From Safety to Benefit in Cell Delivery During Surgical Repair of Ebstein Anomaly: Initial Results.

BACKGROUND: The objective of this study is to assess the safety and early impact of intramyocardial delivery of autologous bone marrow-derived mononuclear cells (BM-MNC) at time of surgical Ebstein repair. METHODS: Patients with Ebstein anomaly (ages 6 months to 30 years) scheduled to undergo repair of the tricuspid valve were eligible to participate in this open-label, non-randomized phase I clinical trial. BM-MNC target dose was 1-3 million cells/kg. Ten patients have undergone surgical intervention and cell delivery to the right ventricle (RV) and completed 6-month follow-up. RESULTS: All patients underwent surgical tricuspid valve repair and uneventful BM-MNC delivery; there were no ventricular arrhythmias and no adverse events related to study product or delivery. Echocardiographic RV myocardial performance index improved and RV fractional area change showed an initial decline and then through study follow-up. There was no evidence of delayed myocardial enhancement or regional wall motion abnormalities at injection sites on 6-month follow-up magnetic resonance imaging. CONCLUSIONS: Intramyocardial delivery of BM-MNC after surgical repair in Ebstein anomaly can be performed safely. Echocardiography variables suggest a positive impact of cell delivery on the RV myocardium with improvements in both RV size and wall motion over time. Additional follow-up and comparison to control groups are required to better characterize the impact of cell therapy on the myopathic RV in Ebstein anomaly.

Clinical Impact of Autologous Cell Therapy on Hypoplastic Left Heart Syndrome After Bidirectional Cavopulmonary Anastomosis.

Preservation of right ventricle function (RV) is a key to favorable outcome in Hypoplastic Left Heart Syndrome (HLHS), but methods to preserve or improve RV function are limited. Our goal was to assess the clinical and functional impact of autologous umbilical cord blood-derived mononuclear cells (UCB-MNC) therapy when given to patients with HLHS at Stage II surgery. UCB-MNC patients were enrolled prospectively in a phase I, FDA monitored trial as previously described (Burkhart et al., 2019). Matched retrospective controls were identified by review of clinical databases. Growth and RV echocardiographic variables were assessed in both groups prestage II through the first 6 months postoperatively. Statistical comparisons between the groups at similar postoperative time points were made to define potential impact of the cell therapy. There were 7 UCB-MNC patients and 17 controls. Prestage II, most parameters showed no differences between groups, although median fractional area change (FAC) was slightly greater in the controls (FAC: controls = 45% vs UCB-MNC = 41% P= 0.02). At dismissal, FAC and estimated Ejection Fraction (EF) decreased in controls, while both were unchanged from baseline in UCB-MNC patients (ΔFAC: -5% vs -1%, P < 0.01; ΔEF: -8% vs 0%, P = 0.03, respectively). Subsequently, median FAC increased slightly in UCB-MNC patients over the 6 month follow-up period, while it decreased in controls (ΔFAC: UCB-MNC +3% vs control -5%, P = 0.03). Preoperative weight percentiles were similar in both groups (UCB-MNC 34%ile vs controls 22%ile, P = 0.93). However, by 6 months postoperative, median weight percentile improved to 63% in the UCB-MNC treated group, but declined to 8% in controls (P = 0.02). UCB-MNC therapy appears to limit the initial negative impact on RV FAC and EF seen after stage II surgery. During early follow up, FAC and weight percentile improved in UCB-MNC patients relative to controls, suggesting a beneficial effect of UCB-MNC therapy.

Health-related quality of life outcomes for the LEAP study-CALGB 70305 (Alliance): A lymphedema prevention intervention trial for newly diagnosed breast cancer patients.

BACKGROUND: Lymphedema is an adverse effect of breast cancer treatment that causes swelling and pain in the arm and hand. We tested 2 lymphedema prevention interventions and their impact on health-related quality of life (HRQOL) in a group-randomized trial at 38 cooperative group sites within the United States. METHODS: Patients were recruited before breast surgery. Sites were randomly assigned to education-only (EO) lymphedema prevention or education plus exercise and physical therapy (LEAP). Lymphedema was defined as a ≥10% difference in arm volume at any time from baseline to 18 months postsurgery. HRQOL was assessed using the Functional Assessment of Cancer Therapy-Breast plus 4 lymphedema items (FACT-B+4). Longitudinal mixed model regression analysis, adjusting for key demographic and clinical variables, examined participants' HRQOL by intervention group and lymphedema status. RESULTS: A total of 547 patients (56% LEAP) were enrolled and completed HRQOL assessments. The results revealed no differences between the interventions in preventing lymphedema (P = .37) or HRQOL (FACT-B+4 total score; P = .8777). At 18 months, the presence of lymphedema was associated with HRQOL at borderline significance (P = .0825). However, African American patients reported greater lymphedema symptoms (P = .0002) and better emotional functioning (P = .0335) than patients of other races or ethnicities. Lower HRQOL during the intervention was associated with younger age (P ≤ .0001), Eastern Cooperative Oncology Group performance status >0 (P = .0002), ≥1 positive lymph nodes (P = .0009), having no education beyond high school (P < .0001), having undergone chemotherapy (P = .0242), and having had only axillary node dissection or sentinel node biopsy versus both (P = .0007). CONCLUSION: The tested interventions did not differ in preventing lymphedema or in HRQOL outcomes. African American women reported greater HRQOL impacts due to lymphedema symptoms than women of other races or ethnicities.

A randomized study to prevent lymphedema in women treated for breast cancer: CALGB 70305 (Alliance).

BACKGROUND: Lymphedema affects many women who are treated for breast cancer. We examined the effectiveness of an education-only (EO) versus education plus sleeve compression/exercise intervention (lymphedema education and prevention [LEAP]) on lymphedema incidence and range of motion (ROM) in a group-randomized trial across 38 cooperative group sites. METHODS: The treating institution was randomly assigned to either EO or LEAP by a study statistician. All patients at a treating institution participated in the same intervention (EO or LEAP) to minimize contamination bias. Participants completed surveys, arm volume measurements, and self-reported ROM assessments before surgery and at 12 and 18 months after surgery. Lymphedema was defined as a ≥10% difference in limb volume at any time post-surgery up to 18 months after surgery or diagnosis by a health provider. Cochran-Mantel-Haenszel tests were used to compare lymphedema-free rates between groups, stratified by lymph node surgery type. Self-reported ROM differences were compared between groups. RESULTS: A total of 554 participants (56% LEAP) were included in the analyses. At 18 months, lymphedema-free rates were 58% (EO) versus 55% (LEAP) (P = .37). ROM for both arms was greater in LEAP versus EO at 12 months; by 18 months, most women reported full ROM, regardless of group. In LEAP, only one-third wore a sleeve ≥75% of the time; 50% performed lymphedema exercises at least weekly. CONCLUSION: Lymphedema incidence did not differ by intervention group at 18 months. Poor adherence in the LEAP group may have contributed. However, physical therapy may speed recovery of ROM. Further research is needed to effectively reduce the incidence and severity of lymphedema in patients who have breast cancer.

Loss of Ventricular Function After Bidirectional Cavopulmonary Connection: Who Is at Risk?

Decline of single ventricle systolic function after bidirectional cavopulmonary connection (BDCPC) is thought to be a transient phenomenon. We analyzed ventricular function after BDCPC according to ventricular morphology and correlated this evolution to long-term prognosis. A review from Mayo Clinic databases was performed. Visually estimated ejection fraction (EF) was reported from pre-BDCPC to pre-Fontan procedure. The last cardiovascular update was collected to assess long-term prognosis. A freedom from major cardiac event survival curve and a risk factor analysis were performed. 92 patients were included; 52 had left ventricle (LV) morphology and 40 had right ventricle (RV) morphology (28/40 had hypoplastic left heart syndrome (HLHS)). There were no significant differences in groups regarding BDCPC procedure or immediate post-operative outcome. EF showed a significant and relevant decrease from baseline to discharge in the HLHS group: 59 ± 4% to 49 ± 7% or - 9% (p < 0.01) vs. 58 ± 3% to 54 ± 6% or - 4% in the non-HLHS RV group (p = 0.04) and 61 ± 4% to 60 ± 4% or - 1% in the LV group (p = 0.14). Long-term recovery was the least in the HLHS group: EF prior to Fontan 54 ± 2% vs. 56 ± 6% and 60 ± 4%, respectively (p < 0.01). With a median follow-up of 8 years post-BDCPC, six patients had Fontan circulation failure, four died, and three had heart transplantation. EF less than 50% at hospital discharge after BDCPC was strongly correlated to these major cardiac events (HR 3.89; 95% Cl 1.04-14.52). Patients with HLHS are at great risk of ventricular dysfunction after BDCPC. This is not a transient phenomenon and contributes to worse prognosis.

Effect of a Behavioral Intervention to Increase Vegetable Consumption on Cancer Progression Among Men With Early-Stage Prostate Cancer: The MEAL Randomized Clinical Trial.

Importance: Guidelines endorsing vegetable-enriched diets to improve outcomes for prostate cancer survivors are based on expert opinion, preclinical studies, and observational data. Objective: To determine the effect of a behavioral intervention that increased vegetable intake on cancer progression in men with early-stage prostate cancer. Design, Setting, and Participants: The Men's Eating and Living (MEAL) Study (CALGB 70807 [Alliance]) was a randomized clinical trial conducted at 91 US urology and medical oncology clinics that enrolled 478 men aged 50 to 80 years with biopsy-proven prostate adenocarcinoma (International Society of Urological Pathology grade group = 1 in those <70 years and ≤2 in those ≥70 years), stage cT2a or less, and serum prostate-specific antigen (PSA) level less than 10 ng/mL. Enrollment occurred from January 2011 to August 2015; 24-month follow-up occurred from January 2013 to August 2017. Interventions: Patients were randomized to a counseling behavioral intervention by telephone promoting consumption of 7 or more daily vegetable servings (MEAL intervention; n = 237) or a control group, which received written information about diet and prostate cancer (n = 241). Main Outcomes and Measures: The primary outcome was time to progression; progression was defined as PSA level of 10 ng/mL or greater, PSA doubling time of less than 3 years, or upgrading (defined as increase in tumor volume or grade) on follow-up prostate biopsy. Results: Among 478 patients randomized (mean [SD] age, 64 [7] years; mean [SD] PSA level, 4.9 [2.1] ng/mL), 443 eligible patients (93%) were included in the primary analysis. There were 245 progression events (intervention: 124; control: 121). There were no significant differences in time to progression (unadjusted hazards ratio, 0.96 [95% CI, 0.75 to 1.24]; adjusted hazard ratio, 0.97 [95% CI, 0.76 to 1.25]). The 24-month Kaplan-Meier progression-free percentages were 43.5% [95% CI, 36.5% to 50.6%] and 41.4% [95% CI, 34.3% to 48.7%] for the intervention and control groups, respectively (difference, 2.1% [95% CI, -8.1% to 12.2%]). Conclusions and Relevance: Among men with early-stage prostate cancer managed with active surveillance, a behavioral intervention that increased vegetable consumption did not significantly reduce the risk of prostate cancer progression. The findings do not support use of this intervention to decrease prostate cancer progression in this population, although the study may have been underpowered to identify a clinically important difference. Trial Registration: ClinicalTrials.gov Identifier: NCT01238172.

Comparative "nocebo effects" in older patients enrolled in cancer therapeutic trials: Observations from a 446-patient cohort.

BACKGROUND: A nocebo is an inert substance associated with adverse events. Although previous studies have examined the positive (placebo) effects of such inert substances, few have examined negative (nocebo) adverse event profiles, particularly in older patients who have higher morbidity and can experience frequent and severe adverse events from cancer therapy. METHODS: This study focused on placebo/nocebo-exposed patients who participated in 2 double-blind, placebo-controlled, cancer therapeutic studies, namely, North Central Cancer Therapy Group trial NCCTG 97-24-51 and American College of Surgeons Oncology Group trial Z9001, with the goal of reporting the comparative, age-based adverse event rates, as reported during the conduct of these trials. RESULTS: Among the 446 patients who received only placebo/nocebo and who were the focus of the current report, 161 were aged ≥65 years at the time of respective trial entry, and 5234 adverse events occurred. Unadjusted adverse event rates did not differ significantly between patients aged ≥65 years and younger patients (rate ratio, 1.01; 99% confidence interval, 0.47-2.02), and the findings were similar findings for grade 2 or worse adverse events and for all symptom-driven adverse events (for example, pain, loss of appetite, anxiety). Adjustment for sex, ethnicity, baseline performance score, and individual trial resulted in no significant age-based differences in adverse event rates. Similar findings were observed with an age threshold of 70 years. CONCLUSIONS: Adverse events are equally common in older and younger cancer patients who are exposed to nocebo and thus require the same degree of clinical consideration regardless of age. Cancer 2017;123:4193-4198. © 2017 American Cancer Society.

Effect of Longer-Interval vs Standard Dosing of Zoledronic Acid on Skeletal Events in Patients With Bone Metastases: A Randomized Clinical Trial.

Importance: Zoledronic acid, a third-generation aminobisphosphonate, reduces the incidence of skeletal-related events and pain in patients with bone metastases. The optimal dosing interval for zoledronic acid is uncertain. Objective: To determine whether zoledronic acid administered every 12 weeks is noninferior to zoledronic acid administered every 4 weeks. Design, Setting, Participants: Randomized, open-label clinical trial conducted at 269 academic and community sites in the United States. Patients (n = 1822) with metastatic breast cancer, metastatic prostate cancer, or multiple myeloma who had at least 1 site of bone involvement were enrolled between May 2009 and April 2012; follow-up concluded in April 2014. Interventions: Patients were randomized to receive zoledronic acid administered intravenously every 4 weeks (n = 911) vs every 12 weeks (n = 911) for 2 years. Main Outcomes and Measures: The primary end point was the proportion of patients having at least 1 skeletal-related event (defined as clinical fracture, spinal cord compression, radiation to bone, or surgery involving bone) within 2 years after randomization and a between-group absolute difference of 7% as the noninferiority margin. Secondary end points included the proportion of patients with at least 1 skeletal-related event by disease type, pain as assessed by the Brief Pain Inventory (range, 0-10; higher scores indicate worse pain), Eastern Cooperative Oncology Group performance status (range, 0-4; higher scores indicate worse disability), incidence of osteonecrosis of the jaw, kidney dysfunction, skeletal morbidity rate (mean number of skeletal-related events per year), and, in a subset of 553 patients, suppression of bone turnover (assessed by C-terminal telopeptide levels). Results: Among 1822 patients who were randomized (median age, 65 years; 980 [53.8%] women; 855 with breast cancer, 689 with prostate cancer, and 278 with multiple myeloma), 795 completed the study at 2 years. A total of 260 patients (29.5%) in the zoledronic acid every 4-week dosing group and 253 patients (28.6%) in the every 12-week dosing group experienced at least 1 skeletal-related event within 2 years of randomization (risk difference of -0.3% [1-sided 95% CI, -4% to ∞]; P < .001 for noninferiority). The proportions of skeletal-related events did not differ significantly between the every 4-week dosing group vs the every 12-week dosing group for patients with breast cancer, prostate cancer, or multiple myeloma. Pain scores, performance status scores, incidence of jaw osteonecrosis, and kidney dysfunction did not differ significantly between the treatment groups. Skeletal morbidity rates were numerically identical in both groups, but bone turnover was greater (C-terminal telopeptide levels were higher) among patients who received zoledronic acid every 12 weeks. Conclusions and Relevance: Among patients with bone metastases due to breast cancer, prostate cancer, or multiple myeloma, the use of zoledronic acid every 12 weeks compared with the standard dosing interval of every 4 weeks did not result in an increased risk of skeletal events over 2 years. This longer interval may be an acceptable treatment option. Trial Registration: clinicaltrials.gov Identifier: NCT00869206.

Accrual of Older Patients With Breast Cancer to Alliance Systemic Therapy Trials Over Time: Protocol A151527.

Purpose Despite increasing awareness of accrual challenges, it is unknown if accrual of older patients to breast cancer treatment trials is improving. Methods We examined accrual of older patients to Alliance for Clinical Trials in Oncology systemic therapy breast cancer trials during 1985-2012 and compared disease characteristics and reasons for therapy cessation for older (age ≥ 65 years and ≥ 70 years) versus younger (age < 65 years and < 70 years) participants. To examine accrual trends, we modeled age as a function of time, using logistic regression. Results Overall, 17% of study participants were ≥ 65 years of age. Approximately 15%, 24%, and 24% of participants in adjuvant, neoadjuvant, and metastatic trials were age ≥ 65 years, and 7%, 15%, and 13% were age ≥ 70 years, respectively. The odds of a patient age ≥ 65 years enrolling significantly increased over time for adjuvant trials (odds ratio [OR] per year, 1.04; 95% CI, 1.04 to 1.05) but decreased significantly for neoadjuvant and metastatic trials (OR, 0.62; 95% CI, 0.58 to 0.67 and OR, 0.98, 95% CI, 0.97 to 1.00). Similar trends were seen for those age ≥ 70 years but these were statistically significant for adjuvant and neoadjuvant trials only (OR, 1.05, 95% CI, 1.04 to 1.07; and OR, 0.57, 95% CI, 0.52 to 0.62). In general, those age ≥ 65 years ( v those < 65 years) in adjuvant studies had a higher mean number of lymph nodes involved and more hormone receptor-negative tumors, although tumor sizes were similar. Early protocol treatment cessation was also more frequent in those age ≥ 65 years (50%) versus < 65 years (35.9%) across trials. Conclusion Older patients with breast cancer remain largely underrepresented in cooperative group therapeutic trials. We observed some improvement in accrual to adjuvant trials but worsening of accrual for neoadjuvant/metastatic trials. Novel strategies to increase accrual of older patients are critical to meaningfully change the evidence base for this growing patient population.

A Randomized Phase IIb Trial of myo-Inositol in Smokers with Bronchial Dysplasia.

Previous preclinical studies and a phase I clinical trial suggested that myo-inositol may be a safe and effective lung cancer chemopreventive agent. We conducted a randomized, double blind, placebo-controlled phase IIb study to determine the chemopreventive effects of myo-inositol in smokers with bronchial dysplasia. Smokers with ≥1 site of dysplasia identified by autofluorescence bronchoscopy-directed biopsy were randomly assigned to receive oral placebo or myo-inositol, 9 g once a day for 2 weeks, and then twice a day for 6 months. The primary endpoint was change in dysplasia rate after 6 months of intervention on a per-participant basis. Other trial endpoints reported herein include Ki-67 labeling index, blood and bronchoalveolar lavage fluid (BAL) levels of proinflammatory, oxidant/antioxidant biomarkers, and an airway epithelial gene expression signature for PI3K activity. Seventy-four (n = 38 myo-inositol and n = 36 placebo) participants with a baseline and 6-month bronchoscopy were included in all efficacy analyses. The complete response and the progressive disease rates were 26.3% versus 13.9% and 47.4% versus 33.3%, respectively, in the myo-inositol and placebo arms (P = 0.76). Compared with placebo, myo-inositol intervention significantly reduced IL6 levels in BAL over 6 months (P = 0.03). Among those with a complete response in the myo-inositol arm, there was a significant decrease in a gene expression signature reflective of PI3K activation within the cytologically normal bronchial airway epithelium (P = 0.002). The heterogeneous response to myo-inositol suggests a targeted therapy approach based on molecular alterations is needed in future clinical trials to determine the efficacy of myo-inositol as a chemopreventive agent. Cancer Prev Res; 9(12); 906-14. ©2016 AACR.

Repeated measures analyses of dermatitis symptom evolution in breast cancer patients receiving radiotherapy in a phase 3 randomized trial of mometasone furoate vs placebo (N06C4 [alliance]).

PURPOSE: Radiotherapy-related dermatological toxicities over time have not been well quantified. We examined during and immediately following radiation therapy skin toxicities over time in a randomized study of mometasone furoate vs placebo during breast radiotherapy. MATERIAL AND METHODS: Patients with breast cancer undergoing radiotherapy to the breast or chest wall were randomized. Symptoms related to skin toxicity were addressed weekly using provider-reported Common Terminology Criteria for Adverse Events (CTCAE v3.0) and 4 patient-reported outcomes (PRO) surveys. We applied repeated measures and risk analysis methodologies. RESULTS: One hundred seventy-six patients were enrolled. By CTCAE, significant differences favoring mometasone were detected over time in all toxicities except skin striae, atrophy, and infection. Statistically significant differences between arms at baseline but not over time occurred for all Linear Analog Self-Assessment. Statistically significant differences occurred for all symptoms in the temporal profile of symptoms as measured by PRO surveys (all P < .001). CONCLUSIONS: The use of longitudinal methods enhanced the ability of PRO tools to detect differences between study arms. Our results strengthened the conclusions of the original report that mometasone reduced acute skin toxicities. PRO surveys can accurately assess patients' experiences of symptom type and intensity over time and should be included in future clinical trials. For radiotherapy-related dermatological toxicity, we hypothesized that clinically significant differences over time, if any, can be found by repeated measures. We examined the acute skin toxicities in a randomized study of mometasone vs placebo during breast radiotherapy. For secondary end points, we showed that longitudinal methods enhanced the detection of differences between study arms and strengthened the conclusions from the original report. Frequent patient-reported outcome surveys over time should be included in future clinical trials.

Effect of Vitamin D Supplementation on Breast Cancer Biomarkers: CALGB 70806 (Alliance) Study Design and Baseline Data.

One in eight women will develop breast cancer over their lifetime with 230,000 women diagnosed in 2015. For this reason, breast cancer prevention efforts are essential. Vitamin D, with anticancer properties, may have a role in prevention of some cancers, including breast cancer. This report discusses the rationale, study protocol, and baseline data for a clinical trial of vitamin D and its effects on breast cancer biomarkers. This study was a randomized controlled trial designed to evaluate the effect of a fixed dose of vitamin D on specfic breast cancer biomarkers. Study participants were randomized to take either vitamin D or placebo for a period of 1 year. All participants had mammograms and blood drawn for serum biomarkers. A subset of participants underwent random periareolar fine needle aspiration to draw tissue for biomarkers. From January 2011 to December 2013, 300 premenopausal women, aged 59 or younger, were recruited from 41 institutions across the United States. A total of 102 women underwent random periareolar fine needle aspiration. The last subject completed the trial in January 2015. Baseline vitamin D levels for all participants ranged from 4-72 ng/mL, with 62% of participants being vitamin D deficient at enrollment (≥30 ng/mL or ≥75 nmo-l/L). The mean body mass index was 27.0 kg/m2 (range 15.1-53.6 kg/m2). 14% and 11.7% of participants were Hispanic or African American, respectively. Accrual and enrollment of participants is feasible for this type of multi-center prevention trial, and it can readily be carried out in a cooperative group setting.

Clinical Course of Oxaliplatin-Induced Neuropathy: Results From the Randomized Phase III Trial N08CB (Alliance).

PURPOSE: Given that the clinical course of oxaliplatin-induced neuropathy is not well defined, the current study was performed to better understand clinical parameters associated with its presentation. METHODS: Acute and chronic neuropathy was evaluated in patients receiving adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) on study N08CB (North Central Cancer Treatment Group, Alliance). Acute neuropathy was assessed by having patients complete daily questionnaires for 6 days with each cycle of FOLFOX. Before each dose of FOLFOX and as long as 18 months after chemotherapy cessation, chronic neurotoxicity was assessed with use of the 20-item, European Organisation for Research and Treatment of Cancer quality-of-life questionnaire for patients with chemotherapy-induced peripheral neuropathy. RESULTS: Three hundred eight (89%) of the 346 patients had at least one symptom of acute neuropathy with the first cycle of FOLFOX; these symptoms included sensitivity to touching cold items (71%), sensitivity to swallowing cold items (71%), throat discomfort (63%), or muscle cramps (42%). Acute symptoms peaked at day 3 and improved, although they did not always resolve completely between treatments. These symptoms were about twice as severe in cycles 2 through 12 as they were in cycle 1. For chronic neurotoxicity, tingling was the most severe symptom, followed by numbness and then pain. During chemotherapy, symptoms in the hands were more prominent than they were in the feet; by 18 months, symptoms were more severe in the feet than they were in the hands. Patients with more severe acute neuropathy during the first cycle of therapy experienced more chronic sensory neurotoxicity (P < .0001). CONCLUSION: Acute oxaliplatin-induced neuropathy symptoms do not always completely resolve between treatment cycles and are only half as severe on the first cycle as compared with subsequent cycles. There is a correlation between the severities of acute and chronic neuropathies.

PROMIS for Laparoscopy.

INTRODUCTION: We tested the responsiveness of the National Institutes of Health-sponsored Patient-Reported Outcomes Measures Information System (PROMIS) global health short form and a linear analog self-assessment for laparoscopy. METHODS: From May 2011 through December 2013, patients undergoing laparoscopy responded to patient reported outcome questionnaires perioperatively. Composite and single item scores were compared. RESULTS: One hundred fifteen patients, mean age 55 years, 58 % female, were enrolled. Visual analog pain scores differed significantly from baseline (mean 1.7 ± 2.3) to postoperative day 1 (mean 4.8 ± 2.6) and 7 (mean 2.5 ± 2.1) (p<0.0001). PROMIS physical subscale and total physical component subscore differed significantly from baseline (14.4 ± 3.0/47.4 ± 8.3) to postoperative day 1 (12.7 ± 3.2/42.1 ± 8.8) (p=0.0007/0.0003), due to everyday physical activities (p=0.0001). Linear analog self-assessment scores differed from baseline for pain frequency (p<0.0001), pain severity (p<0.0001), and social activity (p=0.0052); 40 % of subjects reported worsening in PROMIS physical T-score to postoperative day 1 and 25 % to postoperative day 7. Linear analog self-assessment mental well-being scores were worse in 32 % of patients at postoperative day 7, emotional well-being in 28 %, social activity in 24 %, and fatigue in 20 % of patients. CONCLUSION: Single items and change from baseline are responsive perioperative quality of life assessments for laparoscopy.

Pilot evaluation of Scrambler therapy for the treatment of chemotherapy-induced peripheral neuropathy.

PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN), a common side effect of chemotherapy, needs better effective treatments. Preliminary data support the use of Scrambler therapy, a device which treats pain via noninvasive cutaneous electrostimulation, for the treatment of CIPN. The current manuscript reports data from a pilot trial, performed to investigate the effect of Scrambler therapy for the treatment of established CIPN. METHODS: Eligible patients had CIPN symptoms of ≥1 month duration with tingling and/or pain ≥4/10 during the prior week. Patients were treated with Scrambler therapy to the affected area(s) for up to ten daily 30-min sessions. Symptoms were monitored using a neuropathy questionnaire consisting of numerical analog scales ranging from 0 to 10, daily before therapy as well as weekly for 10 weeks after therapy. Descriptive summary statistics formed the basis of data analysis. RESULTS: Thirty-seven patients were enrolled. Twenty-five patients were treated primarily on their lower extremities while 12 were treated primarily on their upper extremities. There was a 53 % reduction in pain score from baseline to day 10; a 44 % reduction in tingling; and a 37 % reduction in numbness. Benefit appeared to last throughout 10 weeks of follow-up. There were no substantial adverse events. CONCLUSION: Preliminary data support that Scrambler therapy may be effective for the treatment of CIPN: a prospective placebo-controlled clinical trial should be performed.

An analysis of fosaprepitant-induced venous toxicity in patients receiving highly emetogenic chemotherapy.

PURPOSE: Fosaprepitant is an antiemetic used for chemotherapy-induced nausea and vomiting. We recently reported increased infusion site adverse events (ISAE) in a cohort of breast cancer patients receiving chemotherapy with doxorubicin and cyclophosphamide (AC). In this current study, we evaluated the venous toxicity of fosaprepitant use with non-anthracycline platinum-based antineoplastic regimens. METHODS: A retrospective review was conducted of the first 81 patients initiated on fosaprepitant among patients receiving highly emetogenic chemotherapy, on or after January 1, 2011 at Mayo Clinic Rochester. None of these regimens included an anthracycline. Data collected included baseline demographics, chemotherapy regimen, type of intravenous access and type, and severity of ISAE. Data from these patients were compared to previously collected data from patients who had received AC. Statistical analysis using χ 2 and univariate logistic regression was used to evaluate the association between treatment regimen, fosaprepitant, and risk of ISAE. RESULTS: Among these 81 patients, the incidence of ISAE was 7.4% in the non-anthracycline platinum group. The most commonly reported ISAE were swelling (3%), extravasation (3%), and phlebitis (3%). When stratified by regimen, fosaprepitant was associated with a statistically significant increased risk of ISAE in the anthracycline group (OR 8.1; 95% CI 2.0-31.9) compared to the platinum group. CONCLUSIONS: Fosaprepitant antiemetic therapy causes significant ISAE that are appreciably higher than previous reports. Patients receiving platinum-based chemotherapy appear to have less significant ISAE than do patients who receive anthracycline-based regimens.

Metformin does not reduce markers of cell proliferation in esophageal tissues of patients with Barrett's esophagus.

BACKGROUND & AIMS: Obesity is associated with neoplasia, possibly via insulin-mediated cell pathways that affect cell proliferation. Metformin has been proposed to protect against obesity-associated cancers by decreasing serum insulin. We conducted a randomized, double-blind, placebo-controlled, phase 2 study of patients with Barrett's esophagus (BE) to assess the effect of metformin on phosphorylated S6 kinase (pS6K1), a biomarker of insulin pathway activation. METHODS: Seventy-four subjects with BE (mean age, 58.7 years; 58 men [78%; 52 with BE >2 cm [70%]) were recruited through 8 participating organizations of the Cancer Prevention Network. Participants were randomly assigned to groups given metformin daily (increasing to 2000 mg/day by week 4, n = 38) or placebo (n = 36) for 12 weeks. Biopsy specimens were collected at baseline and at week 12 via esophagogastroduodenoscopy. We calculated and compared percent changes in median levels of pS6K1 between subjects given metformin vs placebo as the primary end point. RESULTS: The percent change in median level of pS6K1 did not differ significantly between groups (1.4% among subjects given metformin vs -14.7% among subjects given placebo; 1-sided P = .80). Metformin was associated with an almost significant reduction in serum levels of insulin (median -4.7% among subjects given metformin vs 23.6% increase among those given placebo, P = .08) as well as in homeostatic model assessments of insulin resistance (median -7.2% among subjects given metformin vs 38% increase among those given placebo, P = .06). Metformin had no effects on cell proliferation (on the basis of assays for KI67) or apoptosis (on the basis of levels of caspase 3). CONCLUSIONS: In a chemoprevention trial of patients with BE, daily administration of metformin for 12 weeks, compared with placebo, did not cause major reductions in esophageal levels of pS6K1. Although metformin reduced serum levels of insulin and insulin resistance, it did not discernibly alter epithelial proliferation or apoptosis in esophageal tissues. These findings do not support metformin as a chemopreventive agent for BE-associated carcinogenesis. ClinicalTrials.gov number, NCT01447927.

Antiemetic prescribing practices using a computerized physician order entry system.

PURPOSE: Adherence to guideline-consistent chemotherapy-induced nausea and vomiting (CINV) prophylaxis is suboptimal. The primary aim of this study was to evaluate the magnitude of compliance to institutional guideline-directed antiemetic prophylaxis using a computerized physician order entry system at a single tertiary care institution. A nurse survey was also performed to evaluate how oncology practices, within a cooperative group, managed clinician orders for the prevention of CINV. METHODS: The electronic medical records of 100 consecutive patients were evaluated. The primary endpoint was the incidence of compliance to provide all aspects of scheduled institutional guideline-directed antiemetic prophylaxis for acute (day 1) and delayed (days 2-4) CINV. A descriptive analysis was performed on the convenience sample. Logistic regression was completed to determine the predictors of noncompliance. RESULTS: The incidence of compliance on days 1-4 was 94 %. Half of the noncompliant events (three of six, 50 %) occurred on day 1 alone and involved patients receiving low-emetogenic chemotherapy. There was a high degree of compliance to institutional guidelines for the treatment of delayed CINV (97 %). Patients receiving minimally emetogenic and moderately emetogenic chemotherapy (N = 70) were observed to be 100 % compliant. Patients receiving doxorubicin/cyclophosphamide were numerically less likely to receive institutional guidelines, compared to patients receiving other chemotherapy regimens (OR, 0.24 (0.04, 1.36), p value, 0.05). The nurse survey suggested significant variability amongst the involved institutions with regards to antiemetic prescribing practices. CONCLUSIONS: Computerized physician order entry is associated with impressive adherence to clinician-prescribing practices, according to institutional guidelines, for acute and delayed CINV.