Citations

Variable survival outcomes are seen following treatment for aggressive non‐Hodgkin lymphoma (NHL). This study examined whether outcomes for aggressive B‐cell NHL are associated with single nucleotide polymorphisms (SNPs) in oxidative stress‐related genes, which can alter drug metabolism and immune responses. Genotypes for 53 SNPs in 29 genes were determined for 337 patients given anthracycline‐based therapies. Their associations with progression‐free survival (PFS) and overall survival (OS) were estimated by Cox proportional hazard regression; associations with hematologic toxicity were estimated by logistic regression. To validate the findings, the top three SNPs were tested in an independent cohort of 572 DLBCL patients. The top SNPs associated with PFS in the discovery cohort were the rare homozygotes for MPO rs2243828 (hazard ratio [HR] = 1.87, 95% confidence interval [CI] = 1.14–3.06, P = 0.013), AKR1C3 rs10508293 (HR = 2.09, 95% CI = 1.28–3.41, P = 0.0032) and NCF4 rs1883112 (HR = 0.66, 95% CI = 0.43–1.02, P = 0.06). The association of the NCF4 SNP with PFS was replicated in the validation dataset (HR = 0.66, 95% CI = 0.44–1.01, P = 0.05) and the meta‐analysis was significant (HR = 0.66, 95% CI = 0.49–0.89, P < 0.01). The association of the MPO SNP was attenuated in the validation dataset, while the meta‐analysis remained significant (HR = 1.64, 95% CI = 1.12–2.41). These two SNPs showed similar trends with OS in the meta‐analysis (for NCF4, HR = 0.72, 95% CI = 0.51–1.02, P = 0.07 and for MPO, HR = 2.06, 95% CI = 1.36–3.12, P < 0.01). In addition, patients with the rare homozygote of the NCF4 SNP had an increased risk of hematologic toxicity. We concluded that genetic variations in NCF4 may contribute to treatment outcomes for patients with aggressive NHL. Am. J. Hematol. 89:639–645, 2014. © 2014 Wiley Periodicals, Inc.

Background: The current systems of healthcare delivery in the United States suffer from problems that often leave patients with inadequate quality of care. In their report entitled “Crossing the Quality Chasm,” the Institute of Medicine (IOM) identified reasons for poor and/or inconsistent quality of healthcare delivery and provided recommendations to improve it. The purpose of this review is to describe features of an innovative web-based program called the Thyroid Cancer Care Collaborative (TCCC) and see how it addresses IOM recommendations to improve the quality of healthcare delivery. Summary: The TCCC addresses the three actionable IOM recommendations directed at healthcare organizations and clinicians to redesign the care process. It does so by exploiting information technology (IT) in ways suggested by the IOM, and it fits within a set of 10 rules provided by the IOM. Some features of the TCCC include: (i) automated disease staging based on three validated scoring systems; (ii) highly illustrated educational videos on all aspects of thyroid cancer care; (iii) personalized clinical decision-making modules for clinicians and physicians; (iv) portability of data to share among treating physicians; (v) virtual tumor boards, “ask the expert,” and frequently asked questions modules; (vi) physician workflow integration; and (vii) data for comprehensive analysis to answer difficult questions in thyroid cancer management. Conclusion: The TCCC has the potential to improve thyroid cancer care delivery and offers several benefits to patients, clinicians, and researchers. The TCCC is a valuable example of how IOM initiatives can improve the healthcare system.

Reducing the incidence and mortality rates for clear cell renal cell carcinoma (ccRCC) remains a significant clinical challenge with poor 5‐year survival rates. A unique tissue cohort was assembled of matched ccRCC and distal nontumor tissues (n = 20) associated with moderate risk of disease progression, half of these from individuals who progressed to metastatic disease and the other half who remained disease free. These tissues were used for MALDI imaging MS profiling of proteins in the 2–20 kDa range, resulting in a panel of 108 proteins that had potential disease‐specific expression patterns. Protein lysates from the same tissues were analyzed by MS/MS, resulting in identification of 56 proteins of less than 20 kDa molecular weight. The same tissues were also used for global lipid profiling analysis by MALDI‐FT‐ICR MS. From the cumulative protein and lipid expression profile data, a refined panel of 26 proteins and 39 lipid species was identified that could either distinguish tumor from nontumor tissues, or tissues from recurrent disease progressors from nonrecurrent disease individuals. This approach has the potential to not only improve prognostic assessment and enhance postoperative surveillance, but also to inform on the underlying biology of ccRCC progression.

Abstract The presence of regulatory T cells (Treg) in solid tumors is known to play a role in patient survival in ovarian cancer and other malignancies. We assessed inherited genetic variations via 749 tag single-nucleotide polymorphisms (SNP) in 25 Treg-associated genes (CD28, CTLA4, FOXP3, IDO1, IL10, IL10RA, IL15, 1L17RA, IL23A, IL23R, IL2RA, IL6, IL6R, IL8, LGALS1, LGALS9, MAP3K8, STAT5A, STAT5B, TGFB1, TGFB2, TGFB3, TGFBR1, TGRBR2, and TGFBR3) in relation to ovarian cancer survival. We analyzed genotype and overall survival in 10,084 women with invasive epithelial ovarian cancer, including 5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous carcinoma cases of European descent across 28 studies from the Ovarian Cancer Association Consortium (OCAC). The strongest associations were found for endometrioid carcinoma and IL2RA SNPs rs11256497 [HR, 1.42; 95% confidence interval (CI), 1.22–1.64; P = 5.7 × 10−6], rs791587 (HR, 1.36; 95% CI, 1.17–1.57; P = 6.2 × 10−5), rs2476491 (HR, = 1.40; 95% CI, 1.19–1.64; P = 5.6 × 10−5), and rs10795763 (HR, 1.35; 95% CI, 1.17–1.57; P = 7.9 × 10−5), and for clear cell carcinoma and CTLA4 SNP rs231775 (HR, 0.67; 95% CI, 0.54–0.82; P = 9.3 × 10−5) after adjustment for age, study site, population stratification, stage, grade, and oral contraceptive use. The rs231775 allele associated with improved survival in our study also results in an amino acid change in CTLA4 and previously has been reported to be associated with autoimmune conditions. Thus, we found evidence that SNPs in genes related to Tregs seem to play a role in ovarian cancer survival, particularly in patients with clear cell and endometrioid epithelial ovarian cancer. Cancer Immunol Res; 2(4); 332–40. ©2014 AACR.

AbstractBackgroundWell‐differentiated thyroid cancer (WDTC) recurs in up to 30% of patients. Guidelines from the American Thyroid Association (ATA) and the National Comprehensive Cancer Network (NCCN) provide valuable parameters for the management of recurrent disease, but fail to guide the clinician as to the multitude of factors that should be taken into account. The Thyroid Cancer Care Collaborative (TCCC) is a web‐based repository of a patient's clinical information. Ten clinical decision‐making modules (CDMMs) process this information and display individualized treatment recommendations.MethodsWe conducted a review of the literature and analysis of the management of patients with recurrent/persistent WDTC.ResultsSurgery remains the most common treatment in recurrent/persistent WDTC and can be performed with limited morbidity in experienced hands. However, careful observation may be the recommended course in select patients. Reoperation yields biochemical remission rates between 21% and 66%. There is a reported 1.2% incidence of permanent unexpected nerve paralysis and a 3.5% incidence of permanent hypoparathyroidism. External beam radiotherapy and percutaneous ethanol ablation have been reported as therapeutic alternatives. Radioactive iodine as a primary therapy has been reported previously for metastatic lymph nodes, but is currently advocated by the ATA as an adjuvant to surgery.ConclusionThe management of recurrent lymph nodes is a multifactorial decision and is best determined by a multidisciplinary team. The CDMMs allow for easy adoption of contemporary knowledge, making this information accessible to both patient and clinician. © 2014 Wiley Periodicals, Inc. Head Neck 37: 605–614, 2015

ABSTRACTObjectives:Inflammatory bowel disease (IBD) is heritable, but a total of 163 variants commonly implicated in IBD pathogenesis account for only 25% of the heritability. Rare, highly penetrant genetic variants may also explain mendelian forms of IBD and some of the missing heritability. To test the hypothesis that rare loss‐of‐function mutations can be causative, we performed whole exome sequencing (WES) on 5 members of a 2‐generation family of European ancestry presenting with an early‐onset and atypical form of IBD.Methods:WES was performed for all of the 5 family members; the mother and 3 male offspring were affected, whereas the father was unaffected. Mapping, annotation, and filtering criteria were used to reduce candidate variants. For functional testing we performed forkhead box P3 (FOXP3) staining and a T‐cell suppression assay.Results:We identified a novel missense variant in exon 6 of the X‐linked FOXP3 gene. The c.694A>C substitution in FOXP3 results in a cysteine‐to‐glycine change at the protein position 232 that is completely conserved among all vertebrates. This variant (heterozygous in the mother and hemizygous in all 3 affected sons) did not impair FOXP3 protein expression, but significantly reduced the ability of the host's T regulatory cells to suppress an inappropriate autoimmune response. The variant results in a milder immune dysregulation, polyendocrinopathy, enteropathy, and X‐linked phenotype with early‐onset IBD.Conclusions:Our study illustrates the successful application of WES for making a definitive molecular diagnosis in a case of multiply affected families, with atypical IBD‐like phenotype. Our results also have important implications for disease biology and disease‐directed therapeutic development.

AbstractAlzheimer's disease is the public health crisis of the 21st century. There is a clear need for a widely available, inexpensive and reliable method to diagnosis Alzheimer's disease in the earliest stages, track disease progression, and accelerate clinical development of new therapeutics. One avenue of research being explored is blood based biomarkers. In April 2012, the Alzheimer's Association and the Alzheimer's Drug Discovery Foundation convened top scientists from around the world to discuss the state of blood based biomarker development. This manuscript summarizes the meeting and the resultant discussion, including potential next steps to move this area of research forward.