Citations

AbstractBackgroundIsolated limb infusion and perfusion (ILI/ILP) has been a mainstay treatment for unresectable melanoma in‐transit metastases (ITM), but increased use of immune checkpoint inhibitors (ICI) and intralesional therapy (talimogene laherparepvec [TVEC]) introduced several different management options. This study compares first‐line ILI/ILP, ICI, and TVEC.MethodsRetrospective review from 12 international institutions included patients treated from 1990 to 2022 with first‐line ILI/ILP, ICI, or TVEC for unresectable melanoma ITM.ResultsA total of 551 patients were treated, with ILI/ILP (n = 356), ICI (n = 125), and TVEC (n = 70) with median follow‐up of 5.5 years. Tumor burden was highest with ILI/ILP and lowest with TVEC (p = .002). Breslow thickness was lowest with TVEC (p = .007). TVEC was mostly used in stage IIIB disease versus IIIC for ILI/ILP and ICI (p = .01). Using ICI as the reference category, TVEC had the highest odds of a complete response (CR) (odds ratio, 1.96; p = .029) and a longer local progression‐free survival (PFS) (hazard ratio [HR], 0.40; p = .003). ILI/ILP had shorter local PFS (HR, 1.72; p = .012), PFS (HR, 1.79; p < .001), distant metastasis‐free survival (DMFS) (HR, 1.75; p = .014), overall survival (HR, 1.82; p = .009), and melanoma‐specific survival (HR, 2.29; p = .004). Stage IIIB disease had longer DMFS (HR, 0.24; p < .001) compared to IIIC/D.ConclusionsTVEC as first‐line therapy for unresectable melanoma ITM was associated with superior CR rates and local PFS. Notably, TVEC was used in patients with a lower Breslow thickness, disease stage, and tumor burden. Therefore, when compared to ILI/ILP and ICI, TVEC should be considered as first‐line therapy for unresectable stage IIIB melanoma ITM with minimal tumor burden and lower Breslow thickness.

Purpose: Autologous serum tears (ASTs) are produced from serum obtained by blood draw and used to treat severe dry eye diseases. Multiple cases of failed AST production occurred due to serum becoming a solidified, gel-like substance after centrifugation. The aim of this study was to identify risk factors associated with inability to compound AST. Methods: From January 2019 to December 2022, 99 patients received AST produced at Mayo Clinic in Arizona. Patient demographics, medical diagnoses, medications, laboratory results, and events surrounding blood draws were obtained through an IRB-approved retrospective chart review. The laboratory and pharmacy protocol procedures were observed in person after the occurrence of the last production issue. Results: Ten total clotted serum episodes occurred in 4 patients, each with multiple occurrences. The indication for AST was chronic ocular graft-vs-host disease (n = 3) and Sjögren syndrome (n = 1). Eighty percent of episodes were associated with either a systemic infection (n = 7) or pulmonary embolism (n = 1) within the prior month. At the time of blood draw, all 4 patients were treated with antiplatelet and/or anticoagulation medications, including rivaroxaban, apixaban, aspirin, and low–molecular-weight heparin. Conclusions: The AST protocol was increased from 30 to 60 minutes of resting time to allow clotting before centrifugation. Inadequate clotting during this stasis period likely resulted in fibrinogen remaining suspended in the serum, leading to solidified plasma instead of liquid serum. We hypothesize risk of inadequate clotting would be increased in patients taking anticoagulation or antiplatelet medications. Our recommendations include ensuring 60-minute collection tube resting time for all patients, including those on anticoagulation medication.

AbstractBackground and AimsPhysical activity (PA) is associated with higher gait speed. We aimed to examine the associations between PA and change in spatial and temporal gait measures as well as fall risk in community‐dwelling individuals free of dementia.MethodsLongitudinal study among 4173 individuals aged ≥50 years (mean age 71 years; 2078 males; median follow‐up 4 years) enrolled in the Mayo Clinic Study of Aging. Self‐reported late‐life PA was used to calculate overall PA and moderate‐vigorous PA (MVPA) scores. Gait was assessed using GAITRite® and Zeno™ systems. Incident falls information was based on diagnostic codes retrieved from medical records. We ran linear mixed effects models to examine associations between z‐scored PA variables and longitudinal gait parameters, adjusted for age, sex, education, body mass index (BMI), medical comorbidities, and including interactions between PA and time since baseline. In secondary analyses, we calculated Cox Proportional hazard models with age as time scale predicting incident falls by PA, adjusting for sex, education, BMI, medical comorbidities, and falls history.ResultsAt baseline, higher PA was associated with higher velocity (overall PA: estimate 2.9935; MVPA: 2.2961; p < 0.001), higher cadence (overall PA: 1.0665; MVPA: 0.9073; p < 0.001), greater stride length (overall PA: 2.0805; MVPA: 1.4726; p < 0.001), shorter double support time (overall PA: −0.0257; MVPA: −0.0205; p < 0.001), and lower stance time variability (overall PA: −0.0204, p < 0.001; MVPA: −0.0152; p = 0.006). Overall PA was longitudinally associated with less decline in cadence, and MVPA with less increase in intraindividual stance time variability. Overall PA (Hazard ratio 0.892, 95% confidence interval 0.828–0.961, p = 0.003) and MVPA (HR 0.901; 95% CI 0.835–0.973, p = 0.008) were associated with a decreased risk of incident falls.ConclusionLate‐life PA was associated with favorable gait outcomes and decreased risk of incident falls. Thus, late‐life PA may help to maintain gait performance and decrease fall risk in old age.

Background: Revision anterior cruciate ligament (ACL) reconstruction has been documented to have inferior outcomes compared with primary ACL reconstruction. The reasons why remain unknown. Purpose: To determine whether surgical factors performed at the time of revision ACL reconstruction can influence a patient’s outcome at 6-year follow-up. Study Design: Cohort study; Level of evidence, 2. Methods: Patients who underwent revision ACL reconstruction were identified and prospectively enrolled between 2006 and 2011. Data collected included baseline patient characteristics, surgical technique and pathology, and a series of validated patient-reported outcome instruments: Knee injury and Osteoarthritis Outcome Score (KOOS), International Knee Documentation Committee (IKDC) subjective form, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and Marx activity rating score. Patients were followed up for 6 years and asked to complete the identical set of outcome instruments. Regression analysis was used to control for baseline patient characteristics and surgical variables to assess the surgical risk factors for clinical outcomes 6 years after surgery. Results: A total of 1234 patients were enrolled (716 men, 58%; median age, 26 years), and 6-year follow-up was obtained on 79% of patients (980/1234). Using an interference screw for femoral fixation compared with a cross-pin resulted in significantly better outcomes in 6-year IKDC scores (odds ratio [OR], 2.2; 95% CI, 1.2-3.9; P = .008) and KOOS sports/recreation and quality of life subscale scores (OR range, 2.2-2.7; 95% CI, 1.2-4.8; P < .01). Use of an interference screw compared with a cross-pin resulted in a 2.6 times less likely chance of having a subsequent surgery within 6 years. Use of an interference screw for tibial fixation compared with any combination of tibial fixation techniques resulted in significantly improved scores for IKDC (OR, 1.96; 95% CI, 1.3-2.9; P = .001); KOOS pain, activities of daily living, and sports/recreation subscales (OR range, 1.5-1.6; 95% CI, 1.0-2.4; P < .05); and WOMAC pain and activities of daily living subscales (OR range, 1.5-1.8; 95% CI, 1.0-2.7; P < .05). Use of a transtibial surgical approach compared with an anteromedial portal approach resulted in significantly improved KOOS pain and quality of life subscale scores at 6 years (OR, 1.5; 95% CI, 1.02-2.2; P≤ .04). Conclusion: There are surgical variables at the time of ACL revision that can modify clinical outcomes at 6 years. Opting for a transtibial surgical approach and choosing an interference screw for femoral and tibial fixation improved patients’ odds of having a significantly better 6-year clinical outcome in this cohort.

ABSTRACT Background The sterol regulatory element‐binding protein (SREBP) pathway is essential for maintaining sterol homeostasis during B cell activation and germinal center B cell proliferation. However, its potential as a therapeutic target to treat B‐cell lymphoma remains unclear. Methods We examined SREBP protein expression in human B‐cell lymphoma samples using immunohistochemistry. Additionally, we conducted in vitro studies using SREBP signaling inhibitors in combination with rapamycin to assess their effects on cell proliferation and lipid metabolism in B‐cell lymphoma cells. Results Our analysis revealed high levels of SREBP2 protein expression in human B‐cell lymphoma samples. Inhibiting SREBP signaling or its downstream target HMG‐CoA reductase (HMGCR) with Fatostatin or Simvastatin effectively suppressed B‐cell lymphoma cell proliferation. However, B‐cell lymphoma cells responded to statin treatment by activating the mTORC1‐pS6 pathway, suggesting a compensatory mechanism to overcome statin‐induced cell cycle arrest. Combining low‐dose statin treatment with the mTOR inhibitor rapamycin produced a synergistic effect, significantly inhibiting B‐cell lymphoma proliferation, cell cycle progression, and lipid raft formation. Conclusions These results highlight the potential of a combined therapeutic approach targeting both SREBP and mTORC1 as a novel strategy for treating B‐cell lymphoma.

Background Despite advances in cancer care and detection, >65% of patients with squamous cell cancer of the head and neck (HNSCC) will develop recurrent and/or metastatic disease. The prognosis for these patients is poor with a 5-year overall survival of 39%. Recent treatment advances in immunotherapy, including immune checkpoint inhibitors like pembrolizumab and nivolumab, have resulted in clinical benefit in a subset of patients. There is a critical clinical need to identify patients who benefit from these antiprogrammed cell death protein 1 (anti-PD-1) immune checkpoint inhibitors. Methods Here, we report findings from a multicenter observational study, PREDicting immunotherapy efficacy from Analysis of Pre-treatment Tumor biopsies (PREDAPT), conducted across 17 US healthcare systems. PREDAPT aimed to validate OncoPrism-HNSCC, a clinical biomarker assay predictive of disease control in patients with recurrent or metastatic HNSCC treated with anti-PD-1 immune checkpoint inhibitors as a single agent (monotherapy) and in combination with chemotherapy (chemo-immunotherapy). The test used RNA-sequencing data and machine learning models to score each patient and place them into groups of low, medium, or high. Results The OncoPrism-HNSCC prediction significantly correlated with disease control in both the monotherapy cohort (n=62, p=0.004) and the chemo-immunotherapy cohort (n=50, p=0.01). OncoPrism-HNSCC also significantly predicted progression-free survival in both cohorts (p=0.015 and p=0.037, respectively). OncoPrism-HNSCC had more than threefold higher specificity than programmed death-ligand 1 combined positive score and nearly fourfold higher sensitivity than tumor mutational burden for predicting disease control. Conclusions Here, we demonstrate the clinical validity of the OncoPrism-HNSCC assay in identifying patients with disease control in response to anti-PD-1 immune checkpoint inhibitors. Trial registration number NCT04510129.

BACKGROUND Despite an overall poor prognosis, about 15% of patients with advanced-stage tubo-ovarian high-grade serous carcinoma (HGSC) survive 10 or more years after standard treatment. METHODS We evaluated the tumor microenvironment of this exceptional, understudied group using a large international cohort enriched for long-term survivors (LTS; 10+ years; n = 374) compared with mid-term (MTS; 5–7.99 years; n = 433) and short-term survivors (STS; 2–4.99 years; n = 416). Primary tumor samples were immunostained and scored for intraepithelial and intrastromal densities of 10 immune-cell subsets (including T cells, B cells, plasma cells, myeloid cells, PD-1 + cells, and PD-L1 + cells) and epithelial content. RESULTS Positive associations with LTS compared with STS were seen for 9 of 10 immune-cell subsets. In particular, the combination of intraepithelial CD8 + T cells and intrastromal B cells showed near 5-fold increased odds of LTS compared with STS. All of these associations were stronger in tumors with high epithelial content and/or the C4/Differentiated molecular subtype, despite immune-cell densities generally being higher in tumors with low epithelial content and/or the C2/Immunoreactive molecular subtype. CONCLUSION The tumor microenvironment of HGSC LTS is distinguished by the intersection of T and B cell coinfiltration, high epithelial content, and C4/differentiated molecular subtype, features which may inspire new approaches to immunotherapy. FUNDING Ovarian Cancer Research Program (OCRP) of the Congressionally Directed Medical Research Program (CDMRP), U.S. Department of Defense (DOD); American Cancer Society; BC Cancer Foundation; Canada’s Networks of Centres of Excellence; Canadian Cancer Society; Canadian Institutes of Health Research; Cancer Councils of New South Wales, Victoria, Queensland, South Australia, and Tasmania, Cancer Foundation of Western Australia; Cancer Institute NSW; Cancer Research UK; Deutsche Forschungsgesellschaft; ELAN Funds of the University of Erlangen-Nuremberg; Fred C. and Katherine B. Andersen Foundation; Genome BC; German Cancer Research Center; German Federal Ministry of Education and Research, Programme of Clinical Biomedical Research; Instituto de Salud Carlos III; Mayo Foundation; Minnesota Ovarian Cancer Alliance; Ministerio de Economía y Competitividad; Medical Research Council (MRC); National Center for Advancing Translational Sciences; National Health and Medical Research Council of Australia (NHMRC); Ovarian Cancer Australia; Peter MacCallum Foundation; Sydney West Translational Cancer Research Centre; Terry Fox Research Institute; The Eve Appeal (The Oak Foundation); UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge; University of Pittsburgh School of Medicine; U.S. National Cancer Institute of the National Institutes of Health; VGH & UBC Hospital Foundation; Victorian Cancer Agency.