Predictors and benefits of multiagent chemotherapy for pancreatic adenocarcinoma: Timing matters.

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.

Divergent clinical outcomes in a phase 2B trial of the TLPLDC vaccine in preventing melanoma recurrence and the impact of dendritic cell collection methodology: a randomized clinical trial.

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.

Impact of Mediating and Confounding Variables on the Volume-Outcome Association in the Treatment of Pancreatic Cancer.

BACKGROUND: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Impact of Adherence to Operative Standards and Stage-Specific Guideline-Recommended Therapy in Nonmetastatic Pancreatic Adenocarcinoma.

BACKGROUND: 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. PATIENTS AND METHODS: 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. RESULTS: Overall, SAS was achieved in 39% and GRT in 65% of patients, but only 30% received both SAS and GRT. Increasing age, minority race, uninsured status, and greater comorbidities were associated with a decreased odds of receiving both SAS and GRT (all p < 0.05). SAS (HR 0.79; CI 0.76-0.81; p < 0.001) and GRT (HR 0.67; CI 0.65-0.69; p < 0.001) were each independently associated with a survival advantage. Receipt of both SAS and GRT was associated with significant improvement in median OS compared with receiving neither (2.2 years vs 1.1 years; p < 0.001) which was independently associated with a 78% increased risk of death (HR 1.78; CI 1.70-1.86; p < 0.001). CONCLUSIONS: Despite survival benefits associated with adherence to operative standards and receipt of guideline-recommended therapy, compliance remains poor. Future efforts must be directed toward improved education and implementation efforts around both operative standards and therapy guidelines.

Immunologic and dose dependent effects of rapamycin and its evolving role in chemoprevention.

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 anti-neoplastic 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.

Impact of dermal matrix thickness on split-thickness skin graft survival and wound contraction in a single-stage procedure.

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 ρ 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.

Subgroup analysis of nelipepimut-S plus GM-CSF combined with trastuzumab versus trastuzumab alone to prevent recurrences in patients with high-risk, HER2 low-expressing breast cancer.

HER2-targeted therapy has not benefited patients with low levels of HER2 expression; however, combination therapy may be effective. Primary analysis of a phase IIb trial investigating the HER2-derived vaccine nelipepimut-S (NPS) did not benefit the intention-to-treat population, but subset analysis showed a benefit in triple-negative breast cancer (TNBC) patients. The subset analysis of this multicenter, randomized, single-blind, phase IIb trial identified significant improvement in 36-month disease-free survival (DFS) between NPS (n = 55) and placebo (n = 44) in TNBC (HR 0.25, p = 0.01) and those who express HLA-A24 (HR 0.41, p = 0.05). The TNBC cohort demonstrated improved 36-month DFS in those with HER2 1+ expression (HR 0.17, p = 0.01), HLA-A24 positivity (HR 0.08, p < 0.01), or in those who received neoadjuvant chemotherapy (HR 0.21, p < 0.01). NPS vaccination with trastuzumab was associated with improved 36-month DFS among patients with TNBC. The observed benefit to this high-risk subgroup warrants confirmation in a phase III trial.

Correlation of tumor microenvironment from biopsy and resection specimens in untreated colorectal cancer patients: a surprising lack of agreement.

BACKGROUND: Colorectal cancer (CRC) tumor microenvironment (TME) characteristics, such as tumor infiltrating lymphocyte (TIL) densities and PD-L1 status, are predictive of recurrence, disease-free survival, and overall survival. In many malignancies, TME characteristics are also predictive of response to immunotherapy. As window of opportunity studies using neoadjuvant immunotherapy become more common and treatment guidelines incorporate TME features, accurate assessment of the pre-treatment TME using the biopsy specimen is critical. However, no study has thoroughly evaluated the correlation between the TMEs of the biopsy and resection specimens. METHODS: We conducted a retrospective analysis of patients with stage I-III CRC with matched biopsy and resection specimens. CD3+, CD4+, CD8+, and FoxP3+ lymphocyte populations at the center of tumor (CT) and invasive margin (IM) and tumor PD-L1 status in the biopsy and resection specimens were evaluated. TIL populations were compared using Mann-Whitney U tests or Student's t tests and correlated using Pearson r. RESULTS: CD3+ and CD4+ densities were significantly higher in the CT of the biopsy relative to the resection specimen Comparing biopsy and resection specimens, no TIL population at either the CT or IM had a correlation coefficient > 0.5. Determining PD-L1 status based on biopsy tissue resulted in a sensitivity of 37.1%, specificity of 81.4%, and accuracy of 61.5%. CONCLUSIONS: These findings demonstrate significant discordance between the TME of the biopsy and resection specimens. Caution should be used when basing treatment decisions on pre-treatment endoscopic biopsy findings and when interpreting changes in the TME between pre-treatment biopsy and resection specimens after neoadjuvant therapy.

Adjuvant Chemotherapy in Resectable Gallbladder Cancer is Underutilized Despite Benefits in Node-Positive Patients.

BACKGROUND: Adjuvant chemotherapy (AC) is recommended following surgical resection of gallbladder cancer regardless of stage. However, stage-specific benefits of AC in gallbladder cancer are unclear. PATIENTS AND METHODS: Patients with resected pathologic stage I-III gallbladder cancer were identified using the 2006-2015 National Cancer Database. Utilization trends, predictors of use, and impact of AC on overall survival (OS) were determined. RESULTS: A total of 5656 patients were included. Use of AC increased from 9.9% in 2006 to 24.2% in 2015 (OR 2.91; 95% CI 2.06-4.09; p < 0.001). However, only 17.5% of patients overall and only 32.4% of node-positive (stage IIIb) patients received AC. Patients receiving AC were younger and had fewer comorbidities, shorter hospitalizations, more advanced disease, and more margin-positive resections (all p < 0.01). Higher pathologic T stage and positive nodal status represented the greatest independent predictors of receipt of AC. While AC demonstrated no OS advantage for stage I patients (p = 0.83), AC was associated with improved OS among stage II patients (p = 0.003), though this impact was not independently associated with improved OS on multivariable analysis. AC was independently associated with improved OS among stage IIIb patients, with a 30% reduction in risk of death (HR 0.70; 95% CI 0.58-0.83; p < 0.001). Younger age, fewer comorbidities, and shorter hospitalization all predicted receipt of AC among stage IIIb patients (all p < 0.05). CONCLUSIONS: Systemic therapy remains underprescribed, in particular among patients that would seem to benefit most. Adjuvant chemotherapy likely improves survival in node-positive gallbladder cancer, but its utility in the treatment of node-negative disease has not been demonstrated.

Rates, Predictors, and Outcomes of Portal Lymphadenectomy for Resectable Gallbladder Cancer.

INTRODUCTION: Lymphadenectomy (LND) is recommended following surgical resection of ≥ T1b gallbladder cancer (GBC). However, frequency and stage-specific survival benefits of LND remain unclear. PATIENTS AND METHODS: The National Cancer Database (NCDB; 2006-15) was queried for resected pathologic stage I-III GBC. LND performance, predictors of receiving LND, and LND association with overall survival (OS) were assessed. RESULTS: Of 2302 total patients, 1343 (58.3%) underwent LND. Patients who underwent LND were younger and more frequently had private health insurance, a negative surgical margin, higher pathologic T stage, and received adjuvant chemotherapy (all p < 0.001). LND rates were highest at academic centers (70.1%) relative to all other facility types (p < 0.001). LND was independently associated with improved OS [hazard ratio (HR) 0.52, 95% confidence interval (CI) 0.44-0.61]. LND was associated with improved OS for pT1b, pT2, and pT3 patients (all p < 0.05) on univariate analysis. LND was independently associated with improved OS in pT2 (HR 0.44, CI 0.35-0.56) and pT3 (HR 0.54, CI 0.43-0.69) patients. CONCLUSIONS: LND is associated with a 48% reduction in risk of death in patients with resectable non-metastatic GBC, with greatest impact in pT2-3 patients. Patients without LND have similar OS to patients with node-positive disease, highlighting the importance of LND. Underutilization of LND likely results in undertreatment of patients with undiagnosed nodal disease, which may contribute to unfavorable oncologic outcomes.

An Educational Intervention Reduces Opioids Prescribed Following General Surgery Procedures.

BACKGROUND: Variability exists in opioid prescribing practices among surgeons, frequently resulting in the prescription of excessive opioids. This study evaluated the ability of a single educational intervention targeted toward general surgery residents to reduce the quantity of postoperative opioids prescribed. MATERIALS AND METHODS: This retrospective cohort study evaluated opioid prescribing practices 12 mo prior to and 6 mo following a 30-min lecture for general surgery residents that discussed prescribing guidelines and multimodal analgesia. Opioid volumes (normalized to oral morphine equivalents, OME), opioid type, nonopioid pain medications, and refills requested were analyzed for opioid-naïve adult patients undergoing excisional breast biopsy (EB), mastectomy (M), laparoscopic appendectomy (LA), laparoscopic cholecystectomy (LC), open umbilical hernia repair (OUHR), open inguinal hernia repair (OIHR), or laparoscopic inguinal hernia repair (LIHR). RESULTS: 695 and 376 patients preintervention and postintervention were included, respectively. Median OME prescribed decreased for EB (150 mg to 75 mg, P < 0.001), M (225 mg to 150 mg, P = 0.85), LA (150 mg to 94 mg, P < 0.001), LC (150 mg to 82 mg, P < 0.001), OUHR (150 mg to 103 mg, P < 0.001), OIHR (175 mg to 100 mg, P = 0.001), and LIHR (200 mg to 113 mg, P < 0.001). Fewer patients received opioids alone and more patients received an opioid with two nonopioid adjuncts (P < 0.001). More patients received oxycodone as fewer received acetaminophen-containing opioid combinations (P < 0.001). Patients requiring refills decreased (11.9% to 7.2%) (P = 0.014). CONCLUSIONS: Following this targeted intervention, patients were discharged with fewer OME and more nonopioid analgesics, even as refill requests decreased. Educating residents on opioid prescription guidelines and multimodal therapy is effective and should be part of the annual didactic curriculum.

Examining Perioperative Risk Associated with Simultaneous Resection of Primary Neuroendocrine Tumors and Synchronous Hepatic Metastases.

BACKGROUND: Surgical debulking of primary neuroendocrine tumors (NETs) and hepatic resection of metastatic NET disease may each independently improve overall survival. However, evidence for combined primary site debulking and metastasectomy on survival and impact on short-term perioperative outcomes is limited. METHODS: The 2014-2016 ACS-NSQIP targeted hepatectomy database was queried for all patients undergoing liver resection for metastatic NET. Secondary procedure codes were evaluated for major concurrent operations. Multivariable analysis was performed to determine risk factors for 30-day morbidity and mortality. RESULTS: A total of 472 patients were identified, of whom 153 (32.4%) underwent ≥1 additional concurrent major operation. The most common concurrent procedures were small bowel resection (14.6%), partial colectomy (8.9%), and radical lymphadenectomy (7.4%). Among all patients, overall 30-day mortality and morbidity were 1.5% and 25.6%, respectively. Modifiable and treatment-related factors associated with increased major postoperative morbidity risk included >10% weight loss within six months of surgery (p = 0.05), increasing number of hepatic lesions treated (p = 0.05), and biliary reconstruction (p = 0.001). No major concurrent procedure was associated with increased 30-day morbidity (all p > 0.05). CONCLUSIONS: Approximately one-third of patients with stage IV NET underwent combined hepatic and multi-organ resection. Although modifiable and treatment-related factors predictive of perioperative morbidity were identified, performance of concurrent major procedures did not increase perioperative morbidity. These results support consideration of multi-organ resection in carefully selected patients with metastatic NET.

Fractionated Ablative Carbon Dioxide Laser Therapy Decreases Ultrasound Thickness of Hypertrophic Burn Scar: A Prospective Process Improvement Initiative.

INTRODUCTION: Carbon dioxide (CO2) laser treatment is routinely used to treat hypertrophic burn scars (HBS). Although prior research has documented subjective improvement in HBS after treatment, there is little data evaluating objective changes in scar characteristics after therapy. The aim of our process improvement project was to evaluate changes to scar thickness (ST) using high-frequency ultrasound in patients with HBS undergoing CO2 laser therapy. METHODS: Ultrasound measurements of ST were obtained from patients with HBS before initial and at each subsequent treatment. ST, reduction in ST per treatment, and percentage reduction in ST from baseline were tabulated. Post hoc analyses examining the effect of initial ST and scar maturity on outcome were performed. First, patients were grouped by baseline ST into thicker (group 1, initial ST ≥ median value) and thinner (group 2, initial ST < median value) scar groups. Second, patients were divided into quartiles based on time from injury to treatment. Outcomes at each time point were compared with either Mann-Whitney U or Kruskal-Wallis tests, with Bonferonni corrections performed for post hoc subgroup analyses. Significance was set at P < 0.05. RESULTS: Twenty-one consecutive patients with HBS treated with CO2 laser were included. All patients completed 1 or more treatment, 48% completed 2 or more treatments, and 28% completed 3 treatments. Median initial ST was 0.71 cm (0.44-0.98 cm), and median scar maturity was 7.5 months (4.9-9.8 months). Overall, ST decreased over the treatment course (P < 0.001), with post hoc analysis demonstrating that 2 treatments were required to achieve a significant ST reduction (P < 0.01). On subgroup analysis comparing initial ST, ST decreased significantly in group 1 (thicker scars) overall (P < 0.001) but not in group 2 (P = 0.109). ST reduction was greatest after 1 treatment in group 1 (P = 0.022) and group 2 (P = 0.061). Percent reduction was greater in group 1 relative to group 2 after 1 treatment (P = 0.016). On subgroup analysis of scar maturity, there were no significant differences in either baseline ST or ST at any subsequent visit. CONCLUSIONS: Fractionated ablative CO2 laser treatment improved ST after 1 to 2 treatments. Patients with thicker scars demonstrated greater ST reduction than those with thinner scars. Ultrasound adequately assessed treatment response.

Inhalation Injury Severity Score on Admission Predicts Overall Survival in Burn Patients.

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.

Safety and efficacy of low-titer O whole blood resuscitation in a civilian level I trauma center.

BACKGROUND: Military experience has shown low-titer O whole blood (LTOWB) to be safe and beneficial in the resuscitation of hemorrhaging trauma patients. However, few civilian centers use LTOWB for trauma resuscitation. We evaluated the early experience and safety of a LTOWB program at a level 1 civilian trauma center. METHODS: We retrospectively reviewed our trauma registry from January 2018 to June 2020 for patients admitted in shock (defined as ≥1 of the following: heart rate, >120 beats per minute; systolic blood pressure, <90 mm Hg; or shock index, >0.9) who received blood products within 24 hours. Patients were grouped by resuscitation provided: LTOWB (group 1), component therapy (CT; group 2), and LTOWB-CT (group 3). Safety, outcomes, and variables associated with LTOWB transfusion and mortality were analyzed. RESULTS: 216 patients were included: 34 in Group 1, 95 in Group 2, and 87 in Group 3. Patientsreceiving LTOWB were more commonly male (p<0.001) and had a penetrating injury (p=0.005). Groups 1 and 3 had higher median ISS scores compared to Group 2 (19 and 20 vs 17; p=0.01). Group 3 received more median units of blood product in the first 4h (p<0.001) and in the first 24h (p<0.001). There was no difference between groups in 24h mortality or transfusion-related complications (all p>0.05). Arrival ED SBP was associated with LTOWB transfusion (odds ratio [OR] 0.98, 95% confidence interval [CI] 0.95-1.00, p=0.03). ED lactate was independently associated with 24h mortality. (OR 1.27, CI 1.02-1.58, p=0.03). LTOWB transfusion was not associated with mortality (p=0.49). Abstract. CONCLUSION: Severely injured patients received LTOWB-CT and more overall product units but had similar 24 h mortality when compared with the LTOWB or CT groups. No increase in transfusion-related complications was seen after LTOWB transfusion. Low-titer O whole blood should be strongly considered in the resuscitation of trauma patients at civilian centers. LEVEL OF EVIDENCE: Retrospective, therapeutic, level IV.

Lymph node sampling in resectable hepatocellular carcinoma: national practice patterns and predictors of positive lymph nodes.

BACKGROUND AND OBJECTIVES: Routine lymphadenectomy (LND) for resectable hepatocellular carcinoma (HCC) remains controversial. We evaluated national LND trends to identify pre-operative factors associated with node-positive disease to determine which patients might benefit from LND. METHODS: We identified HCC patients in the National Cancer Database (NCDB) treated with surgical resection between 2004 and 2015. Demographic, operative, pathologic, and survival data were compared. Multivariable regression was performed to determine preoperative predictors of pathologic nodal disease. RESULTS: Of 8095 total resected patients, 1442 (17.8%) underwent hepatectomy with LND. Patients who received LND had higher preoperative clinical T (T3-T4: 20.0% vs 12.1%, p < 0.001) and N (N1: 3.3% vs 0.6%, p < 0.001) stages. The strongest independent predictor of pathologic nodal disease was clinical N stage (OR 106.54, CI 44.10-257.42). Survival was highest in patients whose surgeons omitted LND or were found with LND to be node-negative on final pathology (p < 0.001). Clinical node positivity had high negative predictive value (97.9%) but moderate positive predictive value (56.3%) in estimating pathologic nodal status. CONCLUSIONS: Defining preoperative clinical nodal status is imperative in HCC patients. Clinical node positivity was the strongest predictor of pathologic nodal disease and its associated worse prognosis. LND can be considered selectively in clinically node-positive patients.

Chemoprevention in familial adenomatous polyposis: past, present and future.

Familial adenomatous polyposis (FAP) is a hereditary colorectal cancer syndrome characterized by colorectal adenomas and a near 100% lifetime risk of colorectal cancer (CRC). Prophylactic colectomy, usually by age 40, is the gold-standard therapy to mitigate this risk. However, colectomy is associated with morbidity and fails to prevent extra-colonic disease manifestations, including gastric polyposis, duodenal polyposis and cancer, thyroid cancer, and desmoid disease. Substantial research has investigated chemoprevention medications in an aim to prevent disease progression, postponing the need for colectomy and temporizing the development of extracolonic disease. An ideal chemoprevention agent should have a biologically plausible mechanism of action, be safe and easily tolerated over a prolonged treatment period, and produce a durable and clinically meaningful effect. To date, no chemoprevention agent tested has fulfilled these criteria. New agents targeting novel pathways in FAP are needed. Substantial preclinical literature exists linking the molecular target of rapamycin (mTOR) pathway to FAP. A single case report of rapamycin, an mTOR inhibitor, used as chemoprevention in FAP patients exists, but no formal clinical studies have been conducted. Here, we review the prior literature on chemoprevention in FAP, discuss the rationale for rapamycin in FAP, and outline a proposed clinical trial testing rapamycin as a chemoprevention agent in patients with FAP.