A multi-factorial genetic model for prognostic assessment of high risk melanoma patients receiving adjuvant interferon

Purpose: IFNa was the first cytokine to demonstrate anti-tumor activity in advanced melanoma. Despite the ability of high-dose IFNa reducing relapse and mortality by up to 33%, large majority of patients experience side effects and toxicity which outweigh the benefits. The current study attempts to identify genetic markers likely to be associated with benefit from IFN-a2b treatment and predictive for survival. Experimental design: We tested the association of variants in FOXP3 microsatellites, CTLA4 SNPs and HLA genotype in 284 melanoma patients and their association with prognosis and survival of melanoma patients who received IFNa adjuvant therapy. Results: Univariate survival analysis suggested that patients bearing either the DRB1*15 or HLA-Cw7 allele suffered worse OS while patients bearing either HLA-Cw6 or HLA-B44 enjoyed better OS. DRB1*15 positive patients suffered also worse RFS and conversely HLA-Cw6 positive patients had better RFS. Multivariate analysis revealed that a five-marker genotyping signature was prognostic of OS independent of disease stage. In the multivariate Cox regression model, HLA-B38 (p = 0.021), HLA-C15 (p = 0.025), HLA-C3 (p = 0.014), DRB1*15 (p = 0.005) and CT60*G/G (0.081) were significantly associated with OS with risk ratio of 0.097 (95% CI, 0.013-0.709), 0.387 (95% CI, 0.169-0.889), 0.449 (95% CI, 0.237-0.851), 1.948 (95% CI, 1.221-3.109) and 1.484 (95% IC, 0.953-2.312) respectively. Conclusion: These results suggest that gene polymorphisms relevant to a biological occurrence are more likely to be informative when studied in concert to address potential redundant or conflicting functions that may limit each gene individual contribution. The five markers identified here exemplify this concept though prospective validation in independent cohorts is needed

OPTN/SRTR 2015 Annual Data Report: Heart

The number of heart transplant candidates and transplants performed continued to rise each year. In 2015, 2819 heart transplants were performed. In addition, the number of new adult candidates on the waiting list increased 51% since 2004. The number of adult heart transplant survivors continued to increase, and in 2015, 29,172 recipients were living with heart transplants. Patient mortality following transplant has declined. The number of pediatric candidates and transplants performed also increased. New listings for pediatric heart transplants increased from 451 in 2004 to 644 in 2015. The number of pediatric heart transplants performed each year increased from 297 in 2004 to 460 in 2015. Among pediatric patients who underwent transplant in 2014, death occurred in 7.2% at 6 months and 9.6% at 1 year.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135509/1/ajt14128.pd

OPTN/SRTR 2017 Annual Data Report: Heart

In 2017, 3273 heart transplants were performed in the United States. New listings continued to increase, and 3769 new adults were listed for heart transplant in 2017. Over the past decade, posttransplant mortality has declined. The number of new pediatric listings increased over the past decade, as did the number of pediatric heart transplants, although some fluctuation has occurred more recently. New listings for pediatric heart transplants increased from 481 in 2007 to 623 in 2017. The number of pediatric heart transplants performed each year increased from 330 in 2007 to 432 in 2017, slightly fewer than in 2016. Short‐term and long‐term mortality improved. Among pediatric patients who underwent transplant between 2015‐2016, 4.8% had died by 6 months and 6.2% by 1 year.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/148229/1/ajt15278.pd

OPTN/SRTR 2018 Annual Data Report: Heart

The new adult heart allocation policy was approved in 2016 and implemented in October 2018, so its effect was not yet evident in 2018 data. However, the more granular data being collected are anticipated to allow for improved analyses. In 2018, new listings continued to increase; 3883 new adult and 685 new pediatric candidates were added. In 2018, 3440 heart transplants were performed, an increase of 167 over 2017; 473 transplants occurred in pediatric recipients and 2967 in adult recipients. Short‐term and long‐term posttransplant mortality improved. Overall 1‐year survival for adults who underwent heart transplant in 2011‐2013 was 90.3%, 3‐year survival was 84.7%, and 5‐year survival was 79.6%. Mortality rates for pediatric recipients were 4.5% at 6 months and in 5.9% at 1 year posttransplant, 12.5% at 3 years for transplants in 2014‐2015, 14.8% at 5 years for transplants in 2012‐2013, and 29.8% at 10 years for transplants performed in 2008‐2009.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153233/1/ajt15676.pd

Gene expression profiling in acute allograft rejection: challenging the immunologic constant of rejection hypothesis

In humans, the role and relationship between molecular pathways that lead to tissue destruction during acute allograft rejection are not fully understood. Based on studies conducted in humans, we recently hypothesized that different immune-mediated tissue destruction processes (i.e. cancer, infection, autoimmunity) share common convergent final mechanisms. We called this phenomenon the "Immunologic Constant of Rejection (ICR)." The elements of the ICR include molecular pathways that are consistently described through different immune-mediated tissue destruction processes and demonstrate the activation of interferon-stimulated genes (ISGs), the recruitment of cytotoxic immune cells (primarily through CXCR3/CCR5 ligand pathways), and the activation of immune effector function genes (IEF genes; granzymes A/B, perforin, etc.)

The stable traits of melanoma genetics: an alternate approach to target discovery

<p>Abstract</p> <p>Background</p> <p>The weight that gene copy number plays in transcription remains controversial; although in specific cases gene expression correlates with copy number, the relationship cannot be inferred at the global level. We hypothesized that genes steadily expressed by 15 melanoma cell lines (CMs) and their parental tissues (TMs) should be critical for oncogenesis and their expression most frequently influenced by their respective copy number.</p> <p>Results</p> <p>Functional interpretation of 3,030 transcripts concordantly expressed (Pearson's correlation coefficient p-value < 0.05) by CMs and TMs confirmed an enrichment of functions crucial to oncogenesis. Among them, 968 were expressed according to the transcriptional efficiency predicted by copy number analysis (Pearson's correlation coefficient p-value < 0.05). We named these genes, "genomic delegates" as they represent at the transcriptional level the genetic footprint of individual cancers. We then tested whether the genes could categorize 112 melanoma metastases. Two divergent phenotypes were observed: one with prevalent expression of cancer testis antigens, enhanced cyclin activity, WNT signaling, and a Th17 immune phenotype (Class A). This phenotype expressed, therefore, transcripts previously associated to more aggressive cancer. The second class (B) prevalently expressed genes associated with melanoma signaling including <it>MITF</it>, melanoma differentiation antigens, and displayed a Th1 immune phenotype associated with better prognosis and likelihood to respond to immunotherapy. An intermediate third class (C) was further identified. The three phenotypes were confirmed by unsupervised principal component analysis.</p> <p>Conclusions</p> <p>This study suggests that clinically relevant phenotypes of melanoma can be retraced to stable oncogenic properties of cancer cells linked to their genetic back bone, and offers a roadmap for uncovering novel targets for tailored anti-cancer therapy.</p

An immunologic portrait of cancer

The advent of high-throughput technology challenges the traditional histopathological classification of cancer, and proposes new taxonomies derived from global transcriptional patterns. Although most of these molecular re-classifications did not endure the test of time, they provided bulk of new information that can reframe our understanding of human cancer biology. Here, we focus on an immunologic interpretation of cancer that segregates oncogenic processes independent from their tissue derivation into at least two categories of which one bears the footprints of immune activation. Several observations describe a cancer phenotype where the expression of interferon stimulated genes and immune effector mechanisms reflect patterns commonly observed during the inflammatory response against pathogens, which leads to elimination of infected cells. As these signatures are observed in growing cancers, they are not sufficient to entirely clear the organism of neoplastic cells but they sustain, as in chronic infections, a self-perpetuating inflammatory process. Yet, several studies determined an association between this inflammatory status and a favorable natural history of the disease or a better responsiveness to cancer immune therapy. Moreover, these signatures overlap with those observed during immune-mediated cancer rejection and, more broadly, immune-mediated tissue-specific destruction in other immune pathologies. Thus, a discussion concerning this cancer phenotype is warranted as it remains unknown why it occurs in immune competent hosts. It also remains uncertain whether a genetically determined response of the host to its own cancer, the genetic makeup of the neoplastic process or a combination of both drives the inflammatory process. Here we reflect on commonalities and discrepancies among studies and on the genetic or somatic conditions that may cause this schism in cancer behavior