Implications of leukocytosis following distal pancreatectomy splenectomy (DPS) and association with postoperative complications.

BACKGROUND: Early identification of complications after distal pancreatectomy splenectomy (DPS) poses challenges, as white blood cell count (WBC) is confounded by physiologic leukocytosis. We examined WBC patterns associated with complications after DPS. METHODS: Clinicopathologic data were collected for patients who underwent DPS in our system from 2009 to 2016. We examined WBC, temperature, platelet count (PC), and ratios of these variables as potential early indicators of patients at risk of infections or major complications (MCs). RESULTS: 348 patients met study inclusion, of whom 206 (59%) were women and the median patient age was 59 ± 15 years. Infectious and MC rates were 11% and 16%, respectively, with <1% 30-day mortality. Postoperative WBC peaks were higher in patients with infections and MCs compared with no complication (23 vs. 17, p < 0.0001). WBC peak timing occurred postoperative day (POD) 2-3 for uncomplicated cases while peaks occurred POD9 for patients with infections and MCs. DISCUSSION: These data define patterns of leukocytosis following DPS. Although differences in infection markers were identified for patients with and without complications, no obvious thresholds were identified. Clinical suspicion for complications after DPS remains our best tool for early identification.

Counting the cost: financial implications of complications following pancreaticoduodenectomy.

BACKGROUND: Morbidity after pancreaticoduodenectomy (PD) has been reported to be about 30-53%. These complications can double hospital costs. We sought to explore the financial implications of complications after PD in a large institutional database. METHODS: A retrospective analysis of patients undergoing PD from 2010-2017 was performed. Costs for index hospitalization were divided into categories: operating room, postoperative ward, radiology and interventional radiology. Complications were categorized according to the Clavien-Dindo classification. Univariable and mutivariable analysis were performed. RESULTS: Median cost of index admission for 997 patients who underwent PD was $23,704 (range $10,988-$528,531). Patients with major complications incurred significantly greater median costs compared to those without ($40,005 vs $21,306, p < 0.001). Patients with postoperative pancreatic fistula (POPF) grade A, B and C had progressively increasing costs ($32,164, $50,264 and $102,013, p < 0.001). On multivariable analysis ileus/delayed gastric emptying, respiratory failure, clinically significant POPF, thromboembolic complications, reoperation, duration of surgery >240 minutes and male sex were associated with significantly increased costs. CONCLUSION: Complications after PD significantly increase hospital costs. This study identifies the major contributors towards increased cost post-PD. Initiatives that focus on prevention of complications could reduce associated costs and ease financial burden on patients and healthcare organizations.

Anti-C5 Antibody Tesidolumab Reduces Early Antibody-mediated Rejection and Prolongs Survival in Renal Xenotransplantation.

OBJECTIVE: Pig-to-primate renal xenotransplantation is plagued by early antibody-mediated graft loss which precludes clinical application of renal xenotransplantation. We evaluated whether temporary complement inhibition with anti-C5 antibody Tesidolumab could minimize the impact of early antibody-mediated rejection in rhesus monkeys receiving pig kidneys receiving costimulatory blockade-based immunosuppression. METHODS: Double (Gal and Sda) and triple xenoantigen (Gal, Sda, and SLA I) pigs were created using CRISPR/Cas. Kidneys from DKO and TKO pigs were transplanted into rhesus monkeys that had the least reactive crossmatches. Recipients received anti-C5 antibody weekly for 70 days, and T cell depletion, anti-CD154, mycophenolic acid, and steroids as baseline immunosuppression (n = 7). Control recipients did not receive anti-C5 therapy (n = 10). RESULTS: Temporary anti-C5 therapy reduced early graft loss secondary to antibody-mediated rejection and improved graft survival (P < 0.01). Deleting class I MHC (SLA I) in donor pigs did not ameliorate early antibody-mediated rejection (table). Anti-C5 therapy did not allow for the use of tacrolimus instead of anti-CD154 (table), prolonging survival to a maximum of 62 days. CONCLUSION: Inhibition of the C5 complement subunit prolongs renal xenotransplant survival in a pig to non-human primate model.

The Impact of Neoadjuvant Treatment on Survival in Patients Undergoing Pancreatoduodenectomy With Concomitant Portomesenteric Venous Resection: An International Multicenter Analysis.

OBJECTIVE: The aim of this study was to evaluate whether neoadjuvant therapy (NAT) critically influenced microscopically complete resection (R0) rates and long-term outcomes for patients with pancreatic ductal adenocarcinoma who underwent pancreatoduodenectomy (PD) with portomesenteric vein resection (PVR) from a diverse, world-wide group of high-volume centers. SUMMARY OF BACKGROUND DATA: Limited size studies suggest that NAT improves R0 rates and overall survival compared to upfront surgery in R/BR-PDAC patients. METHODS: This multicenter study analyzed consecutive patients with R/BR-PDAC who underwent PD with PVR in 23 high-volume centers from 2009 to 2018. RESULTS: Data from 1192 patients with PD and PVR were collected and analyzed. The median age was 68 [interquartile range (IQR) 60-73] years and 52% were males. Some 186 (15.6%) and 131 (10.9%) patients received neoadjuvant chemotherapy (NAC) alone and neoadjuvant chemoradiotherapy, respectively. The R0/R1/R2 rates were 57%, 39.3%, and 3.2% in patients who received NAT compared to 46.6%, 49.9%, and 3.5% in patients who did not, respectively (P =0.004). The 1-, 3-, and 5-year OS in patients receiving NAT was 79%, 41%, and 29%, while for those that did not it was 73%, 29%, and 18%, respectively (P <0.001). Multivariable analysis showed no administration of NAT, high tumor grade, lymphovascular invasion, R1/R2 resection, no adjuvant chemotherapy, occurrence of Clavien-Dindo grade 3 or higher postoperative complications within 90 days, preoperative diabetes mellitus, male sex and portal vein involvement were negative independent predictive factors for OS. CONCLUSION: Patients with PDAC of the pancreatic head expected to undergo venous reconstruction should routinely be considered for NAT.

Relationship between Cancer Diagnosis and Complications Following Pancreatoduodenectomy for Duodenal Adenoma.

BACKGROUND: Pancreatoduodenectomy (PD) for duodenal adenoma (DA) resection may be associated with excessive surgical risk for patients with potentially benign lesions, given the absence of pancreatic duct obstruction. We examined factors associated with final malignant pathology and evaluated the postoperative course of patients with DA versus pancreatic ductal adenocarcinoma (PDAC). METHODS: We retrospectively analyzed patients with DA who underwent PD from 2008 to 2018 and assessed the accuracy rate of preoperative biopsy and factors associated with final malignant pathology. Complications for DA patients were compared with those of matched PDAC patients. RESULTS: Forty-five consecutive patients who underwent PD for DA were identified, and the preoperative biopsy false negative rate was 29. Factors associated with final malignant pathology included age over 70 years, preoperative biliary obstruction, and common bile duct diameter > 8 mm (p < 0.05). Compared with patients with PDAC (n = 302), DA patients experienced more major complications (31% vs. 15%, p < 0.01), more grade C postoperative pancreatic fistulas (9% vs. 1%, p < 0.01), and greater mortality (7% vs. 2%, p < 0.05). Propensity score matched patients with DA had more major complications following PD (32% vs. 12%, p < 0.05). CONCLUSIONS: Preoperative biopsy of duodenal adenomas is associated with a high false-negative rate for malignancy, and PD for DA is associated with higher complication rates than PD for PDAC. These results aid discussion among patients and surgeons who are considering observation versus PD for DA, especially in younger patients without biliary obstruction, who are less likely to harbor malignancy.

Defining Benchmark Outcomes for Pancreatoduodenectomy With Portomesenteric Venous Resection.

OBJECTIVE: The aim of this study was to establish clinically relevant outcome benchmark values using criteria for pancreatoduodenectomy (PD) with portomesenteric venous resection (PVR) from a low-risk cohort managed in high-volume centers. SUMMARY BACKGROUND DATA: PD with PVR is regarded as the standard of care in patients with cancer involvement of the portomesenteric venous axis. There are, however, no benchmark outcome indicators for this population which hampers comparisons of patients undergoing PD with and without PVR resection. METHODS: This multicenter study analyzed patients undergoing PD with any type of PVR in 23 high-volume centers from 2009 to 2018. Nineteen outcome benchmarks were established in low-risk patients, defined as the 75th percentile of the median outcome values of the centers (NCT04053998). RESULTS: Out of 1462 patients with PD and PVR, 840 (58%) formed the benchmark cohort, with a mean age was 64 (SD11) years, 413 (49%) were females. Benchmark cutoffs, among others, were calculated as follows: Clinically relevant pancreatic fistula rate (International Study Group of Pancreatic Surgery): ≤14%; in-hospital mortality rate: ≤4%; major complication rate Grade≥3 and the CCI up to 6 months postoperatively: ≤36% and ≤26, respectively; portal vein thrombosis rate: ≤14% and 5-year survival for patients with pancreatic ductal adenocarcinoma: ≥9%. CONCLUSION: These novel benchmark cutoffs targeting surgical performance, morbidity, mortality, and oncological parameters show relatively inferior results in patients undergoing vascular resection because of involvement of the portomesenteric venous axis. These benchmark values however can be used to conclusively assess the results of different centers or surgeons operating on this high-risk group.

Emergency department visits after pancreatoduodenectomy: examining a novel quality metric.

BACKGROUND: Postoperative emergency department (ED) visits represent fragmented care, are costly, and often evolve into readmission. Readmission rates after pancreatoduodenectomy (PD) are defined, while ED visits following PD are not. We examined the pattern of 30-day post-discharge ED visits for PD patients. METHODS: A quaternary institutional database analysis of adult patients who underwent PD between 2010-2017 was reviewed for ED utilization within 30 days from discharge. RESULTS: Of the 1,004 patients who underwent PD, 12% (N = 117) patients sought care in the ED within 30 days from postoperative discharge. The median time to ED presentation was 5 days post-discharge (IQR 3-9). Half of ED visits occurred during nights and weekends (N = 59, 50%). Of ED-utilizing patients, 64% (N = 76) were admitted to the hospital and 29% (N = 34) were discharged from the ED. ED visits were associated with a Clavien-Dindo Classification of 0 in 10.2% (N = 13) of patients, I-II in 62.4% (N = 73), and III-V in 26.5% (N = 31). DISCUSSION: Post-discharge ED utilization is a novel quality metric and represents a potential target population for reducing hospital readmissions. Over two-thirds (72%) of ED visits were associated with low acuity complications, and promoting institutional strategies addressing postoperative ED visits may improve patient care and efficient utilization of healthcare resources.

Benchmarks in Pancreatic Surgery: A Novel Tool for Unbiased Outcome Comparisons.

OBJECTIVE: To use the concept of benchmarking to establish robust and standardized outcome references after pancreatico-duodenectomy (PD). BACKGROUND: Best achievable results after PD are unknown. Consequently, outcome comparisons among different cohorts, centers or with novel surgical techniques remain speculative. METHODS: This multicenter study analyzes consecutive patients (2012-2015) undergoing PD in 23 international expert centers in pancreas surgery. Outcomes in patients without significant comorbidities and major vascular resection (benchmark cases) were analyzed to establish 20 outcome benchmarks for PD. These benchmarks were tested in a cohort with a poorer preoperative physical status (ASA class ≥3) and a cohort treated by minimally invasive approaches. RESULTS: Two thousand three hundred seventy-five (38%) low-risk cases out of a total of 6186 PDs were analyzed, disclosing low in-hospital mortality (≤1.6%) but high morbidity, with a 73% benchmark morbidity rate cumulated within 6 months following surgery. Benchmark cutoffs for pancreatic fistulas (B-C), severe complications (≥ grade 3), and failure-to-rescue rate were 19%, 30%, and 9%, respectively. The ASA ≥3 cohort showed comparable morbidity but a higher in hospital-mortality (3% vs 1.6%) and failure-to-rescue rate (16% vs 9%) than the benchmarks. The proportion of benchmark cases performed varied greatly across centers and continents for both open (9%-93%) and minimally invasive (11%-62%) PD. Centers operating mostly on complex PD cases disclosed better results than those with a majority of low-risk cases. CONCLUSION: The proposed outcome benchmarks for PD, established in a large-scale international patient cohort and tested in 2 different cohorts, may allow for meaningful comparisons between different patient cohorts, centers, countries, and surgical techniques.

Single incision for oncologic breast conserving surgery and sentinel node biopsy in early stage breast cancer: A minimally invasive approach.

INTRODUCTION: Breast conserving surgery (BCS) has a postoperative morbidity up to 30%. We report the feasibility of a single-incision approach for tumor excision and axillary sentinel node biopsy (SNB) sampling intended to minimize patient morbidity and complications. MATERIALS AND METHODS: A tertiary surgical oncology single surgeon database was retrospectively reviewed for all patients undergoing BCS and SNB between January 2013 and December 2015. The single-incision approach used a single breast incision to resect the tumor and the Lymphazurin-tagged SNB. The multi-incision group used a breast incision and a separate axillary incision. RESULTS: The single-incision approach was associated with shorter operative time (56 vs 64 minutes, P = 0.026). Sentinel node retrieval was achieved in 100% in both groups. The single-incision technique was used primarily in the upper outer quadrant (N = 41, 85.4%), but was also selectively applied in other quadrants (N = 5). There was no significant difference in complication rates between the two procedures (P = 0.425), and there were no instances of conversion from single-incision to standard BCS-SNB. CONCLUSIONS: Minimally invasive breast conserving surgery is feasible for patients with early breast cancer located in the upper outer quadrants. This technique may reduce postoperative morbidity and improved cosmetic result.

Pancreatectomy and body mass index: an international evaluation of cumulative postoperative complications using the comprehensive complications index.

BACKGROUND: Overweight and obese patients undergoing pancreatectomy are at increased risk for postoperative complications and readmission. We examined the association between body mass index (BMI) and postoperative complications following major pancreatectomy using the novel Comprehensive Complications Index (CCI), which analyzes the impact of multiple surgical complications rather than just the most severe. METHODS: We performed a retrospective dual institutional international review of 500 consecutive patients who underwent pancreatic resection and assessed the association of BMI with postoperative complications using the CCI and Clavien-Dindo Classification (CDC) with uni- and multivariable analyses. RESULTS: Overweight and obese patients undergoing pancreatic resection demonstrated a higher incidence and severity of CCI-measured complications (29.3 vs. 21.1, P < 0.001), more pancreatic fistulae (15.4 vs. 8.8%, 95% CI 1.005 -1.902), and an increased 30-day readmission rate (21.1 vs. 12.1%, 95% CI 1.067 -1.852) (all p < 0.05) than normal-BMI patients. The CCI was a more sensitive marker of post-pancreatectomy complications relative to the CDC, with a higher multicomplication rate in overweight/obese patients (54.8% vs. 44.5%). CONCLUSION: Patients with overweight and obese body mass index undergoing major pancreatectomy demonstrated higher rates of postoperative complications, pancreatic fistulae, and readmissions. The CCI is a more robust and sensitive tool to assess post-pancreatectomy complications than the CDC.

Emergency department use among kidney transplant recipients in the United States.

Patients with end-stage renal disease use the emergency department (ED) at a 6-fold higher rate than do other US adults. No national studies have described ED use rates among kidney transplant (KTx) recipients, and the factors associated with higher ED use. We examined a cohort of 132 725 adult KTx recipients in the United States Renal Data System (2005-2013). Data on ED visits, hospitalization, and outpatient nephrology visits were obtained from Medicare claims databases. Nearly half (46.1%) of KTx recipients had at least one ED visit (1.61 ED visits/patient-year [PY]), and 39.7% of ED visits resulted in hospitalization in the first year posttransplantation. ED visit rate was high in the first 30 days (5.26 visits/PY) but declined substantially thereafter (1.81 visits/PY in months 1-3; 1.13 visits/PY in months 3-12 posttransplantation). ED visit rates were higher in the first 30 days versus rates for dialysis patients but less than half the rate thereafter. Female sex, public insurance, medical comorbidities, longer pretransplantation dialysis vintage, and delayed graft function were associated with higher ED use in the first year post-KTx. Policies and strategies addressing potentially preventable ED visits should be promoted to help improve patient care and increase efficient use of ED resources.

Invasive Scalp Melanoma: Role for Enhanced Detection Through Professional Training.

BACKGROUND: Scalp and neck melanomas (SNMs) have a relatively poor prognosis compared to other sites, and represent an anatomically challenging area for detection. The aim of this study was to identify the role of the hairdresser in detection of SNMs. METHODS: A tertiary surgical oncology institutional database was retrospectively reviewed for all patients undergoing resection of a scalp, posterior neck, or retro auricular invasive primary melanoma between 2008 and 2014. RESULTS: SNMs accounted for 128 melanoma patients during the study period, with median age 66 years, 88 % male, and median Breslow thickness 1.55 mm. Hairdressers detected 10 % of all SNMs, with hairdresser-detected SNMs presenting 13 years younger (53 vs. 66 years, P = 0.015), and with a trend towards lower Breslow depth (1.15 vs. 1.63) and more frequent discovery in AJCC Stage Ia or Ib (66.7 % vs. 44.8 %) than otherwise-detected SNMs. Women with SNMs were 1.8-fold more likely than men to have their SNMs detected by a hairdresser (P = 0.001), and presented at higher AJCC clinical stage than men and required wider surgical resection margins (P = 0.011). Women with hairdresser-detected SNMs were younger, with lower Breslow thickness and lower AJCC Clinical Stage than women with otherwise-detected SNM. CONCLUSION: This study suggests that hairdressers play a critical role in detection of invasive primary scalp and neck melanoma, accounting for 10 % of all melanomas referred to a tertiary surgical oncology center. Quality improvement initiatives aimed at increasing early detection of scalp and neck melanoma should include members of the cosmetology community.

Geographic variation and neighborhood factors are associated with low rates of pre-end-stage renal disease nephrology care.

Geographic variation of pre-end-stage renal disease (pre-ESRD) nephrology care has not been studied across the United States. Here we sought to identify geographic differences in pre-ESRD care, assess for county-level geographic and sociodemographic risk factors, and correlate with patient outcomes using facility-level mortality. Patients from 5387 dialysis facilities across the United States from 2007 to 2010 were included from the Dialysis Facility Report. Marginal generalized estimating equations were used for modeling with geographic cluster analysis to detect clusters of facilities with low rates of pre-ESRD care. On average, 67% of patients received pre-ESRD care in the United States but with significant variability across regions ranging from 3 to 99%. Five geographic clusters of facilities with low rates of pre-ESRD care were the metropolitan areas of San Francisco, Los Angeles, Chicago, Miami, and Baltimore, along with Southern states along the Mississippi River. Dialysis facilities with the lowest rates of pre-ESRD care were more likely to be located in urban counties with high African-American populations and low educational attainment. A 10% higher proportion of patients receiving pre-ESRD care was associated with 1.3% lower patient mortality as reflected by facility-level mortality. Thus, geographic and sociodemographic factors can be used to design quality improvement initiatives to increase access to nephrology care nationwide and improve patient outcomes.

The Picture of Scientific Surgery: John Hunter and the Reynolds Portrait.

This historical retrospective examines the famous portrait of John Hunter by Sir Joshua Reynolds, focusing on the man and the objects that were chosen to represent his legacy in anatomy and surgery.

The Price of Courage: The Life and Legacy of Dr LaSalle D. Leffall Jr.

This historical retrospective details the life and legacy of Dr LaSalle D. Leffall Jr, a leader in the field of surgical oncology, passionate surgical educator, and indelible mentor. His courage, against the backdrop of the many obstacles presented by American racism, paved the way for the inclusion of multiple generations of women and minority surgeons leaving a lasting impact on the history of American surgery.

Use of Perioperative Advanced Practice Providers to Reduce Cost and Readmission in the Postoperative Hepatopancreatobiliary Population: Results of a Simulation Study.

BACKGROUND: Postoperative healthcare use and readmissions are common among the hepatopancreatobiliary (HPB) population. We evaluated the surgical volume required to sustain advanced practice providers (APPs) in the perioperative setting for cost reduction. STUDY DESIGN: Using decision analysis modeling, we evaluated costs of employing dedicated perioperative APP navigators compared with no APPs navigators. Simulated subjects could: (1) present to an emergency department, with or without readmission, (2) present for direct readmission, (3) require additional office visits, or (4) require no additional care. We informed our model using the most current available published data and performed sensitivity analyses to evaluate thresholds under which dedicated perioperative APP navigators are beneficial. RESULTS: Subjects within the APP navigator cohort accumulated $1,270 and a readmission rate of 6.9%, compared with $2,170 and 13.5% with no APP navigators, yielding a cost savings of $905 and 48% relative reduction in readmission. Based on these estimated cost savings and national salary ranges, a perioperative APPs become financially self-sustaining with 113 to 139 annual HPB cases, equating to 2 to 3 HPB cases weekly. Sensitivity analyses revealed that perioperative APP navigators were no longer cost saving when direct readmission rates exceeded 8.9% (base case 3.7%). CONCLUSIONS: We show that readmissions are reduced by nearly 50% with an associated cost savings of $900 when employing dedicated perioperative APPs. This position becomes financially self-sufficient with an annual HPB case load of 113 to 139 cases. High-volume HPB centers could benefit from postdischarge APP navigators to optimize outcomes, minimize high-value resource use, and ultimately save costs.

From the Base of the Cecum to the Throne of England: King Edward VII's Appendix.

This historical retrospective explores the case of King Edward VII's appendicitis at the time of his planned coronation in 1902, as well as the contributions of the king's surgeons Frederick Treves and Joseph Lister, towards his medical care. The history of appendicitis, as well as a view of the king's medical management in the lens of modern surgical and sociopolitical contexts, is also examined.

"The Most Satisfactory Procedure in the Field of Pediatric Surgery": The History of Hypertrophic Pyloric Stenosis.

This historical retrospective explores the history of hypertrophic pyloric stenosis from its initial observations to the first surgical approaches to modern understandings of pathogenesis. The important work of Hirschsprung, Fredet, and Ramstedt remains a foundational part of management for this complex condition.

Does CPT Modifier 22 Appropriately Reflect a Difficult Pancreaticoduodenectomy? Retrospective Analysis of Operative Outcomes and Cost.

BACKGROUND: CPT coding allows addition of a 2-digit modifier code to denote particularly difficult procedures necessitating additional reimbursement, called the modifier 22. The use of modifier 22 in relation to pancreatic surgery and outcomes, specifically pancreaticoduodenectomy (PD), has not been explored. STUDY DESIGN: All PDs performed from 2010 to 2019 at a quaternary healthcare system were analyzed for differences in preoperative characteristics, outcomes, and cost based on the use of modifier 22. Adjusted logistic regression analysis was used to identify factors predictive of modifier 22 use. RESULTS: A total of 1,284 patients underwent PD between 2010 and 2019; 1,173 with complete data were included, of which 320 (27.3%) were coded with modifier 22. Patients coded with modifier 22 demonstrated a significantly longer duration of surgery (365.9 ± 168.4 vs 227 ± 97.1; p < 0.001). They also incurred significantly higher cost of index admission ($37,446 ± 34,187 vs $28,279 ± 27,980; p = 0.002). An adjusted multivariable analysis (specifically adjusted for surgeon variation) revealed duration of surgery (p < 0.001), neoadjuvant chemotherapy (p = 0.039), class II obesity (p = 0.019), and chronic pancreatitis (p = 0.005) to be predictive of modifier 22 use. CONCLUSIONS: Despite the subjective nature of this CPT modifier, modifier 22 is an appropriate marker of intraoperative difficulty. Preoperative and intraoperative characteristics that lead to its addition may be used to further delineate difficult PDs.

CD28-Selective Inhibition Prolongs Non-Human Primate Kidney Transplant Survival.

Costimulation blockade using belatacept results in improved renal function after kidney transplant as well as decreased likelihood of death/graft loss and reduced cardiovascular risk; however, higher rates and grades of acute rejection have prevented its widespread clinical adoption. Treatment with belatacept blocks both positive (CD28) and negative (CTLA-4) T cell signaling. CD28-selective therapies may offer improved potency by blocking CD28-mediated costimulation while leaving CTLA-4 mediated coinhibitory signals intact. Here we test a novel domain antibody directed at CD28 (anti-CD28 dAb (BMS-931699)) in a non-human primate kidney transplant model. Sixteen macaques underwent native nephrectomy and received life-sustaining renal allotransplantation from an MHC-mismatched donor. Animals were treated with belatacept alone, anti-CD28 dAb alone, or anti-CD28 dAb plus clinically relevant maintenance (MMF, Steroids) and induction therapy with either anti-IL-2R or T cell depletion. Treatment with anti-CD28 dAb extended survival compared to belatacept monotherapy (MST 187 vs. 29 days, p=0.07). The combination of anti-CD28 dAb and conventional immunosuppression further prolonged survival to MST ∼270 days. Animals maintained protective immunity with no significant infectious issues. These data demonstrate CD28-directed therapy is a safe and effective next-generation costimulatory blockade strategy with a demonstrated survival benefit and presumed advantage over belatacept by maintaining intact CTLA-4 coinhibitory signaling.