SnapShot: Enveloped Virus Entry.

In order to initiate successful infection, viruses have to transmit and deliver their genome from one host cell or organism to another. To achieve this, enveloped viruses must first fuse their membrane with those of the target host cell. Here, we describe the sequence of events leading to the entry of representative enveloped viruses, highlighting the strategies they use to gain access to the host cell cytosol.

Structural basis for Marburg virus neutralization by a cross-reactive human antibody.

The filoviruses, including Marburg and Ebola, express a single glycoprotein on their surface, termed GP, which is responsible for attachment and entry of target cells. Filovirus GPs differ by up to 70% in protein sequence, and no antibodies are yet described that cross-react among them. Here, we present the 3.6 Å crystal structure of Marburg virus GP in complex with a cross-reactive antibody from a human survivor, and a lower resolution structure of the antibody bound to Ebola virus GP. The antibody, MR78, recognizes a GP1 epitope conserved across the filovirus family, which likely represents the binding site of their NPC1 receptor. Indeed, MR78 blocks binding of the essential NPC1 domain C. These structures and additional small-angle X-ray scattering of mucin-containing MARV and EBOV GPs suggest why such antibodies were not previously elicited in studies of Ebola virus, and provide critical templates for development of immunotherapeutics and inhibitors of entry.

Neoadjuvant relatlimab and nivolumab in resectable melanoma.

Relatlimab and nivolumab combination immunotherapy improves progression-free survival over nivolumab monotherapy in patients with unresectable advanced melanoma1. We investigated this regimen in patients with resectable clinical stage III or oligometastatic stage IV melanoma (NCT02519322). Patients received two neoadjuvant doses (nivolumab 480 mg and relatlimab 160 mg intravenously every 4 weeks) followed by surgery, and then ten doses of adjuvant combination therapy. The primary end point was pathologic complete response (pCR) rate2. The combination resulted in 57% pCR rate and 70% overall pathologic response rate among 30 patients treated. The radiographic response rate using Response Evaluation Criteria in Solid Tumors 1.1 was 57%. No grade 3-4 immune-related adverse events were observed in the neoadjuvant setting. The 1- and 2-year recurrence-free survival rate was 100% and 92% for patients with any pathologic response, compared to 88% and 55% for patients who did not have a pathologic response (P = 0.005). Increased immune cell infiltration at baseline, and decrease in M2 macrophages during treatment, were associated with pathologic response. Our results indicate that neoadjuvant relatlimab and nivolumab induces a high pCR rate. Safety during neoadjuvant therapy is favourable compared to other combination immunotherapy regimens. These data, in combination with the results of the RELATIVITY-047 trial1, provide further confirmation of the efficacy and safety of this new immunotherapy regimen.

Androgen receptor blockade promotes response to BRAF/MEK-targeted therapy.

Treatment with therapy targeting BRAF and MEK (BRAF/MEK) has revolutionized care in melanoma and other cancers; however, therapeutic resistance is common and innovative treatment strategies are needed1,2. Here we studied a group of patients with melanoma who were treated with neoadjuvant BRAF/MEK-targeted therapy ( NCT02231775 , n = 51) and observed significantly higher rates of major pathological response (MPR; ≤10% viable tumour at resection) and improved recurrence-free survival (RFS) in female versus male patients (MPR, 66% versus 14%, P = 0.001; RFS, 64% versus 32% at 2 years, P = 0.021). The findings were validated in several additional cohorts2-4 of patients with unresectable metastatic melanoma who were treated with BRAF- and/or MEK-targeted therapy (n = 664 patients in total), demonstrating improved progression-free survival and overall survival in female versus male patients in several of these studies. Studies in preclinical models demonstrated significantly impaired anti-tumour activity in male versus female mice after BRAF/MEK-targeted therapy (P = 0.006), with significantly higher expression of the androgen receptor in tumours of male and female BRAF/MEK-treated mice versus the control (P = 0.0006 and P = 0.0025). Pharmacological inhibition of androgen receptor signalling improved responses to BRAF/MEK-targeted therapy in male and female mice (P = 0.018 and P = 0.003), whereas induction of androgen receptor signalling (through testosterone administration) was associated with a significantly impaired response to BRAF/MEK-targeted therapy in male and female patients (P = 0.021 and P < 0.0001). Together, these results have important implications for therapy.

B cells and tertiary lymphoid structures promote immunotherapy response.

Treatment with immune checkpoint blockade (ICB) has revolutionized cancer therapy. Until now, predictive biomarkers1-10 and strategies to augment clinical response have largely focused on the T cell compartment. However, other immune subsets may also contribute to anti-tumour immunity11-15, although these have been less well-studied in ICB treatment16. A previously conducted neoadjuvant ICB trial in patients with melanoma showed via targeted expression profiling17 that B cell signatures were enriched in the tumours of patients who respond to treatment versus non-responding patients. To build on this, here we performed bulk RNA sequencing and found that B cell markers were the most differentially expressed genes in the tumours of responders versus non-responders. Our findings were corroborated using a computational method (MCP-counter18) to estimate the immune and stromal composition in this and two other ICB-treated cohorts (patients with melanoma and renal cell carcinoma). Histological evaluation highlighted the localization of B cells within tertiary lymphoid structures. We assessed the potential functional contributions of B cells via bulk and single-cell RNA sequencing, which demonstrate clonal expansion and unique functional states of B cells in responders. Mass cytometry showed that switched memory B cells were enriched in the tumours of responders. Together, these data provide insights into the potential role of B cells and tertiary lymphoid structures in the response to ICB treatment, with implications for the development of biomarkers and therapeutic targets.

Prophylactic Antibiotic Duration and Infectious Complications in Pancreatoduodenectomy Patients With Biliary Stents: Opportunity for De-escalation.

OBJECTIVE: The aim of this study was to compare infectious complications in pancreatoduodenectomy (PD) patients with biliary stents treated with short, medium, or long durations of prophylactic antibiotics. BACKGROUND: Pre-existing biliary stents have historically been associated with higher infection risk after PD. Patients are administered prophylactic antibiotics, but the optimal duration remains unknown. METHODS: This single-institution retrospective cohort study included consecutive PD patients from October 2016 to April 2022. Antibiotics were continued past the operative dose per surgeon discretion. Infection rates were compared by short (≤24 h), medium (>24 but ≤96 h), and long (>96 h) duration antibiotics. Multivariable regression analysis was performed to evaluate associations with a primary composite outcome of wound infection, organ-space infection, sepsis, or cholangitis. RESULTS: Among 542 PD patients, 310 patients (57%) had biliary stents. The composite outcome occurred in 28% (34/122) short, 25% (27/108) medium, and 29% (23/80) long-duration ( P =0.824) antibiotic patients. There were no differences in other infection rates or mortality. On multivariable analysis, antibiotic duration was not associated with infection rate. Only postoperative pancreatic fistula (odds ratio 33.1, P <0.001) and male sex (odds ratio 1.9, P =0.028) were associated with the composite outcome. CONCLUSIONS: Among 310 PD patients with biliary stents, long-duration prophylactic antibiotics were associated with similar composite infection rates to short and medium durations but were used almost twice as often in high-risk patients. These findings may represent an opportunity to de-escalate antibiotic coverage and promote risk-stratified antibiotic stewardship in stented patients by aligning antibiotic duration with risk-stratified pancreatectomy clinical pathways.

Surgical Eligibility Does Not Imply Surgical Equity: Recommendations for Curative Treatment in Patients With Stage I/II Pancreatic Head Adenocarcinoma Differ by Age and Race.

OBJECTIVE: We sought to characterize differences in pancreatectomy recommendation rates to surgically eligible patients with pancreatic ductal adenocarcinoma of the pancreatic head across age and racial groups. BACKGROUND: Pancreatectomy is not recommended in almost half of otherwise healthy patients with stage I/II pancreatic ductal adenocarcinoma lacking a surgical contraindication. We characterized differences in pancreatectomy recommendation among surgically eligible patients across age and racial groups. METHODS: Non-Hispanic White (NHW) and Non-Hispanic Black (NHB) patients were identified in the National Cancer Database with clinical stage I/II pancreatic head adenocarcinoma, Charlson Comorbidity Index of 0 to 1, and age 40 to 89 years. Rates of surgery recommendation and overall survival (OS) by age and race were compared. A Pancreatectomy Recommendation Equivalence Point (PREP) was defined as the age at which the rate of not recommending surgery matched the rate of recommending and completing surgery. Marginal standardization was used to identify association of age and race with recommendation. OS was compared using Kaplan-Meier and Cox regression models. RESULTS: Among 40,866 patients, 36,133 (88%) were NHW and 4733 (12%) were NHB. For the entire cohort, PREP was 79 years. PREP was 5 years younger in NHB patients than in NHW patients (75 vs 80 years). Adjusted rates of not recommending surgery were significantly higher for NHB than for NHW patients in each age group. After adjusting for surgery recommendation, we found no difference in OS between NHW and NHB patients (hazard ratio 0.98 [95% CI 0.94-1.02]). CONCLUSIONS: PREP of NHB patients was 5 years younger than NHW patients, and in every age group, the rate of not recommending pancreatectomy was higher in NHB patients. Age and race disparities in treatment recommendations may contribute to shorter longevity of NHB patients.

Prognosis Associated With CA19-9 Response Dynamics and Normalization During Neoadjuvant Therapy in Resected Pancreatic Adenocarcinoma.

OBJECTIVE: To characterize associations between carbohydrate antigen 19-9 (CA19-9) dynamics during neoadjuvant therapy (NT) and survival for patients with pancreatic ductal adenocarcinoma (PDAC). BACKGROUND: Although normalization of CA19-9 during NT is associated with improved outcomes following PDAC resection, we hypothesize that CA19-9 dynamics during NT can improve prognostication. METHODS: Characteristics for patients with PDAC undergoing NT (July 2011-October 2018) with ≥3 CA19-9 results (bilirubin<2mg/dL) were collected and grouped by CA19-9 dynamics. Nonproducers (<1 U/ml) were excluded, and normal was ≤35 U/ml. Postresection survival was compared among groups. RESULTS: Of 431 patients, 166 had eligible CA19-9 values. Median baseline CA19-9 was 98 U/ml. Overall 2-year postresection recurrence-free survival (RFS) and overall survival (OS) were 37% and 63%, respectively. Patients with normalization (53%) had improved 2-year RFS (47% vs. 28%, P = 0.01) and OS (75% vs. 49%, P = 0.01). CA19-9 dynamics during NT were analyzed by shape, direction, and normalization creating response types ("A-B-C-D-E"). Type A was "Always" decreasing to normalization, B "Bidirectional" with eventual normalization, C "Consistently" normal, D any "Decrease" without normalization, and E "Elevating" without normalization. Types A and B responses were associated with the longest postresection 2-year RFS (51% and 56%) and OS (75% and 92%, respectively) whereas Types D and E had the worst outcomes. After adjusting for node-positivity, perineural invasion, and margin-positivity, CA19-9 response types were independently associated with both RFS and OS, and predicted outcomes are better than CA19-9 normalization alone (likelihood ratio test RFS P < 0.001, OS P = 0.01). CONCLUSIONS: This novel A-B-C-D-E classification of CA19-9 dynamics during NT was associated with postresection outcomes more precisely than CA19-9 normalization alone.

Classification of Post-Pancreatectomy Readmissions and Opportunities for Targeted Mitigation Strategies.

OBJECTIVE: Within a learning health system paradigm, this study sought to evaluate reasons for readmission to identify opportunities for improvement. SUMMARY BACKGROUND DATA: Post-pancreatectomy readmission rates have remained constant despite improved index hospitalization metrics. METHODS: We performed a single-institution case-control study of consecutive pancreatectomy patients (October 2016 - April 2022). Complications were prospectively graded in biweekly faculty and advanced practice provider meetings. We analyzed risk factors during index hospitalization and categorized indications for 90-day readmissions. RESULTS: A total of 835 patients, median age 65 years and 51% (427/835) males, underwent 64% (534/835) pancreatoduodenectomies, 34% (280/835) distal pancreatectomies, and 3% (21/835) other resections. 24% (204/835) of patients were readmitted. Primary indication for readmission was technical in 51% (105/204), infectious in 17% (35/204), and medical/metabolic in 31% (64/204) of patients. Procedures were required in 77% (81/105) and 60% (21/35) of technical and infectious readmissions, respectively, while 66% (42/64) of medical/metabolic readmissions were managed non-invasively. During the index hospitalization, benign pathology (OR 1.8, P=0.049), biochemical pancreatic leak (OR 2.3, P=0.001), bile/gastric/chyle leak (OR 6.4, P=0.001), organ-space infection (OR 3.4, P=0.007), undrained fluid on imaging (OR 2.4, P=0.045), and increasing white blood cell count (OR 1.7, P=0.045) were independently associated with odds of readmission. CONCLUSIONS: Most readmissions following pancreatectomy were technical in origin. Patients with complications during index hospitalization, increasing white blood cell count, or undrained fluid before discharge were at highest risk for readmission. Pre-discharge risk-stratification of readmission risk factors and augmentation of in-clinic resources may be strategies to reduce readmission rates.

Prospective Study of Perioperative Circulating Tumor DNA Dynamics in Patients Undergoing Hepatectomy for Colorectal Liver Metastases.

OBJECTIVE: To evaluate the association of perioperative ctDNA dynamics on outcomes after hepatectomy for CLM. SUMMARY BACKGROUND DATA: Prognostication is imprecise for patients undergoing hepatectomy for CLM, and ctDNA is a promising biomarker. However, clinical implications of perioperative ctDNA dynamics are not well established. METHODS: Patients underwent curative-intent hepatectomy after preoperative chemotherapy for CLM (2013-2017) with paired prehepatectomy/postoperative ctDNA analyses via plasma-only assay. Positivity was determined using a proprietary variant classifier. Primary endpoint was recurrence-free survival (RFS). Median follow-up was 55 months. RESULTS: Forty-eight patients were included. ctDNA was detected before and after surgery (ctDNA+/+) in 14 (29%), before but not after surgery (ctDNA+/-) in 19 (40%), and not at all (ctDNA-/-) in 11 (23%). Adverse tissue somatic mutations were detected in TP53 (n = 26; 54%), RAS (n = 23; 48%), SMAD4 (n = 5; 10%), FBXW7 (n = 3; 6%), and BRAF (n = 2; 4%). ctDNA+/+ was associated with worse RFS (median: ctDNA+/+, 6.0 months; ctDNA+/-, not reached; ctDNA-/-, 33.0 months; P = 0.001). Compared to ctDNA+/+, ctDNA+/- was associated with improved RFS [hazard ratio (HR) 0.24 (95% confidence interval (CI) 0.1-0.58)] and overall survival [HR 0.24 (95% CI 0.08-0.74)]. Adverse somatic mutations were not associated with survival. After adjustment for prehepatectomy chemotherapy, synchronous disease, and ≥2 CLM, ctDNA+/- and ctDNA-/- were independently associated with improved RFS compared to ctDNA+/+ (ctDNA+/-: HR 0.21, 95% CI 0.08-0.53; ctDNA-/-: HR 0.21, 95% CI 0.08-0.56). CONCLUSIONS: Perioperative ctDNA dynamics are associated with survival, identify patients with high recurrence risk, and may be used to guide treatment decisions and surveillance after hepatectomy for patients with CLM.

Effects of a Pragmatic Home-based Exercise Program Concurrent With Neoadjuvant Therapy on Physical Function of Patients With Pancreatic Cancer: The PancFit Randomized Clinical Trial.

OBJECTIVE: To determine the effects of a preoperative, home-based exercise program on fitness and physical function in patients with pancreatic cancer. BACKGROUND: We previously established a well-tolerated preoperative exercise program after finding a high frequency of sarcopenia and frailty in patients with pancreatic cancer. METHODS: In this randomized, controlled trial (NCT03187951), patients with pancreatic cancer were randomized to Arm A: enhanced usual care or Arm B: prescribed aerobic and resistance exercise during neoadjuvant therapy. Patients received nutrition counseling and activity trackers. The primary endpoint was a 6-minute walk distance (6MWD; ≥14 meters improvement was clinically meaningful). Secondary endpoints included additional physical function tests, health-related quality of life, and clinical outcomes. RESULTS: One hundred fifty-one patients were randomized. Objectively measured weekly activity (153.2±135.6 and 159.8±122.8 min in Arm A and B, respectively, P =0.62) and self-reported weekly moderate-to-strenuous physical activity (107.4±160.4 and 129.6±161.6 min in Arm A and Arm B, respectively, P =0.49) were similar, but weekly strength training sessions increased more in Arm B (by 1.8±1.8 vs 0.1±2.4 sessions, P <0.001). 6MWD improved in both Arm A (mean change 18.6±56.8 m, P =0.01) and Arm B (27.3±68.1 m, P =0.002). Quality of life and clinical outcomes did not significantly differ between arms. Pooling patients in both study groups, exercise, and physical activity was favorably associated with physical performance and clinical outcomes. CONCLUSIONS: In this randomized trial of prescribed exercise versus enhanced usual care during neoadjuvant therapy for pancreatic cancer, a high volume of physical activity and increased exercise capacity were observed in both arms, highlighting the importance of activity among patients preparing for surgery.

Melanoma metastatic to the adrenal gland: An update on the role of adrenalectomy in multidisciplinary management.

BACKGROUND AND OBJECTIVES: Modern systemic therapy (immune checkpoint blockade [ICB], targeted therapy) has improved survival for patients with metastatic melanoma. The role of adrenal metastasectomy is not well characterized in this setting. METHODS: Consecutive patients treated with adrenalectomy 1/1/2007-1/1/2019 were retrospectively compared to patients treated with systemic therapy alone in the same time period. Overall survival and survival after adrenal metastasis were compared, prognostic factors associated with survival after adrenal metastasis development were evaluated. RESULTS: A total of 74 patients underwent adrenalectomy and were compared to 69 treated with systemic therapy alone. The most common indications for adrenalectomy were to render the patient disease-free in the setting of isolated adrenal metastasis (n = 32, 43.2%) or treatment of isolated progression in the setting of other stable/responding metastases (n = 32, 43.2%). Patients treated surgically had longer survival (116.9 vs. 11.0 months after adrenal metastasis diagnosis, p < 0.001). On multivariate analysis, receipt of ICB (hazard ratio [HR]: 0.62, 95% confidence interval [CI]: [0.40-0.95]) and selection for adrenalectomy (HR: 0.27, 95% CI: [0.17-0.42]) were the strongest factors associated with improved survival after adrenal metastasis diagnosis. CONCLUSIONS: Selective application of adrenal metastasectomy is associated with prolonged survival benefit and remains an important consideration in the multidisciplinary management of patients with metastatic melanoma.

Differences in Clinicopathologic Behavior of Oncocytic Adrenocortical Neoplasms and Conventional Adrenocortical Carcinomas.

BACKGROUND: Oncocytic adrenocortical neoplasms (OANs) are rare endocrine tumors that present as a spectrum from benign to malignant. The outcomes after surgical resection of the oncocytic variant of adrenocortical carcinoma remain poorly understood. We sought to characterize the clinicopathologic features of OAN and compare oncocytic adrenocortical carcinoma (OAC) with conventional adrenocortical carcinoma (ACC). PATIENTS AND METHODS: Adult patients who underwent adrenalectomy for OAN or ACC between January 1990 and September 2020 were identified. Demographics, clinicopathologic factors, American Joint Committee on Cancer stage, and cancer-related outcomes were reviewed. A matched cohort analysis of disease-free survival (DFS) and overall survival (OS) was performed between patients with OACs and those with ACCs. RESULTS: Forty-one patients with OAN and 214 patients with ACC were included. The OAN cohort median age was 45.2 years [interquartile ratio (IQR) 38.5-54.0 years], and 61.0% were female. OANs were benign (n = 11), of uncertain malignant potential (UMP, n = 9), or OAC (n = 21). Disease recurrence occurred in 12 (57.1%) patients with OAC compared with 1 (11.1%) and 0 patients with UMP or benign OAN, respectively (p < 0.001). Seven (33.3%) patients with OAC died during follow-up compared with 0 patients with UMP or benign OAN (p = 0.020). Kaplan-Meier survival analysis found no difference in DFS between ACC and OAC groups before (p = 0.218) and after 2:1 matching (p = 0.417). Overall survival was shorter for patients who had ACC compared with those who had OAC (p = 0.031), but the difference was not evident with matched analysis (p = 0.200). CONCLUSIONS: OAN presents as a spectrum from benign indolent tumors to aggressive carcinomas. OACs demonstrate similar clinicopathologic behavior and recurrence-free and overall survival when matched to conventional ACCs.

Early Experience of a Robotic Foregut Surgery Program at a Cancer Center: Video of Shared Steps in Robotic Pancreatoduodenectomy and Gastrectomy.

Over the past few decades, robotic surgery techniques required to resect gastric and pancreatic malignancies have evolved remarkably; however, the safety and generalizability of robotic pancreatoduodenectomy remain unknown. At our cancer center, gastrectomies and pancreatectomies are performed in a combined foregut minimally-invasive surgery program; this effectively increases the composite case volume and shortens the learning curve for any individual surgeon. In this video, we demonstrate the shared steps in pancreatoduodenectomy and gastrectomy and explain how the skills gained through robotic gastrectomy can be used during robotic pancreatoduodenectomy. During the initial 2-year period of our robotic foregut surgery program, we performed 120 pancreatic and gastric operations, including 22 pancreatoduodenectomies and 37 gastrectomies. Our first robotic pancreatoduodenectomy was performed following successful completion of 45 other robotic foregut operations. Of those 22 patients who underwent robotic pancreatoduodenectomy, the median hospital stay was 4 days (range 3-17 days) and the readmission rate was 14% (3/22). The rate of grade B/C pancreatic fistula was 9% (2/22) and there was no 90-day mortality. In conclusion, the presented video showing the shared steps in robotic pancreatoduodenectomy and gastrectomy demonstrates the potential for a combined robotic surgery program to increase composite case volumes and to shorten the learning curve. At our cancer center, implementation of this approach has been helpful in accelerating the development of our new robotic pancreatectomy program, especially in honing the skills necessary to perform robotic pancreatoduodenectomy.

Radiographic and Serologic Response to First-Line Chemotherapy in Unresected Localized Pancreatic Cancer.

BACKGROUND: This study aimed to determine the clinical relevance of putative radiographic and serologic metrics of chemotherapy response in patients with localized pancreatic cancer (LPC) who do not undergo pancreatectomy. Studies evaluating the response of LPC to systemic chemotherapy have focused on histopathologic analyses of resected specimens, but such specimens are not available for patients who do not undergo resection. We previously showed that changes in tumor volume and CA 19-9 levels provide a clinical readout of histopathologic response to preoperative therapy. METHODS: Our institutional database was searched for patients with LPC who were treated with first-line chemotherapy between January 2010 and December 2017 and did not undergo pancreatectomy. Radiographic response was measured using RECIST 1.1 and tumor volume. The volume of the primary tumor was compared between pretreatment and posttreatment images. The percentage change in tumor volume (%Δvol) was calculated as a percentage of the pretreatment volume. Serologic response was measured by comparing pretreatment and posttreatment CA 19-9 levels. We established 3 response groups by combining these metrics: (1) best responders with a decline in %Δvol in the top quartile and in CA 19-9, (2) nonresponders with an increase in %Δvol and in CA 19-9, and (3) other patients. RESULTS: This study included 329 patients. Individually, %Δvol and change in CA 19-9 were associated with overall survival (OS) (P≤.1), but RECIST 1.1 was not. In all, 73 patients (22%) were best responders, 42 (13%) were nonresponders, and there were 214 (65%) others. Best responders lived significantly longer than nonresponders and others (median OS, 24 vs 12 vs 17 months, respectively; P<.01). A multivariable model adjusting for type of chemotherapy regimen, number of chemotherapy doses, and receipt of radiotherapy showed that best responders had longer OS than did the other cohorts (hazard ratio [HR], 0.35; 95% CI, 0.21-0.58 for best responders, and HR, 0.55; 95% CI, 0.37-0.83 for others). CONCLUSIONS: Changes in tumor volume and serum levels of CA 19-9-but not RECIST 1.1-represent reliable metrics of response to systemic chemotherapy. They can be used to counsel patients and families on survival expectations even if pancreatectomy is not performed.

Opioid Discharge Prescriptions After Inpatient Surgery: Risks of Rebound Refills by Length of Stay.

INTRODUCTION: As inpatient stays become shorter, one concern with standardizing discharge opioid prescriptions is the potential risk of "rebound refills." We sought to compare opioid prescription refill rates and volumes for surgical patients discharged on postoperative day (POD) 2-3, 4-7, and 8+. METHODS: In a prospective quality improvement protocol, faculty volunteered to use either a 5x-multiplier (5x) or usual care (UC) for discharge prescriptions after inpatient (≥48 h stay) surgery from Sep-Dec 2019. The 5x-multiplier is 5-times the patient's last 24-h opioid use (by oral morphine equivalents, OME). Cohorts were compared by POD of discharge: POD 2-3 ("SHORT"), POD 4-7 ("INTERMEDIATE"), and POD 8+ ("LONG"). The primary endpoint was 30-d refill rates. Secondary endpoints included 30-d refill OME and inpatient opioid weaning/discharge metrics. RESULTS: From 22 faculty, 409 patients were included. When stratified by POD, 154 (37.7%) were discharged SHORT, 176 (43.0%) INTERMEDIATE, and 79 (19.3%) LONG. SHORT stay patients had a median last 24-h OME of 10 mg (versus 5 mg INTERMEDIATE, 5 mg LONG; P = 0.268), and a median discharge OME of 55 mg (versus 75 mg INTERMEDIATE, 100 mg LONG; P = 0.221). Patients with SHORT stays did not have higher refill rates (11.7% versus 18.2% INTERMEDIATE, 19.0% LONG; P = 0.193) or higher median refill OME (150 mg versus 300 mg INTERMEDAITE, 339 mg LONG; P = 0.154). CONCLUSIONS: Despite concerns of increased refills, patients discharged by POD 2-3 were not associated with "rebound refills." A patient-centered 5x-multiplier standardization of discharge opioid prescriptions is feasible in all inpatient surgery patients, even those discharged following a short inpatient stay.

Association of Patient Controlled Analgesia and Total Inpatient Opioid Use After Pancreatectomy.

INTRODUCTION: The initial settings on an intravenous patient-controlled analgesia (IV-PCA) pump can represent a significant source of postoperative opioid exposure. The primary aim of this study was to evaluate the impact of first day IV-PCA use on total inpatient opioid use after open pancreatectomy, before and after standardization of initial dosing. METHODS: Inpatient oral morphine equivalents (OMEs) were reviewed for pancreatectomy patients treated with IV-PCA at a single institution before and after (3/2016-8/2017 versus 3/2019-11/2020) implementation of a standardized initial IV-PCA dosing regimen (initial limit 0.1 mg hydromorphone, or 1 mg OME, every 10 min as needed). IV-PCA OME in the first 24 h and the total inpatient OME were compared between cohorts. RESULTS: Of 220 total patients, 132 were in the prestandardization (PRE) historical cohort. A first-24-h IV-PCA use was different (PRE median 95 mg versus poststandardization [POST] 15 mg, P < 0.001). The median total inpatient OME was different (P < 0.001) between PRE (525 mg, interquartile range [IQR] 239-951 mg) and POST patients (129 mg, IQR 65-204 mg) with 77% (median 373 mg) of total inpatient OMEs contributed by IV-PCA in the PRE and 56% (median 64 mg) in the POST cohorts. There were similar patient-reported pain scores between groups. CONCLUSIONS: Standardizing initial IV-PCA settings was associated with a reduced first-24-h opioid exposure, proportional and absolute total IV-PCA use, and total inpatient OMEs. Because of the contribution of an IV-PCA to the total inpatient opioid exposure, purposeful reduction or omission of an IV-PCA is critical to perioperative opioid reduction strategies.

Prognostic significance of preoperative and postoperative CA 19-9 normalization in pancreatic adenocarcinoma treated with neoadjuvant therapy or surgery first.

BACKGROUND: Normal(ization) of serum carbohydrate 19-9 (CA19-9) before/after surgery has not been compared in patients with pancreatic adenocarcinoma (PDAC) treated with neoadjuvant therapy (NT) versus surgery-first (SF). METHODS: Characteristics for patients with PDAC who underwent resection from July 2011 to October 2018 were collected. Patients with pre-/postoperative CA19-9, bilirubin <2 mg/dL, and initial CA19-9 > 1 U/ml were included. Overall survival (OS) and recurrence-free survival (RFS) were compared by pre-/postoperative CA19-9. RESULTS: In patients receiving NT, normal pre/postoperative CA19-9 ("NTnl/nl ") was associated with median RFS and OS (26 and 77mo), followed by those who normalized after surgery ("NTabnl/nl " 16 and 44mo). For SF patients, normal pre-/postoperative CA19-9 ("SFnl/nl ") was associated with median RFS and OS (115 and not estimable mo), followed by those who normalized after resection ("SFabnl/nl " 18 and 49mo). Groups "NTabnl/abnl " and "SFabnl/abnl " with elevated CA19-9 both before and after resection had the worst median RFS and OS durations. CONCLUSIONS: While a normal(ized) postoperative CA19-9 may result in similar survival as preoperative normal(ization), postoperative normalization failed to occur in nearly 30% of SF patients. NT should be considered in patients presenting with elevated CA19-9. If considering SF, ideal patients may include those with normal CA19-9 at presentation.