Computational discovery of fast interstitial oxygen conductors.

New highly oxygen-active materials may enhance many energy-related technologies by enabling efficient oxygen-ion transport at lower temperatures, for example, below ~400 °C. Interstitial oxygen conductors have the potential to realize such performance but have received far less attention than vacancy-mediated conductors. Here we combine physically motivated structure and property descriptors, ab initio simulations and experiments to demonstrate an approach to discover new fast interstitial oxygen conductors. Multiple new families were found, which adopt completely different structures from known oxygen conductors. From these families, we synthesized and studied oxygen kinetics in La4Mn5Si4O22+δ, a representative member of the perrierite/chevkinite family. We found that La4Mn5Si4O22+δ has higher oxygen-ion conductivity than the widely used yttria-stabilized ZrO2, and among the highest surface oxygen exchange rates at the intermediate temperature of known materials. The fast oxygen kinetics is the result of simultaneously active interstitial and interstitialcy diffusion pathways. We propose that the essential features for forming an effective interstitial oxygen conductor are the availability of electrons and structural flexibility, enabling a sufficient accessible volume. This work provides a powerful approach for understanding and discovering new interstitial oxygen conductors.

Fixed-duration ibrutinib plus venetoclax for first-line treatment of CLL: primary analysis of the CAPTIVATE FD cohort.

CAPTIVATE (NCT02910583) is an international phase 2 study in patients aged ≤70 years with previously untreated chronic lymphocytic leukemia (CLL). Results from the cohort investigating fixed-duration (FD) treatment with ibrutinib plus venetoclax are reported. Patients received 3 cycles of ibrutinib lead-in then 12 cycles of ibrutinib plus venetoclax (oral ibrutinib [420 mg/d]; oral venetoclax [5-week ramp-up to 400 mg/d]). The primary endpoint was complete response (CR) rate. Hypothesis testing was performed for patients without del(17p) with prespecified analyses in all treated patients. Secondary endpoints included undetectable minimal residual disease (uMRD) rates, progression-free survival (PFS), overall survival (OS), and safety. Of the 159 patients enrolled and treated, 136 were without del(17p). The median time on study was 27.9 months, and 92% of patients completed all planned treatment. The primary endpoint was met, with a CR rate of 56% (95% confidence interval [CI], 48-64) in patients without del(17p), significantly higher than the prespecified 37% minimum rate (P < .0001). In the all-treated population, CR rate was 55% (95% CI, 48-63); best uMRD rates were 77% (peripheral blood [PB]) and 60% (bone marrow [BM]); 24-month PFS and OS rates were 95% and 98%, respectively. At baseline, 21% of patients were in the high tumor burden category for tumor lysis syndrome (TLS) risk; after ibrutinib lead-in, only 1% remained in this category. The most common grade ≥3 adverse events (AEs) were neutropenia (33%) and hypertension (6%). First-line ibrutinib plus venetoclax represents the first all-oral, once-daily, chemotherapy-free FD regimen for patients with CLL. FD ibrutinib plus venetoclax achieved deep, durable responses and promising PFS, including in patients with high-risk features.

Utilization and survival outcomes of neoadjuvant chemotherapy for early-stage gastric cancer.

BACKGROUND AND OBJECTIVES: Given increased utilization of neoadjuvant therapy (NAT) for gastric adenocarcinoma, practice patterns deviating from standard of care (upfront resection) remain unknown. We sought to identify factors associated with NAT use and survival outcomes among early-stage gastric cancers. METHODS: The National Cancer Database identified patients with early-stage (T1N0M0) gastric cancer (2010-2020). Multivariable logistic regression assessed characteristics associated with NAT utilization compared to upfront surgery. After 1:1 propensity score matching, Kaplan-Meier methods and Cox regression assessed overall survival (OS). RESULTS: Of 6452 patients with early-stage gastric cancer, 626 (9.7%) received NAT. Patients who received NAT were more likely treated at community hospitals, had moderate to poorly differentiated disease, and tumors located in the cardia (all p < 0.05). After propensity score matching, 1,248 patients remained. Median OS for NAT was 37.1 months (IQR 20.2-64.0) versus 45.6 months (IQR 22.5-72.8) for resection (p < 0.001). Treatment with NAT remained independently predictive of worse OS on Cox regression (hazard ratio 1.19; 95% confidence interval 1.05-1.34). CONCLUSIONS: Although patients who received NAT had more aggressive prognostic features, NAT was associated with worse OS despite accounting for this selection bias. These results highlight the importance of adhering to guidelines, regardless of differing disease characteristics, which has significant implications on outcomes.

Time to next treatment in patients with chronic lymphocytic leukemia initiating first-line ibrutinib or acalabrutinib.

Aim: To investigate real-world time to next treatment in patients with chronic lymphocytic leukemia initiating first-line (1L) ibrutinib or acalabrutinib. Materials & methods: US specialty pharmacy electronic medical records (21/11/2018-30/4/2022) were used; patients initiated 1L on/after 21/11/2019 (acalabrutinib approval). Results: Among 710 patients receiving ibrutinib, 5.9% initiated next treatment (mean time to initiation = 9.2 months); among 373 patients receiving acalabrutinib, 7.5% initiated next treatment (mean time to initiation = 5.9 months). Adjusting for baseline characteristics, acalabrutinib-treated patients were 89% more likely to initiate next treatment (hazard ratio = 1.89; p = 0.016). Conclusion: This study addresses a need for real-world comparative effectiveness between 1L ibrutinib and acalabrutinib and shows that next treatment (a clinically meaningful measure for real-world progression) occurred less frequently with 1L ibrutinib.

Ibrutinib and acalabrutinib are oral medications taken once-daily and twice-daily, respectively. They are recommended as initial treatment for chronic lymphocytic leukemia (CLL). The goal of this study was to compare the efficacy of these treatments as initial treatment for CLL. To meet this goal, real-world US specialty pharmacy electronic medical records between 11/21/2018­4/30/2022 were used. Patients treated with ibrutinib or acalabrutinib as initial treatment for CLL were studied. Treatment had to be started on or after the date of acalabrutinib approval for CLL (11/21/2019). Time to next treatment was used to estimate real-world disease progression. It was defined as the time from the initiation of initial treatment with ibrutinib or acalabrutinib to the initiation of a next treatment. Study results showed that patients were observed for a median of up to 1.5 years. Over this period, next treatment was more likely for acalabrutinib (7.5%) compared with ibrutinib (5.9%). After adjusting for differences in patient characteristics, next treatment was 89% more likely with acalabrutinib than ibrutinib. This study addresses a need to compare the effectiveness of initial treatment with ibrutinib and acalabrutinib in the real-world. It helps better contextualize results from clinical trial data and shows that next treatment occurred less frequently with ibrutinib.

Electronic Structure-Based Descriptors for Oxide Properties and Functions.

ConspectusThe transition from fossil fuels to renewable energy requires the development of efficient and cost-effective energy storage technologies. A promising way forward is to harness the energy of intermittent renewable sources, such as solar and wind, to perform (electro)catalytic reactions to generate fuels, thus storing energy in the form of chemical bonds. However, current catalysts rely on the use of expensive, rare, or geographically localized elements, such as platinum. Widespread adoption of new (electro)catalytic technologies hinges on the discovery and development of materials containing earth-abundant elements, which can efficiently catalyze an array of (electro)chemical reactions.In the context of catalysis, descriptors provide correlations between fundamental physical properties, such as the electronic structure, and the resulting catalytic activity. The use of easily accessible descriptors has proven to be a powerful method to advance and accelerate discovery and design of new catalyst materials. The position of the oxygen electronic 2p band center has been proposed to capture the basic physical properties of oxides, including oxygen vacancy formation energy, diffusion barrier of oxygen ions, and work function. Moreover, the adsorption strength of relevant reaction intermediates at the surface of oxides can be strongly correlated with the energy of the oxygen 2p states, which affects the catalytic activity of reactions, such as oxygen electrocatalysis, and oxidative dehydrogenation of organic molecules. Such descriptors for catalytic activity can be used to predict the activity of new catalysts and understand trends and behavior among different catalysts.In this Account, we discuss how the energy of the oxygen 2p states can be used as a descriptor for oxide bulk and surface chemical properties. We show how the oxide redox properties vary linearly with the position of the oxygen 2p band center with respect to the Fermi level, and we discuss how this descriptor can be expanded across different materials and structural families, including possible generalizations to compounds outside oxides. We highlight the power of the oxygen 2p band center to predict the catalytic activity of oxides. We conclude with an outlook examining under which conditions this descriptor can be applied to predict oxide properties and possible opportunities for further refining and accelerating property predictions of oxides by leveraging material databases and machine learning.

Allogeneic transplant following CAR T-cell therapy for large B-cell lymphoma.

Allogeneic hematopoietic cell transplantation (alloHCT) can potentially salvage large B-cell lymphoma (LBCL) patients experiencing treatment failure after chimeric antigen receptor T-cell therapy (CAR T). Nonetheless, data on the efficacy and toxicities of alloHCT after receipt of CAR T are limited. We report a multicenter retrospective study assessing the safety, toxicities, and outcomes of alloHCT in LBCL patients following CAR T failure. Eighty-eight patients with relapsed, refractory LBCL received an alloHCT following anti-CD19 CAR T failure. The median number of lines of therapy between CAR T infusion and alloHCT was one (range, 0-7). Low intensity conditioning was used in 77% (n=68) and peripheral blood was the most common graft source (86%, n=76). The most common donor types were matched unrelated donor (39%), followed by haploidentical (30%) and matched related donor (26%). Median follow-up of survivors was 15 months (range, 1-72). One-year overall survival, progression-free survival, and graft-versus-host disease-free relapse-free survival were 59%, 45%, and 39% respectively. One-year non-relapse mortality and progression/relapse were 22% and 33% respectively. On multivariate analysis, <2 lines of intervening therapy between CAR T and alloHCT and complete response at time of alloHCT were associated with better outcomes. In conclusion, alloHCT after CAR T failure can provide durable remissions in a subset of patients.

Deep Learning Approach for High-accuracy Electron Counting of Monolithic Active Pixel Sensor-type Direct Electron Detectors at Increased Electron Dose.

Electron counting can be performed algorithmically for monolithic active pixel sensor direct electron detectors to eliminate readout noise and Landau noise arising from the variability in the amount of deposited energy for each electron. Errors in existing counting algorithms include mistakenly counting a multielectron strike as a single electron event, and inaccurately locating the incident position of the electron due to lateral spread of deposited energy and dark noise. Here, we report a supervised deep learning (DL) approach based on Faster region-based convolutional neural network (R-CNN) to recognize single electron events at varying electron doses and voltages. The DL approach shows high accuracy according to the near-ideal modulation transfer function (MTF) and detector quantum efficiency for sparse images. It predicts, on average, 0.47 pixel deviation from the incident positions for 200 kV electrons versus 0.59 pixel using the conventional counting method. The DL approach also shows better robustness against coincidence loss as the electron dose increases, maintaining the MTF at half Nyquist frequency above 0.83 as the electron density increases to 0.06 e-/pixel. Thus, the DL model extends the advantages of counting analysis to higher dose rates than conventional methods.

Outcomes of COVID-19 in patients with CLL: a multicenter international experience.

Given advanced age, comorbidities, and immune dysfunction, chronic lymphocytic leukemia (CLL) patients may be at particularly high risk of infection and poor outcomes related to coronavirus disease 2019 (COVID-19). Robust analysis of outcomes for CLL patients, particularly examining effects of baseline characteristics and CLL-directed therapy, is critical to optimally manage CLL patients through this evolving pandemic. CLL patients diagnosed with symptomatic COVID-19 across 43 international centers (n = 198) were included. Hospital admission occurred in 90%. Median age at COVID-19 diagnosis was 70.5 years. Median Cumulative Illness Rating Scale score was 8 (range, 4-32). Thirty-nine percent were treatment naive ("watch and wait"), while 61% had received ≥1 CLL-directed therapy (median, 2; range, 1-8). Ninety patients (45%) were receiving active CLL therapy at COVID-19 diagnosis, most commonly Bruton tyrosine kinase inhibitors (BTKi's; n = 68/90 [76%]). At a median follow-up of 16 days, the overall case fatality rate was 33%, though 25% remain admitted. Watch-and-wait and treated cohorts had similar rates of admission (89% vs 90%), intensive care unit admission (35% vs 36%), intubation (33% vs 25%), and mortality (37% vs 32%). CLL-directed treatment with BTKi's at COVID-19 diagnosis did not impact survival (case fatality rate, 34% vs 35%), though the BTKi was held during the COVID-19 course for most patients. These data suggest that the subgroup of CLL patients admitted with COVID-19, regardless of disease phase or treatment status, are at high risk of death. Future epidemiologic studies are needed to assess severe acute respiratory syndrome coronavirus 2 infection risk, these data should be validated independently, and randomized studies of BTKi's in COVID-19 are needed to provide definitive evidence of benefit.

Machine learning for impurity charge-state transition levels in semiconductors from elemental properties using multi-fidelity datasets.

Quantifying charge-state transition energy levels of impurities in semiconductors is critical to understanding and engineering their optoelectronic properties for applications ranging from solar photovoltaics to infrared lasers. While these transition levels can be measured and calculated accurately, such efforts are time-consuming and more rapid prediction methods would be beneficial. Here, we significantly reduce the time typically required to predict impurity transition levels using multi-fidelity datasets and a machine learning approach employing features based on elemental properties and impurity positions. We use transition levels obtained from low-fidelity (i.e., local-density approximation or generalized gradient approximation) density functional theory (DFT) calculations, corrected using a recently proposed modified band alignment scheme, which well-approximates transition levels from high-fidelity DFT (i.e., hybrid HSE06). The model fit to the large multi-fidelity database shows improved accuracy compared to the models trained on the more limited high-fidelity values. Crucially, in our approach, when using the multi-fidelity data, high-fidelity values are not required for model training, significantly reducing the computational cost required for training the model. Our machine learning model of transition levels has a root mean squared (mean absolute) error of 0.36 (0.27) eV vs high-fidelity hybrid functional values when averaged over 14 semiconductor systems from the II-VI and III-V families. As a guide for use on other systems, we assessed the model on simulated data to show the expected accuracy level as a function of bandgap for new materials of interest. Finally, we use the model to predict a complete space of impurity charge-state transition levels in all zinc blende III-V and II-VI systems.

Equal access to care and nurse navigation leads to equitable outcomes for minorities with aggressive large B-cell lymphoma.

BACKGROUND: Aggressive large B-cell lymphomas (LBCLs) are curable, but previous studies have shown inferior outcomes in minorities. Nurse navigation programs can improve patient outcomes by providing patient support. This study presents the outcomes of White and minority patients with aggressive LBCL at an institution with an active nurse navigation program. METHODS: The authors prospectively collected baseline characteristics, treatment regimens, and outcome data for patients with aggressive LBCL. Navigation encounters were characterized as low or high intensity. Overall survival (OS) and progression-free survival (PFS) were calculated with Kaplan-Meier methods. Baseline characteristics were compared with Fisher exact tests. RESULTS: Two hundred four consecutive patients (47 minority patients and 157 White patients) were included. Results were presented as minorities versus Whites. There were no differences in prognostic scores (Revised International Prognostic Index score of 3-5, 43% vs 47%; P = .50), frontline chemotherapy (98% vs 96%; P = .68), or the incidence of relapsed/refractory disease (40% vs 38%; P = .74). For relapsed/refractory LBCL, similar proportions of patients underwent hematopoietic stem cell transplantation (32% vs 29%; P > .99) or chimeric antigen receptor T-cell therapy (16% vs 19%; P > .99). Enrollment in clinical trials was comparable (17% vs 14%; P = .64). More than 85% received nurse navigation, but minorities had higher intensity navigation encounters (42% vs 21%; P = .01). The 2-year OS rates were 81% and 76% for minorities and Whites, respectively (P = .27); the 2-year PFS rates were 62% and 65%, respectively (P = .78). CONCLUSIONS: This study shows similar survival between Whites and minorities with aggressive LBCL, which was likely due to equal access to guideline-concordant therapy. Minorities received higher intensity navigation encounters, which may have helped them to overcome socioeconomic disadvantages.

Graph network based deep learning of bandgaps.

Recent machine learning models for bandgap prediction that explicitly encode the structure information to the model feature set significantly improve the model accuracy compared to both traditional machine learning and non-graph-based deep learning methods. The ongoing rapid growth of open-access bandgap databases can benefit such model construction not only by expanding their domain of applicability but also by requiring constant updating of the model. Here, we build a new state-of-the-art multi-fidelity graph network model for bandgap prediction of crystalline compounds from a large bandgap database of experimental and density functional theory (DFT) computed bandgaps with over 806 600 entries (1500 experimental, 775 700 low-fidelity DFT, and 29 400 high-fidelity DFT). The model predicts bandgaps with a 0.23 eV mean absolute error in cross validation for high-fidelity data, and including the mixed data from all different fidelities improves the prediction of the high-fidelity data. The prediction error is smaller for high-symmetry crystals than for low symmetry crystals. Our data are published through a new cloud-based computing environment, called the "Foundry," which supports easy creation and revision of standardized data structures and will enable cloud accessible containerized models, allowing for continuous model development and data accumulation in the future.

Cost saving, patient centered algorithm for progenitor cell mobilization for autologous hematopoietic cell transplantation.

Administration of plerixafor with granulocyte-colony stimulating factor (G-CSF) mobilizes CD34+ cells much more effectively than G-CSF alone, but cost generally limits plerixafor use to patients at high risk of insufficient CD34+ cell collection based on low peripheral blood (PB) CD34+ counts following 4 days of G-CSF. We analyzed costs associated with administering plerixafor to patients with higher day 4 CD34+ cell counts to decrease apheresis days and explored the use of a fixed split dose of plerixafor instead of weight-based dosing. We analyzed 235 patients with plasma cell disorders or non-Hodgkin's lymphoma who underwent progenitor cell mobilization and autologous hematopoietic cell transplantation (AHCT) between March 2014 and December 2017. Two hundred ten (89%) received G-CSF plus Plerixafor and 25 (11%) received G-CSF alone. Overall, 180 patients (77%) collected in 1 day, 53 (22%) in 2 days and 2 (1%) in 3 days. Based on our data, we present a probabilistic algorithm to identify patients likely to require more than one day of collection using G-CSF alone. CD34+ cell yield, ANC and platelet recovery were not significantly different between fixed and standard dose plerixafor. Plerixafor enabled collection in 1 day and with estimated savings of $5000, compared to patients who did not receive plerixafor and required collection for three days. While collection and processing costs and patient populations vary among institutions, our results suggest re-evaluation of current algorithms.

The efficacy and safety of venetoclax therapy in elderly patients with relapsed, refractory chronic lymphocytic leukaemia.

Elderly chronic lymphocytic leukaemia (CLL) patients treated outside of trials have notably greater toxicity with the Bruton's tyrosine kinase inhibitor ibrutinib compared to younger patients. It is not known whether the same holds true for the B-cell lymphoma 2 inhibitor venetoclax. We provide a comprehensive analysis of key safety measures and efficacy in 342 patients comparing age categories ≥75 and <75 years treated in the relapsed, refractory non-trial setting. We demonstrate that venetoclax has equivalent efficacy and safety in relapsed/refractory CLL patients who are elderly, the majority of whom are previous ibrutinib-exposed and therefore may otherwise have few clear therapeutic options.

Efficacy of quality improvement and patient safety workshops for students: a pilot study.

BACKGROUND: While the Association of American Medical Colleges encourages medical schools to incorporate quality improvement and patient safety (QI/PS) into their curriculum, medical students continue to have limited QI/PS exposure. To prepare medical students for careers that involve QI/PS, the Institute for Healthcare Improvement chapter at an allopathic medical school and school of allied health professions initiated self-directed learning by offering student-led workshops to equip learners with skills to improve the quality and safety of healthcare processes. METHODS: In this prospective cohort study, workshops were hosted for medical students between 2015 and 2018 on five QI/PS topics: Process Mapping, Root-Cause Analysis (RCA), Plan-Do-Study-Act (PDSA) Cycles, Evidence Based Medicine (EBM), and Patient Handoffs. Each workshop included a hands-on component to engage learners in practical applications of QI/PS skills in their careers. Change in knowledge, attitudes, and behaviors was assessed via pre- and post-surveys using 5-point Likert scales, and analyzed using either the McNemar test or non-parametric Wilcoxon signed-rank test. Surveys also gathered qualitative feedback regarding strengths, future areas for improvement, and reasons for attending the workshops. RESULTS: Data was collected from 88.5% of learners (n = 185/209); 19.5% of learners reported prior formal instruction in these topics. Statistically significant improvements in learners' confidence were observed for each workshop. Additionally, after attending workshops, learners felt comfortable teaching the learned QI/PS skill to colleagues (mean pre/post difference 1.96, p < 0.0001, n = 139) and were more likely to pursue QI/PS projects in their careers (mean pre/post difference 0.45, p < 0.0001, n = 139). Lastly, learners demonstrated a statistically significant increase in knowledge in four out of five skills workshop topics. CONCLUSION: Few medical students have formal instruction in QI/PS tools. This pilot study highlights advantages of incorporating an innovative, student-directed modified 'flipped classroom' methodology, with a focus on active experiential learning and minimal didactic instruction.

Massive Vacancy Concentration Yields Strong Room-Temperature Ferromagnetism in Two-Dimensional ZnO.

Two-dimensional (2D) ZnO nanosheets with highly concentrated Zn vacancies (VZn) of up to approximately 33% were synthesized by ionic layer epitaxy at the water-toluene interface. This high cation vacancy concentration is unprecedented for ZnO and may provide unique opportunities to realize exotic properties not attainable in the conventional bulk form. After annealing, the nanosheets showed characteristic magnetic hysteresis with saturation magnetization of 57.2 emu/g at 5 K and 50.9 emu/g at room temperature. This value is 1 order of magnitude higher than other ZnO nanostructures and comparable to the conventional ferrimagnetic Fe3O4. Density functional theory calculations, with the support of experimental results, suggest that a high concentration of VZn (approximately one-third of the Zn sites) can form spontaneously during synthesis when stabilized by H ions, and the formation of VZn could be further facilitated by the presence of grain boundaries. It is essential to remove the H for the nanosheets to show ferromagnetism. The mechanisms identified for the origin of the high magnetism in ZnO nanosheets presents an intriguing example of a kinetically stabilized, non-equilibrium, highly defective 2D nanomaterial with a significantly enhanced physical property.

Higher Incidence of Hemorrhagic Cystitis Following Haploidentical Related Donor Transplantation Compared with Matched Related Donor Transplantation.

Hemorrhagic cystitis (HC) is a common and important complication of allogeneic hematopoietic cell transplantation (HCT). Reactivation of BK virus is its most common cause. The more intense immunosuppressive regimens administered to recipients of grafts from alternative donors have been reported to account for the increased susceptibility to HC in this population. This study compares patients undergoing HCT with either a haploidentical donor or a matched related donor, all of whom received identical immunosuppression with a post-transplantation cyclophosphamide-based regimen. The incidence of HC was significantly higher in the patients receiving a haploidentical graft (P = .01). The higher incidence of HC in haploidentical graft recipients is therefore directly related to the inherent immune deficiency that follows HLA-mismatched transplantation, independent of the intensity of pharmacologic immunosuppression. This finding carries significant clinical impact for the prevention and treatment of HC in haploidentical graft recipients.

Potential Impact of "Take the Volume Pledge" on Access and Outcomes for Gastrointestinal Cancer Surgery.

OBJECTIVE: To quantify the number of US hospitals that would meet "Take the Volume Pledge" (TVP) volume thresholds and compare outcomes at hospitals meeting and not meeting TVP thresholds. SUMMARY BACKGROUND DATA: TVP aims to regionalize complex cancer resections to hospitals meeting established annual average volume thresholds. There is little data describing the potential impact on patient access if this initiative were broadly implemented or the relationship between these volume thresholds and quality of oncologic care. METHODS: Hospitals in the National Cancer Database (2006-2012) performing esophagectomy (n = 968), proctectomy (n = 1250), or pancreatectomy (n = 1068) were categorized based on frequency meeting TVP thresholds: always low volume (LV); low annual average and intermittently low volume (ILV); high annual average and intermittently high volume (IHV); always high volume (HV). Multivariable generalized estimating equations were used to evaluate the association between hospital TVP category, oncologic care processes, and perioperative outcomes. RESULTS: Few hospitals met annual TVP thresholds (HV or IHV)-esophagectomy 1.6%; proctectomy 19.7%; pancreatectomy 6.6%. The majority of esophagectomy (77.8%) and pancreatectomy (53.4%) and 48.1% of proctectomy patients received care at hospitals not meeting annual TVP thresholds (LV or ILV). While performance for all three procedures was generally better at ILV, IHV, and HV hospitals relative to LV hospitals, there were few differences (none of which were consistent) when comparing ILV, IHV, and HV hospitals to each other. CONCLUSIONS AND RELEVANCE: Few hospitals would meet TVP volume thresholds for complex cancer resections with little difference in outcomes between ILV, IHV, and HV hospitals. While a policy to regionalize complex surgical care may have merit, it could also compromise patient autonomy and limit access to care if patients are unable or unwilling to travel.

Targeting both tumour-associated CXCR2+ neutrophils and CCR2+ macrophages disrupts myeloid recruitment and improves chemotherapeutic responses in pancreatic ductal adenocarcinoma.

OBJECTIVE: Chemokine pathways are co-opted by pancreatic adenocarcinoma (PDAC) to facilitate myeloid cell recruitment from the bone marrow to establish an immunosuppressive tumour microenvironment (TME). Targeting tumour-associated CXCR2+neutrophils (TAN) or tumour-associated CCR2+ macrophages (TAM) alone improves antitumour immunity in preclinical models. However, a compensatory influx of an alternative myeloid subset may result in a persistent immunosuppressive TME and promote therapeutic resistance. Here, we show CCR2 and CXCR2 combined blockade reduces total tumour-infiltrating myeloids, promoting a more robust antitumour immune response in PDAC compared with either strategy alone. METHODS: Blood, bone marrow and tumours were analysed from PDAC patients and controls. Treatment response and correlative studies were performed in mice with established orthotopic PDAC tumours treated with a small molecule CCR2 inhibitor (CCR2i) and CXCR2 inhibitor (CXCR2i), alone and in combination with chemotherapy. RESULTS: A systemic increase in CXCR2+ TAN correlates with poor prognosis in PDAC, and patients receiving CCR2i showed increased tumour-infiltrating CXCR2+ TAN following treatment. In an orthotopic PDAC model, CXCR2 blockade prevented neutrophil mobilisation from the circulation and augmented chemotherapeutic efficacy. However, depletion of either CXCR2+ TAN or CCR2+ TAM resulted in a compensatory response of the alternative myeloid subset, recapitulating human disease. This was overcome by combined CCR2i and CXCR2i, which augmented antitumour immunity and improved response to FOLFIRINOX chemotherapy. CONCLUSION: Dual targeting of CCR2+ TAM and CXCR2+ TAN improves antitumour immunity and chemotherapeutic response in PDAC compared with either strategy alone.

Linking tree genetics and stream consumers: isotopic tracers elucidate controls on carbon and nitrogen assimilation.

Leaf litter provides an important nutrient subsidy to headwater streams, but little is known about how tree genetics influence energy pathways from litter to higher trophic levels. Despite the charge to quantify carbon (C) and nitrogen (N) pathways from decomposing litter, the relationship between litter decomposition and aquatic consumers remains unresolved. We measured litter preference (attachments to litter), C and N assimilation rates, and growth rates of a shredding caddisfly (Hesperophylax magnus, Limnephilidae) in response to leaf litter of different chemical and physical phenotypes using Populus cross types (P. fremontii, P. angustifolia, and F1 hybrids) and genotypes within P. angustifolia. We combined laboratory mesocosm studies using litter from a common garden with a field study using doubly labeled litter (13 C and 15 N) grown in a greenhouse and incubated in Oak Creek, Arizona, USA. We found that, in the lab, shredders initially chose relatively labile (low lignin and condensed tannin concentrations, rapidly decomposing) cross type litter, but preference changed within 4 d to relatively recalcitrant (high lignin and condensed tannin concentrations, slowly decomposing) litter types. Additionally, in the lab, shredder growth rates were higher on relatively recalcitrant compared to labile cross type litter. Over the course of a three-week field experiment, shredders also assimilated more C and N from relatively recalcitrant compared to labile cross type litter. Finally, among P. angustifolia genotypes, N assimilation by shredders was positively related to litter lignin and C:N, but negatively related to condensed tannins and decomposition rate. C assimilation was likewise positively related to litter C:N, and also to litter %N. C assimilation was not associated with condensed tannins or lignin. Collectively, these findings suggest that relatively recalcitrant litter of Populus cross types provides more nutritional benefit, in terms of N fluxes and growth, than labile litter, but among P. angustifolia genotypes the specific trait of litter recalcitrance (lignin or tannins) determines effects on C or N assimilation. As shredders provide nutrients and energy to higher trophic levels, the influence of these genetically based plant decomposition pathways on shredder preference and performance may affect community and food web structure.