Discovery of a Tunable Heterocyclic Electrophile 4-Chloro-pyrazolopyridine That Defines a Unique Subset of Ligandable Cysteines.

Electrophilic small molecules with novel reactivity are powerful tools that enable activity-based protein profiling and covalent inhibitor discovery. Here, we report a reactive heterocyclic scaffold, 4-chloro-pyrazolopyridine (CPzP) for selective modification of proteins via a nucleophilic aromatic substitution (SNAr) mechanism. Chemoproteomic profiling reveals that CPzPs engage cysteines within functionally diverse protein sites including ribosomal protein S5 (RPS5), inosine monophosphate dehydrogenase 2 (IMPDH2), and heat shock protein 60 (HSP60). Through the optimization of appended recognition elements, we demonstrate the utility of CPzP for covalent inhibition of prolyl endopeptidase (PREP) by targeting a noncatalytic active-site cysteine. This study suggests that the proteome reactivity of CPzPs can be modulated by both electronic and steric features of the ring system, providing a new tunable electrophile for applications in chemoproteomics and covalent inhibitor design.

High-volume prostate biopsy core involvement is not associated with an increased risk of cancer recurrence following 5-fraction stereotactic body radiation therapy monotherapy.

PURPOSE: Percentage of positive cores involved on a systemic prostate biopsy has been established as a risk factor for adverse oncologic outcomes and is a National Comprehensive Cancer Network (NCCN) independent parameter for unfavorable intermediate-risk disease. Most data from a radiation standpoint was published in an era of conventional fractionation. We explore whether the higher biological dose delivered with SBRT can mitigate this risk factor. METHODS: A large single institutional database was interrogated to identify all patients diagnosed with localized prostate cancer (PCa) treated with 5-fraction SBRT without ADT. Pathology results were reviewed to determine detailed core involvement as well as Gleason score (GS). High-volume biopsy core involvement was defined as ≥ 50%. Weighted Gleason core involvement was reviewed, giving higher weight to higher-grade cancer. The PSA kinetics and oncologic outcomes were analyzed for association with core involvement. RESULTS: From 2009 to 2018, 1590 patients were identified who underwent SBRT for localized PCa. High-volume core involvement was a relatively rare event observed in 19% of our cohort, which was observed more in patients with small prostates (p < 0.0001) and/or intermediate-risk disease (p = 0.005). Higher PSA nadir was observed in those patients with low-volume core involvement within the intermediate-risk cohort (p = 0.004), which was confirmed when core involvement was analyzed as a continuous variable weighted by Gleason score (p = 0.049). High-volume core involvement was not associated with biochemical progression (p = 0.234). CONCLUSIONS: With a median follow-up of over 4 years, biochemical progression was not associated with pretreatment high-volume core involvement for patients treated with 5-fraction SBRT alone. In the era of prostate SBRT and MRI-directed prostate biopsies, the use of high-volume core involvement as an independent predictor of unfavorable intermediate risk disease should be revisited.

Risk and Prognostics of Second Primary Cancer After Prostate Radiation Therapy.

INTRODUCTION: As overall survival in prostate cancer increases due to advances in early detection and management, there is a growing need to understand the long-term morbidity associated with treatment, including secondary tumors. The significance of developing radiation-associated secondary cancers in an elderly population remains unknown. METHODS: Patients diagnosed with prostate cancer between 1975 and 2016 in one of 9 Surveillance, Epidemiology, and End Results registries were included in this study. Risk of second primary pelvic malignancies (SPPMs) were assessed with death as a competing risk using the Fine-Gray model. Time-varying Cox proportional hazard models were employed to analyze risk to overall mortality based on secondary tumor status. RESULTS: A total of 569,167 primary prostate cancers were included in analysis with an average follow-up of 89 months. Among all prostate cancer patients, 4956 SPPMs were identified. After controlling for differences in age, year of diagnosis, and surgery at time of prostate cancer treatment, radiation receipt was associated with a significantly higher incidence of SPPMs (1.1% vs 1.8% at 25 years). Among those who received radiation during initial prostate cancer treatment (n = 195,415), developing an SPPM is significantly associated with worse survival (adjusted hazard ratio = 1.76), especially among younger patients (under age 63, adjusted hazard ratio = 2.36). CONCLUSIONS: While developing a secondary malignancy carries a detrimental effect on overall survival, the absolute risk of developing such tumors is exceedingly low regardless of radiation treatment.

A Tool to Integrate Electrophysiological Mapping for Cardiac Radioablation of Ventricular Tachycardia.

Purpose: Cardiac radioablation is an emerging therapy for recurrent ventricular tachycardia. Electrophysiology (EP) data, including electroanatomic maps (EAM) and electrocardiographic imaging (ECGI), provide crucial information for defining the arrhythmogenic target volume. The absence of standardized workflows and software tools to integrate the EP maps into a radiation planning system limits their use. This study developed a comprehensive software tool to enable efficient utilization of the mapping for cardiac radioablation treatment planning. Methods and Materials: The tool, HeaRTmap, is a Python-scripted plug-in module on the open-source 3D Slicer software platform. HeaRTmap is able to import EAM and ECGI data and visualize the maps in 3D Slicer. The EAM is translated into a 3D space by registration with cardiac magnetic resonance images (MRI) or computed tomography (CT). After the scar area is outlined on the mapping surface, the tool extracts and extends the annotated patch into a closed surface and converts it into a structure set associated with the anatomic images. The tool then exports the structure set and the images as The Digital Imaging and Communications in Medicine Standard in Radiotherapy for a radiation treatment planning system to import. Overlapping the scar structure on simulation CT, a transmural target volume is delineated for treatment planning. Results: The tool has been used to transfer Ensite NavX EAM data into the Varian Eclipse treatment planning system in radioablation on 2 patients with ventricular tachycardia. The ECGI data from CardioInsight was retrospectively evaluated using the tool to derive the target volume for a patient with left ventricular assist device, showing volumetric matching with the clinically used target with a Dice coefficient of 0.71. Conclusions: HeaRTmap smoothly fuses EP information from different mapping systems with simulation CT for accurate definition of radiation target volume. The efficient integration of EP data into treatment planning potentially facilitates the study and adoption of the technique.

Covalent Inhibition by a Natural Product-Inspired Latent Electrophile.

Strategies to target specific protein cysteines are critical to covalent probe and drug discovery. 3-Bromo-4,5-dihydroisoxazole (BDHI) is a natural product-inspired, synthetically accessible electrophilic moiety that has previously been shown to react with nucleophilic cysteines in the active site of purified enzymes. Here, we define the global cysteine reactivity and selectivity of a set of BDHI-functionalized chemical fragments using competitive chemoproteomic profiling methods. Our study demonstrates that BDHIs capably engage reactive cysteine residues in the human proteome and the selectivity landscape of cysteines liganded by BDHI is distinct from that of haloacetamide electrophiles. Given its tempered reactivity, BDHIs showed restricted, selective engagement with proteins driven by interactions between a tunable binding element and the complementary protein sites. We validate that BDHI forms covalent conjugates with glutathione S-transferase Pi (GSTP1) and peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1), emerging anticancer targets. BDHI electrophile was further exploited in Bruton's tyrosine kinase (BTK) inhibitor design using a single-step late-stage installation of the warhead onto acrylamide-containing compounds. Together, this study expands the spectrum of optimizable chemical tools for covalent ligand discovery and highlights the utility of 3-bromo-4,5-dihydroisoxazole as a cysteine-reactive electrophile.

Pulmonary Toxic Effects After Myeloablative Conditioning With Total Body Irradiation Delivered via Volumetric Modulated Arc Therapy With Fludarabine.

We present the case of a 56-year-old female with a diagnosis of acute T-cell lymphoblastic leukemia who received myeloablative conditioning for bone marrow transplant with total body irradiation (TBI) using volumetric modulated arc therapy (VMAT) to the upper body and anterior-posterior/posterior-anterior (AP/PA) open fields to the lower body followed by hematopoietic stem cell transplant. Her clinical course was complicated by high-grade pulmonary toxic effects 55 days after treatment that resulted in death. We discuss the case, planning considerations by radiation oncologists and radiation physicists, and the multidisciplinary medical management of this patient.

Early-onset osteoradionecrosis following adjuvant volumetric-modulated arc therapy to an osteocutaneous free fibula flap with customized titanium plate.

BACKGROUND: Computerized surgical planning (CSP) in osseous reconstruction of head and neck cancer defects has become a mainstay of treatment. However, the consequences of CSP-designed titanium plating systems on planning adjuvant radiation remains unclear. METHODS: Two patients underwent head and neck cancer resection and maxillomandibular free fibula flap reconstruction with CSP-designed plates and immediate placement of osseointegrated dental implants. Surgical treatment was followed by adjuvant intensity modulated radiation therapy (IMRT). RESULTS: Both patients developed osteoradionecrosis (ORN), and one patient had local recurrence. The locations of disease occurred at the areas of highest titanium plate burden, possibly attributed to IMRT dosing inaccuracy caused by the CSP-designed plating system. CONCLUSION: Despite proven benefits of CSP-designed plates in osseous free flap reconstruction, there may be an underreported risk to adjuvant IMRT treatment planning leading to ORN and/or local recurrence. Future study should investigate alternative plating methods and materials to mitigate this debilitating outcome.

Ductal Carcinoma in Situ in Young Women: Increasing Rates of Mastectomy and Variability in Endocrine Therapy Use.

BACKGROUND: Young women with ductal carcinoma in situ (DCIS) represent a unique cohort given considerations for future risk reduction and treatment effects on fertility and quality of life. We evaluated national patterns of care in the treatment of young women and the impact of those treatments on overall survival (OS). METHODS: Women younger than 50 years of age diagnosed with pure DCIS from 2004 to 2016 in the National Cancer Database (NCDB) were identified. Clinical, demographic, and choice of local therapy are summarized and trended over time. OS was analyzed using Cox proportional hazard models. RESULTS: A total of 52,150 women were identified, and the most common surgical treatment was breast-conservation surgery (BCS; 59%). Bilateral mastectomy (BM) increased in frequency from 2004 to 2016 (11-27%; p < 0.001). In women < 40 years of age, BM (39%) surpassed BCS (35%) in 2010 with a continued upward trend. On multivariable analysis, no OS benefit of BM (hazard ratio [HR] 0.99, p = 0.90) or unilateral mastectomy (UM; HR 0.98, p = 0.80) was observed when compared with BCS + radiation therapy (RT). Inferior OS was seen with BCS, Black race, estrogen receptor (ER)-negative, and tumor ≥ 2.5 cm (p ≤ 0.006). In ER+ patients, there was a significant difference in endocrine therapy (ET) use between BM (11%), UM (33%), and BCS (28%) compared with BCS + RT (64%, p < 0.001). CONCLUSION: The use of BM for DCIS is increasing in younger patients and now exceeds breast-conservation approaches in women < 40 years of age with no evidence of improved OS. Among ER+ patients, the rates of ET are lower in the BM, UM, and BCS-alone groups compared with BCS + RT.

Modern Management of High-risk Soft Tissue Sarcoma With Neoadjuvant Chemoradiation: A Single-center Experience.

OBJECTIVE: Neoadjuvant chemoradiation (NA-CRT), followed by resection of high-risk soft tissue sarcoma (STS), may offer good disease control and toxicity outcomes. We report on a single institution's modern NA-CRT experience. MATERIALS AND METHODS: Delay to surgical resection, resection margin status, extent of necrosis, tumor cell viability, presence of hyalinization, positron emission tomography (PET)/computed tomography data, and treatment toxicities were collected. Using the Kaplan-Meier survival analysis, 5-year overall survival, disease-free survival, distant metastasis-free survival, and local control (LC) were estimated. Clinicopathologic features and PET/computed tomography avidity changes were assessed for their potential predictive impact using the log-rank test. RESULTS: From 2011 to 2018, 37 consecutive cases of localized high-risk STS were identified. Twenty-nine patients underwent ifosfamide-based NA-CRT to a median dose of 50 Gy before en bloc resection. At a median follow-up of 40.3 months, estimated 5-year overall survival was 86.1%, disease-free survival 70.2%, distant metastasis-free survival 75.2%, and LC 86.7%. Following NA-CRT, a median reduction of 54.7% was observed in tumor PET avidity; once resected, median tumor necrosis of 60.0% with no viable tumor cells was detected in 13.8% of the cases. Posttreatment resection margins were negative in all patients, with 27.6% having a margin of ≤1 mm. Delays of over 6 weeks following the end of radiation treatment to surgical resection occurred in 20.7% cases and was suggestive of inferior LC (92.8% vs. 68.6%, P=0.025). CONCLUSIONS: This single-institution series of NA-CRT demonstrates favorable disease control. Delay in surgical resection was associated with inferior LC, a finding that deserves further evaluation in a larger cohort. LEVEL OF EVIDENCE: Level III-retrospective cohort study.

Strict bladder filling and rectal emptying during prostate SBRT: Does it make a dosimetric or clinical difference?

BACKGROUND: To evaluate inter-fractional variations in bladder and rectum during prostate stereotactic body radiation therapy (SBRT) and determine dosimetric and clinical consequences. METHODS: Eighty-five patients with 510 computed tomography (CT) images were analyzed. Median prescription dose was 40 Gy in 5 fractions. Patients were instructed to maintain a full bladder and empty rectum prior to simulation and each treatment. A single reviewer delineated organs at risk (OARs) on the simulation (Sim-CT) and Cone Beam CTs (CBCT) for analyses. RESULTS: Bladder and rectum volume reductions were observed throughout the course of SBRT, with largest mean reductions of 86.9 mL (19.0%) for bladder and 6.4 mL (8.7%) for rectum noted at fraction #5 compared to Sim-CT (P < 0.01). Higher initial Sim-CT bladder volumes were predictive for greater reduction in absolute bladder volume during treatment (ρ = - 0.69; P < 0.01). Over the course of SBRT, there was a small but significant increase in bladder mean dose (+ 4.5 ± 12.8%; P < 0.01) but no significant change in the D2cc (+ 0.8 ± 4.0%; P = 0.28). The mean bladder trigone displacement was in the anterior direction (+ 4.02 ± 6.59 mm) with a corresponding decrease in mean trigone dose (- 3.6 ± 9.6%; P < 0.01) and D2cc (- 6.2 ± 15.6%; P < 0.01). There was a small but significant increase in mean rectal dose (+ 7.0 ± 12.9%, P < 0.01) but a decrease in rectal D2cc (- 2.2 ± 10.1%; P = 0.04). No significant correlations were found between relative bladder volume changes, bladder trigone displacements, or rectum volume changes with rates of genitourinary or rectal toxicities. CONCLUSIONS: Despite smaller than expected bladder and rectal volumes at the time of treatment compared to the planning scans, dosimetric impact was minimal and not predictive of detrimental clinical outcomes. These results cast doubt on the need for excessively strict bladder filling and rectal emptying protocols in the context of image guided prostate SBRT and prospective studies are needed to determine its necessity.

Immune Checkpoint Inhibitor-Associated Diabetes: A Single-Institution Experience.

OBJECTIVE: To characterize immune checkpoint inhibitor-associated diabetes mellitus (ICI-DM) in a single-institution case series. RESEARCH DESIGN AND METHODS: Retrospective chart review of 18 patients with new-onset ICI-DM following anti-programmed cell death protein 1 (PD-1)/anti-programmed cell death protein ligand 1 (PD-L1) therapy for advanced carcinomas. RESULTS: Of 18 patients, 9 had diabetic ketoacidosis (median glucose 27.92 mmol/L; median glucose before presentation 6.35 mmol/L). Median C-peptide at ICI-DM diagnosis was low, and it declined during follow-up. Median anti-PD-1/anti-PD-L1 duration before ICI-DM was 3.65 months (range 0.56-12.23 months). Time to ICI-DM onset was a median 1.4 months/3 ICI cycles and 6 months/10 cycles in those patients who were positive and negative for GAD65 autoantibodies, respectively. Time to ICI-DM onset was a median 2.5 months/3 ICI cycles and 4.8 months/8 cycles after anti-PD-L1 or anti-PD-1 therapy, respectively. Significant pancreatic atrophy was seen radiographically. CONCLUSIONS: ICI-DM presents abruptly, appears irreversible, is characterized by pancreatic atrophy, and may occur both earlier following PD-L1 blockade compared with PD-1 inhibition and in those who have positive GAD65 autoantibodies.

Prognostic potential of mid-treatment nodal response in oropharyngeal squamous cell carcinoma.

BACKGROUND: We examine the prognostic implications of mid-course nodal response in oropharyngeal cancer (OPX) to radiation therapy. METHODS: In 44 patients with node-positive OPX undergoing concurrent chemoradiation, nodal volumes were measured on cone beam CTs from days 1, 10, 20, and 35. Nodal decrease (ND) was based on percent shrinkage from day 1. RESULTS: At a median follow-up of 17 months, the 2-year disease-free survival (DFS), locoregional control (LRC), distant metastasis-free survival (DMFS), and overall survival (OS) were 87%, 92%, 89%, and 92%, respectively. Patients with ND ≥43% at D20 had improved LRC (100% vs 78.4%, P = .03) compared to D20 ND <43%. On multivariate analysis, D20 ≥43% was independently prognostic for LRC (HR 1.17, P = .05). CONCLUSION: Patients with low-risk oropharynx cancer with ND of ≥43% by treatment day 20 had significantly improved LRC. The prognostic benefit of ND may assist in identifying candidates for treatment de-escalation.

Regional variation in states' naloxone accessibility laws in association with opioid overdose death rates-Observational study (STROBE compliant).

Though overall death from opioid overdose are increasing in the United States, the death rate in some states and population groups is stabilizing or even decreasing. Several states have enacted a Naloxone Accessibility Laws to increase naloxone availability as an opioid antidote. The extent to which these laws permit layperson distribution and possession varies. The aim of this study is to investigate differences in provisions of Naloxone Accessibility Laws by states mainly in the Northeast and West regions, and the impact of naloxone availability on the rates of drug overdose deaths.This cross-sectional study was based on the National Vital Statistics System multiple cause-of-death mortality files. The average changes in drug overdose death rates between 2013 and 2017 in relevant states of the Northeast and West regions were compared according to availability of naloxone to laypersons.Seven states in the Northeast region and 10 states in the Western region allowed layperson distribution of naloxone. Layperson possession of naloxone was allowed in 3 states each in the Northeast and the Western regions. The average drug overdose death rates increased in many states in the both regions regardless of legalization of layperson naloxone distribution. The average death rates of 3 states that legalized layperson possession in the West region decreased (-0.33 per 100,000 person); however, in states in the West region that did not allow layperson possession and states in the Northeast region regardless of layperson possession increased between 2013 and 2017.The provision to legalize layperson possession of naloxone was associated with decreased average opioid overdose death rates in 3 states of the West region.

Opioid use disorders and hospital palliative care among patients with gastrointestinal cancers: Ten-year trend and associated factors in the U.S. from 2005 to 2014.

This study aimed to analyze the trends of opioid use disorders, cannabis use disorders, and palliative care among hospitalized patients with gastrointestinal cancer and to identify their associated factors.We analyzed the National Inpatient Sample data from 2005 to 2014 and included hospitalized patients with gastrointestinal cancers. The trends of hospital palliative care and opioid or cannabis use disorders were analyzed using the compound annual growth rates (CAGR) with Rao-Scott correction for χ tests. Multivariate logistic regression analyses were performed to identify the associated factors.From 2005 to 2014, among 4,364,416 hospitalizations of patients with gastrointestinal cancer, the average annual rates of opioid and cannabis use disorders were 0.4% (n = 19,520), and 0.3% (n = 13,009), respectively. The utilization rate of hospital palliative care was 6.2% (n = 268,742). They all sharply increased for 10 years (CAGR = 9.61%, 22.2%, and 21.51%, respectively). The patients with a cannabis use disorder were over 4 times more likely to have an opioid use disorder (Odds ratios, OR = 4.029; P < .001). Hospital palliative care was associated with higher opioid use disorder rates, higher in-hospital mortality, shorter length of hospital stay, and lower hospital charges. (OR = 1.527, 9.980, B = -0.054 and -0.386; each of P < .001)The temporal trends of opioid use disorders and hospital palliative care use among patients with gastrointestinal cancer increased from 2005 to 2014, which is mostly attributed to patients with a higher risk of in-hospital mortality. Cannabis use disorders were associated with opioid use disorders. Palliative care was associated with both reduced lengths of stay and hospital charge.

Trends of Hospital Palliative Care Utilization and Its Associated Factors Among Patients With Systemic Lupus Erythematosus in the United States From 2005 to 2014.

OBJECTIVE: To investigate trends and associated factors of utilization of hospital palliative care among patients with systemic lupus erythematosus (SLE) and analyze its impact on length of hospital stay, hospital charges, and in-hospital mortality. METHODS: Using the 2005-2014 National Inpatient Sample in the United States, the compound annual growth rate was used to investigate the temporal trend of utilization of hospital palliative care. Multivariate multilevel logistic regression analyses were performed to analyze the association with patient-related factors, hospital factors, length of stay, in-hospital mortality, and hospital charges. RESULTS: The overall proportion of utilization of hospital palliative care for the patient with SLE was 0.6% over 10 years. It increased approximately 12-fold from 0.1% (2005) to 1.17% (2014). Hospital palliative care services were offered more frequently to older patients, patients with high severity illnesses, and in urban teaching hospitals or large size hospitals. Patients younger than 40 years, the lowest household income group, or Medicare beneficiaries less likely received palliative care during hospitalization. Hospital palliative care services were associated with increased length of stay (ß = 1.407, P < .0001) and in-hospital mortality (odds ratio, 48.18; 95% confidence interval, 41.59-55.82), and reduced hospital charge (ß = -0.075, P = .009). CONCLUSION: Hospital palliative care service for patients with SLE gradually increased during the past decade in US hospitals. However, this showed disparities in access and was associated with longer hospital length of stay and higher in-hospital mortality. Nevertheless, hospital palliative care services yielded a cost-saving effect.

Dissociation between the growing opioid demands and drug policy directions among the U.S. older adults with degenerative joint diseases.

We aim to examine temporal trends of orthopedic operations and opioid-related hospital stays among seniors in the nation and states of Oregon and Washington where marijuana legalization was accepted earlier than any others.As aging society advances in the United States (U.S.), orthopedic operations and opioid-related hospital stays among seniors increase in the nation.A serial cross-sectional cohort study using the healthcare cost and utilization project fast stats from 2006 through 2015 measured annual rate per 100,000 populations of orthopedic operations by age groups (45-64 vs 65 and older) as well as annual rate per 100,000 populations of opioid-related hospital stays among 65 and older in the nation, Oregon and Washington states from 2008 through 2017. Orthopedic operations (knee arthroplasty, total or partial hip replacement, spinal fusion or laminectomy) and opioid-related hospital stays were measured. The compound annual growth rate (CAGR) was used to quantify temporal trends of orthopedic operations by age groups as well as opioid-related hospital stays and was tested by Rao-Scott correction of χ for categorical variables.The CAGR (4.06%) of orthopedic operations among age 65 and older increased (P < .001) unlike the unchanged rate among age 45 to 64. The CAGRs of opioid-related hospital stays among age 65 and older were upward trends among seniors in general (6.79%) and in Oregon (10.32%) and Washington (15.48%) in particular (all P < .001).Orthopedic operations and opioid-related hospital stays among seniors increased over time in the U.S. Marijuana legalization might have played a role of gateway drug to opioid among seniors.

Ten-Year Trends of Utilization of Palliative Care Services and Life-Sustaining Treatments and Hospital Costs Associated With Patients With Terminally Ill Lung Cancer in the United States From 2005 to 2014.

BACKGROUND: Palliative care services and life-sustaining treatments are provided to dying patients with lung cancer in the United States. However, data on the utilization trends of palliative care services and life-sustaining treatments of dying patients with lung cancer are not available. METHODS: This study was a retrospective analysis of the National Inpatient Sample data (2005-2014) and included patients with lung cancer, aged ≥ 18 years, who died in the hospitals. Claims data of palliative care services and life-sustaining treatments that contained systemic procedures, local procedures, or surgeries were extracted. Compound annual growth rates (CAGRs) using Rao-Scott correction for χ2 tests were used to determine the statistical significance of temporal utilization trends of palliative care services and life-sustaining treatments and their hospital costs. Multilevel multivariate regressions were performed to identify factors associated with hospital costs. RESULTS: A total of 120 144 weighted patients with lung cancer died in the hospitals and 41.9% of them received palliative care services. The CAGRs of systemic procedures, local procedures, surgeries, palliative care services, and hospital cost were 3.42%, 3.48%, 6.08%, 18.5%, and 5.0% (all P < .001), respectively. Increased hospital cost was attributed to systemic procedures (50.6%), local procedures (74.4%), and surgeries (68.5%; all P < .001), respectively. Palliative care services were related to decreasing hospital costs by 28.6% (P < .001). CONCLUSION: The temporal trends of palliative care services indicate that their utilization has increased gradually. Palliative care services were associated with reduced hospital costs. However, life-sustaining treatments were associated with increased hospital costs.