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.

Plant G × Microbial E: Plant Genotype Interaction with Soil Bacterial Community Shapes Rhizosphere Composition During Invasion.

It is increasingly recognized that different genetic variants of hosts can uniquely shape their microbiomes. Invasive species often evolve in their introduced ranges, but little is known about the potential for their microbial associations to change during invasion as a result. We asked whether host genotype (G), microbial environment (E), or their interaction (G × E) affected the composition and diversity of host-associated microbiomes in Centaurea solstitialis (yellow starthistle), a Eurasian plant that is known to have evolved novel genotypes and phenotypes and to have altered microbial interactions, in its severe invasion of CA, USA. We conducted an experiment in which native and invading plant genotypes were inoculated with native and invaded range soil microbial communities. We used amplicon sequencing to characterize rhizosphere bacteria in both the experiment and the field soils from which they were derived. We found that native and invading plant genotypes accumulated different microbial associations at the family level in each soil community, often counter to differences in family abundance between soil communities. Root associations with potentially beneficial Streptomycetaceae were particularly interesting, as these were more abundant in the invaded range field soil and accumulated on invading genotypes. We also found that bacterial diversity is higher in invaded soils, but that invading genotypes accumulated a lower diversity of bacteria and unique microbial composition in experimental inoculations, relative to native genotypes. Thus variation in microbial associations of invaders was driven by the interaction of plant G and microbial E, and rhizosphere microbial communities appear to change in composition in response to host evolution during invasion.

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.