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Intraprocedural transesophageal echocardiography imaging is an integral part of percutaneous structural heart disease (SHD) interventions. The rapid growth in the number, scope, and complexity of SHD interventions has outpaced the efforts to develop training and proficiency standards in periprocedural imaging. At the Beth Israel Deaconess Medical Center in Boston, Massachusetts, the authors have developed a 6-month duration fellowship in interventional echocardiography for SHD to address this issue. The purpose of this fellowship is to train cardiac anesthesiologists to address the unique challenges of interventional echocardiography. In this paper, the authors describe the rationale for and specific features of this training program. Their fellowship curriculum follows a multimodal integrative approach to training in SHD imaging, which includes simulation sessions, online modules, deliberate practice in the clinical setting, and interdisciplinary team-based training. In the next several years, there will be an increased need for echocardiographers who are proficient in intraprocedural SHD imaging. In this article, the authors describe their experience with a competency-based curriculum for subspecialty anesthesia training in SHD imaging.

OBJECTIVE: To describe the current nationwide perspectives and practice regarding intraoperative oxygen titration in cardiac surgery. DESIGN: Prospective, observational survey. SETTING: Hospitals across the United States. PARTICIPANTS: Cardiovascular anesthesiologists and perfusionists. INTERVENTIONS: Expert- and consensus-derived electronic surveys were sent to perfusionists and cardiac anesthesiologists to evaluate the current intraoperative practices around oxygen administration. Providers were asked about individual intraoperative oxygen titration practices used at different stages of cardiac surgical procedures. Anonymous responses were collected in the Research Electronic Data Capture (REDCap). MEASUREMENTS AND MAIN RESULTS: A total of 3,335 providers were invited to participate, of whom 554 (317 anesthesiologists and 237 perfusionists) were included in the final analysis (17% response rate). During cardiopulmonary bypass (CPB), perfusionists reported a median (interquartile range [IQR]) target range from 150 (110–220)-to-325 mmHg (250–400), while anesthesiologists reported a significantly lower target range from 90 (70–150)-to-250 mmHg (158–400) (p values

Association between surgical specimen size and rate of PDX establishment.

Hematoxylin and eosin staining showing conformity of grade between patient sample and respective established xenografts from both primary and metastatic sites.

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.

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.

Ribonucleotide Reductase (RNR) converts ribonucleotides to deoxyribonucleotides required for DNA replication and repair. RNR consists of subunits M1 and M2. It has been studied as a prognostic factor in several solid tumors and in chronic hematological malignancies, but not in chronic lymphocytic leukemia (CLL). Peripheral blood samples were collected from 135 CLL patients. M1/M2 gene mRNA levels were measured and expressed as a RRM1-2/GAPDH ratio. M1 gene promoter methylation was studied in a patients’ subgroup. M1 mRNA expression was higher in patients without anemia (p = 0.026), without lymphadenopathy (p = 0.005) and 17p gene deletion (p = 0.031). Abnormal LDH (p = 0.022) and higher Rai stage (p = 0.019) were associated with lower M1 mRNA levels. Higher M2 mRNA levels were found in patients without lymphadenopathy (p = .048), Rai stage 0 (p = 0.025) and Trisomy 12 (p = 0.025). The correlation between RNR subunits and clinic-biological characteristics in CLL patients demonstrate RNR’s potential role as a prognostic factor.

Postoperative morbidity in patients undergoing lower extremity amputation (LEA) has remained high. Studies investigating the influence of the anesthetic modality on the postoperative outcomes have yielded conflicting results. The aim of our study was to assess the effects of regional anesthesia vs general anesthesia on postoperative complications for patients undergoing LEA.We systematically searched PubMed, Embase, MEDLINE, Web of Science, and Google Scholar from 1990 to 2022 for studies investigating the effect of the anesthetic modality on the postoperative outcomes after LEA. Regional anesthesia (RA) included neuraxial anesthesia and peripheral nerve blocks. The outcomes included 30-day mortality, respiratory failure (unplanned postoperative intubation, failure to wean, mechanical ventilation24 hours), surgical site infection, cardiac complications, urinary tract infection, renal failure, sepsis, venous thrombosis, pneumonia, and myocardial infarction.Of the 25 studies identified, we included 10 retrospective observational studies with 81,736 patients, of whom 69,754 (85.3%) had received general anesthesia (GA) and 11,980 (14.7%) had received RA. In the GA group, 50,468 patients were men (63.8%), and in the RA group, 7813 patients were men (62.3%). The results of the meta-analyses revealed that GA was associated with a higher rate of respiratory failure (odds ratio, 1.38; 95% confidence interval, 1.06-1.80; P = .02) and sepsis (odds ratio, 1.21; 95% confidence interval, 1.11-1.33; P .0001) compared with RA. No differences were found in postoperative 30-day mortality, surgical site infection, cardiac complications, urinary tract infection, renal failure, venous thrombosis, pneumonia, and myocardial infarction between the GA and RA groups.The results of our meta-analysis have shown that GA could be associated with a higher rate of respiratory failure and sepsis compared with RA for LEA.

We examined the effects of dexamethasone on postoperative mortality, recurrence-free survival, and side effects in patients undergoing oncologic operations.Dexamethasone prevents nausea and vomiting after anesthesia and may affect cancer proliferation.A total of 30,561 adult patients undergoing solid cancer resection between 2005 and 2020 were included. Multivariable logistic regression was applied to investigate the effect of dexamethasone on 1-year mortality and recurrence-free survival. Effect modification by cancer's potential for immunogenicity, defined as a recommendation for checkpoint inhibitor therapy based on the National Comprehensive Cancer Network guidelines, was investigated through interaction term analysis. Key safety endpoints were dexamethasone-associated risk of hyperglycemia180 mg/dL within 24 hours and surgical site infections within 30 days after surgery.Dexamethasone was administered to 38.2% (11,666/30,561) of patients (6.5±2.3 mg). Overall, 3.2% (n=980/30,561) died and 15.4% (n=4718/30,561) experienced cancer recurrence within 1 year of the operation. Dexamethasone was associated with a -0.6% (95% confidence interval: -1.1, -0.2, P=0.007) 1-year mortality risk reduction [adjusted odds ratio (ORadj): 0.79 (0.67, 0.94), P=0.009; hazard ratio=0.82 (0.69, 0.96), P=0.016] and higher odds of recurrence-free survival [ORadj: 1.28 (1.18, 1.39), P0.001]. This effect was only present in patients with solid cancers who were defined as not to respond to checkpoint inhibitor therapy [ORadj: 0.70 (0.57, 0.87), P=0.001 vs ORadj: 1.13 (0.85, 1.50), P=0.40]. A high (0.09 mg/kg) dose of dexamethasone increased the risk of postoperative hyperglycemia [ORadj: 1.55 (1.32, 1.82), P0.001], but not for surgical site infections [ORadj: 0.84 (0.42, 1.71), P=0.63].Dexamethasone is associated with decreased 1-year mortality and cancer recurrence in patients undergoing surgical resection of cancers that are not candidates for immune modulators. Dexamethasone increased the risk of postoperative hyperglycemia, however, no increase in surgical site infections was identified.