Citations

Abstract Background Appendiceal cancers represent a diverse group of malignancies with varying biological behavior. The significance of lymph node metastases in relation to long‐term survival and chemotherapy response is poorly defined. Methods The National Cancer Database was queried to find patients diagnosed with appendiceal cancer from 1998 to 2012. Kaplan–Meier curves and multivariable Cox regression analyses were used to study the association between lymph node status and overall survival. Stage IV patients were excluded. Results The rate of nodal positivity of the 9841 patients with known node status was: signet ring 47.4%, carcinoid 42.3%, nonmucinous adenocarcinoma 28.8%, goblet cell 21.9%, and mucinous adenocarcinoma 20.4%. Node‐positive patients had worse long‐term survival for all subtypes with the exception of carcinoid tumors ( p < 0.001). The strongest association was for signet cell and goblet cell. Adjuvant chemotherapy in node‐positive patients improved survival for mucinous, nonmucinous, and signet ring cell histology ( p < 0.01), but not for goblet cell. Conclusions Nodal involvement in patients with appendiceal cancer varies in incidence, association with adverse survival, and response to systemic therapy. Individualized treatment algorithms for the management of the subtypes of appendiceal cancer are needed.

Abstract Genomic classification has improved risk assignment of pediatric, but not adult B-lineage acute lymphoblastic leukemia (B-ALL). The international UKALLXII/ECOG-ACRIN E2993 (#NCT00002514) trial accrued 1229 adolescent/adult patients with BCR-ABL1− B-ALL (aged 14 to 65 years). Although 93% of patients achieved remission, 41% relapsed at a median of 13 months (range, 28 days to 12 years). Five-year overall survival (OS) was 42% (95% confidence interval, 39, 44). Transcriptome sequencing, gene expression profiling, cytogenetics, and fusion polymerase chain reaction enabled genomic subtyping of 282 patient samples, of which 264 were eligible for trial, accounting for 64.5% of E2993 patients. Among patients with outcome data, 29.5% with favorable outcomes (5-year OS 65% to 80%) were deemed standard risk (DUX4-rearranged [9.2%], ETV6-RUNX1/-like [2.3%], TCF3-PBX1 [6.9%], PAX5 P80R [4.1%], high-hyperdiploid [6.9%]); 50.2% had high-risk genotypes with 5-year OS of 0% to 27% (Ph-like [21.2%], KMT2A-AFF1 [12%], low-hypodiploid/near-haploid [14.3%], BCL2/MYC-rearranged [2.8%]); 20.3% had intermediate-risk genotypes with 5-year OS of 33% to 45% (PAX5alt [12.4%], ZNF384/-like [5.1%], MEF2D-rearranged [2.8%]). IKZF1 alterations occurred in 86% of Ph-like, and TP53 mutations in patients who were low-hypodiploid (54%) and BCL2/MYC-rearranged (33%) but were not independently associated with outcome. Of patients considered high risk based on presenting age and white blood cell count, 40% harbored subtype-defining genetic alterations associated with standard- or intermediate-risk outcomes. We identified distinct immunophenotypic features for DUX4-rearranged, PAX5 P80R, ZNF384-R/-like, and Ph-like genotypes. These data in a large adult B-ALL cohort treated with a non–risk-adapted approach on a single trial show the prognostic importance of genomic analyses, which may translate into future therapeutic benefits.

Purpose: As patients with mediastinal lymphoma are typically young with curable disease, advanced radiation techniques such as proton therapy are often considered to minimize subacute and late toxicity. However, it is unclear which mediastinal lymphoma patients are treated with proton therapy. Within a prospective, multi-institutional proton registry, we characterized mediastinal lymphoma patients treated with proton therapy and assessed concordance with consensus recommendations published in 2018 by the International Lymphoma Radiation Oncology Group (ILROG). Methods: Eligible patients included those with lymphoma of the mediastinum treated exclusively with proton therapy for whom digital imaging and communications in medicine (DICOM) treatment data were available for review. Given the challenge with reliably visualizing the left mainstem coronary artery, the inferior-most aspect of the left pulmonary artery (PA) was used as a surrogate. Extent of disease was characterized as upper mediastinum (above level of left PA), middle mediastinum (below left PA but at or above level of T8), or low mediastinum (below T8). Results: Between November 2012 and April 2019, 56 patients were treated and met inclusion criteria. Patients treated with proton therapy were young (median, 24 y; range: 12 to 88), with over half being female (55%). Patients were most commonly treated at initial diagnosis (86%) and had Hodgkin lymphoma (79%). Most patients (96%) had mediastinal disease that extended down to the level of the heart: 48% had middle and 48% had low mediastinal involvement. Nearly all patients (96%) met the ILROG consensus recommendations: 95% had lower mediastinal disease, 46% were young females, and 9% were heavily pretreated. Heart (mean) and lung dose (mean, V5, V20) were significantly associated with lowest extent of mediastinal disease. Conclusions: Mediastinal lymphoma patients treated with proton therapy are typically young with lower mediastinal involvement. Within a prospective, multi-institutional proton registry, nearly all treated patients fit the ILROG consensus recommendations regarding which mediastinal lymphoma patients may most benefit from proton therapy.

Human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2) diagnostic testing algorithms recommended by the Centers for Disease Control involve up to three tests and rely mostly on detection of viral antigen and host antibody responses. HIV-1 p24 antigen/HIV-1/HIV-2 antibody-reactive specimens are confirmed with an immunochromatographic HIV-1/HIV-2 antibody differentiation assay, and negative or indeterminate results from the differentiation assay are resolved by an HIV-1-specific nucleic acid amplification test (NAT).

Abstract Objective: Fibromuscular dysplasia (FMD) is an arteriopathy that presents mainly by hypertension, stroke or dissection. Diagnosis is often made in middle-aged women with few cardiovascular risk factors. We aim at identifying common genetic variants associated to FMD. Design and method: We tested ∼6.5 million common genetic variants (MAF > 0.01) in 1962 cases and 7100 controls from 6 studies using variants and gene-based association analyses. Participants were of European ancestry, with similar characteristics (91% multifocal, 88% women), diagnosis methods and inclusion/exclusion criteria. Transcriptome-wide association (TWAS), eQTL, gene expression by sex and colocalization analyses used expression data in arteries from GTEx and/or FMD patients and matched controls. Open chromatin regions were defined using ATAC-Seq on primary human fibroblasts, smooth muscle and endothelial cells. Genetic correlations were assessed using summary statistics from UKBiobank and/or published studies by linkage disequilibrium score regression and multi-trait-based conditional and joint analyses (mtCOJO). Results: We confirmed the previously identified PHACTR1 locus and identified three new loci (LRP1, ATP2B1, and LIMA1) associated with FMD. TWAS in arteries identified one additional locus (SLC24A3). Through integration of annotation datasets, we provided prioritization of variants and genes. These are consistently and specifically expressed in fibroblasts, smooth muscle cells, and arterial tissues. PHACTR1 and SLC24A3 showed sex differences in gene expressions consistent with the direction of effects of FMD risk alleles. FMD genes are involved in regulatory mechanisms related to actin cytoskeleton and intracellular calcium homeostasis, two mechanisms central to vascular contraction. We found significant genetic overlaps between FMD and blood pressure traits, for the associated loci and globally at the genome level, but demonstrated that hypertension is not driving the genetic association with FMD. We also found positive genetic correlations with migraine and intracranial aneurysm, and an inverse correlation with coronary artery disease, independently from the genetics of blood pressure. Conclusions: We describe robustly associated loci and genes with FMD and provide several new leads toward understanding biological mechanisms of stenosis and dissection in young women in the absence of atherosclerosis, which shares part of its genetic basis with more common cardiovascular and neurovascular diseases.

AbstractBackgroundGlutaric acidemia type I (GA1) is an organic acidemia that is often unrecognized in the newborn period until patients suffer an acute encephalopathic crisis, which can be mistaken for nonaccidental trauma. Presymptomatic identification of GA1 patients is possible by newborn screening (NBS). However, the biochemical “low‐excretor” (LE) phenotype with nearly normal levels of disease metabolites can be overlooked, which may result in untreated disease and irreversible neurological sequelae. The LE phenotype is also a potential source of false negative (FN) NBS results that merits further investigation.MethodsSamples from six LE GA1 patients were analyzed by biochemical and molecular methods and newborn screen outcomes were retrospectively investigated.ResultsFive LE GA1 patients were identified that had normal NBS results and three of these presented clinically with GA1 symptoms. One additional symptomatic patient was identified who did not undergo screening. Semiquantitative urine organic acid analysis was consistent with a GA1 diagnosis in two (33%) of the six patients, while plasma glutarylcarnitine was elevated in four (67%) of the six and urine glutarylcarnitine was elevated in four (80%) of five patients. Five GCDH variants were identified in these patients; three of which have not been previously linked to the biochemical LE phenotype.ConclusionsThe data presented here raise awareness of potential FN NBS results for LE GA1 patients. The LE phenotype is not protective against adverse clinical outcomes, and the possibility of FN NBS results calls for high vigilance amongst clinicians, even in the setting of a normal NBS result.

BackgroundEarly detection and grading of pancreatic fibrosis (PF) are important and challenging clinical goals.PurposeTo determine main pancreatic duct (MPD) diameter, pancreatic thickness, and grades of PF via magnetic resonance elastography (MRE), T1 mapping, and intravoxel incoherent motion diffusion‐weighted imaging (IVIM‐DWI), assessing respective diagnostic performances.Study TypeProspective.SubjectsHistopathologic and imaging records (MRE, T1 mapping, and IVIM‐DWI) generated by 144 patients between December 2018 and May 2020 were collected for analysis. Grades of PF were distributed as follows: F0, 82; F1, 22; F2, 22; and F3, 18.Field Strength/Sequence3 T pancreatic MRI, encompassing MRE, T1 mapping, and IVIM‐DWI.AssessmentIn all patients, T1 relaxation times, pancreatic stiffness values, IVIM‐DWI parameters, MPD diameter, and pancreatic thickness were measured.Statistical TestsReceiver operating characteristic (ROC) analysis served to assess imaging parameters useful in diagnosing PF. To identify relations between specific parameters and grades of PF, logistic regression analysis was invoked.ResultsBoth pancreatic stiffness (r = 0.754; P < 0.001) and T1 relaxation time (r = 0.433; P < 0.001) correlated significantly with PF (%). To determine PF grades ≥F1, a combined model (area under the curve [AUC] = 0.906) performed significantly better than pancreatic stiffness (AUC = 0.855; P < 0.001) or T1 relaxation time (AUC = 0.754; P < 0.001) alone. For PF grades ≥F2 or grade F3, both the combined model (≥F2: AUC = 0.910; F3: AUC = 0.939) and pancreatic stiffness (≥F2: AUC = 0.906; F3: AUC = 0.929) outperformed T1 relaxation time (≥F2: AUC = 0.768 [P = 0.005 and P = 0.004, respectively]; F3: AUC = 0.816 [both P < 0.005]). All IVIM‐DWI parameters generated AUC values <0.700.Data ConclusionA combination of MRE and T1 mapping seems promising in diagnosing various grades of PF, particularly at an early stage.Level of Evidence1Technical EfficacyStage 2