ABSTRACT
Monoclonal antibodies targeting the immune checkpoint PD-1 have provided significant clinical benefit across a number of solid tumors, with differences in efficacy and toxicity profiles possibly related to their intrinsic molecular properties. Here, we report that camrelizumab and cemiplimab engage PD-1 through interactions with its fucosylated glycan. Using a combination of protein and cell glycoengineering, we demonstrate that the two antibodies bind preferentially to PD-1 with core fucose at the asparagine N58 residue. We then provide evidence that the concentration of fucosylated PD-1 in the blood of non-small-cell lung cancer patients varies across different stages of disease. This study illustrates how glycoprofiling of surface receptors and related circulating forms can inform the development of differentiated antibodies that discriminate glycosylation variants and achieve enhanced selectivity, and paves the way toward the implementation of personalized therapeutic approaches.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Immune Checkpoint Inhibitors , Programmed Cell Death 1 Receptor , Carcinoma, Non-Small-Cell Lung/drug therapy , Glycosylation , Lung Neoplasms/drug therapyABSTRACT
Background: A significant impediment to opioid cessation or dose reduction is mitigating withdrawal severity that has been shown to affect the course of opioid dependence. Current guidelines recommend the use of buprenorphine and methadone over alpha-2 adrenergic agonists. Baclofen, a GABA-B agonist, has promising results as an adjunct agent for opioid withdrawal but has not been compared to buprenorphine. This study compared the ability of buprenorphine and baclofen to mitigate acute opioid withdrawal. Methods: This was a single-center, retrospective chart review of 63 patients with diagnosed opioid use disorder that received scheduled buprenorphine or baclofen for 3 days, in addition to as-needed medications during 2 distinct time periods (pre-2017 and 2017-2020). Patients were admitted to the inpatient detoxification unit at Gateway Community Services in Jacksonville, FL. Results: The results showed that patients achieving detoxification success were 11.2 times more likely to be exposed to baclofen than buprenorphine (95% CI 3.32 - 37.83, P < .001). Completion of detoxification protocol (baclofen 63.2% vs buprenorphine 72%, P = .649) and incidence of orthostatic hypotension (15.8% versus 0%, P = .073) were not significantly different between the 2 groups. Conclusion: Patients treated with baclofen had a lower frequency of secondary medication use for acute opioid withdrawal than patients treated with buprenorphine. This raises an interesting question of whether baclofen is comparable to buprenorphine for treating opioid withdrawal. A prospective, randomized, controlled trial in a larger patient population is warranted to determine this difference.
ABSTRACT
Colorectal cancer (CRC) remains a leading cause of cancer-related deaths despite being the most preventable and treatable forms of cancer when caught early through screening. There is an unmet need for novel screening approaches with improved accuracy, less invasiveness, and reduced costs. In recent years, evidence has accumulated around particular biological events that happen during the adenoma-to-carcinoma transition, especially focusing on precancerous immune responses in the colonic crypt. Protein glycosylation plays a central role in driving those responses, and recently, numerous reports have been published on how aberrant protein glycosylation both in colonic tissue and on circulating glycoproteins reflects these precancerous developments. The complex field of glycosylation, which exceeds complexity of proteins by several orders of magnitude, can now be studied primarily because of the availability of new high-throughput technologies such as mass spectrometry and artificial intelligence-powered data processing. This has now opened new avenues for studying novel biomarkers for CRC screening. This review summarizes the early events taking place from the normal colon mucosa toward adenoma and adenocarcinoma formation and associated critical protein glycosylation phenomena, both on the tissue level and in the circulation. These insights will help establish an understanding in the interpretation of novel CRC detection modalities that involve high-throughput glycomics.
Subject(s)
Adenoma , Colorectal Neoplasms , Precancerous Conditions , Humans , Glycosylation , Artificial Intelligence , Colorectal Neoplasms/pathology , Adenoma/diagnosis , Adenoma/pathology , Precancerous Conditions/pathologyABSTRACT
BACKGROUND: Our institution (UFHJ) meets the criteria of both a large, specialized medical center (LSCMC) and a safety-net hospital (AEH). Our aim is to compare pancreatectomy outcomes at UFHJ against other LSCMCs, AEHs, and against institutions that meet criteria for both LSCMC and AEH. In addition, we sought to evaluate differences between LSCMCs and AEHs. MATERIALS AND METHODS: Pancreatectomies for pancreatic cancer were queried from the Vizient Clinical Data Base (2018 to 2020). Clinical and cost outcomes were compared between UFHJ and LSCMCs, AEHs, and a combined group, respectively. Indices >1 indicated the observed value was greater than the expected national benchmark value. RESULTS: The mean number of pancreatectomy cases performed per institution in the LSCMC group was 12.15, 11.73, and 14.31 in 2018, 2019, and 2020, respectively. At AEHs, 25.33, 24.56, and 26.37 mean cases per institution per year, respectively. In the combined group of both LSCMCs and AEHs, 8.10, 7.60, and 7.22 mean cases, respectively. At UFHJ, 17, 34, and 39 cases were performed each year, respectively. Length of stay index decreased below national benchmarks at UFHJ (1.08 to 0.82), LSCMCs (0.91 to 0.85), and AEHs (0.94 to 0.93), with an increasing case mix index at UFHJ (3.33 to 4.20) from 2018 to 2020. In contrast, length of stay index increased in the combined group (1.14 to 1.18) and overall was the lowest at LSCMCs (0.89). Mortality index declined at UFHJ (5.07 to 0.00) below national benchmarks compared with LSCMCs (1.23 to 1.29), AEHs (1.19 to 1.45), and the combined group (1.92 to 1.99), and was significantly different between all groups ( P <0.001). Thirty-day re-admissions were lower at UFHJ (6.25% to 10.26%) compared with LSCMCs (17.62% to 16.83%) and AEHs (18.93% to 15.51%), and significantly lower at AEHs compared with LSCMCs ( P <0.001). Notably, 30-day re-admissions were lower at AEHs compared with LSCMCs ( P <0.001) and declined over time and were the lowest in the combined group in 2020 (17.72% to 9.52%). Direct cost index at UFHJ declined (1.00 to 0.67) below the benchmark compared with LSCMCs (0.90 to 0.93), AEHs (1.02 to 1.04), and the combined group (1.02 to 1.10). When comparing LSCMCs and AEHs, there were no significant differences between direct cost percentages ( P =0.56); however, the direct cost index was significantly lower at LSCMCs. CONCLUSION: Pancreatectomy outcomes at our institution have improved over time exceeding national benchmarks and often were significant to LSCMCs, AEHs, and a combined comparator group. In addition, AEHs were able to maintain good quality care when compared with LSCMCs. This study highlights the role that safety-net hospitals can provide high-quality care to a medically vulnerable patient population in the presence of high-case volume.
Subject(s)
Pancreatectomy , Safety-net Providers , Humans , Registries , Quality of Health Care , Length of StayABSTRACT
INTRODUCTION: We evaluated whether Medicaid expansion is associated with earlier stage at diagnosis for pancreatic cancer taking into account key demographic, clinical, and geographic factors. METHODS: We obtained Surveillance, Epidemiology, and End-Results (SEER-18) data on individuals diagnosed with pancreatic cancer from 2007 to 2016 (< 65 years of age). We defined non-metastatic as either local or regional disease (vs. metastatic disease). To estimate the association of Medicaid expansion with pancreatic cancer stage at diagnosis, we used a difference-in-differences model, at the individual level, comparing those from early-adopting states in 2014 to non-early-adopting states. We utilized cluster-robust standard errors and explored the role of demographic factors (race, sex, insurance at diagnosis), clinical indicator (disease in the head of the pancreas), and county characteristics (Urban Influence Code, Social Deprivation Index). RESULTS: In the univariable setting, the probability of non-metastatic disease at diagnosis increased by 3.9 percentage points (ppt) for those from Medicaid expansion states post-expansion (n = 36,609). After adjustment for covariates, the ppt was attenuated to 2.7. Of particular note, we observed evidence of interactions with sex and race. The beneficial effect was less pronounced for men (increase in the probability of non-metastatic stage at diagnosis by 2.1ppt) than women (3.6ppt) and non-existent for blacks (- 3.1ppt) compared to whites (4.9ppt) and other races (4.8ppt). CONCLUSION: Medicaid expansion is associated with increased probability of non-metastatic stage at diagnosis for pancreatic cancer; however, this beneficial effect is not uniform across sex and race. This underscores the need to investigate the impact of policy and implementation strategies on pancreatic cancer survival disparities.
Subject(s)
Medicaid , Pancreatic Neoplasms , Male , United States , Adult , Humans , Female , Insurance Coverage , Insurance, Health , Patient Protection and Affordable Care Act , Pancreatic Neoplasms/diagnosis , Pancreatic NeoplasmsABSTRACT
Introduction: Prehospital evidence-based guidelines (EBGs) are developed to optimize clinical outcomes for emergency medical services (EMS) patients. However, widespread implementation of EBGs is often inconsistent. Therefore, this study aimed to assess the baseline knowledge and practices of EMS leaders related to EBG implementation.Methods: This was a qualitative study using focus groups to assess prehospital implementation awareness and knowledge. Participants were EMS EBG authors, EMS medical directors, and EMS professional organization leaders. Focus groups were held via video conference, audio recorded, and transcribed. Thematic coding used domains and constructs of the Consolidated Framework for Implementation Research (CFIR).Results: Six focus groups were conducted with a total of 18 participants. A total of 1,044 codes were analyzed. "Process" was the CFIR domain with the most codes (n = 350, 33.5%), followed by the "inner setting" (the EMS agency; n = 250, 23.9%), "characteristics of the intervention" (n = 203, 19.4%), "outer setting" (the health care system and community the EMS agency serves, and the broader national EMS professional context; n = 141, 13.5%), and "characteristics of individuals" (n = 100, 9.6%). The ten most frequent constructs across all domains were: reflecting and evaluating, executing, cosmopolitanism, planning, external policy and incentives, design quality and packaging, learning climate, culture, complexity, and other personal attributes.Conclusion: EMS leadership and stakeholder views on EBG implementation identified dominant themes related to the process of implementation and the culture and learning/implementation climate of EMS agencies. Opinions were mixed on the utility of the CFIR as a potential guide for EMS implementation. Further work is required to gain the frontline EMS clinician perspective on implementation and tie key themes to quantitative prehospital implementation outcomes.
Subject(s)
Emergency Medical Services , Humans , Leadership , Delivery of Health Care , Qualitative Research , Focus GroupsABSTRACT
Objective. The COVID-19 pandemic created an unprecedented strain on the health care system, and administrators had to make many critical decisions to respond appropriately. This study sought to understand how health care administrators used data and information for decision making during the first 6 mo of the COVID-19 pandemic. Materials and Methods. We conducted semistructured interviews with administrators across University of Florida (UF) Health. We performed an inductive thematic analysis of the transcripts. Results. Four themes emerged from the interviews: 1) common types of health systems or hospital operations data; 2) public health and other external data sources; 3) data interaction, integration, and exchange; and 4) novelty and evolution in data, information, or tools used over time. Participants illustrated the organizational, public health, and regional information they considered essential (e.g., hospital census, community positivity rate, etc.). Participants named specific challenges they faced due to data quality and timeliness. Participants elaborated on the necessity of data integration, validation, and coordination across different boundaries (e.g., different hospital systems in the same metro areas, public health agencies at the local, state, and federal level, etc.). Participants indicated that even within the first 6 mo of the COVID-19 pandemic, the data and tools used for making critical decisions changed. Discussion. While existing medical informatics infrastructure can facilitate decision making in pandemic response, data may not always be readily available in a usable format. Interoperable infrastructure and data standardization across multiple health systems would help provide more reliable and timely information for decision making. Conclusion. Our findings contribute to future discussions of improving data infrastructure and developing harmonized data standards needed to facilitate critical decisions at multiple health care system levels. Highlights: The study revealed common health systems or hospital operations data and information used in decision making during the first 6 mo of the COVID-19 pandemic.Participants described commonly used internal data sources, such as resource and financial reports and dashboards, and external data sources, such as federal, state, and local public health data.Participants described challenges including poor timeliness and limited local relevance of external data as well as poor integration of data sources within and across organizational boundaries.Results suggest the need for continued integration and standardization of health data to support health care administrative decision making during pandemics or other emergencies.
ABSTRACT
OBJECTIVES: The aim of this study was to determine the long-term overall and disease-free survival and factors associated with overall survival in patients with esophageal cancer undergoing a totally minimally invasive Ivor Lewis esophagectomy (MILE) at a safety-net hospital. METHODS: This was a single-center retrospective review of consecutive patients who underwent MILE from September 2013 to November 2017. Overall and disease-free survival were analyzed by Kaplan-Meier estimates, and hazard ratios (HR) were derived from multivariable Cox regression models. RESULTS: Ninety-six patients underwent MILE during the study period. Overall survival at 1, 3, and 5 years was 83.2%, 61.9%, and 55.9%, respectively. Disease-free survival at 1, 3, and 5 years was 83.2%, 60.6%, and 47.5%, respectively. Overall survival (p < 0.001) and disease-free survival (p < 0.001) differed across pathological stages. By multivariable analysis, increasing age (HR, 1.06; p = 0.02), decreasing Karnofsky performance status score (HR, 0.94; p = 0.002), presence of stage IV disease (HR, 5.62; p = 0.002), locoregional recurrence (HR, 2.94; p = 0.03), and distant recurrence (HR, 4.78; p < 0.001) were negatively associated with overall survival. Overall survival significantly declined within 2 years and was independently associated with stage IV disease (HR, 3.29; p = 0.04) and distant recurrence (HR, 5.78; p < 0.001). CONCLUSION: MILE offers favorable long-term overall and disease-free survival outcomes. Age, Karnofsky performance status score, stage IV, and disease recurrence are shown to be prognostic factors of overall survival. Prospective studies comparing long-term outcomes after different MIE approaches are warranted to validate survival outcomes after MILE.
Subject(s)
Esophageal Neoplasms , Esophagectomy , Esophageal Neoplasms/pathology , Humans , Minimally Invasive Surgical Procedures , Neoplasm Recurrence, Local/surgery , Postoperative Complications/surgery , Prospective Studies , Retrospective Studies , Treatment OutcomeABSTRACT
BACKGROUND: This study examined the effect of Medicaid expansion on 1-year survival of pancreatic cancer for nonelderly adults. We further evaluated whether sociodemographic and county characteristics alter the association of Medicaid expansion and 1-year survival. STUDY DESIGN: We obtained data from the Surveillance Epidemiology and End-Results dataset on individuals diagnosed with pancreatic cancer from 2007 to 2015. A Difference-in-Differences model compared those from early-adopting states to non-early-adopting states, before and after adoption (2014), while taking into consideration sociodemographic and county characteristics to estimate the effect of Medicaid expansion on 1-year survival. RESULTS: In the univariable Difference-in-Differences model, the probability of 1-year survival for pancreatic cancer increased by 4.8 percentage points (ppt) for those from Medicaid expansion states postexpansion (n = 35,347). After adjustment for covariates, the probability of 1-year survival was reduced to 0.8 ppt. Interestingly, after multivariable adjustment the effect of living in an expansion state on 1-year survival was similar for men and women (0.6 ppt for men vs 1.2 ppt for women), was also similar for Whites (2.6 ppt), and was higher in those of other races (5.9 ppt) but decreased for Blacks (-2.0 ppt). Those who were insured (-0.1 ppt) or uninsured (-2.2 ppt) experienced a decrease in the probability of 1-year survival; however, those who were covered by Medicaid at diagnosis experienced an increase in the probability of 1-year survival (7.4 ppt). CONCLUSIONS: Medicaid expansion during or after 2014 is associated with an increase in the probability of 1-year survival for pancreatic cancer; however, this effect is attenuated after adjustment for sociodemographic characteristics. Of note, the positive association was more pronounced in certain categories of key covariates suggesting further inquiry focused on these subgroups.
Subject(s)
Medicaid , Pancreatic Neoplasms , Adult , Female , Humans , Insurance Coverage , Male , Medically Uninsured , Patient Protection and Affordable Care Act , United States/epidemiology , White People , Pancreatic NeoplasmsABSTRACT
BACKGROUND: Anastomotic leak is a serious complication following esophagectomy. The aim of the study was to report our experience with indocyanine green fluorescence angiography (ICG-FA)-PINPOINT® assisted minimally invasive Ivor Lewis esophagectomy (MILE) and assess factors associated with anastomotic leak. METHODS: We reviewed consecutive patients undergoing MILE from 2013 to 2018. Intraoperative real-time assessment of gastric conduit was performed using ICG-FA with PINPOINT®. Perfusion was categorized as good perfusion (brisk ICG visualization to conduit tip) or non-perfusion (any demarcation along the conduit). RESULTS: 100 patients (81 males, median age 68 [60-72]) underwent MILE for malignancy in 96 patients and benign disease in 4 patients. There were six anastomotic leaks all managed with endoscopic stent placement. There was no intraoperative mortality and no 30-day mortality in leak patients. Patients with a leak were more likely to be overweight with BMI > 25 (100% versus 53%, p = 0.03), have pre-existing diabetes (50% versus 13%, p = 0.04), and have higher intraoperative estimated blood loss (260 mL [95-463] versus 75 mL [48-150], p = 0.03). Anastomotic leaks occurred more frequently in the non-perfusion (67%) versus the good perfusion category (33%, p = 0.03). By multivariable analysis, diabetes (odds ratio [OR] 6.42; p = 0.04) and non-perfusion (OR 6.60; p = 0.04) were independently associated with leak. CONCLUSION: Intraoperative use of ICG-FA may be a useful adjunct to assess perfusion of the gastric conduit with non-perfusion being independently associated with a leak. While perfusion plays an important role in anastomotic integrity, development of a leak is multifactorial, and ICG-FA should be used in conjunction with the optimization of patient and procedural components to minimize leak rates. Prospective, randomized studies are required to validate the interpretation, efficacy, and application of this novel technology in minimally invasive esophagectomies.
Subject(s)
Esophageal Neoplasms , Esophagectomy , Aged , Anastomosis, Surgical , Anastomotic Leak/etiology , Anastomotic Leak/surgery , Esophageal Neoplasms/complications , Esophageal Neoplasms/surgery , Esophagectomy/adverse effects , Humans , Indocyanine Green , Male , Perfusion , Prospective Studies , Stomach/surgeryABSTRACT
OBJECTIVE: The aim of this study is to identify factors influencing reoperations following minimally invasive Ivor Lewis esophagectomy and associated mortality and hospital costs. MATERIALS AND METHODS: Between 2013 and 2018, 125 patients were retrospectively analyzed. Outcomes included reoperations, mortality, and hospital costs. Multivariable logistic regression analyses determined factors associated with reoperations. RESULTS: In-hospital reoperations (n=10) were associated with in-hospital mortality (n=3, P<0.01), higher hospital costs (P<0.01), and longer hospital stay (P<0.01). Conversely, reoperations after discharge were not associated with mortality. By multivariable analysis, baseline cardiovascular (P=0.02) and chronic kidney disease (P=0.01) were associated with reoperations. However, anastomotic leaks were not associated with reoperations nor mortality. CONCLUSION: The majority of reoperations occur within 30 days often during index hospitalization. Reoperations were associated with increased in-hospital mortality and hospital costs. Notably, anastomotic leaks did not influence reoperations nor mortality. Efforts to optimize patient baseline comorbidities should be emphasized to minimize reoperations following minimally invasive Ivor Lewis esophagectomy.
Subject(s)
Esophageal Neoplasms , Esophagectomy , Anastomotic Leak , Esophageal Neoplasms/surgery , Humans , Minimally Invasive Surgical Procedures , Postoperative Complications/epidemiology , Postoperative Complications/etiology , Retrospective Studies , Treatment OutcomeABSTRACT
PURPOSE: The aim of this study is to determine the financial impact of clinical complications and outcomes after minimally invasive Ivor Lewis esophagectomy (MILE) at a safety-net hospital. METHODS: This was a single-center retrospective analysis of consecutive patients undergoing MILE from 2013 to 2018. Postoperative complications were classified by Clavien-Dindo grade and associated total and direct recovered costs were assessed. Direct cost and LOS index were defined as the ratio of observed to expected values (>1 denotes above nationwide expectations). Annual outcomes were based on Medicare fiscal years. RESULTS: One hundred twenty-four patients (99 males, mean age 65.7 ± 9.3) were surgically treated for esophageal malignancy (n = 118) and benign disease (n = 6) by MILE between 2014 and 2018. Mean ICU LOS (5.8 ± 6.6 versus 4.3 ± 6.3 days) and LOS index (1.16 versus 0.76) improved from 2014 to 2018. Both direct cost index (1.03 versus 0.99) and indirect costs (43.4% versus 41.4%) decreased over time. However, direct costs recovered (213.6 to 159.0%) and total costs recovered (119.1 to 92.5%) declined during this period. Clinical complications grade was not associated with total costs recovered (p = 0.69). Extent of recovered expenditure was significantly higher from commercial/private payers as compared to government-sponsored payers (p < 0.05). CONCLUSION: Improvement in clinical outcomes and efficiency of care are not reflected by annual recovered expenditure. Furthermore, clinical complications do not correlate with the ability to recover hospital spending. Financial recovery was primary payer dependent. Enhanced collaboration with hospital administration may be needed in an effort to maximize financial fidelity in the presence of good quality of care after highly complex procedures.