Auto-loaded TRAIL-exosomes derived from induced neural stem cells for brain cancer therapy.

Transdifferentiation (TD), a somatic cell reprogramming process that eliminates pluripotent intermediates, creates cells that are ideal for personalized anti-cancer therapy. Here, we provide the first evidence that extracellular vesicles (EVs) from TD-derived induced neural stem cells (Exo-iNSCs) are an efficacious treatment strategy for brain cancer. We found that genetically engineered iNSCs generated EVs loaded with the tumoricidal gene product TRAIL at nearly twice the rate as their parental fibroblasts, and the TRAIL produced by iNSCs were naturally loaded into the lumen of EVs and arrayed across their outer membrane (Exo-iNSC-TRAIL). Uptake studies in ex vivo organotypic brain slice cultures showed Exo-iNSC-TRAIL selectively accumulates within tumor foci, and co-culture assays showed that Exo-iNSC-TRAIL killed metastatic and primary brain cancer cells more effectively than free TRAIL. In an orthotopic mouse model of brain cancer, Exo-iNSC-TRAIL reduced breast-to-brain tumor xenografts around 3000-fold greater than treatment with free TRAIL, with all Exo-iNSC-TRAIL treated animals surviving through 90 days post-treatment. In additional in vivo testing against aggressive U87 and invasive GBM8 glioblastoma tumors, Exo-iNSC-TRAIL also induced a statistically significant increase in survival. These studies establish a new easily generated, stable, tumor-targeted EV to efficaciously treat multiple forms of brain cancer.

Utilizing induced neural stem cell-based delivery of a cytokine cocktail to enhance chimeric antigen receptor-modified T-cell therapy for brain cancer.

Chimeric antigen receptor (CAR)-modified T-cell therapy has shown enormous clinical promise against blood cancers, yet efficacy against solid tumors remains a challenge. Here, we investigated the potential of a new combination cell therapy, where tumor-homing induced neural stem cells (iNSCs) are used to enhance CAR-T-cell therapy and achieve efficacious suppression of brain tumors. Using in vitro and in vivo migration assays, we found iNSC-secreted RANTES/IL-15 increased CAR-T-cell migration sixfold and expansion threefold, resulting in greater antitumor activity in a glioblastoma (GBM) tumor model. Furthermore, multimodal imaging showed iNSC delivery of RANTES/IL-15 in combination with intravenous administration of CAR-T cells reduced established orthotopic GBM xenografts 2538-fold within the first week, followed by durable tumor remission through 60 days post-treatment. By contrast, CAR-T-cell therapy alone only partially controlled tumor growth, with a median survival of only 19 days. Together, these studies demonstrate the potential of combined cell therapy platforms to improve the efficacy of CAR-T-cell therapy for brain tumors.

A living ex vivo platform for functional, personalized brain cancer diagnosis.

Functional precision medicine platforms are emerging as promising strategies to improve pre-clinical drug testing and guide clinical decisions. We have developed an organotypic brain slice culture (OBSC)-based platform and multi-parametric algorithm that enable rapid engraftment, treatment, and analysis of uncultured patient brain tumor tissue and patient-derived cell lines. The platform has supported engraftment of every patient tumor tested to this point: high- and low-grade adult and pediatric tumor tissue rapidly establishes on OBSCs among endogenous astrocytes and microglia while maintaining the tumor's original DNA profile. Our algorithm calculates dose-response relationships of both tumor kill and OBSC toxicity, generating summarized drug sensitivity scores on the basis of therapeutic window and allowing us to normalize response profiles across a panel of U.S. Food and Drug Administration (FDA)-approved and exploratory agents. Summarized patient tumor scores after OBSC treatment show positive associations to clinical outcomes, suggesting that the OBSC platform can provide rapid, accurate, functional testing to ultimately guide patient care.

Association of SARS-CoV-2 Spike Protein Antibody Vaccine Response With Infection Severity in Patients With Cancer: A National COVID Cancer Cross-sectional Evaluation.

Importance: Accurate identification of patient groups with the lowest level of protection following COVID-19 vaccination is important to better target resources and interventions for the most vulnerable populations. It is not known whether SARS-CoV-2 antibody testing has clinical utility for high-risk groups, such as people with cancer. Objective: To evaluate whether spike protein antibody vaccine response (COV-S) following COVID-19 vaccination is associated with the risk of SARS-CoV-2 breakthrough infection or hospitalization among patients with cancer. Design, Setting, and Participants: This was a population-based cross-sectional study of patients with cancer from the UK as part of the National COVID Cancer Antibody Survey. Adults with a known or reported cancer diagnosis who had completed their primary SARS-CoV-2 vaccination schedule were included. This analysis ran from September 1, 2021, to March 4, 2022, a period covering the expansion of the UK's third-dose vaccination booster program. Interventions: Anti-SARS-CoV-2 COV-S antibody test (Elecsys; Roche). Main Outcomes and Measures: Odds of SARS-CoV-2 breakthrough infection and COVID-19 hospitalization. Results: The evaluation comprised 4249 antibody test results from 3555 patients with cancer and 294 230 test results from 225 272 individuals in the noncancer population. The overall cohort of 228 827 individuals (patients with cancer and the noncancer population) comprised 298 479 antibody tests. The median age of the cohort was in the age band of 40 and 49 years and included 182 741 test results (61.22%) from women and 115 737 (38.78%) from men. There were 279 721 tests (93.72%) taken by individuals identifying as White or White British. Patients with cancer were more likely to have undetectable anti-S antibody responses than the general population (199 of 4249 test results [4.68%] vs 376 of 294 230 [0.13%]; P < .001). Patients with leukemia or lymphoma had the lowest antibody titers. In the cancer cohort, following multivariable correction, patients who had an undetectable antibody response were at much greater risk for SARS-CoV-2 breakthrough infection (odds ratio [OR], 3.05; 95% CI, 1.96-4.72; P < .001) and SARS-CoV-2-related hospitalization (OR, 6.48; 95% CI, 3.31-12.67; P < .001) than individuals who had a positive antibody response. Conclusions and Relevance: The findings of this cross-sectional study suggest that COV-S antibody testing allows the identification of patients with cancer who have the lowest level of antibody-derived protection from COVID-19. This study supports larger evaluations of SARS-CoV-2 antibody testing. Prevention of SARS-CoV-2 transmission to patients with cancer should be prioritized to minimize impact on cancer treatments and maximize quality of life for individuals with cancer during the ongoing pandemic.

Spatiotemporal analysis of induced neural stem cell therapy to overcome advanced glioblastoma recurrence.

Genetically engineered neural stem cells (NSCs) are a promising therapy for the highly aggressive brain cancer glioblastoma (GBM); however, treatment durability remains a major challenge. We sought to define the events that contribute to dynamic adaptation of GBM during treatment with human skin-derived induced NSCs releasing the pro-apoptotic agent TRAIL (iNSC-TRAIL) and develop strategies that convert initial tumor kill into sustained GBM suppression. In vivo and ex vivo analysis before, during, and after treatment revealed significant shifts in tumor transcriptome and spatial distribution as the tumors adapted to treatment. To address this, we designed iNSC delivery strategies that increased spatiotemporal TRAIL coverage and significantly decreased GBM volume throughout the brain, reducing tumor burden 100-fold as quantified in live ex vivo brain slices. The varying impact of different strategies on treatment durability and median survival of both solid and invasive tumors provides important guidance for optimizing iNSC therapy.

Next-generation Tumor-homing Induced Neural Stem Cells as an Adjuvant to Radiation for the Treatment of Metastatic Lung Cancer.

The spread of non-small cell lung cancer (NSCLC) to the leptomeninges is devastating with a median survival of only a few months. Radiation offers symptomatic relief, but new adjuvant therapies are desperately needed. Spheroidal, human induced neural stem cells (hiNeuroS) secreting the cytotoxic protein, TRAIL, have innate tumoritropic properties. Herein, we provide evidence that hiNeuroS-TRAIL cells can migrate to and suppress growth of NSCLC metastases in combination with radiation. In vitro cell tracking and post-mortem tissue analysis showed that hiNeuroS-TRAIL cells migrate to NSCLC tumors. Importantly, isobolographic analysis suggests that TRAIL with radiation has a synergistic cytotoxic effect on NSCLC tumors. In vivo, mice treated with radiation and hiNeuroS-TRAIL showed significant (36.6%) improvements in median survival compared to controls. Finally, bulk mRNA sequencing analysis showed both NSCLC and hiNeuroS-TRAIL cells showed changes in genes involved in migration following radiation. Overall, hiNeuroS-TRAIL cells +/- radiation have the capacity to treat NSCLC metastases.

Downhill skiing following total knee arthroplasty: a survey of Alberta orthopedic surgeons.

Background: In older adults facing knee arthroplasty, the ability to resume downhill skiing postoperatively is unclear. This study aimed to determine the perspectives of Alberta orthopedic surgeons and senior residents regarding downhill skiing after total knee arthroplasty (TKA) or unicompartmental knee arthroplasty (UKA). Methods: In May 2019, a Web-based survey was sent through the Alberta Orthopaedic Society to poll orthopedic surgeons performing arthroplasty and senior orthopedic residents (postgraduate year 4 or 5) in Alberta regarding the permissibility of downhill skiing after TKA or UKA. The survey also elicited information regarding under which conditions or restrictions, if any, surgeons would allow patients to return to downhill skiing, whether these recommendations were evidence based, and whether surgeons had seen complications from downhill skiing in their patients who had undergone knee arthroplasty. Results: Of the 41 respondents, 21 (51%) were full-time fellowship-trained orthopedic surgeons, 15 (37%) were specialists with some arthroplasty in their practice, and 5 (12%) were orthopedic residents. Ten of 40 respondents (25%) would allow unrestricted downhill skiing after TKA, and 1 (2%) would not allow any skiing at all. The remaining 29 (72%) indicated that they might allow downhill skiing under specific conditions, with the top 3 being limitations on speed and intensity (29 [71%]), return of full range of motion and strength in the operative knee (26 [63%]), and years of downhill ski experience (23 [56%]). Fourteen respondents (34%) would allow unrestricted downhill skiing after UKA, and 27 (66%) would allow skiing with the same top 3 conditions as for TKA. Thirty-two respondents (78%) reported that their decisions were not evidence based, and 35 (85%) had never seen complications from downhill skiing after TKA or UKA. Conclusion: Alberta orthopedic surgeons and senior residents are cautious regarding skiing after knee arthroplasty. The majority reported that their restrictions were not evidence based, which indicates the need for further investigation to develop an approach for surgeons to consistently and safely address return to downhill skiing after TKA or UKA.

Contexte: Chez les adultes âgés qui doivent subir une arthroplastie du genou, la capacité de reprendre la pratique du ski alpin n'a pas été clairement évaluée. Cette étude visait à clarifier le point de vue des chirurgiens et résidents séniors en orthopédie de l'Alberta au sujet de la pratique du ski alpin après une intervention pour prothèse totale du genou (PTG) ou prothèse partielle du genou (PPG). Méthodes: En mai 2019, un sondage en ligne a été envoyé par l'entremise de l'Alberta Orthopaedic Society afin d'interroger les chirurgiens et résidents séniors (résidents 4 ou 5) en orthopédie pratiquant des arthroplasties en Alberta au sujet de l'autorisation à recommencer le ski alpin après une PTG ou une PPG. Le sondage portait aussi sur les conditions ou les restrictions, le cas échéant, imposées aux patients par leurs chirurgiens pour leur permettre de recommencer à skier, si ces recommandations étaient fondées sur des données probantes, et si les chirurgiens avaient observé des complications chez leurs patients ayant repris le ski après une PTG ou une PPG. Résultats: Sur les 41 répondants, 21 (51 %) étaient des médecins spécialistes en chirurgie orthopédique à temps complet, 15 (37 %) étaient des spécialistes ayant déjà effectué des arthroplasties dans le cadre de leur pratique et 5 (12 %) étaient des résidents en orthopédie. Dix répondants sur 40 (25 %) disaient qu'ils permettraient la pratique du ski alpin sans restrictions après la PTG et 1 (2 %) ne la permettrait pas du tout. Les 29 autres (72 %) ont indiqué qu'ils autoriseraient la pratique du ski alpin à certaines conditions, les 3 principales étant le contrôle de la vitesse et de l'intensité (29 [71 %]), le retour de la pleine amplitude de mouvement et de la force au genou opéré (26 [63 %]) et le nombre d'années d'expérience en ski alpin (23 [56 %]). Quatorze répondants (34 %) permettraient la reprise du ski alpin sans restrictions après la PPG et 27 (66 %) l'autoriseraient en appliquant les 3 mêmes conditions que pour la PTG. Trente-deux répondants (78 %) ont indiqué que leur décision ne reposait pas sur des données probantes et 35 (85 %) n'avaient observé aucune complication après la reprise de la pratique du skin suite à une PTG ou une PPG. Conclusion: Les chirurgiens et les résidents séniors en orthopédie de l'Alberta émettent des réserves relativement à la reprise de la pratique du skin après une arthroplastie du genou. Chez la majorité, les restrictions préconisées ne reposent pas sur des données probantes, ce qui indique que la recherche à ce sujet mérite d'être approfondie afin qu'on puisse élaborer une approche cohérente et sécuritaire en orthopédie pour la reprise de la pratique du ski alpin après une PTG ou une PPG.

Development of next-generation tumor-homing induced neural stem cells to enhance treatment of metastatic cancers.

Engineered tumor-homing neural stem cells (NSCs) have shown promise in treating cancer. Recently, we transdifferentiated skin fibroblasts into human-induced NSCs (hiNSC) as personalized NSC drug carriers. Here, using a SOX2 and spheroidal culture-based reprogramming strategy, we generated a new hiNSC variant, hiNeuroS, that was genetically distinct from fibroblasts and first-generation hiNSCs and had significantly enhanced tumor-homing and antitumor properties. In vitro, hiNeuroSs demonstrated superior migration to human triple-negative breast cancer (TNBC) cells and in vivo rapidly homed to TNBC tumor foci following intracerebroventricular (ICV) infusion. In TNBC parenchymal metastasis models, ICV infusion of hiNeuroSs secreting the proapoptotic agent TRAIL (hiNeuroS-TRAIL) significantly reduced tumor burden and extended median survival. In models of TNBC leptomeningeal carcinomatosis, ICV dosing of hiNeuroS-TRAIL therapy significantly delayed the onset of tumor formation and extended survival when administered as a prophylactic treatment, as well as reduced tumor volume while prolonging survival when delivered as established tumor therapy.

Generation and Profiling of Tumor-Homing Induced Neural Stem Cells from the Skin of Cancer Patients.

The conversion of human fibroblasts into personalized induced neural stem cells (iNSCs) that actively seek out tumors and deliver cytotoxic agents is a highly promising approach for treating various types of cancer. However, the ability to generate iNSCs from the skin of cancer patients has not been explored. Here, we take an important step toward clinical application by generating iNSCs from skin biopsies of human patients undergoing treatment for the aggressive brain cancer, glioblastoma (GBM). We then utilized a panel of functional and genomic studies to investigate the efficacy and tumor-homing capacity of these patient-derived cells, as well as genomic analysis, to characterize the impact of interpatient variability on this personalized cell therapy. From the skin-tissue biopsies, we established fibroblasts and transdifferentiated the cells into iNSCs. Genomic and functional testing revealed marked variability in growth rates, therapeutic agent production, and gene expression during fibroblast-to-iNSC conversion among patient lines. In vivo testing showed patient-derived iNSCs home to tumors, yet rates and expression of homing-related pathways varied among patients. With the use of surgical-resection mouse models of invasive human cluster of differentiation 133+ (CD133+) GBM cells and serial kinetic imaging, we found that "high-performing" patient-derived iNSC lines reduced the volume of GBM cells 60-fold and extended survival from 28 to 45 days. Treatment with "low-performing" patient lines had minimal effect on tumor growth, but the anti-tumor effect could be rescued by increasing the intracavity dose. Together, these data show, for the first time, that tumor-homing iNSCs can be generated from the skin of cancer patients and efficaciously suppress tumor growth. We also begin to define genetic markers that could be used to identify cells that will contain the most effective attributes for tumor homing and kill in human patients, including high gene expression of the semaphorin-3B (SEMA3B), which is known to be involved in neuronal cell migration. These studies should serve as an important guide toward clinical GBM therapy, where the personalized nature of optimized iNSC therapy has the potential to avoid transplant rejection and maximize treatment durability.

Poor Agreement Between Imaging and Histologic and Colonoscopy Findings in Pediatric Patients.

BACKGROUND: Computed tomography scans (CTs), more recently magnetic resonance imaging, are often used to assess the gastrointestinal tract in patients complaining of abdominal pain. We aim to determine the strength of agreement among abdominal imaging, endoscopic, and histologic findings. METHODS: Retrospective chart review of pediatric patients who underwent colonoscopy between January 1, 2012, and December 31, 2014, at Women and Children's Hospital of Buffalo. Patients who had abdominal and pelvic CTs or magnetic resonance imaging within 30 days before or after a colonoscopy were included. RESULTS: One hundred two patients were included: mean age 12.7 ±â€Š3.8 years, 66% girls. A total of 109 imaging studies were performed. Overall 61% of imaging studies were abnormal. The most frequent intestinal radiological findings were colonic wall thickening (CWT) (55%) and colonic wall enhancement (CWH) (24%). Free fluid (20%) and fat stranding (18%) were the most common extra-intestinal findings. Imaging studies agreed with histology in 81% and with colonoscopy in 75% with a moderate strength of agreement (k: 0.59 and 0.466, respectively). CWT agreed with histology in 74% with a moderate strength of agreement (k: 0.47). History of weight loss (OR 5.35, P = 0.041), chronic diarrhea (OR 4.22, P = 0.014), a positive lactoferrin (OR 7.00, P = 0.011), and presence of CWT on imaging study (OR 5.20, P = 0.001) were predictive of having abnormal histology. CONCLUSIONS: The strength of agreement among imaging, endoscopic, and histologic findings was suboptimal. Colonoscopy and imaging are both likely to be necessary in patients with suspected inflammatory bowel disease. Although colonoscopy may be superior in diagnosis of colitis, imaging may provide more information regarding small bowel disease.

Use of raltitrexed as an alternative to 5-fluorouracil and capecitabine in cancer patients with cardiac history.

AIM: Fluoropyrimidines are the backbone of the majority of approved chemotherapy regimens for colorectal cancer (CRC). However, there are reports of fluoropyrimidine treatments being associated with cardiotoxicity which have led to permanent cardiovascular damage and even death. Raltitrexed is indicated for palliative treatment of advanced CRC where 5-fluorouracil (5-FU) is not tolerated or inappropriate. A systematic review was undertaken to determine the incidence of cardiotoxicity associated with 5-FU, capecitabine and raltitrexed. METHODS: An electronic search of PubMed was undertaken to identify articles relating to cardiotoxicity associated with 5-FU, capecitabine or raltitrexed, published between January 1991 and August 2011. Additionally, a retrospective review of cardiotoxicity associated with raltitrexed at our treatment centres was conducted. RESULTS: Twenty studies were examined. The overall incidence of cardiotoxicity associated with 5-FU/capecitabine varied between 0.55% and 19% (mean: 5.0%, median: 3.85%). No published data were identified reporting cardiotoxicity associated with raltitrexed. A retrospective review at our treatment centres revealed that the incidence was 4.5% amongst high-risk patients treated with raltitrexed (n=111) for advanced gastrointestinal cancer with a significant cardiac history and/or previous cardiotoxicity with 5-FU or capecitabine. CONCLUSION: The incidence of cardiotoxicity associated with raltitrexed in patients with advanced CRC treated is favourable in a highly skewed, at-risk patient population, all of whom had documented cardiotoxicity with other fluoropyrimidines or were unable to tolerate capecitabine due to cardiac history. Raltitrexed is therefore a suitable option for patients with fluoropyrimidine-induced cardiotoxicity or significant cardiovascular risk factors.