Development of a Novel Protocol for Germline Testing in Pancreatic Cancer.

BACKGROUND: Guidelines now recommend universal germline genetic testing (GGT) for all pancreatic ductal adenocarcinoma (PDAC) patients. Testing provides information on actionable pathogenic variants and guides management of patients and family. Since traditional genetic counseling (GC) models are time-intensive and GC resources are sparse, new approaches are needed to comply with guidelines without overwhelming available resources. METHODS: A novel protocol was developed for physician-led GGT. Completed test kits were delivered to the GC team, who maintained a prospective database and mailed all orders. If results revealed pathogenic variants for PDAC, patients were offered comprehensive GC, whereas negative and variant of uncertain significance (VUS) test results were reported to patients via brief calls. RESULTS: During protocol implementation between January 2020 and December 2022, 310 (81.5%) patients underwent GGT, with a physician compliance rate of 82.6% and patient compliance rate of 98.7%. Of 310 patients tested, 44 (14.2%) patients had detection of pathogenic variants, while 83 (26.8%) patients had VUS. Pathogenic variants included BRCA1/BRCA2/PALB2 (n = 18, 5.8%), ATM (n = 9, 2.9%), CFTR (n = 4, 1.3%), EPCAM/MLH1/MSH2/MSH6/PMS2 (n = 3, 1.0%), and CDKN2A (n = 2, 0.7%). The GC team successfully contacted all patients with pathogenic variants to discuss results and offer comprehensive GC. CONCLUSION: Our novel protocol facilitated GGT with excellent compliance despite limited GC resources. This framework for GGT allocates GC resources to those patients who would benefit most from GC. As we continue to expand the program, we seek to implement methods to ensure compliance with cascade testing of high-risk family members.

Mueller maneuver attenuates left atrial phasic volumes and myocardial strain in healthy younger adults.

The left atrium (LA) is a key, but incompletely understood, modulator of left ventricular (LV) filling. Inspiratory negative intrathoracic pressure swings alter cardiac loading conditions, which may impact LA function. We studied acute effects of static inspiratory efforts on LA chamber function, LA myocardial strain, and LV diastolic filling. We included healthy adults (10 males/9 females, 24 ± 4 yr) and used Mueller maneuvers to reduce intrathoracic pressure to -30 cmH2O for 15 s. Over six repeated trials, we used echocardiography to acquire LA- and LV-focused two-dimensional (2-D) images, and mitral Doppler inflow and annular tissue velocity spectra. Images were analyzed for LA and LV chamber volumes, tissue relaxation velocities, transmitral filling velocities, and speckle tracking-derived LA longitudinal strain. Repeated measures were made at baseline, early Mueller, late Mueller, then early release, and late release. In the late Mueller compared with baseline, LV stroke volume decreased by -10 ± 4 mL (P < 0.05) and then returned to baseline upon release; this occurred with a -11 ± 9 mL (P < 0.05) end-diastolic volume reduction. Early diastolic LV filling was attenuated, reflected by decreased tissue relaxation velocity (-2 ± 2 cm/s, P < 0.05), E-wave filling velocity (-13 ± 14 cm/s, P < 0.05), and LA passive emptying volume (-5 ± 5 mL, P < 0.05), each returning to baseline with release. LA maximal volume decreased (-5 ± 5 mL, P < 0.05) during the Mueller maneuver, but increased relative to baseline following release (+4 ± 5 mL, P < 0.05), whereas LA peak positive longitudinal strain decreased (-6 ± 6%, P < 0.05) and then returned to baseline. Attenuated LA and in turn, LV filling may contribute to acute stroke volume reductions experienced during forceful inspiratory efforts.NEW & NOTEWORTHY In healthy younger adults, the Mueller maneuver transiently reduces left atrial filling and passive emptying during the reservoir and conduit phases, respectively. Corresponding reductions are seen in left atrial reservoir and conduit phase longitudinal myocardial strain and strain rate. However, left atrial pump phase active function and mechanics are largely preserved compared with baseline. Rapid changes in LA chamber volumes and myocardial strain with recurrent forceful inspiratory efforts and relaxation may reflect acute LA stress.

A Multicenter Phase 1 Trial Evaluating Nanoliposomal Irinotecan for Heated Intraperitoneal Chemotherapy Combined with Cytoreductive Surgery for Patients with Peritoneal Surface Disease.

BACKGROUND: Nanoliposomal irinotecan (nal-IRI) is a promising novel hyperthermic intraperitoneal chemotherapy (HIPEC) agent given its enhanced efficacy against gastrointestinal tumors, safety profile, thermo-synergy, and heat stability. This report describes the first in-human phase 1 clinical trial of nal-IRI during cytoreductive surgery (CRS) and HIPEC. METHODS: Patients with peritoneal surface disease (PSD) from appendiceal and colorectal neoplasms were enrolled in a 3 + 3 dose-escalation trial using nal-IRI (70-280 mg/m2) during HIPEC for 30 min at 41 ± 1 °C. The primary outcome was safety. The secondary outcomes were pharmacokinetics (PK) and disease-free survival. Adverse events (AEs) categorized as grade 2 or higher were recorded. The serious AEs (SAEs) were mortality, grade ≥ 3 AEs, and dose-limiting toxicity (DLT). Irinotecan and active metabolite SN38 were measured in plasma and peritoneal washings. RESULTS: The study enrolled 18 patients, who received nal-IRI during HIPEC at 70 mg/m2 (n = 3), 140 mg/m2 (n = 6), 210 mg/m2 (n = 3), and 280 mg/m2 (n = 6). No DLT or mortality occurred. The overall morbidity for CRS/HIPEC was 39% (n = 7). Although one patient experienced neutropenia, no AE (n = 131) or SAE (n = 3) was definitively attributable to nal-IRI. At 280 mg/m2, plasma irinotecan and SN38 measurements showed maximum concentrations of 0.4 ± 0.6 µg/mL and 3.0 ± 2.4 ng/mL, a median time to maximum concentration of 24.5 and 26 h, and areas under the curve of 22.6 h*µg/mL and 168 h*ng/mL, respectively. At the 6-month follow-up visit, 83% (n = 15) of the patients remained disease-free. CONCLUSIONS: In this phase 1 HIPEC trial (NCT04088786), nal-IRI was observed to be safe, and PK profiling showed low systemic absorption overall. These data support future studies testing the efficacy of nal-IRI in CRS/HIPEC.

Tenuous Inhibitory GABAergic Signaling in the Reticular Thalamus.

Maintenance of a low intracellular Cl- concentration ([Cl-]i) is critical for enabling inhibitory neuronal responses to GABAA receptor-mediated signaling. Cl- transporters, including KCC2, and extracellular impermeant anions ([A]o) of the extracellular matrix are both proposed to be important regulators of [Cl-]i Neurons of the reticular thalamic (RT) nucleus express reduced levels of KCC2, indicating that GABAergic signaling may produce excitation in RT neurons. However, by performing perforated patch recordings and calcium imaging experiments in rats (male and female), we find that [Cl-]i remains relatively low in RT neurons. Although we identify a small contribution of [A]o to a low [Cl-]i in RT neurons, our results also demonstrate that reduced levels of KCC2 remain sufficient to maintain low levels of Cl- Reduced KCC2 levels, however, restrict the capacity of RT neurons to rapidly extrude Cl- following periods of elevated GABAergic signaling. In a computational model of a local RT network featuring slow Cl- extrusion kinetics, similar to those we found experimentally, model RT neurons are predisposed to an activity-dependent switch from GABA-mediated inhibition to excitation. By decreasing the activity threshold required to produce excitatory GABAergic signaling, weaker stimuli are able to propagate activity within the model RT nucleus. Our results indicate the importance of even diminished levels of KCC2 in maintaining inhibitory signaling within the RT nucleus and suggest how this important activity choke point may be easily overcome in disorders such as epilepsy.SIGNIFICANCE STATEMENT Precise regulation of intracellular Cl- levels ([Cl-]i) preserves appropriate, often inhibitory, GABAergic signaling within the brain. However, there is disagreement over the relative contribution of various mechanisms that maintain low [Cl-]i We found that the Cl- transporter KCC2 is an important Cl- extruder in the reticular thalamic (RT) nucleus, despite this nucleus having remarkably low KCC2 immunoreactivity relative to other regions of the adult brain. We also identified a smaller contribution of fixed, impermeant anions ([A]o) to lowering [Cl-]i in RT neurons. Inhibitory signaling among RT neurons is important for preventing excessive activation of RT neurons, which can be responsible for generating seizures. Our work suggests that KCC2 critically restricts the spread of activity within the RT nucleus.

Aerobic exercise training does not alter vascular structure and function in chronic obstructive pulmonary disease.

NEW FINDINGS: What is the central question of this study? Chronic obstructive pulmonary disease (COPD) is associated with endothelial dysfunction, arterial stiffness and systemic inflammation, which are linked to increased cardiovascular disease risk. We asked whether periodized aerobic exercise training could improve vascular structure and function in patients with COPD. What is the main finding and its importance? Eight weeks of periodized aerobic training did not improve endothelial function, arterial stiffness or systemic inflammation in COPD, despite improvements in aerobic capacity, blood pressure and dyspnoea. Short-term training programmes may not be long enough to improve vascular-related cardiovascular risk in COPD. Chronic obstructive pulmonary disease (COPD) has been associated with endothelial dysfunction and arterial stiffening, which are predictive of future cardiovascular events. Although aerobic exercise improves vascular function in healthy individuals and those with chronic disease, it is unknown whether aerobic exercise can positively modify the vasculature in COPD. We examined the effects of 8 weeks of periodized aerobic training on vascular structure and function and inflammation in 24 patients with COPD (age, 69 ± 7 years; forced expiratory volume in 1 second as a percentage of predicted (FEV1 %pred), 68 ± 19%) and 20 matched control subjects (age, 64 ± 5 years; FEV1 %pred, 113 ± 16%) for comparison. Endothelial function was measured using brachial artery flow-mediated dilatation, whereas central and peripheral pulse wave velocity, carotid artery intima-media thickness, carotid compliance, distensibility and ß-stiffness index were measured using applanation tonometry and ultrasound. Peak aerobic power (V̇O2 peak ) was measured using an incremental cycling test. Upper and lower body cycling training was performed three times per week for 8 weeks, and designed to optimize vascular adaptation by increasing and sustaining vascular shear stress. Flow-mediated dilatation was not increased in COPD patients (+0.15 ± 2.27%, P = 0.82) or control subjects (+0.34 ± 3.20%, P = 0.64) and was not different between groups (P = 0.68). No significant improvements in central pulse wave velocity (COPD, +0.30 ± 1.79 m s-1 versus control subjects, -0.34 ± 1.47 m s-1 ) or other markers of vascular structure or function were found within or between groups. The V̇O2 peak increased significantly in COPD and control subjects, and was greater in control subjects (1.6 ± 1.4 versus 4.1 ± 3.7 ml kg min-1 , P = 0.003), while blood pressure and dyspnoea were reduced in COPD patients (P < 0.05). These findings demonstrate that 8 weeks of aerobic training improved cardiorespiratory fitness and blood pressure in COPD but had little effect on other established markers of cardiovascular disease risk.

Heart-lung interaction in a model of COPD: importance of lung volume and direct ventricular interaction.

Chronic obstructive pulmonary disease (COPD) is associated with dynamic lung hyperinflation (DH), increased pulmonary vascular resistance (PVR), and large increases in negative intrathoracic pressure (nITP). The individual and interactive effect of these stressors on left ventricular (LV) filling, emptying, and geometry and the role of direct ventricular interaction (DVI) in mediating these interactions have not been fully elucidated. Twenty healthy subjects were exposed to the following stressors alone and in combination: 1) inspiratory resistive loading of -20 cmH2O (nITP), 2) expiratory resistive loading to cause dynamic hyperinflation (DH), and 3) normobaric-hypoxia to increase PVR (hPVR). LV volumes and geometry were assessed using triplane echocardiography. LV stroke volume (LVSV) was reduced during nITP by 7 ± 7% (mean ± SD; P < 0.001) through a 4 ± 5% reduction in LV end-diastolic volume (LVEDV) (P = 0.002), while DH reduced LVSV by 12 ± 13% (P = 0.001) due to a 9 ± 10% reduction in LVEDV (P < 0.001). The combination of nITP and DH (nITP+DH) caused larger reductions in LVSV (16 ± 16%, P < 0.001) and LVEDV (12 ± 10%, P < 0.001) than nITP alone (P < 0.05). The addition of hPVR to nITP+DH did not further reduce LV volumes. Significant septal flattening (indicating DVI) occurred in all conditions, with a significantly greater leftward septal shift occurring with nITP+DH than either condition alone (P < 0.05). In summary, the interaction of nITP and DH reduces LV filling through DVI. However, DH may be more detrimental to LV hemodynamics than nITP, likely due to mediastinal constraint of the heart amplifying DVI.

The demand for speech pathology services for children: Do we need more or just different?

An inability or difficulty communicating can have a profound impact on a child's future ability to participate in society as a productive adult. Over the past few years the number of interventions for children with speech and language problems has almost doubled; the majority are targeted interventions delivered by speech pathologists. In this paper we examine the distribution of speech pathology services in metropolitan Melbourne and how these are aligned with need as defined by vulnerability in language and social disadvantage. We identified three times as many private sector services compared to public services for the 0-5 year age group. Overall there was poorer availability of services in some of the most vulnerable areas. The profound and long-term impact of impoverished childhood language, coupled with the considerable limitations on public spending, provide a strong impetus to deliver more equitably distributed speech pathology services.

Preterm birth among women with HIV: impact of preconception cART initiation.

OBJECTIVE: To examine the risk of preterm birth (PTB) and small for gestational age (SGA) among women with HIV compared to women without HIV. Secondary objectives were to explore the role of maternal immune activation (IA) and effect of cART timing on these outcomes. DESIGN: Prospective observational cohort. SETTING: Urban government-run clinic at Chawama Hospital in Lusaka, Zambia. PARTICIPANTS: A total of 1481 women with and without HIV with singleton pregnancies enrolled before 26 weeks' gestation by ultrasound dating. METHODS: From August 2019 to November 2022, pregnant women were enrolled in a 1 : 1 ratio of HIV infection. Maternal baseline clinical factors were collected, as well as CD4 + , viral load and CD8 + T-cell IA in women with HIV. Birth outcomes were also collected. The association of HIV-exposure and cART timing on outcomes was assessed by multivariable logistic regression. The independent role of IA was determined by mediation analysis. MAIN OUTCOME MEASURES: PTB (<37 weeks) and SGA. RESULTS: There were 38 fetal deaths and 1230 singleton live births. Maternal HIV infection was associated with PTB [adjusted odds ratio (AOR) 1.60, 95% confidence interval (CI) 1.11-2.32] and to a lesser extent SGA (AOR 1.29, 95% CI 0.98-1.70). Maternal cART timing impacted these associations, with highest risk in women who started cART after conception (PTB AOR 1.77, 95% CI 1.09-2.87, SGA AOR 1.52, 95% CI 1.04-2.22). Maternal IA was not associated with PTB independent of HIV infection. CONCLUSIONS: HIV is associated with PTB. Risk of PTB and SGA was highest in women with HIV who started cART in pregnancy, a modifiable risk factor.

Evaluating the Use of Video Modeling With Voiceover Instructions to Train Therapists to Deliver Caregiver Training Through Telehealth.

Caregiver training is an important component of behavioral intervention; however, many barriers exist for in-person training. Alternatively, behavioral therapists may use telehealth as a service delivery method. To effectively train caregivers through telehealth, therapists should receive explicit training, but there has been limited research on effective methods for teaching this skill. The purpose of the current study was to evaluate video modeling with voice-over instruction (VMVO) to train therapists to implement 11 component skills of caregiver training through telehealth to teach confederate caregivers to implement a guided compliance procedure. We measured the therapist's implementation of the component skills during a scripted role-play before and after video-model training within a multiple baseline design across participants. We also conducted maintenance and generalization probes to a novel skill. All seven therapists learned the skill, but three therapists required a feedback component in addition to the VMVO. The results suggest that VMVO may be an efficient and effective method for training therapists to conduct caregiver training via telehealth. Furthermore, results indicate that component skill analyses may be valuable to monitor skills that require remediation.

Finding New Meaning in the Practice of Medicine: A Quality Improvement Project Evaluating the Remote Communication Liaison Program During the Initial COVID Pandemic Surge.

Background: In spring 2020, the COVID-19 pandemic overwhelmed intensive care teams with severely ill patients. Even at the end of life, families were barred from hospitals, relying solely on remote communication. A Remote Communication Liaison Program (RCLP) was established to ensure daily communication for families, while supporting overstretched intensivists. Objectives: To evaluate the effectiveness and impact of the RCLP on participating liaisons and intensivists. Design: Two quality improvement surveys were developed and administered electronically. Setting/Subjects: Based in the United States, all liaisons and intensivists who participated in this program were invited to take the surveys. Measurements: Descriptive statistics were used to analyze the quantitative Likert-scale data, and qualitative analysis was used to assess themes. Results: Among respondents, all (100%) liaisons and more than 90% of intensivists agreed or strongly agreed that the RCLP provided a valuable service to families. More than 70% of intensivists agreed or strongly agreed that the program lessened their workload. More than 90% of liaisons agreed or strongly agreed that participation in the program improved their confidence and skills in end-of-life decision making, difficult conversations, and comprehension of critical care charts. Themes elicited from the liaisons revealed that participation fostered a renewed sense of purpose as physicians, meaningful connection, and opportunities for growth. Conclusions: RCLP successfully trained and deployed liaisons to rapidly develop skills in communication with beleaguered families during COVID-19 surge. Participation in the program had a profound effect on liaisons, who experienced a renewed sense of meaning and connection to the practice of medicine.

The Development of Investigator-Initiated Clinical Trials in Surgical Oncology.

Investigator-initiated trials (IITs) are designed by principal investigators who identify important, unaddressed clinical gaps and opportunities to answer these questions through clinical trials. Surgical oncologists are poised to lead IITs due to their multidisciplinary clinical practice and substantial research background. The process of developing, organizing, and implementing IITs is multifaceted and involves important steps including (but not limited to) navigating regulatory requirements, obtaining funding, and meeting enrollment targets. Here, the authors explore the steps, methodology, and barriers of IIT development by surgical oncologists and highlight the importance of IITs in oncology.

Lower-limb resistance training reduces exertional dyspnea and intrinsic neuromuscular fatigability in individuals with chronic obstructive pulmonary disease.

Skeletal muscle atrophy, dysfunction, and fatigue are important complications of chronic obstructive pulmonary disease (COPD). Greater reliance on glycolytic metabolism and increased type III/IV muscle afferent activity increase ventilatory drive, promote ventilatory constraint, amplify exertional dyspnea, and limit exercise tolerance. To investigate whether muscular adaptation with resistance training (RT) could improve exertional dyspnea, exercise tolerance, and intrinsic neuromuscular fatigability in individuals with COPD (n = 14, FEV1 = 62 ± 21% predicted), we performed a proof-of-concept single-arm efficacy study utilizing 4 wk of individualized lower-limb RT (3 times/wk). At baseline, dyspnea (Borg scale), ventilatory parameters, lung volumes (inspiratory capacity maneuvers), and exercise time were measured during a constant-load test (CLT) at 75% maximal workload to symptom limitation. On a separate day, fatigability was assessed using 3 min of intermittent stimulation of the quadriceps (initial output of ∼25% maximal voluntary force). Following RT, the CLT and fatigue protocols were repeated. Compared with baseline, isotime dyspnea was reduced (5.9 ± 2.4 vs. 4.5 ± 2.4 Borg units, P = 0.02) and exercise time increased (437 ± 405 s vs. 606 ± 447 s, P < 0.01) following RT. Isotime tidal volume increased (P = 0.01), whereas end-expiratory lung volumes (P = 0.02) and heart rate (P = 0.03) decreased. Quadriceps force, relative to initial force, was higher at the end of the stimulation protocol posttraining (53.2 ± 9.1 vs. 46.8 ± 11.9%, P = 0.04). This study provides evidence that 4 wk of RT attenuates exertional dyspnea and improves exercise tolerance in individuals with COPD, which in part, is likely due to delayed ventilatory constraint and reduced intrinsic fatigability. A pulmonary rehabilitation program beginning with individualized lower-limb RT may help mitigate dyspnea before performing aerobic training in individuals with COPD.NEW & NOTEWORTHY This study presents the novel finding that 4-wk resistance training (RT) focused specifically on the lower limbs can reduce exertional dyspnea during constant-load cycling, improve exercise tolerance, and reduce intrinsic fatigability of the quadriceps in individuals with COPD.

Creation of EGD-Derived Gastric Cancer Organoids to Predict Treatment Responses.

Gastric adenocarcinoma (GAd) is the third leading cause of cancer-related deaths worldwide. Most patients require perioperative chemotherapy, yet methods to accurately predict responses to therapy are lacking. Thus, patients may be unnecessarily exposed to considerable toxicities. Here, we present a novel methodology using patient-derived organoids (PDOs) that rapidly and accurately predicts the chemotherapy efficacy for GAd patients. Methods:Endoscopic GAd biopsies were obtained from 19 patients, shipped overnight, and PDOs were developed within 24 h. Drug sensitivity testing was performed on PDO single-cells with current standard-of-care systemic GAd regimens and cell viability was measured. Whole exome sequencing was used to confirm the consistency of tumor-related gene mutations and copy number alterations between primary tumors, PDOs, and PDO single-cells. Results:Overall, 15 of 19 biopsies (79%) were appropriate for PDO creation and single-cell expansion within 24 h of specimen collection and overnight shipment. With our PDO single-cell technique, PDOs (53%) were successfully developed. Subsequently, two PDO lines were subjected to drug sensitivity testing within 12 days from initial biopsy procurement. Drug sensitivity assays revealed unique treatment response profiles for combination drug regimens in both of the two unique PDOs, which corresponded with the clinical response. Conclusions:The successful creation of PDOs within 24 h of endoscopic biopsy and rapid drug testing within 2 weeks demonstrate the feasibility of our novel approach for future applications in clinical decision making. This proof of concept sets the foundation for future clinical trials using PDOs to predict clinical responses to GAd therapies.

Quantifying subtle but persistent peri-spine inflammation in vivo to submicron cobalt-chromium alloy particles.

PURPOSE: We evaluated the consequences of cobalt-chromium alloy (CoCr) wear debris challenge in the peri-spine region to determine the inflammation and toxicity associated with submicron particulates of CoCr-alloy and nickel on the peri-spine. METHODS: The lumbar epidural spaces of (n = 50) New Zealand white rabbits were challenged with: 2.5 mg CoCr, 5.0 mg CoCr, 10.0 mg CoCr, a positive control (20.0 mg of nickel) and a negative control (ISOVUE-M-300). The CoCr-alloy and Ni particles had a mean diameter of 0.2 and 0.6 µm, respectively. Five rabbits per dose group were studied at 12 and 24 weeks. Local and distant tissues were analyzed histologically and quantitatively analyzed immunohistochemically (TNF-α and IL-6). RESULTS: Histologically, wear particles were observed in all animals. There was no evidence of toxicity or local irritation noted during macroscopic observations in any CoCr-dosed animals. However, Ni-treated control animals experienced bilateral hind leg paralysis and were euthanized at Day 2. Histopathology of the Ni particle-treated group revealed severe neuropathy. Quantitative immunohistochemistry demonstrated a CoCr-alloy dose-dependent increase in cytokines (IL-6, TNF-α, p < 0.05) at 12 and 24 weeks. CONCLUSIONS: Subtle peri-spine inflammation associated with CoCr-alloy implant particles was dose dependent and persistent. Neuropathy can be induced by highly reactive Ni particles. This suggests peri-spine challenge with CoCr-alloy implant debris (e.g., TDA) is consistent with past reports using titanium alloy particles, i.e., mild persistent inflammation.

Current Trends in Cytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for Peritoneal Disease from Appendiceal and Colorectal Malignancies.

Peritoneal carcinomatosis (PC) is a poor prognostic factor for all malignancies. This extent of metastatic disease progression remains difficult to treat with systemic therapies due to poor peritoneal vascularization resulting in limited drug delivery and penetration into tissues. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are surgical interventions that directly target peritoneal tumors and have improved outcomes for PC resulting from appendiceal and colorectal cancer (CRC). Despite these radical therapies, long-term survival remains infrequent, and recurrence is common. The reasons for these outcomes are multifactorial and signal the need for the continued development of novel therapeutics, techniques, and approaches to improve outcomes for these patients. Here, we review landmark historical studies that serve as the foundation for current recommendations, recent discoveries, clinical trials, active research, and areas of future interest in CRS/HIPEC to treat PC originating from appendiceal and colorectal malignancies.

Interaction of immune checkpoint PD-1 and chemokine receptor 4 (CXCR4) promotes a malignant phenotype in pancreatic cancer cells.

Despite recent therapeutic advances, pancreatic ductal adenocarcinoma (PDAC) remains a devastating disease with limited therapeutic options. Immune checkpoint inhibitors (ICIs) have demonstrated promising results in many cancers, but thus far have yielded little clinical benefit in PDAC. Based on recent combined targeting of programmed cell death protein-1 (PD-1) and C-X-C chemokine receptor 4 (CXCR4) in patient-derived xenografts (PDXs) and a pilot clinical trial, we sought to elucidate potential interactions between PD-1 and CXCR4. We observed concomitant expression and direct interaction of PD-1 and CXCR4 in PDAC cells. This interaction was disrupted upon CXCR4 antagonism with AMD3100 and led to increased cell surface expression of PD-1. Importantly, CXCR4-mediated PDAC cell migration was also blocked by PD-1 inhibition. Our work provides a possible mechanism by which prior studies have demonstrated that combined CXCR4 and PD-1 inhibition leads to decreased tumor growth. This is the first report investigating PD-1 and CXCR4 interactions in PDAC cells and our results can serve as the basis for further investigation of combined therapeutic targeting of CXCR4 and PD-1.