Abstract Background With changing weaponry associated with injuries in civilian trauma, there is no clinical census on the utility of presacral drainage (PSD) in penetrating rectal injuries (PRIs), ...particularly in pediatric patients. Methods Patients with PRI from July 2004-June 2014 treated at two free-standing children's hospitals and two adult level 1 trauma centers were compared by age (pediatric patients ≤16 years) and PSD. A stratified analysis was performed based on age. The primary outcome was pelvic/presacral abscess. Results We identified 81 patients with PRI; 19 pediatric, 62 adult. Forty patients had PSD; only three pediatric patients had a drain. Adult patients were more likely to have sustained gunshot wounds (84%), whereas pediatric patients were more likely to sustain impalement injuries (59%). Pediatric patients were more likely to have distal extraperitoneal injuries (56% versus 27% in adults, P = 0.03). PSD was more common in adult patients (59% versus 14%, P = 0.0004), African-Americans (71% versus 11% Caucasian, P < 0.01), and those sustaining GSWs (63% versus 18% impalement, P < 0.01); only race remained significant in stratified analysis for both adult and pediatric patients. There were three cases of pelvic/presacral abscess, all in the adult patients ( P = 0.31); one patient with PSD and two without PSD ( P = 0.58). In stratified analysis, there were no differences in any infectious complication between those with and without PSD. Conclusions Pelvic/presacral abscess is a rare complication of PRI, especially in pediatric patients. PSD is not associated with decreased rates of infectious complications and may not be necessary in the treatment of PRI.
Osteosarcoma, the most common malignant bone tumor in children and adolescents, occurs in a high number of cancer predisposition syndromes that are defined by highly penetrant germline mutations. The ...germline genetic susceptibility to osteosarcoma outside of familial cancer syndromes remains unclear.
To investigate the germline genetic architecture of 1244 patients with osteosarcoma.
Whole-exome sequencing (n = 1104) or targeted sequencing (n = 140) of the DNA of 1244 patients with osteosarcoma from 10 participating international centers or studies was conducted from April 21, 2014, to September 1, 2017. The results were compared with the DNA of 1062 individuals without cancer assembled internally from 4 participating studies who underwent comparable whole-exome sequencing and 27 173 individuals of non-Finnish European ancestry who were identified through the Exome Aggregation Consortium (ExAC) database. In the analysis, 238 high-interest cancer-susceptibility genes were assessed followed by testing of the mutational burden across 736 additional candidate genes. Principal component analyses were used to identify 732 European patients with osteosarcoma and 994 European individuals without cancer, with outliers removed for patient-control group comparisons. Patients were subsequently compared with individuals in the ExAC group. All data were analyzed from June 1, 2017, to July 1, 2019.
The frequency of rare pathogenic or likely pathogenic genetic variants.
Among 1244 patients with osteosarcoma (mean SD age at diagnosis, 16 8.9 years range, 2-80 years; 684 patients 55.0% were male), an analysis restricted to individuals with European ancestry indicated a significantly higher pathogenic or likely pathogenic variant burden in 238 high-interest cancer-susceptibility genes among patients with osteosarcoma compared with the control group (732 vs 994, respectively; P = 1.3 × 10-18). A pathogenic or likely pathogenic cancer-susceptibility gene variant was identified in 281 of 1004 patients with osteosarcoma (28.0%), of which nearly three-quarters had a variant that mapped to an autosomal-dominant gene or a known osteosarcoma-associated cancer predisposition syndrome gene. The frequency of a pathogenic or likely pathogenic cancer-susceptibility gene variant was 128 of 1062 individuals (12.1%) in the control group and 2527 of 27 173 individuals (9.3%) in the ExAC group. A higher than expected frequency of pathogenic or likely pathogenic variants was observed in genes not previously linked to osteosarcoma (eg, CDKN2A, MEN1, VHL, POT1, APC, MSH2, and ATRX) and in the Li-Fraumeni syndrome-associated gene, TP53.
In this study, approximately one-fourth of patients with osteosarcoma unselected for family history had a highly penetrant germline mutation requiring additional follow-up analysis and possible genetic counseling with cascade testing.
Abstract Objective Methotrexate (MTX) alternating with folinic acid is a commonly used treatment regimen for low-risk gestational trophoblastic neoplasia (GTN). In The Netherlands, two courses of MTX ...are administered after normalization of serum human chorionic gonadotrophin (hCG) levels (consolidation courses), whereas in the United Kingdom, three consolidation courses are given. In a retrospective setting we compared relapse rates of women completing MTX therapy for low-risk GTN in The Netherlands and the UK. Methods From 1980 to 2008, 351 patients were collected from the Dutch Central Registry for Hydatidiform Moles and records from the Dutch Working Party on Trophoblastic Disease. From the Charing Cross Hospital Trophoblast Disease Centre (London), 600 low-risk GTN patients were identified from 1992 to 2008. Results In 4.0% of patients relapse occurred after MTX treatment with three consolidation courses, whereas 8.3% of patients relapsed after MTX treatment with two consolidation courses (p = 0.006). Although patients from The Netherlands had a higher level of hCG (p < 0.001) and more patients had metastases before the start of treatment (p = 0.012), the number of courses of MTX to achieve a normal hCG did not differ significantly between patients from The Netherlands and the UK (p = 0.375). Conclusions Relapse rates were higher in patients treated with two consolidation courses of MTX. Although other factors might have influenced the observed difference in relapse rates, three courses of consolidation chemotherapy may be preferable to two in the treatment of low-risk GTN in order to decrease the risk of disease relapse. A prospective randomized study would be required to confirm these findings.
Li-Fraumeni syndrome (LFS) is a rare hereditary cancer syndrome associated with an autosomal-dominant mutation inheritance in the
tumor suppressor gene and a wide spectrum of cancer diagnoses. The ...previously developed R package, LFSPRO, is capable of estimating the risk of an individual being a
mutation carrier. However, an accurate estimation of the penetrance of different cancer types in LFS is crucial to improve the clinical characterization and management of high-risk individuals. Here, we developed a competing risk-based statistical model that incorporates the pedigree structure efficiently into the penetrance estimation and corrects for ascertainment bias while also increasing the effective sample size of this rare population. This enabled successful estimation of
penetrance for three LFS cancer types: breast (BR), sarcoma (SA), and others (OT), from 186 pediatric sarcoma families collected at MD Anderson Cancer Center (Houston, TX). Penetrance validation was performed on a combined dataset of two clinically ascertained family cohorts with cancer to overcome internal bias in each (total number of families = 668). The age-dependent onset probability distributions of specific cancer types were different. For breast cancer, the
penetrance went up at an earlier age than the reported
penetrance. The prediction performance of the penetrance estimates was validated by the combined independent cohorts (BR = 85, SA = 540, and OT = 158). Area under the ROC curves (AUC) were 0.92 (BR), 0.75 (SA), and 0.81 (OT). The new penetrance estimates have been incorporated into the current LFSPRO R package to provide risk estimates for the diagnosis of breast cancer, sarcoma, or other cancers. SIGNIFICANCE: These findings provide specific penetrance estimates for LFS-associated cancers, which will likely impact the management of families at high risk of LFS.
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Survival rates for osteosarcoma, the most common primary bone cancer, have changed little over the past three decades and are particularly low for patients with metastatic disease. We conducted a ...multi‐institutional genome‐wide association study (GWAS) to identify germline genetic variants associated with overall survival in 632 patients with osteosarcoma, including 523 patients of European ancestry and 109 from Brazil. We conducted a time‐to‐event analysis and estimated hazard ratios (HR) and 95% confidence intervals (CI) using Cox proportional hazards models, with and without adjustment for metastatic disease. The results were combined across the European and Brazilian case sets using a random‐effects meta‐analysis. The strongest association after meta‐analysis was for rs3765555 at 9p24.1, which was inversely associated with overall survival (HR = 1.76; 95% CI 1.41–2.18, p = 4.84 × 10−7). After imputation across this region, the combined analysis identified two SNPs that reached genome‐wide significance. The strongest single association was with rs55933544 (HR = 1.9; 95% CI 1.5–2.4; p = 1.3 × 10−8), which localizes to the GLDC gene, adjacent to the IL33 gene and was consistent across both the European and Brazilian case sets. Using publicly available data, the risk allele was associated with lower expression of IL33 and low expression of IL33 was associated with poor survival in an independent set of patients with osteosarcoma. In conclusion, we have identified the GLDC/IL33 locus on chromosome 9p24.1 as associated with overall survival in patients with osteosarcoma. Further studies are needed to confirm this association and shed light on the biological underpinnings of this susceptibility locus.
What's new?
To date, prognostic factors associated with survival in patients with osteosarcoma are scarce. Here, the authors conducted a multi‐institutional genome‐wide association study to explore whether germline genetics may contribute to overall survival in osteosarcoma patients. They identified a common single nucleotide polymorphism, rs55933544, located in the GLDC gene on chromosome 9, associated with poor survival. The rs55933544 risk allele was associated with lower expression of the nearby gene, IL33. These findings, if replicated in additional populations, form the foundation for future studies of the molecular basis of the association of the GLDC/IL33 (rs55933544) variant with survival in osteosarcoma.
Several studies have linked increased risk of osteosarcoma with tall stature, high birthweight, and early puberty, although evidence is inconsistent. We used genetic risk scores (GRS) based on ...established genetic loci for these traits and evaluated associations between genetically inferred birthweight, height, and puberty timing with osteosarcoma.
Using genotype data from two genome-wide association studies, totaling 1,039 cases and 2,923 controls of European ancestry, association analyses were conducted using logistic regression for each study and meta-analyzed to estimate pooled odds ratios (ORs) and 95% confidence intervals (CIs). Subgroup analyses were conducted by case diagnosis age, metastasis status, tumor location, tumor histology, and presence of a known pathogenic variant in a cancer susceptibility gene.
Genetically inferred higher birthweight was associated with an increased risk of osteosarcoma (OR =1.59, 95% CI 1.07-2.38, P=0.023). This association was strongest in cases without metastatic disease (OR =2.46, 95% CI 1.44-4.19, P=9.5×10-04). Although there was no overall association between osteosarcoma and genetically inferred taller stature (OR=1.06, 95% CI 0.96-1.17, P=0.28), the GRS for taller stature was associated with an increased risk of osteosarcoma in cases with a known pathogenic cancer susceptibility gene variant (OR=1.29, 95% CI 1.03-1.63, P=0.031). There were no significant associations between the GRS for puberty timing and osteosarcoma.
A genetic propensity to higher birthweight was associated with increased osteosarcoma risk, suggesting that shared genetic factors or biological pathways that affect birthweight may contribute to osteosarcoma pathogenesis.
•Through a large international collaboration, our study is the first investigation of osteosarcoma risk and genetically inferred birthweight and puberty timing and the largest evaluation of osteosarcoma and genetically inferred height, to date.•We identified a genetic propensity to higher birthweight was associated with increased osteosarcoma risk, suggesting that shared genetic factors or biological pathways that affect birthweight may contribute to osteosarcoma pathogenesis.
Li-Fraumeni syndrome (LFS) is associated with germline
mutations and a very high lifetime cancer risk. Algorithms that assess a patient's risk of inherited cancer predisposition are often used in ...clinical counseling. The existing LFS criteria have limitations, suggesting the need for an advanced prediction tool to support clinical decision making for
mutation testing and LFS management.
Based on a Mendelian model, LFSPRO estimates
mutation probability through the Elston-Stewart algorithm and consequently estimates future risk of cancer. With independent datasets of 1,353 tested individuals from 867 families, we evaluated the prediction performance of LFSPRO.
LFSPRO accurately predicted
mutation carriers in a pediatric sarcoma cohort from MD Anderson Cancer Center in the United States, the observed to expected ratio (OE) = 1.35 (95% confidence interval, 0.99-1.80); area under the receiver operating characteristic curve (AUC) = 0.85 (0.75-0.93); a population-based sarcoma cohort from the International Sarcoma Kindred Study in Australia, OE = 1.62 (1.03-2.55); AUC = 0.67 (0.54-0.79); and the NCI LFS study cohort, OE = 1.28 (1.17-1.39); AUC = 0.82 (0.78-0.86). LFSPRO also showed higher sensitivity and specificity than the classic LFS and Chompret criteria. LFSPRO is freely available through the R packages LFSPRO and BayesMendel.
LFSPRO shows good performance in predicting
mutations in individuals and families in varied situations.
LFSPRO is more broadly applicable than the current clinical criteria and may improve clinical management for individuals and families with LFS.
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Granular cell tumors (GCTs) are generally benign neoplastic tumors of neural origin that have little malignant potential. These tumors may occur in any location, including the tracheobronchial tree. ...Although an endobronchial location is believed to represent a small percentage of cases, GCTs should be included in the differential considerations of any endobronchial lesions leading to airway collapse.
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