Synergistic combination therapy using cowpea mosaic virus intratumoral immunotherapy and Lag-3 checkpoint blockade.

Immune checkpoint therapy (ICT) for cancer can yield dramatic clinical responses; however, these may only be observed in a minority of patients. These responses can be further limited by subsequent disease recurrence and resistance. Combination immunotherapy strategies are being developed to overcome these limitations. We have previously reported enhanced efficacy of combined intratumoral cowpea mosaic virus immunotherapy (CPMV IIT) and ICT approaches. Lymphocyte-activation gene-3 (LAG-3) is a next-generation inhibitory immune checkpoint with broad expression across multiple immune cell subsets. Its expression increases on activated T cells and contributes to T cell exhaustion. We observed heightened efficacy of a combined CPMV IIT and anti-LAG-3 treatment in a mouse model of melanoma. Further, LAG-3 expression was found to be increased within the TME following intratumoral CPMV administration. The integration of CPMV IIT with LAG-3 inhibition holds significant potential to improve treatment outcomes by concurrently inducing a comprehensive anti-tumor immune response, enhancing local immune activation, and mitigating T cell exhaustion.

Intraoperative Multivessel Embolization Reduces Blood Loss and Transfusion Requirements Compared to Internal Iliac Artery Balloon Placement during Cesarean Hysterectomy for Placenta Accreta Spectrum.

PURPOSE: To evaluate the effectiveness and safety of prophylactic multivessel selective embolization (MVSE) compared to those of internal iliac artery occlusion balloon (IIABO) placement in patients undergoing cesarean hysterectomy for placenta accreta spectrum (PAS). MATERIALS AND METHODS: An institutional review board-approved retrospective series was conducted with consecutive patients with PAS at a single institution between 2010 and 2021. MVSE was performed in a hybrid operating room after cesarean section prior to hysterectomy. IIABO was performed with balloons placed into the bilateral internal iliac arteries, which were inflated during hysterectomy. Median blood loss, transfusion requirements, percentage of cases requiring transfusion, and adverse events were recorded. RESULTS: A total of 20 patients treated with embolization and 34 patients with balloon placement were included. Placenta percreta and previa were seen in 60% and 90% of patients, respectively. Median blood loss in the MVSE group was 713 mL (interquartile range [IQR], 475-1,000 mL) compared to 2,000 mL (IQR, 1,500-2,425 mL) in the IIABO group (P < .0001). The median total number of units of packed red blood cell transfusions (0 vs 2.5) and percentage of cases requiring a transfusion (20% vs 65%) were less in the MVSE group (P < .01). A median of 4 vessels (IQR, 3-9) were embolized during MVSE. No major adverse events or nontarget embolization consequences were observed. CONCLUSIONS: Prophylactic MVSE is a safe procedure that reduces operative blood loss and transfusion requirements compared to those of IIABO in patients undergoing cesarean hysterectomy for presumed higher-degree PAS.

May-Thurner syndrome in patients with postural orthostatic tachycardia syndrome and Ehlers-Danlos syndrome: a case series.

Background: Postural orthostatic tachycardia syndrome (POTS), Ehlers-Danlos syndrome (EDS), and May-Thurner syndrome (MTS) are three syndromes that are often misdiagnosed or underdiagnosed. The true prevalence of these syndromes may be higher than currently reported. The following case series is the first to report a three-way association between POTS, EDS, and MTS. Case summary: We describe three patients with concomitant POTS, EDS, and MTS. Although abdominopelvic vasculature evaluation can be difficult via conventional imaging techniques, we present the use of novel dynamic contrast-enhanced magnetic resonance angiography with Differential Subsampling with Cartesian Ordering (DISCO) and four-dimensional flow magnetic resonance imaging to aid vasculature evaluation and the diagnosis of MTS. Two patients underwent left common iliac vein stenting to treat MTS, experiencing significant improvement in their POTS symptoms and quality of life. Discussion: Ehlers-Danlos syndrome, POTS, and MTS may interact synergistically to exacerbate symptoms. Patients with EDS should be evaluated for possible POTS and pelvic venous complications. Left common iliac vein stenting for MTS can mitigate POTS symptoms by decreasing lower extremity venous pooling and should be considered in this patient population. Further research is needed to understand the exact mechanism and intricacies of this syndrome triad.

Inactivated Cowpea Mosaic Virus in Combination with OX40 Agonist Primes Potent Antitumor Immunity in a Bilateral Melanoma Mouse Model.

Viral immunotherapies are being recognized in cancer treatment, with several currently approved or undergoing clinical testing. While contemporary approaches have focused on oncolytic viral therapies, our efforts center on the development of plant virus-based cancer immunotherapies. In a previous work, we demonstrated the potent efficacy of the cowpea mosaic virus (CPMV), a plant virus that does not replicate in animals, applied as an in situ vaccine. CPMV is an immunostimulatory drug candidate, and intratumoral administration remodels the tumor microenvironment leading to activation of local and systemic antitumor immunity. Efficacy has been demonstrated in multiple tumor mouse models and canine cancer patients. As wild-type CPMV is infectious toward various legumes and because shedding of infectious virus from patients may be an agricultural concern, we developed UV-inactivated CPMV (termed inCPMV) which is not infectious toward plants. We report that as a monotherapy, wild-type CPMV outperforms inCPMV in mouse models of dermal melanoma or disseminated colon cancer. Efficacy of inCPMV is less than that of CPMV and similar to that of RNA-free CPMV. Immunological investigation using knockout mice shows that inCPMV does not signal through TLR7 (toll-like receptor); structure-function studies indicate that the RNA is highly cross-linked and therefore unable to activate TLR7. Wild-type CPMV signals through TLR2, -4, and -7, whereas inCPMV more closely resembles RNA-free CPMV which signals through TLR2 and -4 only. The structural features of inCPMV explain the increased potency of wild-type CPMV through the triple pronged TLR activation. Strikingly, when inCPMV is used in combination with an anti-OX40 agonist antibody (administered systemically), exceptional efficacy was demonstrated in a bilateral B16F10 dermal melanoma model. Combination therapy, with in situ vaccination applied only into the primary tumor, controlled the progression of the secondary, untreated tumors, with 10 out of 14 animals surviving for at least 100 days post tumor challenge without development of recurrence or metastatic disease. This study highlights the potential of inCPMV as an in situ vaccine candidate and demonstrates the power of combined immunotherapy approaches. Strategic immunocombination therapies are the formula for success, and the combination of in situ vaccination strategies along with therapeutic antibodies targeting the cancer immunity cycle is a particularly powerful approach.

Combining nanomedicine and immune checkpoint therapy for cancer immunotherapy.

Cancer immunotherapy has emerged as a pillar of the cancer therapy armamentarium. Immune checkpoint therapy (ICT) is a mainstay of modern immunotherapy. Although ICT monotherapy has demonstrated remarkable clinical efficacy in some patients, the majority do not respond to treatment. In addition, many patients eventually develop resistance to ICT, disease recurrence, and toxicity from off-target effects. Combination therapy is a keystone strategy to overcome the limitations of monotherapy. With the integration of ICT and any therapy that induces tumor cell lysis and release of tumor-associated antigens (TAAs), ICT is expected to strengthen the coordinated innate and adaptive immune responses to TAA release and promote systemic, cellular antitumor immunity. Nanomedicine is well poised to facilitate combination ICT. Nanoparticles with delivery and/or immunomodulation capacities have been successfully combined with ICT in preclinical applications. Delivery nanoparticles protect and control the targeted release of their cargo. Inherently immunomodulatory nanoparticles can facilitate immunogenic cell death, modification of the tumor microenvironment, immune cell mimicry and modulation, and/or in situ vaccination. Nanoparticles are frequently multifunctional, combining multiple treatment strategies into a single platform with ICT. Nanomedicine and ICT combinations have great potential to yield novel, powerful treatments for patients with cancer. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Therapeutic Approaches and Drug Discovery > Emerging Technologies.

Plant Viruses and Bacteriophage-Based Reagents for Diagnosis and Therapy.

Viral nanotechnology exploits the prefabricated nanostructures of viruses, which are already abundant in nature. With well-defined molecular architectures, viral nanocarriers offer unprecedented opportunities for precise structural and functional manipulation using genetic engineering and/or bio-orthogonal chemistries. In this manner, they can be loaded with diverse molecular payloads for targeted delivery. Mammalian viruses are already established in the clinic for gene therapy and immunotherapy, and inactivated viruses or virus-like particles have long been used as vaccines. More recently, plant viruses and bacteriophages have been developed as nanocarriers for diagnostic imaging, vaccine and drug delivery, and combined diagnosis/therapy (theranostics). The first wave of these novel virus-based tools has completed clinical development and is poised to make an impact on clinical practice.

Association of chemosensory dysfunction and COVID-19 in patients presenting with influenza-like symptoms.

BACKGROUND: Rapid spread of the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) and concern for viral transmission by ambulatory patients with minimal to no symptoms underline the importance of identifying early or subclinical symptoms of coronavirus disease 2019 (COVID-19) infection. Two such candidate symptoms include anecdotally reported loss of smell and taste. Understanding the timing and association of smell/taste loss in COVID-19 may help facilitate screening and early isolation of cases. METHODS: A single-institution, cross-sectional study evaluating patient-reported symptoms with a focus on smell and taste was conducted using an internet-based platform on adult subjects who underwent testing for COVID-19. Logistic regression was employed to identify symptoms associated with COVID-19 positivity. RESULTS: A total of 1480 patients with influenza-like symptoms underwent COVID-19 testing between March 3, 2020, and March 29, 2020. Our study captured 59 of 102 (58%) COVID-19-positive patients and 203 of 1378 (15%) COVID-19-negative patients. Smell and taste loss were reported in 68% (40/59) and 71% (42/59) of COVID-19-positive subjects, respectively, compared to 16% (33/203) and 17% (35/203) of COVID-19-negative patients (p < 0.001). Smell and taste impairment were independently and strongly associated with COVID-19 positivity (anosmia: adjusted odds ratio [aOR] 10.9; 95% CI, 5.08-23.5; ageusia: aOR 10.2; 95% CI, 4.74-22.1), whereas sore throat was associated with COVID-19 negativity (aOR 0.23; 95% CI, 0.11-0.50). Of patients who reported COVID-19-associated loss of smell, 74% (28/38) reported resolution of anosmia with clinical resolution of illness. CONCLUSION: In ambulatory individuals with influenza-like symptoms, chemosensory dysfunction was strongly associated with COVID-19 infection and should be considered when screening symptoms. Most will recover chemosensory function within weeks, paralleling resolution of other disease-related symptoms.

Comparison of complete and near-complete endovascular embolization of hypervascular spine tumors with partial embolization.

OBJECTIVE: Preoperative endovascular embolization of hypervascular spine tumors can reduce intraoperative blood loss. The extent to which subtotal embolization reduces blood loss has not been clearly established. This study aimed to elucidate a relationship between the extent of preoperative embolization and intraoperative blood loss. METHODS: Sixty-six patients undergoing preoperative endovascular embolization and subsequent resection of hypervascular spine tumors were retrospectively reviewed. Patients were divided into 3 groups: complete embolization (n = 22), near-complete embolization (≥ 90% but < 100%; n = 22), and partial embolization (< 90%; n = 22). Intraoperative blood loss was compared between groups using one-way ANOVA with post hoc comparisons between groups. RESULTS: The average blood loss in the complete embolization group was 1625 mL. The near-complete embolization group had an average blood loss of 2021 mL in surgery. Partial embolization was associated with a mean blood loss of 4009 mL. On one-way ANOVA, significant differences were seen across groups (F-ratio = 6.81, p = 0.002). Significant differences in intraoperative blood loss were also seen between patients undergoing complete and partial embolization (p = 0.001) and those undergoing near-complete and partial embolization (p = 0.006). Pairwise testing showed no significant difference between complete and near-complete embolization (p = 0.57). Analysis of a combined group of complete and near-complete embolization also showed a significantly decreased blood loss compared with partial embolization (p < 0.001). Patient age, tumor size, preoperative coagulation parameters, and preoperative platelet count were not significantly associated with blood loss. CONCLUSIONS: Preoperative endovascular embolization is associated with decreased intraoperative blood loss. In this series, blood loss was significantly less in surgeries for tumors in which preoperative complete or near-complete embolization was achieved than in tumors in which preoperative embolization resulted in less than 90% reduction of tumor vascular blush. These findings suggest that there may be a critical threshold of efficacy that should be the goal of preoperative embolization.

Active Microneedle Administration of Plant Virus Nanoparticles for Cancer in situ Vaccination Improves Immunotherapeutic Efficacy.

The solid tumor microenvironment (TME) poses a significant structural and biochemical barrier to immunotherapeutic agents. To address the limitations of tumor penetration and distribution, and to enhance antitumor efficacy of immunotherapeutics, we present here an autonomous active microneedle (MN) system for the direct intratumoral (IT) delivery of a potent immunoadjuvant, cowpea mosaic virus nanoparticles (CPMV) in vivo. In this active delivery system, magnesium (Mg) microparticles embedded into active MNs react with the interstitial fluid in the TME, generating a propulsive force to drive the nanoparticle payload into the tumor. Active delivery of CPMV payload into B16F10 melanomas in vivo demonstrated substantially more pronounced tumor regression and prolonged survival of tumor-bearing mice compared to that of passive MNs and conventional needle injection. Active MN administration of CPMV also enhanced local innate and systemic adaptive antitumor immunity. Our approach represents an elaboration of conventional CPMV in situ vaccination, highlighting substantial immune-mediated antitumor effects and improved therapeutic efficacy that can be achieved through an active and autonomous delivery system-mediated CPMV in situ vaccination.

Atypical Vertebral Hemangiomas Are Frequently Associated with Radiculomedullary Arteries.

BACKGROUND: Preoperative endovascular embolization of atypical hemangiomas of the spine can reduce intraoperative blood loss. One frequent concern raised about embolizing these tumors is a possible association with arteries feeding the spinal cord, such as the artery of Adamkiewicz. This study aimed to elucidate a relationship between spinal levels affected by atypical spinal hemangiomas and radiculomedullary arteries. METHODS: This was a retrospective review of 8 patients undergoing preoperative embolization of atypical spinal hemangiomas. We evaluated 54 spinal levels by angiography during embolization procedures. Each spinal level was categorized on the basis of the presence or absence of tumor and radiculomedullary artery. RESULTS: Six of 15 (40%) affected levels had an associated radiculomedullary artery. Four of 39 (10.2%) unaffected levels had an associated cord feeding artery. The relative risk of affected spinal levels having an associated radiculomedullary artery was 3.9 (95% confidence interval 1.28-11.91). The attributable risk was 0.40 (95% CI 0.12-0.76). The chi-squared statistic was 6.35, with a P value of 0.01. Six of 8 patients (75%) had a radiculomedullary artery at a level of disease and embolization. CONCLUSIONS: In this study, spinal levels affected by atypical hemangiomas requiring surgery were associated with radiculomedullary arteries. When performing preoperative embolization, great care must be taken to identify and preserve arteries supplying the spinal cord.

Hypervascular Metastatic Spine Tumor Angiographic Relationships with the Artery of Adamkiewicz and Other Radiculomedullary Arteries.

BACKGROUND: Preoperative endovascular embolization of hypervascular metastatic spine tumors can reduce intraoperative blood loss. One frequent objection to embolizing these tumors is the concern for associated arteries feeding the spinal cord, such as the artery of Adamkiewicz. This study aimed to elucidate a relationship between spinal levels affected by hypervascular spine metastases and associated radiculomedullary arteries (RMAs). METHODS: A retrospective review of 46 patients who underwent preoperative embolization of hypervascular metastatic spine tumors was conducted. A total of 484 spinal levels were evaluated by diagnostic spinal angiography during embolization procedures. Each spinal level was categorized based on the presence or absence of tumor and RMA. RESULTS: No statistically significant associations were found. The relative risk of affected spinal levels having an associated RMA was 1.10 (95% confidence interval, 0.66-1.85). The attributable risk was 0.01 (-0.01 to 0.02). Chi-squared statistic was 0.13, with a P value of 0.7. Subgroup analysis in renal cell patients was also statistically insignificant, with a relative risk of 0.97 (95% confidence interval, 0.43-2.16). Chi-square statistic was 0.01, with a P value 0.94. A total of 32 patients (69.6%) had an RMA identified on their regional angiogram. Seventeen patients (37%) had an RMA at an embolized level. CONCLUSIONS: In this study, no association was found between spinal levels affected by hypervascular metastatic spine tumors and RMAs feeding the spinal cord by diagnostic spinal angiography. This suggests that these tumors have little intrinsic affinity for spinal levels with an RMA. However, given that tumor embolization frequently requires accessing multiple levels, the risk of encountering an RMA during embolization remains significant.

The Challenges of Renal Cell Carcinoma Metastatic to the Spine: A Systematic Review of Survival and Treatment.

STUDY DESIGN: Systematic review. OBJECTIVES: The objective of this systematic review was to answer 2 key questions: (1) What is the clinical presentation and probability of symptomatic improvement following treatment for patients with renal cell carcinoma (RCC) of the spine? (2) What is the overall survival of patients diagnosed with spinal metastases from RCC? METHODS: A literature review was performed to identify articles that reported on survival, clinical outcomes, and/or prognostic factors in the RCC population with spinal metastases from 1986 to 2016. RESULTS: Forty-eight articles (807 patients) were included. The Fuhrman Nuclear Grade has been significantly associated with survival in previous studies but was underpowered in the current study. The Memorial Sloan-Kettering Cancer Center Score (MSKCC/Motzer) was also underpowered in the current study. From the time of spinal metastasis, the mean and median survival for patients with previously diagnosed primary RCC was 8.75 and 11.7 months, respectively, whereas synchronously diagnosed patients (primary RCC and spinal metastasis) had a mean and median survival of 6.75 and 11 months, respectively. Patients with a "low" (0-8), "intermediate" (9-11), or "high" (12-15) revised Tokuhashi score at initial presentation had a median survival of 5.4, 11.7, and 32.9 months, respectively. CONCLUSION: Patients with either a synchronous or latent diagnosis of RCC survived greater than 6 months from the time of presentation. Initial Furhman grade, Tokuhashi score, and MSKCC/Motzer can be useful tools in informing patient-specific prognosis for those with metastatic RCC of the spine.

MR-Guided Functional Neurosurgery: Laser Ablation and Deep Brain Stimulation.

Intraoperative magnetic resonance imaging (iMRI) is increasingly implemented for image-guided procedures in functional neurosurgery. iMRI facilitates accurate electrode implantation for deep brain stimulation (DBS) and is currently an alternative method for DBS electrode targeting. The application of iMRI also allows for greater accuracy and precision in laser-induced thermal therapy (LITT). The expanding use of functional neurosurgical procedures makes safety and feasibility of iMRI important considerations, particularly in patients with comorbidities or complex medical histories. We review here the applications of iMRI and discuss its safety, feasibility, and limitations in functional neurosurgery.To motivate discussion of this topic, we also present a 52-year-old patient with an implanted cardioverter-defibrillator (ICD) who successfully underwent iMRI-guided DBS electrode implantation for advanced Parkinson disease (PD). Neither iMRI nor the passage of electrical current through the implanted DBS electrodes demonstrated detectable interference in ICD function. This case demonstrates that, even in complex clinical contexts, iMRI is a promising tool that merits further exploration for procedures requiring highly accurate and precise identification of target structures.

Abnormal Sleep Architecture and Hippocampal Circuit Dysfunction in a Mouse Model of Fragile X Syndrome.

Fragile X syndrome (FXS) is the most common heritable cause of intellectual disability and single-gene cause of autism spectrum disorder. The Fmr1 null mouse models much of the human disease including hyperarousal, sensory hypersensitivity, seizure activity, and hippocampus-dependent cognitive impairment. Sleep architecture is disorganized in FXS patients, but has not been examined in Fmr1 knockout (Fmr1-KO) mice. Hippocampal neural activity during sleep, which is implicated in memory processing, also remains uninvestigated in Fmr1-KO mice. We performed in vivo electrophysiological studies of freely behaving Fmr1-KO mice to assess neural activity, in the form of single-unit spiking and local field potential (LFP), within the hippocampal CA1 region during multiple differentiated sleep and wake states. Here, we demonstrate that Fmr1-KO mice exhibited a deficit in rapid eye movement sleep (REM) due to a reduction in the frequency of bouts of REM, consistent with sleep architecture abnormalities of FXS patients. Fmr1-KO CA1 pyramidal cells (CA1-PCs) were hyperactive in all sleep and wake states. Increased low gamma power in CA1 suggests that this hyperactivity was related to increased input to CA1 from CA3. By contrast, slower sharp-wave ripple events (SWRs) in Fmr1-KO mice exhibited longer event duration, slower oscillation frequency, with reduced CA1-PC firing rates during SWRs, yet the incidence rate of SWRs remained intact. These results suggest abnormal neuronal activity in the Fmr1-KO mouse during SWRs, and hyperactivity during other wake and sleep states, with likely adverse consequences for memory processes.

Impact of smoking on postoperative complications after anterior cervical discectomy and fusion.

The relationship between smoking and the risk of postoperative complications among anterior cervical discectomy and fusion (ACDF) patients remains uncertain. We compared the postoperative complication rates following ACDF surgery among non-smokers, current smokers, and ever-smokers. Baseline and outcome data were obtained from the 2005- to 2014 American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database for patients over the age of 18 who underwent non-emergent ACDF surgery. Information on current smoking and ever-smoking status was extracted. Outcomes included development of at least one complication, development of a major complication, in-hospital mortality, and length of stay. ACDF patients were either current smokers (7847, 30.3%) or not current smokers (18,022, 69.7%); 33.0% of all patients (n=8542) had ever smoked. Current smoking status was not associated with increased odds of any one complication (P=0.584) or any major complication (P=0.138). In addition, using the number of pack-years as the primary independent variable, multivariate logistic regression analysis revealed that the number of pack-years was not significantly associated with greater odds of developing any one complication (P=0.276) or any major complication (P=0.334). However, ever-smoker status did present significantly higher odds of any major complication (OR, 1.333; 95% CI 1.007-1.764; P=0.044) than for non-smokers. These results suggest that any patient with a prior smoking history should be considered a higher risk surgical candidate when attempting ACDF.

The effect of renal dysfunction on short-term outcomes after lumbar fusion.

OBJECTIVE: To compare post-lumbar decompression and fusion complication rates and mortality for patients without preoperative hemodialysis (HD) use with and without renal dysfunction as estimated by glomerular filtration rate (GFR) and creatinine levels. PATIENTS AND METHODS: Baseline and outcome data were obtained from the 2005-2014 American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database for patients over the age of 18 who underwent non-emergent lumbar fusion surgery. Preoperative HD status and GFR and creatinine levels were extracted. Variables analyzed included development of at least one complication, development of a major complication, in-hospital mortality, and length of stay. RESULTS: A total of 29,081 patients were identified. Those with severe preoperative kidney dysfunction as estimated by GFR were more likely to develop a complication (GFR=15-30ml/min/1.73m2; OR, 3.82; 95% CI, 2.061-7.082; P=<0.0001 and GFR=30-45ml/min/1.73m2; OR, 2.124; 95% CI, 1.506-2.996; P<0.0001). Compared to patients with normal preoperative creatinine levels (0.75-1.0mg/dL), patients with elevated creatinine were more likely to develop at least one complication. CONCLUSION: Patients with low estimated GFR and elevated creatinine levels were associated with higher perioperative morbidity. This increased risk should be taken into consideration when counselling this patient population.