Activation of the Interleukin-18 Signaling Pathway via Direct Receptor Dimerization in the Absence of Interleukin-18.

Interleukin 18 (IL-18) is a key cytokine involved in the activation of T and NK cells, which are major effector cells in tumor killing. However, recombinant IL-18 showed limited efficacy in clinical trials. A recent study showed the lack of efficacy was largely due to the existence of IL-18BP, a soluble decoy receptor for IL-18. It was shown that engineered IL-18 variants that maintained pathway activation, but avoided IL-18BP binding, could exert potent antitumor effects. In this study, we demonstrated an alternative strategy to activate IL-18 signaling through direct receptor dimerization. These results provide evidences that the IL-18 pathway can be activated by directly bridging the receptors and, therefore, bypassing the IL-18BP-mediated inhibition.

Online adaptive radiotherapy: Assessment of planning technique and its impact on longitudinal plan quality robustness in pancreatic cancer.

BACKGROUND AND PURPOSE: Planning on a static dataset that reflects the simulation day anatomy is routine for SBRT. We hypothesize the quality of on-table adaptive plans is similar to the baseline plan when delivering stereotactic MR-guided adaptive radiotherapy (SMART) for pancreatic cancer (PCa). MATERIALS AND METHODS: Sixty-seven inoperable PCa patients were prescribed 50 Gy/5-fraction SMART. Baseline planning included: 3-5 mm gastrointestinal (GI) PRV, 50 Gy optimization target (PTVopt) based on GI PRV, conformality rings, and contracted GTV to guide the hotspot. For each adaptation, GI anatomy was re-contoured, followed by re-optimization. Plan quality was evaluated for target coverage (TC = PTVopt V100%/volume), PTV D90% and D80%, homogeneity index (HI = PTVopt D2%/D98%), prescription isodose/target volume (PITV), low-dose conformity (D2cm = maximum dose at 2 cm from PTVopt/Rx dose), and gradient index (R50%=50% Rx isodose volume/PTVopt volume).A novel global planning metric, termed the Pancreas Adaptive Radiotherapy Score (PARTS), was developed and implemented based on GI OAR sparing, PTV/GTV coverage, and conformality. Adaptive robustness (baseline to fraction 1) and stability (difference between two fractions with highest GI PRV variation) were quantified. RESULTS: OAR constraints were met on all baseline (n = 67) and adaptive (n = 318) plans. Coverage for baseline/adaptive plans was mean ± SD at 44.9 ± 5.8 Gy/44.3 ± 5.5 Gy (PTV D80%), 50.1 ± 4.2 Gy/49.1 ± 4.7 Gy (PTVopt D80%), and 80%±18%/74%±18% (TC), respectively. Mean homogeneity and conformality for baseline/adaptive plans were 0.87 ± 0.25/0.81 ± 0.30 (PITV), 3.81 ± 1.87/3.87 ± 2.0 (R50%), 1.53 ± 0.23/1.55 ± 0.23 (HI), and 58%±7%/59%±7% (D2cm), respectively. PARTS was found to be a sensitive metric due to its additive influence of geometry changes on PARTS' sub-metrics. There were no statistical differences (p > 0.05) for stability, except for PARTS (p = 0.04, median difference -0.6%). Statistical differences for robustness when significant were small for most metrics (<2.0% median). Median adaptive re-optimizations were 2. CONCLUSION: We describe a 5-fraction ablative SMART planning approach for PCa that is robust and stable during on-table adaption, due to gradients controlled by a GI PRV technique and the use of rings. These findings are noteworthy given that daily interfraction anatomic GI OAR differences are routine, thus necessitating on-table adaptation. This work supports feasibility towards utilizing a patient-independent, template on-table adaptive approach.

Accelerated hypofractionated magnetic resonance-guided adaptive radiotherapy for oligoprogressive non-small cell lung cancer.

Given the positive results from recent randomized controlled trials in patients with oligometastatic, oligoprogressive, or oligoresidual disease, the role of radiotherapy has expanded in patients with metastatic non-small cell lung cancer (NSCLC). While small metastatic lesions are commonly treated with stereotactic body radiotherapy (SBRT), treatment of the primary tumor and involved regional lymph nodes may require prolonged fractionation schedules to ensure safety especially when treating larger volumes in proximity to critical organs-at-risk (OARs). We have developed an institutional MR-guided adaptive radiotherapy (MRgRT) workflow for these patients. We present a 71-year-old patient with stage IV NSCLC with oligoprogression of the primary tumor and associated regional lymph nodes in which MR-guided, online adaptive radiotherapy was performed, prescribing 60 Gy in 15 fractions. We describe our workflow, dosimetric constraints, and daily dosimetric comparisons for the critical OARs (esophagus, trachea, and proximal bronchial tree [PBT] maximum doses [D0.03cc]), in comparison to the original treatment plan recalculated on the anatomy of the day (i.e., predicted doses). During MRgRT, few fractions met the original dosimetric objectives: 6.6% for esophagus, 6.6% for PBT, and 6.6% for trachea. Online adaptive radiotherapy reduced the cumulative doses to the structures by 11.34%, 4.2%, and 5.62% when comparing predicted plan summations to the final delivered summation. Therefore, this case study presets a workflow and treatment paradigm for accelerated hypofractionated MRgRT due to the significant variations in daily dose to the central thoracic OARs to reduce treatment-related toxicity associated with radiotherapy.

Multi-Institutional Outcomes of Stereotactic Magnetic Resonance Image Guided Adaptive Radiation Therapy With a Median Biologically Effective Dose of 100 Gy10 for Non-bone Oligometastases.

Purpose: Randomized data show a survival benefit of stereotactic ablative body radiation therapy in selected patients with oligometastases (OM). Stereotactic magnetic resonance guided adaptive radiation therapy (SMART) may facilitate the delivery of ablative dose for OM lesions, especially those adjacent to historically dose-limiting organs at risk, where conventional approaches preclude ablative dosing. Methods and Materials: The RSSearch Registry was queried for OM patients (1-5 metastatic lesions) treated with SMART. Freedom from local progression (FFLP), freedom from distant progression (FFDP), progression-free survival (PFS), and overall survival (LS) were estimated using the Kaplan-Meier method. FFLP was evaluated using RECIST 1.1 criteria. Toxicity was evaluated using Common Terminology Criteria for Adverse Events version 4 criteria. Results: Ninety-six patients with 108 OM lesions were treated on a 0.35 T MR Linac at 2 institutions between 2018 and 2020. SMART was delivered to mostly abdominal or pelvic lymph nodes (48.1%), lung (18.5%), liver and intrahepatic bile ducts (16.7%), and adrenal gland (11.1%). The median prescribed radiation therapy dose was 48.5 Gy (range, 30-60 Gy) in 5 fractions (range, 3-15). The median biologically effective dose corrected using an alpha/beta value of 10 was 100 Gy10 (range, 48-180). No acute or late grade 3+ toxicities were observed with median 10 months (range, 3-25) follow-up. Estimated 1-year FFLP, FFDP, PFS, and OS were 92.3%, 41.1%, 39.3%, and 89.6%, respectively. Median FFDP and PFS were 8.9 months (95% confidence interval, 5.2-12.6 months) and 7.6 months (95% confidence interval, 4.5-10.6 months), respectively. Conclusions: To our knowledge, this represents the largest analysis of SMART using ablative dosing for non-bone OM. A median prescribed biologically effective dose of 100 Gy10 resulted in excellent early FFLP and no significant toxicity, likely facilitated by continuous intrafraction MR visualization, breath hold delivery, and online adaptive replanning. Additional prospective evaluation of dose-escalated SMART for OM is warranted.

SARS-CoV-2 B.1.1.529 (Omicron) Variant Transmission Within Households - Four U.S. Jurisdictions, November 2021-February 2022.

The B.1.1.529 (Omicron) variant, first detected in November 2021, was responsible for a surge in U.S. infections with SARS-CoV-2, the virus that causes COVID-19, during December 2021-January 2022 (1). To investigate the effectiveness of prevention strategies in household settings, CDC partnered with four U.S. jurisdictions to describe Omicron household transmission during November 2021-February 2022. Persons with sequence-confirmed Omicron infection and their household contacts were interviewed. Omicron transmission occurred in 124 (67.8%) of 183 households. Among 431 household contacts, 227 were classified as having a case of COVID-19 (attack rate [AR] = 52.7%).† The ARs among household contacts of index patients who had received a COVID-19 booster dose, of fully vaccinated index patients who completed their COVID-19 primary series within the previous 5 months, and of unvaccinated index patients were 42.7% (47 of 110), 43.6% (17 of 39), and 63.9% (69 of 108), respectively. The AR was lower among household contacts of index patients who isolated (41.2%, 99 of 240) compared with those of index patients who did not isolate (67.5%, 112 of 166) (p-value <0.01). Similarly, the AR was lower among household contacts of index patients who ever wore a mask at home during their potentially infectious period (39.5%, 88 of 223) compared with those of index patients who never wore a mask at home (68.9%, 124 of 180) (p-value <0.01). Multicomponent COVID-19 prevention strategies, including up-to-date vaccination, isolation of infected persons, and mask use at home, are critical to reducing Omicron transmission in household settings.

Cortisol promotes breast-to-brain metastasis through the blood-cerebrospinal fluid barrier.

BACKGROUND: Elevated basal cortisol levels are present in women with primary and metastatic breast cancer. Although cortisol's potential role in breast-to-brain metastasis has yet to be sufficiently studied, prior evidence indicates that it functions as a double-edged sword-cortisol induces breast cancer metastasis in vivo, but strengthens the blood-brain-barrier (BBB) to protect the brain from microbes and peripheral immune cells. AIMS: In this study, we provide a novel examination on whether cortisol's role in tumor invasiveness eclipses its supporting role in strengthening the CNS barriers. We expanded our study to include the blood-cerebrospinal fluid barrier (BCSFB), an underexamined site of tumor entry. METHODS AND RESULTS: Utilizing in vitro BBB and BCSFB models to measure barrier strength in the presence of hydrocortisone (HC). We established that lung tumor cells migrate through both CNS barriers equally while breast tumors cells preferentially migrate through the BCSFB. Furthermore, HC treatment increased breast-to-brain metastases (BBM) but not primary breast tumor migratory capacity. When examining the transmigration of breast cancer cells across the BCSFB, we demonstrate that HC induces increased traversal of BBM but not primary breast cancer. We provide evidence that HC increases tightness of the BCSFB akin to the BBB by upregulating claudin-5, a tight junction protein formerly acknowledged as exclusive to the BBB. CONCLUSION: Our findings indicate, for the first time that increased cortisol levels facilitate breast-to-brain metastasis through the BCSFB-a vulnerable point of entry which has been typically overlooked in brain metastasis. Our study suggests cortisol plays a pro-metastatic role in breast-to-brain metastasis and thus caution is needed when using glucocorticoids to treat breast cancer patients.

CT-guided versus MR-guided radiotherapy: Impact on gastrointestinal sparing in adrenal stereotactic body radiotherapy.

BACKGROUND AND PURPOSE: To quantify the indication for adaptive, gated breath-hold (BH) MR-guided radiotherapy (MRgRTBH) versus BH or free-breathing (FB) CT-based image-guided radiotherapy (CT-IGRT) for the ablative treatment of adrenal malignancies. MATERIALS AND METHODS: Twenty adrenal patients underwent adaptive IMRT MRgRTBH to a median dose of 50 Gy/5 fractions. Each patient was replanned for VMAT CT-IGRTBH and CT-IGRTFB on a c-arm linac. Only CT-IGRTFB used an ITV, summed from GTVs of all phases of the 4DCT respiratory evaluation. All used the same 5 mm GTV/ITV to PTV expansion. Metrics evaluated included: target volume and coverage, conformality, mean ipsilateral kidney and 0.5 cc gastrointestinal organ-at-risk (OAR) doses (D0.5cc). Adaptive dose for MRgRTBH and predicted dose (i.e., initial plan re-calculated on anatomy of the day) was performed for CT-IGRTBH and MRgRTBH to assess frequency of OAR violations and coverage reductions for each fraction. RESULTS: The more common VMAT CT-IGRTFB, with its significantly larger target volumes, proved inferior to MRgRTBH in mean PTV and ITV/GTV coverage, as well as small bowel D0.5cc. Conversely, VMAT CT-IGRTBH delivered a dosimetrically superior initial plan in terms of statistically significant (p ≤ 0.02) improvements in target coverage, conformality and D0.5cc to the large bowel, duodenum and mean ipsilateral kidney compared to IMRT MRgRTBH. However, non-adaptive CT-IGRTBH had a 71.8% frequency of predicted indications for adaptation and was 2.8 times more likely to experience a coverage reduction in PTV D95% than predicted for MRgRTBH. CONCLUSION: Breath-hold VMAT radiotherapy provides superior target coverage and conformality over MRgRTBH, but the ability of MRgRTBH to safely provide ablative doses to adrenal lesions near mobile luminal OAR through adaptation and direct, real-time motion tracking is unmatched.

Agreement analysis of three mandibular third molar retention classifications.

INTRODUCTION: Pell & Gregory and Winter classifications are basic in third molar categorization; Sánchez-Torres classification is used in Mexico, but it has not been previously evaluated. OBJECTIVE: To assess the degree of agreement in the radiographic evaluation of impacted mandibular third molar with the use of three classifications: Pell & Gregory, Winter and Sánchez-Torres. METHOD: Observational, descriptive, inter-observer degree of agreement study that included 10 oral and maxillofacial surgeons and 10 training residents, who recorded the radiographic categorization of third mandibular molars (left and right) according to Pell and Gregory, Sánchez-Torres and Winter classifications. Inter-observer degree of agreement was assessed with Fleiss' kappa test. RESULTS: Pell and Gregory classification obtained the lowest degree of agreement (kappa = 0.05 and 0.185), followed by Sánchez-Torres classification (kappa = 0.125 and 0.326); Winter had the best agreement, with kappa = 0.28 and 0.636 for oral and maxillofacial surgeons and training residents, respectively. CONCLUSION: The Winter classification showed an acceptable (moderate) degree of agreement to classify mandibular third molars by training residents.

INTRODUCCIÓN: Las clasificaciones de Pell y Gregory y de Winter son básicas en la categorización de terceros molares; la clasificación de Sánchez Torres es usada en México, pero no había sido evaluada previamente. OBJETIVO: Evaluar el grado de acuerdo en la valoración radiográfica de terceros molares mandibulares impactados, con el empleo de tres clasificaciones: Pell y Gregory, Winter y Sánchez Torres. MÉTODO: Estudio observacional, descriptivo, de concordancia interobservador, que incluyó a 10 cirujanos orales y maxilofaciales y 10 residentes en formación, quienes registraron la categorización radiográfica de terceros molares mandibulares (izquierdos y derechos) de acuerdo con las clasificaciones de Pell y Gregory, Sánchez Torres y Winter. Se evaluó el grado de acuerdo entre observadores mediante la prueba de kappa de Fleiss. RESULTADOS: La clasificación de Pell y Gregory obtuvo el menor grado de acuerdo (kappa = 0.05 y 0.185), seguida de la clasificación de Sánchez Torres (kappa = 0.125 y 0.326); el mejor valor lo obtuvo la clasificación de Winter, con kappa = 0.28 y 0.636 para cirujanos orales y maxilofaciales y residentes en formación, respectivamente. CONCLUSIÓN: La clasificación de Winter mostró un grado de acuerdo aceptable (moderado) para categorizar terceros molares mandibulares en los residentes en formación.

Análisis de concordancia de tres clasificaciones de terceros molares mandibulares retenidos / Agreement analysis of three mandibular third molar retention classifications

Resumen Introducción: Las clasificaciones de Pell y Gregory y de Winter son básicas en la categorización de terceros molares; la clasificación de Sánchez Torres es usada en México, pero no había sido evaluada previamente. Objetivo: Evaluar el grado de acuerdo en la valoración radiográfica de terceros molares mandibulares impactados, con el empleo de tres clasificaciones: Pell y Gregory, Winter y Sánchez Torres. Método: Estudio observacional, descriptivo, de concordancia interobservador, que incluyó a 10 cirujanos orales y maxilofaciales y 10 residentes en formación, quienes registraron la categorización radiográfica de terceros molares mandibulares (izquierdos y derechos) de acuerdo con las clasificaciones de Pell y Gregory, Sánchez Torres y Winter. Se evaluó el grado de acuerdo entre observadores mediante la prueba de kappa de Fleiss. Resultados: La clasificación de Pell y Gregory obtuvo el menor grado de acuerdo (kappa = 0.05 y 0.185), seguida de la clasificación de Sánchez Torres (kappa = 0.125 y 0.326); el mejor valor lo obtuvo la clasificación de Winter, con kappa = 0.28 y 0.636 para cirujanos orales y maxilofaciales y residentes en formación, respectivamente. Conclusión: La clasificación de Winter mostró un grado de acuerdo aceptable (moderado) para categorizar terceros molares mandibulares en los residentes en formación.

Abstract Introduction: Pell & Gregory and Winter classifications are basic in third molar categorization; Sánchez-Torres classification is used in Mexico, but it has not been previously evaluated. Objective: To assess the degree of agreement in the radiographic evaluation of impacted mandibular third molar with the use of three classifications: Pell & Gregory, Winter and Sánchez-Torres. Method: Observational, descriptive, inter-observer degree of agreement study that included 10 oral and maxillofacial surgeons and 10 training residents, who recorded the radiographic categorization of third mandibular molars (left and right) according to Pell and Gregory, Sánchez-Torres and Winter classifications. Inter-observer degree of agreement was assessed with Fleiss' kappa test. Results: Pell and Gregory classification obtained the lowest degree of agreement (kappa = 0.05 and 0.185), followed by Sánchez-Torres classification (kappa = 0.125 and 0.326); Winter had the best agreement, with kappa = 0.28 and 0.636 for oral and maxillofacial surgeons and training residents, respectively. Conclusion: The Winter classification showed an acceptable (moderate) degree of agreement to classify mandibular third molars by training residents.

Age-Related Intraneuronal Aggregation of Amyloid-ß in Endosomes, Mitochondria, Autophagosomes, and Lysosomes.

This work provides new insight into the age-related basis of Alzheimer's disease (AD), the composition of intraneuronal amyloid (iAß), and the mechanism of an age-related increase in iAß in adult AD-model mouse neurons. A new end-specific antibody for Aß45 and another for aggregated forms of Aß provide new insight into the composition of iAß and the mechanism of accumulation in old adult neurons from the 3xTg-AD model mouse. iAß levels containing aggregates of Aß45 increased 30-50-fold in neurons from young to old age and were further stimulated upon glutamate treatment. iAß was 8 times more abundant in 3xTg-AD than non-transgenic neurons with imaged particle sizes following the same log-log distribution, suggesting a similar snow-ball mechanism of intracellular biogenesis. Pathologically misfolded and mislocalized Alz50 tau colocalized with iAß and rapidly increased following a brief metabolic stress with glutamate. AßPP-CTF, Aß45, and aggregated Aß colocalized most strongly with mitochondria and endosomes and less with lysosomes and autophagosomes. Differences in iAß by sex were minor. These results suggest that incomplete carboxyl-terminal trimming of long Aßs by gamma-secretase produced large intracellular deposits which limited completion of autophagy in aged neurons. Understanding the mechanism of age-related changes in iAß processing may lead to application of countermeasures to prolong dementia-free health span.