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.

The benefit of adjuvant chemotherapy following pancreaticoduodenectomy for pancreatic adenocarcinoma depends on response to neoadjuvant therapy.

BACKGROUND: The benefit of adjuvant therapy (AT) remains unclear in pancreatic ductal adenocarcinoma (PDAC) after neoadjuvant therapy (NAT) and surgical resection. METHODS: The 2019 National Cancer Database was queried for patients with non-metastatic PDAC who received NAT followed by pancreaticoduodenectomy. Only patients with data regarding receipt of AT were included. Patients were classified if they had nodal down-staging specifically, or any downstaging (Tumor, Nodal, or overall). Propensity score matching (PSM) adjusted for pretreatment covariate imbalance between groups. The weighted Kaplan-Meier method and log-rank test were used to estimate the cumulative survival. RESULTS: After exclusion criteria and PSM, a total of 2784 patients remained; 1689 (60.7%) received AT and 1095 (39.3%) did not receive AT. Among all, those with additional AT had a significantly improved overall survival (OS) (p < 0.001). Upon evaluation of patients without downstaging after NAT, those who received AT had improved OS (no nodal downstaging or any downstaging; p = 0.002; p = 0.001). When evaluating patients with downstaging after NAT, those receiving AT did not have improved OS (nodal downstaging or any downstaging: p = 0.352; p = 0.99). CONCLUSION: Response to NAT appears to correlate with the benefit of AT following pancreaticoduodenectomy; patients who have a favorable response to NAT may not benefit from AT.

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.

Outcomes of Partial Versus Total Colectomy in Ulcerative Colitis: A Propensity Score-Matched Analysis.

INTRODUCTION: Total abdominal colectomy (TAC) with ileostomy is the standard treatment for severe ulcerative colitis (UC). Partial colectomy (PC) with colostomy may present a less morbid treatment option. METHODS: The 2012-19 ACS-NSQIP database was queried to assess 30-day outcomes among patients undergoing TAC versus PC for UC, utilizing propensity score matching (PSM) techniques to account for differences in disease severity, patient selection, and presentation acuity. RESULTS: Before matching (n = 9888), patients undergoing PC were older, had more comorbidities, and experienced higher complication and 30-day mortality rates (P < 0.001). After matching (n = 1846), patients undergoing TAC experienced higher 30-day overall complications (41.9% versus 36.5%, P = 0.017) and serious complications (37.2% versus 31.5%, P = 0.011). Sensitivity analyses of older patients and those undergoing nonemergency surgery demonstrated higher overall rates of complications for patients receiving TAC. However, among patients undergoing emergency surgery only, no differences in complications were seen between the two surgical approaches. CONCLUSIONS: PC with colostomy in the setting of ulcerative colitis has similar 30-day outcomes to TAC with ileostomy. PC may be an acceptable surgical alternative to TAC in select patients. Studies investigating longer-term outcomes are necessary to further investigate this option.

Minimally invasive versus open distal pancreatectomy: a matched analysis using ACS-NSQIP.

BACKGROUND: Minimally invasive distal pancreatectomy (MIDP) is gaining popularity due to improved perioperative outcomes over open distal pancreatectomy (ODP). The purpose of this study is to compare outcomes of MIDP and ODP using patients within a nationwide cohort. METHODS: The American College of Surgeons' National Quality Improvement Program (2014-2018) was used to evaluate incidence of post-operative pancreatic fistula (POPF) as well as 30-day composite major morbidity for patients undergoing MIDP vs. ODP. Matching was performed with a Mahalanobis-distance model for demographic characteristics, preoperative risk factors, and benign versus malignant pathology. Outcomes were assessed via weighted multiple logistic regression. RESULTS: A total of 3940 patients underwent distal pancreatectomy (1978 MIDP, 1962 ODP). After matching, 2985 patients were included (1978 MIDP, 1007 ODP). The rates of major morbidity (8.65% MIDP vs. 9.76% ODP, p = 0.37) were similar between groups. The MIDP group was found to have significantly decreased length of stay (5.6 vs. 7 days, p ≤ 0.001), but greater rates (12.54% MIDP vs. 9.35% ODP, p = 0.02) of post-operative fistula. CONCLUSIONS: When matched for baseline patient characteristics, MIDP was associated with shorter length of hospitalization with similar rates of morbidity compared to ODP. However, MIDP was associated with significantly increased rates of POPF. Further studies are needed to investigate this difference in POPF rate, and determine how to optimize MIDP surgical technique to reduce this risk.

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.

Downstaging of Pancreatic Adenocarcinoma With Either Neoadjuvant Chemotherapy or Chemoradiotherapy Improves Survival.

BACKGROUND: 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. METHODS: 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. RESULTS: 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) CONCLUSION: Downstaging after neoadjuvant therapies improves survival. The addition of radiation therapy may increase the rate of downstaging without affecting overall oncologic outcomes.

Maximizing Benefit of Virtual Learning: Lessons From the Coronavirus Disease 2019 Pandemic.

INTRODUCTION: The coronavirus disease 2019 pandemic has profoundly impacted surgical education. We assessed resident perceptions of our virtual academic program, which consists of daily lectures or case conferences held via a videoconferencing platform. METHODS: A survey evaluating attitudes and practices for virtual academics was administered to general surgery residents. A focus group was conducted to identify benefits, barriers to engagement, and opportunities for improvement for virtual education. A total of 19 residents completed the education survey, and seven residents participated in the focus group. RESULTS: While expressing preference toward in-person academics (84.2%), residents felt the virtual academics were of good quality (median rating 4/5) and preferred virtual academics to no academic sessions (94.7%). Of respondents, 57.9% believe that the coronavirus pandemic negatively impacted their surgical education. They believe their American Board of Surgery In-Training Examination preparation was not impacted. Residents preferred using a computer over a phone for academics (79% versus 16%). The focus group identified the benefits of virtual academics, including the ability to participate while away and having recordings available. Areas for improvement included reinforcement of protected time for academics, requiring cameras be on, increasing in-lecture polls, and creation of an online repository of recordings for review. Residents hoped a virtual component of academics and recordings would continue past the pandemic. CONCLUSIONS: Although virtual academics are not the preferred mode of learning in our residency, there are multiple unintended benefits. We recommend a hybrid academic model with in-person didactics and recorded video for later review.

Intragastric preloads of l-tryptophan reduce ingestive behavior via oxytocinergic neural mechanisms in male mice.

Human and laboratory animal studies suggest that dietary supplementation of a free essential amino acid, l-tryptophan (TRP), reduces food intake. It is unclear whether an acute gastric preload of TRP decreases consumption and whether central mechanisms underlie TRP-driven hypophagia. We examined the effect of TRP administered via intragastric gavage on energy- and palatability-induced feeding in mice. We sought to identify central mechanisms through which TRP suppresses appetite. Effects of TRP on consumption of energy-dense and energy-dilute tastants were established in mice stimulated to eat by energy deprivation or palatability. A conditioned taste aversion (CTA) paradigm was used to assess whether hypophagia is unrelated to sickness. c-Fos immunohistochemistry was employed to detect TRP-induced activation of feeding-related brain sites and of oxytocin (OT) neurons, a crucial component of satiety circuits. Also, expression of OT mRNA was assessed with real-time PCR. The functional importance of OT in mediating TRP-driven hypophagia was substantiated by showing the ability of OT receptor blockade to abolish TRP-induced decrease in feeding. TRP reduced intake of energy-dense standard chow in deprived animals and energy-dense palatable chow in sated mice. Anorexigenic doses of TRP did not cause a CTA. TRP failed to affect intake of palatable yet calorie-dilute or noncaloric solutions (10% sucrose, 4.1% Intralipid or 0.1% saccharin) even for TRP doses that decreased water intake in thirsty mice. Fos analysis revealed that TRP increases activation of several key feeding-related brain areas, especially in the brain stem and hypothalamus. TRP activated hypothalamic OT neurons and increased OT mRNA levels, whereas pretreatment with an OT antagonist abolished TRP-driven hypophagia. We conclude that intragastric TRP decreases food and water intake, and TRP-induced hypophagia is partially mediated via central circuits that encompass OT.

Increased Accuracy of Varus Stress Radiographs Versus Magnetic Resonance Imaging in Diagnosing Fibular Collateral Ligament Grade III Tears.

PURPOSE: To evaluate the diagnostic accuracy of magnetic resonance imaging and varus stress radiographs for fibular collateral ligament (FCL) tears, and compare these modalities to intraoperative findings. METHODS: All patients who underwent an isolated FCL or combined anterior cruciate ligament (ACL)/FCL reconstruction by a single surgeon between 2010 and 2017 with preoperative varus stress radiographs and magnetic resonance imaging (MRI) were included in this study. A control group was composed of patients with an MRI and intact ACL and FCL. Sensitivity and specificity of diagnosing FCL injuries on MRI were determined based on review by a fellowship-trained musculoskeletal radiologist, blinded to the pathology associated with each patient (FCL injury vs control), and compared with the gold standard of examination under anesthesia, followed by surgical confirmation of an FCL tear at the time of FCL reconstruction. The sensitivity of diagnosing an FCL injury based on varus stress radiographs was also determined. Furthermore, the ability of both imaging modalities to identify an FCL injury was stratified based on acute versus chronic etiology. RESULTS: A total of 232 patients were included: 98 patients in the FCL tear group (mean age: 33.6 ± 12.2 years) and 134 patients in the control group (mean age: 44.0 ± 17.2 years). Varus stress radiographs were determined to be more sensitive in diagnosing FCL injuries compared with MRI, with an overall sensitivity of 70% compared with 66%, respectively. Based on MRI, overall specificity was 68%. Based on chronicity of the injuries, MRI was more accurate for detecting acute FCL injuries than chronic injuries (P = .002), and varus stress radiographs were more accurate for detecting chronic FCL injuries than acute injuries (P = .041). CONCLUSIONS: The results support the use of both varus stress radiographs and MRI in diagnosing FCL injuries, because MRI is more sensitive in diagnosing an acute FCL tear, and varus stress radiographs are more sensitive in diagnosing a chronic FCL tear. Both imaging modalities are recommended to diagnose both acute and chronic FCL injuries. LEVEL OF EVIDENCE: Level II, case-control study.

Skeletal Muscle in Healthy Subjects versus Those with GNE-Related Myopathy: Evaluation with Shear-Wave US--A Pilot Study.

PURPOSE: To determine whether quantitative differences in shear-wave velocity (SWV) exist between normal skeletal muscle and those affected by GNE-related myopathy and to examine the effects of muscle anisotropy, depth, and axial preload on SWV in a healthy control group. MATERIALS AND METHODS: This study was approved by the institutional review board and compliant with HIPAA. Informed consent was obtained from all study volunteers. Eight patients (four women and four men aged 30-50 years) with genetically and biopsy-proved GNE-related myopathy and five healthy volunteers (three women and two men aged 27-33 years) underwent SWV imaging with use of a 9-MHz linear transducer. The gastrocnemius muscles were evaluated in the patients with GNE-related myopathy, and the gastrocnemius, vastus lateralis, and rectus femoris muscles were evaluated in the healthy cohort. The effect of muscle anisotropy, axial preload, and sample volume depth were examined in the healthy cohort. The effect of anisotropy at a fixed depth and preload were examined in the patients with GNE-related myopathy. RESULTS: Irrespective of the muscle, the mean SWV was significantly higher with the transverse orientation than with the longitudinal orientation (P < .001). In the healthy cohort, the mean SWV for superficial measurements was significantly lower than that for deep measurements (P < .02). The mean SWV with preload was significantly higher with compression (P < .001) for the rectus femoris only. The mean SWV was significantly lower in patients with GNE-related myopathy than in control subjects (P < .02). CONCLUSION: SWV parametric imaging may provide a useful quantitative adjunct in the assessment of disease activity in patients with GNE-related myopathy. There is diminished SWV and muscle anisotropy in GNE-related myopathy.

Rapid HIV Testing in a New Orleans Emergency Department is Effective in Identifying New HIV Diagnoses and in Linking Patients to Care.

A retrospective chart review of patients who agreed to a rapid HIV test in the emergency department in the initial year of institution of the rapid test was conducted. Out of 8,204 patients, 99 were newly diagnosed with HIV in the first year of the institution of the rapid HIV test (1.2%). Eighty-five (86%) had a documented referral to the infectious disease clinic, and 59 (60%) were linked to care within one year of diagnosis. The majority (58%) of the patients with a new diagnosis of HIV had been seen in the Interim Louisiana State University Public Hospital (ILPH) healthcare system in the five years prior to their diagnosis. Forty-nine percent of the patients met diagnostic criteria of AIDS at diagnosis. Rapid HIV testing in the emergency department is an effective way to find previously undiagnosed patients and link them to subspecialty care.

Utility of cell-based vaccines as cancer therapy: Systematic review and meta-analysis.

Cell-based therapeutic cancer vaccines use autologous patient-derived tumor cells, allogeneic cancer cell lines or autologous antigen presenting cells to mimic the natural immune process and stimulate an adaptive immune response against tumor antigens. The primary objective of this study is to perform a systematic literature review with an embedded meta-analysis of all published Phase 2 and 3 clinical trials of cell-based cancer vaccines in human subjects. The secondary objective of this study is to review trials demonstrating biological activity of cell-based cancer vaccines that could uncover additional hypotheses, which could be used in the design of future studies. We performed the systematic review and meta-analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The final review included 36 studies - 16 single-arm studies, and 20 controlled trials. Our systematic review of the existing literature revealed largely negative trials and our meta-analysis did not show evidence of clinical benefit from cell-based cancer-vaccines. However, as we looked beyond the stringent inclusion criteria of our systematic review, we identified significant examples of biological activity of cell-based cancer vaccines that are worth highlighting. In conclusion, the existing literature on cell-based cancer vaccines is highly variable in terms of cancer type, vaccine therapies and the clinical setting with no overall statistically significant clinical benefit, but there are individual successes that represent the promise of this approach. As cell-based vaccine technology continues to evolve, future studies can perhaps fulfill the potential that this exciting field of anti-cancer therapy holds.

Tumor infiltrating lymphocytes as an endpoint in cancer vaccine trials.

Checkpoint inhibitors have invigorated cancer immunotherapy research, including cancer vaccination. Classic early phase trial design and endpoints used in developing chemotherapy are not suited for evaluating all forms of cancer treatment. Peripheral T cell response dynamics have demonstrated inconsistency in assessing the efficacy of cancer vaccination. Tumor infiltrating lymphocytes (TILs), reflect the local tumor microenvironment and may prove a superior endpoint in cancer vaccination trials. Cancer vaccines may also promote success in combination immunotherapy treatment of weakly immunogenic tumors. This review explores the impact of TILs as an endpoint for cancer vaccination in multiple malignancies, summarizes the current literature regarding TILs analysis, and discusses the challenges of providing validity and a standardized implementation of this approach.