Introduction: Adjuvant (A) multiagent chemotherapy (MC) is the standard of care for patients with pancreatic adenocarcinoma (PDAC). Tolerating MC following a morbid operation may be difficult, thus neoadjuvant (NA) treatment is preferable. This study examined how the timing of chemotherapy was related to the regimen given and ultimately the overall survival (OS).Methods: The National Cancer Database was queried from 2006 to 2017 for nonmetastatic PDAC patients who underwent surgical resection and received MC or single-agent chemotherapy (SC) pre- or postresection. Predictors of receiving MC were determined using multivariable logistic regression. Five-year OS was evaluated using the Kaplan-Meier and Cox proportional hazards model.Results: A total of 12,440 patients (NA SC, n = 663; NA MC, n = 2313; A SC, n = 6152; A MC, n = 3312) were included. MC utilization increased from 2006-2010 to 2011-2017 (33.1%-49.7%; odds ratio [OR]: 0.59; p < 0.001). Younger age, fewer comorbidities, higher clinical stage, and larger tumor size were all associated with receipt of MC (all p < 0.001), but NA treatment was the greatest predictor (OR 5.18; 95% confidence interval [CI]: 4.63-5.80; p < 0.001). MC was associated with increased median 5-year OS (26.0 vs. 23.9 months; hazard ratio [HR]: 0.92; 95% CI: 0.88-0.96) and NA MC was associated with the highest survival (28.2 months) compared to NA SC (23.3 months), A SC (24.0 months), and A MC (24.6 months; p < 0.001).Conclusion: Use and timing of MC contribute to OS in PDAC with an improved 5-year OS compared to SC. The greatest predictor of receiving MC was being given as NA therapy and the greatest survival benefit was the NA MC subgroup. Randomized studies evaluating the timing of effective MC in PDAC are needed.

Background: The autologous tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine is produced from dendritic cells (DC) loaded ex vivo with autologous tumor lysate (TL). TLPLDC has been shown to decrease recurrence in resected Stage III/IV melanoma patients in a Phase IIb trial. The TL particle only (TLPO) vaccine is produced by loading of yeast cell wall particles with autologous TL and direct injection allowing for in vivo DC loading. We have compared the TLPO and TLPLDC vaccines in an embedded Phase I/IIa trial of a larger Phase IIb trial of the TLPLDC vaccine. Methods: Patients rendered clinically disease-free after surgery were randomized 2:1 to receive the TLPO or TLPLDC vaccine and followed for recurrence and death. Patients had scheduled intradermal inoculations at 0, 1, 2, 6, 12, and 18 months after enrollment. Kaplan-Meier and log-rank analysis were used to compare disease-free survival (DFS) and overall survival (OS) in an intention-to-treat (ITT) analysis. Results: Sixty-three patients were randomized, 43 TLPO and 20 TLPLDC. Patients randomized to the TLPO arm were more likely to be female (37.2% vs. 10.0 %, p = 0.026), but otherwise no significant clinicopathological differences were identified. No differences in related adverse events (AE) were found between treatment arms. At a median follow-up of 20.5 months, the DFS (60.8% vs. 58.7 %, p = 0.714) and OS (94.6% vs. 93.8 %, p = 0.966) were equivalent between the TLPO and TLPLDC groups, respectively. No statistical differences were found in subgroup analyses between vaccine types, which accounted for receipt of immunotherapy and the use of G-CSF pre-blood draw. Conclusions: In a randomized, double-blind Phase I/IIa trial, there were no differences in DFS or OS in resected Stage III/IV melanoma patients receiving adjuvant TLPO versus TLPLDC vaccines. Given manufacturing advantages, further efficacy testing of TLPO is warranted in a Phase III trial.

BACKGROUND:The tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine is made by ex vivo priming matured autologous dendritic cells (DCs) with yeast cell wall particles (YCWPs) loaded with autologous tumor lysate (TL). The tumor lysate, particle only (TLPO) vaccine uses autologous TL-loaded YCWPs coated with silicate for in vivo DC loading. Here we report the 36-month prespecified analyses of this prospective, randomized, double-blind trial investigating the ability of the TLPO and TLPLDC (±granulocyte-colony stimulating factor (G-CSF)) vaccines to prevent melanoma recurrence in high-risk patients.METHODS:Patients with clinically disease-free stage III/IV melanoma were randomized 2:1 initially to TLPLDC versus placebo (n=124) and subsequently TLPO versus TLPLDC (n=63). All patients were randomized and blinded; however, the placebo control arm was replaced in the second randomization scheme with another novel vaccine; some analyses in this paper therefore reflect a combination of the two randomization schemes. Patients receiving the TLPLDC vaccine were further divided by their method of DC harvest (with or without G-CSF pretreatment); this was not randomized. The use of standard of care checkpoint inhibitors was not stratified between groups. Safety was assessed and Kaplan-Meier and log-rank analyses compared disease-free (DFS) and overall survival (OS).RESULTS:After combining the two randomization processes, a total of 187 patients were allocated between treatment arms: placebo (n=41), TLPLDC (n=103), or TLPO (n=43). The allocation among arms created by the addition of patients from the two separate randomization schemes does not reflect concurrent randomization among all treatment arms. TLPLDC was further divided by use of G-CSF in DC harvest: no G-CSF (TLPLDC) (n=47) and with G-CSF (TLPLDC+G) (n=56). Median follow-up was 35.8 months. Only two patients experienced a related adverse event ≥grade 3, one each in the TLPLDC+G and placebo arms. DFS was 27.2% (placebo), 55.4% (TLPLDC), 22.9% (TLPLDC+G), and 60.9% (TLPO) (p<0.001). OS was 62.5% (placebo), 93.6% (TLPLDC), 57.7% (TLPLDC+G), and 94.6% (TLPO) (p=0.002).CONCLUSIONS:The TLPO and TLPLDC (without G-CSF) vaccines were associated with improved DFS and OS in this clinical trial. Given production and manufacturing advantages, the efficacy of the TLPO vaccine will be confirmed in a phase 3 trial.TRIAL REGISTRATION NUMBER:NCT02301611.

Inhalation injury is diagnosed in up to one-third of burn patients and is associated with increased morbidity and mortality. There are multiple scoring systems to grade inhalation injury, but no study has evaluated the ability of these scoring systems to predict outcomes of interest such as overall survival. We conducted a prospective, observational study of 99 intubated burn patients who underwent fiberoptic bronchoscopy within 24 hr of admission and graded inhalation injury using three scoring systems: abbreviated injury score (AIS), inhalation injury severity score (I-ISS), and mucosal score (MS). Agreement between scoring systems was assessed with Krippendorff's alpha (KA). Multivariable analyses were conducted to determine if variables were associated with overall survival. At admission, median AIS, I-ISS, and MS scores were 2 for all scoring systems. Patients who died had higher overall injury burden than those who survived and had similar median admission AIS and MS scores, but higher I-ISS scores. There was strong correlation between the inhalation injury grade at admission using the three scoring systems (KA = 0.85). On regression analysis, the only scoring system independently associated with overall survival was I-ISS (score 3 compared to scores 1-2: OR 13.16, 95% CI 1.65-105.07; P = .02). Progression of injury after initial assessment may contribute to the poor correlation between admission score and overall survival for injuries graded with AIS and MS. Repeated assessment may more accurately identify patients at increased risk for mortality.

Achieving optimal surgical outcomes in pancreatic adenocarcinoma requires a combination of both curative-intent resection to oncologic standards and stage-specific neoadjuvant or adjuvant therapy. This investigation sought to examine factors associated with receipt of standard-adherent surgery (SAS) and guideline-recommended therapy (GRT) and determine the impact of compliance on patient survival. From the 2006–2016 National Cancer Database, 21,304 patients underwent resection for nonmetastatic pancreatic adenocarcinoma. SAS was defined as pancreatic resection with negative margins and ≥ 15 lymph nodes examined. Stage-specific GRT was defined by current National Comprehensive Cancer Network guidelines. Multivariable models were used to determine predictors of adherence to SAS and GRT and prognostic impact on overall survival. Overall, SAS was achieved in 39

Neoadjuvant chemotherapy (NAC) or chemoradiation (NAC+XRT) is incorporated into the treatment of localized pancreatic adenocarcinoma (PDAC), often with the goal of downstaging before resection. However, the effect of downstaging on overall survival, particularly the differential effects of NAC and NAC+XRT, remains undefined. This study examined the impact of downstaging from NAC and NAC+XRT on overall survival. The National Cancer Data Base (NCDB) was queried from 2006 to 2015 for patients with non-metastatic PDAC who received NAC or NAC+XRT. Rates of overall and nodal downstaging, and pathologic complete response (pCR) were assessed. Predictors of downstaging were evaluated using multivariable logistic regression. Overall survival (OS) was assessed with Kaplan–Meier and Cox proportional hazards modeling. The study enrolled 2475 patients (975 NAC and 1500 NAC+XRT patients). Compared with NAC, NAC+XRT was associated with higher rates of overall downstaging (38.3 % vs 23.6 %; p ≤ 0.001), nodal downstaging (16.0 % vs 7.8 %; p ≤ 0.001), and pCR (1.7 % vs 0.7 %; p = 0.041). Receipt of NAC+XRT was independently predictive of overall (odds ratio [OR] 2.28; p < 0.001) and nodal (OR 3.09; p < 0.001) downstaging. Downstaging by either method was associated with improved 5-year OS (30.5 vs 25.2 months; p ≤ 0.001). Downstaging with NAC was associated with an 8-month increase in median OS (33.7 vs 25.6 months; p = 0.005), and downstaging by NAC+XRT was associated with a 5-month increase in median OS (30.0 vs 25.0 months; p = 0.008). Cox regression showed an association of overall downstaging with an 18 % reduction in the risk of death (hazard ratio [HR] 0.82; 95 % confidence interval, 0.71–0.95; p = 0.01) Downstaging after neoadjuvant therapies improves survival. The addition of radiation therapy may increase the rate of downstaging without affecting overall oncologic outcomes.

High-volume centers (HVC), academic centers (AC), and longer travel distances (TD) have been associated with improved outcomes for patients undergoing surgery for pancreatic adenocarcinoma (PAC). Effects of mediating variables on these associations remain undefined. The purpose of this study is to examine the direct effects of hospital volume, facility type, and travel distance on overall survival (OS) in patients undergoing surgery for PAC and characterize the indirect effects of patient-, disease-, and treatment-related mediating variables. Using the National Cancer Database, patients with non-metastatic PAC who underwent resection were stratified by annual hospital volume (< 11, 11–19, and ≥ 20 cases/year), facility type (AC versus non-AC), and TD (≥ 40 versus < 40 miles). Associations with survival were evaluated using multiple regression models. Effects of mediating variables were assessed using mediation analysis. In total, 19,636 patients were included. Treatment at HVC or AC was associated with lower risk of death [hazard ratio (HR) 0.90, confidence interval (CI) 0.88–0.92; HR 0.89, CI 0.86–0.91, respectively]. TD did not impact OS. Patient-, disease-, and treatment-related variables explained 25.5% and 41.8% of the survival benefit attained from treatment at HVC and AC, reducing the survival benefit directly attributable to each variable to 4.9% and 6.4%, respectively. Treatment of PAC at HVC and AC was associated with improved OS, but the magnitude of this benefit was less when mediating variables were considered. From a healthcare utilization and cost–resource perspective, further research is needed to identify patients who would benefit most from selective referral to HVC or AC.

Introduction: Pancreatectomy is associated with high morbidity and mortality. Therefore, patient selection and risk prediction is paramount. In this study, three validated periop-erative risk scoring systems were compared among patients undergoing pancreatectomy to identify the most clinically useful model. Materials and methods: The 2014-2017 American College of Surgeons National Surgical Quality Improvement Program database was queried for pancreatectomy patients. Three models were evaluated: National Surgical Quality Improvement Program Universal Risk Calculator (URC), Model for End-Stage Liver Disease (MELD), and Modified Frailty Index-5 Factor (mFI-5). Out-comes were 30-d mortality and complications. Predictive performance of the models was compared using area under the receiver operating characteristic curve (AUC) and Brier scores.Results: Twenty two thousand one hundred twenty three pancreatectomy patients were identified. The 30-d mortality rate was 1.4% (n = 319). Complications occurred in 6020 cases (27.2%). AUC (95% CI) for 30-d mortality were 0.70 (0.67-0.73), 0.63 (0.60-0.67), and 0.60 (0.57-0.63) for URC, MELD, and mFI-5, respectively, with Brier score of 0.014 for all three models. AUC (95% confidence interval) for any complication was 0.59 (0.58-0.59) for URC, 0.53 (0.52-0.54) for MELD, and 0.53 (0.52-0.54) for mFI-5, with Brier scores 0.193 (URC), 0.200 (MELD), and 0.197 (mFI-5). For individual complications, URC was more predictive than MELD or mFI-5. Conclusions: Of the validated preoperative risk scoring systems, URC was most predictive of both complications and 30-d mortality. None of the models performed better than fair to good. The lack of predictive accuracy of currently existing models highlights the need for development of improved perioperative risk models.Published by Elsevier Inc.

Rapamycin inhibits the mechanistic (formally mammalian) target of rapamycin (mTOR), an evolutionarily conserved intracellular kinase that influences activation of growth signaling pathways and immune responses to malignancy. Rapamycin has been found to have both immunosuppressant and immunostimulatory effects throughout the innate and adaptive responses based on the inhibition of mTOR signaling. While the immunosuppressant properties of rapamycin and mTOR inhibition explain rapamycin's success in the prevention of transplant rejection, the immunostimulatory characteristics are likely partially responsible for rapamycin's antineoplastic effects. The immunologic response to rapamycin is at least partially dependent on the dose and administration schedule, with lower doses inducing immunostimulation and intermittent dosing promoting immune function while limiting metabolic and immunosuppressant toxicities. In addition to its FDA-approved application in advanced malignancies, rapamycin may be effective as a chemopreventive agent, suspending progression of low-grade cancers, preventing invasive conversion of in situ malignancy, or delaying malignant transformation of established pre-malignant conditions.

Planned pancreatoduodenectomy (PD) for pancreatic adenocarcinoma (PDAC) can be aborted due to intraoperative findings. There is little guidance regarding the need for prophylactic bypass following an aborted PD to prevent symptomatic biliary obstruction or gastric outlet obstruction (GOO) postoperatively. The aim of this study was to characterize postoperative interventions and postsurgical survival in patients following aborted PD. Patients with PDAC treated with neoadjuvant therapy and staging laparoscopy prior to planned PD between 2010 and 2015 were reviewed for aborted PDs. Data on postoperative biliary obstruction, GOO, procedural intervention, and postsurgical survival were analyzed. Of 271 planned PDs, 47 (17.3%) were aborted. Thirty-six patients had ≥ 2 months of follow-up data and were included. Six patients underwent hepaticojejunostomy and nine patients underwent gastrojejunostomy at the time of the aborted PD. Sixteen of 30 patients (53%) without a surgical biliary bypass required endoscopic intervention, but none required palliative surgery. Ten of 27 patients (37%) without an operative gastrojejunostomy required intervention, but none required palliative surgery. Endoscopic or percutaneous therapy was required to treat 13/16 (81%) patients who presented with postoperative biliary obstructions and 6/10 (60%) of GOOs. Median survival following aborted PD was 13.3 months (CI 8.9–17.7). There were no differences in survival when comparing patients who developed a biliary obstruction (p = 0.92) or GOO (p = 0.90) to asymptomatic patients. Following aborted PD, patients commonly develop obstructive symptoms. However, these symptoms can generally be managed without surgical intervention. In asymptomatic patients, preemptive surgical bypasses are not required at the time of aborted PD.

Introduction Hypertrophic burn scars (HTBSs) remain a significant source of morbidity. Contemporary treatment has evolved to use CO 2 lasers and/or pulse-dye lasers (PDLs) to reduce scar thickness (ST) and erythema. This study seeks to compare treatment efficacy with CO 2 or PDL individually and in combination. Methods Patients undergoing laser treatments for HTBSs were enrolled. Three 3 × 3 cm squares of HTBSs were randomized to receive treatment with CO 2 laser, PDL or CO 2 + PDL. Patients underwent 3 treatments, 4 to 6 weeks apart and were followed up over 3 to 6 months. Scar assessments occurred at each visit before treatment and consisted of photographs, ultrasound, colorimetry, and the Patient and Observer Scar Assessment Score. Results Twenty-five patients were enrolled. Twenty completed 2 treatments (80%) and 11 completed all 3 treatments (44%). Median initial ST was 0.3 cm. Median time since injury was 8 months. Hypertrophic burn scars treated with CO 2 or PDL showed a significant decrease in Patient and Observer Scar Assessment Scale score from visit 1 to 3 ( P = 0.01 and 0.01, respectively). When separated by ST, thick scars (≥0.3 cm) showed a significant decrease in thickness between visit 1 and 2 using all laser modalities (CO 2 + PDL, P = 0.01; CO 2 , P = 0.02; PDL, P = 0.03). Thin scars (<0.3 cm) showed a reduction in thickness by visit 3 after CO 2 + PDL or PDL alone ( P = 0.01 and 0.04, respectively). Separating scars by age, younger scars (<9 months) showed a significant reduction in thickness between visit 1 and 2 for CO 2 treatment ( P = 0.04), and between visit 2 and 3 for CO 2 + PDL treatment ( P = 0.04). Hypertrophic burn scars treated with PDL did not demonstrate a significant reduction in thickness until visit 3 ( P = 0.002). Older scars (≥9 months) showed a significant reduction in thickness between visit 1 and 2 only after CO 2 + PDL ( P = 0.01). Conclusions Hypertrophic burn scars of varying ages, etiologies, and thicknesses were examined in this study with greater degree of early reduction seen in thicker scars using all laser modalities of CO 2 , PDL or in combination. However, there was no clinically meaningful benefit found with combination as compared with individual treatment. These data support the use of laser to improve HTBS but does not support one modality or combination of modalities over another.

BACKGROUND:Surgical resection of colorectal liver metastasis (CRLM) provides the best opportunity for prolonged survival. Eligibility for metastasectomy has expanded with technical advancements including parenchymal-sparing hepatectomy (PSH). Meanwhile, enthusiasm for minimally invasive surgery (MIS) has increased, though this approach may be preferentially utilized for technically straightforward cases. The purpose of this study is to characterize modern trends in open versus MIS approaches to partial hepatectomy and anatomic hepatectomy for CRLM within a nationwide cohort. METHODS:The American College of Surgeons' National Surgical Quality Improvement Program (ACS-NSQIP) was used to investigate trends in MIS versus open hepatectomy for CRLM from 2015 to 2019. We examined baseline clinicopathologic and disease-related characteristics and compared trends in treatments over the study period. RESULTS:A total of 7457 patients undergoing hepatectomy for CRLM were identified (1367 MIS, 6090 open). Patients had similar clinicopathologic features between the two groups. Patients undergoing MIS resection less frequently received neoadjuvant therapy (51.1% vs 64.0%, p < 0.001) or concurrent intraoperative ablation (15.0% vs 21.3%, p < 0.001). Patients with tumors < 2 cm (34.9% vs 26.8%, p < 0.001) or only one to two tumors (82.8% vs 65.0%, p < 0.001) more commonly underwent MIS. MIS and open partial hepatectomies both significantly increased over the study period, but open partial hepatectomy increased at a greater rate than MIS (p < 0.001). Rates of anatomic resections have remained the same, with a greater proportion performed using an open approach (34.9% vs 16.4%, p < 0.001). Rates of operations consisting of > 1 concurrent partial hepatectomy are stable, but significantly more likely to be performed open (p < 0.001). CONCLUSIONS:Hepatectomy for CRLM has increased from a rise in partial hepatectomy, potentially translating to increased use of PSH. Current trends suggest MIS approaches appear to be increasing, but selectively implemented for patients with less technically demanding disease characteristics. Educational efforts should be directed towards increased dissemination of parenchymal-sparing MIS techniques for more complex resections.

Optimal treatment of full-thickness skin injuries requires dermal and epidermal replacement. To spare donor dermis, dermal substitutes can be used ahead of split-thickness skin graft (STSG) application. However, this two-stage procedure requires an additional general anaesthetic, often prolongs hospitalisation, and increases outpatient services. Although a few case series have described successful single-stage reconstructions, with application of both STSG and dermal substitute at the index operation, we have little understanding of how the physical characteristics of dermal substitutes affects the success of a single-stage procedure. Here, we evaluated several dermal substitutes to optimise single-stage skin replacement in a preclinical porcine model. A porcine full-thickness excisional wound model was used to evaluate the following dermal substitutes: autologous dermal graft (ADG; thicknesses 0.15-0.60 mm), Integra (0.4-0.8 mm), Alloderm (0.9-1.6 mm), and chitosan-based hydrogel (0.1-0.2 mm). After excision, each wound was treated with either a dermal substitute followed by STSG or STSG alone (control). Endpoints included graft take at postoperative days (PODs) 7 and 14, wound closure at POD 28, and wound contracture from POD 28-120. Graft take was highest in the STSG alone and hydrogel groups at POD 14 (86.9% +/- 19.5% and 81.3% +/- 12.3%, respectively; P < .001). There were no differences in graft take at POD 7 or in wound closure at POD 28, though highest rates of wound closure were seen in the STSG alone and hydrogel groups (93.6% +/- 9.1% and 99.8% +/- 0.5%, respectively). ADG-treated wounds demonstrated the least amount of wound contracture at each time point. Increase dermal substitute thickness was associated with worse percent graft take at PODs 14 and 28 (Spearman rho of -0.50 and -0.45, respectively; P < .001). In this preclinical single-stage skin reconstruction model, thinner ADG and hydrogel dermal substitutes outperformed thicker dermal substitutes. Both substitute thickness and composition affect treatment success. Further preclinical and clinical studies to optimise this treatment modality are warranted.

Background A randomized, double-blind, placebo-controlled phase 2b trial of the tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine was conducted in patients with resected stage III/IV melanoma. Dendritic cells (DCs) were harvested with and without granulocyte-colony stimulating factor (G-CSF). This analysis investigates differences in clinical outcomes and RNA gene expression between DC harvest methods. Methods The TLPLDC vaccine is created by loading autologous tumor lysate into yeast cell wall particles (YCWPs) and exposing them to phagocytosis by DCs. For DC harvest, patients had a direct blood draw or were pretreated with G-CSF before blood draw. Patients were randomized 2:1 to receive TLPLDC or placebo. Differences in disease-free survival (DFS) and overall survival (OS) were evaluated. RNA-seq analysis was performed on the total RNA of TLPLDC + G and TLPLDC vaccines to compare gene expression between groups. Results 144 patients were randomized: 103 TLPLDC (47 TLPLDC/56 TLPLDC + G) and 41 placebo (19 placebo/22 placebo + G). Median follow-up was 27.0 months. Both 36-month DFS (55.8% vs. 24.4% vs. 30.0%, p = 0.010) and OS (94.2% vs. 69.8% vs. 70.9%, p = 0.024) were improved in TLPLDC compared to TLPLDC + G or placebo, respectively. When compared to TLPLDC + G vaccine, RNA-seq from TLPLDC vaccine showed upregulation of genes associated with DC maturation and downregulation of genes associated with DC suppression or immaturity. Conclusions Patients receiving TLPLDC vaccine without G-CSF had improved OS and DFS. Outcomes remained similar between patients receiving TLPLDC + G and placebo. Direct DC harvest without G-CSF had higher expression of genes linked to DC maturation, likely improving clinical efficacy.

9548 Background: A randomized, double-blind, placebo-controlled phase IIb trial of the tumor lysate, particle loaded, dendritic cell (TLPLDC) vaccine was conducted to prevent recurrence in patients (pts) with resected stage III/IV melanoma. Two methods for dendritic cell (DC) harvest were used for vaccine production, including no pretreatment or pretreatment with granulocyte-colony stimulating factor (G-CSF) in an attempt to reduce blood draw volumes. This analysis investigates differences in clinical outcomes and RNA gene expression between these DC harvest methods for TLPLDC vaccine creation. Methods: The TLPLDC vaccine is created by loading autologous tumor lysate into yeast cell wall particles (YCWPs) and exposing them to phagocytosis by DCs. By investigator/pt choice, pts had 120mL of blood drawn for DC harvest, or pts received 300μg of G-CSF for pre-DC mobilization and a 50-70 mL blood draw 24-48 hours later. Total vaccine production time was 72 hrs. Pts were randomized 2:1 to receive TLPLDC or placebo (DCs exposed to empty YCWPs). 1-1.5 x10^6 cells/dose were injected intradermally at 0, 1, 2, 6, 12, and 18 months. Differences in disease free survival (DFS) and overall survival (OS) were evaluated by Kaplan Meier analysis between pts who did not receive pretreatment (TLPLDC), pts who did receive pretreatment with G-CSF (TLPLDC+G), and pts receiving placebo. RNA-seq analysis was performed on the total RNA of pts’ prepared TLPLDC vaccines to assess gene expression. Relative RNA expression (RRE) was compared between TLPLDC and TLPLDC+G. Results: As previously reported, 144 pts were randomized: 103 received TLPLDC (46 TLPLDC, 57 TLPLDC+G) and 41 received placebo. There were no significant clinicopathologic or treatment differences between the three treatment arms. Survival was significantly improved in TLPLDC compared to TLPLDC+G or placebo, including 36-month OS (92.9% vs 62.8% vs 72.3% respectively, p = 0.022) and DFS (51.8% vs 23.4% vs 27.1%, p = 0.027). When compared to TLPLDC+G (n = 3) vaccine, RNA-seq from TLPLDC vaccine (n = 3) showed upregulation of genes associated with DC maturation, including HLA-DMB (RRE: 3.60), IFIT1 (3.38), CD27 (3.26), IFI44L (3.24), MX1 (2.96), HLA-DQA1 (2.67), HLA-DRA (2.40), CD49D (2.34) and CD74 (2.09), while downregulated genes were associated with DC suppression or immaturity including SERPINA1 (RRE:7.8), TLR2 (6.65), CCR1 (5.11), IL10 (4.19), CD93 (3.84) and CD14 (3.25). Conclusions: Pts receiving TLPLDC vaccine had significantly improved OS and DFS, while outcomes remained similar between those who received TLPLDC+G vs placebo. Pts who did not receive G-CSF had higher expression of genes linked to DC maturation and antigen processing and presentation, likely explaining the improvement in clinical efficacy. A phase III trial to further assess the TLPLDC vaccine to prevent recurrence is planned. Clinical trial information: NCT02301611.

Abstract Background Checkpoint inhibitors (CPI) in combination with cell‐based vaccines may produce synergistic antitumor immunity. The primary analysis of the randomized and blinded phase IIb trial in resected stage III/IV melanoma demonstrated TLPLDC is safe and improved 24‐month disease‐free survival (DFS) in the per treatment (PT) analysis. Here, we examine efficacy within pre‐specified and exploratory subgroups. Methods Stage III/IV patients rendered disease‐free by surgery were randomized 2:1 to TLPLDC vaccine versus placebo. The pre‐specified PT analysis included only patients completing the primary vaccine/placebo series at 6 months. Kaplan–Meier analysis was used to compare 24‐month DFS among subgroups. Results There were no clinicopathologic differences between subgroups except stage IV patients were more likely to receive CPI. In stage IV patients, 24‐month DFS was 43% for vaccine versus 0% for placebo (p = 0.098) in the ITT analysis and 73% versus 0% (p = 0.002) in the PT analysis. There was no significant difference in 24‐month DFS when stratified by use of immunotherapy or CPI. For patients with resected recurrent disease, 24‐month DFS was 88.9% versus 33.3% (p = 0.013) in the PT analysis. All benefit from vaccination was in the PT analysis; no benefit was found in patients receiving up to three doses. Conclusion The TLPLDC vaccine improved DFS in patients completing the primary vaccine series, particularly in the resected stage IV patients. The efficacy of the TLPLDC vaccine will be confirmed in a phase III study evaluating adjuvant TLPLDC + CPI versus Placebo + CPI in resected stage IV melanoma patients.

Abstract Introduction Skin grafting of poorly vascularized wound beds, (e.g. exposed fascia, tendon, or bone) is often a multi-stage procedure, resulting in persistent open wounds and long-term complications such as scarring and contracture. Single-stage skin replacement could mitigate these downsides. Here we present the addition of topical nutrients and negative-pressure wound therapy (NPWT) + saline instill to improve graft take, and a case report of treatment of a non-healing wound in a single-stage procedure. Methods Ex vivo, STSGs (12/1000ths in) were harvested from swine (Sus scrofa domestica) post-euthanasia and transferred into wells with distilled water, PBS, Tyrode’s Buffer, high (4.5g/L) and low (2g/L) glucose DMEM, EpiLife, or William’s E (WE) media for 7 days, followed by performance of biochemical analyses and immunohistochemistry. In vivo, 20 full-thickness 5cm-diameter excisional wounds on the dorsum of two anesthetized swine were treated with dermal substitutes (DS, 0.4mm, 0.8mm, 1.2mm, or 1.6mm thickness), STSG, and NPWT with or without intermittent saline instill (3x daily, 300mL, 15-minute soak). Re-epithelialization was assessed at day 7 and 14. Lastly, a chronic 800cm2 left knee wound was treated with NPWT + instill (every 3.5 hours, 80mL, 10-minute soak, 3-day duration) over a 12/1000ths inch STSG. Results DMEM with high glucose (DMEM-HG) and WE produced the most lactic acid and enzymatic carbonate. Lactate dehydrogenase activity was lowest with WE. DMEM-HG had the highest glucose consumption but the most unconsumed glucose, with WE resulting in the next highest amount. Immunohistochemistry showed DMEM-HG or WE had the most dividing and least dying cells. In the porcine model, DS of 0.8mm, 1.2mm, and 1.6mm thicknesses inhibited graft take significantly (p< 0.01, p=0.02, p< 0.01, respectively) for all NPWT alone wounds. Addition of saline instill showed significant improvement in graft take (p=0.03) for 0.8mm DS wounds. 1.2mm and 1.6mm DS wounds continued to show significantly decreased graft take (p=0.03 and p=0.02, respectively). All 0.4mm DS wounds performed similar to control. Clinically, following NPWT removal on post-op day 3, almost complete STSG take was observed without exudate, pus, or malodor within the wound bed. Conclusions While additional studies are ongoing to determine the optimal nutrient supplementation, WE performed the best overall thus far. In vivo, 0.8mm DS created a successful model of a poorly vascularized wound bed, as NPWT + instill overcame this thickness. The novel use of NPWT + instill treatment over STSG clinically shows promise to improve graft take in the future.

Background: Traumatic brain injury (TBI) is one of the most prevalent diagnoses among trauma populations and places significant strain on valuable rural hospital resources. Limited studies show safety and efficacy of implementation of a Brain Injury Guideline (BIG) protocol at a Department of Defense (DoD) Level 1 trauma center. Materials and Methods: Data from patients diagnosed with traumatic brain injury during the study period were collected from our institutional trauma database. A retrospective review was performed on patients identified in the database to collect demographic and injury related data. All primary and secondary outcome data were analyzed using two-tailed Fischer's exact tests, Pearson Chi-square tests, and non-parametric Mann Whitney U tests. Results: A total of 354 patients were included in the study, 189 pre-implementation and 165 post-implementation. Demographics, head injury severity, initial HCT findings, and BIG classification distributions were well-matched. There was a significant reduction in neurosurgical consultations (NSC) (98.4% pre-to 77.0% post-implementation, P < 0.001) and ICU admissions (84.1% pre-, 74.5% post-implementation, P = 0.025) following protocol implementation. There were no differences between groups in ICU LOS ( P = 0.239), incidence of worsening findings on RHCT ( P = 0.894), or in-hospital mortality ( P = 0.814). There was a slight reduction in hospital LOS from 4.0d pre-implementation to 3.0d post-implementation ( P = 0.043). Conclusions: Implementation of a BIG protocol at our Level 1 trauma center suggested at a relationship with fewer NSCs and ICU admissions. Management of mild and moderate TBI by acute care and trauma surgeons without direct neurosurgical oversight is safe and implies a reduction in utilization of hospital resources. Published by Elsevier Inc.

BACKGROUND:Surgical management of hepatic metastases in patients with stage IV breast cancer remains controversial. The purpose of this study was to examine the impact of hepatic metastasectomy on long-term outcomes. METHODS:The 2004-2015 National Cancer Database was queried for all patients diagnosed with stage IV breast cancer with metastases isolated to the liver. Patient demographics, disease-, treatment- and outcome-related data were analyzed. RESULTS:Of 2,895 patients, only 90 (3.1%) underwent hepatic resection. Compared to patients who did not undergo metastasectomy, patients treated with metastasectomy tended to be younger (52 ± 12.7 versus 59.2 ± 14.6; P < 0.001) and have private insurance (74.4% versus 45.3%; P < 0.001). Independent predictors of metastasectomy included younger age (OR 0.98; CI 0.96-0.99; P = 0.01), lobular carcinoma (OR 2.26; CI 1.06-4.82; P = 0.03), and prior surgery of the primary site (partial mastectomy (OR 6.96; CI 3.47-13.95; P < 0.001) or total mastectomy (OR 5.74; CI 3.06-10.76; P < 0.001)). Compared to no metastasectomy, hepatic metastasectomy was independently associated with a 37% reduction in the risk of death (HR 0.63; CI 0.44-0.91; P = 0.01). CONCLUSIONS:Stage IV breast cancer with metastases to the liver is rare and few patients undergo hepatic resection. However, in this select patient population, hepatic metastasectomy was associated with a significant survival advantage when included in the multimodal treatment of synchronous stage IV breast cancer.