PD-L1 Immune Checkpoint Targeted Photoactivable Liposomes (iTPALs) Prime the Stroma of Pancreatic Tumors and Promote Self-Delivery.

Desmoplasia in pancreatic ductal adenocarcinoma (PDAC) limits the penetration and efficacy of therapies. It has been previously shown that photodynamic priming (PDP) using EGFR targeted photoactivable multi-inhibitor liposomes remediates desmoplasia in PDAC and doubles overall survival. Here, bifunctional PD-L1 immune checkpoint targeted photoactivable liposomes (iTPALs) that mediate both PDP and PD-L1 blockade are presented. iTPALs also improve phototoxicity in PDAC cells and induce immunogenic cell death. PDP using iTPALs reduces collagen density, thereby promoting self-delivery by 5.4-fold in collagen hydrogels, and by 2.4-fold in syngeneic CT1BA5 murine PDAC tumors. PDP also reduces tumor fibroblast content by 39.4%. Importantly, iTPALs also block the PD-1/PD-L1 immune checkpoint more efficiently than free α-PD-L1 antibodies. Only a single sub-curative priming dose using iTPALs provides 54.1% tumor growth inhibition and prolongs overall survival in mice by 42.9%. Overall survival directly correlates with the extent of tumor iTPAL self-delivery following PDP (Pearson's r = 0.670, p = 0.034), while no relationship is found for sham non-specific IgG constructs activated with light. When applied over multiple cycles, as is typical for immune checkpoint therapy, PDP using iTPALs promises to offer durable tumor growth delay and significant survival benefit in PDAC patients, especially when used to promote self-delivery of integrated chemo-immunotherapy regimens.

Biomechanical analysis of complications following T10-Pelvis spinal fusion: A population based computational study.

Proximal junctional kyphosis (PJK) and proximal junctional failure (PJF) are challenging complications of long fusion constructs for the treatment of adult spinal deformity. The objective of this study is to understand the biomechanical stresses proximal to the upper instrumentation of a T10-pelvis fusion in a large patient cohort. The pre-fusion models were subject-specific thoracolumbar spine models that incorporate the height, weight, spine curvature, and muscle morphology of 250 individuals from the Framingham Heart Study Multidetector CT Study. To create post-fusion models, the subject-specific models were further modified to eliminate motion between the intervertebral joints from T10 to the pelvis. OpenSim analysis tools were used to calculate the medial lateral shear force, anterior posterior shear force, and compressive force on the T9 vertebra during the static postures. Differences between pre-fusion and post-fusion T9 biomechanics were consistent between increased segmental mobility and unchanged segmental mobility conditions. For all static postures, compression decreased (p < 0. 0005). Anterior-posterior shear force significantly increased (p < 0. 0005) during axial twist and significantly increased (p < 0. 0005) during trunk flexion. Medial lateral shear force significantly increased (p < 0. 0005) during axial twist. This computational study provided the first use of subject-specific models to investigate the biomechanics of long spinal fusions. Patients undergoing T10-Pelvis fusion were predicted to have increased shear forces and decreased compressive force at the T9 vertebra, independent of change in segmental mobility. The computational model shows potential for the investigation of spinal fusion biomechanics to reduce the risk of PJK or PJF.

A rigorous benchmarking of alignment-based HLA typing algorithms for RNA-seq data.

Accurate identification of human leukocyte antigen (HLA) alleles is essential for various clinical and research applications, such as transplant matching and drug sensitivities. Recent advances in RNA-seq technology have made it possible to impute HLA types from sequencing data, spurring the development of a large number of computational HLA typing tools. However, the relative performance of these tools is unknown, limiting the ability for clinical and biomedical research to make informed choices regarding which tools to use. Here we report the study design of a comprehensive benchmarking of the performance of 12 HLA callers across 682 RNA-seq samples from 8 datasets with molecularly defined gold standard at 5 loci, HLA-A, -B, -C, -DRB1, and -DQB1. For each HLA typing tool, we will comprehensively assess their accuracy, compare default with optimized parameters, and examine for discrepancies in accuracy at the allele and loci levels. We will also evaluate the computational expense of each HLA caller measured in terms of CPU time and RAM. We also plan to evaluate the influence of read length over the HLA region on accuracy for each tool. Most notably, we will examine the performance of HLA callers across European and African groups, to determine discrepancies in accuracy associated with ancestry. We hypothesize that RNA-Seq HLA callers are capable of returning high-quality results, but the tools that offer a good balance between accuracy and computational expensiveness for all ancestry groups are yet to be developed. We believe that our study will provide clinicians and researchers with clear guidance to inform their selection of an appropriate HLA caller.

Comparison of clinical outcomes in patients undergoing one- and two-level minimally invasive lumbar microdiscectomy.

OBJECTIVE: Herniated nucleus pulposus (HNP) is one of the most common lumbar spine conditions treated surgically, often through a minimally invasive surgery (MIS) microdiscectomy approach. This technique attempts to reduce damage to the paraspinal muscular-ligamentous envelope. However, there are currently limited data regarding comparative outcomes using patient-reported outcome measures (PROMs) for one- and two-level MIS discectomies. The aim of this study was to quantify comparative clinical outcomes in patients undergoing one-level and two-level MIS lumbar microdiscectomy for HNP using PROMs. METHODS: The authors performed a retrospective review of patients undergoing MIS lumbar microdiscectomy between 2004 and 2019 for the primary diagnosis of HNP at a single academic institution. All patients had a minimum 1-year follow-up. Patient demographics and comorbidities were collected to establish baselines between cohorts. PROMs and minimal clinically important differences (MCIDs) were used to examine the patient's perception of operative success. Bivariate and multivariate linear/logistic regression analyses were used to compare one- and two-level discectomies. The bivariate analysis included the t-test and chi-square test, which were used to assess continuous and categorical variables, respectively. Statistical significance was established at p < 0.05. RESULTS: A total of 293 patients underwent one-level (n = 250) or two-level (n = 43) MIS discectomies. The mean follow-ups for the one- and two-level cohorts were 50.4 (SD 35.5) months and 61.6 (SD 39.8) months, respectively. Fewer female patients underwent two-level discectomies, and BMI and operative duration were higher in the two-level group (p < 0.001). Recurrent herniation requiring reoperation was recorded at rates of 6.80% and 11.6% in the one- and two-level groups, respectively (p = 0.270). Pre- and postoperative PROMs were largely similar between the cohorts; however, patients undergoing one-level discectomy had greater improvement in leg pain, and a significantly greater proportion of these patients achieved MCID for the leg pain visual analog scale score (p < 0.001). CONCLUSIONS: At the 1-year clinical follow-up, patients who underwent two-level discectomy had significantly less improvement in leg pain scores with lower achievement of MCID for leg pain improvement than patients undergoing one-level procedures. At the 1-year follow-up, there were no other significant differences in PROMs between the two cohorts. Given these findings, patients should be counseled regarding the anticipated outcomes to better manage expectations. Further studies are warranted to examine the long-term clinical outcomes associated with single- and multilevel MIS discectomy.

A small-molecule TLR4 antagonist reduced neuroinflammation in female E4FAD mice.

BACKGROUND: APOE genotype is the greatest genetic risk factor for sporadic Alzheimer's disease (AD). APOE4 increases AD risk up to 12-fold compared to APOE3, an effect that is greater in females. Evidence suggests that one-way APOE could modulate AD risk and progression through neuroinflammation. Indeed, APOE4 is associated with higher glial activation and cytokine levels in AD patients and mice. Therefore, identifying pathways that contribute to APOE4-associated neuroinflammation is an important approach for understanding and treating AD. Human and in vivo evidence suggests that TLR4, one of the key receptors involved in the innate immune system, could be involved in APOE-modulated neuroinflammation. Consistent with that idea, we previously demonstrated that the TLR4 antagonist IAXO-101 can reduce LPS- and Aß-induced cytokine secretion in APOE4 glial cultures. Therefore, the goal of this study was to advance these findings and determine whether IAXO-101 can modulate neuroinflammation, Aß pathology, and behavior in mice that express APOE4. METHODS: We used mice that express five familial AD mutations and human APOE3 (E3FAD) or APOE4 (E4FAD). Female and male E4FAD mice and female E3FAD mice were treated with vehicle or IAXO-101 in two treatment paradigms: prevention from 4 to 6 months of age or reversal from 6 to 7 months of age. Learning and memory were assessed by modified Morris water maze. Aß deposition, fibrillar amyloid deposition, astrogliosis, and microgliosis were assessed by immunohistochemistry. Soluble levels of Aß and apoE, insoluble levels of apoE and Aß, and IL-1ß were measured by ELISA. RESULTS: IAXO-101 treatment resulted in lower Iba-1 coverage, lower number of reactive microglia, and improved memory in female E4FAD mice in both prevention and reversal paradigms. IAXO-101-treated male E4FAD mice also had lower Iba-1 coverage and reactivity in the RVS paradigm, but there was no effect on behavior. There was also no effect of IAXO-101 treatment on neuroinflammation and behavior in female E3FAD mice. CONCLUSION: Our data supports that TLR4 is a potential mechanistic therapeutic target for modulating neuroinflammation and cognition in APOE4 females.

A single photodynamic priming protocol augments delivery of ⍺-PD-L1 mAbs and induces immunogenic cell death in head and neck tumors.

Photodynamic priming (PDP) leverages the photobiological effects of subtherapeutic photodynamic therapy (PDT) regimens to modulate the tumor vasculature and stroma. PDP also sensitizes tumors to secondary therapies, such as immunotherapy by inducing a cascade of molecular events, including immunogenic cell death (ICD). We and others have shown that PDP improves the delivery of antibodies, among other theranostic agents. However, it is not known whether a single PDP protocol is capable of both inducing ICD in vivo and augmenting the delivery of immune checkpoint inhibitors. In this rapid communication, we show for the first time that a single PDP protocol using liposomal benzoporphyrin derivative (Lipo-BPD, 0.25 mg/kg) with 690 nm light (75 J/cm2 , 100 mW/cm2 ) simultaneously doubles the delivery of ⍺-PD-L1 antibodies in murine AT-84 head and neck tumors and induces ICD in vivo. ICD was observed as a 3-11 fold increase in tumor cell exposure of damage-associated molecular patterns (Calreticulin, HMGB1, and HSP70). These findings suggest that this single, highly translatable PDP protocol using clinically relevant Lipo-BPD holds potential for improving immunotherapy outcomes in head and neck cancer. It can do so by simultaneously overcoming physical barriers to the delivery of immune checkpoint inhibitors, and biochemical barriers that contribute to immunosuppression.

Short-term and Long-term Complications of Cervical Disc Arthroplasty.

STUDY DESIGN: A narrative review. OBJECTIVE: This review discusses the short and long-term complications associated with cervical disc arthroplasty (CDA). SUMMARY OF BACKGROUND DATA: CDA is a safe and effective motion-sparing alternative to fusion for the treatment of cervical disc pathology in patients with cervical radiculopathy or myelopathy. Although CDA offers advantages over fusion within a narrower set of indications, it introduces new technical challenges and potential complications. METHODS: A systematic search of several large databases, including Cochrane Central, PubMed, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry, was conducted from January 2005 to August 2023 to identify published studies and clinical trials evaluating cervical disc replacement complications and outcomes. RESULTS: Short-term complications are primarily related to surgical approach and include dysphagia reported as high as ~70%, laryngeal nerve injury ~0%-1.25%, Horner syndrome ~0.06%, hematoma ~0.01%, gross device extrusion ~0.3%, whereas long-term complications include adjacent segment disease reported at ~3.8%, osteolysis ~44%-64%, heterotopic ossification ~7.3%-69.2%, implant failure ~3.3%-3.7%, and implant wear, which varies depending on design. CONCLUSIONS: Approaches for mitigating complications broadly include meticulous dissection, intraoperative techniques, and diligent postoperative follow-up. This review emphasizes the need for a comprehensive understanding and management of complications to enhance the safety, reproducibility, and success of CDA. As CDA continues to evolve, there remains a critical need for ongoing research to delve deeper into evaluating risk for complications and long-term patient outcomes.

The Effect of Changes in Segmental Lordosis on Global Lumbar and Adjacent Segment Lordosis After L5-S1 Anterior Lumbar Interbody Fusion.

STUDY DESIGN: Retrospective Cohort Study. OBJECTIVE: Restoration of lordosis in lumbar fusion reduces low back pain, decreases adjacent segment degeneration, and improves postoperative outcomes. However, the potential effects of changes in segmental lordosis on adjacent-level and global lordosis remain less understood. This study aims to examine the relationships between segmental (SL), adjacent-level, and global lumbar lordosis following L5-S1 Anterior Lumbar Interbody Fusion (ALIF). METHODS: 80 consecutive patients who underwent single-level L5-S1 ALIF were divided into 3 groups based on the degree of change (∆) in index-level segmental lordosis: <5° (n = 23), 5°-10° (n = 29), >10° (n = 28). Radiographic parameters measured included global lumbar, segmental, and adjacent level lordosis, sacral slope, pelvic tilt, pelvic incidence, and PI-LL mismatch. RESULTS: Patients with ∆SL 5°-10° or ∆SL >10° both showed significant increases in global lumbar lordosis from preoperative to final follow-up. However, patients with ∆SL >10° showed statistically significant losses in adjacent level lordosis at both immediate postoperative and final follow-up compared to preoperative. When comparing patients with ∆SL >10° to those with ∆SL 5-10°, there were no significant differences in global lumbar lordosis at final follow-up, due to significantly greater losses of adjacent level lordosis in these patients. CONCLUSION: The degree of compensatory loss of lordosis at the adjacent level L4-L5 correlated with the extent of segmental lordosis creation at the index L5-S1 level. This may suggest that the L4 to S1 segment acts as a "harmonious unit," able to accommodate only a certain amount of lordosis and further increases in segmental lordosis may be mitigated by loss of adjacent-level lordosis.

Increased cage angle effects on radiographic outcomes after stand-alone anterior lumbar interbody fusion.

OBJECTIVE: Anterior lumbar interbody fusion (ALIF) is a well-accepted surgical technique used to treat various lumbar degenerative pathologies. Recently, hyperlordotic cages have been introduced to create higher degrees of lordosis to the lumbar spine. There are little data currently available to define the radiographic benefits that these cages provide with stand-alone ALIF. The goal of the present study was to assess the effect of increasing cage angles on postoperative subsidence, sagittal alignment, and foraminal and disc height in patients who underwent single-level stand-alone ALIF surgery. METHODS: A retrospective cohort study was performed of consecutive patients who underwent single-level ALIF by a single spine surgeon. Radiographic analysis included global lordosis, operative level of segmental lordosis, cage subsidence, sacral slope, pelvic tilt, pelvic incidence, pelvic incidence-lumbar lordosis mismatch, edge loading, foraminal height, posterior disc height, anterior disc height, and adjacent-level lordosis. Multivariate linear and logistic regressions were performed to analyze the relationship between cage angle and radiographic outcomes. RESULTS: Seventy-two patients were included in the study and divided into three groups based on cage angle: < 10° (n = 17), 10°-15° (n = 36), and > 15° (n = 19). Within the entire study cohort, there were significant improvements in disc and foraminal height, as well as segmental and global lordosis, at the final follow-up after single-level ALIF. However, when stratified by cage angle groups, patients with > 15° cages did not have any additional significant changes in global or segmental lordosis compared with those patients with smaller cage angles, but patients with > 15° cages showed greater risk of subsidence while also having significantly less improvements in foraminal height, posterior disc height, and average disc height compared with the other groups. CONCLUSIONS: Patients with < 15° stand-alone ALIF cages showed improved average foraminal and disc (posterior, anterior, and average) height without sacrificing improvements in sagittal parameters or increasing risk of subsidence when compared to patients with hyperlordotic cages. The use of hyperlordotic cages > 15° did not provide spinal lordosis commensurate with the lordotic angle of the cage and had a greater risk of subsidence. Although this study was limited by a lack of patient-reported outcomes to correlate with radiographic results, these findings support the judicious use of hyperlordotic cages in stand-alone ALIF.

Rates of Postoperative Complications and Approach-related Neurological Symptoms After L4-L5 Lateral Transpsoas Lumbar Interbody Fusion Compared With Upper Lumbar Levels.

STUDY DESIGN: This was a retrospective comparative study. OBJECTIVE: To compare the likelihood of approach-related complications for patients undergoing single-level lateral lumbar interbody fusion (LLIF) at L4-L5 to those undergoing the procedure at upper lumbar levels. SUMMARY OF BACKGROUND DATA: LLIF has been associated with a number of advantages when compared with traditional interbody fusion techniques. However, potential risks with the approach include vascular or visceral injury, thigh dysesthesias, and lumbar plexus injury. There are concerns of a higher risk of these complications at the L4-L5 level compared with upper lumbar levels. MATERIALS AND METHODS: A retrospective cohort review was completed for consecutive patients undergoing single-level LLIF between 2004 and 2019 by a single surgeon. Indication for surgery was symptomatic degenerative lumbar stenosis and/or spondylolisthesis. Patients were divided into 2 cohorts: LLIF at L4-L5 versus a single level between L1 and L4. Baseline characteristics, intraoperative complications, postoperative approach-related neurological symptoms, and patient-reported outcomes were compared and analyzed between the cohorts. RESULTS: A total of 122 were included in analysis, of which 58 underwent LLIF at L4-L5 and 64 underwent LLIF between L1 and L4. There were no visceral or vascular injuries or lumbar plexus injuries in either cohort. There was no significant difference in the rate of postoperative hip pain, anterior thigh dysesthesias, and/or hip flexor weakness between the cohorts (53.5% L4-L5 vs. 37.5% L1-L4; P =0.102). All patients reported complete resolution of these symptoms by 6-month postoperative follow-up. DISCUSSION: LLIF surgery at the L4-L5 level is associated with a similar infrequent likelihood of approach-related complications and postoperative hip pain, thigh dysesthesias, and hip flexor weakness when compared with upper lumbar level LLIF. Careful patient selection, meticulous use of real-time neuromonitoring, and an understanding of the anatomic location of the lumbar plexus to the working corridor are critical to success.

Minimal observed impact of HLA genotype on hospitalization and severity of SARS-CoV-2 infection.

HLA is a critical component of the viral antigen presentation pathway. We investigated the relationship between the severity of SARS-CoV-2 disease and HLA type in 3235 individuals with confirmed SARS-CoV-2 infection. We found only the DPB1 locus to be associated with the binary outcome of whether an individual developed any COVID-19 symptoms. The number of peptides predicted to bind to an HLA allele had no significant relationship with disease severity both when stratifying individuals by ancestry or age and in a pooled analysis. Overall, at the population level, we found HLA type is significantly less predictive of COVID-19 disease severity than certain demographic factors and clinical comorbidities.

High-Intensity Zones on MRI of the Cervical Spine in Patients: Epidemiology and Association With Pain and Disability.

STUDY DESIGN: Retrospective cohort study. OBJECTIVES: This study aimed to address the prevalence, distribution, and clinical significance of cervical high-intensity zones (HIZs) on magnetic resonance imaging (MRI) with respect to pain and other patient-reported outcomes in the setting of patients that will undergo an anterior cervical discectomy and fusion (ACDF) procedure. METHODS: A retrospective cohort study of ACDF patients surgically treated at a single center from 2008 to 2015. Based on preoperative MRI, HIZ subtypes were identified as either traditional T2-hyperintense, T1-hypointense ("single-HIZs"), or combined T1- and T2-hyperintense ("dual-HIZs"), and their level-specific prevalence was assessed. Preoperative symptoms, patient-reported outcomes, and disc degeneration pathology were assessed in relation to HIZs and HIZ subtypes. RESULTS: Of 861 patients, 58 demonstrated evidence of HIZs in the cervical spine (6.7%). Single-HIZs and dual-HIZs comprised 63.8% and 36.2% of the overall HIZs, respectively. HIZs found outside of the planned fusion segment reported better preoperative Neck Disability Index (NDI; P = .049) and Visual Analogue Scale (VAS) Arm (P = .014) scores relative to patients without HIZs. Furthermore, patients with single-HIZs found inside the planned fusion segment had worse VAS Neck (P = .045) and VAS Arm (P = .010) scores. In general, dual-HIZ patients showed no significant differences across all clinical outcomes. CONCLUSIONS: This is the first study to evaluate the clinical significance of HIZs in the cervical spine, noting level-specific and clinical outcome-specific variations. Single-HIZs were associated with significantly more pain when located inside the fusion segment, while dual-HIZs showed no associations with patient-reported outcomes. The presence of single-HIZs may correlate with concurrent spinal pathologies and should be more closely evaluated.

Reasons for revision following stand-alone anterior lumbar interbody fusion and lateral lumbar interbody fusion.

OBJECTIVE: Anterior lumbar interbody fusion (ALIF) and lateral lumbar interbody fusion (LLIF) are alternative and less invasive techniques to stabilize the spine and indirectly decompress the neural elements compared with open posterior approaches. While reoperation rates have been described for open posterior lumbar surgery, there are sparse data on reoperation rates following these less invasive procedures without direct posterior decompression. This study aimed to evaluate the overall rate, cause, and timing of reoperation procedures following anterior or lateral lumbar interbody fusions without direct posterior decompression. METHODS: This was a retrospective cohort study of all consecutive patients indicated for an ALIF or LLIF for lumbar spine at a single academic institution. Patients who underwent concomitant posterior fusion or direct decompression surgeries were excluded. Rates, causes, and timing of reoperations were analyzed. Patients who underwent a revision decompression were matched with patients who did not require a reoperation, and preoperative imaging characteristics were analyzed to assess for risk factors for the reoperation. RESULTS: The study cohort consisted of 529 patients with an average follow-up of 2.37 years; 40.3% (213/529) and 67.3% (356/529) of patients had a minimum of 2 years and 1 year of follow-up, respectively. The total revision rate was 5.7% (30/529), with same-level revision in 3.8% (20/529) and adjacent-level revision in 1.9% (10/529) of patients. Same-level revision patients had significantly shorter time to revision (7.14 months) than adjacent-level revision patients (31.91 months) (p < 0.0001). Fifty percent of same-level revisions were for a posterior decompression. After further analysis of decompression revisions, an increased preoperative canal area was significantly associated with a lower risk of further decompression revision compared to the control group (p = 0.015; OR 0.977, 95% CI 0.959-0.995). CONCLUSIONS: There was a low reoperation rate after anterior or lateral lumbar interbody fusions without direct posterior decompression. The majority of same-level reoperations were due to a need for further decompression. Smaller preoperative canal diameters were associated with the need for revision decompression.

Preoperative Risk Factors for Postoperative Urinary Tract Infection After Primary Total Hip and Knee Arthroplasties.

BACKGROUND: Establishing clear risk factors for complications such as urinary tract infection (UTI) after arthroplasty procedures helps guide clinical practice and provides more information to both surgeons and patients. This study aims to assess selected preoperative patient characteristics as risk factors for postoperative UTI after primary total hip and knee arthroplasties (THA and TKA). METHODS: This was a retrospective analysis using current procedural terminology codes to investigate the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database for patients who underwent THA or TKA from 2010 to 2017. Patients were classified for UTI by NSQIP guidelines. Patient samples with all possible covariates were included for multivariate logistic regression analysis and assessed for independent associations. RESULTS: In a cohort of 983 identified patients (983 of 119,096; 0.83%): ages 57+ years, preoperative red blood cell (RBC) transfusion, perioperative RBC transfusion, bleeding disorders, operative time 110+ minutes, preoperative steroid use, diabetes, pulmonary comorbidities, body mass index 30+ kg/m2 were independent risk factors for postoperative UTI after THA. In a cohort of 1503 identified patients (1503 of 189,327; 0.8%): ages 60+ years, preoperative RBC transfusion, perioperative RBC transfusion, anemia, platelets less than 150k, preoperative steroid use, diabetes, and body mass index 30+ kg/m2 were independent risk factors for postoperative UTI after TKA. Male sex was associated with a decreased risk of UTI in both THA and TKA. CONCLUSION: This study provides novel evidence on risk factors associated with the development of UTI after THA or TKA. Clinicians should be aware of risk factors in the manifestation of postoperative UTI after primary THA or TKA procedures.

Cervical Spine Endplate Abnormalities and Association With Pain, Disability, and Adjacent Segment Degeneration After Anterior Cervical Discectomy and Fusion.

STUDY DESIGN: A retrospective study with prospectively-collected data. OBJECTIVE: To determine how type, location, and size of endplate lesions on magnetic resonance imaging (MRI) may be associated with symptoms and clinical outcomes after anterior cervical discectomy and fusion (ACDF). SUMMARY OF BACKGROUND DATA: Structural endplate abnormalities are important, yet understudied, phenomena in the cervical spine. ACDF is a common surgical treatment for degenerative disc disease; however, adjacent segment degeneration/disease (ASD) may develop. METHODS: Assessed the imaging, symptoms and clinical outcomes of 861 patients who underwent ACDF at a single center. MRI and plain radiographs of the cervical spine were evaluated. Endplate abnormalities on MRI were identified and stratified by type (atypical, typical), location, relation to operative levels, presence at the adjacent level, and size. These strata were assessed for association with presenting symptoms, patient-reported, and postoperative outcomes. RESULTS: Of 861 patients (mean follow-up: 17.4 months), 57.3% had evidence of endplate abnormalities, 39.0% had typical abnormalities, while 18.2% had atypical abnormalities. Patients with any endplate abnormality had greater odds of myelopathy irrespective of location or size, while sensory deficits were associated with atypical lesions (P = 0.016). Typical and atypical abnormalities demonstrated differences in patient-reported outcomes based on location relative to the fused segment. Typical variants were not associated with adverse surgical outcomes, while atypical lesions were associated with ASD (irrespective of size/location; P = 0.004) and reoperations, when a large abnormality was present at the proximal adjacent level (P = 0.025). CONCLUSION: This is the first study to examine endplate abnormalities on MRI of the cervical spine, demonstrating distinct risk profiles for symptoms, patient-reported, and surgical outcomes after ACDF. Patients with typical lesions reported worsening postoperative pain/disability, while those with atypical abnormalities experienced greater rates of ASD and reoperation. This highlights the relevance of a degenerative spine phenotypic assessment, and suggests endplate abnormalities may prognosticate clinical outcomes after surgery. LEVEL OF EVIDENCE: 3.

Human Leukocyte Antigen Susceptibility Map for Severe Acute Respiratory Syndrome Coronavirus 2.

Genetic variability across the three major histocompatibility complex (MHC) class I genes (human leukocyte antigen A [HLA-A], -B, and -C genes) may affect susceptibility to and severity of the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19). We performed a comprehensive in silico analysis of viral peptide-MHC class I binding affinity across 145 HLA-A, -B, and -C genotypes for all SARS-CoV-2 peptides. We further explored the potential for cross-protective immunity conferred by prior exposure to four common human coronaviruses. The SARS-CoV-2 proteome was successfully sampled and was represented by a diversity of HLA alleles. However, we found that HLA-B*46:01 had the fewest predicted binding peptides for SARS-CoV-2, suggesting that individuals with this allele may be particularly vulnerable to COVID-19, as they were previously shown to be for SARS (M. Lin, H.-T. Tseng, J. A. Trejaut, H.-L. Lee, et al., BMC Med Genet 4:9, 2003, https://bmcmedgenet.biomedcentral.com/articles/10.1186/1471-2350-4-9). Conversely, we found that HLA-B*15:03 showed the greatest capacity to present highly conserved SARS-CoV-2 peptides that are shared among common human coronaviruses, suggesting that it could enable cross-protective T-cell-based immunity. Finally, we reported global distributions of HLA types with potential epidemiological ramifications in the setting of the current pandemic.IMPORTANCE Individual genetic variation may help to explain different immune responses to a virus across a population. In particular, understanding how variation in HLA may affect the course of COVID-19 could help identify individuals at higher risk from the disease. HLA typing can be fast and inexpensive. Pairing HLA typing with COVID-19 testing where feasible could improve assessment of severity of viral disease in the population. Following the development of a vaccine against SARS-CoV-2, the virus that causes COVID-19, individuals with high-risk HLA types could be prioritized for vaccination.

Pediatric cellular neurothekeoma: Seven cases and systematic review of the literature.

BACKGROUND/OBJECTIVES: Neurothekeoma is a rare, benign, cutaneous neoplasm consisting of Schwann cells and perineural cells in myxoid stroma. Cellular neurothekeoma (CNT) was previously thought to represent a morphologic variant of neurothekeoma, but recent studies have shown that CNTs are unrelated to neurothekeomas and are more likely of histiocytic lineage. METHODS: Herein, we describe seven cases of CNT in pediatric patients. A comprehensive search of PubMed was performed, and 71 cases of cellular neurothekeoma in pediatric patients were reviewed. RESULTS: The clinical differential diagnosis for these lesions included Spitz nevi, keloid, juvenile xanthogranuloma, cutaneous lymphoid hyperplasia, and lymphomatoid papulosis. All cases were treated by excision or excisional biopsy. Histopathologically, all demonstrated multilobular, primarily intradermal neoplasms composed of plump spindled or epithelioid mononuclear cells with abundant eosinophilic pale-staining cytoplasm. Immunophenotypic findings included CD68 and NKI/C3 positivity, and negative staining with cytokeratin, S-100, Melan-A, and SOX-10. CONCLUSION: Cellular neurothekeoma is distinguished from conventional neurothekeoma by increased cellularity, a lack of myxoid stroma, and a lack of neural expression with immunohistochemical stains. These uncommon neoplasms should be included in the differential diagnosis of dermal nodules in children. Accurate diagnosis of these lesions is essential, as they can be mistaken for malignancy leading to unnecessary treatment.

neoepiscope improves neoepitope prediction with multivariant phasing.

MOTIVATION: The vast majority of tools for neoepitope prediction from DNA sequencing of complementary tumor and normal patient samples do not consider germline context or the potential for the co-occurrence of two or more somatic variants on the same mRNA transcript. Without consideration of these phenomena, existing approaches are likely to produce both false-positive and false-negative results, resulting in an inaccurate and incomplete picture of the cancer neoepitope landscape. We developed neoepiscope chiefly to address this issue for single nucleotide variants (SNVs) and insertions/deletions (indels). RESULTS: Herein, we illustrate how germline and somatic variant phasing affects neoepitope prediction across multiple datasets. We estimate that up to ∼5% of neoepitopes arising from SNVs and indels may require variant phasing for their accurate assessment. neoepiscope is performant, flexible and supports several major histocompatibility complex binding affinity prediction tools. AVAILABILITY AND IMPLEMENTATION: neoepiscope is available on GitHub at https://github.com/pdxgx/neoepiscope under the MIT license. Scripts for reproducing results described in the text are available at https://github.com/pdxgx/neoepiscope-paper under the MIT license. Additional data from this study, including summaries of variant phasing incidence and benchmarking wallclock times, are available in Supplementary Files 1, 2 and 3. Supplementary File 1 contains Supplementary Table 1, Supplementary Figures 1 and 2, and descriptions of Supplementary Tables 2-8. Supplementary File 2 contains Supplementary Tables 2-6 and 8. Supplementary File 3 contains Supplementary Table 7. Raw sequencing data used for the analyses in this manuscript are available from the Sequence Read Archive under accessions PRJNA278450, PRJNA312948, PRJNA307199, PRJNA343789, PRJNA357321, PRJNA293912, PRJNA369259, PRJNA305077, PRJNA306070, PRJNA82745 and PRJNA324705; from the European Genome-phenome Archive under accessions EGAD00001004352 and EGAD00001002731; and by direct request to the authors. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Population-level distribution and putative immunogenicity of cancer neoepitopes.

BACKGROUND: Tumor neoantigens are drivers of cancer immunotherapy response; however, current prediction tools produce many candidates requiring further prioritization. Additional filtration criteria and population-level understanding may assist with prioritization. Herein, we show neoepitope immunogenicity is related to measures of peptide novelty and report population-level behavior of these and other metrics. METHODS: We propose four peptide novelty metrics to refine predicted neoantigenicity: tumor vs. paired normal peptide binding affinity difference, tumor vs. paired normal peptide sequence similarity, tumor vs. closest human peptide sequence similarity, and tumor vs. closest microbial peptide sequence similarity. We apply these metrics to neoepitopes predicted from somatic missense mutations in The Cancer Genome Atlas (TCGA) and a cohort of melanoma patients, and to a group of peptides with neoepitope-specific immune response data using an extension of pVAC-Seq (Hundal et al., pVAC-Seq: a genome-guided in silico approach to identifying tumor neoantigens. Genome Med 8:11, 2016). RESULTS: We show neoepitope burden varies across TCGA diseases and HLA alleles, with surprisingly low repetition of neoepitope sequences across patients or neoepitope preferences among sets of HLA alleles. Only 20.3% of predicted neoepitopes across TCGA patients displayed novel binding change based on our binding affinity difference criteria. Similarity of amino acid sequence was typically high between paired tumor-normal epitopes, but in 24.6% of cases, neoepitopes were more similar to other human peptides, or bacterial (56.8% of cases) or viral peptides (15.5% of cases), than their paired normal counterparts. Applied to peptides with neoepitope-specific immune response, a linear model incorporating neoepitope binding affinity, protein sequence similarity between neoepitopes and their closest viral peptides, and paired binding affinity difference was able to predict immunogenicity (AUROC = 0.66). CONCLUSIONS: Our proposed prioritization criteria emphasize neoepitope novelty and refine patient neoepitope predictions for focus on biologically meaningful candidate neoantigens. We have demonstrated that neoepitopes should be considered not only with respect to their paired normal epitope, but to the entire human proteome, and bacterial and viral peptides, with potential implications for neoepitope immunogenicity and personalized vaccines for cancer treatment. We conclude that putative neoantigens are highly variable across individuals as a function of cancer genetics and personalized HLA repertoire, while the overall behavior of filtration criteria reflects predictable patterns.

Clinical Features and Treatment of Fibrous Histiocytomas of the Tongue: A Systematic Review.

Introduction Benign fibrous histiocytomas are common lesions of the skin that rarely affect the tongue. Such cases are available in the literature exclusively as case reports. Similarly, malignant fibrous histiocytoma, now classified as undifferentiated pleomorphic sarcoma, is exceedingly rare in the tongue and not fully understood. Objectives This study systematically reviews the available literature discussing the clinical and pathological features of malignant and benign fibrous histiocytomas. Data Synthesis A total of 20 cases were included in this review. Patient-level data were extracted from cases to include clinical presentation, workup, treatment, and outcome. Conclusion Benign fibrous histiocytomas are consistent in clinical and histopathologic presentation. Surgical treatment provides excellent outcome, with no recurrence in all excised cases. Malignant tumors have a more aggressive clinical and pathological presentation. Surgical treatment with possible adjuvant radiotherapy resulted in recurrence in 40% of cases (follow-up of 24 months), and death due to disease in 47% of patients (follow-up of 19 months).