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Objective Inability of home discharge occurs in nearly a third of patients undergoing cardiac surgery and is associated with increased mortality. The authors aimed to evaluate the incidence and risk factors for adverse discharge disposition (ADD) after cardiac surgery and develop a prediction tool for preoperative risk assessment. Design This retrospective cohort study included adult patients undergoing cardiac surgery between 2010 and 2018. The primary outcome was ADD, defined as in-hospital mortality, discharge to a skilled nursing facility, or transfer to a long-term care hospital. The authors created a prediction tool using stepwise backward logistic regression and used 5-fold and leave-one-out cross-validation. Setting University hospital network. Participants Adult patients living at home prior to surgery, who underwent coronary artery bypass grafting and/or valve procedures at the authors’ institution. Interventions None. Measurements and Main Results A total of 3,760 patients were included in the final study cohort. The observed rate of ADD was 33.3%. The prediction model showed good discrimination and accuracy, with C-statistic of 0.78 (95% confidence interval [CI] 0.76-0.79) and unmodified Brier score of 0.177 (reliability 0.001). The final model comprised 14 predictors. Patients who experienced ADD were more likely to be older, of female sex, to have had higher length of hospital stay prior to surgery, and to have undergone emergency surgery. Conclusions The authors present an instrument for prediction of loss of the ability to live independently in patients undergoing cardiac surgery. The authors’ score may be useful in identifying high-risk patients such that earlier coordination of care can be initiated in this vulnerable patient population.

Background Metastatic colorectal cancer (mCRC) is a highly heterogeneous disease from a clinical, molecular, and immunological perspective. Current predictive models rely primarily in tissue based genetic analysis, which not always correlate with inflammatory response. Here we evaluated the role of a circulating inflammatory signature as a prognostic marker in mCRC. Methods Two hundred eleven newly diagnosed patients with mCRC were enrolled in the study. One hundred twenty-one patients had unresectable metastases, whereas ninety patients had potentially resectable liver metastases at presentation. Analysis of miR-21, IL-6, and IL-8 in the plasma of peripheral blood was performed at baseline. Patients with high circulating levels of ≥2 of the three inflammation markers (miR-21, IL-6, and IL-8) were considered to have the “Inflammation phenotype-positive CISIG”. Results Positive CISIG was found in 39/90 (43%) and 50/121 (45%) patients in the resectable and unresectable cohort, respectively. In the resectable population the median relapse-free survival was 18.4 compared to 31.4 months (p = 0.001 HR 2.09, 95% CI 1.2–3.67) for positive vs. negative CISIG. In contrast, the individual components were not significant. In the same population the median overall survival was 46.2 compared to 66.0 months (p = 0.0003, HR 2.57, 95% CI 1.26–5.27) for positive vs. negative CISIG, but not significant for the individual components. In the unresectable population, the median overall survival was 13.5 compared to 25.0 months (p = 0.0008, HR 2.49, 95% CI 1.46–4.22) for positive vs. negative CISIG. IL-6 was independently prognostic with overall survival of 16.2 compared to 27.0 months (p = 0.004, HR 1.96, 95% CI 1.24–3.11) for high vs. low IL-6, but not the other components. Using a Cox regression model, we demonstrated that CISIG is an independent predictive marker of survival in patients with unresectable disease (HR 1.8, 95% CI 1.2, 2.8, p

Developing realistic preclinical models using clinical samples that mirror complex tumor biology and behavior are vital to advancing cancer research. While cell line cultures have been helpful in generating preclinical data, the genetic divergence between these and corresponding primary tumors has limited clinical translation. Conversely, patient-derived xenografts (PDX) in colorectal cancer are highly representative of the genetic and phenotypic heterogeneity in the original tumor. Coupled with high-throughput analyses and bioinformatics, these PDXs represent robust preclinical tools for biomarkers, therapeutic target, and drug discovery. Successful PDX engraftment is hypothesized to be related to a series of anecdotal variables namely, tissue source, cancer stage, tumor grade, acquisition strategy, time to implantation, exposure to prior systemic therapy, and genomic heterogeneity of tumors. Although these factors at large can influence practices and patterns related to xenotransplantation, their relative significance in determining the success of establishing PDXs is uncertain. Accordingly, we systematically examined the predictive ability of these factors in establishing PDXs using 90 colorectal cancer patient specimens that were subcutaneously implanted into immunodeficient mice. Fifty (56%) PDXs were successfully established. Multivariate analyses showed tissue acquisition strategy [surgery 72.0% (95% confidence interval (CI): 58.2–82.6) vs. biopsy 35% (95% CI: 22.1%–50.6%)] to be the key determinant for successful PDX engraftment. These findings contrast with current empiricism in generating PDXs and can serve to simplify or liberalize PDX modeling protocols. Better understanding the relative impact of these factors on efficiency of PDX formation will allow for pervasive integration of these models in care of colorectal cancer patients. Mol Cancer Ther; 16(7); 1435–42. ©2017 AACR.

Background We aimed to examine the predictive value of a novel mathematical formula based on the law of conservation of mass in calculating sodium changes in intensive care unit patients and compare its performance with previously published formulae. Methods 178 patients were enrolled from 01/2010 to 10/2013. Plasma and urine were collected in two consecutive 8-hour intervals and the sodium was measured. The predicted sodium concentration was calculated based on previous equations and our formula. The two 8-hour period (epoch 1 and 2) results were compared. Variability of predicted values among the measured range of serum sodium levels were provided by Bland-Altman plots with bias and precision statistics. Comparison of the results was performed with the statistical model of the Percentage Similarity. Results 47.19% patients had dysnatremias. The bias ± SD with 95% limits of agreement for sodium levels were -1.395±3.491 for epoch 1 and -1.623 ±11.1 for epoch 2 period. Bland-Altman analysis for the epoch 1 study period had the following results: -0.8079±3.447 for Adrogue–Madias, 0.56±9.687 for Barsoum–Levine, 0.1412±3.824 for EFWC and 0.294±4.789 for Kurtz–Nguyen formula. The mean similarity, SD and coefficient variation for the methods compared with the measured sodium are: 99.56%, 3.873, 3.89% epoch 1, 99.56%, 1.255, 1.26% for epoch 2, 99.77%, 1.245, 1.26% for Adrogue-Madias, 100.1%, 1.337, 1.34% for Barsoum-Levine, 100.1%, 1.704, 1.7% for Nguyen, 100.1%, 1.370, 1.37% for ECFW formula. Conclusions The law of conservation of mass can be successfully applied for the prediction of sodium changes in critically ill patients.

Purpose: Aberrant activation of the intracellular tyrosine kinase Src has been implicated as a mechanism of acquired chemotherapy resistance in metastatic colorectal cancer (mCRC). Here, the oral tyrosine kinase Src inhibitor, dasatinib, was investigated in combination with FOLFOX and cetuximab. Experimental Design: We performed a phase IB/II study of 77 patients with previously treated mCRC. Primary objectives were to determine the maximum tolerated dose, dose-limiting toxicities (DLT), pharmacodynamics, and efficacy. Using a 3 + 3 design, patients received FOLFOX6 with cetuximab and escalating doses of dasatinib (100, 150, 200 mg daily), followed by a 12-patient expansion cohort at 150 mg. Phase II studies evaluated FOLFOX plus dasatinib 100 mg in KRAS c12/13mut patients or in combination with cetuximab if KRAS c12/13WT. FAK and paxillin were utilized as surrogate blood biomarkers of Src inhibition, and paired biopsies of liver metastases were obtained in patients in the expansion cohort. Results: In phase IB, the DLTs were grade 3/4 fatigue (20%) and neutropenia (23%). In phase II, grade 3/4 fatigue (23%) and pleural effusions (11%) were present. Response rates were 20% (6 of 30) in the phase IB escalation and expansion cohort and 13% (3 of 24) and 0% (0 of 23) in the KRAS c12/13WT and mutant cohorts of phase II, respectively. Median progression-free survival was 4.6, 2.3, and 2.3 months, respectively. There was no evidence of Src inhibition based on surrogate blood biomarkers or paired tumor biopsies. Conclusions: The combination of dasatinib plus FOLFOX with or without cetuximab showed only modest clinical activity in refractory colorectal cancer. This appears to be primarily due to a failure to fully inhibit Src at the achievable doses of dasatinib. The combination of dasatinib plus FOLFOX with or without cetuximab did not show meaningful clinical activity in refractory colorectal cancer due to failure to fully inhibit Src. Clin Cancer Res; 23(15); 4146–54. ©2017 AACR.

Purpose: Liquid biopsies allow the tracking of clonal dynamics and detection of mutations during treatment.Experimental Design: We evaluated under blinded conditions the ability of cell-free DNA (cfDNA) to detect RAS/BRAF mutations in the plasma of 42 metastatic colorectal cancer patients treated on a phase Ib/II trial of FOLFOX and dasatinib, with or without cetuximab.Results: Prior to treatment, sequencing of archival tissue detected mutations in 25 of 42 patients (60%), while the cfDNA assay detected mutations in 37 of 42 patients (88%). Our cfDNA assay detected mutations with allele frequencies as low as 0.01%. After exposure to treatment, 41 of 42 patients (98%) had a cfDNA-detected RAS/BRAF mutation. Of 21 patients followed with serial measurements who were RAS/BRAF mutant at baseline, 11 (52%) showed additional point mutation following treatment and 3 (14%) no longer had detectable levels of another mutant allele. Of RAS/BRAF wild-type tumors at baseline, 4 of 5 (80%) showed additional point mutations. cfDNA quantitative measurements from this study closely mirrored changes in CEA and CT scan results, highlighting the importance of obtaining quantitative data beyond the mere presence of a mutation.Conclusions: Our findings demonstrate the development of new RAS/BRAF mutations in patients regardless of whether they had preexisting mutations in the pathway, demonstrating a convergent evolutionary pattern. Clin Cancer Res; 23(16); 4578–91. ©2017 AACR.