Neoadjuvant chemo-immunotherapy is improved with a novel pulsed electric field technology in an immune-cold murine model.

Chemo-immunotherapy uses combined systemic therapies for resectable and unresectable tumors. This approach is gaining clinical momentum, but survival increases leave considerable room for improvement. A novel form of Pulsed Electric Field (PEF) ablation combines focal tissue destruction with immune activation in preclinical settings. The PEFs induce lethal cell damage without requiring thermal processes, leaving cellular proteins intact. This affords PEF a favorable safety profile, improved antigenicity, and significant immunostimulatory damage-associated molecular pattern release compared to other focal therapies. Preclinical investigations demonstrate a combinatorial benefit of PEF with immunostimulation. This study evaluates whether this proprietary PEF therapy induces an immunostimulatory effect sufficient to augment systemic neoadjuvant chemotherapy and immunotherapy to reverse metastatic disease in an immune-cold murine tumor model. To determine whether PEF improves a neoadjuvant chemo-immunotherapy standard-of-care, partial PEF ablation was delivered to orthotopically inoculated 4T1 metastatic tumors in addition to combinations of cisplatin chemotherapy and/or αPD-1 immunotherapy, followed by resection. In addition, to determine whether PEF combined with chemo-immunotherapy improves local and metastatic response in unresectable populations, partial PEF ablation was added to chemo-immunotherapy in mice that did not receive resection. Blood cytokines and flow cytometry evaluated immune response. Partial PEF ablation generates an immunostimulatory tumor microenvironment, increases systemic immune cell populations, slows tumor growth, and prolongs survival relative to neoadjuvant systemic therapies-alone. These data suggest the addition of this proprietary PEF locoregional therapy may synergize with systemic standard-of-care paradigms to improve outcomes with potential or demonstrated metastatic disease in both resectable and unresectable patient cohorts.

Substance P-Botulinum Mediates Long-term Silencing of Pain Pathways that can be Re-instated with a Second Injection of the Construct in Mice.

Chronic pain presents an enormous personal and economic burden and there is an urgent need for effective treatments. In a mouse model of chronic neuropathic pain, selective silencing of key neurons in spinal pain signalling networks with botulinum constructs resulted in a reduction of pain behaviours associated with the peripheral nerve. However, to establish clinical relevance it was important to know how long this silencing period lasted. Now, we show that neuronal silencing and the concomitant reduction of neuropathic mechanical and thermal hypersensitivity lasts for up to 120d following a single injection of botulinum construct. Crucially, we show that silencing and analgesia can then be reinstated with a second injection of the botulinum conjugate. Here we demonstrate that single doses of botulinum-toxin conjugates are a powerful new way of providing long-term neuronal silencing and pain relief. PERSPECTIVE: This research demonstrates that botulinum-toxin conjugates are a powerful new way of providing long-term neuronal silencing without toxicity following a single injection of the conjugate and have the potential for repeated dosing when silencing reverses.

Mangrove removal exacerbates estuarine infilling through landscape-scale bio-morphodynamic feedbacks.

Changes in upstream land-use have significantly transformed downstream coastal ecosystems around the globe. Restoration of coastal ecosystems often focuses on local-scale processes, thereby overlooking landscape-scale interactions that can ultimately determine restoration outcomes. Here we use an idealized bio-morphodynamic model, based on estuaries in New Zealand, to investigate the effects of both increased sediment inputs caused by upstream deforestation following European settlement and mangrove removal on estuarine morphology. Our results show that coastal mangrove removal initiatives, guided by knowledge on local-scale bio-morphodynamic feedbacks, cannot mitigate estuarine mud-infilling and restore antecedent sandy ecosystems. Unexpectedly, removal of mangroves enhances estuary-scale sediment trapping due to altered sedimentation patterns. Only reductions in upstream sediment supply can limit estuarine muddification. Our study demonstrates that bio-morphodynamic feedbacks can have contrasting effects at local and estuary scales. Consequently, human interventions like vegetation removal can lead to counterintuitive responses in estuarine landscape behavior that impede restoration efforts, highlighting that more holistic management approaches are needed.

Contrast-enhanced US Evaluation of Hepatocellular Carcinoma Response to Chemoembolization: A Prospective Multicenter Trial.

Background Contrast-enhanced (CE) US has been studied for use in the detection of residual viable hepatocellular carcinoma (HCC) after locoregional therapy, but multicenter data are lacking. Purpose To compare two-dimensional (2D) and three-dimensional (3D) CE US diagnostic performance with that of CE MRI or CT, the current clinical standard, in the detection of residual viable HCC after transarterial chemoembolization (TACE) in a prospective multicenter trial. Materials and Methods Participants aged at least 21 years with US-visible HCC scheduled for TACE were consecutively enrolled at one of three participating academic medical centers from May 2016 to March 2022. Each underwent baseline 2D and 3D CE US before TACE, 2D and 3D CE US 1-2 weeks and/or 4-6 weeks after TACE, and CE MRI or CT 4-6 weeks after TACE. CE US and CE MRI or CT were evaluated by three fellowship-trained radiologists for the presence or absence of viable tumors and were compared with reference standards of pathology (18%), angiography on re-treatment after identification of residual disease at 1-2-month follow-up imaging (31%), 4-8-month CE MRI or CT (42%), or short-term (approximately 1-2 months) CE MRI or CT if clinically decompensated and estimated viability was greater than 50% at imaging (9%). Diagnostic performance criteria, including sensitivity and specificity, were obtained for each modality and time point with generalized estimating equation analysis. Results A total of 132 participants were included (mean age, 64 years ± 7 [SD], 87 male). Sensitivity of 2D CE US 4-6 weeks after TACE was 91% (95% CI: 84, 95), which was higher than that of CE MRI or CT (68%; 95% CI: 58, 76; P < .001). Sensitivity of 3D CE US 4-6 weeks after TACE was 89% (95% CI: 81, 94), which was higher than that of CE MRI or CT (P < .001), with no evidence of a difference from 2D CE US (P = .22). CE MRI or CT had 85% (95% CI: 76, 91) specificity, higher than that of 4-6-week 2D and 3D CE US (70% [95% CI: 56, 80] and 67% [95% CI: 53, 78], respectively; P = .046 and P = .023, respectively). No evidence of differences in any diagnostic criteria were observed between 1-2-week and 4-6-week 2D CE US (P > .21). Conclusion The 2D and 3D CE US examinations 4-6 weeks after TACE revealed higher sensitivity in the detection of residual HCC than CE MRI or CT, albeit with lower specificity. Importantly, CE US performance was independent of follow-up time. Clinical trial registration no. NCT02764801 © RSNA, 2023 Supplemental material is available for this article.

New Developments in Image-Guided Percutaneous Irreversible Electroporation of Solid Tumors.

PURPOSE OF REVIEW: This review will describe the various applications, benefits, risks, and approaches of conventional irreversible electroporation (IRE), as well as highlight the new technological developments of this procedure along with their clinical applications. RECENT FINDINGS: Minimally invasive image-guided percutaneous IRE ablation has emerged as a newer, non-thermal ablation technique for tumors in the solid organs, particularly within the liver, pancreas, kidney, and prostate. IRE allows for ablation near heat-sensitive structures, including major blood vessels and nerves, and is not susceptible to the heat sink effect. However, it is limited by certain requirements, such as the need for precise parallel placement of at least two probes with a maximum inter-probe distance of 2.5 cm to reduce the risk of arching phenomenon, the requirement for general anesthesia with muscle relaxant, and the need for cardiac synchronization. However, new technological advancements in the ablation system and image guidance tools have been introduced to improve the efficiency and efficacy of IRE. IRE is a safe and effective treatment option for solid tumor ablation within the liver, pancreas, kidney, and prostate. Compared with other ablation techniques, IRE has several advantages, such as the absence of heat sink effect and minimal injury to blood vessels and bile ducts while activating the immune system. Novel techniques such as H-FIRE, needle placement systems, and robotics have enhanced the accuracy and performance in placement of IRE probes. IRE can be especially beneficial when combined with chemotherapy, immunomodulation, and immunotherapy.

New botulinum neurotoxin constructs for treatment of chronic pain.

Chronic pain affects one in five people across human societies, with few therapeutic options available. Botulinum neurotoxin (BoNT) can provide long-lasting pain relief by inhibiting local release of neuropeptides and neurotransmitters, but its highly paralytic nature has limited its analgesic potential. Recent advances in protein engineering have raised the possibility of synthesising non-paralysing botulinum molecules for translation to pain sufferers. However, the synthesis of these molecules, via several synthetic steps, has been challenging. Here, we describe a simple platform for safe production of botulinum molecules for treating nerve injury-induced pain. We produced two versions of isopeptide-bonded BoNT from separate botulinum parts using an isopeptide bonding system. Although both molecules cleaved their natural substrate, SNAP25, in sensory neurons, the structurally elongated iBoNT did not cause motor deficit in rats. We show that the non-paralytic elongated iBoNT targets specific cutaneous nerve fibres and provides sustained pain relief in a rat nerve injury model. Our results demonstrate that novel botulinum molecules can be produced in a simple and safe manner and be useful for treating neuropathic pain.

Outcomes of Transarterial Embolization for Acute Nonvariceal Upper Gastrointestinal Bleeding: Correlation with Periprocedural Endoscopy.

PURPOSE: To evaluate gastric and intestinal mucosal changes on postembolic endoscopy and mortality after transarterial embolization (TAE) for upper gastrointestinal bleeding (UGIB). MATERIALS AND METHODS: An institutional review board-approved retrospective review of patients who underwent arteriography for refractory UGIB at a multicenter health system from December 2003 to August 2019 was performed. Two hundred sixty-nine patients underwent TAE for UGIB. Data on etiology of bleeding, embolization technique, pre-embolic and postembolic endoscopic results, blood product requirements, and mortality were collected from the medical record. Endoscopy results were compared at the site of the target lesion before and after TAE. Multivariable logistic regressions were performed to assess predictors of new adverse mucosal responses and mortality. RESULTS: The most common etiology of UGIB was peptic ulcer. Twenty-five percent (n = 68) of the patients had clinical evidence of rebleeding after TAE, and the 30-day mortality rate was 26% (n = 73). Eighty-eight (32%) patients underwent post-TAE endoscopy, with only 15% showing new adverse mucosal changes after embolization. Procedural characteristics, including vascular territory and embolic choice, were not significantly predictive of increased risk of development of adverse mucosal response after TAE or increased mortality risk. No patients in the study were found to have bowel lumen stenosis at the time of post-TAE endoscopy or at 6 year follow-up. CONCLUSIONS: TAE is a safe and effective intervention for patients with UGIB. Post-TAE endoscopy demonstrated that most patients had either stability or improvement in the target lesion after TAE, and only a minority of patients demonstrated adverse mucosal changes.

A Practical Review of Suicide Among Veterans: Preventive and Proactive Measures for Health Care Institutions and Providers.

Suicide rates among veterans are higher than those of the general US population. Although veterans compose only 7.6% of the US population, nearly 14% of American adult suicides are among veterans. The rate of suicide is 1.5 times higher among all veterans and 2.1 times higher among female veterans compared with the general population. Only 47% of all veterans are enrolled in the US Department of Veterans Affairs (VA) Healthcare System, leaving a large number either not receiving health care or receiving it outside the VA. Recent legislation has improved access to care for veterans outside the VA, highlighting the need for a broad public health approach to address veteran suicide and the need for all health care institutions and clinicians to be familiar with the unique health concerns in this population. The purpose of this narrative review was to summarize the risk factors contributing to veteran suicide and to provide guidance on how to assess and mitigate these risks. Suicide is preventable through recognition of risk and prompt intervention. Health care providers both inside and outside the VA system are uniquely situated at the intersection of the many contributing factors to veteran suicide and should have a structured, proactive approach to address the problem.

The development of independent colleges and their separation from their parent public universities in China.

With the highest number of students in private higher education in the world, China is updating the governance system for this sector. This process involves independent colleges, which were founded by and remain associated with public universities, but which are privately funded. As one of the strategies to improve the development of independent colleges, in 2008 the Ministry of Education asked these colleges to separate from their parent public universities. However, by the end of 2020, over half of the 2008 colleges had still not separated but, over the next year, the outstanding figure suddenly dropped by one-third. This paper analyses the factors affecting the separation from the viewpoints of different stakeholders. Private funders have an interest in making use of the parent universities' resources and controlling and gaining financial returns from the colleges; for the parent universities, the management fees paid by the colleges are an important priority, while, for local government, more and better higher education places with less public finance is a key goal. Currently, there are few studies in the English language literature on independent colleges. By disseminating experiences of higher education reform in China, our findings could have important implications for government policymakers and for senior and practicing managers in universities.

Online Patient Reviews of Breast Reconstruction: RealSelf Analysis.

RealSelf is an online community that hosts an expansive number of online reviews for cosmetic and reconstructive plastic surgery procedures. The purpose of this study is to analyze patient satisfaction with breast reconstruction procedures from RealSelf to determine factors contributing to a positive or negative patient experience. Methods: The breast reconstruction category from RealSelf.com was analyzed using a web crawler-based application built from Python and Selenium. Reviews were collected from May 2009 to November 2021. Information including RealSelf's inherent "worth it" ranking system, review text, the number of submitted photographs, and the number of readers who found the review helpful was captured. The content of the review was then independently reviewed by the authors and was categorized with key factors that determined positive or negative reviews. Results: A total of 3451 breast reconstruction reviews were collected. After the authors analyzed each review, 3225 (94.33%) were identified as positive reviews. The most common factors associated with positive reviews were physician demeanor (n = 2600, 31.7%), aesthetic outcome (n = 1955, 23.8%), or staff (n = 1543, 18.8%), while negative reviews were associated with unfavorable aesthetic outcome (n = 94, 28.9%), physician demeanor (n = 82, 25.2%), or postoperative complications (n = 75, 23.1%). Conclusions: Although there are surveys that analyze patient satisfaction for breast reconstruction, there has not been a study that analyzed a large online review database. Predominating factors in both positive and negative reviews were physician demeanor and aesthetic outcome.

Role of Fluorodeoxyglucose-PET in Interventional Radiology.

Fluorodeoxyglucose (FDG)-PET has expanding applications in the field of interventional radiology. FDG-PET provides both qualitative and quantitative assessments of malignancy, infection, and inflammation. These assessments can assist interventional radiologists in selecting the most appropriate treatment options for their oncology patients. FDG-PET is also useful for evaluating the response to interventional treatments and in predicting the prognosis of oncology patients. Finally, FDG-PET can assist the interventional radiologist in diagnosing and monitoring response to treatment of infection and inflammation. Nevertheless, there is a need for additional prospective studies to further establish the role of FDG-PET in these applications.

Multicenter assessment of augmented reality registration methods for image-guided interventions.

PURPOSE: To evaluate manual and automatic registration times and registration accuracies on HoloLens 2 for aligning a 3D CT phantom model onto a CT grid, a crucial step for intuitive 3D navigation during CT-guided interventions; to compare registration times between HoloLens 1 and 2. METHODS: Eighteen participants in various stages of clinical training across two academic centers performed registration of a 3D CT phantom model onto a CT grid using HoloLens 2. Registration times and accuracies were compared among different registration methods, clinical experience levels, and consecutive attempts. Registration times were also compared retrospectively to prior HoloLens 1 results. RESULTS: Mean aggregate manual registration times were 27.7 s, 24.3 s, and 72.8 s for one-handed gesture, two-handed gesture, and Xbox controller, respectively; mean automatic registration time was 5.3 s (ANOVA p < 0.0001). No significant difference in registration times was found among attendings, residents and fellows, and medical students (p > 0.05). Significant improvements in registration times were detected across consecutive attempts using hand gestures (p < 0.01). Compared to prior HoloLens 1 data, hand gesture registration was 81.7% faster with HoloLens 2 (p < 0.05). Registration accuracies were not significantly different across manual registration methods, measuring at 5.9 mm, 9.5 mm, and 8.6 mm with one-handed gesture, two-handed gesture, and Xbox controller, respectively (p > 0.05). CONCLUSIONS: Manual registration times decreased significantly on HoloLens 2, approaching those of automatic registration and outperforming Xbox controller registration. Fast, adaptive, and accurate registration of holographic models of cross-sectional imaging is paramount for the implementation of augmented reality-assisted 3D navigation during CT-guided interventions.

Neurology and the histiocytoses: a case of Rosai-Dorfman-Destombes disease.

The histiocytoses are a group of rare disorders characterised by the accumulation of neoplastic or non-neoplastic activated histiocytes in various tissues. Phenotypes vary widely from cutaneous lesions or lymphadenopathy that regress spontaneously to disseminated disease with poor prognosis. Neurological symptoms can be a presenting feature or appear during the course of disease. We present a challenging diagnostic and management case of Rosai-Dorfman-Destombes disease in a 48-year-old woman with a relapsing, partially steroid-responsive syndrome comprising patchy, non-length-dependent radiculoneuropathy with diffuse pachymeningitis and widespread systemic disease, and recent dramatic response to novel mitogen-activated kinase pathway inhibition. We discuss the clinical characteristics, diagnosis, recent breakthroughs in pathogenesis and emerging treatment options for Rosai-Dorfman disease and for the histiocytoses with neurological sequelae, including Langerhans cell histiocytosis and Erdheim-Chester disease.

Preintervention Computed Tomography Improves the Performance of Endovascular Intervention in Patients with Abdominopelvic Trauma.

PURPOSE: To evaluate the role of computed tomography (CT) and CT angiography in guiding endovascular arteriography (EA) and embolization in hemodynamically (HD) stable and unstable patients with abdominal and/or pelvic (AP) trauma. MATERIALS AND METHODS: A retrospective review was performed of patients with AP trauma who underwent EA with or without embolization (from January 2012 to August 2020) at an urban, level I trauma center. Patients aged <18 years or those undergoing EA outside of the abdomen and/or pelvis were excluded. Demographics, imaging findings, procedure length, contrast agent administration, laboratory values, and outcomes were compared on the basis of preprocedural imaging technique and hemodynamic status. RESULTS: A total of 190 patients with AP trauma underwent EA with or without embolization; among them, 123 were HD stable and underwent CT/CT angiography, whereas 67 were initially HD unstable and underwent operative management prior to EA. Of these patients, 38 underwent CT/CT angiography after hemodynamic stability was achieved prior to postoperative EA. The incidence of therapeutic embolization for arterial injury on EA was significantly higher in patients with preprocedural CT/CT angiography (65.8% vs 44.8%, P = .04). The positive and negative predictive values of CT angiography for arterial injury at the time of EA were 92.3% and 100%, respectively. Prior imaging was associated with a reduced contrast agent requirement at the time of EA and reduced transfusion requirement (P = .05 and P = .02). No significant differences were observed in adverse outcomes for patients undergoing preprocedural imaging. CONCLUSIONS: CT or CT angiography prior to EA for HD stable and unstable patients with AP trauma may improve the likelihood of therapeutic embolization and enable improved procedure metrics without increasing adverse outcomes.

Molecular imaging in management of colorectal metastases by the interventional oncologist.

Interventional oncologists provide several effective treatment options for patients with metastatic colorectal cancer (mCRC), including embolization and ablation-based techniques. Molecular imaging methods such as positron emission tomography (PET) can play an important role in managing mCRC patients. In this review, we aim to highlight the role of molecular imaging in mCRC management by interventional oncologists including: initial staging and pretreatment planning; predicting molecular subtypes, prognosis, and treatment outcomes; intraprocedural guidance; and assessing treatment response and post-procedural monitoring.

Management of Chronic Multisymptom Illness: Synopsis of the 2021 US Department of Veterans Affairs and US Department of Defense Clinical Practice Guideline.

In 2019, senior leaders within the US Department of Veterans Affairs and the US Department of Defense commissioned the update of a clinical practice guideline for managing chronic multisymptom illness. Clinical experts were assembled across both agencies to systematically review evidence and to develop treatment recommendations based on that evidence. This effort resulted in the development of 29 evidence-based recommendations for providing care for individuals with chronic multisymptom illness.

Transarterial Embolization Modulates the Immune Response within Target and Nontarget Hepatocellular Carcinomas in a Rat Model.

Background Transarterial embolization (TAE) is the most common treatment for hepatocellular carcinoma (HCC); however, there remain limited data describing the influence of TAE on the tumor immune microenvironment. Purpose To characterize TAE-induced modulation of the tumor immune microenvironment in a rat model of HCC and identify factors that modulate this response. Materials and Methods TAE was performed on autochthonous HCCs induced in rats with use of diethylnitrosamine. CD3, CD4, CD8, and FOXP3 lymphocytes, as well as programmed cell death protein ligand-1 (PD-L1) expression, were examined in three cohorts: tumors from rats that did not undergo embolization (control), embolized tumors (target), and nonembolized tumors from rats that had a different target tumor embolized (nontarget). Differences in immune cell recruitment associated with embolic agent type (tris-acryl gelatin microspheres [TAGM] vs hydrogel embolics) and vascular location were examined in rat and human tissues. A generalized estimating equation model and t, Mann-Whitney U, and χ2 tests were used to compare groups. Results Cirrhosis-induced alterations in CD8, CD4, and CD25/CD4 lymphocytes were partially normalized following TAE (CD8: 38.4%, CD4: 57.6%, and CD25/CD4: 21.1% in embolized liver vs 47.7% [P = .02], 47.0% [P = .01], and 34.9% [P = .03], respectively, in cirrhotic liver [36.1%, 59.6%, and 4.6% in normal liver]). Embolized tumors had a greater number of CD3, CD4, and CD8 tumor-infiltrating lymphocytes relative to controls (191.4 cells/mm2 vs 106.7 cells/mm2 [P = .03]; 127.8 cells/mm2 vs 53.8 cells/mm2 [P < .001]; and 131.4 cells/mm2 vs 78.3 cells/mm2 [P = .01]) as well as a higher PD-L1 expression score (4.1 au vs 1.9 au [P < .001]). A greater number of CD3, CD4, and CD8 lymphocytes were found near TAGM versus hydrogel embolics (4.1 vs 2.0 [P = .003]; 3.7 vs 2.0 [P = .01]; and 2.2 vs 1.1 [P = .03], respectively). The number of lymphocytes adjacent to embolics differed based on vascular location (17.9 extravascular CD68+ peri-TAGM cells vs 7.0 intravascular [P < .001]; 6.4 extravascular CD68+ peri-hydrogel embolic cells vs 3.4 intravascular [P < .001]). Conclusion Transarterial embolization-induced dynamic alterations of the tumor immune microenvironment are influenced by underlying liver disease, embolic agent type, and vascular location. © RSNA, 2022 Online supplemental material is available for this article. See also the editorials by Kennedy et al and by White in this issue.

Under-recognition of medically unexplained symptom conditions among US Veterans with Gulf War Illness.

OBJECTIVE: Conditions defined by persistent "medically unexplained" physical symptoms and syndromes (MUS) are common and disabling. Veterans from the Gulf War (deployed 1990-1991) have notably high prevalence and disability from MUS conditions. Individuals with MUS report that providers do not recognize their MUS conditions. Our goal was to determine if Veterans with MUS receive an ICD-10 diagnosis for a MUS condition or receive disability benefits available to them for these conditions. METHODS: A chart review was conducted with US Veterans who met case criteria for Gulf War Illness, a complex MUS condition (N = 204, M = 53 years-old, SD = 7). Three coders independently reviewed Veteran's medical records for MUS condition diagnosis or service-connection along with comorbid mental and physical health conditions. Service-connection refers to US Veterans Affairs disability benefits eligibility for conditions or injuries experienced during or exacerbated by military service. RESULTS: Twenty-nine percent had a diagnosis of a MUS condition in their medical record, the most common were irritable colon/irritable bowel syndrome (16%) and fibromyalgia (11%). Slightly more Veterans were service-connected for a MUS condition (38%) as compared to diagnosed. There were high rates of diagnoses and service-connection for mental health (diagnoses 76% and service-connection 74%), musculoskeletal (diagnoses 86%, service-connection 79%), and illness-related conditions (diagnoses 98%, service-connection 49%). CONCLUSION: Given that all participants were Gulf War Veterans who met criteria for a MUS condition, our results suggest that MUS conditions in Gulf War Veterans are under-recognized with regard to clinical diagnosis and service-connected disability. Veterans were more likely to be diagnosed and service-connected for musculoskeletal-related and mental health conditions than MUS conditions. Providers may need education and training to facilitate diagnosis of and service-connection for MUS conditions. We believe that greater acknowledgement and validation of MUS conditions would increase patient engagement with healthcare as well as provider and patient satisfaction with care.