Larger Tumor Size and Elevated Serum Chromogranin A Levels Predict Metastatic Disease on DOTATATE Imaging in Patients with Gastroenteropancreatic Neuroendocrine Tumors.

PURPOSE: DOTATATE PET/CT (DOTATATE) is superior to conventional imaging in detecting metastasis for gastroenteropancreatic neuroendocrine tumors (GEP-NETs). However, limited availability, high-cost, and additive radiation exposure necessitate guidelines for its use. This study seeks to investigate the relationship between clinical characteristics and metastasis on DOTATATE. METHODS: This was a retrospective analysis of 815 patients who underwent DOTATATE at UCLA from 2014 to 2022. After applying inclusion and exclusion criteria, the study cohort consisted of 163 patients with pathologically diagnosed GEP-NETs, who either underwent primary tumor resection within 1-year prior, or had not undergone resection at the time of DOTATATE imaging. The presence of metastasis was determined using DOTATATE. Fisher's exact test, chi-squared test, and Mann-Whitney test were conducted to compare intergroup difference. Multivariate analysis was performed to identify clinical characteristics associated with metastasis on DOTATATE. RESULTS: Of patients with GEP-NETs, 40.5% (n = 66) were diagnosed with metastases by using DOTATATE. Those with metastatic disease were more likely to exhibit a larger primary tumor size (median 3.4 vs. 1.2, cm, P < 0.001), elevated serum chromogranin A level (CgA, median 208 vs. 97, mg/ml, P = 0.005), and higher tumor grade (P < 0.001). Primary tumor size ≥2 cm and serum CgA level ≥150 ng/mL for metastatic disease had a sensitivity and specificity of 64% and 89%, and 72% and 59%, respectively. Multivariate analysis demonstrated that primary tumor size (≥2/<2, cm, odds ratio [OR] 47.90, P < 0.001), tumor functionality (functional/nonfunctional, adjusted OR 10.17 P = 0.008), serum CgA level (≥150/<150, ng/ml, OR 6.25, P = 0.005), and tumor grade G2 (G2/G1, OR 9.6, P < 0.001) were independently associated with metastases on DOTATATE. CONCLUSIONS: Among patients with GEP-NETs, primary tumor size ≥2 cm, serum CgA level ≥150 ng/mL, and tumor grade G2 are associated with an increased risk of metastases on DOTATATE, and these predictors may be helpful to identify patients where DOTATATE is indicated for complete staging.

Clinical and pathological factors associated with survival in patients with pancreatic cancer who receive adjuvant therapy after neoadjuvant therapy: A retrospective multi-institutional analysis.

BACKGROUND: Neoadjuvant therapy is being increasingly used for patients with pancreatic cancer. The role of adjuvant therapy in these patients is unclear. The purpose of this study was to identify clinical and pathologic characteristics that are associated with longer overall survival in patients with pancreatic cancer who receive adjuvant therapy after neoadjuvant therapy. METHODS: This study was conducted using multi-institutional data. All patients underwent surgery after at least 1 cycle of neoadjuvant therapy for pancreatic cancer. Patients who died within 3 months after surgery and were known to have distant metastasis or macroscopic residual disease were excluded. Mann-Whitney U test, χ2 analysis, Kaplan-Meier plot, and univariate and multivariate Cox regression analysis were performed as statistical analyses. RESULTS: In the present study, 529 patients with resected pancreatic cancer after neoadjuvant therapy were reviewed. For neoadjuvant therapy, 177 (33.5%) patients received neoadjuvant chemotherapy, and 352 (66.5%) patients received neoadjuvant chemoradiotherapy. The median duration of neoadjuvant therapy was 7.0 months (interquartile range, 5.0-8.7). Patients were followed for a median of 23.0 months after surgery. Adjuvant therapy was administered to 297 (56.1%) patients and was not associated with longer overall survival for the entire cohort (24 vs 22 months, P = .31). Interaction analysis showed that adjuvant therapy was associated with longer overall survival in patients who received less than 4 months neoadjuvant therapy (hazard ratio 0.40; 95% confidence interval 0.17-0.95; P = .03) or who had microscopic margin positive surgical resections (hazard ratio 0.56; 95% confidence interval 0.33-0.93; P = .03). CONCLUSION: In this retrospective study, there was a survival benefit associated with adjuvant therapy for patients who received less than 4 months of neoadjuvant therapy or had microscopic positive margins.

Association of Inpatient Palliative Care Consultation with Clinical and Financial Outcomes for Pancreatic Cancer.

BACKGROUND: Palliative care consultation (PCC) has been shown to improve quality of life and reduce costs for various chronic life-threatening diseases. Despite PCC incorporation into modern pancreatic cancer care guidelines, limited data regarding its specific utilization and impact on resource use is available. METHODS: The 2016-2020 Nationwide Readmissions Database was used to identify all adult hospitalizations entailing pancreatic cancer. Only patients with at least one readmission within 90 days were included to account for uncaptured out-of-hospital mortality. Multivariable regression models were used to ascertain the relationship between inpatient PCC during initial hospitalization and index as well as cumulative costs, overall length of stay (LOS), readmission rate, and number of repeat hospitalizations. RESULTS: Of an estimated 175,805 patients with pancreatic cancer, 11.1% had inpatient PCC during the index admission. PCC utilization significantly increased from 10.5% in 2016 to 11.6% in 2020 (nptrend < 0.001). After adjustment, PCC was associated with reduced index hospitalization costs [ß: - $1100; 95% confidence interval (CI) - 1500, - 800; P < 0.001] and cumulative 90-day costs (ß: - $11,700; 95% CI - 12,700, - 10,000; P < 0.001). PCC was associated with longer index LOS (ß: + 1.12 days, 95% CI 0.92-1.31, P < 0.001) but significantly reduced cumulative LOS (ß: - 3.16 days; 95% CI - 3.67, - 2.65; P < 0.001). Finally, PCC was linked with decreased odds of 30-day nonelective readmission (AOR: 0.48, 95% CI 0.45-0.50, P < 0.001). DISCUSSION: PCC was associated with decreased costs, readmission rates, and number of hospitalizations among patients with pancreatic cancer. Directed strategies to increase utilization and reduce barriers to consultation should be implemented to encourage practitioners to maximize inpatient PCC referral rates.

Machine Learning Based Prediction of Postoperative Pancreatic Fistula Following Pancreaticoduodenectomy.

OBJECTIVE: To develop a novel machine learning (ML) model to predict clinically relevant postoperative pancreatic fistula (CR-POPF) following pancreaticoduodenectomy (PD). SUMMARY BACKGROUND DATA: Accurate prognostication of CR-POPF may allow for risk stratification and adaptive treatment strategies for potential PD candidates. However, antecedent models, such as the modified Fistula Risk Score (mFRS), are limited by poor discrimination and calibration. METHODS: All records entailing PD within the 2014-2018 ACS NSQIP were identified. Additionally, patients undergoing PD at our institution between 2013 and 2021 were queried from our local data repository. An eXtreme Gradient Boosting (XGBoost) model was developed to estimate the risk of CR-POPF using data from the ACS NSQIP and evaluated using institutional data. Model discrimination was estimated using the area under the receiver operating characteristic (AUROC) and precision recall curve (AUPRC). RESULTS: Overall, 12,281 and 445 patients undergoing PD were identified within the 2014-2018 ACS NSQIP and our institutional registry, respectively. Application of the XGBoost and mFRS scores to the internal validation dataset revealed that the former model had significantly greater AUROC (0.72 vs. 0.68, P<0.001) and AUPRC (0.22 vs. 0.18, P<0.001). Within the external validation dataset, the XGBoost model remained superior to the mFRS with an AUROC of 0.79 (95% CI 0.74-0.84) versus 0.75 (95% CI 0.70-0.80, P<0.001). In addition, AUPRC was higher for the XGBoost model, compared to the mFRS. CONCLUSIONS: Our novel ML model consistently outperformed the previously validated mFRS within internal and external validation cohorts, thereby demonstrating its generalizability and utility for enhancing prediction of CR-POPF.

Dual antiplatelet management in the perioperative period: updated and expanded systematic review.

BACKGROUND: Antiplatelet agents are central in the management of vascular disease. The use of dual antiplatelet therapy (DAPT) for the management of thromboembolic complications must be weighed against bleeding risk in the perioperative setting. This balance is critical in patients undergoing cardiac or non-cardiac surgery. The management of patients on DAPT for any indication (including stents) is not clear and there is limited evidence to guide decision-making. This review summarizes current evidence since 2015 regarding the occurrence of major adverse events associated with continuing, suspending, or varying DAPT in the perioperative period. METHODS: A research librarian searched PubMed and Cochrane from November 30, 2015 to May 17, 2022, for relevant terms regarding adult patients on DAPT for any reason undergoing surgery, with a perioperative variation in DAPT strategy. Outcomes of interest included the occurrence of major adverse cardiac events, major adverse limb events, all-cause death, major bleeding, and reoperation. We considered withdrawal or discontinuation of DAPT as stopping either aspirin or a P2Y12 inhibitor or both agents; continuation of DAPT indicates that both drugs were given in the specified timeframe. RESULTS: Eighteen observational studies met the inclusion criteria. No RCTs were identified, and no studies were judged to be at low risk of bias. Twelve studies reported on CABG. Withholding DAPT therapy for more than 2 days was associated with less blood loss and a slight trend favoring less transfusion and surgical re-exploration. Among five observational CABG studies, there were no statistically significant differences in patient death across DAPT management strategies. Few studies reported cardiac outcomes. The remaining studies, which were about procedures other than exclusively CABG, demonstrated mixed findings with respect to DAPT strategy, bleeding, and ischemic outcomes. CONCLUSION: The evidence base on the benefits and risks of different perioperative DAPT strategies for patients with stents is extremely limited. The strongest signal, which was still judged as low certainty evidence, is that suspension of DAPT for greater than 2 days prior to CABG surgery is associated with less bleeding, transfusions, and re-explorations. Different DAPT strategies' association with other outcomes of interest, such as MACE, remains uncertain. SYSTEMATIC REVIEW REGISTRATION: A preregistered protocol for this review can be found on the PROSPERO International Prospective Register of systematic reviews ( http://www.crd.york.ac.uk/PROSPERO/ ; registration number: CRD42022371032).

MEK Inhibition Sensitizes Pancreatic Cancer to STING Agonism by Tumor Cell-intrinsic Amplification of Type I IFN Signaling.

PURPOSE: Stimulator of interferon genes (STING) agonists are currently in development for treatment of solid tumors, including pancreatic ductal adenocarcinoma (PDAC). Response rates to STING agonists alone have been promising yet modest, and combination therapies will likely be required to elicit their full potency. We sought to identify combination therapies and mechanisms that augment the tumor cell-intrinsic effect of therapeutically relevant STING agonists apart from their known effects on tumor immunity. EXPERIMENTAL DESIGN: We screened 430 kinase inhibitors to identify synergistic effectors of tumor cell death with diABZI, an intravenously administered and systemically available STING agonist. We deciphered the mechanisms of synergy with STING agonism that cause tumor cell death in vitro and tumor regression in vivo. RESULTS: We found that MEK inhibitors caused the greatest synergy with diABZI and that this effect was most pronounced in cells with high STING expression. MEK inhibition enhanced the ability of STING agonism to induce type I IFN-dependent cell death in vitro and tumor regression in vivo. We parsed NFκB-dependent and NFκB-independent mechanisms that mediate STING-driven type I IFN production and show that MEK signaling inhibits this effect by suppressing NFκB activation. CONCLUSIONS: Our results highlight the cytotoxic effects of STING agonism on PDAC cells that are independent of tumor immunity and that these therapeutic benefits of STING agonism can be synergistically enhanced by MEK inhibition.

Generation of liver metastases in a mouse model using ultrasound-guided intravenous injection.

Here, we present a protocol to generate a murine model of liver metastasis by directly injecting tumor cells into the portal vein under ultrasound guidance. We describe steps for animal and cell preparation and two techniques for injecting tumor cells. One technique is freehand, while the other technique is device-assisted using a 3D-printed prototype device. Finally, we describe tumor surveillance with bioluminescent imaging.

Racial disparities in surgical management and outcomes of acute limb ischemia in the United States.

BACKGROUND: Although significant racial disparities in the surgical management of lower extremity critical limb threatening ischemia have been previously reported, data on disparities in lower extremity acute limb ischemia are lacking. METHODS: The 2012-2018 National Inpatient Sample was queried for all adult hospitalizations for acute limb ischemia (N = 225,180). Hospital-specific observed-to-expected rates of major lower extremity amputation were tabulated. Multivariable logistic and linear models were developed to assess the impact of race on amputation and revascularization. RESULTS: Nonwhite race was associated with significantly increased odds of overall (adjusted odds ratio: 1.16, 95% confidence interval 1.06-1.28) and primary (adjusted odds ratio: 1.34, 95% confidence interval 1.17-1.53) major amputation, decreased odds of revascularization (adjusted odds ratio 0.79, 95% confidence interval 0.73-0.85), but decreased in-hospital mortality (adjusted odds ratio: 0.86, 95% confidence interval 0.74-0.99). The nonwhite group incurred increased adjusted index hospitalization costs (ß: +$4,810, 95% confidence interval 3,280-6,350), length of stay (ß: + 1.09 days, 95% confidence interval 0.70-1.48), and nonhome discharge (adjusted odds ratio: 1.15, 95% confidence interval 1.06-1.26). CONCLUSION: Significant racial disparities exist in the management of and outcomes of lower extremity acute limb ischemia despite correction for variations in hospital amputation practices and other relevant hospital and patient characteristics. Whether the etiology lies primarily in patient, institution, or healthcare provider-specific factors has not yet been determined. Further studies of race-based disparities in management and outcomes of acute limb ischemia are warranted to provide effective and equitable care to all.

Resident and elicited murine macrophages differ in expression of their glycomes and glycan-binding proteins.

The pleiotropic functions of macrophages in immune defense, tissue repair, and maintenance of tissue homeostasis are supported by the heterogeneity in macrophage sub-populations that differ both in ontogeny and polarization. Although glycans and glycan-binding proteins (GBPs) are integral to macrophage function and may contribute to macrophage diversity, little is known about the factors governing their expression. Here, we provide a resource for characterizing the N-/O-glycomes of various murine peritoneal macrophage sub-populations, demonstrating that glycosylation primarily reflects developmental origin and, to a lesser degree, cellular polarization. Furthermore, comparative analysis of GBP-coding genes in resident and elicited macrophages indicated that GBP expression is consistent with specialized macrophage functions and correlates with specific types of displayed glycans. An integrated, semi-quantitative approach was used to confirm distinct expression patterns of glycans and their binding proteins across different macrophages. The data suggest that regulation of glycan-protein complexes may be central to macrophage residence and recruitment.

Modulation of lymphocyte-mediated tissue repair by rational design of heterocyclic aryl hydrocarbon receptor agonists.

Aryl hydrocarbon receptor (AHR) is an essential regulator of gut immunity and a promising therapeutic target for inflammatory bowel disease (IBD). Current AHR agonists are inadequate for clinical translation due to low activity, inadequate pharmacokinetics, or toxicity. We synthesized a structurally diverse library and used integrated computational and experimental studies to discover mechanisms governing ligand-receptor interaction and to design potent drug leads PY109 and PY108, which display physiochemical drug-likeness properties, desirable pharmacokinetic profiles, and low toxicity. In a murine model of dextran sulfate sodium-induced colitis, orally administered compounds increase interleukin-22 (IL-22) production and accelerate mucosal healing by modulating mucosal adaptive and innate lymphoid cells. AHR and IL-22 pathway induction was confirmed using RNA sequencing and characterization of the lymphocyte protein-protein interaction network. Significant induction of IL-22 was also observed using human T cells from patients with IBD. Our findings support rationally designed AHR agonists for IBD therapy.

Ticagrelor or prasugrel vs. clopidogrel in combination with anticoagulation for treatment of acute coronary syndrome in patients with atrial fibrillation.

For patients with atrial fibrillation (AF) and acute coronary syndrome (ACS), it is often challenging to find the optimal balance between the risk for ischemic and hemorrhagic complication when using both antiplatelet therapy and oral anticoagulation (OAC) with vitamin K antagonist (VKA) or direct oral anticoagulants (DOACs). Current guidelines recommended: (I) double therapy with a P2Y12 inhibitor and dose adjusted VKA is reasonable post-stenting; (II) double therapy with clopidogrel and low-dose rivaroxaban (15 mg daily) may be reasonable post-stenting; (III) double therapy with a P2Y12 inhibitor and dabigatran 150 mg twice daily is reasonable post-stenting. In the AUGUSTUS trial, most patients were given clopidogrel as part a DAPT regimen, however prasugrel and ticagrelor use allowed albeit in a small percentage of the trial population, underestimating its effect. Ticagrelor and prasugrel are known to have a stronger antiplatelet effect compared to clopidogrel, however randomized studies have not been adequately powered to date allowing comparisons between ticagrelor, prasugrel and clopidogrel together in the setting of anticoagulation for the treatment of patients with ACS and AF. Careful consideration should be given to this scenario to avoid falling into the concept of sacrificing efficacy for safety.

Novel Treatment of Cryptococcal Meningitis via Neurapheresis Therapy.

Cryptococcal meningitis (CM) has emerged as the most common life-threatening fungal meningitis worldwide. Current management involves a sequential, longitudinal regimen of antifungals; despite a significant improvement in survival compared with uniform mortality without treatment, this drug paradigm has not led to a consistent cure. Neurapheresis therapy, extracorporeal filtration of yeasts from cerebrospinal fluid (CSF) in infected hosts, is presented here as a novel, one-time therapy for CM. In vitro filtration of CSF through this platform yielded a 5-log reduction in concentration of the yeast and a 1-log reduction in its polysaccharide antigen over 24 hours. Additionally, an analogous closed-loop system achieved 97% clearance of yeasts from the subarachnoid space in a rabbit model over 4-6 hours. This is the first publication demonstrating the direct ability to rapidly clear, both in vitro and in vivo, the otherwise slowly removed fungal pathogen that directly contributes to the morbidity and mortality seen in CM.

Prevalence, healthcare resource utilization and overall burden of fungal meningitis in the United States.

PURPOSE: Previous epidemiological and cost studies of fungal meningitis have largely focused on single pathogens, leading to a poor understanding of the disease in general. We studied the largest and most diverse group of fungal meningitis patients to date, over the longest follow-up period, to examine the broad impact on resource utilization within the United States. METHODOLOGY: The Truven Health Analytics MarketScan database was used to identify patients with a fungal meningitis diagnosis in the United States between 2000 and 2012. Patients with a primary diagnosis of cryptococcal, Coccidioides, Histoplasma, or Candida meningitis were included in the analysis. Data concerning healthcare resource utilization, prevalence and length of stay were collected for up to 5 years following the original diagnosis. RESULTS: Cryptococcal meningitis was the most prevalent type of fungal meningitis (70.1 % of cases over the duration of the study), followed by coccidioidomycosis (16.4 %), histoplasmosis (6.0 %) and candidiasis (7.6 %). Cryptococcal meningitis and candidiasis patients accrued the largest average charges ($103 236 and $103 803, respectively) and spent the most time in the hospital on average (70.6 and 79 days). Coccidioidomycosis and histoplasmosis patients also accrued substantial charges and time in the hospital ($82 439, 48.1 days; $78 609, 49.8 days, respectively). CONCLUSION: Our study characterizes the largest longitudinal cohort of fungal meningitis in the United States. Importantly, the health economic impact and long-term morbidity from these infections are quantified and reviewed. The healthcare resource utilization of fungal meningitis patients in the United States is substantial.

Specialty-Based Variations in Spinal Cord Stimulation Success Rates for Treatment of Chronic Pain.

OBJECTIVES: Spinal cord stimulation (SCS) has emerged as an appropriate modality of treatment for intractable chronic pain. The present study examines variations in SCS trial-to-permanent conversion rates based on provider types performing the procedure. MATERIALS AND METHODS: We designed a large, retrospective analysis using the Truven MarketScan data base analyzing adult SCS patients with provider information available, with or without IPG implantation from the years 2007-2012. Patients were categorized based on provider type performing the implantation including anesthesiologists, neurosurgeons, orthopedic surgeons, and physical medicine and rehabilitation (PM&R). Univariate and multivariate models identified factors associated with successful conversion. RESULTS: A total of 7667 unique instances of SCS implants were identified across five providers. Overall, 4842 (63.2%) of those receiving trials underwent permanent SCS system implantation. Anesthesiology performed the majority of implants (62.8%), followed by neurosurgery (22.0%), orthopedic surgery (10.2%), and PM&R (5.3%). Compared to anesthesiologists, both neurosurgeons (OR 10.99, 95% CI [9.11, 13.25]; p < 0.001) and orthopedic surgeons (OR 4.64, 95% CI [3.81, 5.65]; p < 0.001) had significantly higher conversion rates, while PM&R (OR 0.71, 95% CI [0.58, 0.87]; p = 0.001) had significantly lower. Percutaneous implants comprised 5473 (71.4%) of all implants. Neurosurgeons and orthopedic surgeons performed a significantly greater number of paddle implants among the different providers (p < 0.0001). Explant rates were similar across all cohorts analyzed (average 11.6%; p = 0.546). CONCLUSIONS: In this nationwide analysis, our results suggest that over a recent five-year period, conversion rates are highest when SCS trials are performed by neurosurgeons and orthopedic surgeons. The study has important implications for establishing uniform guidelines for training, patient selection, and education of physicians across multiple disciplines.