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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.

Validation of peripheral blood mononuclear cells as a biomarker of Src inhibition. Freshly collected peripheral blood mononuclear cells from a healthy volunteer were treated ex-vivo with dasatinib 300 nM or hydrogen peroxide 0.05 mM. The peripheral blood mononuclear cell lysates were generated and immunoblotted for phosphoFAK [Y861] and phophopaxillin [Y118].

Operating characteristics. A summary of the probability of stopping the trial early for the indicated true response rates.

Supplemental material

Lack of correlation between Src activity in PBMCs and hepatic tumors. For the patients in the expansion cohort, the change in the expression of pSrc and total Src was not correlated with a change in the phosphorlyation of the Src substrate paxillin. Patients with no change or a decrease in the expression of pSrc or Src from baseline to C2D8 were included in the "no increase" category.

Supplemental Figure Legends

Prespecified dose modifications for adverse events related to study drug in Phase IB and Phase II.

Legend Supplemental Table S1 : Point mutations tested by plasma analysis in the KPLEX R study, (A). Comparison of point mutations tested by tumor tissue and plasma analysis, (B). Legend Supplemental Table S2: Concordance between tumor-tissue analysis and cfDNA analysis before treatments. Legend Supplemental Table S3: Mutation load at baseline in mutant patients with the equivalent type of mutation as determined by tumor tissue and plasma analysis are heterogneous from 31.83% to 0.009% Legend Supplemental Table S4: Mutation load values of emerging mutant subclones during treatments for both cohorts are reported in (A). Most emerging mutant subclones appears with a mutation load below 0.5% including down to 0.1%, (B). Sensitive methods is needed to track emergence of mutant subclones during targeted therapies. ND, non detected; NQ, scored positive but non quantified. Legend Supplemental table S5 : Compilation of cfDNA data, CEA level and imaging for both cohorts before and during treatments. Legend Supplemental Table S6: Concordance between tumor-tissue analysis and cfDNA analysis before treatments when considering if patients having primary tumor in place or not in place when entering in the study. Legend Supplemental Table S7: Mutant patients and point mutations determined at baseline with different mA% thresholds. Legend supplemental table S8: Description of all point mutations found from plasma analysis at baseline according to increasing allelic frequencies and the mutational status as determined with tumor tissue analysis. Legend Supplementary Table S9: Evolution of increasing mA% from baseline to end of treatment Supplemental Figure S1: Patient's Flow chart Legend Supplemental Figure S2 : Time lag between tumor tissue collection and blood drawing. Legend Supplemental Figure S3A: Total concentration of cfDNA (RefA) at baseline as determined by targeting BRAF and KRAS wild type sequence. Legend Supplemental Figure S3B: KRAS/BRAF ratio before treatment as determined by targeting BRAF and KRAS wild type sequence. KRAS/BRAF ratio before initiation of treatments (n=41). Supplemental Figure S4: RefA values do not differ at baseline between cohorts 1 and 2 Supplemental Figure S5: RefA values do not differ at baseline between patients stopped treatment before C4 and others Supplemental Figure S6: Concentrations of mutant cfDNA do not differ at baseline between cohorts 1 and 2 Supplemental Figure S7: Concentration of mutant cfDNA do not differ at baseline between patients stopped treatment before C4 and others Supplemental Figure S8: Mutation load do not differ at baseline between cohorts 1 and 2 Legend supplementary Figure S9: Validation of point mutation detection/quantification under the Poisson law. Supplemental Figure S10: Illustration of point mutation detection at very low frequency with IntPlex ASB QPCR method in mCRC patients in the study.

Symptom-specific dose adjustment tables.

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.

INTRODUCTION: In this report we describe the clinical presentation, laboratory findings and outcomes of four patients that were referred for urgent cardiothoracic intervention and tested positive for COVID-19. METHODS: The St. Elizabeth's Medical Center Institutional Review Board exempted the study from review (waived review). In each case, verbal informed consent was obtained by the study participant or health care proxy. RESULTS: The majority of the patients undergoing surgery had low Society of Thoracic Surgeons score and uneventful operating time. The mortality was very high and driven primarily by the viral syndrome. Laboratory markers that have been associated with disease severity in the general population were also prognostic in our population. CONCLUSION: Our study shows that these patients have very high mortality, whereas prevention and preoperative screening is required in preventing nosocomial spreading of the disease.

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.

Malignant tumors shed cell free DNA into the blood stream. Analyzing this new biological source may have important implications in a shift towards personalized medicine for diagnosing and/or monitoring malignancies. We recently showed the first clinical validation and clinical utility of circulating DNA (cfDNA) analysis in oncology by testing RAS/BRAF hotspot mutations in plasma from metastatic colorectal cancer patients (mCRC) (Nat Med. 2014 Apr;20(4):430-5). In addition, liquid biopsies allow the tracking of clonal dynamics and detection of mutations during treatment. We evaluated under blinded conditions the ability of cfDNA to detect RAS/BRAF mutations in the plasma of 42 mCRC patients treated on a phase Ib/II trial of FOLFOX and dasatnib, with or without cetuximab. Prior to treatment, sequencing of archival tissue detected mutations in 25/42 patients (60%), while the cfDNA assay detected mutations in 37/42 patients (88%). Our cfDNA assay was able to detect mutations with allele frequencies as low as 0.01%. After exposure to treatment, 41/42 patients (98%) had a cfDNA detected RAS/BRAF mutation. Of 22 patients followed with serial measurements who were RAS/BRAF mutant at baseline, 11 (50%) developed a second mutation following treatment and 3 (14%) no longer had detectable levels of another mutant allele. Of RAS/BRAF wild type tumors at baseline, 4/5 (80%) developed new mutations. Patients may harbor mutations at very low frequency down to 0.01% before initiation or during treatment revealing the need of a high sensitive technique to detect mutant subclones. 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. Combined qualitative and quantitative cfDNA analysis allows tracking acquired resistance by studying the real-time clonal evolution of the tumor and might help physicians to adjust patient treatment. Our findings demonstrate the development of new RAS/BRAF mutations in patients regardless of whether they had pre-existing mutations in the pathway, demonstrating a convergent evolutionary pattern. Note: This abstract was not presented at the meeting. Citation Format: Alain R. Thierry, Brice Pastor, Zhi-Qin Camilla Jiang, anastasia Katsiampoura, Christine Parseghian, Jonathan Loree, Michael J. Overman, Cynthia Sanchez, Safia El Messaoudi, Marc Ychou, Scott Kopetz. Circulating DNA demonstrates convergent evolution and common resistance mechanisms during treatment of colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2924. doi:10.1158/1538-7445.AM2017-2924

Background: There are few predictors of difficult mask ventilation and a simple, objective, predictive system to identify patients at risk of difficult mask ventilation does not currently exist. We present a retrospective - subgroup analysis aimed at identifying predictive factors for difficult mask ventilation (DMV) in patients undergoing pre-operative airway assessment before elective surgery at a major teaching hospital.Methods: Data for this retrospective analysis were derived from a database of airway assessments, management plans, and outcomes that were collected prospectively from August 2008 to May 2010 at a Level 1 academic trauma center. Patients were stratified into two groups based on the difficulty of mask ventilation and the cohorts were analyzed using univariate analysis and stepwise selection method.Results: A total of 1399 pre-operative assessments were completed with documentation stating that mask ventilation was attempted. Of those 1399, 124 (8.9%) patients were found to be difficult to mask ventilate. A comparison of patients with and without difficult mask ventilation identified seven risk factors for DMV: age, body mass index (BMI), neck circumference, history of difficult intubation, presence of facial hair, perceived short neck and obstructive sleep apnea. Although seven risk factors were identified, no individual subject had more than four risk factors.Conclusion: The results of this study confirm that in a real world clinical setting, the incidence of DMV is not negligible and suggest the use of a simple bedside predictive score to improve the accuracy of DMV prediction, thereby improving patient safety. Further prospective studies to validate this score would be useful.

Background: Laryngeal mask airway (LMA) placement is now considered a common airway management practice. Although there are many studies which focus on various airway techniques, research regarding difficult LMA placement is limited, particularly for anesthesiologist trainees. In our retrospective analysis we tried to identify predictive factors of difficult LMA placement in an academic training program.Methods: This retrospective analysis was derived from a research airway database, where data were collected prospectively at the Memorial Hermann Hospital, Texas Medical Center, Houston, TX, USA, from 2008 to 2010. All non-obstetric adult patients presenting for elective surgery requiring general anesthesia, were enrolled in this study: anesthesiology residents primarily managed the airways. The level of difficulty, number of attempts, and type of the extraglottic device placement were retrieved.Results: Sixty-nine unique Laryngeal Mask Airways (uLMAs) were utilized as a primary airway device. Two independent predictors for difficult LMA placement were identified: gender and neck circumference. The sensitivity for one factor is 87.5% with a specificity of 50%. However with two risk factors, the specificity increases to the level of 93% and the sensitivity is 63%.Conclusion: In a large academic training program, besides uLMA not been used routinely, two risk factors for LMA difficulty were identified, female gender and large neck circumference. Neck circumference is increasingly being recognized as a significant predictor across the spectrum of airway management difficulties while female gender has not been previously reported as a risk factor for difficult LMA placement.

BackgroundDifficult Mask Ventilation (DMV), is a situation in which it is impossible for an unassisted anesthesiologist to maintain oxygen saturation >90% using 100% oxygen and positive pressure ventilation to prevent or reverse signs of inadequate ventilation during mask ventilation. The incidence varies from 0.08 – 15%. Patient-related anatomical features are by far the most significant cause. We analyzed data from an obese surgical population (BMI> 30 kg/m2) to identify specific risk and predictive factors for DMV.MethodsFive hundred and fifty seven obese patients were identified from a database of 1399 cases associated with preoperative airway examinations where mask ventilation was attempted. Assessment of mask ventilation in this group was stratified by a severity score (0-3), and a step-wise selection method was used to identify independent predictors. The area under the curve of the receiver-operating-characteristic was then used to evaluate the model’s predictive value. Adjusted odds ratios and their 95% confidence intervals were also calculated.ResultsDMV was observed in 80/557 (14%) patients. Three independent predictive factors for DMV in obese patients were identified: age 49 years, short neck, and neck circumference 43 cm. In the current study th sensitivity for one factor is 0.90 with a specificity 0.35. However, the specificity increased to 0.80 with inclusion of more than one factor.ConclusionAccording to the current investigation, the three predictive factors are strongly associated with DMV in obese patients. Each independent risk factor alone provides a good screening for DMV and two factors substantially improve specificity. Based on our analysis, we speculate that the absence of at least 2 of the factors we identified might have a significant negative predictive value and can reasonably exclude DMV, with a negative likelihood ratio 0.81.