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Frailer Patients Undergoing Robotic Colectomies for Colon Cancer Experience Increased Complication Rates Compared With Open or Laparoscopic Approaches

Lo, Brian D; Leeds, Ira L; Sundel, Margaret H; Gearhart, Susan; Nisly, Gabriela R C; Safar, Bashar; Atallah, Chady; Fang, Sandy H
BACKGROUND:Minimally invasive surgical techniques are routinely promoted as alternatives to open surgery because of improved outcomes. However, the impact of robotic surgery on certain subsets of the population, such as frail patients, is poorly understood. OBJECTIVE:The purpose of our study was to examine the association between frailty and minimally invasive surgical approaches with colon cancer surgery. DESIGN:This is a retrospective study of prospectively collected outcomes data. Thirty-day surgical outcomes were compared by frailty and surgical approach using doubly robust multivariable logistic regression with propensity score weighting, and testing for interaction effects between frailty and surgical approach. SETTING:Patients undergoing an open, laparoscopic, or robotic colectomy for primary colon cancer, 2012 to 2016, were identified from the American College of Surgeons National Surgical Quality Improvement Program database. PATIENTS:Patients undergoing a colectomy with an operative indication for primary colon cancer were selected. MAIN OUTCOME MEASURES:The primary outcomes measured were 30-day postoperative complications. RESULTS:After propensity score weighting of patients undergoing colectomy, 33.8% (n = 27,649) underwent an open approach versus 34.3% (n = 28,058) underwent laparoscopic surgery versus 31.9% (n = 26,096) underwent robotic surgery. Robotic (OR, 0.53; 95% CI, 0.42-0.69, p < 0.001) and laparoscopic (OR, 0.58; 95% CI, 0.52-0.66, p < 0.001) surgeries were independently associated with decreased rates of major complications. Frailer patients had increased complication rates (OR, 1.56; 95% CI, 1.07-2.25, p = 0.018). When considering the interaction effects between surgical approach and frailty, frailer patients undergoing robotic surgery were more likely to develop a major complication (combined adjusted OR, 3.15; 95% CI, 1.34-7.45, p = 0.009) compared with patients undergoing open surgery. LIMITATIONS:Use of the modified Frailty Index as an associative proxy for frailty was a limitation of this study. CONCLUSIONS:Although minimally invasive surgical approaches have decreased postoperative complications, this effect may be reversed in frail patients. These findings challenge the belief that robotic surgery provides a favorable alternative to open surgery in frail patients. See Video Abstract at http://links.lww.com/DCR/B163. LOS PACIENTES MÁS FRÁGILES SOMETIDOS A COLECTOMÍA ROBÓTICA POR CÁNCER DE COLON EXPERIMENTAN MAYORES TASAS DE COMPLICACIONES EN COMPARACIÓN CON ABORDAJES LAPAROSCÓPICO O ABIERTO: Las técnicas quirúrgicas mínimamente invasivas estan frecuentement promovidas como alternativas a la cirugía abierta debido a sus mejores resultados. Sin embargo, el impacto de la cirugía robótica en ciertos subgrupos de población, como el caso de los pacientes endebles, es poco conocido.El propósito de nuestro estudio fue examinar la asociación entre la fragilidad de los pacientes y el aborgaje quirúrgico mínimamente invasivo para la cirugía de cáncer de colon.Estudio retrospectivo de datos de resultados recolectados prospectivamente. Los resultados quirúrgicos a 30 días se compararon entre fragilidad y abordaje quirúrgico utilizando la regresión logística multivariable doblemente robusta con ponderación de puntaje de propensión y pruebas de efectos de interacción entre fragilidad y abordaje quirúrgico.Los pacientes identificados en la base de datos del Programa Nacional de Mejora de la Calidad Quirúrgica del Colegio Estadounidense de Cirujanos, que fueron sometidos a una colectomía abierta, laparoscópica o robótica por cáncer de colon primario, de 2012 a 2016.Todos aquellos pacientes seleccionados con indicación quirúrgica de cáncer primario de colon que fueron sometidos a una colectomía.Las complicaciones postoperatorias a 30 días.Luego de ponderar el puntaje de propensión de los pacientes colectomizados, el 33.8% (n = 27,649) fué sometido a laparotomía versus el 34.3% (n = 28,058) operados por laparoscopía versus el 31.9% (n = 26,096) operados con tecnica robótica. Las cirugías robóticas (OR 0.53, IC 95% 0.42-0.69, p < 0.001) y laparoscópicas (OR 0.58, IC 95% 0.52-0.66, p < 0.001) se asociaron de forma independiente con una disminución de las tasas de complicaciones mayores. Los pacientes más delicados tenían mayores tasas de complicaciones (OR 1.56, IC 95% 1.07-2.25, p = 0.018). Al considerar los efectos de interacción entre el abordaje quirúrgico y la fragilidad, los pacientes más débiles sometidos a cirugía robótica tenían más probabilidades de desarrollar una complicación mayor (OR ajustado combinado 3.15, IC 95% 1.34-7.45, p = 0.009) en comparación con los pacientes sometidos a cirugía abierta.El uso del índice de fragilidad modificado como apoderado asociativo de la fragilidad.Si bien los abordajes quirúrgicos mínimamente invasivos han disminuido las complicaciones postoperatorias, este efecto puede revertirse en pacientes lábiles. Estos hallazgos desafían la creencia de que la cirugía robótica proporciona una alternativa favorable a la cirugía abierta en pacientes frágiles. Consulte Video Resumen en http://links.lww.com/DCR/B163. (Traducción-Dr. Xavier Delgadillo).
PMID: 32032198
ISSN: 1530-0358
CID: 5239622

Aggressive Multimodal Treatment and Metastatic Colorectal Cancer Survival

Zhang, George Q; Taylor, James P; Stem, Miloslawa; Almaazmi, Hamda; Efron, Jonathan E; Atallah, Chady; Safar, Bashar
BACKGROUND:We aimed to assess patient and demographic factors, treatment trends, and survival outcomes of patients with colorectal cancer with metastasis to the liver, lung, or both sites. Differences remain among national guidelines about the optimal management strategy. METHODS:Adults from the National Cancer Database (2010 to 2015) with a primary diagnosis of colorectal liver, lung, or liver and lung metastases were included and stratified by metastasis site. The primary end point was 5-year overall survival, analyzed using Kaplan-Meier survival curves, log-rank test, and the Cox proportional hazards model. RESULTS:Among 82,609 included patients, 70.42% had liver, 8.74% had lung, and 20.85% had simultaneous liver and lung metastases. Treatment with chemotherapy alone was used the most (21.11%), followed by chemotherapy with colorectal radical resection (CRRR) (19.4%), no treatment (14.35%), CRRR alone (9.03%), and chemotherapy with CRRR and liver/lung resection (8.22%). Patients with lung metastasis had significantly better 5-year overall survival rates than the other 2 metastatic groups (15.99%, 16.70%, and 5.51%; p < 0.001), even after stratifying by treatment type and adjusting for other factors. Chemotherapy with CRRR and liver/lung resection was associated with the greatest reduction in mortality risk for all sites in both unadjusted (35.15%, 44.52%, and 20.10%; p < 0.001) and adjusted analyses (hazard ratio 0.42; 95% CI, 0.38 to 0.47; p < 0.001; hazard ratio 0.31; 95% CI, 0.18 to 0.53; p < 0.001; and hazard ratio 0.79; 95% CI, 0.62 to 1.01; p = 0.064 for trend), and forgoing treatment or CRRR alone offered the worst overall survival. CONCLUSIONS:Patients with metastasis to lung had increased overall survival compared with other sites of metastases, regardless of treatment modality. Combined resection of primary tumor, metastasectomy, and chemotherapy appears to offer the greatest chance of survival.
PMID: 32014570
ISSN: 1879-1190
CID: 5239612

Anal Squamous Cell Carcinoma: Radiation Therapy Alone Must Be Avoided

Almaazmi, Hamda; Taylor, James P; Stem, Miloslawa; Yu, David; Lo, Brian D; Safar, Bashar; Efron, Jonathan E
BACKGROUND:Anal squamous cell carcinoma (ASCC) is the most common histological subtype of anal cancer. Rates have been observed to increase in recent years. Combined chemoradiotherapy (CCRT) is currently the gold standard of treatment. The aim of this study is to assess ASCC prevalence, treatment trends, and overall survival (OS) in the United States. METHODS:Patients diagnosed with stage I-IV ASCC were identified from the National Cancer Database from 2004 to 2015. The primary outcome was 5-year OS, which was analyzed using Kaplan-Meier survival curves, log-rank test, and Cox proportional hazards models. RESULTS:34,613 cases were included (stage I: 21.45%; II: 41.00%; III: 31.62%; IV: 5.94%), with an increasing trend in prevalence. CCRT was the most used treatment. Multimodal treatment, combining surgery with CCRT, offered the best OS rates for stage I, II, and IV cancers (I: 84.87%; II: 75.12%; IV: 33.08%), comparable with survival of stage III patients treated with CCRT (III: 61.14%). Radiation alone had the worse OS rates, and on adjusted analysis, radiation treatment alone had the greatest risk of mortality (I: hazard ratio, 2.01; 95% confidence interval, 1.14-3.54; P = 0.016; II: 2.05, 1.44-2.93, P < 0.001; IV: 1.99, 0.99-4.02, P = 0.054). CONCLUSIONS:ASCC has increased in prevalence, notably in stage III and IV disease. Although CCRT is the most commonly used treatment type for all stages of ASCC, multimodal treatment offers better OS in stages I, II, and IV. Treatment with radiation alone offers the worst OS no matter the stage and should no longer be used as a solitary treatment modality.
PMID: 31648811
ISSN: 1095-8673
CID: 5272462

Justifying Total Costs of Extended Venothromboembolism Prophylaxis After Colorectal Cancer Surgery

Leeds, Ira L; Canner, Joseph K; DiBrito, Sandra R; Safar, Bashar
BACKGROUND:Current guidelines recommend extended venothromboembolism (VTE) prophylaxis for most patients following colorectal cancer surgery, but provider uptake has been limited. The purpose of this study was to identify thresholds for when such extended prophylaxis (ePpx) may be value-appropriate. METHODS:All colorectal cancer postoperative discharges were identified within a private payer administrative database (MarketScan® 2010-2014, IBM Truven Health Analytics). Outcomes of interest were VTE event rate, mortality, and overall costs of care. The data along with published literature were used as parameter estimations for a decision analysis model with probabilistic sensitivity analysis. RESULTS:We identified 22,463 colorectal cancer surgical patients (4.0% with ePpx) that served as the parameter estimates for the decision model with a VTE event rate of 0.2%. Decision analysis demonstrated that prescribing ePpx was dominated by usual practice with the former having higher probability-adjusted incremental costs ($1078.68 per person) and lower probability-adjusted benefits (- 0.000098 quality adjusted life years). Broad sensitivity analysis found that probability of a VTE event, bleeding case fatality rate, and probability of an ePpx-associated bleeding event were the primary effectors of the model. VTE event rates of greater than 3.0% benefited from prescribing ePpx to all patients. CONCLUSIONS:Very few patients are discharged on ePpx following colorectal cancer surgery despite its endorsement by national guidelines. A decision analysis model does not support the use of ePpx except in cases of markedly high VTE rates. Clinical guidance could be improved by further recognizing the role of risk stratification in the determination of high-risk patients requiring ePpx.
PMCID:6776724
PMID: 30945086
ISSN: 1873-4626
CID: 5272432

The Impact of Imatinib on Survival and Treatment Trends for Small Bowel and Colorectal Gastrointestinal Stromal Tumors

Almaazmi, Hamda; Stem, Miloslawa; Lo, Brian D; Taylor, James P; Fang, Sandy H; Safar, Bashar; Efron, Jonathan E; Atallah, Chady
BACKGROUND:The aim of this study is to assess treatment trends and overall survival (OS) in small bowel (SB) and colorectal (CR) gastrointestinal stromal tumors (GIST) with respect to the introduction of imatinib in 2008. METHODS:Patients diagnosed with SB and CR GIST were identified from the National Cancer Database (2004-2015). The primary outcome was 5- and 10-year OS. Patients were stratified by tumor site, time period (before and after imatinib), and treatment type. OS was analyzed using Kaplan-Meier survival curves, log-rank test, and Cox proportional hazards models. RESULTS:A total of 8441 cases were included (SB 81.66%; CR 18.34%). Radical resection was the most common treatment (SB 42.33%; CR 38.69%). The addition of chemotherapy to radical resection for SB GIST increased between the two time periods (31.76 to 40.43%; p < 0.001), and was associated with improved unadjusted and adjusted OS (2009-2015: adjusted HR [AHR] 0.73, 95% CI 0.59-0.89, p = 0.002). Patients with SB GIST had better 5- and 10-year OS compared with CR (SB 69.83% and 47.68%; CR 61.33% and 45.39%; p < 0.001), even after stratifying by treatment type and tumor size and adjusting for other factors (SB 5-year AHR 1.35, 95% CI 1.19-1.53; 10-year AHR 1.23, 95% CI 1.09-1.38; each p < 0.001). CONCLUSION:CR GIST are associated with lower OS than SB GIST. Radical resection is the most common treatment type for both sites. Chemotherapy with radical resection offers better OS in SB GIST, but not in CR GIST. Further studies are needed to assess the biology of CR GIST to explain the worse OS.
PMID: 31388887
ISSN: 1873-4626
CID: 5239602

Assessing the Effectiveness of External Beam Radiation Therapy when compared to Brachytherapy in Rectal Cancer [Meeting Abstract]

Taylor, James; Eltahir, Ahmed; Stem, Miloslawa; Zhang, George; Narang, Amol; Efron, Jonathan; Safar, Bashar; Atallah, Chady
ISI:000579885400072
ISSN: 0360-3016
CID: 5242172

CRC COVID: Colorectal cancer services during COVID-19 pandemic. Study protocol for service evaluation

Courtney, Alona; Howell, Ann-Marie; Daulatzai, Najib; Savva, Nicos; Warren, Oliver; Mills, Sarah; Rasheed, Shahnawaz; Milind, Goel; Tekkis, Nicholas; Gardiner, Matthew; Dai, Tinglong; Safar, Bashar; Efron, Jonathan E; Darzi, Ara; Tekkis, Paris; Kontovounisios, Christos
INTRODUCTION/BACKGROUND:COVID-19 has had an impact on the provision of colorectal cancer care. The aim of the CRC COVID study is to describe the changes in colorectal cancer services in the UK and USA in response to the pandemic and to understand the long-term impact. METHODS AND ANALYSIS/METHODS:This study comprises 4 phases. Phase 1 is a survey of colorectal units that aims to evaluate adherences and deviations from the best practice guidelines during the COVID-19 pandemic. Phase 2 is a monthly prospective data collection of service provision that aims to determine the impact of the service modifications on the long-term cancer specific outcomes compared to the national standards. Phase 3 aims to predict costs attributable to the modifications of the CRC services and additional resources required to treat patients whose treatment has been affected by the pandemic. Phase 4 aims to compare the impact of COVID-19 on the NHS and USA model of healthcare in terms of service provision and cost, and to propose a standardised model of delivering colorectal cancer services for future outbreaks. ETHICS AND DISSEMINATION/BACKGROUND:This study is a service evaluation and does not require HRA Approval or Ethical Approval in the UK. Local service evaluation registration is required for each participating centre. In the USA, Ethical Approval was granted by the Research and Development Committee. The results of this study will be disseminated to stakeholders, submitted for peer review publications, conference presentations and circulated via social media. REGISTRATION DETAILS/BACKGROUND:Nil.
PMCID:7417919
PMID: 32835148
ISSN: 2468-3574
CID: 5272502

Cost-Benefit Limitations of Extended, Outpatient Venous Thromboembolism Prophylaxis Following Surgery for Crohn's Disease

Leeds, Ira L; DiBrito, Sandra R; Canner, Joseph K; Haut, Elliott R; Safar, Bashar
BACKGROUND:Patients with Crohn's disease are at increased risk of postoperative venous thromboembolism. Historically, extended outpatient prophylaxis has not met conventional measures of societal cost-benefit advantage. However, extended prophylaxis for patients with Crohn's disease may be more cost-effective because of the patients' high thrombotic risk and long life expectancy. OBJECTIVE:This study aimed to assess the cost-effectiveness of extended prophylaxis in patients with Crohn's disease after abdominal surgery. DESIGN:A decision tree model was used to assess the incremental cost-effectiveness and cost per case averted with extended-duration venous thromboembolism prophylaxis following abdominal surgery. SETTING:The risk of a postdischarge thrombotic event, age at surgery, type of thrombotic event, prophylaxis risk reduction, bleeding complications, and mortality were estimated by using existing published sources. PATIENTS:Studied were patients with Crohn's disease versus routine care. INTERVENTION:We constructed a decision analysis to compare costs and outcomes in patients with Crohn's disease postoperatively with and without extended prophylaxis over a lifetime horizon. MAIN OUTCOME MEASURES:Productivity costs ($) and benefits (quality-adjusted life-year) were used to reflect a societal perspective and were time discounted at 3%. Multivariable probabilistic sensitivity analysis accounted for uncertainty in probabilities, costs, and utility weights. RESULTS:With the use of reference parameters, the individual expected societal total cost of care was $399.83 without and $1387.95 with prophylaxis. Preventing a single mortality with prophylaxis would cost $43.00 million (number needed to treat: 39,839 individuals). The incremental cost was $1.90 million per quality-adjusted life-year. Adjusting across a range of scenarios upheld these conclusions 88% of the time. With further sensitivity testing, subpopulations with postdischarge thrombosis rates greater than 4.9% favors postoperative extended-duration venous thromboembolism prophylaxis. LIMITATIONS:Further investigation is needed to determine if specific high-risk individuals can be preemptively identified in the Crohn's surgical population for targeted prophylaxis. CONCLUSION:Extended prophylaxis in patients with Crohn's disease postoperatively is not cost-effective when the cumulative incidence of posthospital thrombosis remains less than 4.9%. These findings are driven by the low absolute risk of thrombosis in this population and the considerable cost of universal treatment. See Video Abstract at http://links.lww.com/DCR/A998. LIMITACIONES DE COSTO-BENEFICIO DE LA PROFILAXIS AMBULATORIA PROLONGADA DEL TROMBOEMBOLISMO VENOSO DESPUÉS DE CIRUGÍA EN CASOS DE ENFERMEDAD DE CROHN:: Los pacientes con enfermedad de Crohn tienen un mayor riesgo de tromboembolismo venoso postoperatorio. Históricamente, la profilaxis ambulatoria prolongada no ha cumplido con las medidas convencionales de ventajas en costo-beneficio para la sociedad. Sin embargo, la profilaxis prolongada en los pacientes con Crohn puede ser más rentable debido al alto riesgo trombótico y a una larga esperanza de vida en estos pacientes.Evaluar la rentabilidad de la profilaxis prolongada en pacientes postoperados de un Crohn.Se utilizó un modelo de árbol de decisión para evaluar el incremento de rentabilidad y el costo por cada caso evitado con la profilaxis prolongada de tromboembolismo venoso después de cirugía abdominal.Se calcularon utilizando fuentes publicadas el riesgo de evento trombótico posterior al alta, la edad del paciente al momento de la cirugía, el tipo de evento trombótico, la reducción del riesgo de profilaxis, las complicaciones hemorrágicas y la mortalidad.Se estudiaron los pacientes de atención rutinaria versus aquellos portadores de Crohn.Construimos un arbol de análisis decisional para comparar costos y resultados de pacientes portadores de Crohn, con y sin profilaxis prolongada en el postoperatorio en un horizonte de por vida.Los costos de productividad ($) y los beneficios (año de vida ajustado por calidad) se utilizaron para reflejar la perspectiva social y se descontaron en el tiempo de un 3%. El análisis de sensibilidad probabilística multivariable dió cuenta de la incertidumbre en las probabilidades, costos y peso de utilidades.Usando parámetros de referencia, el costo total social esperado de la atención individual fue de $ 399.83 sin y $ 1,387.95 con profilaxis. La prevención del deceso de un paciente con profilaxis costaría $ 43.00 millones (valor requerido para tratar: 39,839 individuos). El costo incrementado fue de $ 1.90 millones por año de vida ajustado por la calidad. El ajuste a través de una gama de escenarios confirmó estas conclusiones el 88% del tiempo. Con pruebas de sensibilidad adicionales, las subpoblaciones con tasas de trombosis posteriores al alta fueron superiores al 4,9% y favorecían la profilaxis prolongada del tromboembolismo venoso en el postoperatorio.Se necesita más investigación para determinar si se puede identificar de manera preventiva los individuos específicos de alto riesgo en la población quirúrgica de Crohn en casos de profilaxis dirigida.La profilaxis prolongada en pacientes postoperados de un Crohn no es rentable cuando la incidencia acumulada de trombosis posthospitalaria sigue siendo inferior al 4,9%. Estos hallazgos son impulsados por el bajo riesgo absoluto de trombosis en esta población y el costo considerable del tratamiento universal. Vea el resumen del video en http://links.lww.com/DCR/A998.
PMCID:6788772
PMID: 31596763
ISSN: 1530-0358
CID: 5272452

Readmission Adversely Affects Survival in Surgical Rectal Cancer Patients

Chen, Sophia Y; Stem, Miloslawa; Gearhart, Susan L; Safar, Bashar; Fang, Sandy H; Azad, Nilofer S; Murphy, Adrian G; Narang, Amol K; Wolfgang, Christopher L; Efron, Jonathan E
BACKGROUND:Readmission has received attention as a potential healthcare quality metric. No studies have investigated the relationship between readmission and survival in patients undergoing rectal cancer surgery. The aims of this study were to identify factors associated with 30-day readmission after rectal cancer surgery and to determine the impact of readmission on overall survival (OS). METHODS:Patients who underwent surgical treatment for rectal/rectosigmoid adenocarcinoma stages I-IV were identified using the National Cancer Database (2004-2014). Multivariable logistic regression was used to identify factors for readmission. 2:1 nearest neighbor caliper matching without replacement was used to ensure similarity of patients being compared. Survival analyses were performed using Kaplan-Meier method along with log-rank test and Cox proportional hazards model. RESULTS:Of 110,167 patients, 7045 (6.39%) were readmitted. Factors associated with readmission included higher Charlson comorbidity score, non-private or no insurance, procedure type, hospitals in the Northeast, South, and Midwest regions, and prolonged length of stay. Within the matched cohort (13,756 non-readmitted and 6878 readmitted), readmitted patients had worse 5- and 10-year OS regardless of cancer stage (p < 0.001) and procedure type. Five- and 10-year OS were 58.98% and 41.01% for readmitted patients, 64.96% and 43.50% for non-readmitted patients. Readmitted patients had shorter OS by 13.14 months and increased risk of mortality (HR 1.20, 95% CI 1.15-1.25, p < 0.001). CONCLUSIONS:Thirty-day readmission after rectal cancer surgery is associated with decreased OS. Efforts to reduce readmissions should be considered to advance cancer care and enhance the potential for improved patient survival.
PMID: 31222644
ISSN: 1432-2323
CID: 4741242

The Safety of Outpatient Stoma Closure: on the Verge of a Paradigm Shift?

Taylor, James P; Stem, Miloslawa; Chen, Sophia Y; Yu, David; Fang, Sandy H; Gearhart, Susan L; Safar, Bashar; Efron, Jonathan E
BACKGROUND:An area of contention among colorectal surgeons is when it is safe to discharge patients who have undergone closure of diverting ostomies. This study aimed to review the trends in outpatient stoma closure (OSC), to assess the safety of this practice, and to identify appropriate surgical candidates for the outpatient procedure. METHODS:Patients were queried from the ACS National Surgical Quality Improvement Program database (2005-2016). Main outcomes included Clavien-Dindo (C-D) III-V class surgical complications, and readmission. Outpatient stay was defined as a hospital stay of less than or equal to 1 day. Multivariable logistic regression analysis was used to identify risk factors for C-D III-V complications and readmission. RESULTS:Of 24,393 patients, 668 (2.74%) underwent an OSC. OSC has increased over the last decade (3.16% 2005-2006, 4.14% 2016, p < 0.001). Outpatients had significantly lower ASA class and fewer comorbidities than inpatients. Outpatient complication rate was significantly lower than the inpatient rate (2.99% vs. 7.25%, p < 0.001). Readmissions were comparable (8.92% outpatient vs. 9.77% inpatient, p = 0.54). ASA > 2, smoking, COPD, dyspnea, steroid use, bleeding disorder, and partial/total dependency were associated with increased risk of complications and readmission. Patients without any risk factors had lower complication (4.75%) and readmission rates (8.09%) compared to those with ≥ 2 risk factors (11.50% complication and 13.07% readmission rate, p < 0.001). CONCLUSIONS:There is an increasing trend in the percentage of stoma closures being performed as outpatient procedures. Appropriate selection of patients preoperatively who are suitable candidates for OSC can be helpful in managing patient expectations and hospital resources.
PMID: 30350192
ISSN: 1873-4626
CID: 5272392