Integrating Patient-Reported Outcomes Into Prognostication in Gastroesophageal Cancer: Results of a Population-Based Retrospective Cohort Analysis.

BACKGROUND: Patient-reported outcomes measures (PROM) are self-reflections of an individual's physical functioning and emotional well-being. The Edmonton Symptom Assessment Scale (ESAS) is a simple and validated PRO tool of 10 common symptoms and a patient-reported functional status (PRFS) measure. The prognostic value of this tool is unknown in patients with gastroesophageal cancer (GEC). In this study, we examined the association between the ESAS score and overall survival (OS) in patients with GEC, the prognostication difference between ESAS and Eastern Cooperative Oncology Group (ECOG), and assessed the correlation between PRFS and the physician-reported ECOG performance status (PS). METHODS: The study was a retrospective cohort study of 211 patients with GEC with localized (stages I-III) and metastatic disease who completed at least one baseline ESAS prior to treatment. Patients were grouped into 3 cohorts based on ESAS score. OS was assessed using the Kaplan-Meier method, and the concordance index (c-index) was calculated for ESAS and physician-reported ECOG. The agreement between PRFS and physician-ECOG was also assessed. RESULTS: In total, 211 patients were included. The median age was 60.8 years; 90% of patients were ECOG PS 0-1; 38% of patients were stages I-III, while 62% were de novo metastatic patients. Median OS in low, moderate, high symptom burden (SB) patients' cohorts was 19.17 m, 16.39 mm, and 12.68 m, respectively (P < .04). The ability to predict death was similar between physician-ECOG and ESAS (c-index 0.56 and 0.5753, respectively) and PRFS and physician-ECOG (c-index of 0.5615 and 0.5545, respectively). The PS agreement between patients and physicians was 50% with a weighted Kappa of 0.27 (95% CI: 0.17-0.38). CONCLUSION: Patient's SB seems to carry a prognostic significance. ESAS and physician-reported ECOG exhibit comparable prognostic values. Physicians and patients can frequently have divergent opinions on PS. ESAS takes a patient-centered approach and should be encouraged in practice among patients with GEC as an additional tool for prognostication.

Changes in New Patient Consultations During the COVID-19 Pandemic at a Canadian Comprehensive Cancer Center.

BACKGROUND: The impact of COVID-19 pandemic-related disruptions on cancer services is emerging. We evaluated the impact of the first 2 years of the pandemic on new patient consultations for all cancers at a comprehensive cancer center within a publicly funded health care system and assessed whether there was evidence of stage shift. METHODS: We performed a retrospective study using the Princess Margaret Cancer Registry. New consultations with medical, radiation, or surgical oncology were categorized by year and quarter. Logistic regression was used to assess the effect of period before and during the COVID-19 pandemic on cancer stage at consultation, adjusting for age, sex, and diagnosis location (our hospital network vs elsewhere). RESULTS: In all, 53,759 new patient consultations occurred from January 1, 2018, to June 30, 2022. After the pandemic was declared, there was a decrease in all types of consultations by 43.3% in the second quarter of 2020, and referral volumes did not recover during the first year. There was no evidence of stage shift for all cancer types during the later quarters of the pandemic for the overall population. CONCLUSIONS: New patient consultations decreased across cancer stages, referral type, and most disease sites at our tertiary cancer center. We did not observe evidence of stage shift in this population. Further research is needed to determine whether this reflects the resilience of our health care system in maintaining cancer services or a delay in the presentation of advanced cancer cases. These data are important for shaping future cancer care delivery and recovery strategies.

Leptomeningeal carcinomatosis and brain metastases in gastroesophageal carcinoma: a real-world analysis of clinical and pathologic characteristics and outcomes.

BACKGROUND: Brain metastasis (BrM) and Leptomeningeal Carcinomatosis (LMC) are uncommon complications in gastroesophageal carcinoma (GEC) patients. These patients have a poor prognosis and are challenging to treat. We described the clinicopathologic features and outcomes in the largest cohort of Central Nervous System (CNS) metastasis in GEC patients. METHODS: single-center retrospective study of GEC treated from 2007 to 2021. Clinicopathologic characteristics and treatment modalities were reviewed. Survival was calculated from the date of CNS diagnosis until date of death/last follow-up using the Kaplan-Meier method. A multivariable Cox proportional hazards regression model was used. RESULTS: Of 3283 GEC patients, 100 (3.04%) were diagnosed with BrM and 20 with LMC (0.61%). Patients with known human epidermal growth factor receptor 2 (HER2) status (N = 48), 60% were HER2 positive (defined as IHC 3 + or IHC 2+/FISH+). Among LMC patients most were signet-ring subtype (85%), and only 15% (2/13) were HER2 positive. Median survival was 0.7; 3.8; and 7.7 months in BrM patients treated with best supportive care, radiation, and surgery, respectively (p < 0.001). In LMC, median survival was 0.7 month in patients who had best supportive care (7/19) and 2.8 months for those who had whole brain radiation therapy (p = 0.015). Multivariate analysis showed worse outcomes in ECOG ≥ 2 (p = 0.002), number of BrM ≥ 4 (p < 0.001) and number of metastatic sites (p = 0.009). CONCLUSION: HER2 expression were enriched in patients with BrM, while it is uncommon in LMC. Patients treated with surgery followed by radiation had an improved OS in BrM and WBRT benefited patients with LMC.

Surrogate Humane Endpoints in Small Animal Models of Acute Lung Injury: A Modified Delphi Consensus Study of Researchers and Laboratory Animal Veterinarians.

OBJECTIVES: In many jurisdictions, ethical concerns require surrogate humane endpoints to replace death in small animal models of acute lung injury. Heterogenous selection and reporting of surrogate endpoints render interpretation and generalizability of findings between studies difficult. We aimed to establish expert-guided consensus among preclinical scientists and laboratory animal veterinarians on selection and reporting of surrogate endpoints, monitoring of these models, and the use of analgesia. DESIGN: A three-round consensus process, using modified Delphi methodology, with researchers who use small animal models of acute lung injury and laboratory animal veterinarians who provide care for these animals. Statements on the selection and reporting of surrogate endpoints, monitoring, and analgesia were generated through a systematic search of MEDLINE and Embase. Participants were asked to suggest any additional potential statements for evaluation. SETTING: A web-based survey of participants representing the two stakeholder groups (researchers, laboratory animal veterinarians). Statements were rated on level of evidence and strength of support by participants. A final face-to-face meeting was then held to discuss results. SUBJECTS: None. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Forty-two statements were evaluated, and 29 were rated as important, with varying strength of evidence. The majority of evidence was based on rodent models of acute lung injury. Endpoints with strong support and evidence included temperature changes and body weight loss. Behavioral signs and respiratory distress also received support but were associated with lower levels of evidence. Participants strongly agreed that analgesia affects outcomes in these models and that none may be necessary following nonsurgical induction of acute lung injury. Finally, participants strongly supported transparent reporting of surrogate endpoints. A prototype composite score was also developed based on participant feedback. CONCLUSIONS: We provide a preliminary framework that researchers and animal welfare committees may adapt for their needs. We have identified knowledge gaps that future research should address.

Adjuvant Trastuzumab Therapy: Can We Balance Efficacy and Safety?

Trastuzumab is an effective treatment for HER2-positive breast cancer. Current guidelines recommend withholding trastuzumab in patients experiencing a significant asymptomatic decline in left ventricular function. In this commentary, we discuss the survival benefits afforded by trastuzumab juxtaposed against the risk of trastuzumab-mediated cardiotoxicity. It is not known whether the net benefit of continuing trastuzumab in the setting of mild cardiotoxicity outweighs the associated risks. We describe a potential approach undertaken by our group, and others, and call for a randomized trial.

Coronary artery disease affects cortical circuitry associated with brain-heart integration during volitional exercise.

This study tested the hypothesis that coronary artery disease (CAD) alters the cortical circuitry associated with exercise. Observations of changes in heart rate (HR) and in cortical blood oxygenation level-dependent (BOLD) images were made in 23 control subjects [control; 8 women; 63 ± 11 yr; mean arterial pressure (MAP): 90 ± 9 mmHg] (mean ± SD) and 17 similarly aged CAD patients (4 women; 59 ± 9 yr; MAP: 87 ± 10 mmHg). Four repeated bouts each of 30%, 40%, and 50% of maximal voluntary contraction (MVC) force (LAB session), and seven repeated bouts of isometric handgrip (IHG) at 40% MVC force (fMRI session), were performed, with each contraction lasting 20 s and separated by 40 s of rest. There was a main effect of group (P = 0.03) on HR responses across all IHG intensities. Compared with control, CAD demonstrated less task-dependent deactivation in the posterior cingulate cortex and medial prefrontal cortex, and reduced activation in the right anterior insula, bilateral precentral cortex, and occipital lobe (P < 0.05). When correlated with HR, CAD demonstrated reduced activation in the bilateral insula and posterior cingulate cortex, and reduced deactivation in the dorsal anterior cingulate cortex, and bilateral precentral cortex (P < 0.05). The increased variability in expected autonomic regions and decrease in total cortical activation in response to the IHG task are associated with a diminished HR response to volitional effort in CAD. Therefore, relative to similarly aged and healthy individuals, CAD impairs the heart rate response and modifies the cortical patterns associated with cardiovascular control during IHG.

Ultrasound-Guided Subclavian Vein Catheterization: A Systematic Review and Meta-Analysis.

OBJECTIVE: Although ultrasound guidance for subclavian vein catheterization has been well described, evidence for its use has not been comprehensively appraised. Thus, we conducted a systematic review and meta-analysis to determine whether ultrasound guidance of subclavian vein catheterization reduces catheterization failures and adverse events compared to the traditional "blind" landmark method. All forms of ultrasound were included (dynamic 2D ultrasound, static 2D ultrasound, and Doppler). DATA SOURCES: Medline, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and CINAHL (from inception to September 2014). STUDY SELECTION: Randomized controlled trials of ultrasound compared to landmark technique for subclavian catheterization in adult populations were considered. Outcomes of interest included safety and failure of catheterization. DATA EXTRACTION: Adverse event data were analyzed according to Peto's method and expressed as odd ratios and 95% CIs. Failure of catheterization was analyzed with inverse variance random effects modeling and expressed as risk ratios and 95% CI. DATA SYNTHESIS: Six hundred and one studies were reviewed and 10 met inclusion criteria (n = 2,168 participants). Six used dynamic 2D ultrasound (n = 719), one used static 2D ultrasound (n = 821), and three used Doppler-guided insertion techniques (n = 628). Overall complication rates were reduced with ultrasound use compared to the landmark group (odd ratio, 0.53; 95% CI, 0.41-0.69). Subgroup analysis demonstrated that dynamic 2D ultrasound reduced inadvertent arterial puncture, pneumothorax, and hematoma formation. No difference in failure of catheterization was noted between the ultrasound group and the landmark method (risk ratio, 0.85; 95% CI, 0.48-1.51). Subgroup analysis of dynamic 2D ultrasound demonstrated a significant decrease in failed catheterization (risk ratio, 0.24; 95% CI, 0.06-0.92). CONCLUSIONS: Ultrasound-guided subclavian catheterization reduced the frequency of adverse events compared with the landmark technique. Our findings support the use of dynamic 2D ultrasound for subclavian catheterization to reduce adverse events and failed catheterization.

Sex difference in the influence of central blood volume mobilization on the exercise pressor response.

PURPOSE: To determine the sex difference in the impact of central venous pressure (CVP) on the pressor response induced by ischemic handgrip exercise. METHODS: Twelve young healthy individuals (six males, 25 ± 3 years) performed ischemic handgrip exercise during mild levels of lower body negative pressure (LBNP, -5 mmHg) and during a 10° head-down tilt (HDT) to lower and increase CVP, respectively. The protocol consisted of 3 min of baseline ischemia, followed by 2 min of isometric handgrip exercise at 35 % of maximal voluntary contraction force, and 2 min of post-exercise circulatory occlusion. Mean arterial pressure (MAP) was assessed continuously by finger plethysmography and CVP was estimated from the venous pressure of the non-exercising dependent arm. RESULTS: Baseline CVP was greater during HDT than LBNP (8.4 ± 1.8 vs. 6.5 ± 1.8 mmHg, p < 0.01). MAP was greater during LBNP than HDT throughout the protocol (p = 0.05). During ischemic handgrip exercise, CVP increased in males but not in females (Group × protocol interaction: p = 0.01). A group × condition interaction was also observed for MAP, with males showing a greater MAP during LBNP than HDT (110 ± 2 vs. 103 ± 2 mmHg, p < 0.01). CONCLUSIONS: Baseline CVP inversely affected the pressor response to handgrip exercise in all individuals, with a greater MAP response observed during LBNP than HDT. Increase in CVP in males may be due to a greater splanchnic vasoconstrictor response to ischemic handgrip exercise. Therefore, combined baseline CVP and changes in CVP likely contributed to the greater MAP response observed during LBNP in males.

Inhibition of human lung cancer cell proliferation and survival by wine.

BACKGROUND: Compounds of plant origin and food components have attracted scientific attention for use as agents for cancer prevention and treatment. Wine contains polyphenols that were shown to have anti-cancer and other health benefits. The survival pathways of Akt and extracellular signal-regulated kinase (Erk), and the tumor suppressor p53 are key modulators of cancer cell growth and survival. In this study, we examined the effects of wine on proliferation and survival of human Non-small cell lung cancer (NSCLC) cells and its effects on signaling events. METHODS: Human NSCLC adenocarcinoma A549 and H1299 cells were used. Cell proliferation was assessed by thymidine incorporation. Clonogenic assays were used to assess cell survival. Immunoblotting was used to examine total and phosphorylated levels of Akt, Erk and p53. RESULTS: In A549 cells red wine inhibited cell proliferation and reduced clonogenic survival at doses as low as 0.02%. Red wine significantly reduced basal and EGF-stimulated Akt and Erk phosphorylation while it increased the levels of total and phosphorylated p53 (Ser15). Control experiments indicated that the anti-proliferative effects of wine were not mediated by the associated contents of ethanol or the polyphenol resveratrol and were independent of glucose transport into cancer cells. White wine also inhibited clonogenic survival, albeit at a higher doses (0.5-2%), and reduced Akt phosphorylation. The effects of both red and white wine on Akt phosphorylation were also verified in H1299 cells. CONCLUSIONS: Red wine inhibits proliferation of lung cancer cells and blocks clonogenic survival at low concentrations. This is associated with inhibition of basal and EGF-stimulated Akt and Erk signals and enhancement of total and phosphorylated levels of p53. White wine mediates similar effects albeit at higher concentrations. Our data suggest that wine may have considerable anti-tumour and chemoprevention properties in lung cancer and deserves further systematic investigation in animal models of lung cancer.

Real-life experiences with omalizumab for the treatment of chronic urticaria.

BACKGROUND: Evidence has shown that omalizumab, a subcutaneous anti-IgE monoclonal antibody, is highly effective for the treatment of chronic urticaria. OBJECTIVE: To evaluate omalizumab 150 mg/month in severe, difficult-to-treat, chronic urticaria in a real-life setting. METHODS: This prospective open-label study evaluated of 150 mg of omalizumab in severe urticaria defined by a 7-day urticaria activity score (UAS-7) higher than 30, a history of oral glucocorticoid use, and by suboptimal response to previous treatments. Two subgroups of patients at different centers (Toronto and Quebec City, Canada) were included. The primary efficacy evaluation was a change in UAS-7 from baseline. A quantitative medication score assessed the use of other anti-urticarial medications. RESULTS: Sixty-eight patients were included: 61 with chronic spontaneous urticaria, 6 with cold urticaria, and 1 with urticarial vasculitis. Patients were followed for up to 25 months. In Toronto, mean UAS-7 decreased from 32.2 at baseline to 5.7 after the last omalizumab treatment. Seventy-nine percent achieved complete remission during omalizumab therapy (UAS-7 0) and 6 (18%) showed improvement but never achieved complete remission. The most common maintenance dosing intervals were 1 to 3 months. In Quebec City, from baseline to 18 months, mean UAS-7 decreased from 24.4 to 2.2 and the quantitative medication score decreased from 13.3 to 3.0. All 6 patients with cold urticaria became symptom free, with a significant decrease of their cold stimulation tolerance test. CONCLUSION: Omalizumab 150 mg was effective in difficult to treat patients with severe, chronic urticaria refractory to recommended treatments who usually required prednisone. Omalizumab induced a long-lasting positive response and was well tolerated without side effects.

Neoadjuvant Strategies for Esophageal Cancer: Role of Immunotherapy and Positron emission tomography (PET)-Guided Strategies.

Neoadjuvant strategies with multimodal therapy including chemotherapy and radiation are the standard of care in locally advanced esophageal cancer. The role of immunotherapy in the perioperative management of esophageal cancer is expanding, and adjuvant nivolumab for patients with residual disease following trimodality therapy has been shown to improve disease-free survival. Applications of checkpoint blockade and positron emission tomography (PET)-directed therapy in the neoadjuvant setting are under investigation in several clinical trials. We review the perioperative management of locally advanced esophageal cancer and recent evidence exploring the role of immune checkpoint inhibitors and PET in guiding neoadjuvant management.

Chronic immune-related adverse events in patients with cancer receiving immune checkpoint inhibitors: a systematic review.

Immune-related adverse events (irAEs) are toxicities resulting from use of immune checkpoint inhibitors (ICIs). These side effects persist in some patients despite withholding therapy and using immunosuppressive and immune-modulating agents. Little is known about chronic irAEs and they are felt to be rare. We performed a systematic review to characterize non-endocrine chronic irAEs reported in the literature and describe their management. Ovid MEDLINE and Embase databases were searched for reports of adult patients with solid cancers treated with ICIs who experienced chronic (>12 weeks) non-endocrine irAEs. Patient, treatment and toxicity data were collected. Of 6843 articles identified, 229 studies including 323 patients met our inclusion criteria. The median age was 65 (IQR 56-72) and 58% were male. Most patients (75%) had metastatic disease and the primary cancer site was melanoma in 43% and non-small cell lung cancer in 31% of patients. The most common ICIs delivered were pembrolizumab (24%) and nivolumab (37%). The chronic irAEs experienced were rheumatological in 20% of patients, followed by neurological in 19%, gastrointestinal in 16% and dermatological in 14%. The irAE persisted for a median (range) of 180 (84-2370) days and 30% of patients had ongoing symptoms or treatment. More than half (52%) of patients had chronic irAEs that persisted for >6 months. The ICI was permanently discontinued in 60% of patients and 76% required oral and/or intravenous steroids. This is the first systematic review to assess and report on moderate/severe chronic non-endocrine irAEs after treatment with ICI in the literature. These toxicities persisted for months-years and the majority required discontinuation of therapy and initiation of immunosuppression. Further research is needed to better understand chronic irAEs, which hold potential substantial clinical significance considering the expanded use of ICIs and their integration into the (neo)adjuvant settings.

First impressions: A prospective evaluation of patient-physician concordance and satisfaction following the initial medical oncology consultation.

BACKGROUND: An especially significant event in the patient-oncologist relationship is the initial consultation, where many complex topics-diagnosis, treatment intent, and often, prognosis-are discussed in a relatively short period of time. This study aimed to measure patients' understanding of the information discussed during their first medical oncology visit and their satisfaction with the communication from medical oncologists. METHODS: Between January and August 2021, patients without prior systemic treatment of their gastrointestinal malignancy (GI) attending the Princess Margaret Cancer Centre (PMCC) were approached within 24 h of their initial consultation to complete a paper-based questionnaire assessing understanding of their disease (diagnosis, treatment plan/intent, and prognosis) and satisfaction with the consultation. Medical oncology physicians simultaneously completed a similar questionnaire about the information discussed at the initial visit. Matched patient-physician responses were compared to assess the degree of concordance. RESULTS: A total of 184 matched patient-physician surveys were completed. The concordance rates for understanding of diagnosis, treatment plan, treatment intent, and prognosis were 92.9%, 59.2%, 66.8%, and 59.8%, respectively. After adjusting for patient and physician variables, patients who reported treatment intent to be unclear at the time of the consultation were independently associated with lower satisfaction scores (global p = 0.014). There was no statistically significant association between patient satisfaction and whether prognosis was disclosed (p = 0.08). CONCLUSION: An in-depth conversation as to what treatment intent and prognosis means is reasonable during the initial medical oncology consultation to ensure patients and caregivers have a better understanding about their cancer.

ALK inhibitor-induced bradycardia: A systematic-review and meta-analysis.

INTRODUCTION: Anaplastic Lymphoma Kinase (ALK) inhibitors have revolutionized the treatment of advanced ALK-positive non-small cell lung cancer (NSCLC), improving progression-free survival. Bradycardia is a potential adverse effect of these agents. We aimed to determine the risk of bradycardia associated with ALK inhibitors in patients with advanced NSCLC. MATERIALS AND METHODS: We conducted a systematic search of MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, National clinical trial registry, and Web of Science Core Collection. We included all randomized controlled trials in which an ALK-inhibitor was compared with another ALK-inhibitor or standard chemotherapy. Meta-analyses were conducted to evaluate the pooled incidence rates of bradycardia and dizziness using fixed effect models. RESULTS: The pooled incidence of bradycardia among 1737 individuals prescribed ALK inhibitors was 8% during a mean follow-up of 1.26 years. Crizotinib led to more bradycardia than standard chemotherapy (relative risk, RR 24.68, 95% CI 7.11-85.), while no difference was seen between crizotinib and alectinib (RR 1.12, 95% CI 0.79-1.59). The next-generation ALK inhibitors alectinib, brigatinib and lorlatinib combined resulted in a similar rate of bradycardia when compared to crizotinib (RR 0.77, 95% CI 0.57-1.04). All ALK inhibitors (as an aggregate) caused more dizziness (as a potential symptom of bradycardia) than standard chemotherapy (RR 1.88, 95% CI 1.44-2.44). CONCLUSION: Crizotinib for the treatment of NSCLC is associated with a higher risk for bradycardia compared to standard chemotherapy. There is no evidence of a difference in bradycardia risk between crizotinib and newer ALK inhibitors.

Clinical relevance assessment of animal preclinical research (RAA) tool: development and explanation.

BACKGROUND: Only a small proportion of preclinical research (research performed in animal models prior to clinical trials in humans) translates into clinical benefit in humans. Possible reasons for the lack of translation of the results observed in preclinical research into human clinical benefit include the design, conduct, and reporting of preclinical studies. There is currently no formal domain-based assessment of the clinical relevance of preclinical research. To address this issue, we have developed a tool for the assessment of the clinical relevance of preclinical studies, with the intention of assessing the likelihood that therapeutic preclinical findings can be translated into improvement in the management of human diseases. METHODS: We searched the EQUATOR network for guidelines that describe the design, conduct, and reporting of preclinical research. We searched the references of these guidelines to identify further relevant publications and developed a set of domains and signalling questions. We then conducted a modified Delphi-consensus to refine and develop the tool. The Delphi panel members included specialists in evidence-based (preclinical) medicine specialists, methodologists, preclinical animal researchers, a veterinarian, and clinical researchers. A total of 20 Delphi-panel members completed the first round and 17 members from five countries completed all three rounds. RESULTS: This tool has eight domains (construct validity, external validity, risk of bias, experimental design and data analysis plan, reproducibility and replicability of methods and results in the same model, research integrity, and research transparency) and a total of 28 signalling questions and provides a framework for researchers, journal editors, grant funders, and regulatory authorities to assess the potential clinical relevance of preclinical animal research. CONCLUSION: We have developed a tool to assess the clinical relevance of preclinical studies. This tool is currently being piloted.

A case of failure to thrive secondary to primary hyperoxaluria type 1.

Primary hyperoxaluria type 1 is a rare genetic condition characterized by oxalate deposition in the kidneys. We report findings of an 8-month old female presenting with failure to thrive, poor oral intake, and kidney stones resulting in the diagnosis of primary hyperoxaluria type 1. The patient exhibits a unique presentation without renal failure at the time of diagnosis suggesting a previously unreported comorbidity in early stages of disease.

Effects of 6 Months of Exercise-Based Cardiac Rehabilitation on Autonomic Function and Neuro-Cardiovascular Stress Reactivity in Coronary Artery Disease Patients.

Background Autonomic dysregulation represents a hallmark of coronary artery disease (CAD). Therefore, we investigated the effects of exercise-based cardiac rehabilitation (CR) on autonomic function and neuro-cardiovascular stress reactivity in CAD patients. Methods and Results Twenty-two CAD patients (4 women; 62±8 years) were studied before and following 6 months of aerobic- and resistance-training-based CR. Twenty-two similarly aged, healthy individuals (CTRL; 7 women; 62±11 years) served as controls. We measured blood pressure, muscle sympathetic nerve activity, heart rate, heart rate variability (linear and nonlinear), and cardiovagal (sequence method) and sympathetic (linear relationship between burst incidence and diastolic blood pressure) baroreflex sensitivity during supine rest. Furthermore, neuro-cardiovascular reactivity during short-duration static handgrip (20s) at 40% maximal effort was evaluated. Six months of CR lowered resting blood pressure (P<0.05), as well as muscle sympathetic nerve activity burst frequency (48±8 to 39±11 bursts/min; P<0.001) and burst incidence (81±7 to 66±17 bursts/100 heartbeats; P<0.001), to levels that matched CTRL and improved sympathetic baroreflex sensitivity in CAD patients (P<0.01). Heart rate variability (all P>0.05) and cardiovagal baroreflex sensitivity (P=0.11) were unchanged following CR, yet values were not different pre-CR from CTRL (all P>0.05). Furthermore, before CR, CAD patients displayed greater blood pressure and muscle sympathetic nerve activity reactivity to static handgrip versus CTRL (all P<0.05); yet, responses were reduced following CR (all P<0.05) to levels observed in CTRL. Conclusions Six months of exercise-based CR was associated with marked improvement in baseline autonomic function and neuro-cardiovascular stress reactivity in CAD patients, which may play a role in the reduced cardiac risk and improved survival observed in patients following exercise training.