Durvalumab plus tremelimumab in advanced or metastatic soft tissue and bone sarcomas: a single-centre phase 2 trial.

BACKGROUND: Few standard treatment options are available for patients with metastatic sarcomas. We did this trial to evaluate the efficacy, safety, and changes in the tumour microenvironment for durvalumab, an anti-PD-L1 drug, and tremelimumab, an anti-CTLA-4 drug, across multiple sarcoma subtypes. METHODS: In this single-centre phase 2 trial, done at The University of Texas MD Anderson Cancer Center (Houston, TX USA), patients aged 18 years or older with advanced or metastatic sarcoma with an Eastern Cooperative Oncology Group performance status of 0 or 1 who had received at least one previous line of systemic therapy were enrolled in disease subtype-specific groups (liposarcoma, leiomyosarcoma, angiosarcoma, undifferentiated pleomorphic sarcoma, synovial sarcoma, osteosarcoma, alveolar soft-part sarcoma, chordoma, and other sarcomas). Patients received 1500 mg intravenous durvalumab and 75 mg intravenous tremelimumab for four cycles, followed by durvalumab alone every 4 weeks for up to 12 months. The primary endpoint was progression-free survival at 12 weeks in the intention-to-treat population (all patients who received at least one dose of treatment). Safety was also analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02815995, and is completed. FINDINGS: Between Aug 17, 2016, and April 9, 2018, 62 patients were enrolled, of whom 57 (92%) received treatment and were included in the intention-to-treat population. With a median follow-up of 37·2 months (IQR 1·8-10·1), progression-free survival at 12 weeks was 49% (95% CI 36-61). 21 grade 3-4 treatment-related adverse events were reported, the most common of which were increased lipase (four [7%] of 57 patients), colitis (three [5%] patients), and pneumonitis (three [5%] patients). Nine (16%) patients had a treatment related serious adverse event. One patient had grade 5 pneumonitis and colitis. INTERPRETATION: The combination of durvalumab and tremelimumab is an active treatment regimen for advanced or metastatic sarcoma and merits evaluation in specific subsets in future trials. FUNDING: AstraZeneca.

Evolutionary analysis of globin domains from kinetoplastids.

Globin (Gb) domains function in sensing gaseous ligands like oxygen and nitric oxide. In recent years, Gb domain containing heme binding adenylate cyclases (OsAC or GbAC) emerged as significant modulator of Leishmania response to hypoxia and oxidative stress. During progression of life cycle stages, kinetoplastids experience altered condition in insect vectors or other hosts. Moreover, marked diversity in life style has been accounted among kinetoplastids. Distribution and abundance of Gb-domains vary between different groups of kinetoplastids. While in bodonoids, Gbs are not combined with any other functional domains, in trypanosomatids it is either fused with adenylate cyclase (AC) or oxidoreductase (OxR) domains. In salivarian trypanosomatids and Leishmania (Viannia) subtypes, no gene product featuring Gbs can be identified. In this context, evolution of Gb-domains in kinetoplastids was explored. GbOxR derived Gbs clustered with bacterial flavohemoglobins (fHb) including one fHb from Advenella, an endosymbiont of monoxeneous trypanosomatids. Codon adaptation and other evolutionary analysis suggested that OsAC (LmjF.28.0090), the solitary Gb-domain featuring gene product in Leishmania, was acquired via possible horizontal gene transfer. Substantial functional divergence was estimated between orthologues of genes encoding GbAC or GbOxR; an observation also reflected in structural alignment and heme-binding residue predictions. Orthologue-paralogue and synteny analysis indicated genomic reduction in GbOxR and GbAC loci for dixeneous trypanosomatids.

B-cell lymphoma/leukaemia 11B (BCL11B) expression status helps distinguish early T-cell precursor acute lymphoblastic leukaemia/lymphoma (ETP-ALL/LBL) from other subtypes of T-cell ALL/LBL.

B-cell lymphoma/leukaemia 11B (BCL11B) is an essential transcription factor for T-cell lineage commitment and maturation. We investigated BCL11B expression by immunohistochemistry in T-lymphoblastic leukaemia/lymphoma (T-ALL/LBL) (n = 115). The majority (83%) of early T-cell precursor T-ALL/LBL (ETP-ALL) cases showed negative BCL11B expression, while most (84%) of non-ETP-ALL/LBL were positive for BCL11B. A simplified three-marker [BCL11B, cluster of differentiation 5 (CD5), CD13] immunophenotypic score discriminated reliably between ETP-ALL and non-ETP-ALL/LBL. In ETP-ALL, patients with positive BCL11B expression had a better overall survival than those with negative BCL11B (P = 0·009). In summary, BCL11B is a valuable marker for T-ALL/LBL subtyping and serves as a potential prognostic marker in patients with ETP-ALL.

Quorum quenching activity of pentacyclic triterpenoids leads to inhibition of biofilm formation by Acinetobacter baumannii.

The quorum quenching (QQ) potential of three pentacyclic triterpenoids, glycyrrhetinic acid (GRA), ursolic acid (UA) and betulinic acid (BA), representing distinct groups of compounds, was evaluated. Violacein production by Chromobacterium violaceum and pyocyanin production by Pseudomonas aeruginosa were severely affected by GRA, UA and BA, suggesting a perturbation of N-acyl homoserine lactone (ASL) based signaling. Molecular docking analysis revealed a possible interaction between ASL-synthase and ASL-dependent transcriptional activator homologs from P. aeruginosa and Acinetobacter baumannii with common binding pockets for GRA, UA and BA. The triterpenoids inhibited biofilm formation by A. baumannii and affected the overall structure of biofilms. When administered in combination, two of the three molecules fostered antibiotic action against A. baumannii biofilms, widening the scope for developing novel combinations against the pathogen.

Unlocking the Potential of Obestatin: A Novel Peptide Intervention for Skeletal Muscle Regeneration and Prevention of Atrophy.

Obestatin is derived from the same gene as that of ghrelin and their functions were perceived to be antagonistic. Recent developments have shown that although they are known to have contradictory functions, effect of obestatin on skeletal muscle regeneration is similar to that of ghrelin. Obestatin works through a receptor called GPR39, a ghrelin and motilin family receptor and transduces signals in skeletal muscle similar to that of ghrelin. Not only there is a similarity in the receptor family, but also obestatin targets similar proteins and transcription factors as that of ghrelin (for example, FoxO family members) for salvaging skeletal muscle atrophy. Moreover, like ghrelin, obestatin also works by inducing the transcription of Pax7 which is required for muscle stem cell mobilisation. Hence, there are quite some evidences which points to the fact that obestatin can be purposed as a peptide intervention to prevent skeletal muscle wasting and induce myogenesis. This review elaborates these aspects of obestatin which can be further exploited and addressed to bring obestatin as a clinical intervention towards preventing skeletal muscle atrophy and sarcopenia.

Dynamic Changes in Circulating Tumor Fraction as a Predictor of Real-World Clinical Outcomes in Solid Tumor Malignancy Patients Treated with Immunotherapy.

INTRODUCTION: A dynamic molecular biomarker that can identify early efficacy of immune checkpoint inhibitor (ICI) therapy remains an unmet clinical need. Here we evaluate if a novel circulating tumor DNA (ctDNA) assay, xM, used for treatment response monitoring (TRM), that quantifies changes in ctDNA tumor fraction (TF), can predict outcome benefits in patients treated with ICI alone or in combination with chemotherapy in a real-world (RW) cohort. METHODS: This retrospective study consisted of patients with advanced cancer from the Tempus de-identified clinical genomic database who received longitudinal liquid-based next-generation sequencing. Eligible patients had a blood sample ≤ 40 days prior to the start of ICI initiation and an on-treatment blood sample 15-180 days post ICI initiation. TF was calculated via an ensemble algorithm that utilizes TF estimates derived from variants and copy number information. Patients with molecular response (MR) were defined as patients with a ≥ 50% decrease in TF between tests. In the subset of patients with rw-imaging data between 2 and 18 weeks of ICI initiation, the predictive value of MR in addition to rw-imaging was compared to a model of rw-imaging alone. RESULTS: The evaluable cohort (N = 86) was composed of 14 solid cancer types. Patients received either ICI monotherapy (38.4%, N = 33) or ICI in combination with chemotherapy (61.6%, N = 53). Patients with MR had significantly longer rw-overall survival (rwOS) (hazard ratio (HR) 0.4, P = 0.004) and rw-progression free survival (rwPFS) (HR 0.4, P = 0.005) than patients with molecular non-response (nMR). Similar results were seen in the ICI monotherapy subcohort; HR 0.2, P = 0.02 for rwOS and HR 0.2, P = 0.01 for rwPFS. In the subset of patients with matched rw-imaging data (N = 51), a model incorporating both MR and rw-imaging was superior in predicting rwOS than rw-imaging alone (P = 0.02). CONCLUSIONS: xM used for TRM is a novel serial quantitative TF algorithm that can be used clinically to evaluate ICI therapy efficacy.

Sunburst quantum Ising model under interaction quench: Entanglement and role of initial state coherence.

We study the nonequilibrium dynamics of an isolated bipartite quantum system, the sunburst quantum Ising model, under interaction quench. The prequench limit of this model is two noninteracting integrable systems, namely a transverse Ising chain and finite number of isolated qubits. As a function of interaction strength, the spectral fluctuation property goes from Poisson to Wigner-Dyson statistics. We chose entanglement entropy as a probe to study the approach to thermalization or lack of it in postquench dynamics. In the near-integrable limit, as expected, the linear entropy displays oscillatory behavior, while in the chaotic limit it saturates. Along with the chaotic nature of the time evolution generator, we show the importance of the role played by the coherence of the initial state in deciding the nature of thermalization. We further show that these findings are general by replacing the Ising ring with a disordered XXZ model with disorder strength putting it in the many-body localized phase.

The elusive role of myostatin signaling for muscle regeneration and maintenance of muscle and bone homeostasis.

Skeletal muscle is one of the leading frameworks of the musculo-skeletal system, which works in synergy with the bones. Long skeletal muscles provide stability and mobility to the human body and are primarily composed of proteins. Conversely, improper functioning of various skeletal muscles leads to diseases and disorders, namely, age-related muscle disorder called sarcopenia, a group of genetic muscle disorders such as muscular dystrophies, and severe muscle wasting in cancer known as cachexia. However, skeletal muscle has an excellent ability to undergo hypertrophy and enhanced functioning during sustained exercise over time. Indeed, these processes of skeletal muscle regeneration/hypertrophy, as well as degeneration and atrophy, involve an interplay of various signaling pathways. Myostatin is one such chemokine/myokine with a significant contribution to muscle regeneration or atrophy in multiple conditions. In this review, we try to put together the role and regulation of myostatin as a function of muscle regeneration extrapolated to multiple aspects of its molecular functions.

Mitigation of chronic glucotoxicity-mediated skeletal muscle atrophy by arachidonic acid.

Toxicity caused by chronic hyperglycemia is a significant factor affecting skeletal muscle myogenesis, resulting in diabetic myopathy. Chronic and persistent hyperglycemia causes activation of the atrophy-related pathways in the skeletal muscles, which eventually results in inflammation and muscle degeneration. To counteract this process, various bioactive compound has been studied for their reversal or hypertrophic effect. In this study, we explored the molecular mechanisms associated with reversing glucotoxicity's effect in C2C12 cells by arachidonic acid (AA). We found a substantial increase in the pro-inflammatory cytokines and ROS production in hyperglycemic conditions, mitigated by AA supplementation. We found that AA supplementation restored protein synthesis that was downregulated under glucotoxicity conditions. AA enhanced myogenesis by suppressing high glucose induced inflammation and ROS production and enhancing protein synthesis. These results imply that AA has cytoprotective actions against hyperglycemia-induced cytotoxicity.

Sodium fluoride induces skeletal muscle atrophy via changes in mitochondrial and sarcomeric proteomes.

Sodium Fluoride (NaF) can change the expression of skeletal muscle proteins. Since skeletal muscle is rich in mitochondrial and contractile (sarcomeric) proteins, these proteins are sensitive to the effects of NaF, and the changes are dose-and time-dependent. In the current study, we have analysed the effect of high concentrations of NaF (80ppm) on mouse skeletal muscle at two different time points, i.e., 15 days and 60 days. At the end of the experimental time, the animals were sacrificed, skeletal muscles were isolated, and proteins were extracted and subjected to bioinformatic (Mass Spectrometric) analysis. The results were analysed based on changes in different mitochondrial complexes, contractile (sarcomeric) proteins, 26S proteasome, and ubiquitin-proteasome pathway. The results showed that the mitochondrial proteins of complex I, II, III, IV and V were differentially regulated in the groups treated with 80ppm of NaF for 15 days and 60 days. The network analysis indicated more changes in mitochondrial proteins in the group treated with the higher dose for 15 days rather than 60 days. Furthermore, differential expression of (sarcomeric) proteins, downregulation of 26S proteasome subunits, and differential expression in proteins related to the ubiquitin-proteasome pathway lead to muscle atrophy. The differential expression might be due to the adaptative mechanism to counteract the deleterious effects of NaF on energy metabolism. Data are available via ProteomeXchange with identifier PXD035014.

Immunogenomic intertumor heterogeneity across primary and metastatic sites in a patient with lung adenocarcinoma.

BACKGROUND: Lung cancer is the leading cause of cancer death, partially owing to its extensive heterogeneity. The analysis of intertumor heterogeneity has been limited by an inability to concurrently obtain tissue from synchronous metastases unaltered by multiple prior lines of therapy. METHODS: In order to study the relationship between genomic, epigenomic and T cell repertoire heterogeneity in a rare autopsy case from a 32-year-old female never-smoker with left lung primary late-stage lung adenocarcinoma (LUAD), we did whole-exome sequencing (WES), DNA methylation and T cell receptor (TCR) sequencing to characterize the immunogenomic landscape of one primary and 19 synchronous metastatic tumors. RESULTS: We observed heterogeneous mutation, methylation, and T cell patterns across distinct metastases. Only TP53 mutation was detected in all tumors suggesting an early event while other cancer gene mutations were later events which may have followed subclonal diversification. A set of prevalent T cell clonotypes were completely excluded from left-side thoracic tumors indicating distinct T cell repertoire profiles between left-side and non left-side thoracic tumors. Though a limited number of predicted neoantigens were shared, these were associated with homology of the T cell repertoire across metastases. Lastly, ratio of methylated neoantigen coding mutations was negatively associated with T-cell density, richness and clonality, suggesting neoantigen methylation may partially drive immunosuppression. CONCLUSIONS: Our study demonstrates heterogeneous genomic and T cell profiles across synchronous metastases and how restriction of unique T cell clonotypes within an individual may differentially shape the genomic and epigenomic landscapes of synchronous lung metastases.

Vertebral Artery Dissections With Concurrent Intracranial Hemorrhage: A Case Series of 13 Patients Among a Cohort of 301.

BACKGROUND: Vertebral artery dissections (VADs) are a rare cause of ischemic stroke that can occasionally lead to intracranial hemorrhage (ICH). This study aims to identify differences in predisposing factors, event characteristics, and outcomes between patients with only a VAD and patients with VAD and concomitant ICH. METHODS: We conducted a retrospective chart review of 301 patients who presented with VADs at our institution from 2004-2018. A total of 13 patients were identified with VAD and concomitant ICH. Data were collected on demographics, event characteristics, treatments, and neurologic outcomes, measured using the modified Rankin Scale (mRS). RESULTS: VAD+ICH and VAD-only groups were similar in terms of age, sex, and recorded comorbidities. Additionally, etiology of the dissections did not seem to vary between groups (P = 0.6), even when selecting for traumatic causes such as motor vehicle accidents (P = 0.22) and violence (P = 0.25). Concomitant strokes and aneurysms/pseudoaneurysms occurred in similar proportions as well, but cervical fractures were more common in the VAD+ICH group (P = 0.003). Using the mRS as a measure of neurological outcome, we found that the VAD+ICH group had worse neurologic function at discharge, 3-month follow-up, and last follow-up (P < 0.001). CONCLUSIONS: Patients who experienced an ICH in addition to a VAD did not have any identifiable risk factors. Cervical spine fractures were more common in patients with VAD and ICH. VAD patients with a concomitant ICH have worse neurologic outcomes than patients with only a VAD.

Characteristics and Predictors of Outcome of Pseudoaneurysms Associated With Vertebral Artery Dissections: A 310-Patient Case Series.

BACKGROUND: Vertebral artery dissections (VADs) are a common cause of stroke in young patients and can result in various secondary effects, including pseudoaneurysm formation. OBJECTIVE: To identify differences in predisposing factors and outcomes for VADs with and without concomitant pseudoaneurysms. METHODS: We retrospective chart reviewed patients who presented to our institution at the time of VAD with at least a 3-mo clinical follow-up. Demographics, VAD characteristics, treatment, and outcomes represented as modified Rankin scale (mRS) scores were collected. RESULTS: Of 310 patients with a VAD included in this study, 301 patients had an identified pseudoaneurysm status, with 54 pseudoaneurysm-associated VADs and 247 VADs not associated with pseudoaneurysm. VAD patients with associated pseudoaneurysms were more likely to be female (P < .004), have bilateral VADs (P < .001), and have fewer vertebral artery segments affected (P = .018), and less likely to have stroke (P < .008) or occlusion of the vertebral artery (P < .001). There was no difference in the proportion of patients treated with antiplatelet agents (P = .12) or anticoagulants (P = .27) between the groups. VAD patients with associated pseudoaneurysms were more likely to have a higher mRS at 3-mo follow-up (P = .044) but not discharge (P = .18) or last follow-up (P = .05). VAD patients with pseudoaneurysms were equally likely to have resolution of occlusion (P = .40) and stenosis (P = .19). CONCLUSION: Demographics and clinical and radiological characteristics of VADs associated with pseudoaneurysms are different from those without associated pseudoaneurysms. Vertebral artery dissections with concomitant pseudoaneurysms are neither associated with worse functional nor radiographic outcomes.

Traumatic and Spontaneous Vertebral Artery Dissections: An Analysis of Tertiary-Center 310 Patient Cohort.

BACKGROUND: Vertebral artery dissections (VADs) are rare yet potentially devastating events. While the etiology of these events is either traumatic or spontaneous, there is a paucity of quantitative literature comparing the two. OBJECTIVE: To identify differences in predisposing factors, event characteristics, and clinical outcomes between traumatic VADs (tVADs) and spontaneous VADs (sVADs). METHODS: We retrospectively identified patients with VADs presenting to our institution at VAD onset with at least a 3-mo follow-up. Demographics, event characteristics, treatment details, and neurological outcomes as modified Rankin scale (mRS) scores were collected. RESULTS: Of the 310 patients sustaining 366 VADs total, 187 (60.3%) patients experienced a total of 221 (60.4%) sVADs and 123 (39.7%) patients experienced a total of 145 (39.6%) tVADs. sVADs were more likely to occur in the intracranial course of the artery (P = .042) and have a lower mRS at discharge, 3-month, and last clinical follow-up (P = 003, .002, and .001, respectively). tVADs were more likely associated with concomitant fractures (P < .001). CONCLUSION: Despite similar patient populations, tVADs are associated with higher mRS scores at all time points. Although further study is needed, this may suggest other concomitant trauma rather than the VAD itself is contributing to worse neurological status in patients with tVADs.

Clinical Characteristics, Course, and Outcomes of Vertebral Artery Dissections in the Postpartum Period.

BACKGROUND: Postpartum vertebral artery dissections (ppVADs) are rare but potentially morbid conditions that occur in otherwise healthy patients. OBJECTIVE: To evaluate clinical characteristics of ppVADs. METHODS: Demographic, clinical, treatment, and outcome data were collected on ppVADs and are presented in a case series of 12 patients and compared to the general cohort. RESULTS: In total, 12 patients had ppVADs in our cohort of 310 patients with vertebral artery dissections (VADs). They occurred 11.27 days (95% CI, -0.85 to 23.39) postdelivery. Of these, there were 5 (42%) with a hypertensive disorder of pregnancy, and 4 (33%) who had migraines. A total of 3 (25%) had ischemic strokes and 1 (8%) had a subarachnoid hemorrhage. In total, 2 patients (17%) had unfavorable modified Rankin Scale (mRS, 2-6) at discharge from hospital. Patients with ppVADs more often had bilateral VADs (42% vs 17%, P = .03), had pseudoaneurysms (50% vs 18%, P = .0068), were younger (33.83 years vs 44.32 years, P = .018), and had lower Charlson Comorbidity Index (CCI = 0 vs 0.99, P = .0038). Anticoagulant treatment was used in a similar percentage of patients. Multivariate analysis revealed 3 factors were predictive of change in mRS: CCI (OR = 1.09, 95% CI, 1.02-1.15), stroke (OR = 0.78, 95% CI, 0.65-0.95), and mRS at hospital discharge (OR = 0.80, 95% CI, 0.74-0.87). CONCLUSION: There are only 15 isolated ppVADs reported in the literature; this study adds 12 patients with 17 ppVADs. Postpartum VADs occur in younger, healthier patients than in the general cohort, raising questions about mechanism of injury. The majority of ppVADs have good neurological outcomes.

Chiropractic associated vertebral artery dissection: An analysis of 34 patients amongst a cohort of 310.

BACKGROUND: Vertebral artery dissections (VAD) are a rare but important cause of ischemic stroke, especially in younger patients. Many etiologies have been identified, including MVAs, cervical fractures, falls, physical exercise, and cervical chiropractic manipulation. The goal of this study was to investigate the subgroup of patients who suffered a chiropractor-associated injury and determine how their prognosis compared to other-cause VAD. METHODS: We conducted a retrospective chart review of 310 patients with vertebral artery dissections who presented at our institution between January 2004 and December 2018. Variables included demographic data, event characteristics, treatment, radiographic outcomes, and clinical outcomes measured using the modified Rankin Scale. FINDINGS: Overall, 34 out of our 310 patients suffered a chiropractor-associated injury. These patients tended to be younger (p = 0.01), female (p = 0.003), and have fewer comorbidities (p = 0.005) compared to patients with other-cause VADs. The characteristics of the injuries were similar, but chiropractor-associated injuries appeared to be milder at discharge and at follow-up. A higher proportion of the chiropractor-associated group had injuries in the 0-2 mRS range at discharge and at 3 months (p = 0.05, p = 0.04) and no patients suffered severe long-term neurologic consequences or death (0% vs. 9.8%, p = 0.05). However, when a multivariate binomial regression was performed, these effects dissipated and the only independent predictor of a worse injury at discharge was the presence of a cervical spine fracture (p < 0.001). INTERPRETATION: Chiropractor-associated injuries are similar to VADs of other causes, and apparent differences in the severity of the injury are likely due to demographic differences between the two populations.

Synthesis and Characterization of Rapidly Degrading Polyanhydrides as Vaccine Adjuvants.

There is a currently a need to develop adjuvants that are best suited to simultaneously enhance immune responses, induce immunologic memory, improve patient compliance (i.e., reduce doses and inflammation), and provide vaccine shelf stability for stockpiling and global deployment to challenging environments. Biodegradable polyanhydrides have been investigated extensively to overcome such challenges. It has been shown that controlling copolymer composition can result in chemistry-dependent immunomodulatory capabilities. These studies have revealed that copolymers rich in sebacic acid (SA) are highly internalized by antigen presenting cells and confer improved shelf stability of encapsulated proteins, while copolymers rich in 1,8-bis(p-carboxyphenoxy)-3,6-dioxaoctane (CPTEG) also exhibit enhanced internalization by and activation of antigen presenting cells (APCs), in addition to providing superior retention of protein stability following encapsulation and release. However, to date, CPTEG:SA copolymers have not been synthesized and described. In this work, we hypothesized that new copolymers composed of CPTEG and SA would combine the advantages of both monomers in terms of enhanced thermal properties, maintaining antigenicity of encapsulated proteins following nanoparticle synthesis, and superior cellular internalization and activation by APCs, demonstrated by the upregulation of costimulatory markers CD80, CD86, and CD40, as well as the secretion of proinflammatory cytokines IL-6, IL-1ß, and TNF-α. Herein, we describe the synthesis and design of novel CPTEG:SA nanoparticles with improved thermal properties, payload stability, and internalization by antigen presenting cells for applications in vaccine delivery. The performance of these new CPTEG:SA formulations was compared to that of traditional polyanhydride copolymers.

Vertebral artery dissections with and without cervical spine fractures: Analysis of 291 patients.

OBJECTIVES: Vertebral artery dissections occur when tears in the intimal layer of the vertebral artery and are associated with trauma, infection, and spontaneous etiologies. We aimed to identify differences in predisposing factors and outcomes in vertebral artery dissections associated with cervical spine fractures compared to those not associated with cervical spine fractures. PATIENTS AND METHODS: We conducted a retrospective chart review of patients with vertebral artery dissections who presented to our institution at the time of dissection and had a minimum of 3 month follow-up and collected data on demographics, event characteristics, treatments, and outcomes in the form of modified Rankin scale scores. RESULTS: In total, 291 patients with VAD were included in this study. Thirty-nine patients with VADs had associated fracture, while 252 patients had VADs without fracture. VAD patients with associated cervical fractures were more likely to be male (p < 0.001), have a greater number of comorbid conditions (p < 0.01), be smokers (p = 0.045), or have violence (p < 0.001) or motor vehicle accidents (p < 0.001) as the cause of their VADs. VAD patients with associated cervical fractures were less likely to have associated aneurysms or pseudoaneurysms (p = 0.002). VAD patients with associated cervical fractures were more likely to have higher mRS at discharge from the hospital (p < 0.001), 3 month follow-up (p < 0.001), and last follow-up (p < 0.001). CONCLUSION: Cervical spine fracture is likely the primary driver of poor neurological outcomes following vertebral artery dissection with associated cervical spine fracture.

Immuno-genomic landscape of osteosarcoma.

Limited clinical activity has been seen in osteosarcoma (OS) patients treated with immune checkpoint inhibitors (ICI). To gain insights into the immunogenic potential of these tumors, we conducted whole genome, RNA, and T-cell receptor sequencing, immunohistochemistry and reverse phase protein array profiling (RPPA) on OS specimens from 48 pediatric and adult patients with primary, relapsed, and metastatic OS. Median immune infiltrate level was lower than in other tumor types where ICI are effective, with concomitant low T-cell receptor clonalities. Neoantigen expression in OS was lacking and significantly associated with high levels of nonsense-mediated decay (NMD). Samples with low immune infiltrate had higher number of deleted genes while those with high immune infiltrate expressed higher levels of adaptive resistance pathways. PARP2 expression levels were significantly negatively associated with the immune infiltrate. Together, these data reveal multiple immunosuppressive features of OS and suggest immunotherapeutic opportunities in OS patients.

Spatially resolved analyses link genomic and immune diversity and reveal unfavorable neutrophil activation in melanoma.

Complex tumor microenvironmental (TME) features influence the outcome of cancer immunotherapy (IO). Here we perform immunogenomic analyses on 67 intratumor sub-regions of a PD-1 inhibitor-resistant melanoma tumor and 2 additional metastases arising over 8 years, to characterize TME interactions. We identify spatially distinct evolution of copy number alterations influencing local immune composition. Sub-regions with chromosome 7 gain display a relative lack of leukocyte infiltrate but evidence of neutrophil activation, recapitulated in The Cancer Genome Atlas (TCGA) samples, and associated with lack of response to IO across three clinical cohorts. Whether neutrophil activation represents cause or consequence of local tumor necrosis requires further study. Analyses of T-cell clonotypes reveal the presence of recurrent priming events manifesting in a dominant T-cell clonotype over many years. Our findings highlight the links between marked levels of genomic and immune heterogeneity within the physical space of a tumor, with implications for biomarker evaluation and immunotherapy response.