Prevalence and Characteristics of CKD in the US Military Health System: A Retrospective Cohort Study.

Rationale & Objective: The US Military Health System (MHS) is a global health care network with a diverse population that is more representative of the US population than other study cohorts and with fewer disparities in health care access. We aimed to examine the prevalence of chronic kidney disease (CKD) in the MHS and within demographic subpopulations. Study Design: Multiple cross-sectional analyses of demographic and claims-based data extracted from the MHS Data Repository, 1 for each fiscal year from 2006-2015. Setting & Population: Multicenter health care network including active-duty military, retirees, and dependents. The average yearly sample size was 3,285,348 individuals. Exposures: Age, sex, race, active-duty status, and active-duty rank (a surrogate for socioeconomic status). Outcome: CKD, defined as the presence of matching International Classification of Diseases, Ninth Revision, codes on either 1 or more inpatient or 2 or more outpatient encounters. Analytical Approach: t test for continuous variables and χ2 test for categorical variables; multivariable logistic regression for odds ratios. Results: For 2015, the mean (standard deviation) age was 38 (16). Crude CKD prevalence was 2.9%. Age-adjusted prevalence was 4.9% overall-1.9% active-duty and 5.4% non-active-duty individuals. ORs for CKD were calculated with multiple imputations to account for missing data on race. After adjustment, the ORs for CKD (all P < 0.001) were 1.63 (95% CI, 1.62-1.64) for an age greater than 40 years, 1.16 (95% CI, 1.15-1.17) for Black race, 1.15 (95% CI, 1.14-1.16) for senior enlisted rank, 0.94 (95% CI, 0.93-0.95) for women, and 0.50 (95% CI, 0.49-0.51) for active-duty status. Limitations: Retrospective study based on International Classification of Diseases, Ninth Revision, coding. Conclusions: Within the MHS, older age, Black race, and senior enlisted rank were associated with a higher risk of CKD, whereas female sex and active-duty status were associated with a lower risk.

Racial and Socioeconomic Disparities in CKD in the Context of Universal Health Care Provided by the Military Health System.

RATIONALE & OBJECTIVE: Health-impeding social determinants of health-including reduced access to care-contribute to racial and socioeconomic disparities in chronic kidney disease (CKD). The Military Health System (MHS) provides an opportunity to assess a large, diverse population for CKD disparities in the context of universal health care. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: MHS beneficiaries aged 18 to 64 years receiving care between October 1, 2015, and September 30, 2018. PREDICTORS: Race, sponsor's rank (a proxy for socioeconomic status and social class), median household income by sponsor's zip code, and marital status. OUTCOME: CKD prevalence, defined by International Classification of Diseases, Tenth Revision codes and/or a validated, laboratory value-based electronic phenotype. ANALYTICAL APPROACH: Multivariable logistic regression compared CKD prevalence by predictors, controlling separately for confounders (age, sex, active-duty status, sponsor's service branch, and depression) and mediators (hypertension, diabetes, HIV, and body mass index). RESULTS: Of 3,330,893 beneficiaries, 105,504 (3.2%) had CKD. In confounder-adjusted models, the CKD prevalence was higher in Black versus White beneficiaries (OR, 1.67; 95% CI, 1.64-1.70), but lower in single versus married beneficiaries (OR, 0.77; 95% CI, 0.76-0.79). The prevalence of CKD was increased among those with a lower military rank and among those with a lower median household income in a nearly dose-response fashion (P < 0.0001). Associations were attenuated when further adjusting for suspected mediators. LIMITATIONS: The cross-sectional design prevents causal inferences. We may have underestimated the CKD prevalence, given a lack of data for laboratory tests conducted outside the MHS and the use of a specific CKD definition. The transient nature of the MHS population may limit the accuracy of zip code-level median household income data. CONCLUSIONS: Racial and socioeconomic CKD disparities exist in the MHS despite universal health care coverage. The existence of CKD disparities by rank and median household income suggests that social risks may contribute to both racial and socioeconomic disparities despite access to universal health care coverage.

CKD Prevalence in the Military Health System: Coded Versus Uncoded CKD.

RATIONALE & OBJECTIVE: Chronic kidney disease (CKD) is common but often goes unrecorded. STUDY DESIGN: Cross-sectional. SETTING & PARTICIPANTS: Military Health System (MHS) beneficiaries aged 18 to 64 years who received care during fiscal years 2016 to 2018. PREDICTORS: Age, sex, active duty status, race, diabetes, hypertension, and numbers of kidney test results. OUTCOMES: We defined CKD by International Classification of Diseases, Tenth Revision (ICD-10) code and/or a positive result on a validated electronic phenotype that uses estimated glomerular filtration rate and measures of proteinuria with evidence of chronicity. We defined coded CKD by the presence of an ICD-10 code. We defined uncoded CKD by a positive e-phenotype result without an ICD-10 code. ANALYTICAL APPROACH: We compared coded and uncoded populations using 2-tailed t tests (continuous variables) and Pearson χ2 test for independence (categorical variables). RESULTS: The MHS population included 3,330,893 beneficiaries. Prevalence of CKD was 3.2%, based on ICD code and/or positive e-phenotype result. Of those identified with CKD, 63% were uncoded. Compared with beneficiaries with coded CKD, those with uncoded CKD were younger (aged 45 ± 13 vs 52 ± 11 years), more often women (54.4% vs 37.6%) and active duty (20.2% vs 12.5%), and less often of Black race (18.5% vs 31.5%) or with diabetes (23.5% vs 43.5%) or hypertension (46.6% vs 77.1%; P < 0.001). Beneficiaries with coded (vs uncoded) CKD had greater numbers of kidney test results (P < 0.001). LIMITATIONS: Use of cross-sectional administrative data prevents inferences about causality. The CKD e-phenotype may fail to capture CKD in individuals without laboratory data and may underestimate CKD. CONCLUSIONS: The prevalence of CKD in the MHS is ~3.2%. Beneficiaries with well-known CKD risk factors, such as older age, male sex, Black race, diabetes, and hypertension, were more likely to be coded, suggesting that clinicians may be missing CKD in groups traditionally considered lower risk, potentially resulting in suboptimal care.

Mutations in DNA Repair Genes and Clinical Outcomes of Patients With Metastatic Colorectal Cancer Receiving Oxaliplatin or Irinotecan-containing Regimens.

OBJECTIVES: First-line regimens in the treatment of metastatic colorectal cancer (mCRC) combine a fluoropyrimidine with oxaliplatin (FOLFOX/XELOX) or irinotecan (FOLFIRI). There is limited efficacy data to guide the selection of one treatment over the other. This study investigated whether mutations affecting DNA damage response (DDR) could differentially influence the response to oxaliplatin and irinotecan-containing regimens. METHODS: We retrospectively analyzed 49 patients with mCRC for whom treatment outcomes and results of comprehensive genomic profiling of tumors were available. Specimens with at least 1 pathogenic mutation involving BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, or RAD54L were classified as DDR-mutated, while those without mutations were DDR-wild-type (WT). We compared the overall survival (OS), disease control rate, and response rate (RR) between the DDR-mutated and DDR-WT groups. RESULTS: DDR mutations occurred in 11 patients (22%). First-line treatment with an oxaliplatin-containing regimen was administered to 33 patients (31 FOLFOX, 2 XELOX), while 16 patients received FOLFIRI. Among DDR-mutated cases, first-line treatment with FOLFOX/XELOX correlated with a statistically significant improvement in median OS compared with FOLFIRI (3.4 vs.1.8 y; P=0.042) and numerically higher RR (50% vs. 33%; P=0.58). No significant difference in OS (2.4 vs. 2.5 y; P=0.42), RR, disease control rate was observed between the 2 regimens in patients with DDR-WT tumors. CONCLUSIONS: Mutations in DDR genes were present in 22% of patients with mCRC. In patients with DDR-mutated tumors, initial treatment with FOLFOX/XELOX correlated with improved OS and a numerically higher RR compared with FOLFIRI.

The Electronic Medical Record and Nephrology Fellowship Education in the United States: An Opinion Survey.

BACKGROUND AND OBJECTIVES: An unintended consequence of electronic medical record use in the United States is the potential effect on graduate physician training. We assessed educational burdens and benefits of electronic medical record use on United States nephrology fellows by means of a survey. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We used an anonymous online opinion survey of all United States nephrology program directors (n=148), their faculty, and fellows. Program directors forwarded survey links to fellows and clinical faculty, indicating to how many they forwarded the link. The three surveys had parallel questions to permit comparisons. RESULTS: Twenty-two percent of program directors (n=33) forwarded surveys to faculty (n=387) and fellows (n=216; 26% of United States nephrology fellows). Faculty and fellow response rates were 25% and 33%, respectively; 51% of fellows agreed/strongly agreed that the electronic medical record contributed positively to their education. Perceived positive effects included access flexibility and ease of obtaining laboratory/radiology results. Negative effects included copy-forward errors and excessive, irrelevant documentation. Electronic medical record function was reported to be slow, disrupted, or completely lost monthly or more by >40%, and these were significantly less likely to agree that the electronic medical record contributed positively to their education. Electronic medical record completion time demands contributed to fellow reluctance to do procedures (52%), participate in conferences (57%), prolong patient interactions (74%), and do patient-directed reading (55%). Sixty-five percent of fellows reported often/sometimes exceeding work-hours limits due to documentation time demands; 85% of faculty reported often/sometimes observing copy-forward errors. Limitations include potential nonresponse and social desirability bias. CONCLUSIONS: Respondents reported that the electronic medical record enhances fellow education with efficient and geographically flexible patient data access, but the time demands of data and order entry reduce engagement in educational activities, contribute to work-hours violations, and diminish direct patient interactions.

Genomic and Molecular Abnormalities in Gynecologic Clear Cell Carcinoma.

Gynecologic clear cell carcinoma is a rare histology, accounting for ~5% of all ovarian and endometrial cancers in the United States. Compared to other types of gynecologic cancer, they are generally less responsive to standard therapy and have an overall worse prognosis. In addition, mounting evidence suggests that the landscape of genetic and molecular abnormalities observed in these tumors is distinct from other cancers that arise from the same sites of origin. On a molecular level, these tumors characteristically display upregulation of the PI3K-AKT-mTOR and RAS-RAF-MAPK signaling axes, frequent loss of ARID1a, and overexpression of MDM2. Evidence also suggests that these tumors are more likely to express programmed death ligand 1 or demonstrate microsatellite instability than other gynecologic cancers. Despite these important differences, there has been relatively little investigation into histology-specific treatment of clear cell gynecologic cancers, representing an opportunity for new drug development. In this article, we review the unique genetic and molecular features of gynecologic clear cell cancers with an emphasis on potential therapeutic targets. The results of completed studies of treatment for clear cell carcinoma are also presented. We conclude with a discussion of ongoing clinical trials and potential avenues for future study.

Sickle cell trait and renal disease among African American U.S. Army soldiers.

Sickle cell trait and certain renal disorders are disproportionately prevalent among African American individuals, so a clear understanding of their association is important. We conducted a longitudinal study using the Stanford Military Data Repository to examine sickle cell trait in relation to the incidence of acute kidney injury (AKI) and chronic kidney disease (CKD). Our study population consisted of African American U.S. Army soldiers on active duty between January 2011 and December 2014. The cumulative incidence was 0·51% for AKI (236 cases out of 45 901 soldiers) and 0·56% for CKD (255 cases out of 45 882 soldiers). Discrete time logistic regression models adjusting for demographic-, military- and healthcare-related covariates showed that sickle cell trait was associated with significantly higher adjusted odds of both AKI [odds ratio (OR): 1·74; 95% confidence interval (CI): 1·17-2·59] and CKD (OR: 2·00; 95% CI: 1·39-2·88). Elevated odds of AKI and CKD were also observed in association with prior CKD and AKI, respectively, and with obesity and prior hypertension. Individuals with sickle cell trait and their providers should be aware of the possibility of increased risk of AKI and CKD to allow for timely intervention and possible prevention.

ROS1-GOPC/FIG: a novel gene fusion in hepatic angiosarcoma.

Hepatic angiosarcoma (HAS) is a rare and highly lethal malignancy with few effective systemic treatments. Relatively little is known about the genetic abnormalities that drive this disease. As a result, there has been minimal progress towards applying targeted therapies to the treatment of HAS. We describe the first reported case of a patient with HAS that harbored a fusion of ROS1 with GOPC/FIG. Similar to other rearrangements involving ROS1, the resulting fusion protein is believed to act as a major driver of carcinogenesis and may be subject to inhibition by drugs that target ROS1 such as crizotinib. We then queried the MSK-IMPACT clinical sequencing cohort and cBioportal datasets, demonstrating the previously unknown prevalence of ROS1-GOPC fusions in soft tissue sarcomas and hepatobiliary cancers. Amplification of these genes was also found to correlate with reduced overall survival. This is followed by a review of the role played by ROS1 rearrangements in cancer, as well as the evidence supporting the use of targeted therapies against the resulting fusion protein. We suggest that testing for ROS1 fusion and, if positive, treatment with a targeted therapy could be considered at the time of diagnosis for patients with angiosarcoma. This report also highlights the need for further investigation into the molecular pathophysiology of this deadly disease.

Association of Nonsteroidal Anti-inflammatory Drug Prescriptions With Kidney Disease Among Active Young and Middle-aged Adults.

Importance: Concern about the renal effects of nonsteroidand al anti-inflammatory drugs (NSAIDs) among young, healthy adults has been limited, but more attention may be warranted given the prevalent use of these agents. Objective: To test for associations between dispensed NSAIDs and incident acute kidney injury and chronic kidney disease while controlling for other risk factors. Design, Setting, and Participants: This retrospective, longitudinal cohort study used deidentified medical and administrative data on 764 228 active-duty US Army soldiers serving between January 1, 2011, and December 31, 2014. Analysis was conducted from August 1 to November 30, 2018. All individuals new to Army service were included in the analysis. Persons already serving in January 2011 were required to have at least 7 months of observable time to eliminate those with kidney disease histories. Exposures: Mean total defined daily doses of prescribed NSAIDs dispensed per month in the prior 6 months. Main Outcomes and Measures: Incident outcomes were defined by diagnoses documented in health records and a military-specific digital system. Results: Among the 764 228 participants (655 392 [85.8%] men; mean [SD] age, 28.6 [7.9] years; median age, 27.0 years [interquartile range, 22.0-33.0 years]), 502 527 (65.8%) were not dispensed prescription NSAIDs in the prior 6 months, 137 108 (17.9%) were dispensed 1 to 7 mean total defined daily doses per month, and 124 594 (16.3%) received more than 7 defined daily doses per month. There were 2356 acute kidney injury outcomes (0.3% of participants) and 1634 chronic kidney disease outcomes (0.2%) observed. Compared with participants who received no medication, the highest exposure level was associated with significantly higher adjusted hazard ratios (aHRs) for acute kidney injury (aHR, 1.2; 95% CI, 1.1-1.4) and chronic kidney disease (aHR, 1.2; 95% CI, 1.0-1.3), with annual outcome excesses per 100 000 exposed individuals totaling 17.6 cases for acute kidney injury and 30.0 cases for chronic kidney disease. Conclusions and Relevance: Modest but statistically significant associations were noted between the highest observed doses of NSAID exposure and incident kidney problems among active young and middle-aged adults.

High turnover of extracellular matrix reflected by specific protein fragments measured in serum is associated with poor outcomes in two metastatic breast cancer cohorts.

Increased extracellular matrix (ECM) formation and matrix metalloprotease (MMP)-mediated ECM degradation are parts of tumorgenesis and generates collagen fragments that are released into circulation. We evaluated the association of specific collagen fragments measured in serum with outcomes in two independent metastatic breast cancer (MBC) cohorts. ELISAs were used to measure C1M (MMP-generated type I collagen fragment), C3M (MMP-generated type III collagen fragment), C4M (MMP-generated type IV collagen fragment), and PRO-C3 (pro-peptide of type III collagen) in pretreatment serum from a phase 3 randomized clinical trial of second-line hormone therapy (HR+, n = 148), and a first-line trastuzumab-treated cohort (HER2+, n = 55). All sites of metastases were included. The collagen fragments were evaluated by Cox-regression analysis for their association with time-to-progression (TTP) and overall survival (OS). In the HR+ cohort, higher C1M and C3M levels (75th percentile cut-off) were associated with shorter TTP; all fragments were associated with shorter OS. In the HER2+ cohort, higher levels of all fragments were associated with shorter TTP; higher PRO-C3 was associated with shorter OS. In multivariate analysis of the HR+ trial for OS, higher levels of all fragments were significant for reduced OS when added separately (C1M HR = 2.1, p < 0.001; C3M HR = 1.8, p = 0.028; C4M HR = 1.8, p = 0.018; PRO-C3 HR = 1.8, p = 0.017); none other clinical covariates were significant. In conclusion, collagen fragments quantified in pretreatment serum was associated with shorter TTP and OS in two independent MBC cohorts receiving systemic therapy. If validated, quantification of ECM remodeling in serum has potential as prognostic and/or predictive biomarkers in MBC.

Molecular genetics and targeted therapeutics in biliary tract carcinoma.

The primary malignancies of the biliary tract, cholangiocarcinoma and gallbladder cancer, often present at an advanced stage and are marginally sensitive to radiation and chemotherapy. Accumulating evidence indicates that molecularly targeted agents may provide new hope for improving treatment response in biliary tract carcinoma (BTC). In this article, we provide a critical review of the pathogenesis and genetic abnormalities of biliary tract neoplasms, in addition to discussing the current and emerging targeted therapeutics in BTC. Genetic studies of biliary tumors have identified the growth factors and receptors as well as their downstream signaling pathways that control the growth and survival of biliary epithelia. Target-specific monoclonal antibodies and small molecules inhibitors directed against the signaling pathways that drive BTC growth and invasion have been developed. Numerous clinical trials designed to test these agents as either monotherapy or in combination with conventional chemotherapy have been completed or are currently underway. Research focusing on understanding the molecular basis of biliary tumorigenesis will continue to identify for targeted therapy the key mutations that drive growth and invasion of biliary neoplasms. Additional strategies that have emerged for treating this malignant disease include targeting the epigenetic alterations of BTC and immunotherapy. By integrating targeted therapy with molecular profiles of biliary tumor, we hope to provide precision treatment for patients with malignant diseases of the biliary tract.

Molecular Genetics and Targeted Therapy in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a highly lethal disease, therefore effective and tolerable treatment is urgently needed. In this article, we provide an updated review of the genetic abnormalities and mechanisms that drive carcinogenesis of HCC, and discuss the targeted therapeutics that are being investigated in HCC. Hepatocellular carcinogenesis typically begins with chronic inflammation of hepatocytes that progressively transform into invasive carcinoma. These events are associated with molecular abnormalities and chromosomal alterations. Multiple analyses of HCC have revealed aberrant expression or activity of growth factors and receptors, and the associated signaling pathways. These molecular alterations are implicated in the development and progression of HCC, and they have been exploited as targets for therapy. Targeted agents that inhibit receptor tyrosine kinases and their downstream signal mediators, angiogenesis, and immunomodulators have been developed and clinically investigated. Among these targeted agents, the multi-kinase inhibitor sorafenib has become the standard treatment for advanced HCC, though its therapeutic benefit is limited. Continued research is essential for improving treatment response and minimizing toxicity for patients with HCC. Future investigation will need to focus on utilizing patterns of gene expression to classify HCC into groups that display similar prognosis and treatment sensitivity, and combining targeted therapeutics with conventional chemotherapy that produce enhanced anti-tumor effect. By integration of tumor profiling and targeted therapeutics in HCC, we hope to advance towards the goal of precision treatment for patients with this malignant disease.

Immunotherapeutic approaches in biliary tract carcinoma: Current status and emerging strategies.

For biliary tract carcinoma (BTC), complete surgical resection of tumor is only feasible in a minority of patients, and the treatment options for patients with unresectable or metastatic disease are limited. Advances in cancer immunology have led to identification of tumor-infiltrating immune cells as indicators of prognosis and response to treatment in BTC. This has also facilitated development of immunotherapy that focuses on enhancing the immune system against biliary tumors. This includes peptide- and dendritic cell-based vaccines that stimulate in-vivo immune responses against tumor-specific antigens. Adoptive immunotherapy, which entails the ex-vivo expansion of tumor-infiltrating immune cells for subsequent reintroduction, and cytokine-based therapies have been developed in BTC. Clinical studies indicate that this type of therapy is generally well tolerated. Combination therapy with dendritic cell-based vaccines and adoptive immunotherapy has shown particularly good potential. Emerging strategies through discovery of novel antigen targets and by reversal of tumor-associated immunosuppression are expected to improve the efficacy of immunotherapy in BTC. Collaborative efforts by integration of targeted immunotherapeutics with molecular profiling of biliary tumor will hopefully make a positive impact on advancing towards the goal of developing precision treatment of patients with this highly lethal disease.

Regorafenib with a fluoropyrimidine for metastatic colorectal cancer after progression on multiple 5-FU-containing combination therapies and regorafenib monotherapy.

We present 2 patients with metastatic colorectal cancer who had progressed despite treatment with first-line FOLFOX and second-line FOLFIRI combination chemotherapy regimens. After failing these fluoropyrimidine-based regimens, both patients received additional cytotoxic and targeted therapies with eventual disease progression. These therapies included capecitabine plus dabrafenib and trametinib, regorafenib monotherapy, and regorafenib with panitumumab. After exhausting available options, both patients were offered regorafenib with either 5-fluorouracil (5-FU) or capecitabine. These therapies are individually approved for the treatment of colorectal cancer but have not yet been studied in combination. This regimen produced stable disease in both patients with acceptable toxicity. One patient continued therapy for 17 months. Although these patients previously progressed during treatment with regorafenib, capecitabine or 5-FU, the combination had some activity in both cases of refractory metastatic colorectal cancer and may be considered in the palliative setting. In bedside-to-bench cell culture experiments performed after the clinical observations, we observed sensitivity of human colorectal cancer cell lines (N = 4) to single agent regorafenib or 5-FU and evidence of synergy with the combination therapy. Synergistic effects were noted in colorectal cancer cells with KRAS mutation, BRAF mutation, and p53 mutation, as well as mismatch repair deficient cells. Regorafenib suppressed Mcl-1 and Bcl-XL in treated cancer cells that may have contributed to the anticancer efficacy including in combination with 5-FU. The safety and efficacy of regorafenib with 5-FU or capecitabine in combination should be further investigated as a therapy for patients with refractory metastatic colorectal cancer, including individuals who had progressed on regorafenib monotherapy.

Correlation of CEA but not CA 19-9 as serum biomarkers of disease activity in a case of metastatic rectal adenocarcinoma.

We present the case of a 62-year-old-man with moderately differentiated adenocarcinoma of the rectum. This patient underwent neoadjuvant chemoradiation and surgical resection followed by adjuvant chemotherapy. After completing therapy, this patient had 2 instances of CEA elevation, both of which preceded the discovery of recurrent disease. While on treatment for these recurrences, CA 19-9 increased rapidly to 4,405. This CA 19-9 elevation persisted for approximately 4 months in the absence of clinical, radiographic or additional serologic evidence of progressive disease before returning to baseline. Shortly after this tumor marker normalized, a small area of locally recurrent disease was discovered. This case highlights the utility and pitfalls of colorectal cancer disease monitoring with CEA and CA 19-9. The differential diagnosis of CA 19-9 elevation is discussed in this report.

A case of heterogeneous sensitivity to panitumumab in cetuximab-refractory colorectal adenocarcinoma metastases.

We present the case of a 43-year-old-man with wild-type KRAS and BRAF colorectal adenocarcinoma that was metastatic to the liver and lung. The patient initially received neoadjuvant chemotherapy with FOLFOX and bevacizumab, followed by surgical resection of the primary tumor and hepatic metastases. His disease recurred shortly after surgery and he was treated with FOLFIRI plus the anti-EGFR antibody cetuximab. After this regimen failed to arrest his disease progression, treatment with FOLFIRI in combination with another anti-EGFR antibody, panitumumab was started. While on this therapy, the patient's lung nodules remained largely stable but metastatic lesions within the liver continued to progress. Our case highlights the differences between panitumumab and cetuximab, and contemplates the possible explanations for this patient's apparently heterogeneous disease progression within the liver despite stabilization of multiple pulmonary nodules.

Updates on first-line therapy for metastatic pancreatic adenocarcinoma.

Pancreatic adenocarcinoma is the 10th most common malignancy in the United States but is responsible for the 4th most cancer related deaths. This disease can only be potentially cured through early discovery and complete surgical resection. Unfortunately, nearly half of patients have metastatic spread at presentation. Combination chemotherapy with FOLFIRINOX or gemcitabine with nab-paclitaxel can prolong survival in selected patients, but at the cost of significant toxicity. In the 2014 ASCO Gastrointestinal Cancers Symposium, several studies were presented that focus on the management of metastatic pancreatic cancer. A phase II trial by Le et al. (Abstract #177) found that the addition of CRS-207, a strain of Listeria modified to stimulate an anti-tumor immune response, improves survival in patients being treated with GVAX. Goldstein et al. (Abstract #178) presented a post-hoc survival analysis for the phase III MPACT trial that shows the addition of nab-paclitaxel to gemcitabine produces a persistent survival benefit. Ramanathan et al. (Abstract #224) demonstrated that, with appropriate dose adjustments and delays, induction nab-paclitaxel and gemcitabine followed by mFOLFIRINOX consolidation is a feasible treatment option for metastatic pancreatic cancer. Despite these advances, it is imperative that we continue to work towards developing additional treatment options that are better tolerated and further prolong survival for these patients. This highlight article focuses on the first-line therapy of metastatic pancreatic adenocarcinoma.