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AbstractBackgroundAdipocyte-derived adiponectin may play a role in the host inflammatory response to cancer. We examined the association of plasma adiponectin with the density of tumor-infiltrating lymphocytes (TILs) in colon cancers and with vitamin D, clinicopathological features, and patient survival.MethodsPlasma adiponectin and 25-hydroxyvitamin D [25(OH)D] were analyzed by radioimmunoassay in 600 patients with stage III colon cancer who received FOLFOX-based adjuvant chemotherapy (NCCTG N0147 [Alliance]). TIL densities were determined in histopathological sections. Associations with disease-free survival (DFS), time to recurrence, and overall survival were evaluated by multivariable Cox regression adjusting for potential confounders (ie, body mass index, race, TILs, and N stage). All statistical tests were 2-sided.ResultsWe found a statistically significant reduction in adiponectin, but not 25(OH)D, levels in tumors with high vs low TIL densities (median = 6845 vs 8984 ng/mL; P = .04). A statistically significant reduction in adiponectin was also observed in obese (body mass index >30 kg/m2) vs nonobese patients (median = 6608 vs 12 351 ng/mL; P < .001), in men vs women (median = 8185 vs 11 567 ng/mL; P < .001), in Blacks vs Whites or Asians (median = 6412 vs 8847 vs 7858 ng/mL; P < .03), and in those with fewer lymph node metastases (N1 vs N2: median = 7768 vs 9253 ng/mL; P = .01). Insufficiency of 25(OH)D (<30 ng/mL) was detected in 291 (48.5%) patients. In multivariable analyses, neither adiponectin nor 25(OH)D were associated with a statistically significant difference in DFS, overall survival , or time to recurrence in models adjusted for potential confounders. We found a statistically significant association of TILs with prognosis, yet no such interaction was observed for the association of adiponectin with TILs for DFS.ConclusionsLower circulating adiponectin levels were associated with a statistically significant increase in TIL densities in colon cancers, indicating an enhanced antitumor immune response. In contrast to TILs, neither adiponectin nor 25(OH)D was independently prognostic.

Abstract BACKGROUND Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) is an increasingly utilized treatment of drug-resistant epilepsy. To date, the effect of high-frequency stimulation (HFS) vs low-frequency stimulation (LFS) in ANT DBS is poorly understood. OBJECTIVE To assess differences in the acute effect of LFS vs HFS in ANT DBS utilizing blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI). METHODS In this prospective study of 5 patients with ANT DBS for epilepsy, BOLD activation and deactivation were modeled for 145-Hz and 30-Hz ANT stimulation using an fMRI block design. Data were analyzed with a general linear model and combined via 2-stage mixed-effects analysis. Z-score difference maps were nonparametrically thresholded using cluster threshold of z > 3.1 and a (corrected) cluster significance threshold of P = .05. RESULTS HFS produced significantly greater activation within multiple regions, in particular the limbic and default mode network (DMN). LFS produced minimal activation and failed to produce significant activation within these same networks. HFS produced widespread cortical and subcortical deactivation sparing most of the limbic and DMN regions. Meanwhile, LFS produced deactivation in most DMN and limbic structures. CONCLUSION Our results show that HFS and LFS produce substantial variability in both local and downstream network effects. In particular, largely opposing effects were identified within the limbic network and DMN. These findings may serve as a mechanistic basis for understanding the potential of HFS vs LFS in various epilepsy syndromes.

Expanding the US Food and Drug Administration–approved indications for immune checkpoint inhibitors in patients with cancer has resulted in therapeutic success and immune-related adverse events (irAEs). Neurologic irAEs (irAE-Ns) have an incidence of 1%–12% and a high fatality rate relative to other irAEs. Lack of standardized disease definitions and accurate phenotyping leads to syndrome misclassification and impedes development of evidence-based treatments and translational research. The objective of this study was to develop consensus guidance for an approach to irAE-Ns including disease definitions and severity grading. A working group of four neurologists drafted irAE-N consensus guidance and definitions, which were reviewed by the multidisciplinary Neuro irAE Disease Definition Panel including oncologists and irAE experts. A modified Delphi consensus process was used, with two rounds of anonymous ratings by panelists and two meetings to discuss areas of controversy. Panelists rated content for usability, appropriateness and accuracy on 9-point scales in electronic surveys and provided free text comments. Aggregated survey responses were incorporated into revised definitions. Consensus was based on numeric ratings using the RAND/University of California Los Angeles (UCLA) Appropriateness Method with prespecified definitions. 27 panelists from 15 academic medical centers voted on a total of 53 rating scales (6 general guidance, 24 central and 18 peripheral nervous system disease definition components, 3 severity criteria and 2 clinical trial adjudication statements); of these, 77% (41/53) received first round consensus. After revisions, all items received second round consensus. Consensus definitions were achieved for seven core disorders: irMeningitis, irEncephalitis, irDemyelinating disease, irVasculitis, irNeuropathy, irNeuromuscular junction disorders and irMyopathy. For each disorder, six descriptors of diagnostic components are used: disease subtype, diagnostic certainty, severity, autoantibody association, exacerbation of pre-existing disease or de novo presentation, and presence or absence of concurrent irAE(s). These disease definitions standardize irAE-N classification. Diagnostic certainty is not always directly linked to certainty to treat as an irAE-N (ie, one might treat events in the probable or possible category). Given consensus on accuracy and usability from a representative panel group, we anticipate that the definitions will be used broadly across clinical and research settings.

PURPOSE CMB305 is a heterologous prime-boost vaccination regimen created to prime NY-ESO-1–specific CD8 T-cell populations and then activate the immune response with a potent TLR-4 agonist. This open-label randomized phase II trial was designed to investigate the efficacy and safety of adding the CMB305 regimen to atezolizumab (anti–programmed death ligand-1 therapy) in comparison with atezolizumab alone in patients with synovial sarcoma or myxoid liposarcoma. PATIENTS AND METHODS Patients with locally advanced, relapsed, or metastatic synovial sarcoma or myxoid liposarcoma (any grade) were randomly assigned to receive CMB305 with atezolizumab (experimental arm) or atezolizumab alone (control arm). The primary end points were progression-free survival (PFS) and overall survival (OS) analyzed using the Kaplan-Meier method. Safety and immune responses were assessed. RESULTS A total of 89 patients were enrolled; 55.1% had received ≥ 2 prior lines of chemotherapy. Median PFS was 2.6 months and 1.6 months in the combination and control arms, respectively (hazard ratio, 0.9; 95% CI, 0.6 to 1.3). Median OS was 18 months in both treatment arms. Patients treated with combination therapy had a significantly higher rate of treatment-induced NY-ESO-1–specific T cells ( P = .01) and NY-ESO-1–specific antibody responses ( P < .0001). In a post hoc analysis of all dosed patients, OS was longer (36 months) in the subset who developed anti-NY-ESO-1 T-cell immune response (hazard ratio, 0.3; P = .02). CONCLUSION Although the combination of CMB305 and atezolizumab did not result in significant increases in PFS or OS compared with atezolizumab alone, some patients demonstrated evidence of an anti-NY-ESO-1 immune response and appeared to fare better by imaging than those without such an immune response. Combining prime-boost vaccines such as CMB305 with anti–programmed death ligand-1 therapies merits further evaluation in other clinical contexts.

Background We hypothesize that different positions of the wrist in the coronal plane makes the carpus susceptible to ulnar impaction. Methods We prospectively enrolled 10 adult volunteers and obtained fluoroscopic images of each wrist in 12 different positions using a standardized protocol. Distances from the ulna to the lunate (UL) and ulna to the triquetrum (UT) were digitally measured as was the portion of the lunate surface area that was uncovered (LUR) with wrist deviation. Results A wrist position of Pronation, Neutral Deviation, and Grip (P-ND-G) significantly shortened the ulnocarpal distance when compared to a position of Neutral Rotation, Neutral Deviation, and No Grip (NR-ND-NG). Radial deviation during pronation and gripping (Pronated, Radial Deviation, Gripping [P-RD-G]) resulted in the lowest mean UL distance (1.2 mm). UT distance was minimized by a position of ulnar deviation during a pronated grip (Pronated, Ulnar Deviation, Gripping [P-UD-G]) (3.1 mm). The lunate becomes more uncovered with radial deviation. Conclusion Radial deviation minimizes the UL distance while ulnar deviation minimizes the UT distance during a wrist position of pronation and gripping. Further, there is more proximal lunate surface area uncoverage during all positions of radial deviation compared to ulnar deviation.

OBJECTIVE The impact of the type of pain presentation on outcomes of spine surgery remains elusive. The aim of this study was to assess the impact of predominant symptom location (predominant arm pain vs predominant neck pain vs equal neck and arm pain) on postoperative improvement in patient-reported outcomes. METHODS The Quality Outcomes Database cervical spine module was queried for patients undergoing 1- or 2-level anterior cervical discectomy and fusion (ACDF) for degenerative spine disease. RESULTS A total of 9277 patients were included in the final analysis. Of these patients, 18.4% presented with predominant arm pain, 32.3% presented with predominant neck pain, and 49.3% presented with equal neck and arm pain. Patients with predominant neck pain were found to have higher (worse) 12-month Neck Disability Index (NDI) scores (coefficient 0.24, 95% CI 0.15–0.33; p < 0.0001). The three groups did not differ significantly in odds of return to work and achieving minimal clinically important difference in NDI score at the 12-month follow-up. CONCLUSIONS Analysis from a national spine registry showed significantly lower odds of patient satisfaction and worse NDI score at 1 year after surgery for patients with predominant neck pain when compared with patients with predominant arm pain and those with equal neck and arm pain after 1- or 2-level ACDF. With regard to return to work, all three groups (arm pain, neck pain, and equal arm and neck pain) were found to be similar after multivariable analysis. The authors’ results suggest that predominant pain location, especially predominant neck pain, might be a significant determinant of improvement in functional outcomes and patient satisfaction after ACDF for degenerative spine disease. In addition to confirmation of the common experience that patients with predominant neck pain have worse outcomes, the authors’ findings provide potential targets for improvement in patient management for these specific populations.

Objective To systematically analyse prior reports of carotid endarterectomy (CEA) performed in cases of ≤50% carotid stenosis in order to understand patient tolerance and potential benefit. Methods A systematic review and descriptive analysis was performed in concordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. An English-language search was performed of online databases using librarian-selected search terms. Abstracts were reviewed for relevance which included mention of carotid endarterectomy and stenosis. Prospective or retrospective observational cohort studies that reported series of patients who underwent endarterectomy for minimal (≤50%) luminal stenosis with reported outcomes were included. Results Six studies (which included our institutional series) with a total of 143 patients met the inclusion criteria. The weighted mean age at the time of CEA was 72.3 years; 113 (79.0%) were male. 55.8% of patients with available data had recurrent ipsilateral ischaemic events despite medical therapy. Two patients out of 129 with available perioperative data (1.6%) had perioperative MRI findings of acute ischaemic stroke, both within the hemisphere contralateral to the side of CEA. Of the 138 patients with available follow-up (mean, 36 months), none had recurrent ipsilateral ischaemic events. Conclusions Endarterectomy for symptomatic carotid disease causing ≤50% stenosis may be a potentially beneficial strategy to prevent stroke recurrence. Studies with robust methodology are needed to draw more definitive conclusions in terms of the safety and efficacy of endarterectomy for minimal stenosis with vulnerable features relative to intensive medical therapy.

Background Human telomerase reverse transcriptase (hTERT) is frequently classified as a ‘universal’ tumor associated antigen due to its expression in a vast number of cancers. We evaluated plasmid DNA-encoded hTERT as an immunotherapy across nine cancer types. Methods A phase 1 clinical trial was conducted in adult patients with no evidence of disease following definitive surgery and standard therapy, who were at high risk of relapse. Plasmid DNA encoding one of two hTERT variants (INO-1400 or INO-1401) with or without plasmid DNA encoding interleukin 12 (IL-12) (INO-9012) was delivered intramuscularly concurrent with the application of the CELLECTRA constant-current electroporation device 4 times across 12 weeks. Safety assessments and immune monitoring against native (germline, non-mutated, non-plasmid matched) hTERT antigen were performed. The largest cohort of patients enrolled had pancreatic cancer, allowing for additional targeted assessments for this tumor type. Results Of the 93 enrolled patients who received at least one dose, 88 had at least one adverse event; the majority were grade 1 or 2, related to injection site. At 18 months, 54.8% (51/93) patients were disease-free, with median disease-free survival (DFS) not reached by end of study. For patients with pancreatic cancer, the median DFS was 9 months, with 41.4% of these patients remaining disease-free at 18 months. hTERT immunotherapy induced a de novo cellular immune response or enhanced pre-existing cellular responses to native hTERT in 96% (88/92) of patients with various cancer types. Treatment with INO-1400/INO-1401±INO-9012 drove hTERT-specific IFN-γ production, generated hTERT-specific CD4+ and CD8+ T cells expressing the activation marker CD38, and induced hTERT-specific activated CD8 +CTLs as defined by cells expressing perforin and granzymes. The addition of plasmid IL-12 adjuvant elicited higher magnitudes of cellular responses including IFN-γ production, activated CD4+ and CD8+ T cells, and activated CD8+CTLs. In a subset analysis of pancreatic cancer patients, the presence of immunotherapy-induced activated CD8+ T cells expressing PD-1, granzymes and perforin correlated with survival. Conclusions Plasmid DNA-encoded hTERT/IL-12 DNA immunotherapy was well-tolerated, immune responses were noted across all tumor types, and a specific CD8+ phenotype increased by the immunotherapy was significantly correlated with survival in patients with pancreatic cancer.

Purpose This study sought to validate whether the signal intensity ratio (SIR) of carotid intraplaque hemorrhage (IPH) was associated with acute ischemic neurologic events. Methods A retrospective review was completed of consecutive patients that underwent neck magnetic resonance angiography using magnetization prepared-rapid gradient echo (MP-RAGE) and T1-CUBE sequences between 2017 and 2020. Patients with magnetic resonance evidence of IPH were included. SIRs were measured by comparing the maximum IPH signal with the mean intramuscular signal from the adjacent sternocleidomastoid. Patients were stratified into ischemic or non-ischemic groups based on the presence of acute ipsilateral ischemic events (stroke, retinal artery occlusion). Logistic regression analysis was performed to determine if increasing IPH SIR was associated with an increased risk of ipsilateral ischemic events. Results Of 85 included patients (85 arteries), 66 were male (77.6%). Mean age was 71.0 (SD ± 11.1). There were 70 arteries with IPH that were ipsilateral to an ischemic event, and 15 that belonged to patients without an ischemic event. No association was found between increasing IPH SIR seen on MP-RAGE (odds ratio (OR): 0.82; 95% confidence interval (CI): 0.58–1.4; P = 0.43) or T1-CUBE sequences (OR: 0.85; 95% CI: 0.53–1.5; P = 0.56). Conclusions There was no association between the SIR of IPH and acute ischemia on either MP-RAGE or T1-CUBE sequences. Further investigation is required prior to widespread acceptance of SIR as a predictive imaging marker of symptomatic carotid plaque.