Citations

PURPOSE The outcomes of anti–PD-1 agents plus fluoropyrimidine/platinum in frontline advanced gastroesophageal adenocarcinomas (aGEAs) remain poor. We investigated the safety, tolerability, and activity of fluoropyrimidine/oxaliplatin and tislelizumab with the DKK1-neutralizing antibody DKN-01 in aGEAs in a phase IIa open-label study. PATIENTS AND METHODS Patients had untreated human epidermal growth factor receptor 2–negative aGEAs, RECIST v1.1 measurable disease, Eastern Cooperative Oncology Group (ECOG) performance status 0-1, and adequate organ function. Patients received intravenous DKN-01 300 mg once every 2 weeks, tislelizumab 200 mg once every 3 weeks, oxaliplatin 130 mg/m 2 once every 3 weeks, and capecitabine 1,000 mg/m 2 twice daily on days 1-15 of each 21-day cycle. The primary end point was safety and tolerability. Key secondary end points included objective response rate (ORR) by RECISTv1.1, progression-free survival (PFS), and overall survival (OS). RESULTS Between September 18, 2020, and April 8, 2021, 25 patients were enrolled. All patients who received at least one dose of DKN-01 were included in the safety analysis. Most patients had gastroesophageal junction tumors, median age was 61 years, 76% were male, and 55% were ECOG of 0. All patients reported at least one treatment-emergent adverse event. The ORR was 73% (95% CI, 49.8 to 89.3), with a disease control rate of 95%. The ORR was 90% (95% CI, 55.5 to 99.7) in the DKK1-high tumor patients and 67% (95% CI, 29.9 to 92.5) in the DKK1-low tumor patients. The median PFS was 11.3 months (95% CI, 5.8 to 12.0) and the 12-month PFS rate was 33%. The median OS was 19.5 months (95% CI, 15.2 to 24.4) with a 12-month OS rate of 76% and an 18-month OS rate of 55%. CONCLUSION DKN-01 can be safely combined with frontline fluoropyrimidine/oxaliplatin and tislelizumab and demonstrates encouraging activity independent of PD-L1 expression levels. A randomized phase II trial is ongoing (ClinicalTrials.gov identifier: NCT04363801 ).

AbstractBackgroundThe E‐cadherin, α‐ and β‐Catenin interaction at the cell adherens junction plays a key role in cell adhesion; alteration in the expression and function of these genes are associated with disease progression in several solid tumors including prostate cancer. The membranous β‐Catenin is dynamically linked to the cellular cytoskeleton through interaction with α‐Catenin at amino acid positions threonine 120 (T120) to 151 of β‐Catenin. Nuclear presence of α‐Catenin modulates the sensitivity of cells to DNA damage. The objective of this study is to determine the role of α‐Catenin and protein kinase D1 (PrKD1) in DNA damage response.MethodsProstate cancer cells; LNCaP, LNCaP (Sh‐PrKD1; silenced PrKD1), C4‐2 and C4‐2 PrKD1 were used for various sets of experiments to determine the role of DNA damage in PrKD1 overexpression and silencing cells. These cells were treated with compound‐10 (100 nM) and Etoposide (30 µM), total cell lysates, cytosolic and nuclear fractions were prepared to observe various protein expressions. We performed single cell gel electrophoresis (COMET assay) to determine the etoposide induce DNA damage in C4‐2 and C4‐2 PrKD1 cells. The animal experiments were carried out to determine the tolerability of compound‐10 by mice and generate preliminary data on efficacy of compound‐10 in modulating the α‐Catenin and PrKD1 expressions in inhibiting tumor progression.ResultsPrKD1, a novel serine threonine kinase, phosphorylates β‐Catenin T120. In silico analysis, confirmed that T120 phosphorylation alters β‐ to α‐Catenin binding. Forced expression of PrKD1 in prostate cancer cells increased β‐ and α‐Catenin protein levels associated with reduced etoposide induced DNA damage. Downregulation of α‐Catenin abrogates the PrKD1 mitigation of DNA damage. The in vitro results were corroborated in vivo using mouse prostate cancer patient derived xenograft model by inhibition of PrKD1 kinase activity with compound‐10, a selective PrKD inhibitor, demonstrating decreased total β‐ and α‐Catenin protein levels, and β‐Catenin T120 phosphorylation.ConclusionsAlteration in DNA damage response pathways play major role in prostate cancer progression. The study identifies a novel mechanism of α‐Catenin dependent DNA damage mitigation role for PrKD1 in prostate cancer.

Abstract Purpose To investigate the feasibility of rapid CEST MRI acquisition for evaluating oxidative phosphorylation (OXPHOS) in human skeletal muscle at 3T, utilizing ultrafast Z‐spectroscopy (UFZ) combined with MRI and the Polynomial and Lorentzian line‐shape Fitting (PLOF) technique. Methods UFZ MRI on muscle was evaluated with turbo spin echo (TSE) and 3D EPI readouts. Five healthy subjects performed in‐magnet plantar flexion exercise (PFE) and subsequent changes of amide, PCr, and partial PCr mixed Cr (Cr + ) CEST dynamic signals post‐exercise were enabled by PLOF fitting. PCr/Cr CEST signal was further refined through pH correction by using the ratios between PCr/Cr and amide signals, named PCAR/CAR, respectively. Results UFZ MRI with TSE readout significantly reduces acquisition time, achieving a temporal resolution of <50 s for collecting high‐resolution Z‐spectra. Following PFE, the recovery/decay times (τ) for both PCr and Cr in the gastrocnemius muscle of the calf were notably longer when determined using PCr/Cr CEST compared to those after pH correction with amideCEST, namely = 87.1 ± 15.8 s and = 98.1 ± 20.4 s versus = 32.9 ± 19.7 s and = 43.0 ± 13.0 s, respectively. obtained via 31 P MRS ( = 50.3 ± 6.2 s) closely resemble those obtained from pH‐corrected PCr/Cr CEST signals. Conclusion The outcomes suggest potential of UFZ MRI as a robust tool for non‐invasive assessment of mitochondrial function in skeletal muscles. pH correction is critical for the reliable OXPHOS measurement by CEST.

Background: Value is defined as the ratio of patient outcomes to the cost of care. One method to assess value is through patient-level value analysis (PLVA). To our knowledge, this tool has not previously been implemented in the setting of total hip arthroplasty (THA). The purposes of this study were to perform PLVA for a 1-year episode of care among patients undergoing primary THA and to identify characteristics that affect value in a metropolitan health-care system. Methods: The patient-reported outcome (PRO) measure database of the institution was queried for all primary THAs from 2018 to 2019. The PRO measure that was utilized was the Hip disability and Osteoarthritis Outcome Score, Joint Replacement (HOOS-JR). Cost was evaluated with use of time-driven activity-based costing (TDABC) for a 1-year episode of care (consisting of the day of surgery, inpatient stay, discharge facility, postoperative appointments, and physical therapy). The primary outcome was the 1-year value quotient, or the ratio of the 1-year change in HOOS-JR to the cost of the episode of care (V HOOS ). The value quotient was compared among all included patients and evaluated for variables that may affect the overall value of the episode of care. Results: In total, 480 patients were included in the analysis. The mean improvement in the HOOS-JR was +34.9 ± 16.1 (95% confidence interval [CI]: 33.5, 36.3). The mean cost was $13,835 ± $3,471 (95% CI: $13,524, $14,146). The largest contributor to cost was implants (39.0%), followed by post-recovery care (i.e., inpatient stay and specialized nursing facilities; 24.1%). Change in the HOOS-JR was poorly correlated with the cost of care (r = −0.06; p = 0.19). THAs performed at an ambulatory surgery center (ASC) with discharge to home demonstrated higher value (V HOOS = 0.42) than THAs performed at a hospital with discharge to a rehabilitation facility (V HOOS = 0.15; analysis of variance F-test, p < 0.01). Conclusions: Our study found that PROs did not correlate with costs in the setting of primary THA. Implants were the largest cost driver. Surgical setting (an ASC versus a hospital) and discharge destination influenced value as well. PLVA is a value measurement tool that can be utilized to optimize components of the care delivery pathway. Level of Evidence: Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.

AbstractIntroductionPulsed field ablation (PFA) has emerged as an innovative therapy for cardiac arrhythmias. Drawing parallels with PFA's application in solid tumors, calcium chloride (CaCl2) as an adjuvant therapy, known as calcium electroporation, may amplify PFA's apoptotic effects. We propose that PFA in the atrium could enhance calcium uptake through PFA‐created pores, thereby increasing ablation efficacy even at reduced power levels by exploiting PFA's permeabilization effects.MethodsWe conducted in vivo ablations on the atria of seven pigs using low PFA power (250 V, 20 μs for 50 pulses at 200 ms intervals). Post‐PFA, we randomly administered an infusion of either 200 mg/2 ml CaCl2 (calcium group) or saline (control) directly to the ablation site via the catheter tip. We evaluated reduction in electrogram voltage amplitude, electrocardiography (ECG) parameters, ablation lesion parameters, and histology after PFA.ResultsNineteen lesions from control and calcium groups were examined. Control lesions showed no voltage decrease post‐PFA, whereas calcium‐treated lesions exhibited a significant voltage reduction. Gross pathology indicated marked differences in maximum lesion surface diameter, depth, and volume between the lesion groups. Histologically, calcium group lesions were characterized by a more severe acute PFA response with contraction band necrosis, myocytolysis and nuclear pyknosis in adjacent myocardium, in addition to microhemorrhages.ConclusionInfusing calcium chloride locally after PFA markedly improves the immediate efficacy of electroporation in porcine atria. This study suggests that calcium electroporation could bolster PFA outcomes without higher energy levels, potentially diminishing associated risks. These preliminary findings warrant further research into the long‐term efficacy and potential clinical application of calcium electroporation in PFA.

Reconstruction of the abductor mechanism remains a primary challenge with contemporary proximal femoral replacement (PFR) surgery. Previously, techniques such as trochanteric preservation or direct repair to the implant have been described; however, these strategies are limited in their ability to tension the repair and reattach other muscles of the hip girdle. The aim of this study was to evaluate the outcomes of patients undergoing oncologic PFR using a novel technique of mesh augmentation for soft tissue repair. Methods: We reviewed 18 (mean age 64 years; 8 female: 10 male) consecutive patients undergoing PFR with Marlex mesh augmentation between 2018 and 2023 at a single institution. The most common indication was metastatic disease (n = 13). The mean follow-up in the 14 surviving patients was 27 months (range 12–34). Results: All patients were ambulatory at final follow-up. There were no post-operative dislocations, infections, or wound issues. At the final follow-up, the mean total MSTS score was 77%. Conclusion: Mesh augmentation of PFRs allowed for adequate soft tissue tensioning and muscular attachment to the body of the implant. In our series, this technique was durable, with no dislocations and no mesh-related complications. In summary, mesh augmentation of PFRs may be considered during reconstruction for oncologic indications.

Abstract Objective The presence of comorbidities can substantially affect patients’ quality of life, but data regarding their impact on idiopathic inflammatory myopathies (IIMs) are limited. Methods We examined the prevalence of comorbidities in IIM patients, other autoimmune rheumatic diseases (oAIRDs) and healthy controls (HCs), using data from the self-reported COVAD-2 survey. We defined basic multimorbidity (BM) as the presence of ≥2 non-rheumatic chronic conditions and complex multimorbidity (CM) as the presence of ≥3 non-rheumatic chronic conditions affecting ≥3 organ systems. Hierarchical clustering on principal components was performed for grouping. Results Among the COVAD respondents, 1558 IIMs, 4591 oAIRDs and 3652 HCs were analysed. IIMs exhibited a high burden of comorbidities (odds ratio [OR]: 1.62 vs oAIRDs and 2.95 vs HCs, P &lt; 0.01), BM (OR: 1.66 vs oAIRDs and 3.52 vs HCs, P &lt; 0.01), CM (OR: 1.69 vs AIRDs and 6.23 vs HCs, P &lt; 0.01) and mental health disorders (MHDs) (OR: 1.33 vs oAIRDs and 2.63 vs HCs, P &lt; 0.01). Among the IIM patients, those with comorbidities or MHDs had lower PROMIS Global Physical (PGP), PROMIS Global Mental (PGM), and PROMIS Physical Function (SF10) scores, and higher fatigue (F4a) scores (all P &lt; 0.001). PGP, PGM, SF10a and F4a were influenced by age, active disease, BM and MHDs. Four distinct clusters were identified among the IIMs according to comorbidities and PROMIS scores. Conclusion Patients with IIMs have a higher burden of comorbidities that influence physical and mental health, identifiable as clinical clusters for optimized and holistic management approaches.

Humans with monogenic inborn errors responsible for extreme disease phenotypes can reveal essential physiological pathways. We investigated germline mutations in GNAI2 , which encodes G αi2 , a key component in heterotrimeric G protein signal transduction usually thought to regulate adenylyl cyclase–mediated cyclic adenosine monophosphate (cAMP) production. Patients with activating G αi2 mutations had clinical presentations that included impaired immunity. Mutant G αi2 impaired cell migration and augmented responses to T cell receptor (TCR) stimulation. We found that mutant G αi2 influenced TCR signaling by sequestering the guanosine triphosphatase (GTPase)–activating protein RASA2, thereby promoting RAS activation and increasing downstream extracellular signal–regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)–AKT S6 signaling to drive cellular growth and proliferation.

Background and Aims: This investigation examined the association of pancreatitis and pancreatitis-related pain with serum levels of two endocannabinoid molecules such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG) and two paracannabinoid molecules such as oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). Methods: A case–control study was conducted within the Prospective Evaluation of Chronic Pancreatitis for Epidemiological and Translational Studies, including participants with no pancreas disease ( N = 56), chronic abdominal pain of suspected pancreatic origin or indeterminate chronic pancreatitis (CP) ( N = 22), acute pancreatitis ( N = 33), recurrent acute pancreatitis ( N = 57), and definite CP ( N = 63). Results: Circulating AEA concentrations were higher in women than in men ( p = 0.0499), and PEA concentrations were higher in obese participants than those who were underweight/normal or overweight ( p = 0.003). Asymptomatic controls with no pancreatic disease had significantly ( p = 0.03) lower concentrations of AEA compared with all disease groups combined. The highest concentrations of AEA were observed in participants with acute pancreatitis, followed by those with recurrent acute pancreatitis, chronic abdominal pain/indeterminant CP, and definite CP. Participants with pancreatitis reporting abdominal pain in the past year had significantly ( p = 0.04) higher concentrations of AEA compared with asymptomatic controls. Levels of 2-AG were significantly lower ( p = 0.02) among participants reporting abdominal pain in the past week, and pain intensity was inversely associated with concentrations of 2-AG and OEA. Conclusions: Endocannabinoid levels may be associated with stage of pancreatitis, perhaps through activation of the CB1 receptor. Validation of our findings would support the investigation of novel therapeutics, including cannabinoid receptor-1 antagonists, in this patient population.

Background: Synovial sarcoma is rare and may present as a small, slow-growing mass. These tumors are often mistaken as benign and are therefore prone to unplanned and/or non-oncologic excision. We sought to identify the rate of unplanned excision of synovial sarcoma and risk factors for recurrence and survival among this cohort. Methods: The medical records of 246 patients evaluated at a single institution for synovial sarcoma between 1997 and 2022 were retrospectively reviewed. Of these, 87 (35%) underwent unplanned, non-oncologic excision. The mean age of the cohort was 49 years. Primary tumors were located in the extremity (n = 63), abdomen (n = 6), thorax (n = 7), head/neck (n = 8), and paraspinal region (n = 3). The median maximum pre-treatment dimension of the primary tumor was 4.8 cm (IQR 7–2.4). Seventy-seven (86%) patients underwent re-excision of the tumor bed, 39 (45%) received chemotherapy, and 63 (72%) received radiation therapy. Results: Among patients who underwent unplanned excision, local recurrence-free survival (LRFS) was 98% at 1 year and 82% at 5 years. Metastasis-free survival (MFS) was 91% at 1 year and 72% at 5 years. Disease-specific survival (DSS) was 98% at 1 year and 72% at 5 years. When adjusting for tumor size, tumors which underwent unplanned excision did not have worse recurrence or survival compared to those which had planned excision (p > 0.10). Size > 5 cm, monophasic subtype, and axial location were associated with increased risk of disease recurrence. Forty-six patients had residual tumor following re-excision, which was associated with worse MFS (HR 8.17, 95% CI [1.89, 35.2], p < 0.01) and DSS (HR 7.66, 95% CI [1.76, 33.4], p < 0.01). Patients who received radiotherapy had improved MFS (HR 6.4, 95% CI [1.42, 29.0], p = 0.02) and DSS (HR 5.86, 95% CI [1.27, 26.9], p = 0.02). Conclusions: One-third of patients presenting with synovial sarcoma were diagnosed after unplanned, non-oncologic excision. Patients with large, axial tumors had worse survival. Approximately half of patients who underwent unplanned excision had no residual tumor after pre-operative radiation. The use of radiation was associated with decreased rates of recurrence and improved disease-specific survival. Our results suggest that margin-negative re-resection and radiotherapy should be considered when feasible following unplanned excision of synovial sarcoma.