Gender Bias in the Evaluation of Surgical Performance: Results of a Prospective Randomized Trial.

OBJECTIVE: The study aims to determine the influence of trainee gender on assessments of coronary anastomosis performance. SUMMARY OF BACKGROUND DATA: Understanding the impact of gender bias on the evaluation of trainees may enable us to identify and utilize assessment tools that are less susceptible to potential bias. METHODS: Cardiothoracic surgeons were randomized to review the video performance of trainees who were described by either male or female pronouns. All participants viewed the same video of a coronary anastomosis and were asked to grade technique using either a Checklist or Global Rating Scale (GRS). Effect of trainee gender on scores by respondent demographic was evaluated using regression analyses. Inter-rater reliability was assessed using the Cronbach's alpha. RESULTS: 103 cardiothoracic surgeons completed the Checklist (trainee gender: male n=50, female n=53) and 112 completed the GRS (trainee gender: male n=56, female n=56). For the Checklist, male cardiothoracic surgeons who were in practice <10 years ( P = 0.036) and involved in training residents ( P = 0.049) were more likely to score male trainees higher than female trainees. The GRS demonstrated high inter-rater reliability across male and female trainees by years and scope of practice for the respondent (alpha >0.900) when compared to the Checklist assessment tool. CONCLUSIONS: Early career male surgeons may exhibit gender bias against women when evaluating trainee performance of coronary anastomoses. The GRS demonstrates higher interrater reliability and robustness against gender bias in the assessment of technical performance than the Checklist, and such scales should be emphasized in educational evaluations.

Induction chemotherapy with or without erlotinib in patients with head and neck squamous cell carcinoma amenable for surgical resection.

PURPOSE: Neoadjuvant chemotherapy prior to definitive surgery has been utilized widely for locally advanced oral squamous cell carcinoma (OSCC). We evaluated neoadjuvant erlotinib with platinum-docetaxel vs. placebo with platinum-docetaxel in stage III-IVB OSCC patients. EXPERIMENTAL DESIGN: Patients with newly diagnosed stage III, IVA, IVB (AJCC 7th) OSCC amenable to surgical resection were included. Patients were randomized to receive up to 3 cycles of chemotherapy with concurrent erlotinib or placebo, followed by surgery. The primary endpoint was major pathologic response (MPR) rate, secondary endpoints included safety, overall (OS) and progression-free survival (PFS). RESULTS: Fifty-two patients received at least one cycle of treatment and 47 were evaluable with surgical resection. MPR rate was not different between erlotinib (30%, 7/23) and placebo arms (41.7%, 10/24) (p=0.55). At median follow up of 26.5 months, there was no difference on OS or PFS between groups. Patients who received erlotinib with chemotherapy and achieved MPR (n=7) had no recurrence. The treatment-related adverse event rates were not different between the two groups (96% vs. 96%). However, rash, mostly low grade, was more common in the erlotinib arm (79% vs. 50%). Transcriptomic analysis in the pre-treatment samples indicated that genes in protein glycosylation and Wnt signaling pathways were associated with benefit in those treated with erlotinib plus chemotherapy. CONCLUSIONS: The addition of erlotinib to platinum-taxane chemotherapy was well-tolerated but did not induce higher rates of MPR or PFS or OS survival benefit. Patients who received chemotherapy with erlotinib and achieved major pathological responses had excellent clinical outcome.

Pilot Phase II Trial of Neoadjuvant Immunotherapy in Locoregionally Advanced, Resectable Cutaneous Squamous Cell Carcinoma of the Head and Neck.

PURPOSE: In locoregionally advanced, resectable cutaneous squamous cell carcinoma of the head and neck (CSCC-HN), surgery followed by radiotherapy is standard but can be cosmetically and functionally devastating, and many patients will have recurrence. PATIENTS AND METHODS: Newly diagnosed or recurrent stage III-IVA CSCC-HN patients amenable to curative-intent surgery received two cycles of neoadjuvant PD-1 inhibition. The primary endpoint was ORR per RECIST 1.1. Secondary endpoints included pathologic response [pathologic complete response (pCR) or major pathologic response (MPR; ≤10% viable tumor)], safety, DSS, DFS, and OS. Exploratory endpoints included immune biomarkers of response. RESULTS: Of 20 patients enrolled, 7 had recurrent disease. While only 6 patients [30%; 95% confidence interval (CI), 11.9-54.3] had partial responses by RECIST, 14 patients (70%; 95% CI, 45.7-88.1) had a pCR (n = 11) or MPR (n = 3). No SAEs ocurred during or after the neoadjuvant treatment. At a median follow-up of 22.6 months (95% CI, 21.7-26.1), one patient progressed and died, one died without disease, and two developed recurrence. The 12-month DSS, DFS, and OS rates were 95% (95% CI, 85.9-100), 89.5% (95% CI, 76.7-100), and 95% (95% CI, 85.9-100), respectively. Gene expression studies revealed an inflamed tumor microenvironment in patients with pCR or MPR, and CyTOF analyses demonstrated a memory CD8+ T-cell cluster enriched in patients with pCR. CONCLUSIONS: Neoadjuvant immunotherapy in locoregionally advanced, resectable CSCC-HN is safe and induces a high pathologic response rate. Pathologic responses were associated with an inflamed tumor microenvironment.

Referral Patterns and Treatment Delays in Medulloblastoma: A Large Academic Proton Center Experience.

PURPOSE: Patient travel time can cause treatment delays when providers and families decide to seek proton therapy. We examined whether travel distance or referral pattern (domestic versus international) affects time to radiation therapy and subsequent disease outcomes in patients with medulloblastoma at a large academic proton center. PATIENTS AND METHODS: Children with medulloblastoma treated at MD Anderson (MDA) with a protocol of proton beam therapy (PBT) between January 4, 2007, and June 25, 2014, were included in the analysis. The Wilcoxon rank-sum test was used to study the association between time to start of radiation and distance. Classification- and regression-tree analyses were used to explore binary thresholds for continuous covariates (ie, distance). Failure-free survival was defined as the time interval between end of radiation and failure or death. RESULTS: 96 patients were included in the analysis: 17 were international (18%); 19 (20%) were from Houston, Texas; 21 were from other cities inside Texas (21%); and 39 (41%) were from other US states. The median time from surgery to start of radiation was not significantly different for international patients (median = 1.45 months) compared with US patients (median = 1.15 months; P = .13). However, time from surgery to start of radiation was significantly longer for patients residing > 1716 km (> 1066 miles) from MDA (median = 1.31 months) than for patients residing ≤ 1716 km (≤ 1066 miles) from MDA (median = 1.05 months; P = .01). This 1- to 2-week delay (median = 7.8 days) did not affect failure-free survival (hazard ratio = 1.34; P = .43). CONCLUSION: We found that short delays in proton access can exist for patients traveling long distances to proton centers. However, in this study, treatment delays did not affect outcomes. This highlights the appropriateness of PBT in the face of travel coordination. Investment by proton centers in a rigorous intake process is justified to offer timely access to curative PBT.

Factors Influencing Exercise Following Pancreatic Tumor Resection.

BACKGROUND: We previously demonstrated associations between exercise during pancreatic cancer treatment and quality of life and physical fitness prior to pancreatectomy. In this study, we quantified exercise among survivors following pancreatic tumor resection and characterized concordance with established guidelines. METHODS: We quantified exercise frequency, duration, and intensity among survivors who underwent pancreatectomy for adenocarcinoma or a neuroendocrine tumor at our center from 2000 to 2017 and compared them with American College of Sports Medicine Guidelines for Cancer Survivors. Additional surveys measured motivation to exercise, barrier self-efficacy, quality of life, and fatigue. Multivariable models were constructed to evaluate associations between clinicodemographic and psychosocial variables and guideline concordance, and between guideline concordance and quality of life and fatigue. RESULTS: Of 504 eligible survivors, 262 (52%) returned surveys. Only 62 participants (24%) reported meeting both aerobic and strengthening guidelines; 103 (39%) reported meeting neither. Adjusted analyses demonstrated that higher autonomous motivation was associated with higher aerobic and strengthening guideline concordance (both p < 0.01). Higher barrier self-efficacy and older age were associated with higher aerobic guideline concordance (p < 0.01). We identified no significant associations between guideline concordance and tumor type, time since surgery, or recent cancer therapy (all p > 0.05). We found favorable associations between aerobic guideline concordance and both quality of life and fatigue (both p < 0.001). CONCLUSIONS: Less than one-quarter of participants exercised sufficiently to meet national exercise guidelines following pancreatectomy. To maximize exercise and related benefits, interventions should help survivors increase intrinsic motivation and overcome barriers to exercise.

Association Between Multimodal Analgesia Administration and Perioperative Opioid Requirements in Patients Undergoing Head and Neck Surgery With Free Flap Reconstruction.

Importance: The opioid epidemic has reignited interest in opioid-sparing strategies in managing pain. However, few studies have focused on opioid use during perioperative care in patients undergoing head and neck surgery with free flap reconstruction. Objectives: To examine the association between multimodal analgesia (MMA) administration and perioperative opioid requirements in patients undergoing head and neck surgery with free flap reconstruction and to investigate whether MMA alters the duration of stay in the postanesthesia care unit (PACU). Design, Setting, and Participants: In this retrospective case-control study, data were collected between April 1, 2016, and December 31, 2017. The study was conducted at a single cancer center in the United States. Participants were 357 patients 18 years or older scheduled for head and neck surgery with free flap reconstruction. Exposures: Patients in the treatment group received oral celecoxib, gabapentin, and/or tramadol hydrochloride before surgery. Control group patients did not receive any of these medications. Main Outcomes and Measures: The amount of opioid administered in the operating room and in the PACU was converted to morphine equivalent daily dose (MEDD) for comparison between the 2 groups. The duration of stay in the PACU was based on the start time and end time of PACU care recorded by nurses in the PACU. Results: In total, 149 patients (mean [SD] age, 60.3 [13.7] years; 104 [69.8%] men) were included in the treatment group, and 208 patients (mean [SD] age, 64.2 [13.6] years; 146 [70.2%] men) were included in the control group. The mean (SD) MEDD of opioid given during surgery was 51.7 (19.8) in the treatment group and 67.9 (24.7) in the control group, for a difference in the means (treatment vs control) of -16.17 (95% CI, -20.81 to -11.52). In the PACU, the mean (SD) MEDD of opioid given was 11.7 (13.3) in the treatment group and 14.9 (15.7) in the control group, for a difference in the means (treatment vs control) of -3.22 (95% CI, -6.40 to -0.03). The MMA treatment remained largely associated with reduced amount of opioid given during surgery, in the PACU, and both combined after controlling for other important factors. Conclusions and Relevance: This case-control study found that the patients who received MMA before head and neck surgery with free flap reconstruction required less opioid medication. The treatment group also had shorter duration of stay in the PACU compared with the control group.

Persistent and Chronic Postoperative Opioid Use in a Cohort of Patients with Oral Tongue Squamous Cell Carcinoma.

BACKGROUND: Recently, the concept of persistent postsurgical opioid use has been described for patients undergoing cancer surgery. Our hypothesis was based on the premise that patients with oral tongue cancer require high dosages of opioids before, during, and after surgery, and thus a large percentage of patients might develop persistent postsurgical opioid use. METHODS: After institutional review board approval, we conducted a retrospective study that included a cohort of patients with oral tongue cancers who underwent curative-intent surgery in our institution. Multivariable logistic regression models were fit to study the association of the characteristics of several patients with persistent (six months after surgery) and chronic (12 months after surgery) postoperative opioid use. RESULTS: A total of 362 patients with oral tongue malignancies were included in the study. The rate of persistent use of opioids after surgery was 31%. Multivariate analysis showed that patients taking opioids before surgery and those receiving adjuvant therapy were 2.9 and 1.78 times more likely to use opioids six months after surgery. Fifteen percent of the patients were taking opioids 12 months after surgery. After adjusting for clinically relevant covariates, patients complaining of moderate tongue pain before surgery and those taking opioids preoperatively had at least three times higher risk of still using these analgesics one year after surgery. CONCLUSIONS: Patients with oral tongue cancers have a high risk of developing persistent and chronic postsurgical opioid use.

Prognosis of Six-Month Glasgow Outcome Scale in Severe Traumatic Brain Injury Using Hospital Admission Characteristics, Injury Severity Characteristics, and Physiological Monitoring during the First Day Post-Injury.

Gold standard prognostic models for long-term outcome in patients with severe traumatic brain injury (TBI) use admission characteristics and are considered useful in some areas but not for clinical practice. In this study, we aimed to build prognostic models for 6-month Glasgow Outcome Score (GOS) in patients with severe TBI, combining baseline characteristics with physiological, treatment, and injury severity data collected during the first 24 h after injury. We used a training dataset of 472 TBI subjects and several data mining algorithms to predict the long-term neurological outcome. Performance of these algorithms was assessed in an independent (test) sample of 158 subjects. The least absolute shrinkage and selection operator (LASSO) led to the highest prediction accuracy (area under the receiving operating characteristic curve = 0.86) in the test set. The most important post-baseline predictor of GOS was the best motor Glasgow Coma Scale (GCS) recorded in the first day post-injury. The LASSO model containing the best motor GCS and baseline variables as predictors outperformed a model with baseline data only. TBI patient physiology of the first day-post-injury did not have a major contribution to patient prognosis six months after injury. In conclusion, 6-month GOS in patients with TBI can be predicted with good accuracy by the end of the first day post-injury, using hospital admission data and information on the best motor GCS achieved during those first 24 h post-injury. Passed the first day after injury, important physiological predictors could emerge from landmark analyses, leading to prediction models of higher accuracy than the one proposed in the current research.

Effect of Hemoglobin Transfusion Threshold on Cerebral Hemodynamics and Oxygenation.

Cerebral dysfunction caused by traumatic brain injury may adversely affect cerebral hemodynamics and oxygenation leading to worse outcomes if oxygen capacity is decreased due to anemia. In a randomized clinical trial of 200 patients comparing transfusion thresholds <7 g/dl versus 10 g/dl, where transfusion of leukoreduced packed red blood cells was used to maintain the assigned hemoglobin threshold, no long-term neurological difference was detected. The current study examines secondary outcome measures of intracranial pressure (ICP), cerebral perfusion pressure (CPP), and brain tissue oxygenation (PbtO2) in patients enrolled in this randomized clinical trial. We observed a lower hazard for death (hazard ratio [HR]=0.12, 95% confidence interval [CI]=0.02-0.99) during the first 3 days post-injury, and a higher hazard for death after three days (HR=2.55, 95% CI=1.00-6.53) in the 10 g/dl threshold group as compared to the 7 g/dL threshold group. No significant differences were observed for ICP and CPP but MAP was slightly lower in the 7 g/dL group, although the decreased MAP did not result in increased hypotension. Overall brain tissue hypoxia events were not significantly different in the two transfusion threshold groups. When the PbtO2 catheter was placed in normal brain, however, tissue hypoxia occurred in 25% of patients in the 7 g/dL threshold group, compared to 10.2% of patients in the 10 g/dL threshold group (p=0.04). Although we observed a few differences in hemodynamic outcomes between the transfusion threshold groups, none were of major clinical significance and did not affect long-term neurological outcome and mortality.

Effect of erythropoietin and transfusion threshold on neurological recovery after traumatic brain injury: a randomized clinical trial.

IMPORTANCE: There is limited information about the effect of erythropoietin or a high hemoglobin transfusion threshold after a traumatic brain injury. OBJECTIVE: To compare the effects of erythropoietin and 2 hemoglobin transfusion thresholds (7 and 10 g/dL) on neurological recovery after traumatic brain injury. DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial of 200 patients (erythropoietin, n = 102; placebo, n = 98) with closed head injury who were unable to follow commands and were enrolled within 6 hours of injury at neurosurgical intensive care units in 2 US level I trauma centers between May 2006 and August 2012. The study used a factorial design to test whether erythropoietin would fail to improve favorable outcomes by 20% and whether a hemoglobin transfusion threshold of greater than 10 g/dL would increase favorable outcomes without increasing complications. Erythropoietin or placebo was initially dosed daily for 3 days and then weekly for 2 more weeks (n = 74) and then the 24- and 48-hour doses were stopped for the remainder of the patients (n = 126). There were 99 patients assigned to a hemoglobin transfusion threshold of 7 g/dL and 101 patients assigned to 10 g/dL. INTERVENTIONS: Intravenous erythropoietin (500 IU/kg per dose) or saline. Transfusion threshold maintained with packed red blood cells. MAIN OUTCOMES AND MEASURES: Glasgow Outcome Scale score dichotomized as favorable (good recovery and moderate disability) or unfavorable (severe disability, vegetative, or dead) at 6 months postinjury. RESULTS: There was no interaction between erythropoietin and hemoglobin transfusion threshold. Compared with placebo (favorable outcome rate: 34/89 [38.2%; 95% CI, 28.1% to 49.1%]), both erythropoietin groups were futile (first dosing regimen: 17/35 [48.6%; 95% CI, 31.4% to 66.0%], P = .13; second dosing regimen: 17/57 [29.8%; 95% CI, 18.4% to 43.4%], P < .001). Favorable outcome rates were 37/87 (42.5%) for the hemoglobin transfusion threshold of 7 g/dL and 31/94 (33.0%) for 10 g/dL (95% CI for the difference, -0.06 to 0.25, P = .28). There was a higher incidence of thromboembolic events for the transfusion threshold of 10 g/dL (22/101 [21.8%] vs 8/99 [8.1%] for the threshold of 7 g/dL, odds ratio, 0.32 [95% CI, 0.12 to 0.79], P = .009). CONCLUSIONS AND RELEVANCE: In patients with closed head injury, neither the administration of erythropoietin nor maintaining hemoglobin concentration of greater than 10 g/dL resulted in improved neurological outcome at 6 months. The transfusion threshold of 10 g/dL was associated with a higher incidence of adverse events. These findings do not support either approach in this setting. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00313716.

Enrollment of racially/ethnically diverse participants in traumatic brain injury trials: effect of availability of exception from informed consent.

BACKGROUND: The Final Rule regulations were developed to allow exception from informed consent (EFIC) to enable clinical trial research in emergency settings where major barriers exist for informed consent. There is little known evidence of the effect of the Final Rule in minority enrollment in clinical trials, particularly in traumatic brain injury (TBI) trials. A clinical trial funded by the National Institute of Neurological Disorders and Stroke was conducted to study the effects of erythropoietin on cerebral vascular dysfunction and anemia in subjects with TBI. There were periods of time when EFIC was and was not available for enrollment into the study. PURPOSE: To explore the effect of EFIC availability on TBI trial enrollment of minority versus non-minority subjects. METHODS: Minority status of screened (n = 289) and enrolled (n = 191) TBI subjects was determined for this study. We tested for the presence of a minority and EFIC availability interaction in a multiple logistic regression model after controlling for EFIC and minority group main effects and other covariates. RESULTS: An interaction between the availability of EFIC minority and non-minority enrollment was not detected (odds ratio = 1.22; 95% confidence interval (CI) = 0.29-5.16). LIMITATIONS: Our study was conducted at a single site, and the CI for the EFIC and minority interaction term was wide. Therefore, a small interaction effect cannot be ruled out. CONCLUSION: EFIC increased the odds of being enrolled regardless of minority status.