Discovery and Optimization of N-Arylated Tetracyclic Dicarboximides That Target Primary Glioma Stem-like Cells.

We recently discovered a novel N-aryl tetracyclic dicarboximide MM0299 (1) with robust activity against glioma stem-like cells that potently and selectively inhibits lanosterol synthase leading to the accumulation of the toxic shunt metabolite 24(S),25-epoxycholesterol. Herein, we delineate a systematic and comprehensive SAR study that explores the structural space surrounding the N-aryl tetracyclic dicarboximide scaffold. A series of 100 analogs were synthesized and evaluated for activity against the murine glioma stem-like cell line Mut6 and for metabolic stability in mouse liver S9 fractions. This study led to several analogs with single-digit nanomolar activity in Mut6 glioblastoma cells that were metabolically stable in S9 fractions. In vivo pharmacokinetic analysis of selected analogs identified compound 52a (IC50 = 63 nM; S9 T1/2 > 240 min) which was orally available (39% plasma; 58% brain) and displayed excellent brain exposure. Chronic oral dosing of 52a during a 2-week tolerability study indicated no adverse effect on body weight nor signs of hematologic, liver, or kidney toxicity.

Pre-existing Immunocompromising Conditions and Outcomes of Acute COVID-19 Patients Admitted for Pediatric Intensive Care.

BACKGROUND: We aimed to determine if pre-existing immunocompromising conditions (ICCs) were associated with the presentation or outcome of patients with acute coronavirus disease 2019 (COVID-19) admitted for pediatric intensive care. METHODS: 55 hospitals in 30 U.S. states reported cases through the Overcoming COVID-19 public health surveillance registry. Patients <21 years admitted March 12, 2020-December 30, 2021 to the pediatric intensive care unit (PICU) or high acuity unit for acute COVID-19 were included. RESULTS: Of 1,274 patients, 105 (8.2%) had an ICC including 33 (31.4%) hematologic malignancies, 24 (22.9%) primary immunodeficiencies and disorders of hematopoietic cells, 19 (18.1%) nonmalignant organ failure with solid organ transplantation, 16 (15.2%) solid tumors and 13 (12.4%) autoimmune disorders. Patients with ICCs were older, had more underlying renal conditions, and had lower white blood cell and platelet counts than those without ICCs, but had similar clinical disease severity upon admission. In-hospital mortality from COVID-19 was higher (11.4% vs. 4.6%, p = 0.005) and hospitalization was longer (p = 0.01) in patients with ICCs. New major morbidities upon discharge were not different between those with and without ICC (10.5% vs 13.9%, p = 0.40). In patients with ICC, bacterial co-infection was more common in those with life-threatening COVID-19. CONCLUSIONS: In this national case series of patients <21 years of age with acute COVID-19 admitted for intensive care, existence of a prior ICCs were associated with worse clinical outcomes. Reassuringly, most patients with ICCs hospitalized in the PICU for severe acute COVID-19 survived and were discharged home without new severe morbidities.

Ataxia-Telangiectasia Mutated Loss-of-Function Displays Variant and Tissue-Specific Differences across Tumor Types.

PURPOSE: Mutations in the ATM gene are common in multiple cancers, but clinical studies of therapies targeting ATM-aberrant cancers have yielded mixed results. Refinement of ATM loss of function (LOF) as a predictive biomarker of response is urgently needed. EXPERIMENTAL DESIGN: We present the first disclosure and preclinical development of a novel, selective ATR inhibitor, ART0380, and test its antitumor activity in multiple preclinical cancer models. To refine ATM LOF as a predictive biomarker, we performed a comprehensive pan-cancer analysis of ATM variants in patient tumors and then assessed the ATM variant-to-protein relationship. Finally, we assessed a novel ATM LOF biomarker approach in retrospective clinical data sets of patients treated with platinum-based chemotherapy or ATR inhibition. RESULTS: ART0380 had potent, selective antitumor activity in a range of preclinical cancer models with differing degrees of ATM LOF. Pan-cancer analysis identified 10,609 ATM variants in 8,587 patient tumors. Cancer lineage-specific differences were seen in the prevalence of deleterious (Tier 1) versus unknown/benign (Tier 2) variants, selective pressure for loss of heterozygosity, and concordance between a deleterious variant and ATM loss of protein (LOP). A novel ATM LOF biomarker approach that accounts for variant classification, relationship to ATM LOP, and tissue-specific penetrance significantly enriched for patients who benefited from platinum-based chemotherapy or ATR inhibition. CONCLUSIONS: These data help to better define ATM LOF across tumor types in order to optimize patient selection and improve molecularly targeted therapeutic approaches for patients with ATM LOF cancers.

Drug-resilient Cancer Cell Phenotype Is Acquired via Polyploidization Associated with Early Stress Response Coupled to HIF2α Transcriptional Regulation.

Therapeutic resistance and recurrence remain core challenges in cancer therapy. How therapy resistance arises is currently not fully understood with tumors surviving via multiple alternative routes. Here, we demonstrate that a subset of cancer cells survives therapeutic stress by entering a transient state characterized by whole-genome doubling. At the onset of the polyploidization program, we identified an upregulation of key transcriptional regulators, including the early stress-response protein AP-1 and normoxic stabilization of HIF2α. We found altered chromatin accessibility, ablated expression of retinoblastoma protein (RB1), and enrichment of AP-1 motif accessibility. We demonstrate that AP-1 and HIF2α regulate a therapy resilient and survivor phenotype in cancer cells. Consistent with this, genetic or pharmacologic targeting of AP-1 and HIF2α reduced the number of surviving cells following chemotherapy treatment. The role of AP-1 and HIF2α in stress response by polyploidy suggests a novel avenue for tackling chemotherapy-induced resistance in cancer. SIGNIFICANCE: In response to cisplatin treatment, some surviving cancer cells undergo whole-genome duplications without mitosis, which represents a mechanism of drug resistance. This study presents mechanistic data to implicate AP-1 and HIF2α signaling in the formation of this surviving cell phenotype. The results open a new avenue for targeting drug-resistant cells.

Prognostic factors for liver, blood and kidney adverse events from glucocorticoid sparing immune-suppressing drugs in immune-mediated inflammatory diseases: a prognostic systematic review.

BACKGROUND: Immune-suppressing drugs can cause liver, kidney or blood toxicity. Prognostic factors for these adverse-events are poorly understood. PURPOSE: To ascertain prognostic factors associated with liver, blood or kidney adverse-events in people receiving immune-suppressing drugs. DATA SOURCES: MEDLINE, Web of Science, EMBASE and the Cochrane library (01 January 1995 to 05 January 2023), and supplementary sources. DATA EXTRACTION AND SYNTHESIS: Data were extracted by one reviewer using a modified CHARMS-PF checklist and validated by another. Two independent reviewers assessed risk of bias using Quality in Prognostic factor Studies tool and assessed the quality of evidence using a Grading of Recommendations Assessment, Development and Evaluation-informed framework. RESULTS: Fifty-six studies from 58 papers were included. High-quality evidence of the following associations was identified: elevated liver enzymes (6 studies) and folate non-supplementation (3 studies) are prognostic factors for hepatotoxicity in those treated with methotrexate; that mercaptopurine (vs azathioprine) (3 studies) was a prognostic factor for hepatotoxicity in those treated with thiopurines; that mercaptopurine (vs azathioprine) (3 studies) and poor-metaboliser status (4 studies) were prognostic factors for cytopenia in those treated with thiopurines; and that baseline elevated liver enzymes (3 studies) are a prognostic factor for hepatotoxicity in those treated with anti-tumour necrosis factors. Moderate and low quality evidence for several other demographic, lifestyle, comorbidities, baseline bloods/serologic or treatment-related prognostic factors were also identified. LIMITATIONS: Studies published before 1995, those with less than 200 participants and not published in English were excluded. Heterogeneity between studies included different cut-offs for prognostic factors, use of different outcome definitions and different adjustment factors. CONCLUSIONS: Prognostic factors for target-organ damage were identified which may be further investigated for their potential role in targeted (risk-stratified) monitoring. PROSPERO REGISTRATION NUMBER: CRD42020208049.

What matters to adolescents with obesity, and their caregivers, when considering bariatric surgery or weight loss devices? A qualitative evidence synthesis.

BACKGROUND: Bariatric surgery and weight loss devices have been considered as a therapeutic option in some settings for adolescents with severe obesity. We conducted a systematic review and qualitative evidence synthesis of factors affecting adolescent and caregiver decision-making processes around such interventions, as well as post-surgery demands and challenges, so that their experiences might be better understood and improved support given. No previous qualitative evidence synthesis has been published on this topic. METHODS AND FINDINGS: We searched 10 bibliographic databases and followed-up gray literature and citations sources. We performed a qualitative evidence synthesis on 19 primary qualitative research studies in adolescents aged 13 years or older. They reported diverse motivations and incentives for considering these interventions, including the physical and social problems resulting from living with obesity, and an awareness of the benefits and limitations of interventions. They reported that they need: information, physical and emotional support and, in some cases, financial assistance. There was high confidence in a majority of these findings (GRADE CERQual). CONCLUSIONS: We found that supportive interventions accompanying bariatric surgery should be in place to offer: practical help; address anxieties and uncertainties; and facilitate both appropriate decision-making and the achievement of young people's desired outcomes.

Long-Term Results of Endoscopic Endonasal Marsupialization of Rathke Cleft Cysts With Bioabsorbable Steroid-Eluting Stents-Technical Case Series and Review of the Literature.

BACKGROUND: Rathke cleft cysts (RCCs) are common benign skull-base lesions arising from embryologic remnants of Rathke pouch. Though frequently asymptomatic, RCCs can become symptomatic because of compression of adjacent neural structures. Transcranial and neuroendoscopic surgical treatments have been described for symptomatic RCCs, but recurrence rates remain as high as 30%. Bioabsorbable steroid-eluting (BASE) stents significantly decrease adhesions and recurrent ostia obstruction after endoscopic sinus surgery. We sought to use BASE stents to aid marsupialization of symptomatic RCCs. OBJECTIVE: To present long-term results of our initial experience with endoscopic-endonasal fenestration and placement of BASE stents for RCCs. METHODS: Patients undergoing neuroendoscopic transsphenoidal fenestration of RCCs with BASE stent placement were identified and their medical records retrospectively reviewed. RESULTS: Four patients underwent neuroendoscopic transsphenoidal fenestration and BASE stent placement from March 2016 to April 2018 for symptomatic RCCs. After the cyst contents were evacuated, a BASE stent was deployed in the cyst fenestration to prevent cyst wall regrowth or closure and facilitate marsupialization to the sphenoid sinus. No perioperative complications were encountered, and all patients reported symptom resolution by 2 weeks postoperatively. Postoperative endoscopic evaluation demonstrated epithelization of the cyst wall opening and patent marsupialization into the sphenoid sinus in all cases. After a mean follow-up of 56 ± 12 months, all patients remained asymptomatic with baseline visual function and no radiographic evidence of recurrence. CONCLUSION: Bioabsorbable steroid-eluting stent placement is a safe, facile, viable augmentation of neuroendoscopic technique for symptomatic RCCs with the potential to reduce long-term recurrence rates.

Chronic Pain: Prevalence and Management.

Chronic pain is a distinct complication that profoundly affects the lives of individuals with sickle cell disease (SCD). Chronic SCD pain emerges with increasing age and is very prevalent in adults. The pathophysiology of chronic SCD pain is likely distinct from acute SCD pain and therefore needs a different treatment approach. Clinical trials evaluating the treatment of chronic SCD pain are lacking and treatment currently relies on evidence from other chronic pain conditions. Continued investigations into the underlying causes of chronic SCD pain are needed, and clinical trials focused on chronic pain therapy are imperative.

Targeting hypoxia regulated sodium driven bicarbonate transporters reduces triple negative breast cancer metastasis.

Regions of low oxygen (hypoxia) are found in >50% of breast tumours, most frequently in the more aggressive triple negative breast cancer subtype (TNBC). Metastasis is the cause of 90% of breast cancer patient deaths. Regions of tumour hypoxia tend to be more acidic and both hypoxia and acidosis increase tumour metastasis. In line with this the metastatic process is dependent on pH regulatory mechanisms. We and others have previously identified increased hypoxic expression of Na+ driven bicarbonate transporters (NDBTs) as a major mechanism of tumour pH regulation. Hypoxia induced the expression of NDBTs in TNBC, most frequently SLC4A4 and SLC4A5. NDBT inhibition (S0859) and shRNA knockdown suppressed migration (40% reduction) and invasion (70% reduction) in vitro. Tumour xenograft metastasis in vivo was significantly reduced by NDBT knockdown. To investigate the mechanism by which NDBTs support metastasis, we investigated their role in regulation of phospho-signalling, epithelial-to-mesenchymal transition (EMT) and metabolism. NDBT knockdown resulted in an attenuation in hypoxic phospho-signalling activation; most notably LYN (Y397) reduced by 75%, and LCK (Y394) by 72%. The metastatic process is associated with EMT. We showed that NDBT knockdown inhibited EMT, modulating the expression of key EMT transcription factors and ablating the expression of vimentin whilst increasing the expression of E-cadherin. NDBT knockdown also altered metabolic activity reducing overall ATP and extracellular lactate levels. These results demonstrate that targeting hypoxia-induced NDBT can be used as an approach to modulate phospho-signalling, EMT, and metabolic activity and reduce tumour migration, invasion, and metastasis in vivo.

Screening for pediatric abusive head trauma: Are three variables enough?

BACKGROUND: The PediBIRN 4-variable clinical decision rule (CDR) detects abusive head trauma (AHT) with 96% sensitivity in pediatric intensive care (PICU) settings. Preliminary analysis of its performance in Pediatric Emergency Department settings found that elimination of its fourth predictor variable enhanced screening accuracy. OBJECTIVE: To compare the AHT screening performances of the "PediBIRN-4" CDR vs. the simplified 3-variable CDR in PICU settings. PARTICIPANTS AND SETTINGS: 973 acutely head-injured children <3 years hospitalized for intensive care across 18 sites between February 2011 and March 2021. METHODS: Retrospective, secondary analysis of the combined, prospective PediBIRN data sets. AHT definitional criteria and physicians' diagnoses were applied iteratively to sort patients into abusive vs. other head trauma cohorts. Outcome measures of CDR performance included sensitivity, specificity, predictive values, likelihood ratios, ROC AUC, and the correlation between each CDR's patient-specific estimates of AHT probability and the overall positive yield of patients' completed abuse evaluations. RESULTS: Applied accurately and consistently, both CDR's would have performed with sensitivity ≥93% and negative predictive value ≥91%. Eliminating the PediBIRN-4's fourth predictor variable resulted in significantly higher specificity (↑'d ≥19%), positive predictive value (↑'d ≥8%), and ROC AUC (↑'d ≥5%), but a 3% reduction in sensitivity. Both CDRs provided patient-specific estimates of abuse probability very strongly correlated with the positive yield of patients' completed abuse evaluations (Pearson's r = 0.95 and 0.91, p = .13). CONCLUSION: The PediBIRN 3-variable CDR performed with greater AHT screening accuracy than the 4-variable CDR. Both are good predictors of the results of patients' subsequent completed abuse evaluations.

Discovery of 6-[(3S,4S)-4-Amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-3-(2,3-dichlorophenyl)-2-methyl-3,4-dihydropyrimidin-4-one (IACS-15414), a Potent and Orally Bioavailable SHP2 Inhibitor.

Src homology 2 (SH2) domain-containing phosphatase 2 (SHP2) plays a role in receptor tyrosine kinase (RTK), neurofibromin-1 (NF-1), and Kirsten rat sarcoma virus (KRAS) mutant-driven cancers, as well as in RTK-mediated resistance, making the identification of small-molecule therapeutics that interfere with its function of high interest. Our quest to identify potent, orally bioavailable, and safe SHP2 inhibitors led to the discovery of a promising series of pyrazolopyrimidinones that displayed excellent potency but had a suboptimal in vivo pharmacokinetic (PK) profile. Hypothesis-driven scaffold optimization led us to a series of pyrazolopyrazines with excellent PK properties across species but a narrow human Ether-à-go-go-Related Gene (hERG) window. Subsequent optimization of properties led to the discovery of the pyrimidinone series, in which multiple members possessed excellent potency, optimal in vivo PK across species, and no off-target activities including no hERG liability up to 100 µM. Importantly, compound 30 (IACS-15414) potently suppressed the mitogen-activated protein kinase (MAPK) pathway signaling and tumor growth in RTK-activated and KRASmut xenograft models in vivo.

Mammary-specific expression of Trim24 establishes a mouse model of human metaplastic breast cancer.

Conditional overexpression of histone reader Tripartite motif containing protein 24 (TRIM24) in mouse mammary epithelia (Trim24COE) drives spontaneous development of mammary carcinosarcoma tumors, lacking ER, PR and HER2. Human carcinosarcomas or metaplastic breast cancers (MpBC) are a rare, chemorefractory subclass of triple-negative breast cancers (TNBC). Comparison of Trim24COE metaplastic carcinosarcoma morphology, TRIM24 protein levels and a derived Trim24COE gene signature reveals strong correlation with human MpBC tumors and MpBC patient-derived xenograft (PDX) models. Global and single-cell tumor profiling reveal Met as a direct oncogenic target of TRIM24, leading to aberrant PI3K/mTOR activation. Here, we find that pharmacological inhibition of these pathways in primary Trim24COE tumor cells and TRIM24-PROTAC treatment of MpBC TNBC PDX tumorspheres decreased cellular viability, suggesting potential in therapeutically targeting TRIM24 and its regulated pathways in TRIM24-expressing TNBC.

A Cluster Randomized Trial to Reduce Missed Abusive Head Trauma in Pediatric Intensive Care Settings.

OBJECTIVE: To estimate the impact of the PediBIRN (Pediatric Brain Injury Research Network) 4-variable clinical decision rule (CDR) on abuse evaluations and missed abusive head trauma in pediatric intensive care settings. STUDY DESIGN: This was a cluster randomized trial. Participants included 8 pediatric intensive care units (PICUs) in US academic medical centers; PICU and child abuse physicians; and consecutive patients with acute head injures <3 years (n = 183 and n = 237, intervention vs control). PICUs were stratified by patient volumes, pair-matched, and randomized equally to intervention or control conditions. Randomization was concealed from the biostatistician. Physician-directed, cluster-level interventions included initial and booster training, access to an abusive head trauma probability calculator, and information sessions. Outcomes included "higher risk" patients evaluated thoroughly for abuse (with skeletal survey and retinal examination), potential cases of missed abusive head trauma (patients lacking either evaluation), and estimates of missed abusive head trauma (among potential cases). Group comparisons were performed using generalized linear mixed-effects models. RESULTS: Intervention physicians evaluated a greater proportion of higher risk patients thoroughly (81% vs 73%, P = .11) and had fewer potential cases of missed abusive head trauma (21% vs 32%, P = .05), although estimated cases of missed abusive head trauma did not differ (7% vs 13%, P = .22). From baseline (in previous studies) to trial, the change in higher risk patients evaluated thoroughly (67%→81% vs 78%→73%, P = .01), and potential cases of missed abusive head trauma (40%→21% vs 29%→32%, P = .003), diverged significantly. We did not identify a significant divergence in the number of estimated cases of missed abusive head trauma (15%→7% vs 11%→13%, P = .22). CONCLUSIONS: PediBIRN-4 CDR application facilitated changes in abuse evaluations that reduced potential cases of missed abusive head trauma in PICU settings. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03162354.

Allosteric SHP2 Inhibitor, IACS-13909, Overcomes EGFR-Dependent and EGFR-Independent Resistance Mechanisms toward Osimertinib.

Src homology 2 domain-containing phosphatase (SHP2) is a phosphatase that mediates signaling downstream of multiple receptor tyrosine kinases (RTK) and is required for full activation of the MAPK pathway. SHP2 inhibition has demonstrated tumor growth inhibition in RTK-activated cancers in preclinical studies. The long-term effectiveness of tyrosine kinase inhibitors such as the EGFR inhibitor (EGFRi), osimertinib, in non-small cell lung cancer (NSCLC) is limited by acquired resistance. Multiple clinically identified mechanisms underlie resistance to osimertinib, including mutations in EGFR that preclude drug binding as well as EGFR-independent activation of the MAPK pathway through alternate RTK (RTK-bypass). It has also been noted that frequently a tumor from a single patient harbors more than one resistance mechanism, and the plasticity between multiple resistance mechanisms could restrict the effectiveness of therapies targeting a single node of the oncogenic signaling network. Here, we report the discovery of IACS-13909, a specific and potent allosteric inhibitor of SHP2, that suppresses signaling through the MAPK pathway. IACS-13909 potently impeded proliferation of tumors harboring a broad spectrum of activated RTKs as the oncogenic driver. In EGFR-mutant osimertinib-resistant NSCLC models with EGFR-dependent and EGFR-independent resistance mechanisms, IACS-13909, administered as a single agent or in combination with osimertinib, potently suppressed tumor cell proliferation in vitro and caused tumor regression in vivo. Together, our findings provide preclinical evidence for using a SHP2 inhibitor as a therapeutic strategy in acquired EGFRi-resistant NSCLC. SIGNIFICANCE: These findings highlight the discovery of IACS-13909 as a potent, selective inhibitor of SHP2 with drug-like properties, and targeting SHP2 may serve as a therapeutic strategy to overcome tumor resistance to osimertinib.

Protecting children from iatrogenic harm during COVID19 pandemic.

Critical care management of patients with COVID-19 has been influenced by a mixture of public, media and societal pressure, as well as clinical and anecdotal observations from many prominent researchers and key opinion leaders. These factors may have affected the principles of evidence-based medicine and encouraged the widespread use of non-tested pharmacological and aggressive respiratory support therapies, even in intensive care units (ICUs). The COVID-19 pandemic has predominantly affected adult populations, while children appear to be relatively spared of severe disease. Notwithstanding, paediatric intensive care (PICU) clinicians may already have been influenced by changes in practices of adult ICUs, and these changes may pose unintended consequences to the vulnerable population in the PICU. In this article, we analyse several potential iatrogenic causes of the detrimental effects of the current pandemic to children and highlight the risks underlying a sudden change of clinical practice.

Assessing Frequency of Respiratory Complications in Children Undergoing Adenotonsillectomy.

OBJECTIVES: To determine the frequency of respiratory complications in children admitted to the ICU after adenotonsillectomy and to identify factors associated with the risk of respiratory complications in this cohort. DESIGN: Retrospective observational study. SETTING: PICU. PATIENT POPULATION: All children admitted to the ICU following adenotonsillectomy from September 30, 2009, to March 30, 2014. MEASUREMENTS AND MAIN RESULTS: Of the 165 children included in the study, 150 (91%) received no respiratory support other than oxygen in the first 2 hours postoperatively. Of the 15 who required support following 2 hours, 14 required nasopharyngeal airways, one required invasive mechanical ventilation, and seven required supplemental oxygen for more than 2 hours. None of the children who received respiratory support for less than 2 hours required subsequent ICU level care. When comparing those who received support for more than 2 hours to those who did not, there were no differences in clinical characteristics except that those who received support were more likely to have chronic neurologic disease including autism, seizures, or cerebral palsy (odds ratio, 3.7; 95% CI, 1.1-11.9; p = 0.04). Intraoperative events were not predictive of need for respiratory support. Most of the children (n = 117/165 or 71%) had sleep studies preoperatively. Abnormal sleep studies (apnea-hypopnea index > 20 [n = 68] or oxygen saturation nadir < 80% [n = 48]) were not associated with need for postoperative respiratory support. CONCLUSIONS: Most children admitted to the ICU following adenotonsillectomy in this population required no support after 2 hours. Preoperative factors such as obesity and abnormal sleep studies were not predictive of need for postoperative respiratory support. Need for respiratory support at 2 hours may be a useful criterion for need for ICU level care in this population.

Interventions to reduce the risk of surgically transmitted Creutzfeldt-Jakob disease: a cost-effective modelling review.

BACKGROUND: Creutzfeldt-Jakob disease is a fatal neurological disease caused by abnormal infectious proteins called prions. Prions that are present on surgical instruments cannot be completely deactivated; therefore, patients who are subsequently operated on using these instruments may become infected. This can result in surgically transmitted Creutzfeldt-Jakob disease. OBJECTIVE: To update literature reviews, consultation with experts and economic modelling published in 2006, and to provide the cost-effectiveness of strategies to reduce the risk of surgically transmitted Creutzfeldt-Jakob disease. METHODS: Eight systematic reviews were undertaken for clinical parameters. One review of cost-effectiveness was undertaken. Electronic databases including MEDLINE and EMBASE were searched from 2005 to 2017. Expert elicitation sessions were undertaken. An advisory committee, convened by the National Institute for Health and Care Excellence to produce guidance, provided an additional source of information. A mathematical model was updated focusing on brain and posterior eye surgery and neuroendoscopy. The model simulated both patients and instrument sets. Assuming that there were potentially 15 cases of surgically transmitted Creutzfeldt-Jakob disease between 2005 and 2018, approximate Bayesian computation was used to obtain samples from the posterior distribution of the model parameters to generate results. Heuristics were used to improve computational efficiency. The modelling conformed to the National Institute for Health and Care Excellence reference case. The strategies evaluated included neither keeping instruments moist nor prohibiting set migration; ensuring that instruments were kept moist; prohibiting instrument migration between sets; and employing single-use instruments. Threshold analyses were undertaken to establish prices at which single-use sets or completely effective decontamination solutions would be cost-effective. RESULTS: A total of 169 papers were identified for the clinical review. The evidence from published literature was not deemed sufficiently strong to take precedence over the distributions obtained from expert elicitation. Forty-eight papers were identified in the review of cost-effectiveness. The previous modelling structure was revised to add the possibility of misclassifying surgically transmitted Creutzfeldt-Jakob disease as another neurodegenerative disease, and assuming that all patients were susceptible to infection. Keeping instruments moist was estimated to reduce the risk of surgically transmitted Creutzfeldt-Jakob disease cases and associated costs. Based on probabilistic sensitivity analyses, keeping instruments moist was estimated to on average result in 2.36 (range 0-47) surgically transmitted Creutzfeldt-Jakob disease cases (across England) caused by infection occurring between 2019 and 2023. Prohibiting set migration or employing single-use instruments reduced the estimated risk of surgically transmitted Creutzfeldt-Jakob disease cases further, but at considerable cost. The estimated costs per quality-adjusted life-year gained of these strategies in addition to keeping instruments moist were in excess of £1M. It was estimated that single-use instrument sets (currently £350-500) or completely effective cleaning solutions would need to cost approximately £12 per patient to be cost-effective using a £30,000 per quality-adjusted life-year gained value. LIMITATIONS: As no direct published evidence to implicate surgery as a cause of Creutzfeldt-Jakob disease has been found since 2005, the estimations of potential cases from elicitation are still speculative. A particular source of uncertainty was in the number of potential surgically transmitted Creutzfeldt-Jakob disease cases that may have occurred between 2005 and 2018. CONCLUSIONS: Keeping instruments moist is estimated to reduce the risk of surgically transmitted Creutzfeldt-Jakob disease cases and associated costs. Further surgical management strategies can reduce the risks of surgically transmitted Creutzfeldt-Jakob disease but have considerable associated costs. STUDY REGISTRATION: This study is registered as PROSPERO CRD42017071807. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 11. See the NIHR Journals Library website for further project information.

The aims of this report were to summarise evidence relating to surgically transmitted Creutzfeldt­Jakob disease and to explore the value for money of strategies to reduce the chance of any future surgically transmitted Creutzfeldt­Jakob disease cases. Current recommendations include keeping sets of surgical instruments together for high-risk operations and using separate instruments for people born after 1996. The project involved reviewing published papers, speaking with experts and building a computer model. The literature reviews found that Creutzfeldt­Jakob disease occurs in around 1­2 per million people and that no definite cases of surgically transmitted Creutzfeldt­Jakob disease have been observed since the 1970s. The reviews also looked for information on the possibility of patients being infected with Creutzfeldt­Jakob disease after having surgery on high-risk tissues, such as the brain and the back of the eye. They found that there was a great deal of uncertainty regarding who might have Creutzfeldt­Jakob disease, but not yet have symptoms, as well as the risk of transmission and the ability of strategies to reduce this risk. The computer model aimed to estimate value for money of different strategies to reduce the risks of surgically transmitted Creutzfeldt­Jakob disease. However, the reviews found that some of the numbers needed for the model were not known, so experts were asked to estimate this information instead along with the range of possible values. This information included the effectiveness of different cleaning practices and the chances of infected tissue being transmitted between patients undergoing high-risk surgery. The model found that keeping surgical instruments moist prior to cleaning was likely to save money and reduce the chance of future surgically transmitted Creutzfeldt­Jakob disease cases. However, additional measures, such as using only sets of single-use instruments, ensuring that instruments were kept together in their sets or using separate instruments for those born after 1996, appeared to be poor value for money.

Neuropilin-1 Regulates the Secondary CD8 T Cell Response to Virus Infection.

Neuropilin-1 (Nrp1) plays important roles in axonal guidance in neurons and in the growth of new blood vessels. There is also a growing appreciation for roles played by neuropilin-1 in the immune response. This molecule is important for the function of regulatory T cells; however, roles in other T cell populations have not been identified. Here, we show that neuropilin-1 is expressed during the peak of the antiviral CD8 T cell response during murine gammaherpesvirus infection. Using a conditional knockout model, we deleted Nrp1 either before infection or after CD8 T cell memory had been established. We found that deletion of Nrp1 skewed the acute CD8 T cell response toward a memory precursor-like phenotype; however, the ensuing resting memory response was similar regardless of Nrp1 expression. Interestingly, Nrp1 deletion had differing effects on the recall response depending on the timing of deletion. When deleted before infection, Nrp1 deficiency inhibited the secondary response. Deletion just prior to reexposure to virus led to an enhanced secondary response. Interestingly, these effects were observed only in mice infected with a persistent strain of murine gammaherpesvirus and not with a nonpersistent mutant strain. These data highlight a multifaceted role for neuropilin-1 in memory CD8 T cell differentiation, dependent upon the stage of the T cell response and characteristics of the infectious agent. Several therapeutic anticancer therapies focus on inhibition of Nrp1 to restrict tumor growth, and so knowledge of how Nrp1 blockade may affect the CD8 T cell response will provide a better understanding of treatment consequences.IMPORTANCE CD8 T cell responses are critical to control both virus infections and tumors. The ability of these cells to persist for long periods of time can result in lifelong immunity, as relatively small populations of cells can expand rapidly to counter reexposure to the same insult. Understanding the molecules necessary for this rapid secondary expansion is critical if we are to develop therapies that can provide lifelong protection. This report shows an important and complex role for the molecule neuropilin-1 in the secondary response. Several cancer therapies targeting neuropilin-1 are in development, and this work will lead to better understanding of the effect these therapies could have upon the protective CD8 T cell response.

MKL1-actin pathway restricts chromatin accessibility and prevents mature pluripotency activation.

Actin cytoskeleton is well-known for providing structural/mechanical support, but whether and how it regulates chromatin and cell fate reprogramming is far less clear. Here, we report that MKL1, the key transcriptional co-activator of many actin cytoskeletal genes, regulates genomic accessibility and cell fate reprogramming. The MKL1-actin pathway weakens during somatic cell reprogramming by pluripotency transcription factors. Cells that reprogram efficiently display low endogenous MKL1 and inhibition of actin polymerization promotes mature pluripotency activation. Sustained MKL1 expression at a level seen in typical fibroblasts yields excessive actin cytoskeleton, decreases nuclear volume and reduces global chromatin accessibility, stalling cells on their trajectory toward mature pluripotency. In addition, the MKL1-actin imposed block of pluripotency can be bypassed, at least partially, when the Sun2-containing linker of the nucleoskeleton and cytoskeleton (LINC) complex is inhibited. Thus, we unveil a previously unappreciated aspect of control on chromatin and cell fate reprogramming exerted by the MKL1-actin pathway.

Cabozantinib and vandetanib for unresectable locally advanced or metastatic medullary thyroid cancer: a systematic review and economic model.

BACKGROUND: Medullary thyroid cancer (MTC) is a rare form of cancer that affects patients' health-related quality of life (HRQoL) and survival. Cabozantinib (Cometriq®; Ipsen, Paris, France) and vandetanib (Caprelsa®; Sanofi Genzyme, Cambridge, MA, USA) are currently the treatment modality of choice for treating unresectable progressive and symptomatic MTC. OBJECTIVES: (1) To evaluate the clinical effectiveness and safety of cabozantinib and vandetanib. (2) To estimate the incremental cost-effectiveness of cabozantinib and vandetanib versus each other and best supportive care. (3) To identify key areas for primary research. (4) To estimate the overall cost of these treatments in England. DATA SOURCES: Peer-reviewed publications (searched from inception to November 2016), European Public Assessment Reports and manufacturers' submissions. REVIEW METHODS: A systematic review [including a network meta-analysis (NMA)] was conducted to evaluate the clinical effectiveness and safety of cabozantinib and vandetanib. The economic analysis included a review of existing analyses and the development of a de novo model. RESULTS: The systematic review identified two placebo-controlled trials. The Efficacy of XL184 (Cabozantinib) in Advanced Medullary Thyroid Cancer (EXAM) trial evaluated the efficacy and safety of cabozantinib in patients with unresectable locally advanced, metastatic and progressive MTC. The ZETA trial evaluated the efficacy and safety of vandetanib in patients with unresectable locally advanced or metastatic MTC. Both drugs significantly improved progression-free survival (PFS) more than the placebo (p < 0.001). The NMA suggested that, within the symptomatic and progressive MTC population, the effects on PFS were similar (vandetanib vs. cabozantinib: hazard ratio 1.14, 95% credible interval 0.41 to 3.09). Neither trial demonstrated a significant overall survival benefit for cabozantinib or vandetanib versus placebo, although data from ZETA were subject to potential confounding. Both cabozantinib and vandetanib demonstrated significantly better objective response rates and calcitonin (CTN) and carcinoembryonic antigen (CEA) response rates than placebo. Both cabozantinib and vandetanib produced frequent adverse events, often leading to dose interruption or reduction. The assessment group model indicates that, within the EU-label population (symptomatic and progressive MTC), the incremental cost-effectiveness ratios (ICERs) for cabozantinib and vandetanib are > £138,000 per quality-adjusted life-year (QALY) gained. Within the restricted EU-label population (symptomatic and progressive MTC with CEA/CTN doubling times of ≤ 24 months), the ICER for vandetanib is expected to be > £66,000 per QALY gained. The maximum annual budget impact within the symptomatic and progressive population is estimated to be ≈£2.35M for cabozantinib and ≈£5.53M for vandetanib. The costs of vandetanib in the restricted EU-label population are expected to be lower. LIMITATIONS: The intention-to-treat populations of the EXAM and ZETA trials are notably different. The analyses of ZETA subgroups may be subject to confounding as a result of differences in baseline characteristics and open-label vandetanib use. Attempts to statistically adjust for treatment switching were unsuccessful. No HRQoL evidence was identified for the MTC population. CONCLUSIONS: The identified trials suggest that cabozantinib and vandetanib improve PFS more than the placebo; however, significant OS benefits were not demonstrated. The economic analyses indicate that within the EU-label population, the ICERs for cabozantinib and vandetanib are > £138,000 per QALY gained. Within the restricted EU-label population, the ICER for vandetanib is expected to be > £66,000 per QALY gained. FUTURE RESEARCH PRIORITIES: (1) Primary research assessing the long-term effectiveness of cabozantinib and vandetanib within relevant subgroups. (2) Reanalyses of the ZETA trial to investigate the impact of adjusting for open-label vandetanib use using appropriate statistical methods. (3) Studies assessing the impact of MTC on HRQoL. STUDY REGISTRATION: This study is registered as PROSPERO CRD42016050403. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Medullary thyroid carcinoma (MTC) is a rare form of cancer that presents as a mass of tumours in the thyroid gland of the neck. MTC affects both patients' health-related quality of life and survival. Targeted therapies (cabozantinib and vandetanib) are currently used to treat unresectable progressive and symptomatic MTC. The evidence for the use of cabozantinib and vandetanib in patients with unresectable locally advanced or metastatic MTC was reviewed, and two clinical trials were identified. The trials suggest that both drugs improve progression-free survival. Neither trial demonstrated significant survival benefits for cabozantinib or vandetanib. Both drugs produced frequent adverse events, often leading to dose interruption or reduction. Whether or not these therapies represent good value for money for the NHS was also assessed. Analyses indicate that the incremental cost-effectiveness ratios (ICERs) (a measure of cost-effectiveness) for cabozantinib and vandetanib versus best supportive care (BSC) in patients with symptomatic and progressive MTC are > £138,000 per quality-adjusted life-year (QALY) gained. Within a subgroup of patients with symptomatic and progressive MTC and carcinoembryonic antigen and/or calcitonin doubling times of ≤ 24 months, the ICER for vandetanib versus BSC remains > £66,000 per QALY gained.