Patient metabolic profile defined by liver and muscle 18F-FDG PET avidity is independently associated with overall survival in gastric cancer.

BACKGROUND: PET-CT-based patient metabolic profiling is a novel concept to incorporate patient-specific metabolism into gastric cancer care. METHODS: Staging PET-CTs, demographics, and clinicopathologic variables of gastric cancer patients were obtained from a prospectively maintained institutional database. PET-CT avidity was measured in tumor, liver, spleen, four paired muscles, and two paired fat areas in each patient. The liver to rectus femoris (LRF) ratio was defined as the ratio of SUVmean of liver to the average SUVmean of the bilateral rectus femoris muscles. Kaplan-Meier and Cox-proportional hazards models were used to identify the impact of LRF ratio on OS. RESULTS: Two hundred and one patients with distal gastroesophageal (48%) or gastric (52%) adenocarcinoma were included. Median age was 65 years, and 146 (73%) were male. On univariate analysis, rectus femoris PET-CT avidity and LRF ratio were significantly associated with overall survival (p < 0.05). LRF ratio was significantly higher in males, early-stage cancer, patients with an ECOG 0 or 1 performance status, patients with albumin > 3.5 mg/dL, and those with moderately differentiated tumor histology. In multivariable regression, gastric cancer stage, albumin, and LRF ratio were significant independent predictors of overall survival (LRF ratio HR = 0.73 (0.56-0.96); p = 0.024). Survival curves showed that the prognostic impact of LRF was associated with metastatic gastric cancer (p = 0.009). CONCLUSIONS: Elevated LRF ratio, a patient-specific PET-CT-based metabolic parameter, was independently associated with an improvement in OS in patients with metastatic gastric cancer. With prospective validation, LRF ratio may be a useful, host-specific metabolic parameter for prognostication in gastric cancer.

Myosin Light-Chain Kinase Inhibition Potentiates the Antitumor Effects of Avapritinib in PDGFRA D842V-Mutant Gastrointestinal Stromal Tumor.

PURPOSE: To create an in vivo model of PDGFRA D842V-mutant gastrointestinal stromal tumor (GIST) and identify the mechanism of tumor persistence following avapritinib therapy. EXPERIMENTAL DESIGN: We created a patient-derived xenograft (PDX) of PDGFRA D842V-mutant GIST and tested the effects of imatinib, avapritinib, and ML-7, an inhibitor of myosin light-chain kinase (MYLK). Bulk tumor RNA sequencing and oncogenic signaling were evaluated. Apoptosis, survival, and actin cytoskeleton were evaluated in GIST T1 cells and isolated PDX cells in vitro. Human GIST specimens were analyzed for MYLK expression. RESULTS: The PDX was minimally responsive to imatinib but sensitive to avapritinib. Avapritinib therapy increased tumor expression of genes related to the actin cytoskeleton, including MYLK. ML-7 induced apoptosis and disrupted actin filaments in short-term cultures of PDX cells and decreased survival in GIST T1 cells in combination with imatinib or avapritinib. Combined therapy with ML-7 improved the antitumor effects of low-dose avapritinib in vivo. Furthermore, MYLK was expressed in human GIST specimens. CONCLUSIONS: MYLK upregulation is a novel mechanism of tumor persistence after tyrosine kinase inhibition. Concomitant MYLK inhibition may enable the use of a lower dose of avapritinib, which is associated with dose-dependent cognitive side effects.

Tyrosine Kinase Inhibition Alters Intratumoral CD8+ T-cell Subtype Composition and Activity.

Targeted therapy with a tyrosine kinase inhibitor (TKI) such as imatinib is effective in treating gastrointestinal stromal tumor (GIST), but it is rarely curative. Despite the presence of a robust immune CD8+ T-cell infiltrate, combining a TKI with immune-checkpoint blockade (ICB) in advanced GIST has achieved only modest effects. To identify limitations imposed by imatinib on the antitumor immune response, we performed bulk RNA sequencing (RNA-seq), single-cell RNA-seq, and flow cytometry to phenotype CD8+ T-cell subsets in a genetically engineered mouse model of GIST. Imatinib reduced the frequency of effector CD8+ T cells and increased the frequency of naïve CD8+ T cells within mouse GIST, which coincided with altered tumor chemokine production, CD8+ T-cell recruitment, and reduced CD8+ T-cell intracellular PI3K signaling. Imatinib also failed to induce intratumoral T-cell receptor (TCR) clonal expansion. Consistent with these findings, human GISTs sensitive to imatinib harbored fewer effector CD8+ T cells but more naïve CD8+ T cells. Combining an IL15 superagonist (IL15SA) with imatinib restored intratumoral effector CD8+ T-cell function and CD8+ T-cell intracellular PI3K signaling, resulting in greater tumor destruction. Combination therapy with IL15SA and ICB resulted in the greatest tumor killing and maintained an effector CD8+ T-cell population in the presence of imatinib. Our findings highlight the impact of oncogene inhibition on intratumoral CD8+ T cells and support the use of agonistic T-cell therapy during TKI and/or ICB administration.

Dermatofibrosarcoma Protuberans: What Is This?

Dermatofibrosarcoma protuberans (DFSP) is a rare, locally aggressive dermal-based sarcoma. Metastatic potential is extremely low, primarily in the setting of fibrosarcomatous transformation. DFSP is characterized by a t(17;22) (q22;q13) translocation that results in active PDGFB signaling. Surgical resection with negative margins (typically including the underlying fascia) is the potentially curative treatment. Delayed wound closure should be considered for cases requiring extensive resection or tissue rearrangement. Tyrosine kinase inhibitors, such as imatinib, have shown response rates of 50% to 60% in patients with locally advanced or metastatic disease. Radiation can be useful for residual or recurrent diseases.

Systemic therapy for duodenal adenocarcinoma: An analysis of the National Cancer Database (NCDB).

BACKGROUND: National Comprehensive Cancer Network guidelines recommend resection and adjuvant chemotherapy for patients with locally advanced duodenal adenocarcinoma. Outcomes after systemic treatment in this rare malignancy have not been well studied. We examined utilization patterns of systemic treatment and compared overall survival of patients receiving neoadjuvant therapy, surgery alone, and adjuvant therapy. METHODS: Patients with stage 0 to III duodenal adenocarcinoma undergoing curative-intent surgery were identified within the National Cancer Database from 2006 to 2015. Outcomes, including median overall survival and 30- and 90-day mortality, were compared based on treatment sequence (neoadjuvant, adjuvant, or surgery alone). Propensity score matching on likelihood of receiving systemic treatment and landmark analysis were performed to mitigate bias. RESULTS: Of the 2,956 patients meeting inclusion criteria, most patients with known clinical stage had locally advanced disease (72%), of which 53% received systemic therapy (8% neoadjuvant, 45% adjuvant). After landmark analysis on the propensity matched cohort, patients with locally advanced disease who received systemic treatment had longer median overall survival compared to patients who underwent surgery alone (49 vs 40 months, P = .018) and a 20% lower hazard of mortality (hazard ratio 0.80, 95% confidence interval 0.69-0.93, P = .003). Patients who received neoadjuvant and adjuvant therapy had similar survival outcomes. CONCLUSION: Adjuvant therapy was underutilized in patients with National Comprehensive Cancer Network guideline indications, despite an association with longer median overall survival and decreased hazard of mortality. Neoadjuvant therapy, although rarely used, had similar survival to adjuvant therapy. Given its other potential benefits, systemic treatment in the neoadjuvant setting may be a reasonable option in adequately selected patients with clinically advanced duodenal adenocarcinoma.

Surgical Treatment of Patients with Poorly Differentiated Pancreatic Neuroendocrine Carcinoma: An NCDB Analysis.

BACKGROUND: Consensus guidelines discourage resection of poorly differentiated pancreatic neuroendocrine carcinoma (panNEC) given its association with poor long-term survival. This study assessed treatment patterns and outcomes for this rare malignancy using the National Cancer Database (NCDB). METHODS: Patients with non-functional pancreatic neuroendocrine tumors in the NCDB (2004-2016) were categorized based on pathologic differentiation. Logistic and Cox proportional hazard regressions identified associations with resection and overall survival (OS). Survival was compared using Kaplan-Meier and log-rank tests. RESULTS: Most patients (83%) in the cohort of 8560 patients had well-differentiated tumors (panNET). The median OS was 47 months (panNET, 63 months vs panNEC, 17 months; p < 0.001). Surgery was less likely for older patients (odds ratio [OR], 0.97), patients with panNEC (OR, 0.27), and patients with metastasis at diagnosis (OR, 0.08) (all p < 0.001). After propensity score-matching of these factors, surgical resection was associated with longer OS (82 vs 29 months; p < 0.001) and a decreased hazard of mortality (hazard ratio [HR], 0.37; p < 0.001). Surgery remained associated with longer OS when stratified by differentiation (98 vs 41 months for patients with panNET and 36 vs 8 months for patients with panNEC). Overall survival did not differ between patients with panNEC who underwent surgery and patients with panNET who did not (both 39 months; p = 0.294). CONCLUSIONS: Poorly differentiated panNEC exhibits poorer survival than well-differentiated panNET. In the current cohort, surgical resection was strongly and independently associated with improved OS, suggesting that patients with panNEC who are suitable operative candidates should be considered for multimodality therapy, including surgery.

Acral Lentiginous Melanoma: A United States Multi-Center Substage Survival Analysis.

BACKGROUND: Acral lentiginous melanoma is associated with worse survival than other subtypes of melanoma. Understanding prognostic factors for survival and recurrence can help better inform follow-up care. OBJECTIVES: To analyze the clinicopathologic features, melanoma-specific survival, and recurrence-free survival by substage in a large, multi-institutional cohort of primary acral lentiginous melanoma patients. METHODS: Retrospective review of the United States Melanoma Consortium database, a multi-center prospectively collected database of acral lentiginous melanoma patients treated between January 2000 and December 2017. RESULTS: Of the 433 primary acral lentiginous melanoma patients identified (median [range] age: 66 [8-97] years; 53% female, 83% white), 66% presented with stage 0-2 disease and the median time of follow-up for the 392 patients included in the survival analysis was 32.5 months (range: 0-259). The 5-year melanoma-specific survivals by stage were 0 = 100%, I = 93.8%, II = 76.2%, III = 63.4%, IIIA = 80.8%, and IV = 0%. Thicker Breslow depth ((HR) = 1.13; 95% CI = 1.05-1.21; P < .001)) and positive nodal status ((HR) = 1.79; 95% CI = 1.00-3.22; P = .050)) were independent prognostic factors for melanoma-specific survival. Breslow depth ((HR = 1.13; 95% CI = 1.07-1.20; P < .001), and positive nodal status (HR = 2.12; 95% CI = 1.38-3.80; P = .001) were also prognostic factors for recurrence-free survival. CONCLUSION: In this cohort of patients, acral lentiginous melanoma was associated with poor outcomes even in early stage disease, consistent with prior reports. Stage IIB and IIC disease were associated with particularly low melanoma-specific and recurrence-free survival. This suggests that studies investigating adjuvant therapies in stage II patients may be especially valuable in acral lentiginous melanoma patients.

Clinical Presentation Patterns and Survival Outcomes of Hispanic Patients With Gastric Cancer.

BACKGROUND: Hispanic patients have a higher incidence of gastric cancer when compared to non-Hispanics. Outlining clinicodemographic characteristics and assessing the impact of ethnicity on stage-specific survival may identify opportunities to improve gastric cancer care for this population. METHODS: Patients with gastric cancer in the US Safety Net Collaborative (2012-2014) were retrospectively reviewed. Demographics, clinicopathologic characteristics, operative details, and outcomes were compared between Hispanic and non-Hispanic patients. Early onset gastric cancer was defined as age <50 years. Kaplan-Meier and Cox proportional-hazards models were used to identify the impact of ethnicity on disease-specific survival (DSS). RESULTS: Seven hundred and ninety-seven patients were included, of which 219 (28%) were Hispanic. Hispanic patients were more likely to seek care at safety-net hospitals (66 vs 39%) and be uninsured (36 vs 17%), and less likely to have a primary care provider (PCP) (46 vs 75%; all P<0.05). Hispanic patients were twice as likely to present with early onset gastric cancer (28 vs 15%) and were more frequently diagnosed in the emergency room (54 vs 37%) with both abdominal pain and weight loss (44 vs 31%; all P <0.05). Treatment paradigms, operative outcomes, and DSS were similar between Hispanic and non-Hispanic patients when accounting for cancer stage. Cancer stage, pathologically positive nodes, and negative surgical margins were independently associated with DSS. CONCLUSIONS: A diagnosis of gastric cancer must be considered in previously healthy Hispanic patients who present to the emergency room with both abdominal pain and weight loss. Fewer than 50% of Hispanic patients have a PCP, indicating poor outpatient support. Efforts to improve outpatient support and screening may improve gastric cancer outcomes in this vulnerable population.

Oncogenic KIT Modulates Type I IFN-Mediated Antitumor Immunity in GIST.

Type I IFNs are implicated in tumor immunogenicity and response to systemic therapy, but their interaction with oncogene signaling is not well understood. Here, we studied oncogenic KIT, which drives gastrointestinal stromal tumor (GIST), the most common sarcoma. Using mouse models of GIST, we found that KIT inhibition reduced type I IFN production and signaling, which downregulated tumor MHC class I expression. Absence of type I IFN signaling increased tumor size, in part due to CD8+ T-cell impairment. Oncogenic KIT was required for GIST type I IFN signal transduction via STAT1. In human GIST cell lines and surgical specimens, type I IFN signaling contributed to human lymphocyte antigen class I expression and correlated with tumor immunogenicity. Augmenting the type I IFN response partially compensated for the immunosuppressive effects of KIT inhibition. Thus, KIT signaling contributes to type I IFN signaling, whereas KIT inhibition attenuates tumor immunogenicity and is partly rescued by innate immune stimulation.See related Spotlight on p. 489.

Surgical resection of early stage hepatocellular carcinoma improves patient survival at safety net hospitals.

BACKGROUND AND OBJECTIVES: Surgical resection is indicated for hepatocellular carcinoma (HCC) patients with Child A cirrhosis. We hypothesize that surgical intervention and survival are limited by advanced HCC presentation at safety net hospitals (SNHs) versus academic medical centers (AMCs). METHODS: Patients with HCC and Child A cirrhosis in the US Safety Net Collaborative (2012-2014) were evaluated. Demographics, clinicopathologic features, operative characteristics, and outcomes were compared between SNHs and AMCs. Liver transplantation was excluded. Kaplan-Meier and Cox proportional-hazards models were used to identify the effect of surgery on overall (OS). RESULTS: A total of 689 Child A patients with HCC were identified. SNH patients frequently presented with T3/T4 stage (35% vs. 24%) and metastases (17% vs. 8%; p < .05). SNH patients were as likely to undergo surgery as AMC patients (17% vs. 18%); however, SNH patients were younger (56 vs. 64 years), underwent minor hepatectomy (65% vs. 38%), and frequently harbored well-differentiated tumors (23% vs. 2%; p < .05). On multivariate analysis, surgical resection and stage, but not hospital type, were associated with improved OS. CONCLUSIONS: Although SNH patients present with advanced HCC, survival outcomes for early stage HCC are similar at SNHs and AMCs. Identifying barriers to early diagnosis at SNH may increase surgical candidacy and improve outcomes.

The V654A second-site KIT mutation increases tumor oncogenesis and STAT activation in a mouse model of gastrointestinal stromal tumor.

Gastrointestinal stromal tumor (GIST) is the most common human sarcoma and arises in the gastrointestinal tract. Most GISTs are caused by activating mutations in the KIT receptor tyrosine kinase, such as the exon 11 KIT V559Δ mutation. The small molecule imatinib inhibits KIT and has been a mainstay of therapy in GIST. Unfortunately, imatinib-treated patients typically relapse, most often due to clonal emergence of the resistance-associated KIT V654A mutation. To determine the biologic impact of this second-site mutation in vivo, we created a mouse model with the corresponding V558Δ;V653A Kit double mutation restricted (a) spatially to ETV1+ cells, which include the interstitial cells of Cajal (ICCs) from which GISTs presumably originate, and (b) temporally through tamoxifen treatment after birth. This resulted in the first in vivo model of the most common second-site mutation associated with imatinib resistance in GIST and the first in vivo demonstration that cell-autonomous expression of mutant KIT in the ICC lineage leads to GIST. GISTs driven by the V558Δ;V653A Kit double mutation were resistant to imatinib, while cabozantinib was more effective in overcoming resistance than sunitinib. Compared to control mice with a single V558Δ Kit mutation, mice with a double V558Δ; V653A Kit mutation had increased tumor oncogenesis and associated KIT-dependent STAT activation. Our findings demonstrate that the biologic consequences of a second-site mutation in an oncogenic driver may include not only a mechanism for drug resistance, but changes in tumor oncogenic potential and differential activation of signaling pathways.

Targeting the interleukin-17 immune axis for cancer immunotherapy.

The role of IL-17 in cancer remains controversial. Emerging evidence suggests that during early oncogenesis IL-17 supports tumor growth, whereas in established tumors IL-17 production by γδ and Th17 cells potentiates antitumor immunity. Consequently, γδ and Th17 cells are attractive targets for immunotherapy in the IL-17 immune axis. To optimize IL-17-based immunotherapy, a deeper understanding of the cytokines dictating IL-17 production and the polarity of γδ and Th17 cells is critical. Here, we delve into the dichotomous roles of IL-17 in cancer and provide insight into the tumor microenvironment conducive for successful IL-17-based γδ and Th17 cell immunotherapy.

Harnessing the Microbiome for Pancreatic Cancer Immunotherapy.

Late-stage pancreatic cancer harbors a fibrotic and immune-excluded tumor microenvironment that impedes immunotherapy success. A key to unlocking pancreatic cancer immunotherapy may be treating early-stage pancreatic cancer, when peripancreatic inflammation promoted by the microbiome potentiates oncogenic signaling and suppresses innate and adaptive immunity. Hence, understanding the role of microbiota in pancreatic cancer initiation, progression, and immunosuppression is crucial. We propose that not only are microbiota targets for immunomodulation in this disease, but also that microbiome profiling has a potential role in pancreatic cancer screening. Furthermore, combining microbiome profiling with liquid and tissue biopsy may validate the early pancreatic cancer treatment approach of microbiome modulation and immunotherapy.

Oncogenic kinase inhibition limits Batf3-dependent dendritic cell development and antitumor immunity.

Gastrointestinal stromal tumor (GIST) is driven by an activating mutation in the KIT proto-oncogene. Using a mouse model of GIST and human specimens, we show that intratumoral murine CD103+CD11b- dendritic cells (DCs) and human CD141+ DCs are associated with CD8+ T cell infiltration and differentiation. In mice, the antitumor effect of the Kit inhibitor imatinib is partially mediated by CD103+CD11b- DCs, and effector CD8+ T cells initially proliferate. However, in both mice and humans, chronic imatinib therapy decreases intratumoral DCs and effector CD8+ T cells. The mechanism in our mouse model depends on Kit inhibition, which reduces intratumoral GM-CSF, leading to the accumulation of Batf3-lineage DC progenitors. GM-CSF is produced by γδ T cells via macrophage IL-1ß. Stimulants that expand and mature DCs during imatinib treatment improve antitumor immunity. Our findings identify the importance of tumor cell oncogene activity in modulating the Batf3-dependent DC lineage and reveal therapeutic limitations for combined checkpoint blockade and tyrosine kinase inhibition.

Differential immune profiles distinguish the mutational subtypes of gastrointestinal stromal tumor.

Gastrointestinal stromal tumor (GIST) is the most common human sarcoma, frequently characterized by an oncogenic mutation in the KIT or platelet-derived growth factor receptor alpha (PDGFRA) genes. We performed RNA sequencing of 75 human GIST tumors from 75 patients, comprising the largest cohort of GISTs sequenced to date, in order to discover differences in the immune infiltrates of KIT and PDGFRA-mutant GIST. Through bioinformatics, immunohistochemistry, and flow cytometry, we found that PDGFRA-mutant GISTs harbored more immune cells with increased cytolytic activity when compared to KIT-mutant GISTs. PDGFRA-mutant GISTs expressed many chemokines, such as CXCL14, at a significantly higher level when compared to KIT-mutant GISTs and exhibited more diverse driver-derived neoepitope:HLA binding, both of which may contribute to PDGFRA-mutant GIST immunogenicity. Through machine learning, we generated gene expression-based immune profiles capable of differentiating KIT and PDGFRA-mutant GISTs, and also identified additional immune features of high PD-1 and PD-L1 expressing tumors across all GIST mutational subtypes, which may provide insight into immunotherapeutic opportunities and limitations in GIST.

The Role of the Microbiome in Immunologic Development and its Implication For Pancreatic Cancer Immunotherapy.

Our understanding of the microbiome and its role in immunity, cancer initiation, and cancer progression has evolved significantly over the past century. The "germ theory of cancer" was first proposed in the early 20th century, and shortly thereafter the bacterium Helicobacter pylori, and later Fusobacterium nucleatum, were implicated in the development of gastric and colorectal cancers, respectively. However, with the development of reliable mouse models and affordable sequencing technologies, the most fascinating aspect of the microbiome-cancer relationship, where microbes undermine cancer immune surveillance and indirectly promote oncogenesis, has only recently been described. In this review, we highlight the essential role of the microbiome in immune system development and maturation. We review how microbe-induced immune activation promotes oncogenesis, focusing particularly on pancreatic carcinogenesis, and show that modulation of the microbiome augments the anti-cancer immune response and enables successful immunotherapy against pancreatic cancer.

Macrophages and CD8+ T Cells Mediate the Antitumor Efficacy of Combined CD40 Ligation and Imatinib Therapy in Gastrointestinal Stromal Tumors.

Tyrosine kinase inhibition of gastrointestinal stromal tumors (GIST) is effective but typically culminates in resistance and is rarely curative. Immunotherapy has potential application to GIST, as we previously showed that T-cell checkpoint blockade increases the antitumor effects of imatinib. Here, we showed that ligation of CD40 using an agonistic antibody (anti-CD40) activated tumor-associated macrophages (TAMs) in vivo in a knock-in mouse model of GIST harboring a germline mutation in Kit exon 11. Activated TAMs had greater TNFα production and NFκB signaling and directly inhibited tumor cells in vitro Anti-CD40 required concomitant therapy with imatinib for efficacy and depended on TAMs, and to a lesser extent CD8+ T cells, but not on CD4+ T cells or B cells. In an analysis of 50 human GIST specimens by flow cytometry, we found that CD40 was expressed on human TAMs and tumor cells yet was downregulated after response to imatinib. CD40 ligation did not have a direct inhibitory effect on human GIST cells. Our findings provide the rationale for combining anti-CD40 and tyrosine kinase inhibition to treat human GIST. Cancer Immunol Res; 6(4); 434-47. ©2018 AACR.

Mitochondrial Inhibition Augments the Efficacy of Imatinib by Resetting the Metabolic Phenotype of Gastrointestinal Stromal Tumor.

Purpose: Imatinib dramatically reduces gastrointestinal stromal tumor (GIST) 18F-FDG uptake, providing an early indicator of treatment response. Despite decreased glucose internalization, many GIST cells persist, suggesting that alternative metabolic pathways are used for survival. The role of mitochondria in imatinib-treated GIST is largely unknown.Experimental Design: We quantified the metabolic activity of several human GIST cell lines. We treated human GIST xenografts and genetically engineered KitV558del/+ mice with the mitochondrial oxidative phosphorylation inhibitor VLX600 in combination with imatinib and analyzed tumor volume, weight, histology, molecular signaling, and cell cycle activity. In vitro assays on human GIST cell lines were also performed.Results: Imatinib therapy decreased glucose uptake and downstream glycolytic activity in GIST-T1 and HG129 cells by approximately half and upregulated mitochondrial enzymes and improved mitochondrial respiratory capacity. Mitochondrial inhibition with VLX600 had a direct antitumor effect in vitro while appearing to promote glycolysis through increased AKT signaling and glucose transporter expression. When combined with imatinib, VLX600 prevented imatinib-induced cell cycle escape and reduced p27 expression, leading to increased apoptosis when compared to imatinib alone. In KitV558del/+ mice, VLX600 alone did not induce tumor cell death, but had a profound antitumor effect when combined with imatinib.Conclusions: Our findings show that imatinib alters the metabolic phenotype of GIST, and this may contribute to imatinib resistance. Our work offers preclinical proof of concept of metabolic targeting as an effective strategy for the treatment of GIST. Clin Cancer Res; 24(4); 972-84. ©2017 AACR.

Endovascular Treatment of Spontaneous Renal Artery Dissection After Failure of Medical Management.

Spontaneous renal artery dissection (SRAD) is a rare disease with approximately 200 cases reported in the literature. The severity of renal compromise, the anatomic location of the dissection, and the presence of uncontrollable hypertension are used to guide the initial management of SRAD. However, there are no reported guidelines for managing the progression of SRAD after acute failure of medical management. In this case, a 40-year-old man with a recently diagnosed SRAD was managed appropriately with therapeutic anticoagulation, yet presented with progression of his dissection and a new acute renal infarct. A covered endovascular stent was used to successfully control dissection progression and prevent further renal compromise.

Genetic Variation in Choline-Metabolizing Enzymes Alters Choline Metabolism in Young Women Consuming Choline Intakes Meeting Current Recommendations.

Single nucleotide polymorphisms (SNPs) in choline metabolizing genes are associated with disease risk and greater susceptibility to organ dysfunction under conditions of dietary choline restriction. However, the underlying metabolic signatures of these variants are not well characterized and it is unknown whether genotypic differences persist at recommended choline intakes. Thus, we sought to determine if common genetic risk factors alter choline dynamics in pregnant, lactating, and non-pregnant women consuming choline intakes meeting and exceeding current recommendations. Women (n = 75) consumed 480 or 930 mg choline/day (22% as a metabolic tracer, choline-d9) for 10-12 weeks in a controlled feeding study. Genotyping was performed for eight variant SNPs and genetic differences in metabolic flux and partitioning of plasma choline metabolites were evaluated using stable isotope methodology. CHKA rs10791957, CHDH rs9001, CHDH rs12676, PEMT rs4646343, PEMT rs7946, FMO3 rs2266782, SLC44A1 rs7873937, and SLC44A1 rs3199966 altered the use of choline as a methyl donor; CHDH rs9001 and BHMT rs3733890 altered the partitioning of dietary choline between betaine and phosphatidylcholine synthesis via the cytidine diphosphate (CDP)-choline pathway; and CHKA rs10791957, CHDH rs12676, PEMT rs4646343, PEMT rs7946 and SLC44A1 rs7873937 altered the distribution of dietary choline between the CDP-choline and phosphatidylethanolamine N-methyltransferase (PEMT) denovo pathway. Such metabolic differences may contribute to disease pathogenesis and prognosis over the long-term.