Citations

Abstract Lessons learned Intravenous paricalcitol did not improve the efficacy of pembrolizumab, likely related to the short half-life. Background Immunotherapy has limited benefit in the treatment of advanced pancreatic cancer with the tumor microenvironment playing a key role in immune resistance. In preclinical studies, vitamin D receptor (VDR) agonists have been shown to sensitize pancreatic tumors to PD-1 blockade. Methods This was a randomized, double-blinded, placebo-controlled, phase II trial to evaluate pembrolizumab with or without paricalcitol as maintenance therapy for patients with metastatic pancreatic ductal adenocarcinoma (PDAC). Participants were ≥18 years; histologically or cytologically confirmed metastatic PDAC showing no disease progression after frontline systemic therapy, and achieving maximal cytoreduction (eg, with no further antitumor effect), Eastern Cooperative Oncology Group (ECOG) status of 0 or 1; adequate organ function. Study treatment included: pembrolizumab 200 mg IV every 3 weeks and either paricalcitol 25 mcg IV 3 times per week or placebo. The primary objective was to evaluate 6-month progression free survival (PFS). Secondary objectives include evaluating the toxicity of the combination and overall survival (OS). Results There was no significant difference in 6-month PFS, median PFS, median OS, nor treatment-related AEs between the 2 arms. Conclusions and relevance Paricalcitol did not improve the efficacy of pembrolizumab likely related to its short half-life of only 5-7 hours. Microbiome analysis revealed significant difference between long-term (>12 weeks) and short-term (<12 weeks) survival groups across treatment arms. Modulation of the tumor microenvironment will likely require more sustained VDR activity. Trial Registration Clinicaltrials.gov, ID: NCT03331562.

Abstract Background Sarcomatoid carcinomas (SC) are rare tumors with both epithelial and mesenchymal characteristics, linked to aggressive behavior and poor prognosis. Sarcomatoid carcinoma of unknown primary (SCUP) is an exceedingly rare subset with limited literature and no standardized management guidelines. This study aims to characterize the clinical presentations, treatment patterns, and genomic landscape of SCUP. Patients and Methods Data were retrospectively collected from the Mayo Clinic Rochester Cancer of Unknown Primary Registry. Patients included had biopsy-proven SC with no identifiable primary tumor despite comprehensive diagnostic evaluations. Baseline characteristics, immunohistochemistry (IHC) results, next-generation sequencing (NGS) data, and treatment outcomes were analyzed. Statistical analyses included descriptive statistics, Kaplan–Meier survival estimates, and Cox proportional hazards regression. Results Fifty-two SCUP patients were identified, with a median age of 60 years. Most patients presented with widely metastatic disease, particularly lytic bone lesions. Elevated alkaline phosphatase (ALP) was noted in nearly half of the patients. IHC showed high positivity for AE1/AE3 and OSCAR antibodies. Tumor NGS revealed 247 alterations, with TP53 being the most common mutation. Patients receiving definitive therapy had a median overall survival (OS) of 72 months, significantly longer than those receiving systemic therapy (14 months). Immunotherapy was a significant prognostic factor, reducing the risk of death by 90%. Conclusions This study provides essential insights into the clinical and genomic characteristics of SCUP, advocating for the integration of definitive therapy and immunotherapy in treatment protocols. Further prospective studies are needed to validate these findings and improve patient outcomes.

Background Lipoprotein(a) [Lp(a)] is an independent, causal risk factor for cardiovascular disease. However, it is still unclear whether controlling low-density lipoprotein cholesterol (LDL-C) to optimal levels can attenuate cardiovascular risk mediated by elevated Lp(a), especially in the setting of secondary prevention. Methods Adult patients with a baseline Lp(a) measurement who underwent percutaneous coronary intervention (PCI) and reached their LDL-C target levels (<70 mg/dl) at Mayo Clinic sites between 2006 and 2017 were included. Primary outcomes included major adverse cardiovascular events (MACE) and all-cause mortality. Kaplan–Meier curves were created to compare the survival probabilities among patients with Lp(a) ≥ 50 mg/dl compared with Lp(a) < 50 mg/dl. Multivariable Cox regression analyses were performed to quantify the association of elevated Lp(a) with our relevant outcomes and to control for possible confounders. Results In total, 878 patients (median age: 68 years, and 74% males) who underwent PCI were included for analysis. Of them, 29.7% had elevated Lp(a) ≥ 50 mg/dl. Kaplan–Meier curves did not reveal any significant difference in survival probabilities for elevated Lp(a) for any outcome including MACE (P = 0.91), all-cause mortality (P = 0.26), or the separate MACE components. Similarly, the multivariable analysis showed no significant association for MACE (hazard ratio: 1.07, 95% confidence interval: 0.84–1.37) or all-cause mortality (hazard ratio: 0.98, 95% confidence interval: 0.74–1.30). Conclusion In patients who underwent PCI and have their LDL-C controlled below 70 mg/dl, no significant association was found between elevated Lp(a) ≥ 50 mg/dl and risk for MACE or all-cause mortality.

Chronic myelomonocytic leukemia (CMML) is a severe myeloid malignancy with limited therapeutic options. Single-cell analysis of clonal architecture demonstrates early clonal dominance with few residual WT hematopoietic stem cells. Circulating myeloid cells of the leukemic clone and the cytokines they produce generate a deleterious inflammatory climate. Our hypothesis is that therapeutic control of the inflammatory component in CMML could contribute to stepping down disease progression. The present study explored the contribution of immature granulocytes (iGRANs) to CMML progression. iGRANs were detected and quantified in the peripheral blood of patients by spectral and conventional flow cytometry. Their accumulation was a potent and independent poor prognostic factor. These cells belong to the leukemic clone and behaved as myeloid-derived suppressor cells. Bulk and single-cell RNA-Seq revealed a proinflammatory status of iGRAN that secreted multiple cytokines of which CXCL8 was at the highest level. This cytokine inhibited the proliferation of WT but not CMML hematopoietic stem and progenitor cells (HSPCs) in which CXCL8 receptors were downregulated. CXCL8 receptor inhibitors and CXCL8 blockade restored WT HSPC proliferation, suggesting that relieving CXCL8 selective pressure on WT HSPCs is a potential strategy to slow CMML progression and restore some healthy hematopoiesis.

Ambulatory anesthesia for same-day surgery is a fast-growing and ever-improving branch of modern anesthesia. This is primarily driven by the involvement of anesthesiologists as perioperative physicians working in multidisciplinary groups. These groups work together to improve patient safety, patient outcomes, and overall efficiency of both in-patient and out-patient surgery. Appropriate patient selection and optimization are critical to maintain and improve the foundational entities of best ambulatory anesthesia practice. In this review article, a selection of considerations in the field of ambulatory anesthesia are featured, such as the aging population, sleep apnea, obesity, diabetes, cardiac disease, substance abuse, preoperative medication management, multimodal analgesia, social determinants of health, and surgical facility resources.

BACKGROUND AND OBJECTIVES: Despite standard of care with maximal safe resection and chemoradiation, glioblastoma (GBM) is the most common and aggressive type of primary brain cancer. Surgical resection provides a window of opportunity to locally treat gliomas while the patient is recovering and before initiating concomitant chemoradiation. The objective was to assess the safety and establish the maximum tolerated dose of adipose-derived mesenchymal stem cells (AMSCs) for the treatment of recurrent GBM. Secondary objectives were to assess the toxicity profile and long-term survival outcomes of patients enrolled in the trial. In addition, biospecimens will be collected to explore the local and systemic responses to this therapy. METHODS: We will conduct a phase 1, dose-escalated, nonrandomized, open-label, clinical trial of patients with GBM who are undergoing surgical resection for recurrence. Up to 18 patients will receive intracavitary application of AMSCs encapsulated in fibrin glue during surgical resection. All patients will be followed for up to 5 years for safety and survival data. Adverse events will be recorded using the CTCAE V5.0. EXPECTED OUTCOMES: This study will explore the maximum tolerated dose of AMSCs along with the toxicity profile of this therapy in patients with recurrent GBM. In addition, preliminary long-term survival and progression-free survival outcome analysis will be used to power further randomized studies. Finally, cerebrospinal fluid and blood will be obtained throughout the treatment period to investigate circulating molecular and inflammatory tumoral/stem cell markers and explore the mechanism of action of the therapeutic intervention. DISCUSSION: This prospective translational study will determine the initial safety and toxicity profile of local delivery of AMSCs for recurrent GBM. It will also provide additional survival metrics for future randomized trials.

INTRODUCTION: Gastroparesis is a debilitating gastroduodenal disorder for which gastric peroral endoscopic myotomy (GPOEM) has emerged as an efficacious treatment option. However, response to GPOEM varies between 50% and 80%, such that preoperative predictors of treatment success are needed to guide patient selection. METHODS: We performed a systematic review to identify predictors of clinical and functional response to GPOEM among adult patients with gastroparesis (PROSPERO: CRD42023457359). MEDLINE, Embase, and CENTRAL databases were searched systematically for studies reporting outcomes after GPOEM in September 2023. A narrative synthesis of predictive factors on univariable and multivariable analysis was performed with consideration of response rates through meta-analysis and evaluation of discrimination if prognostic models were developed. Risk Of Bias In Non-randomized Studies - of Exposures (ROBINS-E) was used for risk of bias assessment. RESULTS: Of 1899 articles reviewed, 30 were included. The GPOEM response rate was 63.1% (95% confidence interval 56.3%–69.5%) with most studies defining clinical success on the basis of improvement in gastroparesis cardinal symptom index (87%, 26/30). Older age, shorter duration of gastroparesis, nondiabetic etiology, lower body mass index, and response to intrapyloric botulinum toxin were associated with positive response to GPOEM on multivariable analyses. Predictors on physiological tests such as EndoFLIP or gastric emptying scintigraphy were inconsistent. No prognostic models underwent external validation. DISCUSSION: Currently, there are limited reproducible predictors of response to GPOEM among patients with refractory gastroparesis. Robust prospective studies investigating scalable, reproducible, and actionable biomarkers of treatment response are required.

INTRODUCTION: The performance of a high quality esophagogastroduodenoscopy (EGD) is dependent on the mucosal cleanliness. Recently, the Polprep: Effective Assessment of Cleanliness in EGD (PEACE) scale was created to assess the degree of mucosal cleanliness during EGD. The aim of this study was to validate this scoring system in a cohort of international endoscopists. METHODS: In total, 39 EGD videos, with different degrees of mucosal cleanliness were retrieved from a previously conducted prospective trial. All experts rated the cleanliness of the mucosa on each video using the PEACE scale. To evaluate agreement of all scores (0–3), intraclass correlation coefficient 2.1 was used. The agreement on adequate (scores 2 and 3) and inadequate (scores 0 and 1) cleanliness was assessed using kappa values. RESULTS: Videos evaluating esophagus, stomach, and duodenum cleanliness were reviewed by 16 endoscopists. The PEACE scores demonstrated good agreement (intraclass correlation coefficient 0.82, 95% CI 0.75–0.89), especially for esophagus (0.84; 95% CI 0.71–0.95) and stomach (0.81; 95% CI 0.69–0.91), while agreement was moderate for the duodenum (0.69; 95% CI 0.51–0.87). The agreement was similar between Eastern (0.86; 95% CI 0.79–0.92) and Western experts (0.80; 95% CI 0.72–0.88). Similarly, agreement regarding adequate cleanliness was comparable between Eastern (0.70; 95% CI 0.55–0.85) and Western (0.74; 95% CI 0.64–0.84) endoscopists being overall 0.75 (95% CI 0.65–0.85). DISCUSSION: The PEACE scoring system is a simple and reliable scale to assess the cleanliness during EGD. The score is now validated among international experts with high concordance, justifying its use in clinical practice.

Introduction: Gray-white matter ratio (GWR) on non-contrast head computed tomography (HCT) is a helpful tool in neuro-prognostication in post-cardiac arrest patients. Its usage is unclear for those with angiography due to residual contrast. Hypothesis: GWR remains valid for neuro-prognostication in comatose patients undergoing extracorporeal cardiopulmonary resuscitation (ECPR) followed by coronary angiography (CAG) after out-hospital cardiac arrest (OHCA). Methods: We performed a retrospective study of comatose OHCA adults post ECPR and CAG at University of Minnesota from January to June 2022 with dual energy HCT within 12 hours. GWR was measured at basal ganglia, centrum semiovale, and high convexity levels. Gray matter areas of interest included caudate nucleus, putamen, thalamus, and medial cortex. The white matter areas of interest included the genu of the corpus callosum, posterior limb of the internal capsule, and medial white matter. Circular regions of interest (ROI, 10-15 mm 2 ) were placed bilaterally in corresponding areas to record the average attenuation in Hounsfield unit (HU). The basal ganglia, cerebrum, and overall GWRs were calculated as the ratio of average HU between the gray and white matter ROIs within the area. Primary outcome was inpatient death, further categorized by the primary cause being neurological or not. Logistic regression followed by receiver operating characteristic (ROC) curves was used to validate GWR in predicting death. All data analysis was performed by StataCorp Software (STATA 14). Result: 25 patients were included in the study. 18 (72%) were male with a median age of 60 (interquartile range (IQR): 45-67). The initial HCT was obtained at 2.08 hours (median, IQR: 1.37–2.43) post ECPR cannulation. 7 (28%) patients died from brain death or herniation and 15 (60%) died from non-neurological causes. None had intracranial bleeding. 1 patient had unilateral hypodensity on initial HCT, suggesting an acute embolic infarct. Patients who died had lower GWRs on initial HCT (Figure 1). ROC regression showed all GWRs demonstrated good prognostic performance on inpatient death with area under the curve (AUC) of 0.6970 (basal ganglia), 0.8485 (cerebrum), and 0.7576 (overall) (Figure 2). Conclusions: GWR in early HCT has prognostic value in predicting neurological outcomes despite residual contrast. It may be used as a risk stratification tool for comatose OHCA patients undergoing ECPR and angiography.