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Summary The management of high-risk benign breast disease (BBD) is changing because of improvements in radiological and pathological analysis. We sought to determine the current practice recommendations of breast health professionals in managing patients with high-risk BBD. We surveyed members of the Canadian Society of Surgical Oncology, Canadian Association of General Surgeons and Canadian Association of Radiologists. The survey contained demographic and case-based questions concerning management of high-risk benign breast lesions. Participants were asked for their recommendations and opinions regarding future risk of breast cancer as well as the role of chemoprevention. There was no consistency among the 41 respondents in the treatment recommendations for any of the high-risk benign conditions, and the lifetime risk associated with classic lobular carcinoma in situ was vastly underestimated. Education and evidenced-based guidelines are urgently needed to ensure more uniform practice nationally.

FGFR2 fusions, amplifications, and mutations are oncogenic drivers that occur across multiple tumor types. Clinical efficacy observed with pan-FGFR inhibitors has validated the driver status of FGFR2 in FGFR2 fusion-positive intrahepatic cholangiocarcinoma (ICC), however, FGFR1-mediated toxicities (hyperphosphatemia, tissue mineralization) and the emergence of on-target FGFR2 resistance mutations limit the efficacy of pan-FGFR inhibitors. To overcome these limitations, we designed RLY-4008, a potent and highly selective, FGFR2 inhibitor. Despite significant investment in traditional structure-based drug design, selective targeting of FGFR2 has not been achieved. We leveraged differences in conformational dynamics between FGFR2 and other FGFR isoforms observed through molecular dynamics simulations to enable the design of RLY-4008. RLY-4008 inhibits FGFR2 with low nanomolar potency and demonstrates > 200-fold selectivity over FGFR1, and > 80- and > 5000-fold selectivity over FGFR3 and FGFR4, respectively, in biochemical assays. Additionally, RLY-4008 demonstrates high kinome selectivity for FGFR2 against a panel of > 400 human kinases. RLY-4008 has strong activity against primary and acquired FGFR2 resistance mutations in cellular assays, and potent antiproliferative effects on FGFR2-altered human tumor cell lines. In vivo, RLY-4008 demonstrates dose-dependent FGFR2 inhibition and induces regression in multiple human xenograft tumor models, including FGFR2 fusion-positive ICC, gastric, and lung cancers, FGFR2-amplified gastric cancer, and FGFR2-mutant endometrial cancer. Strikingly, RLY-4008 induces regression in an FGFR2 fusion-positive ICC model harboring the FGFR2V564F gatekeeper mutation and an endometrial cancer model harboring the FGFR2N549K mutation, two mutations that drive clinical progression on current pan-FGFR inhibitors. In the FGFR2V564F model, pan-FGFR inhibitors are ineffective, even at maximally tolerated doses. Notably, treatment of these tumors with RLY-4008 induces rapid regression and restores body weight. In rat and dog toxicology studies, RLY-4008 is well tolerated and is not associated with hyperphosphatemia or tissue mineralization at exposures significantly above those required to induce regression in all models. In contrast to pan-FGFR inhibitors, RLY-4008 is highly selective for FGFR2 and demonstrates strong activity against FGFR2 resistance mutations, suggesting that RLY-4008 may have broader therapeutic potential via preventing and overcoming therapeutic resistance. Together, these data and the favorable pharmaceutical properties of RLY-4008 strongly support its clinical development in FGFR2-altered tumors. Citation Format: Jessica Casaletto, Dejan Maglic, B. Barry Toure, Alex Taylor, Heike Schoenherr, Brandi Hudson, Kamil Bruderek, Songping Zhao, Patrick O'Hearn, Nastaran Gerami-Moayed, Demetri Moustakas, Roberto Valverde, Lindsey Foster, Hakan Gunaydin, Pelin Ayaz, Dina Sharon, Donald Bergstrom, James Watters. RLY-4008, a novel precision therapy for FGFR2-driven cancers designed to potently and selectively inhibit FGFR2 and FGFR2 resistance mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1455.

Background: Patients requiring assessment for cancer surgery encounter a complex series of steps in their cancer journey. Further complicating the process is the fact that care is often delivered in a fragmented, silo-based system. Isolated strategies to improve cancer outcomes within those systems have had inconsistent results. Methods: A regional quality improvement collaborative was developed based on a community of practice (cop) platform, a hub-and-spoke infrastructure, and a regional steering committee linking cop improvement projects with affiliated hospitals and their strategic priorities. The cop provided an avenue for multidisciplinary teams to collect and compare their performance data and to institute regional standards through literature review, discussion, and consensus. Regional interdisciplinary teams developed a set of quality indicators linked to mutually agreed-upon care standards. A limited regional database supported feedback about performance against both provincial and regional standards. Results: The cop approach helped to develop a multihospital collaboration that facilitated care quality improvements on a regional scale, with clinical outcomes of the improvements able to be measured. The 9 participating hospitals delivered cancer surgery in the specific disease sites according to practitioner-developed and provincially- or regionally-generated care standards and clinical pathways. Compliance with provincial evidence-based clinical guidelines improved (20% increase in 2010–2011 compared with 2006–2007). Other significant improvements included standardization and implementation of regional perioperative pathways in breast, colorectal, and prostate cancer disease sites; rectal cancer surgery centralization; increased use of sentinel lymph node biopsies in breast cancer surgery; and decreased positive surgical margin rates in prostate cancer. Conclusions: Improved quality is likely a result of diverse confounding factors. The deliberately cultivated multihospital multidisciplinary cops have contributed to positive structural and functional change in cancer surgery in the region. This regional cop model has the potential to play an important role in the development of successful collaborations in care quality improvement.

Background The objective of this study was to compare the effect of thoracic paravertebral block (TPVB) and local anesthetic (LA) on persistent postoperative pain (PPP) 1 year following breast cancer surgery. Secondary objectives were to compare the effect on arm morbidity and quality of life. Methods Women scheduled for elective breast cancer surgery were randomly assigned to either TPVB or LA followed by general anesthesia. An NRS value of >3 at rest or with movement 1 year following surgery defined PPP. Blinded interim analysis suggested rates of PPP much lower than anticipated, making detection of the specified 20 % absolute reduction in the primary outcome impossible. Recruitment was stopped, and all enrolled patients were followed to 1 year. Results A total of 145 participants were recruited; 65 were randomized to TPVB and 64 to LA. Groups were similar with respect to demographic and treatment characteristics. Only 9 patients (8 %; 95 % CI 4–14 %) met criteria for PPP 1 year following surgery; 5 were in the TPVB and 4 in the LA group. Brief Pain Inventory severity and interference scores were low in both groups. Arm morbidity and quality of life were similar in both groups. The 9 patients with PPP reported shoulder-arm morbidity and reduced quality of life. Conclusions This study reports a low incidence of chronic pain 1 year following major breast cancer surgery. Although PPP was uncommon at 1 year, it had a large impact on the affected patients’ arm morbidity and quality of life.

The diagnostic phase of care is an anxiety-provoking and stressful experience for the potential breast cancer patient. A multidisciplinary team of breast cancer specialists embarked on a new initiative to pilot a Rapid Diagnosis and Support (RADS) Clinic to coordinate the diagnostic workup and nursing support for patients with a high probability of breast cancer.Consecutive patients with an initial diagnostic imaging classified as BI-RADS 5 were invited to participate in this 1-year prospective study. Coordination of diagnostic imaging workup and nursing support were provided by a nurse navigator. Wait times were evaluated at several intervals of care. Satisfaction surveys were given to study participants and compared to scores from patients who did not go through RADS clinic.A total of 211 patients participated in the RADS clinic. Biopsy wait times improved from a mean of 7 to 3 days (p0.001), pathology from 3.9 to 3.3 days (p0.001), surgical consultation from 16.1 to 5.9 days (p0.001), and operative wait times from 31.5 to 24.1 days (p = 0.042). There was a 95.3 % satisfaction rate with the RADS clinic with significantly improvement in patients' sense of an understanding of the treatment plan (p = 0.031), timeliness of tests (p = 0.045), and timeliness of results (p = 0.0419).The RADS clinic significantly improved diagnostic wait times and satisfaction scores for patients with a high probability of diagnosis of breast cancer and can serve as an innovative service delivery model for other breast care centers.

To determine whether patients with isolated systolic hypertension (ISH) undergoing non-cardiac surgery have a higher incidence of perioperative myocardial ischemia than normotensive patients and hence a greater risk for perioperative adverse events.After obtaining Research Ethics Board approval, patients were recruited to either an ISH group (systolic blood pressure [SBP] 140 mmHg with diastolic blood pressure [DBP] 90 mmHg) or a normotensive group (SBP 140 mmHg and DBP 90 mmHg), according to their resting preoperative blood pressure. The primary outcome was the overall incidence of perioperative myocardial ischemia (PMI) as determined by 48-hr ambulatory Holter monitoring. P values ≤ 0.05 were considered to be statistically significant.A total of 312 (150 ISH and 162 normotensive) patients completed the study. Orthopedic surgery was the most frequent surgical procedure in both groups. The overall incidence of PMI was 19.7% in the ISH group compared with 18.8% in the normotensive group (difference 0.9%; 95% confidence interval [CI], -7.9% to 9.8%). The overall incidence of adverse events was 4.0% in the ISH group compared with 1.9% in the normotensive group (difference 2.2%; 95% CI, -1.6% to 5.9%).In this study, we chose to examine ISH as potential cardiac risk factor for patients undergoing non-cardiac surgery. The incidence of myocardial ischemia, a surrogate outcome, was similar in the two groups. The relatively high incidence of myocardial ischemia (19.2%) was of particular interest in this relatively low cardiac risk surgical population. (ClinicalTrials.gov number, NCT01237652).

Background: A systematic review of the literature identifying regional collaborations in surgical practice examining practices related to quality improvement. Methods: The MEDLINE, EMBASE, and Cochrane Library databases, were searched for published reports of regional collaborations in the surgical community relating to initiatives to enhance quality improvement, quality of care, patient safety, knowledge transfer, or communities of practice. Results: Seven collaborative initiatives met the inclusion criteria and were included in the systematic review of the evidence. Motivations for initiating collaborations were often in response to external demands for performance data. Changes in the processes of clinical care and improvements in clinical outcomes were reported on the basis of the collaborative efforts. Significant improvements in clinical outcomes such as decreases in mortality rates, lower duration of postoperative intubations, and fewer surgical-site infections were reported. Quality improvement process measures were also reported to be improved across all of the collaborative initiatives. Success factors included (a) the establishment of trust among health professionals and health institutions; (b) the availability of accurate, complete, relevant data; (c) clinical leadership; (d) institutional commitment; and (e) the infrastructure and methodological support for quality management. Conclusions: A community of practice framework incorporating the success elements described in the systematic review of the literature can be used as a valuable model for collaboration amongst surgeons and healthcare organizations to improve quality of care and foster continuing professional development.

Background Surgeons, other healthcare professionals, and patients may identify different health-related concerns related to the quality of life of patients undergoing major surgery. Methods Semistructured interviews were conducted with surgeons (n =14), other healthcare professionals (n =19), and patients undergoing major elective surgery (n = 52). Themes were extracted by content analysis and organized into major domains. The frequencies with which specific themes were mentioned were compared among groups. Results A total of 85 themes were extracted from the interviews, 15 of which were mentioned by 50% or more of participants in each group, representing 5 of the 6 domains. The greatest differences were observed in the domains of social well-being, wherein 5 themes were mentioned less often by surgeons than other groups, and spiritual well-being, wherein 2 themes were mentioned more often by patients than other groups. Differences in the physical, emotional, cognitive preparation, and concern about quality of care domains were minimal. Conclusions Surgeons, other healthcare professionals, and patients identified many similar concerns related to the well-being of patients undergoing major surgery. However, the importance of social and spiritual themes to patients may be underestimated by surgeons.

To evaluate the influence of aging on the increase in endogenous glucose production that follows injury, we studied 22 fully resuscitated, clinically stable, previously healthy patients agedor = 30 yr oror = 60 yr admitted to hospital following injury, and 11 healthy volunteers in the same age groups. Endogenous glucose production was determined using a primed constant infusion of D-glucose-6,6-2d2. Urine cortisol and C-peptide were markedly higher in patients than volunteers (both P0.01), and urine C-peptide was lower in older than in younger patients (P0.05). Urine cortisol increased as a function of the interaction of age and Injury Severity Score (ISS) (r2 = 0.40, P0.001). Intracellular water was markedly lower and extracellular water greater in patients compared with volunteers (both P0.001), reflecting the loss of body cell mass and expansion of the extracellular space following injury. Endogenous glucose production (milligrams per minute per liter intracellular water) was best described as a function of ISS and age-ISS interaction (r2 = 0.35, all P0.05), and was increased 56% and 78% in younger and older patients, respectively, in comparison with the respective volunteer groups. Endogenous glucose production following injury increases in relation to the severity of injury and patient age. Greater cortisol elaboration and diminished insulin secretion in older patients may contribute to this age effect.

Elderly individuals will continue to make up a major portion of patients requiring critical care. Age and chronic disease-related factors blunt the reserves with which the elderly can meet the demands of critical surgical illness. The clinician must remain vigilant to subtle changes in the patient's course which may indicate a developing complication and must pay attention to all the details of comprehensive critical care management. With careful attention and timely physiologic support, the elderly patient has as good a chance of surviving as a similarly ill younger patient, although his or her course may be more prolonged. The priorities are the same. Thus, the primary disease must be addressed: necrotic tissue débrided, pus drained, wounds closed, fractures set. Cardiopulmonary performance (oxygen delivery) must be maintained sufficiently to meet the heightened oxygen needs associated with critical illness. This may require invasive hemodynamic monitoring and pharmacologic support. Gas exchange in the lungs must be maintained without compromising cardiovascular function or exhausting the patient. Patients should be kept warm, pain free, and calm. Intravascular volume and the composition of the extracellular fluid must be maintained. Nutritional support should be provided early in amounts sufficient to meet the patient's basal nutritional requirements and increased needs associated with the critical illness. If at all possible, some or all of this nutritional support should be provided via the gastrointestinal tract. The use of specialized nutrients or of agents designed to minimize the catabolism of critical illness or to enhance anabolism is an area of active investigation. The indications for these therapeutic strategies in the elderly should become clearer in the years ahead.

OBJECTIVE To quantify glucose balance related to continuous arteriovenous hemofiltration (CAVH) when a glucose-rich replacement fluid is used for the plasma ultrafiltrate removed. DESIGN Prospective, nonintervention study. SETTING Medical/surgical and cardiac surgical intensive care units of a university hospital. PATIENTS Critically ill patients (n = 20) with acute oliguric renal failure undergoing CAVH. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Timed collections of CAVH effluent were analyzed and other observations were made. Serum creatinine and blood urea nitrogen concentrations decreased substantially during CAVH in each patient. The mean measured glucose concentration of the replacement fluid (Dianeal 1.5%) was 1.40 +/- 0.11 (SD) g/dL (77 +/- 6 mmol/L) and rate of infusion was 1.39 +/- 0.43 L/hr. Effluent volume was 1.51 +/- 0.49 L/hr and glucose was 0.47 +/- 0.10 g/dL (26 +/- 5 mmol/L). The glucose content of the replacement fluid infused was consistently and substantially greater than that value of the effluent removed during the same period. Thus, the average net glucose uptake in relation to the CAVH circuit was 11.9 +/- 3.1 g/hr (range 4.3 to 17.6). Serum glucose concentrations increased in each patient with initiation of CAVH (from 135 +/- 44 to 278 +/- 80 mg/dL [7.4 +/- 2.4 to 15.3 +/- 4.4 mmol/L]; p < .001). Negative fluid balance achieved during CAVH was approximately 100 mL/hr. CONCLUSIONS CAVH using predilution with replacement fluid is effective in managing uremia and fluid overload in critically ill patients. The use of a glucose-rich replacement fluid is accompanied by the net uptake of large amounts of glucose, approaching 300 g/day on average in our patients and representing a major exogenous calorie source. This finding has important implications for the metabolic management of critically ill patients during CAVH and should be taken into account in prescribing their nutritional support.

Advancing age tends to be accompanied by predictable changes in organ-system function and body composition, as well as an increased prevalence of various diseases. Our knowledge of the metabolic responses to surgical stress is derived largely from studies of young and middle-aged individuals. Whether these responses are altered in the elderly is not well established; the characteristic changes in metabolic function and body composition that occur in the elderly may limit their ability to respond adequately and to survive severe or complicated surgical procedures. To evaluate the effects of age and differences in body composition on the metabolic responses to surgery, we studied 20 active and otherwise healthy men aged 43 to 77 years, before and after elective colon resection. Age was not related to weight or total body water (TBW) in the patients studied. Resting preoperative energy expenditure was strongly dependent on TBW (reflecting lean body mass) and age (r2 = 0.80, p less than 0.001), and to TBW and creatinine excretion (reflecting muscle mass) (r2 = 0.85, p less than 0.001). Energy expenditure increased 18 +/- 2% (range, 4% to 40%) after operation but this response was unrelated to age. Postoperative urine nitrogen was related to body weight or TBW, but not to age. Serum glucose, cortisol, white blood cell count count, and C-reactive protein responses were also independent of patient age. The metabolic responses of generally healthy men to a moderate surgical stress do not vary with age in the range studied. The metabolic responses to more severe or prolonged stress may be altered with advancing age and changes in body composition, and in patients with concomitant diseases.

This study examined themes relevant to health-related quality of life as identified by patients undergoing major surgery and by health care providers. Semi-structured interviews were conducted with 52 patients undergoing major abdominal, cardiac, orthopedic, thoracic, or vascular surgical procedures and 33 health professionals from various disciplines. A total of 58 themes were identified by content analysis. These themes were categorized into 6 domains. These were: physical well-being (14 themes), emotional well-being (13 themes), concern about quality of care (12 themes), social well-being (12 themes), cognitive preparation (4 themes), and spiritual well-being (3 themes). In general, we found that most aspects of health-related quality of life were common across various major surgical procedures and between patients and health care providers. However, when we examined the coverage of these themes in seven commonly-used health-related quality of life instruments, we found that many of the most frequently mentioned themes were not assessed with the available measures. A new evaluative instrument tailored to patients undergoing major surgery may therefore be warranted.

Older trauma patients are less tolerant of glucose loads than are young patients, in part as a result of diminished insulin response. We hypothesized that diminished insulin responses result from reduced pancreatic sensitivity to beta-adrenergic stimulation.We studied healthy subjects prospectively at a clinical investigation unit, to compare young (n = 6, mean age 21 [standard deviation {SD} 2] yr) and older people (n = 6, mean 63 [SD 2] yr). Paired studies of isoproterenol infusion, alone and in conjunction with a 2-hour hyperglycemic glucose clamp, were conducted in each subject. Heart rate, serum insulin concentration and other hemodynamic, biochemical, and physiologic variables were measured.Heart rate increased less markedly in response to isoproterenol in older than in young subjects (p0.01). Serum insulin during infusion accompanied by hyperglycemic clamp was also lower (467 [SD 135] pmol/L in older v. 755 [SD 284] pmol/L in young subjects, p0.05), despite similar hyperglycemia. Whole-body disposal of exogenous glucose was lower in older (5.8 [SD 1.7] mg/kg/min) than in young subjects (9.6 [SD 3.9], p0.05).Heart rate and serum insulin responses to combined isoproterenol infusion and glucose loading were both lower in healthy older subjects than in the young. Diminished tissue sensitivity to beta-adrenergic signals may contribute to the impaired insulin response and exaggerated glucose intolerance displayed by older patients after injury and during acute illness.

Background: Tissue injury following ischemia–reperfusion is mediated in part by free oxygen radicals. We hypothesized that perioperative micronutrient supplementation would augment antioxidant defenses, minimize muscle injury, and minimize postoperative decreases in muscle strength and physical function following abdominal aortic aneurysmectomy. Setting: A university-affiliated hospital and regional referral center. Design: A randomized, double-blind, placebo-controlled trial of supplementation with beta-carotene, vitamins C and E, zinc, and selenium for a period of 2––3 weeks prior to surgery and 1 week thereafter. Study population: Patients undergoing elective abdominal aortic aneurysmectomy ( n =18 per group). Principal measurements: Handgrip and other measures of strength and physical function. Results: Handgrip and quadriceps strength decreased following surgery, but not to a significantly different extent in the placebo and supplemented groups. Self-rated physical function decreased following surgery in the placebo group and was preserved in the supplemented group. Conclusions: Perioperative supplementation with micronutrients with antioxidant properties has limited effects on strength and physical function following major elective surgery.

Disruption of the interaction between p53 and MDM2 with small molecules, and subsequent reactivation of p53, is an attractive treatment strategy for p53 wild-type tumors that has shown striking pre-clinical activity in models exhibiting genomic amplification of the MDM2 gene. However, MDM2 amplified tumors represent only a small proportion of the p53 wild-type tumor population, and single agent regressions may be limited outside of the MDM2 amplified context. In order to increase the potential clinical benefit of MDM2-p53 protein-protein interaction (PPI) inhibitors beyond tumors exhibiting amplification of MDM2, we performed an enhancer library combination screen to identify optimal combination partners for MDM2-p53 PPI inhibitors in p53 wild-type, MDM2 non-amplified tumor cells. The MDM2-p53 PPI inhibitor SAR405838 and a related molecule were examined in combination with an enhancer library of 200 oncology drugs representing a broad molecular diversity of targets across a panel of twenty p53 wild-type cancer cell lines. Analysis results showed that MEK inhibitors were the most statistically significant synergistic combination partners in this screen, with synergy observed in cell lines harboring mutations that activated MAP kinase pathway signaling. These synergy results were validated in independent experiments using the ray design methodology, and extended to multiple K-ras, N-ras and B-raf mutant contexts in vitro. In K-ras, N-ras or B-raf mutant cell lines, the combination of SAR405838 with the MEK inhibitor pimasertib resulted in p53 pathway activation, inhibition of pERK levels, induction of the apoptotic mediators PUMA and BIM, induction of phosphatidyl serine exposure, and induction of caspase activity. In the Ras/Raf wild-type cell line MCF7, no synergy was observed. In cell line and patient-derived xenografts in vivo, the combination of SAR405838 and pimasertib resulted in greater anti-tumor activity than single agents and induced regression in K-ras, N-ras and B-raf mutant tumor models derived from different tissue types, including complete regressions in multiple models. These data indicate that MEK inhibitors synergize with MDM2-p53 PPI inhibitors in tumor models that exhibit activated MAP kinase pathway signaling and p53 wild-type status. Given the relative lack of overlapping clinically significant toxicities of MDM2-p53 PPI inhibitors and MEK inhibitors, such a combination merits further investigation for the treatment of K-ras, N-ras, or B-raf mutant, p53 wild-type tumors, representing a large patient population with significant unmet medical need. Citation Format: Isabelle Meaux, Jean-Paul Nicolas, Steve Rowley, Sukhvinder Sidhu, Francoise Herve, Laurent Dassencourt, Fanny Windenberger, Dimitri Gorge-Bernat, Pascal Pannier, Donald Bergstrom, Laurent Debussche, James Watters. Disruption of the MDM2-p53 interaction synergizes with MEK inhibition to induce cell death and promote tumor regression in p53 wild-type, Ras or Raf-mutant tumor models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 805. doi:10.1158/1538-7445.AM2014-805

Age and gender are important variables relevant to the design and analysis of many clinical studies. Aging is accompanied by physiologic changes that alter host responses to surgical illness, changing patterns of disease (e.g., a preponderance of perforated vs. nonperforated appendicitis), changing disease frequency (e.g., increased incidence of many types of cancer), and greater morbidity and mortality following surgery, trauma, and critical illness. Gender-dependent differences in clinical outcomes from trauma, sepsis, and other conditions have been identified in a number of studies, although such findings are not universal or fully consistent. However, they are nonspecific descriptors in that they convey a range of biological, cultural and other influences, and are surrogates for other variables. The investigator must focus and formulate the research question carefully with this in mind. When age or gender is the primary variable, human studies are necessarily observational, because randomization on age and gender are not feasible. Descriptive and prognostic analyses of such studies are straightforward; establishing causal inferences requires careful study design and planning of the statistical analysis.

470 Background: A comprehensive molecular characterization of primary colorectal cancers (CRC) was recently reported. Less is known about mutation patterns in CRC metastases and association with survival. Our sequencing analysis focused on CRC liver metastases with RAS/RAF mutations, representing a patient population with limited therapeutic options. Methods: DNA was extracted from formalin-fixed paraffin-embedded CRC liver metastases. Fifty tumors found by Sequenom MassARRAY to harbor KRAS, NRAS or BRAF mutations underwent next generation sequencing on the Ion AmpliSeq Comprehensive Cancer Panel of 409 genes. Co-investigators were blinded to Sequenom mutations identified at UCSF. Variants called by Strelka and VarScan were extensively filtered to control the False Positive Rate and find mutations occurring with > 5-10% variant allele frequency compared to normals. The dataset was evaluated for significant co-mutations, biclustering, and population probabilities of mutations. Results: Following sequencing, 37,744 variants were called in 409 genes with a median coverage depth of 1053x. After filtering to minimize false positives, 2335 variants in 315 genes remained. ARID1A and PIK3R1 were the most significantly associated co-mutation pair, P < 3.5e-5. Biclustering showed no stratification of patients; genes stratified only by mutation frequency. Further filtering yielded 1,186 variants present at < 1% allele frequency within 1,000 Genomes, of which 131 variants in 24 genes are referenced in the Catalog of Somatic Mutations in Cancer. In addition to anticipated mutations in mismatch repair genes and the RTK/RAS/PI3K, Wnt, TP53, and TGF beta pathways, infrequent mutations were found in Akt1, mTOR, MET and PPP2R1a. After APC, TP53 was the most commonly mutated gene, in 44% of the tumors (95% cl: 31.1% - 57.8%). Survival was similar with mutation of RAS/RAF plus either TP53 or PIK3CA. Conclusions: Next generation sequencing was used to characterize co-variants in RAS/RAF mutated CRC liver metastases. The complexity of our results is consistent with the clinical observation that targeting RAS/RAF mutated metastatic CRC is a formidable challenge. These analyses may nonetheless inform the design of future clinical trials.

OBJECTIVE: The authors set out to determine whether immediate enteral feeding minimizes early postoperative decreases in handgrip and respiratory muscle strength. SUMMARY BACKGROUND DATA: Muscle strength decreases considerably after major surgical procedures. Enteral feeding has been shown to restore strength rapidly in other clinical settings. METHODS: A randomized, controlled, nonblinded clinical trial was conducted in patients undergoing esophagectomy or pancreatoduodenectomy who received immediate postoperative enteral feeding via jejunostomy (fed, n = 13), or no enteral feeding during the first 6 postoperative days (unfed, n = 15). Handgrip strength, vital capacity, forced expiratory volume in one second (FEV1), and maximal inspiratory pressure (MIP) were measured before surgery and on postoperative days 2, 4, and 6. Fatigue and vigor were evaluated before surgery and on postoperative day 6. Mobility was assessed daily after surgery using a standardized descriptive scale. Postoperative urine biochemistry was evaluated in daily 24-hour collections. RESULTS: Postoperative vital capacity (p < 0.05) and FEV1 (p = 0.07) were consistently lower (18%-29%) in the fed group than in the unfed group, whereas grip strength and maximal inspiratory pressure were not significantly different. Postoperative mobility also was lower in the fed patients (p < 0.05) and tended to recover less rapidly (p = 0.07). Fatigue increased and vigor decreased after surgery (both p < or = 0.001), but changes were similar in the fed and unfed groups. Intensive care unit and postoperative hospital stay did not differ between groups. CONCLUSIONS: Immediate postoperative jejunal feeding was associated with impaired respiratory mechanics and postoperative mobility and did not influence the loss of muscle strength or the increase in fatigue, which occurred after major surgery. Immediate postoperative enteral feeding should not be routine in well-nourished patients at low risk of nutrition-related complications.

68 Background: The Ottawa CoP model for developing multidisciplinary practitioner networks and integrating them with organizational processes was established in 2007 as a platform improving access to quality cancer surgery in one of the health regions (population 1,276,370) of Ontario, Canada. The three inter-disciplinary CoP collaboratives in breast, colorectal, and prostate cancer involve 230 care providers from 9 hospitals performing over 2,000 cancer surgeries per year. Objectives: 1) to address lack of coordination and standardization of care, 2) develop a regional platform for quality initiatives, and 3) bridge the gap between academic and community hospitals. Methods: Using the model, an academic tertiary care hospital and eight community hospitals partnered to support a regional quality improvement initiative that combines 1) educational outreach with audit and feedback to address variations in practice and 2) a unique platform for knowledge generation and innovation. Regional interdisciplinary teams developed a set of regional quality indicators (18) linked to mutually agreed standards and pathways. Regional registry was established to provide data feedback on performance against both provincial and regional standards. Best practices, innovations, and implementation progress are reviewed through sustained interactions between CoP members. Patient and care provider surveys are conducted. Results: The development and implementation of regional care standards and clinical pathways for three disease sites in 9 hospitals. Regional pathway compliance ranged 65-94%. Other significant improvements include: rectal cancer surgery centralization (80-90% per annum), increase in use of sentinel lymph node biopsies in breast cancer surgery (60-77% per annum) and a decreased positive prostate cancer surgical margin rate form 45% to 22%. Compliance with provincial guidelines for colon cancer surgery improved (20% increase 2006/2007 vs. 2010/2011). Increase in patient access to high-quality cancer surgery closer to home. Conclusions: Participation in the regional CoPs is associated with quality improvements at the system, patient, and professional levels.

Hyperglycemia and glucose intolerance are characteristic of both the metabolic responses to injury and normal aging. To evaluate the interaction of such changes we conducted hyperglycemic glucose clamp studies (2-hour) in previously healthy young (20 +/- 4 years, Mean +/- SD) and older (73 +/- 9 years) trauma patients and volunteers (23 +/- 1 and 68 +/- 5 years), determining whole-body glucose disposal and insulin responses to hyperglycemia. Injury Severity Scores were similar in the young and older patient groups (range, 17-30). Plasma glucose levels were greater in patients than volunteers in both the basal and hyperglycemic periods. Basal serum insulin and C-peptide levels were similar among groups, but during hyperglycemia both were markedly higher in young patients than older (and both volunteer groups). Whole-body disposal of exogenous glucose was substantially lower in patients than volunteers and in the older groups. Aging has a major impact on postinjury metabolism, being associated with exaggerated glucose intolerance and diminished insulin responses to glucose infusion. These findings have important implications for the metabolic and nutritional care of older patients following trauma and during critical illness.

Our objective was to determine the effect of perioperative epidural anaesthesia and analgesia on the increase in energy expenditure which accompanies major elective abdominal surgery in a prospective, randomized study. Eight patients undergoing elective resections of the colon and/or rectum received general anaesthesia alone (nitrous oxide, oxygen, and isoflurane, supplemented with intravenous fentanyl to a maximum of 10 μg · kg−1), and 12 patients received perioperative epidural anaesthesia and analgesia using lidocaine (carbonated lidocaine 2% with epinephrine 1:200,000, 20 ml over 30 min) and morphine (preservative-free morphine 0.10 mg · kg−1 after catheter insertion and 0.05 to 0.10 mg · kg−1 every 12 hr as needed until the morning following surgery) via a lower lumbar catheter in addition to general anaesthesia. Respiratory gas exchange was measured using a metabolic cart and canopy system early on the morning of surgery, six hours postoperatively, and on the first and second postoperative mornings. Parenteral analgesic administration (P < 0.001) and visual analogue pain scores (P < 0.05) were lower in the patients receiving epidural anaesthesia and time to first parenteral analgesia was longer (P< 0.005). Oxygen consumption, carbon dioxide production, and energy expenditure increased after surgery (all P < 0.001) but were very similar in the two groups (all P ≥ 0.8) before and after surgery. Despite substantial effects on postoperative pain, we conclude that oxygen consumption and energy expenditure following major abdominal surgery are not diminished by perioperative epidural anaesthesia and analgesia.

To investigate the role of hormones as mediators of the metabolic response to injury, nine normal male volunteers received a continuous 74-hour infusion of the three 'stress' hormones: cortisol, glucagon, and epinephrine. As a control, each subject received a saline infusion during another 4-day period. Diets were constant and matched on both occasions. Hormonal infusion achieved hormone concentrations similar to those seen following mild-moderate injury. With this alteration in the endocrine environment significant hypermetabolism, negative nitrogen and potassium balances, glucose intolerance, hyperinsulinemia, insulin resistance, sodium retention, and peripheral leukocytosis were observed. Additional studies with single hormone infusions indicated that these responses resulted from both additive and synergistic interactions of the hormones. Triple hormone infusion simulated many of the metabolic responses observed following mild-moderate injury and other catabolic illnesses.

Although gastroduodenal ulcers rarely perforate during critical illness, this occurrence causes specific and difficult problems of diagnosis and management. In our review of the records of 19 critically ill patients whose ulcers perforated, we found that classical symptoms were frequently absent. The perforations often were manifested by nonspecific clinical events, such as unexplained ileus or hypotension. Diagnosis was typically delayed and on occasion was first suspected after observing pneumoperitoneum on a routine x-ray. While the ulcers were characteristically very large (greater than 2 cm), minimal inflammation surrounded them. Mortality was 56% in the 16 patients whose perforations were diagnosed before death or discharge. Fifteen patients were treated with simple patching of the ulcer. Perforated ulcers in critically ill patients differ in several important ways from those occurring in otherwise healthy individuals.

Peripheral parenteral nutrition can provide perioperative nutritional support to patients with inadequate oral intake in whom total parenteral nutrition with hypertonic dextrose administered by a central vein cannot be undertaken because of sepsis, subclavian vein thrombosis, or lack of expertise and familiarity. Peripheral parenteral nutrition may be indicated in patients with marginal nutritional status whose postoperative course and period of starvation are unpredictable and in patients being started on a total enteral nutrition regimen. In patients with increased requirements because of stress or malnutrition who need full nutritional support by a peripheral method, the lipid system is indicated. In certain instances, large enough volumes can be infused to provide sufficient calories and protein for nutritional repletion. Protein-sparing therapy is indicated for nutritional maintenance in patients who do not clearly require full support by total parenteral nutrition but who are taking insufficient calories and protein orally. Peripheral parenteral nutrition avoids the risks of subclavian vein catheterization but requires that adequate peripheral veins are available. The metabolic complications are minimal compared with those of total parenteral nutrition, and the nutritional management of the diabetic patient is greatly simplified. Several techniques of preserving peripheral veins and prolonging their use have been discussed.

• Host responses to sepsis and trauma are complex and their mediators are not well understood. To examine the roles of "endocrine" and "inflammatory" mediators, we studied healthy volunteers in four experimental groups: continuous 72-hour infusion of normal saline; continuous 72-hour infusion of hydrocortisone, glucagon, and epinephrine; daily intramuscular injection of the inflammatory agent etiocholanolone; and combined etiocholanolone injection—hormone infusion. In this model hypermetabolism, hyperglycemia, hyperinsulinemia, insulin resistance, negative nitrogen balance, and accelerated protein flux were mediated predominantly by infusion of the counterregulatory hormones. Etiocholanolone injection resulted in fever, acute-phase—protein synthesis, and hypoferremia. Leukocyte, temperature, and C-reactive—protein responses reflected major interactions between these stimuli. Both inflammatory and endocrine mediators are necessary for the complete manifestation of host responses to critical illness. (Arch Surg1986;121:179-190)

• Acute infection initiates fever, acute-phase changes, and catabolic responses in the host, resulting in weight loss, hypermetabolism, and accelerated proteolysis. To test the hypothesis that cyclo-oxygenase inhibition might attenuate these responses, we administered Escherichia coli endotoxin intravenously to seven normal volunteers and to seven additional subjects pretreated with a cyclo-oxygenase inhibitor (ibuprofen). Control studies were also performed following administration of saline and ibuprofen alone. Vital signs, metabolic rate, and concentrations of pituitary and stress hormones, as well as those of other substrates, were serially measured. Endotoxin administration produced a response similar to an acute illness, with flulike symptoms, fever, tachycardia, increased metabolic rate, and stimulation of stress hormone release. These changes were markedly attenuated by cyclo-oxygenase inhibition. The leukocytosis, hypoferremia, and elevation of the C-reactive protein level induced by endotoxin were unaffected by cyclo-oxygenase inhibition. These data indicate that activation of the cyclooxygenase pathway is necessary to produce many of the metabolic changes observed during critical illness. ( Arch Surg 1988;123:162-170)