Esophagectomy Enhanced Recovery After Surgery Initiative Results in Improved Outcomes.

BACKGROUND: Esophagectomy for esophageal cancer is a procedure with high morbidity and mortality. This study developed a Multidisciplinary Esophagectomy Enhanced Recovery Initiative (MERIT) pathway and analyzed implementation outcomes in a single institution. METHODS: The MERIT pathway was developed as a practice optimization and quality improvement initiative. Patients were studied from November 1, 2021 to June 20, 2022 and were compared with historical control subjects. The Wilcoxon rank sum test and the Fisher exact test were used for statistical analysis. RESULTS: The study compared 238 historical patients (January 17, 2017 to December 30, 2020) with 58 consecutive MERIT patients. There were no significant differences between patient characteristics in the 2 groups. In the MERIT group, 49 (85%) of the patients were male, and their mean age was 65 years (range, 59-71 years). Most cases were performed for esophageal cancer after neoadjuvant therapy. Length of stay improved by 27% from 11 to 8 days (P = .27). There was a 12% (P = .05) atrial arrhythmia rate reduction, as well as a 9% (P = .01) decrease in postoperative ileus. Overall complications were reduced from 54% to 35% (-19%; P = .01). CONCLUSIONS: This study successfully developed and implemented an enhanced recovery after surgery pathway for esophagectomy. In the first year, study investigators were able to reduce overall complications, specifically atrial arrhythmias, and postoperative ileus.

Sublobar Resection, Stereotactic Body Radiation Therapy, and Percutaneous Ablation Provide Comparable Outcomes for Lung Metastasis-Directed Therapy.

BACKGROUND: Prolonged survival of patients with metastatic disease has furthered interest in metastasis-directed therapy (MDT). RESEARCH QUESTION: There is a paucity of data comparing lung MDT modalities. Do outcomes among sublobar resection (SLR), stereotactic body radiation therapy (SBRT), and percutaneous ablation (PA) for lung metastases vary in terms of local control and survival? STUDY DESIGN AND METHODS: Medical records of patients undergoing lung MDT at a single cancer center between January 2015 and December 2020 were reviewed. Overall survival, local progression, and toxicity outcomes were collected. Patient and lesion characteristics were used to generate multivariable models with propensity weighted analysis. RESULTS: Lung MDT courses (644 total: 243 SLR, 274 SBRT, 127 PA) delivered to 511 patients were included with a median follow-up of 22 months. There were 47 local progression events in 45 patients, and 159 patients died. Two-year overall survival and local progression were 80.3% and 63.3%, 83.8% and 9.6%, and 4.1% and 11.7% for SLR, SBRT, and PA, respectively. Lesion size per 1 cm was associated with worse overall survival (hazard ratio, 1.24; P = .003) and LP (hazard ratio, 1.50; P < .001). There was no difference in overall survival by modality. Relative to SLR, there was no difference in risk of local progression with PA; however, SBRT was associated with a decreased risk (hazard ratio, 0.26; P = .023). Rates of severe toxicity were low (2.1%-2.6%) and not different among groups. INTERPRETATION: This study performs a propensity weighted analysis of SLR, SBRT, and PA and shows no impact of lung MDT modality on overall survival. Given excellent local control across MDT options, a multidisciplinary approach is beneficial for patient triage and longitudinal management.

Determinants of Long-term Survival Decades After Esophagectomy for Esophageal Cancer.

BACKGROUND: Long-term survival in esophagectomy patients with esophageal cancer is low due to tumor-related characteristics, with few reports of modifiable variables influencing outcome. We identified determinants of overall survival, time to recurrence, and disease-free survival in this patient cohort. METHODS: Adult patients who underwent esophagectomy for primary esophageal cancer from January 5, 2000, through December 30, 2010, at our institution were identified. Univariate Cox models and multivariable logistic regression analyses were used to identify associations between modifiable and unmodifiable patient and clinical variables and outcome of survival for the total cohort and a subgroup with locally advanced disease. RESULTS: We identified 870 patients with esophageal cancer who underwent esophagectomy. The median follow-up time was 15 years, and the 15-year overall survival rate was 25.2%, survival free of recurrence was 57.96%, and disease-free survival was 24.21%. Decreased overall survival was associated with the following unmodifiable variables: older age, male sex, active smoking status, history of coronary artery disease, advanced clinical stage, and tumor location. Decreased overall survival was associated with the following modifiable variables: use of neoadjuvant therapy, advanced pathologic stage, resection margin positivity, surgical reintervention, and blood transfusion requirement. The overall survival probability 6 years after esophagectomy was 0.920 (95% CI, 0.895-0.947), and time-to-recurrence probability was 0.988 (95% CI, 0.976-1.000), with a total of 17 recurrences and 201 deaths. CONCLUSIONS: Once patients survive 5 years, recurrence is rare. Long-term survival can be achieved in high-volume centers adhering to National Comprehensive Cancer Network guidelines using multidisciplinary care teams that is double what has been previously reported in the literature from national databases.

Impact of FDG PET Standardized Uptake Value in Resected Clinical Stage IA Non-Small Cell Lung Cancer.

BACKGROUND: A significant proportion of patients with clinical stage IA non-small cell lung cancer (NSCLC) experience will recurrence and decreased survival after surgery. This study examined the impact of preoperative primary tumor positron emission tomography (PET) scan maximum standardized uptake value (SUVmax) on oncologic outcomes after surgery. METHODS: This was a retrospective review of 251 patients who underwent surgical treatment of clinical stage IA NSCLC at an academic medical center (2005-2014). Patients were classified according to PET SUVmax level (low vs high) for analysis of upstaging, tumor recurrence, and overall survival. RESULTS: Median SUVmax values were higher in squamous cell carcinoma than in adenocarcinoma (median 3.3 vs 7.2; P < .0001). There were 109 (43.4%) patients in the SUVmax low group and 142 (56.6%) in the SUVmax high group. Patients with SUVmax high had larger tumors. SUVmax high was associated with higher rates of nodal upstaging (16.2% vs 4.6% in SUVmax low; P = .004), particularly in N1 nodes. SUVmax high was independently associated with nodal upstaging (adjusted odds ratio, 3.95; 95% CI, 1.36-11.46; P = .011). SUVmax high was associated with time to recurrence (hazard ratio, 1.62; 95% CI, 1.03-2.54; P = .036), but this association was lost on multivariable analysis (hazard ratio, 1.52; 95% CI, 0.91-2.54; P = .106). SUVmax was not associated with overall survival. CONCLUSIONS: Preoperative PET SUVmax level is strongly associated with nodal upstaging, particularly in N1 nodes, in patients with clinical stage IA NSCLC who undergo resection. PET SUVmax should be regarded as a risk factor when considering candidacy for sublobar resections and in future trials involving patients with stage I NSCLC.

Preoperative Type and Screen Before General Thoracic Surgery: A Nomogram to Reduce Unnecessary Tests.

BACKGROUND: A preoperative type and screen (T&S) is traditionally routinely obtained before noncardiac thoracic surgery; however an intraoperative blood transfusion is rare. This practice is overly cautious and expensive. METHODS: We included adult patients undergoing major thoracic surgery at the Mayo Clinic from 2007 to 2016. Patients receiving a T&S blood test ≤72 hours of surgery was the main exposure. We randomly split the cohort into derivation and validation datasets. We used multiple logistic regression to create a parsimonious nomogram predicting the need for a T&S in relation to the likelihood of intraoperative blood transfusion. We validated the nomogram in terms of discrimination, calibration, and negative predictive value. RESULTS: Of 6280 patients 46.1% had a preoperative T&S, but only 7.1% received intraoperative transfusions. The derivation dataset had 4196 patients. Patients who had a T&S were more likely to have baseline hemoglobin level <10 g/dL (7.9% vs 3.6%, P < .001) and less likely to have minimally invasive operations (36.1% vs 43.5%, P < .001) but were otherwise similar in baseline age and comorbidities. A transfusion threshold of 5% was selected a priori. The nomogram included age, planned operation, approach, body mass index, and preoperative hemoglobin. The nomogram was validated with a c-statistic of 86% and a negative predictive value of 97.9%. Patients who needed a blood transfusion but who did not have a preoperative T&S did not have a higher rate of mortality (P = .121). CONCLUSIONS: An intraoperative blood transfusion during major thoracic surgery is a rare event. Patient who required transfusion but did not have a T&S did not have worse outcomes. A simple nomogram can aid in the selective use of T&S orders preoperatively.

The Endangered State of Medicare Reimbursement for Cardiothoracic Surgery: A Call to Action.

Reimbursement for cardiothoracic surgery continues to be threatened with enormous financial cuts ranging from 5% to 10% in recent years. In this policy perspective, we describe the history of reimbursement for cardiothoracic surgery, highlight areas in need of urgent reform, propose possible solutions that Congress and the Executive Branch may enact, and call cardiothoracic surgeons to action on this critical issue. Meaningful engagement of members of The Society of Thoracic Surgeons with their elected representatives is the only way to prevent these cuts.

Autologous blood patch pleurodesis for prolonged postoperative air leaks.

BACKGROUND: A prolonged air leak (PAL) is the most frequent complication after pulmonary resection. This study aimed to assess the safety and efficacy of autologous blood patch pleurodesis (ABPP) to treat PAL. METHODS: A prospectively maintained database identified patients with a PAL after pulmonary resection for lung cancer between 2015-2019. In this observational cohort study, clinical data were collected to retrospectively compare patients undergoing ABPP to no ABPP in a propensity-matched analysis. Kaplan Meier estimates and Cox models accounting for inverse probability weighting (IPTW) were used to assess the association of ABPP with each outcome. RESULTS: Of the 740 patients undergoing lung resection, 110 (15%) were identified as having a PAL at postoperative day (POD) 5. There was no difference between baseline characteristics among those undergoing ABPP (n=34) versus no ABPP (n=76). Propensity-weighted analysis did not reveal a significant association of ABPP treatment with in-hospital complication (P=0.18), hospital length of stay (LOS) (P=0.13), or post-discharge complication (P=0.13). However, ABPP treatment was associated with a lower risk of hospital readmission [P=0.02, hazard ratio (HR) 0.16] and reoperation for air leak or empyema (P=0.05, HR 0.11). Although not statistically significant, the mean chest tube (CT) removal of 11 days for the ABPP group was less than the no ABPP group (16 days) (P=0.14, HR 1.5-2). Those treated with ABPP were less likely to be discharged with a CT (ABPP 7/34, 21% vs. no ABPP 40/76, 53%). There was no statistical difference in empyema development between groups (ABPP 0/34, 0% vs. no ABPP 4/76, 5%, P=0.39, HR 0.24). CONCLUSIONS: ABPP administration is safe compared to traditional PAL management. In a retrospective propensity-matched analysis, postoperative patients treated with ABPP required less readmission and reoperation for PAL. Larger powered randomized trials may demonstrate the magnitude of benefit from treatment with ABPP.

Management of Epiphrenic Diverticula and Short-term Outcomes.

Epiphrenic diverticulum is a rare and benign condition with significant surgical morbidity and evolving surgical management. The objective of this study was to analyze short-term clinical outcomes after surgery for epiphrenic diverticula. We conducted a retrospective cohort study in a single tertiary care center of all patients who underwent treatment for epiphrenic esophageal diverticula from June 1990 to December 2016. Data collection included demographics, operative details and short-term outcomes (esophageal leak, other complications, 30-day mortality). In addition, all preoperative imaging was reviewed by an esophageal radiologist in order to describe epiphrenic diverticula characteristics in a uniform and blinded manner. Of the 94 patients in the study, 84 patients were managed with an open surgical approach and 10 with minimally invasive techniques. Median size of diverticula was 5.5 cm and mean height above gastroesophageal junction was 4 cm. A myotomy was completed in 95% of patients and a fundoplication in 58%. The MIS group had a shorter length of stay (4 vs 6 days). Overall complication rate was 27% with an esophageal leak rate of 7% with 60% grade I leaks that sealed with conservative management. Complete resection of the diverticulum, closure of the muscle over the resection, contralateral myotomy, and consideration for partial fundoplication are common strategies utilized to surgically treat patients with epiphrenic diverticulum. Minimally invasive approaches are increasingly utilized.

The Man Behind the Clagett Procedure: Dr Oscar Theron "Jim" Clagett.

Dr O.T. "Jim" Clagett was a pioneer in surgery of the great vessels and thorax. The procedure that bears his name for treatment of postpneumonectomy empyema was only one of his many innovations in aortic, lung, and esophageal surgery. He performed over 35,000 operations and trained over 115 residents during his tenure at Mayo Clinic. His distinguished career highlights include: helping develop the field of cardiothoracic surgery during its infancy, starting the Thoracic Surgery Residency Program at Mayo Clinic, serving in numerous institutional and national leadership roles, and countless awards.

Contemporary Practice Patterns of Lung Volume Reduction Surgery in the United States.

BACKGROUND: Contemporary data on lung volume reduction surgery (LVRS) is sparse, particularly in regard to utilization and surgical outcomes. In this context, we analyzed the practice patterns and outcomes of LVRS nationally. METHODS: We identified all patients (n = 1617) undergoing LVRS at 165 hospitals between 2001 and 2017 from The Society of Thoracic Surgeons (STS) General Thoracic Database. Practice patterns were assessed at the hospital and STS regional levels. In addition, we obtained regional chronic obstructive pulmonary disease prevalence data from the Centers for Disease Control. We used hierarchical logistic regression to estimate associations with each outcome of interest and calculate risk- and reliability-adjusted outcome rates. RESULTS: Since 2011, national LVRS utilization has been increasing with decreasing mortality rates (3.1% risk-adjusted mortality in 2016). There is wide regional variation in LVRS average caseload that is not congruent with national chronic obstructive pulmonary disease prevalence (Pearson correlation coefficient -0.11). On multivariable analysis, only older age (adjusted odds ratio 1.05, P < .001), male sex (adjusted odds ratio 1.5, P = .007), underweight body mass index (adjusted odds ratio 1.94, P = .027), and ECOG score of 4 (adjusted odds ratio 5.17, Z-score 3.91, P = .001) were associated with the occurrence of the composite outcome of major morbidity or mortality. At the hospital level, six hospitals performed 40% of all LVRS nationally with adjusted national 30-day mortality rate of 4.3% and composite outcome rate of 15.8%. Despite this, there was minimal variation in adjusted outcome rates. CONCLUSIONS: National utilization of LVRS is increasing and it has become safer overall, even at lower volume hospitals. There is regional variation in LVRS use that does not mirror national chronic obstructive pulmonary disease prevalence, suggesting access disparities. The findings have potential policy implications.

Cardiac Surgery After Extraanatomic Esophageal Reconstruction: A Single Institution's Experience.

BACKGROUND: Extraanatomic retrosternal and presternal esophageal reconstruction performed after esophagectomy poses a significant technical challenge to those patients who require cardiac surgery. This study reviewed a single-center experience with cardiac surgical procedures in patients with extraanatomic esophageal conduits, to examine the relative advantages of median sternotomy and thoracotomy approaches. METHODS: This case series identified patients who underwent cardiac surgery after extraanatomic esophageal reconstruction between January 1, 1999 and October 1, 2019 at the Mayo Clinic in Rochester, Minnesota. Electronic medical records were reviewed for patient demographics, surgical indications, characteristics, and outcomes. Continuous variables were reported as the mean or as the median and range, as appropriate. RESULTS: Seven individual patients had 8 cardiac surgical procedures after extraanatomic esophageal reconstruction (5 retrosternal, 2 presternal). All were male, with a median age of 65.5 years (range, 51 to 71 years). Preoperative computed tomography was obtained in all but 1 patient. Median sternotomy was performed in 4 patients, left thoracotomy in 2, right thoracotomy in 1, and right anterior thoracotomy in 1. Median bypass time was 91 minutes (interquartile range, 113.5 minutes). The median cross-clamp time was 57.5 minutes (interquartile range, 27.0 minutes). There was 1 delayed injury to a retrosternal conduit after median sternotomy approach. There were no injuries to the blood supply of any conduit. In-hospital mortality was 0%. The median length of stay was 7.5 days (range, 5 to 34 days). CONCLUSIONS: Different cardiac surgical procedures can be performed safely in patients with extraanatomic esophageal reconstructions through median sternotomy or thoracotomy. Preoperative planning with computed tomography with intravenous contrast enhancement of the chest, abdomen, and pelvis is essential for individualization of the surgical approach.

Predictors of Patient-Reported Reflux After Esophagectomy.

BACKGROUND: Patient-reported reflux is among the most common symptoms after esophagectomy. This study aimed to determine predictors of patient-reported reflux and to ascertain whether a preserved pylorus would protect patients from symptomatic reflux. METHODS: A prospective clinical study recorded patient-reported reflux after esophagectomy from August 2015 to July 2018. Eligible patients were at least 6 months from creation of a traditional posterior mediastinal gastric conduit, had completed at least 1 reflux questionnaire, and had the pylorus treated either temporarily (≥100 IU Botox [onabotulinumtoxinA]) or permanently (pyloromyotomy or pyloroplasty). RESULTS: Of the 110 patients meeting inclusion criteria, the median age was 65 years, and 88 of the 110 (80%) were male. Botox was used in 15 (14%) patients, pyloromyotomy in 88 (80%), and pyloroplasty in 7 (6%). A thoracic anastomosis was performed in 78 (71%) patients, and a cervical anastomosis was performed in 32 (29%). Esophagectomy was performed for malignant disease in 105 of 110 (95%), and 78 of 110 (71%) patients were treated with perioperative chemoradiation. Multivariable linear regression analysis revealed that patient-reported reflux was significantly worse in patients with shorter gastric conduit lengths (P = .02) and in patients who did not undergo perioperative chemoradiation (P = .01). No significant difference was found between patients treated with pyloric drainage and those treated with Botox. CONCLUSIONS: The absence of perioperative chemoradiation therapy and a shorter gastric conduit were predictors of patient-reported reflux after esophagectomy. Although few patients had Botox, preservation of the pylorus did not appear to affect patient-reported reflux. Further objective studies are needed to confirm these findings.

Surgery for Mesothelioma After Radiation Therapy (SMART); A Single Institution Experience.

Background: The optimal treatment sequence for localized malignant pleural mesothelioma (MPM) is controversial. We aimed to assess outcomes and toxicities of treating localized MPM with neoadjuvant radiation therapy (RT) followed by extrapleural pneumonectomy (EPP). Methods: Patients were enrolled on an institutional protocol of surgery for mesothelioma after radiation therapy (SMART) between June 2016 and May 2017. Eligible patients were adults with MPM localized to the ipsilateral pleura. Patients underwent staging with PET/CT, pleuroscopy, bronchoscopy/EBUS, mediastinoscopy, and laparoscopy. Five fractions of RT were delivered using intensity modulated radiation therapy (IMRT), with 30 Gy delivered to gross disease and 25 Gy to the entire pleura. EPP was performed 4-10 days following completion of RT. Results: Five patients were treated on protocol. Median age was 62 years (range 36-66). Histology was epithelioid on initial biopsy in all patients, but one was found to have biphasic histology after surgery. Three patients had surgeon-assessed gross total resection, and two had gross residual disease. While all patients were clinically node negative by pretreatment staging, three had positive nodal disease at surgery. Patients were hospitalized for a median 24 days (range 5-69) following surgery. Two patients developed empyema, one of whom developed respiratory failure and subsequently renal failure requiring dialysis, while the other required multiple surgical debridements. Two patients developed atrial fibrillation with rapid ventricular response after surgery, one of whom developed acute respiratory distress requiring intubation and tracheostomy. At last follow-up, one patient died at 1.4 years after local and distant progression, two were alive with local and distant progression, and the remaining two were alive without evidence of disease at 0.1 and 2.7 years. Median time to progression was 9 months. Three patients received salvage chemotherapy. Conclusions: SMART provided promising oncologic outcomes at the cost of significant treatment related morbidity. Due to the significant treatment associated morbidity and favorable treatment alternatives, we have not broadly adopted SMART at our institution.

Multicenter Study of Metastatic Lung Tumors Targeted by Interventional Cryoablation Evaluation (SOLSTICE).

OBJECTIVE: To assess the safety and local recurrence-free survival in patients after cryoablation for treatment of pulmonary metastases. METHODS: This multicenter, prospective, single-arm, phase 2 study included 128 patients with 224 lung metastases treated with percutaneous cryoablation, with 12 and 24 months of follow-up. The patients were enrolled on the basis of the outlined key inclusion criteria, which include one to six metastases from extrapulmonary cancers with a maximal diameter of 3.5 cm. Time to progression of the index tumor(s), metastatic disease, and overall survival rates were estimated using the Kaplan-Meier method. Complications were captured for 30 days after the procedure, and changes in performance status and quality of life were also evaluated. RESULTS: Median size of metastases was 1.0 plus or minus 0.6 cm (0.2-4.5) with a median number of tumors of 1.0 plus or minus 1.2 cm (one to six). Local recurrence-free response (local tumor efficacy) of the treated tumor was 172 of 202 (85.1%) at 12 months and 139 of 180 (77.2%) at 24 months after the initial treatment. After a second cryoablation treatment for recurrent tumor, secondary local recurrence-free response (local tumor efficacy) was 184 of 202 (91.1%) at 12 months and 152 of 180 (84.4%) at 24 months. Kaplan-Meier estimates of 12- and 24-month overall survival rates were 97.6% (95% confidence interval: 92.6-99.2) and 86.6% (95% confidence interval: 78.7-91.7), respectively. Rate of pneumothorax that required pleural catheter placement was 26% (44/169). There were eight grade 3 complication events in 169 procedures (4.7%) and one (0.6%) grade 4 event. CONCLUSION: Percutaneous cryoablation is a safe and effective treatment for pulmonary metastases.

Postoperative Opioid Consumption in Thoracic Surgery Patients: How Much Is Actually Used?

BACKGROUND: The objective of this initiative was to perform a prospective, multicenter survey of patients after lung resection to assess the amount of opioid medication consumed and the disposition of unused opioids to inform the development of evidence-based prescribing guidelines. METHODS: Adults undergoing lung resection with either minimally invasive surgery (MIS; n = 108) or thoracotomy (n = 45) were identified prospectively from 3 academic centers (from March 2017 to January 2018) to complete a 28-question telephone survey 21 to 35 days after discharge. Discharge opioids were converted into morphine milligram equivalents (MME) and were compared across patient and surgical details. RESULTS: Of the 153 patients who completed the survey, 89.5% (137) received opioids at discharge with a median prescription of 320 MME (interquartile range [IQR], 225, 450 MME) after MIS and 450 MME (IQR, 300, 600 MME) after thoracotomy (P = .001). Median opioid consumption varied by surgical approach: 90 MME (IQR, 0, 262.5) after MIS and 300 MME (IQR, 50, 382.5 MME) after thoracotomy (P < .001). The majority of patients (73.7%; 101) had residual opioid medication at the time of the survey, and patients after MIS had a relative increase in amount of remaining opioid medication: 58.3% vs 33.3% (P = .05) of the original prescription. Only 5.9% of patients with opioids remaining had properly disposed of them. CONCLUSIONS: Although patients undergoing MIS lung resection used significantly less opioid medication over a shorter duration of time than did patients after thoracotomy, they had relatively more excess opioid prescription. Evidence-based, procedure-specific guidelines with tailored pain regimens should be developed and implemented to reduce the amount of postoperative opioid medication remaining in the community.

Periprocedural Major Bleeding Risk of Image-Guided Percutaneous Chest Tube Placement in Patients with an Elevated International Normalized Ratio.

PURPOSE: To evaluate the incidence of major hemorrhage after image-guided percutaneous chest tube placement in patients with an abnormal international normalized ratio (INR) measured before the procedure. MATERIALS AND METHODS: Between January 2013 and September 2017, 49 image-guided percutaneous chest tubes were placed in 45 adult patients who had an elevated INR of greater than 1.6. Data collected included routine serum pre-procedure coagulation studies, indication for chest tube placement, insertion technique, size of chest tube, and presence of complications after drain placement. Major bleeding complications were defined using the Society of Interventional Radiology classification system. RESULTS: Mean patient age was 62 years (range, 22-94 years), with median American Society of Anesthesiologists score of 4. Mean INR was 2.1 (range, 1.7-3), with 21 (43%) procedures with an INR between 1.7 and 1.9, 20 (41%) procedures with an INR between 2.0 and 2.4, and 8 (16%) procedures with an INR between 2.5 and 3.0. Computed tomography guidance was used for 27 (55%) procedures; ultrasound guidance was used for 22 (45%) procedures. Median size of chest tube was 10 Fr (range, 8-14 Fr) used in 27 (55%) procedures. No major bleeding complications were observed. There was a small, significant decrease in mean hemoglobin after the procedure (mean = 0.9g/dL; P < .0001), which correlated to increasing chest tube size (P = .0269). CONCLUSIONS: No major bleeding complications were observed after image-guided percutaneous chest tube placement in patients with an elevated INR. Major bleeding complications in these patients may be safer than initially considered, and this study encourages the conduct of larger trials for further evaluation.