Optogenetic Spreading Depolarizations Do Not Worsen Acute Ischemic Stroke Outcome.

BACKGROUND: Spreading depolarizations (SDs) are believed to contribute to injury progression and worsen outcomes in focal cerebral ischemia because exogenously induced SDs have been associated with enlarged infarct volumes. However, previous studies used highly invasive methods to trigger SDs that can directly cause tissue injury (eg, topical KCl) and confound the interpretation. Here, we tested whether SDs indeed enlarge infarcts when induced via a novel, noninjurious method using optogenetics. METHODS: Using transgenic mice expressing channelrhodopsin-2 in neurons (Thy1-ChR2-YFP), we induced 8 optogenetic SDs to trigger SDs noninvasively at a remote cortical location in a noninjurious manner during 1-hour distal microvascular clip or proximal an endovascular filament occlusion of the middle cerebral artery. Laser speckle imaging was used to monitor cerebral blood flow. Infarct volumes were then quantified at 24 or 48 hours. RESULTS: Infarct volumes in the optogenetic SD arm did not differ from the control arm in either distal or proximal middle cerebral artery occlusion, despite a 6-fold and 4-fold higher number of SDs, respectively. Identical optogenetic illumination in wild-type mice did not affect the infarct volume. Full-field laser speckle imaging showed that optogenetic stimulation did not affect the perfusion in the peri-infarct cortex. CONCLUSIONS: Altogether, these data show that SDs induced noninvasively using optogenetics do not worsen tissue outcomes. Our findings compel a careful reexamination of the notion that SDs are causally linked to infarct expansion.

Propensity-score matched analysis of patent foramen ovale closure in real-world study cohort with cryptogenic ischemic stroke.

INTRODUCTION: Patent foramen ovale (PFO) occurs in 25% of the general population and in 40% of cryptogenic ischemic stroke patients. Recent trials support PFO closure in selected patients with cryptogenic stroke. We examined the outcomes of transcatheter PFO closure in a real-world study cohort with cryptogenic stroke. METHODS: Consecutive ischemic stroke patients who were classified as cryptogenic on the TOAST aetiology and diagnosed with a PFO were included. All patients underwent either transcatheter PFO closure or medical therapy. A 2:1 propensity score matching by sex and Risk-of-Paradoxical-Embolism (RoPE) score was performed. Multivariable regression models adjusted for sex and RoPE score. RESULTS: Our cohort comprised 232 patients with mean age 44.3 years (SD 10.8) and median follow-up 1486.5 days. 33.2% were female. PFO closure (n=84) and medical therapy (n=148) groups were well-matched with <10% mean-difference in sex and RoPE score. Two patients in the treated group (2.4%) and seven in the control group (4.7%) had a recurrent ischemic stroke event. Multivariable Cox regression demonstrated a hazard-ratio of 0.26 (95%CI 0.03-2.13, P=0.21) for PFO closure compared to control. The incidence of atrial fibrillation (AF) detected post-PFO closure was similar between the treated and control (1.19% vs 1.35%, multivariable logistic regression odds-ratio 0.90, 95%CI 0.04-9.81, P=0.94). There were no major periprocedural complications documented. The difference in restricted mean survival-time free from stroke at two years between treated and control was 26.2 days (95%CI 5.52-46.85, P=0.013). CONCLUSIONS: In this Asian cohort, we report a low incidence of ischemic stroke recurrence and new-onset AF in patients who underwent PFO closure. When compared to the medical therapy group, there was no significant difference in the incidence of stroke recurrence and new-onset AF. Further studies involving larger real-world cohorts are warranted to identify patients who are more likely to benefit from PFO closure.

Assessment of Lymphoma and Other Hematologic Malignancies Training Needs Among Radiation Oncology Residents: a Brief Report.

The role of radiation therapy (RT) varies across hematologic malignancies (HM). Radiation oncology (RO) resident comfort with specific aspects of HM patient management is unknown. The International Lymphoma RO Group (ILROG) assessed resident HM training opportunities and interest in an HM away elective. RO residents (PGY2-5) in the Association of Residents in RO (ARRO) database (n = 572) were emailed an anonymous, web-based survey in January 2019 including binary, Likert-type scale (1 = not at all, 5 = extremely, reported as median [interquartile range]), and multiple-choice questions. Of 134 resident respondents (23%), 86 (64%) were PGY4/5 residents and 36 (27%) were in larger programs (≥ 13 residents). Residents reported having specialized HM faculty (112, 84%) and a dedicated HM rotation (95, 71%). Residents reported "moderate" preparedness to advocate for RT in multidisciplinary conferences (3 [2-3]); make HM-related clinical decisions (3 [2-4]); and critique treatment planning (3 [2-4]). They reported feeling "moderately" to "quite" prepared to contour HM cases (3.5 [3-4]) and "quite" prepared to utilize the PET-CT five-point scale (4 [3-5]). Overall, residents reported feeling "moderately" prepared to treat HM patients (3 [2-3]); 24 residents (23%) felt "quite" or "extremely" prepared. Sixty-six residents (49%) were potentially interested in an HM away elective, commonly to increase comfort with treating HM patients (65%). Therefore, HM training is an important component of RO residency, yet a minority of surveyed trainees felt quite or extremely well prepared to treat HM patients. Programs should explore alternative and additional educational opportunities to increase resident comfort with treating HM patients.

NCCN Guidelines® Insights: Hodgkin Lymphoma, Version 2.2022.

Hodgkin lymphoma (HL) is an uncommon malignancy of B-cell origin. Classical HL (cHL) and nodular lymphocyte-predominant HL are the 2 main types of HL. The cure rates for HL have increased so markedly with the advent of modern treatment options that overriding treatment considerations often relate to long-term toxicity. These NCCN Guidelines Insights discuss the recent updates to the NCCN Guidelines for HL focusing on (1) radiation therapy dose constraints in the management of patients with HL, and (2) the management of advanced-stage and relapsed or refractory cHL.

Low grade, indolent lymphomas of the head and neck: Comparative toxicity of standard versus very low dose radiation therapy.

National Comprehensive Cancer Network guidelines recommend radiation therapy (RT) for localized indolent non-Hodgkin lymphomas (iNHL). Many referring physicians avoid RT to the head and neck (HN) due to fears of toxicity. Very low-dose radiation (4 Gy) for select patients produces sustained local control and recently gained popularity. We compared early and late toxicities of standard 24-30 Gy to 4 Gy in patients with HN iNHL. We retrospectively analyzed 266 consecutive patients with HN iNHL receiving RT from 1994 to 2017. Patient characteristics, outcomes, and toxicities were collected from medical records. Early (≤2 months post-RT) and late (>2 months post-RT) toxicities were graded per Common Terminology Criteria for Adverse Events version 4. Grades 1-2 were defined as "low-grade" and 3-4 "high-grade." Toxicity incidence was compared between 4 and >4 Gy, grouped by treated site (orbit, nonorbital head, neck, skin) and early versus late. Median follow-up was 23 months (2-145) and 68 months (2-256) for 4Gy and >4 Gy cohorts, respectively. Median dose for the >4 Gy cohort was 30 Gy (10.5-54 Gy). Early and late toxicity incidences were lower in the 4 Gy cohort compared to >4 Gy across all RT-sites: early toxicity, orbit, 42% versus 96%; nonorbital head, 24% versus 96%; neck, 22% versus 94%; skin, 31% versus 87%; late toxicity, orbit, 20% versus 71%; nonorbital head, 6% versus 66%; neck, 6% versus 57%; skin, 0% versus 46% (4 Gy vs. >4 Gy, respectively). Toxicities among both cohorts were largely low-grade. High-grade early and late toxicities did not occur in the 4 Gy cohort. There was 1 high-grade early toxicity (Grade 3 dry mouth) and 17 high-grade late toxicities (Grade 3 cataracts) in the >4 Gy cohort. RT to HN for iNHL is associated with minimal short- and long-term toxicity and excellent local control among 4 Gy and >4 Gy treatments. In this setting, "toxicity" concerns should not deter oncologists from potentially curative RT. In select patients where toxicity remains a concern, very low dose 4 Gy could be considered.

Early palliative radiation versus observation for high-risk asymptomatic or minimally symptomatic bone metastases: study protocol for a randomized controlled trial.

BACKGROUND: In patients with metastatic cancer, the bone is the third-most common site of involvement. Radiation to painful bone metastases results in high rates of pain control and is an integral part of bone metastases management. Up to one-third of inpatient consults are requested for painful bone metastases, and up to 60% of these patients had evidence of these lesions visible on prior imaging. Meanwhile recent advances have reduced potential side effects of radiation. Therefore, there is an opportunity to further improve outcomes for patients using prophylactic palliative radiation to manage asymptomatic bone metastases. METHODS/STUDY DESIGN: In this trial, 74 patients with metastatic solid tumors and high-risk asymptomatic or minimally symptomatic bone metastases will be enrolled and randomized to early palliative radiation or standard of care. This will be the first trial to assess the efficacy of prophylactic palliative radiation in preventing skeletal related events (SREs), the primary endpoint. This endpoint was selected to encompass patient-centered outcomes that impact quality of life including pathologic fracture, spinal cord compression, and intervention with surgery or radiation. Secondary endpoints include hospitalizations, Bone Pain Index, pain-free survival, pain-related quality of life, and side effects of radiation therapy. DISCUSSION: In this study, we propose a novel definition of high-risk bone metastases most likely to benefit from preventive radiation and use validated questionnaires to assess pain and impact on quality of life and health resource utilization. Observations from early patient enrollment have demonstrated robustness of the primary endpoint and need for minor modifications to Bone Pain Index and data collection for opioid use and hospitalizations. With increasing indications for radiation in the oligometastatic setting, this trial aims to improve patient-centered outcomes in the polymetastatic setting. TRIAL REGISTRATION: ISRCTN Number/Clinical trials.gov, ID: NCT03523351 . Registered on 14 May 2018.

Outcomes of Relapsed and Refractory Primary Mediastinal (Thymic) Large B Cell Lymphoma Treated with Second-Line Therapy and Intent to Transplant.

Primary mediastinal (thymic) large B cell lymphoma is a subtype of diffuse large B cell lymphoma with distinct clinical, molecular, and genetic features, many of which overlap with Hodgkin lymphoma. Increasingly, initial therapy for these patients has used dose-dense chemotherapy with or without radiation with excellent results. In patients with relapsed and primary refractory disease, outcomes of second-line therapy followed by consolidation with high-dose therapy and autologous stem cell transplantation remains largely undefined. We reviewed the outcomes of 60 transplant-eligible patients with relapsed or refractory primary mediastinal (thymic) large B cell lymphoma enrolled on sequential protocols with uniform second-line therapy with intent to consolidate with autologous stem cell transplant. The estimated 3-year overall and event-free survivals for all patients were 61% and 57%, respectively, and 68% and 65%, respectively, for patients proceeding to stem cell transplant. Multivariable analysis of risk factors before transplant revealed that an incomplete response to initial therapy, advanced Ann Arbor stage at disease progression, and failure to achieve a partial remission or better to second-line therapy to be independently associated with inferior event-free and overall survival. A risk score based on these variables was able to identify patients who are unlikely to respond to conventional second-line strategies. These results suggest that salvage chemoradiotherapy with intent of subsequent high-dose therapy and autologous stem cell transplant is successful in most patients with relapsed and refractory primary mediastinal (thymic) large B cell lymphoma. Alternative strategies are warranted for a significant subset of patients with high-risk disease who are unlikely to be cured with this strategy.

Adolescent mental health education InSciEd Out: a case study of an alternative middle school population.

BACKGROUND: Mental illness contributes substantially to global disease burden, particularly when illness onset occurs during youth and help-seeking is delayed and/or limited. Yet, few mental health promotion interventions target youth, particularly those with or at high risk of developing mental illness ("at-risk" youth). Community-based translational research has the capacity to identify and intervene upon barriers to positive health outcomes. This is especially important for integrated care in at-risk youth populations. METHODS: Here the Integrated Science Education Outreach (InSciEd Out) program delivered a novel school-based anti-stigma intervention in mental health to a cohort of seventh and eighth grade at-risk students. These students were assessed for changes in mental health knowledge, stigmatization, and help-seeking intentions via a classroom activity, surveys, and teacher interviews. Descriptive statistics and Cohen's d effect sizes were employed to assess pre-post changes. Inferential statistical analyses were also conducted on pilot results to provide a benchmark to inform future studies. RESULTS: Elimination of mental health misconceptions (substance weakness p = 0.00; recovery p = 0.05; prevention p = 0.05; violent p = 0.05) was accompanied by slight gains in mental health literacy (d = 0.18) and small to medium improvements in help-seeking intentions (anxiety d = 0.24; depression d = 0.48; substance d = 0.43; psychosis d = 0.53). Within this particular cohort of students, stigma was exceptionally low at baseline and remained largely unchanged. Teacher narratives revealed positive teacher views of programming, increased student openness to talk about mental illness, and higher peer and self-acceptance of mental health diagnoses and help-seeking. CONCLUSIONS: Curricular-based efforts focused on mental illness in an alternative school setting are feasible and integrated well into general curricula under the InSciEd Out framework. Preliminary data suggest the existence of unique help-seeking barriers in at-risk youth. Increased focus upon community-based programming has potential to bridge gaps in translation, bringing this critical population to clinical care in pursuit of improved mental health for all. Trial registration ClinicalTrials.gov, ID:NCT02680899. Registered 12 February 2016, https://clinicaltrials.gov/ct2/show/NCT02680899.

Brentuximab vedotin and AVD followed by involved-site radiotherapy in early stage, unfavorable risk Hodgkin lymphoma.

This multicenter pilot study assessed the safety and efficacy of brentuximab vedotin (BV) and AVD (adriamycin, vinblastine, and dacarbazine) followed by 30 Gy involved site radiation therapy (ISRT). Patients with newly diagnosed, early stage classical Hodgkin lymphoma (HL) with unfavorable-risk features were treated with 4 cycles of BV and AVD. Patients who achieved a negative positron emission tomography (PET) scan (Deauville score of 1-3) received 30 Gy ISRT. Thirty patients received treatment and were assessable for toxicity. Twenty-nine patients completed 4 cycles of BV + AVD, and 25 patients BV + AVD + 30 Gy ISRT. No clinically significant noninfectious pneumonitis was observed. Serious adverse events (≥grade 3) were reported in 4 patients, including febrile neutropenia, peripheral neuropathy, and hypertension. After 2 and 4 cycles of BV + AVD, 90% (26 of 29) and 93% (27 or 29) of patients achieved a negative PET scan, respectively. Two patients with biopsy-proven primary refractory HL were treated off-study. All 25 patients who completed BV + AVD + ISRT achieved a complete response. With a median follow-up of 18.8 months, by intent to treat, the 1-year progression-free survival is 93.3% (95% confidence interval, 84-102). Overall, the treatment was well-tolerated with no evidence of significant pulmonary toxicity. The majority of patients (≥90%) achieved negative interim PET scans after 2 and 4 cycles of BV + AVD. Excluding the 2 primary refractory patients, all patients are disease free, suggesting that this is a highly active treatment program even in patients with substantial disease bulk. This trial was registered at www.clinicaltrials.gov as #NCT01868451.

Intensity-Modulated Radiation Therapy With Dose Painting: A Brain-Sparing Technique for Intracranial Germ Cell Tumors.

BACKGROUND: We sought to assess patterns of failure in pediatric patients with intracranial germ cell tumors (GCT) treated with intensity-modulated radiation therapy with dose painting (DP-IMRT). PROCEDURE: Between July 2007 and October 2013, 11 patients with localized GCT-five germinomas and six nongerminoma GCT (NGGCT)-received definitive treatment with DP-IMRT. Three representative patients were selected for replanning with (i) whole ventricular irradiation (WVI) with opposed lateral beams plus IMRT to the primary tumor and (ii) sequential IMRT. These plans were compared to the patients' original DP-IMRT plans for dosimetric analyses. RESULTS: Four patients with germinoma received radiation therapy alone: 45 Gy in 1.8 Gy fractions to the primary tumor and 25 Gy in 1.0 Gy fractions to whole ventricles using a dose-painting plan. One patient with germinoma received a reduced dose of 30.6 Gy to the primary tumor after neoadjuvant chemotherapy. Patients with NGGCT (n = 6) underwent multimodality treatment including chemotherapy (n = 6) and surgery (n = 3). These patients received 54 Gy to the primary tumor and 32.4-36 Gy to the whole ventricles. Dosimetric analyses showed DP-IMRT delivered decreased mean dose to whole brain, temporal lobes, hippocampi, cochleae, and optic nerves. With median follow-up of 4 years, 3-year failure-free survival was 100% for patients with germinoma and 67% for patients with NGGCT. One patient with a pineal NGGCT experienced a local recurrence within the high dose-volume while another experienced an isolated biochemical failure. CONCLUSIONS: DP-IMRT is dosimetrically superior to standard IMRT techniques for sparing of normal tissues. Disease control in this small series appears at least comparable to published results.

Comparing the Impact of Stenting vs. Medical Therapy for Intracranial Arterial Stenosis : A Systematic Review and One-stage and Two-stage Meta-Analysis of Randomized Clinical Trials.

PURPOSE: In the treatment of intracranial arterial stenosis (ICAS), controversies remain regarding the optimal treatment strategy. Our study aims to conduct an individual patient-level data meta-analysis of existing RCTs comparing PTAS versus best medical therapy and to identify differences in outcomes such as incidence of ischemic stroke or death. METHODS: Randomised controlled trials comparing the outcomes of stenting versus best medical therapy for patients who had symptomatic ICAS of >50%. Excluded studies included case reports, case series, reviews, observational studies,  letters or studies evaluating isolated angioplasty techniques without stenting. Data was extracted in accordance with PRISMA guidelines. RESULTS: 7 studies involving 1425 participants were included. There was an increased risk in the incidence of stroke and death within the first 30 days post-procedure for patients treated with PTAS over best medical therapy (RR = 2.22 [1.28-3.86], I²â€¯= 0%). Patients who underwent stenting also had a significantly higher risk of intracranial haemorrhage (RR = 12.66 [2.41-66.45], I²â€¯= 0%) and death (RR = 5.41 [1.20-24.28], I²â€¯= 0%).Under the shared frailty model, stenting when compared to medical therapy has a HR of 1.81 (95% CI:1.25-2.6) of stroke or death across 1 year. Under the parametric Royston-Parmar model, stenting has a significant decrease in the RMST(-0.83 months; 95% CI: -1.30-0.37). Stenting continued to show worse outcomes up to the 3 year mark with a HR of 1.60 (95% CI: 1.11-2.32). CONCLUSIONS AND RELEVANCE: There is an increased risk of peri- and post-procedural stroke and death over best medical therapy in patients with symptomatic ICAS who undergo PTAS. Further work is required to refine patient selection and mitigate peri-procedural risks.

Characteristics of Opioid Toxicity Deaths Among Adolescents and Young Adults in Ontario Prior To and During the COVID-19 Pandemic.

PURPOSE: To characterize opioid toxicity deaths among adolescents and young adults in Ontario, Canada, prior to and during the first year of the COVID-19 pandemic. METHODS: We conducted a descriptive, cross-sectional study of opioid toxicity deaths among individuals aged 15-24 in Ontario in the year prior to (March 17, 2019, to March 16, 2020) and the first year of the pandemic (March 17, 2020, to March 16, 2021) using administrative health databases. We analyzed circumstances surrounding death, substances contributing to death, and health-care encounters prior to death. RESULTS: We identified 284 deaths among Ontarians aged 15-24, including 115 in the year preceding and 169 in the first year of the pandemic. Fentanyl contributed to 84.3% of deaths in the prepandemic year, rising to 93.5% (p = .012) the following year. Stimulants contributed to approximately half of deaths in both periods (41.7% prepandemic and 49.1% during pandemic). In both periods, roughly one in 4 decedents had a health-care encounter in the week prior to death and less than 20% of those with an opioid use disorder received opioid agonist treatment in the 30 days prior to death. DISCUSSION: Among young Ontarians, the number of opioid-related deaths increased by 47% in the first year of the COVID-19 pandemic. Fentanyl contributed to the vast majority of deaths, with non-opioid substances (primarily stimulants) also contributing to approximately half of deaths. Patterns of health-care utilization prior to death suggest opportunities to better connect this population to services that address opioid use disorder needs and promote harm reduction.

Prophylactic Radiation Therapy Versus Standard of Care for Patients With High-Risk Asymptomatic Bone Metastases: A Multicenter, Randomized Phase II Clinical Trial.

PURPOSE: External-beam radiation therapy (RT) is standard of care (SOC) for pain relief of symptomatic bone metastases. We aimed to evaluate the efficacy of radiation to asymptomatic bone metastases in preventing skeletal-related events (SRE). METHODS: In a multicenter randomized controlled trial, adult patients with widely metastatic solid tumor malignancies were stratified by histology and planned SOC (systemic therapy or observation) and randomly assigned in a 1:1 ratio to receive RT to asymptomatic high-risk bone metastases or SOC alone. The primary outcome of the trial was SRE. Secondary outcomes included hospitalizations for SRE and overall survival (OS). RESULTS: A total of 78 patients with 122 high-risk bone metastases were enrolled between May 8, 2018, and August 9, 2021, at three institutions across an affiliated cancer network in the United States. Seventy-three patients were evaluable for the primary end point. The most common primary cancer types were lung (27%), breast (24%), and prostate (22%). At 1 year, SRE occurred in one of 62 bone metastases (1.6%) in the RT arm and 14 of 49 bone metastases (29%) in the SOC arm (P < .001). There were significantly fewer patients hospitalized for SRE in the RT arm compared with the SOC arm (0 v 4, P = .045). At a median follow-up of 2.5 years, OS was significantly longer in the RT arm (hazard ratio [HR], 0.49; 95% CI, 0.27 to 0.89; P = .018), which persisted on multivariable Cox regression analysis (HR, 0.46; 95% CI, 0.23 to 0.85; P = .01). CONCLUSION: Radiation delivered prophylactically to asymptomatic, high-risk bone metastases reduced SRE and hospitalizations. We also observed an improvement in OS with prophylactic radiation, although a confirmatory phase III trial is warranted.

Intensity-modulated radiation therapy with dose-painting for pediatric sarcomas with pulmonary metastases.

BACKGROUND: We examined patterns of failure in pediatric patients with thoracic sarcoma and pulmonary metastases treated with intensity-modulated radiation therapy with dose-painting (DP-IMRT). PROCEDURE: Eleven pediatric patients, five with Ewing sarcoma family tumors (ESFT) and six with rhabdomyosarcoma (RMS), with primary thoracic tumors and pulmonary metastases underwent DP-IMRT with chemotherapy for definitive treatment. Eight patients also underwent surgery. Median time to RT was 21 (15-31) weeks. Nine patients received 45-50.4-Gy in 1.8 Gy fractions to the primary tumor (n = 3) or post-operative tumor bed (n = 6). Two patients ≤4 years received 12 Gy intraoperative radiation therapy and 30.6-36 Gy IMRT postoperatively to the tumor bed. All patients received 14-16.8 Gy in 0.54-0.88 Gy fractions to the whole lungs (n = 6) or hemithorax (n = 5) using dose-painting technique. A representative case was re-planned with IMRT plus standard AP/PA whole lung irradiation (WLI) for dosimetric comparison. RESULTS: With 27-month median follow-up, 3-year pulmonary relapse-free survival in all patients was 61%: 80% for RMS and 40% for ESFT. Five patients (4 ESFT and 1 RMS) experienced pulmonary relapse at median 16 (9-41) months. There were no local failures. Our representative case demonstrated more homogeneous target volume coverage of the whole lungs and decreased mean dose to esophagus (15%), heart (31%), spinal cord (15%), and liver (19%) with DP-IMRT. CONCLUSIONS: The treatment of children with a primary thoracic tumor and pulmonary metastases poses a significant challenge. DP-IMRT is one solution to this technical problem. Initial data from this small series suggest DP-IMRT is feasible and produces superior sparing of critical normal tissues.

Nonviral nanoparticle gene delivery into the CNS for neurological disorders and brain cancer applications.

Nonviral nanoparticles have emerged as an attractive alternative to viral vectors for gene therapy applications, utilizing a range of lipid-based, polymeric, and inorganic materials. These materials can either encapsulate or be functionalized to bind nucleic acids and protect them from degradation. To effectively elicit changes to gene expression, the nanoparticle carrier needs to undergo a series of steps intracellularly, from interacting with the cellular membrane to facilitate cellular uptake to endosomal escape and nucleic acid release. Adjusting physiochemical properties of the nanoparticles, such as size, charge, and targeting ligands, can improve cellular uptake and ultimately gene delivery. Applications in the central nervous system (CNS; i.e., neurological diseases, brain cancers) face further extracellular barriers for a gene-carrying nanoparticle to surpass, with the most significant being the blood-brain barrier (BBB). Approaches to overcome these extracellular challenges to deliver nanoparticles into the CNS include systemic, intracerebroventricular, intrathecal, and intranasal administration. This review describes and compares different biomaterials for nonviral nanoparticle-mediated gene therapy to the CNS and explores challenges and recent preclinical and clinical developments in overcoming barriers to nanoparticle-mediated delivery to the brain. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease Therapeutic Approaches and Drug Discovery > Emerging Technologies Nanotechnology Approaches to Biology > Nanoscale Systems in Biology.

Adding caplacizumab to standard of care in thrombotic thrombocytopenic purpura: a systematic review and meta-analysis.

Immune thrombotic thrombocytopenic purpura (iTTP) is an acquired, fatal microangiopathy if untreated. Randomized controlled trials (RCTs) demonstrated faster time to response with addition of caplacizumab to standard of care (SOC). However, concerns about RCT selection bias and the high cost of caplacizumab warrant examination of all evidence, including real-world observational studies. In this systematic review and meta-analysis, we searched for comparative studies evaluating SOC with or without caplacizumab for the treatment of iTTP. We assessed risk of bias using the Cochrane risk-of-bias-2 tool (RCTs) and the Newcastle-Ottawa Scale (observational studies). The primary efficacy and safety outcomes were all-cause mortality and treatment-emergent bleeding, respectively. Secondary outcomes included exacerbation and relapse, refractory iTTP, and time to response. We included 2 high-quality RCTs and 3 observational studies at high risk of bias comprising 632 total participants. Compared with SOC, caplacizumab was associated with a nonsignificant reduction in the relative risk [RR] of death in RCTs (RR, 0.21; 95% confidence interval [CI], 0.05-1.74) and observational studies (RR, 0.62; 95% CI, 0.07-4.41). Compared with SOC, caplacizumab was associated with an increased bleeding risk in RCTs (RR, 1.37; 95% CI, 1.06-1.77). In observational studies, bleeding risk was not significantly increased (RR, 7.10; 95% CI, 0.90-56.14). Addition of caplacizumab was associated with a significant reduction in refractory iTTP and exacerbation risks and shortened response time but increased relapse risk. Frontline addition of caplacizumab does not significantly reduce all-cause mortality compared with SOC alone, although it reduces refractory disease risk, shortens time to response, and improves exacerbation rates at the expense of increased relapse and bleeding risk.

Modifiable Post-Mastectomy Radiation Therapy Factors and Impact on Implant-Based Breast Reconstruction Outcomes.

INTRODUCTION: Intensity modulated radiation therapy (IMRT) and other modifiable radiation factors have been associated with decreased radiation toxicity. These factors could allow for improved reconstructive outcomes in patients requiring post-mastectomy radiation therapy (PMRT). However, they have not yet been well-studied in implant-based breast reconstruction (IBBR). METHODS: We performed a retrospective chart review of patients who underwent mastectomy with immediate tissue expander placement followed by PMRT. Radiation characteristics were collected, including radiation technique, bolus regimen, X-ray energy, fractionation, maximum radiation hot spot (DMax), and tissue volume receiving >105% (V105%) or >107% (V107%) of the prescription dose. Reconstructive complications occurring after initiation of PMRT were analyzed with respect to these radiation characteristics. RESULTS: 68 patients (70 breasts) were included in this study. The overall complication rate was 28.6%, with infection being the most common complication (24.3%), requiring removal of the tissue expander or implant in greater than half of infections (15.7%). DMax was greater in patients who required explant after PMRT, and this approached statistical significance (114.5+/-7.2% v. 111.4+/-4.4%, p=0.059). V105% and V107% were also greater in patients who required explant after PMRT (42.1+/-17.1% v. 33.0+/-20.9% and 16.4+/-14.5% v. 11.3+/-14.6%, respectively), however this was not statistically significant (p=0.176 and p=0.313, respectively). There were no significant differences in complication rates between patients with respect to radiation technique or other radiation characteristics studied. CONCLUSIONS: Minimizing the radiation hot spots and volumes of tissue receiving greater than the prescription dose of radiation may improve reconstructive outcomes in patients undergoing IBBR followed by PMRT.

Intrinsic tumor resistance to CAR T cells is a dynamic transcriptional state that is exploitable with low-dose radiation.

Chimeric antigen receptor (CAR) T-cell therapy represents a major advancement for hematologic malignancies, with some patients achieving long-term remission. However, the majority of treated patients still die of their disease. A consistent predictor of response is tumor quantity, wherein a higher disease burden before CAR T-cell therapy portends a worse prognosis. Focal radiation to bulky sites of the disease can decrease tumor quantity before CAR T-cell therapy, but whether this strategy improves survival is unknown. We find that substantially reducing systemic tumor quantity using high-dose radiation to areas of bulky disease, which is commonly done clinically, is less impactful on overall survival in mice achieved by CAR T cells than targeting all sites of disease with low-dose total tumor irradiation (TTI) before CAR T-cell therapy. This finding highlights another predictor of response, tumor quality, the intrinsic resistance of an individual patient's tumor cells to CAR T-cell killing. Little is known about whether or how an individual tumor's intrinsic resistance may change under different circumstances. We find a transcriptional "death receptor score" that reflects a tumor's intrinsic sensitivity to CAR T cells can be temporarily increased by low-dose TTI, and the timing of this transcriptional change correlates with improved in vivo leukemia control by an otherwise limited number of CAR T cells. This suggests an actionable method for potentially improving outcomes in patients predicted to respond poorly to this promising therapy and highlights that intrinsic tumor attributes may be equally or more important predictors of CAR T-cell response as tumor burden.

Patient-centered outcomes for gastrointestinal cancer care: a scoping review protocol.

INTRODUCTION: Following a cancer diagnosis, patients and their caregivers face crucial decisions regarding goals of care and treatment, which have consequences that can persist throughout their cancer journey. To foster informed and value-driven treatment choices, evidence-based information on outcomes relevant to patients is needed. Traditionally, clinical studies have largely focused on a few concrete and easily measurable outcomes such as survival, disease progression and immediate treatment toxicities. These outcomes do not capture other important factors that patients consider when making treatment decisions. Patient-centred outcomes (PCOs) reflect the patients' individual values, preferences, needs and circumstances that are essential to directing meaningful and informed healthcare discussions. Often, however, these outcomes are not included in research protocols in a standardised and practical fashion. This scoping review will summarise the existing literature on PCOs in gastrointestinal (GI) cancer care as well as the tools used to assess these outcomes. A comprehensive list of these PCOs will be generated for future efforts to develop a core outcome set. METHODS AND ANALYSIS: This scoping review will follow Arksey and O'Malley's expanded framework for scoping reviews. We will systematically search Medline, Embase, CINAHL, Cochrane Library and APA PsycINFO databases for studies examining PCOs in the context of GI cancer. We will include studies published in or after the year 2000 up to the date of the final searches, with no language restrictions. Studies involving adult patients with GI cancers and discussion of any PCOs will be included. Opinion pieces, protocols, case reports and abstracts will be excluded. Two authors will independently perform two rounds of screening to select studies for inclusion. The data from full texts will be extracted, charted and summarised both quantitatively and qualitatively. ETHICS AND DISSEMINATION: No ethics approval is required for this scoping review. Results will be disseminated through scientific publication and presentation at relevant conferences.

PET-Based Staging Is Cost-Effective in Early-Stage Follicular Lymphoma.

The objective was to assess the cost-effectiveness of staging PET/CT in early-stage follicular lymphoma (FL) from the Canadian health-care system perspective. Methods: The study population was FL patients staged as early-stage using conventional CT imaging and planned for curative-intent radiation therapy (RT). A decision analytic model simulated the management after adding staging PET/CT versus using staging CT alone. In the no-PET/CT strategy, all patients proceeded to curative-intent RT as planned. In the PET/CT strategy, PET/CT information could result in an increased RT volume, switching to a noncurative approach, or no change in RT treatment as planned. The subsequent disease course was described using a state-transition cohort model over a 30-y time horizon. Diagnostic characteristics, probabilities, utilities, and costs were derived from the literature. Baseline analysis was performed using quality-adjusted life years (QALYs), costs (2019 Canadian dollars), and the incremental cost-effectiveness ratio. Deterministic sensitivity analyses were conducted, evaluating net monetary benefit at a willingness-to-pay threshold of $100,000/QALY. Probabilistic sensitivity analysis using 10,000 simulations was performed. Costs and QALYs were discounted at a rate of 1.5%. Results: In the reference case scenario, staging PET/CT was the dominant strategy, resulting in an average lifetime cost saving of $3,165 and a gain of 0.32 QALYs. In deterministic sensitivity analyses, the PET/CT strategy remained the preferred strategy for all scenarios supported by available data. In probabilistic sensitivity analysis, the PET/CT strategy was strongly dominant in 77% of simulations (i.e., reduced cost and increased QALYs) and was cost-effective in 89% of simulations (i.e., either saved costs or had an incremental cost-effectiveness ratio below $100,000/QALY). Conclusion: Our analysis showed that the use of PET/CT to stage early-stage FL patients reduces cost and improves QALYs. Patients with early-stage FL should undergo PET/CT before curative-intent RT.