Learning Curve of a Laparoscopic Pancreaticoduodenectomy Program at a Second Institution.

BACKGROUND: Historically, pancreaticoduodenectomy (PD) has been performed via a laparotomy, but increasingly, laparoscopic and robotic platforms are being employed for PD. Laparoscopic PD has a steep surgeon specific learning curve and programmatic elements that must be optimized. These factors may limit a surgeon who is proficient at laparoscopic PD to develop a program at another institution. We hypothesize that the learning curve for a surgeon transferring a program to a second institution is shorter than the initial laparoscopic PD learning curve for the same surgeon. METHODS: A retrospective review of patients who underwent laparoscopic PD for any indication at the first institution (FI) from 2012 to 2017 and the second institution (SI) from 2018 to 2021 was conducted. Standard statistical analysis was performed. The learning curve was identified using one-sided CUSUM analysis of operative times. RESULT: We identified 110 participants, 90 from the FI and 20 from the SI. More patients at the FI were diagnosed with periampullary adenocarcinoma on final pathology compared to the SI (65.6% vs 40.0%, P = .0132). FI operative times stabilized after the 25th laparoscopic PD and SI operative times stabilized after the 5th operation. No statistically significant difference was identified in postoperative complications. CONCLUSIONS: The learning curve and average operative time of an SI laparoscopic PD program was shorter than the initial learning curve for a single surgeon with comparable outcomes. This suggests that complex minimally invasive surgical programs can be safely transferred to another high-volume institution without significant loss of progress.

Autogenic splenic implantation versus splenectomy in patients undergoing distal pancreatectomy for benign or low-grade malignant lesions of the distal pancreas: study protocol for a multicentre, open-label, randomized controlled trial (RESTORE).

BACKGROUND: The spleen plays a significant role in the clearance of circulating microorganisms. Sequelae of splenectomy, especially immunodeficiency, can have a deleterious effect on a patient's health and even lead to death. Hence, splenectomy should be avoided and spleen preservation during elective surgery has become a treatment goal. However, this cannot be achieved in every patient due to intraoperative technical difficulties or oncological reasons. Autogenic splenic implantation (ASI) is currently the only possible way to preserve splenic function when a splenectomy is necessary. Experience largely stems from trauma patients with a splenic rupture. Splenic immune function can be measured by the body's clearing capacity of encapsulated bacteria. The aim of this study is to assess the splenic immune function after ASI was performed during minimally invasive (laparoscopic or robotic) distal pancreatectomy with splenectomy. METHODS: This is the protocol for a multicentre, randomized, open-labelled trial. Thirty participants with benign or low-grade malignant lesions of the distal pancreas requiring minimally invasive distal pancreatectomy and splenectomy will be allocated to either additional intraoperative ASI (intervention) or no further intervention (control). An additional 15 patients who will undergo spleen-preserving distal pancreatectomy serve as the control group with normal splenic function. Six months postoperatively, after assumed restoration of splenic function, patients will be given a Salmonella typhi (Typhim Vi™) vaccine. The Salmonella typhi vaccine is a polysaccharide vaccine. The specific antibody titres immediately before and 4 to 6 weeks after vaccination will be measured. The ratio between pre- and post-vaccination antibody count is the primary outcome measure and secondary outcome measures include intraoperative details, length of hospital stay, 30-day mortality and morbidity. DISCUSSION: This study will investigate the splenic immune function of patients who undergo ASI during minimally invasive distal pancreatectomy with splenectomy. The splenic immune function will be measured using the surrogate outcome of specific antibody titre after vaccination with a Salmonella typhi vaccine. The results will reveal details about splenic function after ASI and guide further treatment options for patients when a splenectomy cannot be avoided. It might eventually lead to a new standard of care making sometimes more demanding and time-consuming spleen-preserving procedures redundant. TRIAL REGISTRATION: International Standard Randomized Controlled Trials Number (ISRCTN) ISRCTN10171587. Prospectively registered on 18 February 2019.

Intraoperative Imaging in Hepatopancreatobiliary Surgery.

Hepatopancreatobiliary surgery belongs to one of the most complex fields of general surgery. An intricate and vital anatomy is accompanied by difficult distinctions of tumors from fibrosis and inflammation; the identification of precise tumor margins; or small, even disappearing, lesions on currently available imaging. The routine implementation of ultrasound use shifted the possibilities in the operating room, yet more precision is necessary to achieve negative resection margins. Modalities utilizing fluorescent-compatible dyes have proven their role in hepatopancreatobiliary surgery, although this is not yet a routine practice, as there are many limitations. Modalities, such as photoacoustic imaging or 3D holograms, are emerging but are mostly limited to preclinical settings. There is a need to identify and develop an ideal contrast agent capable of differentiating between malignant and benign tissue and to report on the prognostic benefits of implemented intraoperative imaging in order to navigate clinical translation. This review focuses on existing and developing imaging modalities for intraoperative use, tailored to the needs of hepatopancreatobiliary cancers. We will also cover the application of these imaging techniques to theranostics to achieve combined diagnostic and therapeutic potential.

Not all cholecystitis is created equal: Disparities contributing to ED presentation and failure of the outpatient algorithm.

BACKGROUND: The majority of final surgical pathology (FSP) from both emergency department (ED) and outpatient clinic (OC) patients is chronic cholecystitis. We aimed to differentiate these presentations and identify disparities associated with ED utilization and OC failure. METHODS: Retrospective chart review of single institution ED and OC cholecystectomies for cholelithiasis. Clinical presentation, FSP, demographics, and zip code poverty (ZCP) levels were evaluated. Data analysis by summary statistics, bivariate comparisons, and logistic regression. RESULTS: Of 299 OC and 308 ED patients, OC was more likely to be Caucasian (78% vs 46%, p < 0.0001) and insured (89% vs. 32%, p < 0.0001). 71.8% of OC with ZCP <10% had insurance versus only 32.5% in ZCP >20%. Uninsured ED OR was 13.1 (95% CI 8.7-22.9). CONCLUSION: Uninsured ED patients are vulnerable to fail the outpatient algorithm, especially when misdiagnosed by US. Clinical diagnosis of cholecystitis in this population should warrant offering of urgent cholecystectomy.

Surgical and Oncological Outcomes After Preoperative FOLFIRINOX Chemotherapy in Resected Pancreatic Cancer: An International Multicenter Cohort Study.

BACKGROUND: Preoperative FOLFIRINOX chemotherapy is increasingly administered to patients with borderline resectable (BRPC) and locally advanced pancreatic cancer (LAPC) to improve overall survival (OS). Multicenter studies reporting on the impact from the number of preoperative cycles and the use of adjuvant chemotherapy in relation to outcomes in this setting are lacking. This study aimed to assess the outcome of pancreatectomy after preoperative FOLFIRINOX, including predictors of OS. METHODS: This international multicenter retrospective cohort study included patients from 31 centers in 19 European countries and the United States undergoing pancreatectomy after preoperative FOLFIRINOX chemotherapy (2012-2016). The primary end point was OS from diagnosis. Survival was assessed using Kaplan-Meier analysis and Cox regression. RESULTS: The study included 423 patients who underwent pancreatectomy after a median of six (IQR 5-8) preoperative cycles of FOLFIRINOX. Postoperative major morbidity occurred for 88 (20.8%) patients and 90-day mortality for 12 (2.8%) patients. An R0 resection was achieved for 243 (57.4%) patients, and 259 (61.2%) patients received adjuvant chemotherapy. The median OS was 38 months (95% confidence interval [CI] 34-42 months) for BRPC and 33 months (95% CI 27-45 months) for LAPC. Overall survival was significantly associated with R0 resection (hazard ratio [HR] 1.63; 95% CI 1.20-2.20) and tumor differentiation (HR 1.43; 95% CI 1.08-1.91). Neither the number of preoperative chemotherapy cycles nor the use adjuvant chemotherapy was associated with OS. CONCLUSIONS: This international multicenter study found that pancreatectomy after FOLFIRINOX chemotherapy is associated with favorable outcomes for patients with BRPC and those with LAPC. Future studies should confirm that the number of neoadjuvant cycles and the use adjuvant chemotherapy have no relation to OS after resection.

Innovative Imaging Techniques Used to Evaluate Borderline-Resectable Pancreatic Adenocarcinoma.

A diagnosis of pancreatic cancer carries a 5-y survival rate of less than 10%. Furthermore, the detection of pancreatic cancer occurs most often in later stages of the disease due to its location in the retroperitoneum and lack of symptoms (in most cases) until tumors become more advanced. Once diagnosed, cross-sectional imaging techniques are heavily utilized to determine the tumor stage and the potential for surgical resection. However, a major determinant of resectability is the extent of local vascular involvement of the mesenteric vessels and critical tributaries; current imaging techniques have limited capacity to accurately determine vascular involvement. Surrounding inflammation and fibrosis can be difficult to discriminate from viable tumor, making determination of the degree of vascular involvement unreliable. New innovations in fluorescence and optoacoustic imaging techniques may overcome these limitations and make determination of resectability more accurate. These imaging modalities are able to more clearly discern between viable tumor tissue and non-neoplastic inflammation or desmoplasia, allowing clinicians to more reliably characterize vascular involvement and develop individualized treatment plans for patients. This review will discuss the current imaging techniques used to diagnose pancreatic cancer, the barriers that current techniques raise to accurate staging, and novel fluorescence and optoacoustic imaging techniques that may provide more accurate clinical staging of pancreatic cancer.

Risk Factors Associated With Readmission After Pancreatectomy: A Single-Institution Retrospective Cohort Study.

BACKGROUND: Pancreatectomy has a significant rate of procedure-specific morbidity which can result in readmission. Readmission has been proposed as a measure of quality. The goal of this study is to determine what factors are associated with readmission after pancreatectomy and whether readmission can be prevented. METHODS: A retrospective review of a single institution's pancreatectomies between January 2011 and April 2015 was performed. Demographic, perioperative, and outpatient data were collected from the medical record. Primary outcome was 90-day readmission. Univariate and multivariable analyses were performed to determine which factors were associated with increased risk for readmission. RESULTS: A total of 257 patients met inclusion criteria; the 90-day readmission rate was 32.7%. The median time to readmission was 13 days. Readmitted patients were more likely to have a postoperative pancreatic fistula (POPF) on univariate analysis. Surgical site infections were more common in readmitted patients (18% vs 6.4%, P = .0138). Upon multivariable adjustment, only POPF (P = .0005) remained significant. A positive dose-response relationship was noted between POPF grade and the odds of readmission with odds ratios (ORs) ranging from 1.6 (95% Confidence Interval (CI): .6-4.1) for grade A to 16.7 (95% CI: 1.8-156.8) for grade C, albeit with limited precision. CONCLUSIONS: Readmission after pancreatectomy is a common occurrence despite the many advancements in perioperative care. Our data suggest that POPF is a risk factor for readmission after pancreatectomy. Presently, this factor is not clearly preventable. This suggests that readmission may not be the best measure of quality to utilize in the evaluation of pancreatic surgery.

Evaluation of Adjuvant Chemotherapy in Patients With Resected Pancreatic Cancer After Neoadjuvant FOLFIRINOX Treatment.

IMPORTANCE: The benefit of adjuvant chemotherapy after resection of pancreatic cancer following neoadjuvant combination treatment with folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) is unclear. OBJECTIVE: To assess the association of adjuvant chemotherapy with overall survival (OS) in patients after pancreatic cancer resection and neoadjuvant FOLFIRINOX treatment. DESIGN, SETTING, AND PARTICIPANTS: This international, multicenter, retrospective cohort study was conducted from January 1, 2012, to December 31, 2018. An existing cohort of patients undergoing resection of pancreatic cancer after FOLFIRINOX was updated and expanded for the purpose of this study. All consecutive patients who underwent pancreatic surgery after at least 2 cycles of neoadjuvant FOLFIRINOX chemotherapy for nonmetastatic pancreatic cancer were retrospectively identified from institutional databases. Patients with resectable pancreatic cancer, borderline resectable pancreatic cancer, and locally advanced pancreatic cancer were eligible for this study. Patients with in-hospital mortality or who died within 3 months after surgery were excluded. EXPOSURES: The association of adjuvant chemotherapy with OS was evaluated in different subgroups including interaction terms for clinicopathological parameters with adjuvant treatment in a multivariable Cox model. Overall survival was defined as the time starting from surgery plus 3 months (moment eligible for adjuvant therapy), unless mentioned otherwise. RESULTS: We included 520 patients (median [interquartile range] age, 61 [53-66] years; 279 [53.7%] men) from 31 centers in 19 countries. The median number of neoadjuvant cycles of FOLFIRINOX was 6 (interquartile range, 5-8). Overall, 343 patients (66.0%) received adjuvant chemotherapy, of whom 68 (19.8%) received FOLFIRINOX, 201 (58.6%) received gemcitabine-based chemotherapy, 14 (4.1%) received capecitabine, 45 (13.1%) received a combination or other agents, and 15 (4.4%) received an unknown type of adjuvant chemotherapy. Median OS was 38 months (95% CI, 36-46 months) after diagnosis and 31 months (95% CI, 29-37 months) after surgery. No survival difference was found for patients who received adjuvant chemotherapy vs those who did not (median OS, 29 vs 29 months, univariable hazard ratio [HR], 0.99; 95% CI, 0.77-1.28; P = .93). In multivariable analysis, only the interaction term for lymph node stage with adjuvant therapy was statistically significant: In patients with pathology-proven node-positive disease, adjuvant chemotherapy was associated with improved survival (median OS, 26 vs 13 months; multivariable HR, 0.41 [95% CI, 0.22-0.75]; P = .004). In patients with node-negative disease, adjuvant chemotherapy was not associated with improved survival (median OS, 38 vs 54 months; multivariable HR, 0.85; 95% CI, 0.35-2.10; P = .73). CONCLUSIONS AND RELEVANCE: These results suggest that adjuvant chemotherapy after neoadjuvant FOLFIRINOX and resection of pancreatic cancer was associated with improved survival only in patients with pathology-proven node-positive disease. Future randomized studies should be conducted to confirm this finding.

Development and external validation of a prediction model for survival in patients with resected ampullary adenocarcinoma.

INTRODUCTION: Ampullary adenocarcinoma (AAC) is a rare malignancy with great morphological heterogeneity, which complicates the prediction of survival and, therefore, clinical decision-making. The aim of this study was to develop and externally validate a prediction model for survival after resection of AAC. MATERIALS AND METHODS: An international multicenter cohort study was conducted, including patients who underwent pancreatoduodenectomy for AAC (2006-2017) from 27 centers in 10 countries spanning three continents. A derivation and validation cohort were separately collected. Predictors were selected from the derivation cohort using a LASSO Cox proportional hazards model. A nomogram was created based on shrunk coefficients. Model performance was assessed in the derivation cohort and subsequently in the validation cohort, by calibration plots and Uno's C-statistic. Four risk groups were created based on quartiles of the nomogram score. RESULTS: Overall, 1007 patients were available for development of the model. Predictors in the final Cox model included age, resection margin, tumor differentiation, pathological T stage and N stage (8th AJCC edition). Internal cross-validation demonstrated a C-statistic of 0.75 (95% CI 0.73-0.77). External validation in a cohort of 462 patients demonstrated a C-statistic of 0.77 (95% CI 0.73-0.81). A nomogram for the prediction of 3- and 5-year survival was created. The four risk groups showed significantly different 5-year survival rates (81%, 57%, 22% and 14%, p < 0.001). Only in the very-high risk group was adjuvant chemotherapy associated with an improved overall survival. CONCLUSION: A prediction model for survival after curative resection of AAC was developed and externally validated. The model is easily available online via www.pancreascalculator.com.

Neuroendocrine Tumors of the Pancreatobiliary and Gastrointestinal Tracts.

Incidence of neuroendocrine tumors (NETs) is increasing, including those of the gastroenteropancreatic tract. A proper understanding of the management of this disease has become necessary for the general surgeon. This article addresses current guidelines for diagnosis and localization of NETs, including somatostatin receptor PET. Updated treatment and outcomes of NETs by primary tumor site are discussed as well as those metastatic to the liver.

Practicing on the Advanced Training in Laparoscopic Suturing Curriculum (ATLAS): Is Mastery Learning in Residency Feasible to Achieve Expert-Level Performance in Laparoscopic Suturing?

BACKGROUND: Mastery learning assumes that given enough time and appropriate instructional strategies, most trainees will be able to achieve proficiency. Expert-level performance requires numerous hours of intensive and focus practice. We aimed to study whether it was possible for surgical trainees to achieve expert-derived proficiency level in laparoscopic suturing using the Advanced Training in Laparoscopic Suturing (ATLAS) curriculum over a short period of time. STUDY DESIGN: A multicenter IRB approved prospective study included surgery residents and minimally invasive fellows. Participants underwent weekly supervised instruction and assessments of ATLAS skills and self-directed practice between sessions over 12 weeks. Participants were asked to practice until they achieved previously established proficiency benchmarks of expert laparoscopic surgeons. RESULTS: Fifteen participants, PGY2 to PGY6, from 3 institutions practiced on the ATLAS curriculum. Three participants were able to achieve proficiency on the entire curriculum, with a cumulative practice time varying between 3.4 and 7.6 hours. Individual tasks had varying degrees of difficulty ranging from 85% proficiency on task 1 to 33.3% proficiency for task 6. Using a mixed-method model, the mean cumulative hours of practice to reach the benchmark threshold was estimated for each task and varied from 4.5 to 13.2 hours. The improved performance was associated with higher PGY level and proficiency in FLS. CONCLUSIONS: This study demonstrates that it is possible for some senior surgical trainees to achieve proficiency in an expert-level laparoscopic suturing curriculum. This study establishes a learning curve for each ATLAS individual task. Some learners may not be able to achieve proficiency on the entire curriculum over a short period of practice. Additional studies are needed to assess how to shorten the learning curve with effective instructional methods such as expert-guided training with immediate feedback.

Central pancreatectomy with pancreaticogastrostomy reconstruction: A brief report and video technique.

Low grade tumors located in the neck of the pancreas present a unique surgical challenge. Subtotal pancreatectomy results in significant loss of pancreatic gland and function, while pancreaticoduodenectomy may be too aggressive for these lesions. We present a case of a patient with a well differentiated neuroendocrine tumor in the neck of the pancreas who underwent a central pancreatectomy with pancreaticogastrostomy reconstruction. Patient selection and technical aspects of the procedure are described. The decision to perform a central pancreatectomy should not be made lightly as complications are frequent. Careful patient selection is imperative.

Current Imaging Standards for Nonmetastatic Benign and Malignant Liver Tumors.

The accurate diagnosis of a liver mass can usually be established with a thorough history, examination, laboratory inquiry, and imaging. The necessity of a liver biopsy to determine the nature of a liver mass is rarely necessary. Contrast-enhanced computed tomography and magnetic resonance are the standard of care for diagnosing liver lesions and high-quality imaging should be performed before performing a biopsy. This article discusses current consensus guidelines for imaging of liver masses, as well as masses found on surveillance imaging. The ability to accurately characterize lesions requires proper use and understanding of the technology and expert interpretation.

Contemporary Review of Borderline Resectable Pancreatic Ductal Adenocarcinoma.

Borderline resectable pancreatic adenocarcinoma (PDAC) presents challenges in definition and treatment. Many different definitions exist for this disease. Some are based on anatomy alone, while others include factors such as disease biology and patient performance status. Regardless of definition, evidence suggests that borderline resectable PDAC is a systemic disease at the time of diagnosis. There is high-level evidence to support the use of neoadjuvant systemic therapy in these cases. Evidence to support the use of radiation therapy is ongoing. There are ongoing trials investigating the available neoadjuvant therapies for borderline resectable PDAC that may provide clarity in the future.

Choledochal cysts: Similarities and differences between Asian and Western countries.

Choledochal cysts (CCs) are rare bile duct dilatations, intra-and/or extrahepatic, and have higher prevalence in the Asian population compared to Western populations. Most of the current literature on CC disease originates from Asia where these entities are most prevalent. They are thought to arise from an anomalous pancreaticobiliary junction, which are congenital anomalies between pancreatic and bile ducts. Some similarities in presentation between Eastern and Western patients exist such as female predominance, however, contemporary studies suggest that Asian patients may be more symptomatic on presentation. Even though CC disease presents with an increased malignant risk reported to be more than 10% after the second decade of life in Asian patients, this risk may be overstated in Western populations. Despite this difference in cancer risk, management guidelines for all patients with CC are based predominantly on observations reported from Asia where it is recommended that all CCs should be excised out of concern for the presence or development of biliary tract cancer.

Tobacco Smoking Associated With Increased Anastomotic Disruption Following Pancreaticoduodenectomy.

BACKGROUND: The effect of cigarette smoking on postoperative morbidity following pancreaticoduodenectomy (PD) for cancer is unclear. We hypothesize that smoking is associated with higher morbidity following PD. METHODS: A retrospective review of patients undergoing PD for cancer from 2010 to 2016 at a single institution was performed. Patients who had never smoked were compared to current or past-smokers with at least 1 pack-year history. Univariate and multivariable analyses were performed. RESULTS: Two hundred fifty-two patients met inclusion criteria. On univariate analysis, there was a significant difference between smokers and never-smokers in age at diagnosis (65.5 versus 68.6 y, P = 0.013) and fistula rate (28.5% versus 16.2%, P = 0.024). Male sex was significantly associated with fistula rate compared with female sex (15.5% versus 7.1%, P = 0.023). Comparing males and females separately, smoking correlated with higher fistula development only in the male cohort (22.5% versus 5.8%, P = 0.016 in men and 7.3% versus 9.1%, P = 1.00 in women). On multivariable analysis, current and past smoking was independently predictive of developing a fistula: odds ratio of 2.038 (P = 0.030). For current and past-smokers, male sex was an independent risk factor for developing a fistula: odds ratio 2.817 (P = 0.022). There were no other significant differences between groups in rates of postoperative complications. CONCLUSIONS: Smoking status is independently predictive of postoperative pancreatic fistula following PD for cancer. Among smokers, male sex is an independent risk factor for fistula. Further studies are needed to determine if smoking cessation before surgery decreases this risk, and if so, the optimal duration of cessation.

The paralyzing effect of insurance status on throughput of acute spinal cord patients.

OBJECTIVE: To determine whether lack of insurance is a predictor of poor outcomes and increased healthcare expenditure for SCI patients. METHODS: Retrospective cohort study of trauma patients admitted with an acute, severe (AIS ≥ 3) SCI and admission score of ASIA-A to a Level 1 trauma center (2012-2016). Patient characteristics and outcomes (LOS, complications) were compared between insured and uninsured patients. Multivariable adjustment was performed using linear regression. RESULTS: Of 76 patients who met eligibility, 44 had insurance and 32 were uninsured (NOINSUR). Despite having similar ventilator days (13 vs. 12.1) and ICU LOS (20.1 vs. 16.8), the NOINSUR group had more ventilator-free days (22.3 vs 6.6; p < 0.0001), longer Stepdown Unit length of stay (10.2 vs 2.3; p = 0.0036), and a longer hospital length of stay (35.3 vs 18.7; p = 0.0062). CONCLUSION: Uninsured SCI patients face longer hospital LOS due to their insurance status and lack of funding for timely rehabilitation placement. This utilizes valuable hospital resources and puts them at risk for hospital related complications and further increased healthcare expenditures.

Adequacy and accuracy of nontrauma center computed tomography: What are we missing?

BACKGROUND: Timely and appropriate use of computed tomography (CT) scans is critical to the evaluation of traumatic injuries. The objective of this study was to assess the adequacy of CT scans performed at nontrauma centers (NTCs) as they pertain to the management of trauma patients. METHODS: Adult patients transferred to our ACS-verified Level I trauma center from any NTC between May and December 2012 were enrolled prospectively. Available CT images from NTCs were reviewed in a blinded fashion by our facility's trauma radiologist; his interpretations were compared with those from the NTC. Interpretations of the trauma centers (TCs) images were compared with the NTC interpretations. Means and proportions were used to summarize the data. RESULTS: A total of 235 consecutive patients with a complete dataset were included, of which, 203 (86.4%) had a CT scan performed at an NTC. Additional imaging was obtained at the TC in 76% of patients with outside CT (154 of 203), with inadequacy of outside CTs for patient workup based on mechanism of injury (76%) and technical inadequacy of outside images (31%) being the main, nonexclusive reasons to repeat imaging. Image interpretation by the trauma radiologist at the TC using NTC images identified missed injuries in 49% of the patients, and 90% of these missed injuries were deemed clinically significant, meaning the injury would have altered patient care had they been identified. When the same body region was imaged at the TC, 54% had missed injuries, of which 76% were deemed significant. CONCLUSION: This study demonstrates inaccuracy in the interpretation of NTC images, which can lead to inappropriate management of trauma patients. Parameters other than imaging need to be used to identify patients requiring a higher level of care. LEVEL OF EVIDENCE: Therapeutic and care management study, level V.