary hospitals treating childhood cancers. MATERIALS AND METHODS WT patients diagnosed between January 2008 and January 2012 were identified. Files were abstracted for demographic characteristics, treatment regimens, and enrollment in the Kenyan National Hospital Insurance Fund (NHIF). Children under 15 years of age having both a primary kidney tumor on imaging and concordant histology consistent with WT were included. RESULTS Two-year event-free survival (EFS) was 52.7% for all patients (n=133), although loss to follow up (LTFU) was 50%. For the 33 patients who completed all scheduled standard therapy, 2-year EFS was 94%. Patients enrolled in NHIF tended to complete more standard therapy and had a lower hazard of death (Cox 0.192, p < 0.001). CONCLUSION Survival of Kenyan WT patients has increased slightly since last report. Notably, WT patients completing all phases of standard therapy experienced 2-year survival approaching the benchmarks of developed nations. Efforts in Kenya should be made to enhance compliance with WT treatment through NHIF enrollment.

Assessing gonadal function after childhood ovarian surgery.

PURPOSE We aimed to assess the late effects of ovarian salvage or oophorectomy on gonadal function and fertility as measured by menstrual regularity. METHODS We performed a 10-year retrospective review of females aged 20 years or younger who required surgery to treat an ovarian disorder. A mail survey was distributed to these patients to evaluate the effects of ovarian surgery on menarche, menstrual regularity, and pregnancy. RESULTS A total of 180 females had surgery to treat an ovarian disorder. Eighty-six of these underwent unilateral oophorectomy (48%), whereas 94 (52%) had an ovary sparing procedure. Eighty-one patients (45%) returned completed surveys. Of the respondents, 44 had oophorectomy, and 37 had ovarian salvage. Ages of menarche were similar between surgical groups. Symptoms of menstrual irregularity differed most significantly according to painful menses (oophorectomy, 27.3%; salvage, 59.5%; P < .04). Interestingly, continuation of regular menses after surgery was higher in the oophorectomy group (oophorectomy, 70%; salvage, 15%; P = .013). CONCLUSIONS Unilateral oophorectomy does not appear to impair late gonadal function when compared with ovarian salvage. Surprisingly, oophorectomy appears to maintain more normal ovarian activity as estimated by menstrual regularity. Oophorectomy may be performed without apparent adverse effect on gonadal activity.

Race Disparities in Wilms Tumor Incidence and Biology

BACKGROUND Wilms tumor (WT) is thought to arise in children of Black African ancestry with greater frequency than in Whites. To clarify the biological basis for race disparities in WT, we first verified that Black children residing in Tennessee have an increased incidence of WT, and second, established molecular profiles in WT that are specific to race. MATERIALS AND METHODS To assess race disparities in WT epidemiology, the Tennessee Cancer Registry (TCR) was queried for all in-state patients less than 20 y of age and registered between 1999 and 2008. To explore race disparities in WT biology, six Black and four White WT specimens acquired in Tennessee were analyzed using imaging mass spectrometry (IMS). RESULTS TCR data show that Black children are over-represented among WT patients (29%) relative to all other childhood cancers (18.5%; P = 0.01). WT ranked the fifth most common cancer diagnosis among Blacks, but ninth among Whites. The diagnosis of WT occurred 79% more frequently among Blacks (n = 28) than Whites (n = 69; P = 0.01), and proportionally more Blacks tended to present with distant disease. Although overall survival from WT was not statistically different between Blacks (92.9%) and Whites (94.0%), Black males showed the lowest survival (85%; P = 0.21). IMS analysis identified peptide spectra from both WT blastema and stroma that independently classify specimens according to race with greater than 80% accuracy. CONCLUSIONS In Tennessee, Black children appear more susceptible than Whites to develop WT. Race-specific molecular profiles can be determined that may help to clarify pathways of Wilms tumorigenesis and the biological basis for race disparities in WT incidence and biology.

Race disparities in peptide profiles of North American and Kenyan Wilms tumor specimens.

BACKGROUND Wilms tumor (WT) is the most common childhood kidney cancer worldwide and arises in children of black African ancestry with greater frequency and severity than other race groups. A biologic basis for this pediatric cancer disparity has not been previously determined. We hypothesized that unique molecular fingerprints might underlie the variable incidence and distinct disease characteristics of WT observed between race groups. STUDY DESIGN To evaluate molecular disparities between WTs of different race groups, the Childrens Oncology Group provided 80 favorable histology specimens divided evenly between black and white patients and matched for disease characteristics. As a surrogate of black sub-Saharan African patients, we also analyzed 18 Kenyan WT specimens. Tissues were probed for peptide profiles using matrix-assisted laser desorption ionization time of flight imaging mass spectrometry. To control for histologic variability within and between specimens, cellular regions were analyzed separately as triphasic (containing blastema, epithelia, and stroma), blastema only, and stroma only. Data were queried using ClinProTools and statistically analyzed. RESULTS Peptide profiles, detected in triphasic WT regions, recognized race with good accuracy, which increased for blastema- or stroma-only regions. Peptide profiles from North American WTs differed between black and white race groups but were far more similar in composition than Kenyan specimens. Individual peptides were identified that also associated with WT patient and disease characteristics (eg, treatment failure and stage). Statistically significant peptide fragments were used to sequence proteins, revealing specific cellular signaling pathways and candidate drug targets. CONCLUSIONS Wilms tumor specimens arising among different race groups show unique molecular fingerprints that could explain disparate incidences and biologic behavior and that could reveal novel therapeutic targets.

Risk factors for abandonment of Wilms tumor therapy in Kenya

Survival from Wilms tumor (WT) in sub‐Saharan Africa remains dismal as a result of on‐therapy mortality and treatment abandonment. Review of patients diagnosed from 2008 to 2011 in our Kenyan Wilms Tumor Registry showed a loss to follow up (LTFU) rate approaching 50%. The purpose of this study was to trace those LTFU, estimate the survival rate, and identify risk factors for treatment abandonment.

Genetic and chromosomal alterations in Kenyan Wilms Tumor

Wilms tumor (WT) is the most common childhood kidney cancer worldwide and poses a cancer health disparity to black children of sub‐Saharan African ancestry. Although overall survival from WT at 5 years exceeds 90% in developed countries, this pediatric cancer is alarmingly lethal in sub‐Saharan Africa and specifically in Kenya (36% survival at 2 years). Although multiple barriers to adequate WT therapy contribute to this dismal outcome, we hypothesized that a uniquely aggressive and treatment‐resistant biology compromises survival further. To explore the biologic composition of Kenyan WT (KWT), we completed a next generation sequencing analysis targeting 10 WT‐associated genes and evaluated whole‐genome copy number variation. The study cohort was comprised of 44 KWT patients and their specimens. Fourteen children are confirmed dead at 2 years and 11 remain lost to follow‐up despite multiple tracing attempts. TP53 was mutated most commonly in 11 KWT specimens (25%), CTNNB1 in 10 (23%), MYCN in 8 (18%), AMER1 in 5 (11%), WT1 and TOP2A in 4 (9%), and IGF2 in 3 (7%). Loss of heterozygosity (LOH) at 17p, which covers TP53, was detected in 18% of specimens examined. Copy number gain at 1q, a poor prognostic indicator of WT biology in developed countries, was detected in 32% of KWT analyzed, and 89% of these children are deceased. Similarly, LOH at 11q was detected in 32% of KWT, and 80% of these patients are deceased. From this genomic analysis, KWT biology appears uniquely aggressive and treatment‐resistant.

Castleman disease in a pediatric liver transplant recipient: A case report and literature review

Bonatti HJR, Axt J, Hunter EB, Lott SL, Frangoul H, Gillis L, Correa H, Kelly B. Castleman disease in a pediatric liver transplant recipient: A case report and literature review. 
Pediatr Transplantation 2011.