Neoadjuvant Chemotherapy Versus Upfront Surgery for Resectable Pancreatic Adenocarcinoma: An Updated Nationwide Study.

OBJECTIVE: The objective of this study was to assess the association of survival with neoadjuvant chemotherapy (NAC) in resectable pancreatic adenocarcinoma (PDAC). BACKGROUND: The early control of potential micrometastases and patient selection using NAC has been advocated for patients with PDAC. However, the role of NAC for resectable PDAC remains unclear. METHODS: Patients with clinical T1 and T2 PDAC were identified in the National Cancer Database from 2010 to 2017. Kaplan-Meier estimates, and Cox regression models were used to compare survival. To address immortal time bias, landmark analysis was performed. Interactions between preoperative factors and NAC were investigated in subgroup analyses. A propensity score analysis was performed to compare survival between multiagent NAC and upfront surgery. RESULTS: In total, 4041 patients were treated with upfront surgery and 1,175 patients were treated with NAC (79.4% multiagent NAC, 20.6% single-agent NAC). Using a landmark time of 6 months after diagnosis, patients treated with multiagent NAC had longer median overall survival compared with upfront surgery and single-agent NAC. (35.8 vs 27.1 vs 27.4 mo). Multiagent NAC was associated with lower mortality rates compared with upfront surgery (adjusted hazard ratio, 0.77; 95% CI, 0.70-0.85), whereas single-agent NAC was not. The association of survival with multiagent NAC were consistent in analyses using the matched data sets. Interaction analysis revealed that the association between multiagent NAC and a lower mortality rate did not significantly differ across age, facility type, tumor location, CA 19-9 levels, and clinical T/N stages. CONCLUSIONS: The findings suggest that multiagent NAC followed by resection is associated with improved survival compared with upfront surgery.

Adjuvant Chemotherapy With or Without Radiotherapy for Resected Pancreatic Cancer After Multiagent Neoadjuvant Chemotherapy.

BACKGROUND: Adjuvant therapy is associated with improved pancreatic cancer survival after neoadjuvant chemotherapy and surgery. However, whether adjuvant treatment should include radiotherapy is unclear in this setting. METHODS: This study queried the National Cancer Database for pancreatic adenocarcinoma patients who underwent curative resection after multiagent neoadjuvant chemotherapy between 2010 and 2019 and received adjuvant treatment. Adjuvant chemotherapy plus radiotherapy (external beam, 45-50.4 gray) was compared with adjuvant chemotherapy alone. Uni- and multivariable Cox regression was used to assess survival associations. Analyses were repeated in a propensity score-matched subgroup. RESULTS: Of 1983 patients who received adjuvant treatment after multiagent neoadjuvant chemotherapy and resection, 1502 (75.7%) received adjuvant chemotherapy alone and 481 (24.3%) received concomitant adjuvant radiotherapy (chemoradiotherapy). The patients treated with adjuvant chemoradiotherapy were younger, were treated at non-academic facilities more often, and had higher rates of lymph node metastasis (ypN1-2), positive resection margins (R1), and lymphovascular invasion (LVI+). The median survival was shorter for the chemoradiotherapy-treated patients according to the unadjusted analysis (26.8 vs 33.2 months; p = 0.0017). After adjustment for confounders, chemoradiotherapy was associated with better outcomes in the multivariable model (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.61-0.93; p = 0.008). The association between chemoradiotherapy and improved outcomes was stronger for the patients with grade III tumors (HR, 0.53; 95% CI, 0.37-0.74) or LVI+ tumors (HR, 0.58; 95% CI, 0.44-0.75). In a subgroup of 396 propensity-matched patients, chemoradiotherapy was associated with a survival benefit only for the patients with LVI+ or grade III tumors. CONCLUSION: After multiagent neoadjuvant chemotherapy and resection for pancreatic cancer, additional adjuvant chemoradiotherapy versus adjuvant chemotherapy alone is associated with improved survival for patients with LVI+ or grade III tumors.

Radiologic Occult Metastases in Pancreatic Cancer: Analysis of Risk Factors and Survival Outcomes in the Age of Contemporary Neoadjuvant Multi-agent Chemotherapy.

BACKGROUND: Radiologic occult metastatic disease (ROMD) in patients with pancreatic ductal adenocarcinoma (PDAC) who undergo contemporary neoadjuvant chemotherapy (NAC) has not been well studied. This study sought to analyze the incidence, risk factors, and oncologic outcomes for patients who underwent the NAC approach for PDAC. METHODS: A retrospective review analyzed a prospectively maintained database of patients who had potentially resectable PDAC treated with NAC and were offered pancreatectomy at our institution from 2011 to 2022. Multivariable regression analysis was performed to assess risk factors associated with ROMD. Kaplan-Meier curves with log-rank analyses were generated to estimate time-to-event end points. RESULTS: The study enrolled 366 patients. Upfront and borderline resectable anatomic staging comprised 80% of the cohort, whereas 20% had locally advanced disease. The most common NAC regimen was FOLFIRINOX (n = 274, 75%). For 55 patients (15%) who harbored ROMD, the most common site was liver-only metastases (n = 33, 60%). The independent risk factors for ROMD were increasing CA19-9 levels during NAC (odds ratio [OR], 7.01; confidence interval [CI], 1.97-24.96; p = 0.008), indeterminate liver lesions (OR, 2.19; CI, 1.09-4.39; p = 0.028), and enlarged para-aortic lymph nodes (OR, 6.87; CI, 2.07-22.74; p = 0.002) on preoperative cross-sectional imaging. Receipt of palliative chemotherapy (p < 0.001) and eventual formal pancreatectomy (p = 0.04) were associated with survival benefit in the log-rank analysis. The median overall survival (OS) of the patients with ROMD was nearly 15 months from the initial diagnosis, with radiologic evidence of metastases occurring after a median of 2 months. CONCLUSIONS: Radiologic occult metastatic disease remains a clinical challenge associated with poor outcomes for patients who have PDAC treated with multi-agent NAC.

Optimal balancing of xylem efficiency and safety explains plant vulnerability to drought.

In vast areas of the world, forests and vegetation are water limited and plant survival depends on the ability to avoid catastrophic hydraulic failure. Therefore, it is remarkable that plants take hydraulic risks by operating at water potentials (ψ) that induce partial failure of the water conduits (xylem). Here we present an eco-evolutionary optimality principle for xylem conduit design that explains this phenomenon based on the hypothesis that conductive efficiency and safety are optimally co-adapted to the environment. The model explains the relationship between the tolerance to negative water potential (ψ50 ) and the environmentally dependent minimum ψ (ψmin ) across a large number of species, and along the xylem pathway within individuals of two species studied. The wider hydraulic safety margin in gymnosperms compared to angiosperms can be explained as an adaptation to a higher susceptibility to accumulation of embolism. The model provides a novel optimality-based perspective on the relationship between xylem safety and efficiency.

Re-examining the evidence for the mother tree hypothesis - resource sharing among trees via ectomycorrhizal networks.

Seminal scientific papers positing that mycorrhizal fungal networks can distribute carbon (C) among plants have stimulated a popular narrative that overstory trees, or 'mother trees', support the growth of seedlings in this way. This narrative has far-reaching implications for our understanding of forest ecology and has been controversial in the scientific community. We review the current understanding of ectomycorrhizal C metabolism and observations on forest regeneration that make the mother tree narrative debatable. We then re-examine data and conclusions from publications that underlie the mother tree hypothesis. Isotopic labeling methods are uniquely suited for studying element fluxes through ecosystems, but the complexity of mycorrhizal symbiosis, low detection limits, and small carbon discrimination in biological processes can cause researchers to make important inferences based on miniscule shifts in isotopic abundance, which can be misleading. We conclude that evidence of a significant net C transfer via common mycorrhizal networks that benefits the recipients is still lacking. Furthermore, a role for fungi as a C pipeline between trees is difficult to reconcile with any adaptive advantages for the fungi. Finally, the hypothesis is neither supported by boreal forest regeneration patterns nor consistent with the understanding of physiological mechanisms controlling mycorrhizal symbiosis.

A Cross-Sectional and Longitudinal Analysis of Pre-Diagnostic Blood Plasma Biomarkers for Early Detection of Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a major cause of cancer death that typically presents at an advanced stage. No reliable markers for early detection presently exist. The prominent tumor stroma represents a source of circulating biomarkers for use together with cancer cell-derived biomarkers for earlier PDAC diagnosis. CA19-9 and CEA (cancer cell-derived biomarkers), together with endostatin and collagen IV (stroma-derived) were examined alone, or together, by multivariable modelling, using pre-diagnostic plasma samples (n = 259 samples) from the Northern Sweden Health and Disease Study biobank. Serial samples were available for a subgroup of future patients. Marker efficacy for future PDAC case prediction (n = 154 future cases) was examined by both cross-sectional (ROC analysis) and longitudinal analyses. CA19-9 performed well at, and within, six months to diagnosis and multivariable modelling was not superior to CA19-9 alone in cross-sectional analysis. Within six months to diagnosis, CA19-9 (AUC = 0.92) outperformed the multivariable model (AUC = 0.81) at a cross-sectional level. At diagnosis, CA19-9 (AUC = 0.995) and the model (AUC = 0.977) performed similarly. Longitudinal analysis revealed increases in CA19-9 up to two years to diagnosis which indicates a window of opportunity for early detection of PDAC.

The mycorrhizal tragedy of the commons.

Trees receive growth-limiting nitrogen from their ectomycorrhizal symbionts, but supplying the fungi with carbon can also cause nitrogen immobilization, which hampers tree growth. We present results from field and greenhouse experiments combined with mathematical modelling, showing that these are not conflicting outcomes. Mycorrhizal networks connect multiple trees, and we modulated C provision by strangling subsets of Pinus sylvestris trees, assuming that carbon supply to fungi was reduced proportionally to the strangled fraction. We conclude that trees gain additional nitrogen at the expense of their neighbours by supplying more carbon to the fungi. But this additional carbon supply aggravates nitrogen limitation via immobilization of the shared fungal biomass. We illustrate the evolutionary underpinnings of this situation by drawing on the analogous tragedy of the commons, where the shared mycorrhizal network is the commons, and explain how rising atmospheric CO2 may lead to greater nitrogen immobilization in the future.

Tree water uptake enhances nitrogen acquisition in a fertilized boreal forest - but not under nitrogen-poor conditions.

Understanding how plant water uptake interacts with acquisition of soil nitrogen (N) and other nutrients is fundamental for predicting plant responses to a changing environment, but it is an area where models disagree. We present a novel isotopic labelling approach which reveals spatial patterns of water and N uptake, and their interaction, by trees. The stable isotopes 15 N and 2 H were applied to a small area of the forest floor in stands with high and low soil N availability. Uptake by surrounding trees was measured. The sensitivity of N acquisition to water uptake was quantified by statistical modelling. Trees in the high-N stand acquired twice as much 15 N as in the low-N stand and around half of their N uptake was dependent on water uptake (2 H enrichment). By contrast, in the low-N stand there was no positive effect of water uptake on N uptake. We conclude that tree N acquisition was only marginally dependent on water flux toward the root surface under low-N conditions whereas under high-N conditions, the water-associated N uptake was substantial. The results suggest a fundamental shift in N acquisition strategy under high-N conditions.

Eco-evolutionary optimality as a means to improve vegetation and land-surface models.

Global vegetation and land-surface models embody interdisciplinary scientific understanding of the behaviour of plants and ecosystems, and are indispensable to project the impacts of environmental change on vegetation and the interactions between vegetation and climate. However, systematic errors and persistently large differences among carbon and water cycle projections by different models highlight the limitations of current process formulations. In this review, focusing on core plant functions in the terrestrial carbon and water cycles, we show how unifying hypotheses derived from eco-evolutionary optimality (EEO) principles can provide novel, parameter-sparse representations of plant and vegetation processes. We present case studies that demonstrate how EEO generates parsimonious representations of core, leaf-level processes that are individually testable and supported by evidence. EEO approaches to photosynthesis and primary production, dark respiration and stomatal behaviour are ripe for implementation in global models. EEO approaches to other important traits, including the leaf economics spectrum and applications of EEO at the community level are active research areas. Independently tested modules emerging from EEO studies could profitably be integrated into modelling frameworks that account for the multiple time scales on which plants and plant communities adjust to environmental change.

Hyperglycemia as a risk factor in pancreatic cancer: A nested case-control study using prediagnostic blood glucose levels.

OBJECTIVE: To determine the risk association between fasting glucose levels and pancreatic cancer using systematically collected prediagnostic blood glucose samples. METHODS: Prospective nested case-control study of participants from the Northern Sweden Health and Disease Study, including 182 cases that developed pancreatic cancer and four matched controls per case. Blood glucose levels collected up to 24 years before pancreatic cancer diagnosis were analyzed. The association between fasting glucose levels and pancreatic cancer risk was determined using unconditional and conditional logistic regression models. The association between fasting glucose and the time to pancreatic cancer diagnosis, tumor stage and survival was determined using likelihood-ratio test, t-test and log rank test. RESULTS: The unadjusted risk of developing pancreatic cancer increased with increasing fasting glucose levels (OR 1.30, 95% CI 1.05-1.60, P = .015). Impaired fasting glucose (≥6.1 mmol/L) was associated with an adjusted risk of 1.77 for developing pancreatic cancer (95% CI 1.05-2.99, P = .032). In subgroup analysis, fasting glucose levels were associated with an increased risk in never-smokers (OR 4.02, 95% CI 1.26-12.77, P = .018) and non-diabetics (OR 3.08, 95% CI 1.08-8.79, P = .035) (non-significant for interaction). The ratio between fasting glucose and BMI was higher among future pancreatic cancer patients and an increased ratio was associated with elevated risk of pancreatic cancer (OR 1.66, 95% CI 1.04-2.66, P = .034). Fasting glucose levels were not associated with TNM stage at diagnosis or survival. CONCLUSIONS: High fasting glucose is associated with an increased risk of being diagnosed with pancreatic cancer.

Postoperative pain after colorectal surgery.

PURPOSE: Postoperative pain is a keystone in perioperative programs, as pain negatively impacts recovery. This study aimed to evaluate pain after elective colorectal surgery and to identify risk factors for postoperative pain. METHODS: This prospective cohort study comprised consecutive patients undergoing elective colorectal surgery within the Enhanced Recovery after Surgery (ERAS) perioperative program between March 2013 and April 2017. The numeric rating scale (NRS) was used to estimate maximum pain. Logistic regression was used to model associations with the type of surgery, age, gender, and comorbidities. RESULTS: The cohort comprised 434 of 459 eligible patients. On the day of surgery to postoperative day 3, 50-64% of patients reported moderate to severe pain (NRS 4-10). Postoperative pain was similar for open and minimally invasive rectal surgery, while patients undergoing minimally invasive colonic surgery experienced more pain on the day of surgery and less pain on postoperative days 2 and 3 vs. open colonic surgery. Younger age was associated with more pain every postoperative day and by 0.7 NRS/10 years (95% CI 0.5-0.9, P < 0.001) on the day of surgery, while having diabetes type 2 was associated with less postoperative pain by - 1.3 NRS (95% CI - 2.4 to - 0.2) on the day of surgery. CONCLUSIONS: The majority, and young patients in particular, experience moderate to severe pain after open and minimally invasive colorectal surgery, despite following ERAS perioperative program. There is a need for effective and individualized analgesia after colorectal surgery, since the individual pain response to surgery is difficult to predict.

A Framework for Global Twenty-First Century Scenarios and Models of Biological Invasions.

Biological invasions have emerged as an eminent feature of global change, with substantial impacts on the environment and human livelihoods. Current research demonstrates that the numbers and impacts of alien species are rising unabatedly. At the same time, we lack a thorough understanding of potential future trajectories for the decades to come. With the recent establishment of comprehensive global databases, it is, for the first time, feasible to develop and quantify future scenarios of biological invasions. Therefore, we propose a conceptual framework for how to develop alien species scenarios for the twenty-first century and how to identify relevant steps and challenges along the way. The concept will be important to inform research, policy, stakeholders, and the general public. Furthermore, we call for the scientific community to join forces and to operationalize the framework for scenarios and models of biological invasions to develop an important baseline for understanding and managing future biological invasions.

VEGF receptor-2/neuropilin 1 trans-complex formation between endothelial and tumor cells is an independent predictor of pancreatic cancer survival.

Unstable and dysfunctional tumor vasculature promotes cancer progression and spread. Signal transduction by the pro-angiogenic vascular endothelial growth factor (VEGF) receptor-2 (VEGFR2) is modulated by VEGFA-dependent complex formation with neuropilin 1 (NRP1). NRP1 expressed on tumor cells can form VEGFR2/NRP1 trans-complexes between tumor cells and endothelial cells which arrests VEGFR2 on the endothelial surface, thus interfering with productive VEGFR2 signaling. In mouse fibrosarcoma, VEGFR2/NRP1 trans-complexes correlated with reduced tumor vessel branching and reduced tumor cell proliferation. Pancreatic ductal adenocarcinoma (PDAC) strongly expressed NRP1 on both tumor cells and endothelial cells, in contrast to other common cancer forms. Using proximity ligation assay, VEGFR2/NRP1 trans-complexes were identified in human PDAC tumor tissue, and its presence was associated with reduced tumor vessel branching, reduced tumor cell proliferation, and improved patient survival after adjusting for other known survival predictors. We conclude that VEGFR2/NRP1 trans-complex formation is an independent predictor of PDAC patient survival. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Plasma Micro-RNA Alterations Appear Late in Pancreatic Cancer.

OBJECTIVES: The aim of this research was to study whether plasma microRNAs (miRNA) can be used for early detection of pancreatic cancer (PC) by analyzing prediagnostic plasma samples collected before a PC diagnosis. BACKGROUND: PC has a poor prognosis due to late presenting symptoms and early metastasis. Circulating miRNAs are altered in PC at diagnosis but have not been evaluated in a prediagnostic setting. METHODS: We first performed an initial screen using a panel of 372 miRNAs in a retrospective case-control cohort that included early-stage PC patients and healthy controls. Significantly altered miRNAs at diagnosis were then measured in an early detection case-control cohort wherein plasma samples in the cases are collected before a PC diagnosis. Carbohydrate antigen 19-9 (Ca 19-9) levels were measured in all samples for comparison. RESULTS: Our initial screen, including 23 stage I-II PC cases and 22 controls, revealed 15 candidate miRNAs that were differentially expressed in plasma samples at PC diagnosis. We combined all 15 miRNAs into a multivariate statistical model, which outperformed Ca 19-9 in receiver-operating characteristics analysis. However, none of the candidate miRNAs, individually or in combination, were significantly altered in prediagnostic plasma samples from 67 future PC patients compared with 132 matched controls. In comparison, Ca 19-9 levels were significantly higher in the cases at <5 years before diagnosis. CONCLUSION: Plasma miRNAs are altered in PC patients at diagnosis, but the candidate miRNAs found in this study appear late in the course of the disease and cannot be used for early detection of the disease.

Prognosis of sporadic resected small (≤2 cm) nonfunctional pancreatic neuroendocrine tumors - a multi-institutional study.

BACKGROUND: Malignant potential of small (≤20 mm) nonfunctional pancreatic neuroendocrine tumors (sNF-PNET) is difficult to predict and management remain controversial. The aim of this study was to assess the prognosis of sporadic nonmetastatic sNF-PNETs. METHODS: Patients were identified from databases of 16 centers. Outcomes and risk factors for recurrence were identified by uni- and multivariate analyses. RESULTS: sNF-PNET was resected in 210 patients, and 66% (n = 138) were asymptomatic. Median age was 60 years, median tumor size was 15 mm, parenchyma-sparing surgery was performed in 42%. Postoperative mortality was 0.5% (n = 1), severe morbidity rate was 14.3% (n = 30), and 14 of 132 patients (10.6%) with harvested lymph nodes had metastatic lymph nodes. Tumor size, presence of biliary or pancreatic duct dilatation, and WHO grade 2-3 were independently associated with recurrence. Patients with tumors sized ≤10 mm were disease free at last follow-up. The 1-, 3- and 5-year disease-free survival rates for patients with tumors sized 11-20 mm on preoperative imaging were 95.1%, 91.0%, and 87.3%, respectively. CONCLUSIONS: In sNF-PNETs, the presence of biliary or pancreatic duct dilatation or WHO grade 2-3 advocate for surgical treatment. In the remaining patients, a wait-and-see policy might be considered.

The carbon bonus of organic nitrogen enhances nitrogen use efficiency of plants.

The importance of organic nitrogen (N) for plant nutrition and productivity is increasingly being recognized. Here we show that it is not only the availability in the soil that matters, but also the effects on plant growth. The chemical form of N taken up, whether inorganic (such as nitrate) or organic (such as amino acids), may significantly influence plant shoot and root growth, and nitrogen use efficiency (NUE). We analysed these effects by synthesizing results from multiple laboratory experiments on small seedlings (Arabidopsis, poplar, pine and spruce) based on a tractable plant growth model. A key point is that the carbon cost of assimilating organic N into proteins is lower than that of inorganic N, mainly because of its carbon content. This carbon bonus makes it more beneficial for plants to take up organic than inorganic N, even when its availability to the roots is much lower - up to 70% lower for Arabidopsis seedlings. At equal growth rate, root:shoot ratio was up to three times higher and nitrogen productivity up to 20% higher for organic than inorganic N, which both are factors that may contribute to higher NUE in crop production.

Biodiversity, productivity, and the spatial insurance hypothesis revisited.

Accelerating rates of biodiversity loss have led ecologists to explore the effects of species richness on ecosystem functioning and the flow of ecosystem services. One explanation of the relationship between biodiversity and ecosystem functioning lies in the spatial insurance hypothesis, which centers on the idea that productivity and stability increase with biodiversity in a temporally varying, spatially heterogeneous environment. However, there has been little work on the impact of dispersal where environmental risks are more or less spatially correlated, or where dispersal rates are variable. In this paper, we extend the original Loreau model to consider stochastic temporal variation in resource availability, which we refer to as "environmental risk", and heterogeneity in species dispersal rates. We find that asynchronies across communities and species provide community-level stabilizing effects on productivity, despite varying levels of species richness. Although intermediate dispersal rates play a role in mitigating risk, they are less effective in insuring productivity against global (metacommunity-level) than local (individual community-level) risks. These results are particularly interesting given the emergence of global sources of risk such as climate change or the closer integration of world markets. Our results offer deeper insights into the Loreau model and new perspectives on the effectiveness of spatial insurance in the face of environmental risks.

Microbial community dynamics alleviate stoichiometric constraints during litter decay.

Under the current paradigm, organic matter decomposition and nutrient cycling rates are a function of the imbalance between substrate and microbial biomass stoichiometry. Challenging this view, we demonstrate that in an individual-based model, microbial community dynamics alter relative C and N limitation during litter decomposition, leading to a system behaviour not predictable from stoichiometric theory alone. Rather, the dynamics of interacting functional groups lead to an adaptation at the community level, which accelerates nitrogen recycling in litter with high initial C : N ratios and thus alleviates microbial N limitation. This mechanism allows microbial decomposers to overcome large imbalances between resource and biomass stoichiometry without the need to decrease carbon use efficiency (CUE), which is in contrast to predictions of traditional stoichiometric mass balance equations. We conclude that identifying and implementing microbial community-driven mechanisms in biogeochemical models are necessary for accurately predicting terrestrial C fluxes in response to changing environmental conditions.