Hypoxia-Preconditioned BMSC-Derived Exosomes Induce Mitophagy via the BNIP3-ANAX2 Axis to Alleviate Intervertebral Disc Degeneration.

Intervertebral disc degeneration (IVDD) is a chronic degenerative disease involving the aging and loss of proliferative capacity of nucleus pulposus cells (NPCs), processes heavily dependent on mitochondrial dynamics and autophagic flux. This study finds that the absence of BCL2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3) is associated with senescence-related NPC degeneration, disrupting mitochondrial quality control. Bone marrow mesenchymal stem cells (BMSCs) have multidirectional differentiation potential and produce extracellular vesicles containing cellular activators. Therefore, in this study, BMSCs are induced under hypoxic stimulation to deliver BNIP3-rich extracellular vesicles to NPCs, thereby alleviating aging-associated mitochondrial autophagic flux, promoting damaged mitochondrial clearance, and restoring mitochondrial quality control. Mechanistically, BNIP3 is shown to interact with the membrane-bound protein annexin A2 (ANXA2), enabling the liberation of the transcription factor EB (TFEB) from the ANXA2-TFEB complex, promoting TFEB nuclear translocation, and regulating autophagy and lysosomal gene activation. Furthermore, a rat model of IVDD is established and verified the in vivo efficacy of the exosomes in repairing disc injuries, delaying NPC aging, and promoting extracellular matrix (ECM) synthesis. In summary, hypoxia-induced BMSC exosomes deliver BNIP3-rich vesicles to alleviate disc degeneration by activating the mitochondrial BNIP3/ANXA2/TFEB axis, providing a new target for IVDD treatment.

Development and validation of an MR-driven dose-of-the-day procedure for online adaptive radiotherapy in upper gastrointestinal cancer patients.

Objective.To develop and validate a dose-of-the-day (DOTD) treatment plan verification procedure for liver and pancreas cancer patients treated with an magnetic resonance (MR)-Linac system.Approach.DOTD was implemented as an automated process that uses 3D datasets collected during treatment delivery. Particularly, the DOTD pipeline's input included the adapt-to-shape (ATS) plan-i.e. 3D-MR dataset acquired at beginning of online session, anatomical contours, dose distribution-and 3D-MR dataset acquired during beam-on (BON). The DOTD automated analysis included (a) ATS-to-BON image intensity-based deformable image registration (DIR), (b) ATS-to-BON contours mapping via DIR, (c) BON-to-ATS contours copying through rigid registration, (d) determining ATS-to-BON dosimetric differences, and (e) PDF report generation. The DIR process was validated by two expert reviewers. ATS-plans were recomputed on BON datasets to assess dose differences. DOTD analysis was performed retrospectively for 75 treatment fractions (12-liver and 5-pancreas patients).Main results.The accuracy of DOTD process relied on DIR and mapped contours quality. Most DIR-generated contours (99.6%) were clinically acceptable. DICE correlated with depreciation of DIR-based region of interest mapping process. The ATS-BON plan difference was found negligible (<1%). The duodenum and large bowel exhibited highest variations, 24% and 39% from fractional values, for 5-fraction liver and pancreas. For liver 1-fraction, a 62% variation was observed for duodenum.Significance.The DOTD methodology provides an automated approach to quantify 3D dosimetric differences between online plans and their delivery. This analysis offers promise as a valuable tool for plan quality assessment and decision-making in the verification stage of the online workflow.

Fractionated radiotherapy after gross-total resection of spinal chordoma: a systematic review of survival outcomes using individualized patient data.

OBJECTIVE: Spinal chordoma treatment guidelines recommend resection. However, in patients in whom gross-total resection (GTR) is achieved, the benefits of radiation therapy (RT) are unclear. Therefore, the authors performed a systematic review to determine if RT is associated with postoperative progression-free survival (PFS) or overall survival (OS) after achieving GTR of spinal chordoma. METHODS: The PubMed database was searched for studies including individualized data of patients undergoing GTR with or without RT for spinal chordoma. Patients < 18 years of age or those who underwent stereotactic body RT were excluded. Qualitative assessment was performed using Newcastle-Ottawa Scale guidelines. Log-rank tests for time-to-event data and a Cox proportional-hazards model were generated for a multivariable statistical model. RESULTS: Complete data of 132 patients were retrieved, with 37 (28%) patients receiving adjuvant RT and 95 (72%) not receiving adjuvant RT. The mean follow-up was not statistically significantly different between those undergoing RT and not undergoing RT (54.02 months and 65.43 months, respectively). Patients were more likely not to undergo RT if their disease was located in the sacrum versus the mobile spine (p < 0.001). When controlling for age ≥ 65 years, male sex, disease location, and treatment year ≥ 2010, patients undergoing RT had similar PFS and OS when compared with those not undergoing RT on multivariable survival analysis (HR 0.935 [95% CI 0.703-2.340], p = 0.844 and HR 2.078 [95% CI 0.848-5.090], p = 0.110, respectively). However, age ≥ 65 years was associated with poorer OS in adjusted analyses (HR 2.761 [95% CI 1.185-6.432], p = 0.018) relative to patients < 65 years of age. CONCLUSIONS: After achieving GTR of spinal chordoma, the utility of RT on PFS and OS remains unclear. Age ≥ 65 years appears to be associated with OS in spinal chordoma patients. Additional multicenter prospective studies are needed to determine the utility of RT in this patient population.

The incidence of brain metastases in breast cancer according to molecular subtype and stage: a 10-year single institution analysis.

BACKGROUND: Breast cancer (BC) is the second most common etiology of brain metastases (BrM). We aimed to examine the incidence of BrM among all BC patients presenting to a large tertiary cancer centre over one decade. METHODS: We included all BC patients presenting consecutively between 2009 and 2019 and cross referenced that cohort to a radiotherapy database, identifying patients treated for BrM at any time following their initial presentation. Cumulative incidences (CI) of BrM diagnoses were calculated using death as a competing risk and compared using the Fine-Gray method. Overall survival was estimated using the Kaplan Meier method. RESULTS: We identified 12,995 unique patients. The CI of BrM in patients who initially presented with Stage 0-4 disease was 2.1%, 3.7%, 9.4%, 10.6%, and 28.7%, respectively at 10 years. For 8,951 patients with available molecular subtype data, 6,470 (72%), 961 (11%), 1,023 (11%), and 497 (6%) had hormone-receptor (HR)-positive/ERBB2-, HR-negative/ERBB2-, HR-positive/ERBB2 + , and HR-negative/ERBB2 + disease, respectively; the CI of BrM in each was 7.6%, 25.3%, 24.1%, and 26.6%, at 10 years following BC diagnosis, respectively. Median overall survival (OS) following BC diagnosis and BrM diagnosis was 28 years 95% CI [25, 32] and 10 months 95% CI [9, 12], respectively. CONCLUSIONS: From a large, registry-based study, we observed that patients with ERBB2 + and triple negative BC have the highest incidence of BrM. Our data supports prospective surveillance brain MRI studies. Given advancements in BrM treatment, clinicians should have a low threshold for brain imaging in BC patients with high risk subtypes.

A population-based analysis of the management of symptoms of depression among patients with stage IV non-small cell lung cancer (NSCLC) in Ontario, Canada.

PURPOSE: Patients with lung cancer can experience significant psychological morbidities including depression. We characterize patterns and factors associated with interventions for symptoms of depression in stage IV non-small cell lung cancer (NSCLC). METHODS: We conducted a population-based cohort study using health services administrative data in Ontario, Canada of stage IV NSCLC diagnosed from January 2007 to September 2018. A positive symptom of depression score was defined by reporting at least one ESAS (Edmonton Symptom Assessment System) depression score ≥ 2 following diagnosis until the end of follow-up (September 2019). Patient factors included age, sex, comorbidity burden, rurality of residence, and neighbourhood income quintile. Interventions included psychiatry assessment, psychology referral, social work referral and anti-depressant medical therapy (for patients ≥ 65 years with universal drug coverage). Multivariable modified Poisson regression models were used to examine the association between patient factors and intervention use for patients who reported symptoms of depression. RESULTS: In the cohort of 13,159 patients with stage IV NSCLC lung cancer, symptoms of depression were prevalent (71.4%, n = 9,397). Patients who reported symptoms of depression were more likely to receive psychiatry assessment/psychology referral (7.8% vs 3.5%; SD [standardized difference] 0.19), social work referral (17.4% vs 11.9%; SD 0.16) and anti-depressant prescriptions (23.8% vs 13.8%; SD 0.26) when compared to patients who did not report symptoms of depression respectively. In multivariable analyses, older patients were less likely to receive any intervention. Females were more likely to obtain a psychiatry assessment/psychology referral or social work referral. In addition, patients from non-major urban or rural residences were less likely to receive psychiatry assessment/psychology referral or social work referral, however patients from rural residences were more likely to be prescribed anti-depressants. CONCLUSIONS: There is high prevalence of symptoms of depression in stage IV NSCLC. We identify patient populations, including older patients and rural patients, who are less likely to receive interventions that will help identifying and screening for symptoms of depression.

Palliative Care as a Component of High-Value and Cost-Saving Care During Hospitalization for Metastatic Cancer.

PURPOSE: Randomized controlled trials have demonstrated that palliative care (PC) can improve quality of life and survival for outpatients with advanced cancer, but there are limited population-based data on the value of inpatient PC. We assessed PC as a component of high-value care among a nationally representative sample of inpatients with metastatic cancer and identified hospitalization characteristics significantly associated with high costs. METHODS: Hospitalizations of patients 18 years and older with a primary diagnosis of metastatic cancer from the National Inpatient Sample from 2010 to 2019 were analyzed. We used multivariable mixed-effects logistic regression to assess medical services, patient demographics, and hospital characteristics associated with higher charges billed to insurance and hospital costs. Generalized linear mixed-effects models were used to determine cost savings associated with provision of PC. RESULTS: Among 397,691 hospitalizations from 2010 to 2019, the median charge per admission increased by 24.9%, from $44,904 in US dollars (USD) to $56,098 USD, whereas the median hospital cost remained stable at $14,300 USD. Receipt of inpatient PC was associated with significantly lower charges (odds ratio [OR], 0.62 [95% CI, 0.61 to 0.64]; P < .001) and costs (OR, 0.59 [95% CI, 0.58 to 0.61]; P < .001). Factors associated with high charges were receipt of invasive medical ventilation (P < .001) or systemic therapy (P < .001), Hispanic patients (P < .001), young age (18-49 years, P < .001), and for-profit hospitals (P < .001). PC provision was associated with a $1,310 USD (-13.6%, P < .001) reduction in costs per hospitalization compared with no PC, independent of the receipt of invasive care and age. CONCLUSION: Inpatient PC is associated with reduced hospital costs for patients with metastatic cancer, irrespective of age and receipt of aggressive interventions. Integration of inpatient PC may de-escalate costs incurred through low-value inpatient interventions.

Prospective evaluation of patient-reported anxiety and experiences with adaptive radiation therapy on an MR-linac.

Purpose: An integrated magnetic resonance scanner and linear accelerator (MR-linac) was implemented with daily online adaptive radiation therapy (ART). This study evaluated patient-reported experiences with their overall hospital care as well as treatment in the MR-linac environment. Methods: Patients pre-screened for MR eligibility and claustrophobia were referred to simulation on a 1.5 T MR-linac. Patient-reported experience measures were captured using two validated surveys. The 15-item MR-anxiety questionnaire (MR-AQ) was administered immediately after the first treatment to rate MR-related anxiety and relaxation. The 40-item satisfaction with cancer care questionnaire rating doctors, radiation therapists, the services and care organization and their outpatient experience was administered immediately after the last treatment using five-point Likert responses. Results were analyzed using descriptive statistics. Results: 205 patients were included in this analysis. Multiple sites were treated across the pelvis and abdomen with a median treatment time per fraction of 46 and 66 min respectively. Patients rated MR-related anxiety as "not at all" (87%), "somewhat" (11%), "moderately" (1%) and "very much so" (1%). Positive satisfaction responses ranged from 78 to 100% (median 93%) across all items. All radiation therapist-specific items were rated positively as 96-100%. The five lowest rated items (range 78-85%) were related to general provision of information, coordination, and communication. Overall hospital care was rated positively at 99%. Conclusion: In this large, single-institution prospective cohort, all patients had low MR-related anxiety and completed treatment as planned despite lengthy ART treatments with the MR-linac. Patients overall were highly satisfied with their cancer care involving ART using an MR-linac.

Meta-Analysis of Stereotactic Body Radiation ThERapy in Nonspine BONE Metastases (MASTER-BONES).

PURPOSE: The efficacy and safety of stereotactic body radiation therapy (SBRT) for patients with nonspine bone metastases remains in question. A systematic review and meta-analysis were performed to evaluate SBRT treatment outcomes in nonspine bone metastases. METHODS AND MATERIALS: Eligible studies were retrieved from MEDLINE, Embase, Scielo, the Cochrane Library, and annual meeting proceedings through July 6, 2023. We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Meta-analysis of Observational Studies in Epidemiology (MOOSE) guideline recommendations. Quantitative synthesis was performed using a random-effects model. Meta-regression was performed to determine correlation between clinical and treatment factors with the local failure (LF) and fracture rate. P values ≤.05 were deemed statistically significant. RESULTS: Seven retrospective studies, with a total of 807 patients (1048 lesions) treated with SBRT were included, with median follow-up ranging from 7.6 to 26.5 months. The most common SBRT sites were pelvis (39.2%), ribs (25.8%), femur (16.7%), and humerus/shoulder region (8.7%). At 1 year, the LF and fracture rate were 7% (95% CI, 5.5%-8.5%; I2 = 0; n = 75/1048) and 5.3% (95% CI, 3%-7.5%; I2 = 0; n = 65/1010). The 2-year cumulative LF incidence was 12.1% (95% CI, 10%-15.5%). The overall survival and progression-free survival at 1 year were 82% (95% CI, 75%-88%; I2 = 82%; n = 746/867) and 33.5% (95% CI, 26%-41%; I2 = 0%; n = 51/152), with a median of 20.2 months (95% CI, 10.9-49.1 months) and 8.3 months (95% CI, 6.3-10.3 months) for overall survival and progression-free survival, respectively. Meta-regression analysis revealed a significant relationship between planning target volume and fracture rate (P < .05). Ribs (2.5%) followed by the femur (1.9%; 95% CI, 0%-6.1%) were the most common fracture sites. The occurrence of pain flare, fatigue, and dermatitis were 7%, 5.4%, and 0.65%, respectively. CONCLUSIONS: Stereotactic body radiation proves both safety and efficacy for non-spine bone metastases, and although serious complications (grade 3) are rare, one case of grade 5 complication was reported. Careful consideration of target volume is crucial due to its link with a higher fracture risk.

Advances and Challenges in Trials of Local Therapy for Patients With Oligometastatic or Oligoprogressive Disease.

The paradigm of oligometastatic disease (OMD), characterized by a limited number of metastases potentially amenable to local therapies, presents unique opportunities and challenges in clinical trial design and implementation. Although local ablative therapies, such as stereotactic body radiation therapy, have shown promise in improving outcomes for patients with OMD, there is a lack of large-scale randomized phase III trials supporting their widespread use. This paper outlines the key challenges in trial design and implementation in the oligometastatic setting, including appropriate patient selection, the definition of the oligometastatic state, trial design considerations, endpoint selection, and logistical considerations related to enrollment and follow-up. We suggest potential strategies to address these challenges, emphasizing the importance of a comprehensive, patient-centric approach, and the integration of multidisciplinary teams in trial design and implementation. The aim is to encourage the design of well-structured clinical trials, ultimately refining best practices and enhancing patient outcomes in the management of OMD.

Stereotactic body radiotherapy for Ultra-Central lung Tumors: A systematic review and Meta-Analysis and International Stereotactic Radiosurgery Society practice guidelines.

BACKGROUND: Stereotactic body radiotherapy (SBRT) is an effective and safe modality for early-stage lung cancer and lung metastases. However, tumors in an ultra-central location pose unique safety considerations. We performed a systematic review and meta-analysis to summarize the current safety and efficacy data and provide practice recommendations on behalf of the International Stereotactic Radiosurgery Society (ISRS). METHODS: We performed a systematic review using PubMed and EMBASE databases of patients with ultra-central lung tumors treated with SBRT. Studies reporting local control (LC) and/or toxicity were included. Studies with <5 treated lesions, non-English language, re-irradiation, nodal tumors, or mixed outcomes in which ultra-central tumors could not be discerned were excluded. Random-effects meta-analysis was performed for studies reporting relevant endpoints. Meta-regression was conducted to determine the effect of various covariates on the primary outcomes. RESULTS: 602 unique studies were identified of which 27 (one prospective observational, the remainder retrospective) were included, representing 1183 treated targets. All studies defined ultra-central as the planning target volume (PTV) overlapping the proximal bronchial tree (PBT). The most common dose fractionations were 50 Gy/5, 60 Gy/8, and 60 Gy/12 fractions. The pooled 1- and 2-year LC estimates were 92 % and 89 %, respectively. Meta-regression identified biological effective dose (BED10) as a significant predictor of 1-year LC. A total of 109 grade 3-4 toxicity events, with a pooled incidence of 6 %, were reported, most commonly pneumonitis. There were 73 treatment related deaths, with a pooled incidence of 4 %, with the most common being hemoptysis. Anticoagulation, interstitial lung disease, endobronchial tumor, and concomitant targeted therapies were observed risk factors for fatal toxicity events. CONCLUSION: SBRT for ultra-central lung tumors results in acceptable rates of local control, albeit with risks of severe toxicity. Caution should be taken for appropriate patient selection, consideration of concomitant therapies, and radiotherapy plan design.

A Phase II Study of Optimized Individualized Adaptive Radiotherapy for Hepatocellular Carcinoma.

PURPOSE: We hypothesized that optimizing the utility of stereotactic body radiotherapy (SBRT) based on the individual patient's probability for tumor control and risk of liver injury would decrease toxicity without sacrificing local control in patients with impaired liver function or tumors not amenable to thermal ablation. PATIENTS AND METHODS: Patients with Child-Pugh (CP) A to B7 liver function with aggregate tumor size >3.5 cm, or CP ≥ B8 with any size tumor were prospectively enrolled on an Institutional Review Board-approved phase II clinical trial to undergo SBRT with baseline and midtreatment dose optimization using a quantitative, individualized utility-based analysis. Primary endpoints were change in CP score of ≥2 points within 6 months and local control. Protocol-treated patients were compared with patients receiving conventional SBRT at another cancer center using overlap weighting. RESULTS: A total of 56 patients with 80 treated tumors were analyzed with a median follow-up of 11.2 months. Two-year cumulative incidence of local progression was 6.4% [95% confidence interval (CI, 2.4-13.4)]. Twenty-one percent of patients experienced treatment-related toxicity within 6 months, which is similar to the rate for SBRT in patients with CP A liver function. An analysis using overlap weighting revealed similar local control [HR, 0.69; 95% CI (0.25-1.91); P = 0.48] and decreased toxicity [OR, 0.26; 95% CI (0.07-0.99); P = 0.048] compared with conventional SBRT. CONCLUSIONS: Treatment of individuals with impaired liver function or tumors not amenable to thermal ablation with a treatment paradigm designed to optimize utility may decrease treatment-related toxicity while maintaining tumor control.

Dyspnea in patients with stage IV non-small cell lung cancer: a population-based analysis of disease burden and patterns of care.

Background: Patients with metastatic non-small cell lung cancer (NSCLC) experience significant morbidity with dyspnea being a common symptom with a prevalence of 70%. The objective of this study was to determine factors associated with a moderate-to-severe dyspnea score based on the Edmonton Symptom Assessment System (ESAS), as well as resultant patterns of intervention and factors correlated to intervention receipt. Methods: Using health services administrative data, we conducted a population-based study of all patients diagnosed with metastatic NSCLC treated from January 2007 to September 2018 in the province of Ontario. The primary outcomes of interest are the prevalence of moderate-to-severe dyspnea scores, and the receipt of dyspnea-directed intervention. Differences in baseline characteristic between moderate-to-severe dyspnea and low dyspnea score cohorts were assessed by comparative statistics. Predictors of intervention receipt for patients with moderate-to-severe dyspnea scores were estimated using multivariable modified Poisson regression. Results: The initial study cohort included 13,159 patients diagnosed with metastatic NSCLC and of these, 9,434 (71.7%) reported a moderate-to-severe dyspnea score. Compared to patients who did not report moderate-to-severe dyspnea scores, those who reported a moderate-to-severe dyspnea score were more likely to complete a greater number of ESAS surveys, be male, have a higher Elixhauser comorbidity index (ECI) score, and receive subsequent systemic therapy after diagnosis. Most patients with a moderate-to-severe dyspnea score received intervention (96%), of which the most common were palliative care management (87%), thoracic radiotherapy (56%) and thoracentesis (37%). Multivariable regression identified older patients to be less likely to undergo pleurodesis. Thoracentesis was less common for patients living in rural and non-major urban areas, lower income areas, and earlier year of diagnosis. Receipt of thoracic radiotherapy was less common for older patients, females, those with ECI ≥4, patients living in major urban areas, and those with later year of diagnosis. Finally, palliative care referrals were less frequent for patients with ECI ≥4, age 60-69, residence outside of major urban areas, earlier year of diagnosis, and lower income areas. Conclusions: Dyspnea is a prevalent symptom amongst patients with metastatic NSCLC. Subpopulations of patients with moderate-to-severe dyspnea scores were in which inequities may exist in access to care that require further attention and evaluation.

Pain and Interventions in Stage IV Non-Small Cell Lung Cancer: A Province-Wide Analysis.

Pain is a common symptom in stage IV non-small cell lung cancer (NSCLC). The objective of the study was to examine the use of interventions and factors associated with interventions for pain. A population-based cohort study in Ontario, Canada was conducted with patients diagnosed with stage IV NSCLC from January 2007 to September 2018. An Edmonton Symptom Assessment System (ESAS) score of ≥4 defined moderate-to-severe pain following diagnosis. The study cohort included 13,159 patients, of which 68.5% reported at least one moderate-to-severe pain score. Most patients were assessed by a palliative care team (85.4%), and the majority received radiation therapy (73.2%). The use of nerve block was rare (0.8%). For patients ≥65 years of age who had drug coverage, 59.6% received an opiate prescription. Patients with moderate-to-severe pain were more likely to receive palliative assessment or radiation therapy compared to patients with none or mild pain. Patients aged ≥70 years and with a greater comorbidity burden were associated with less likelihood to receive radiation therapy. Patients from rural/non-major urban residence and with a greater comorbidity burden were also less likely to receive palliative care assessment. Factors associated with interventions for pain are described to inform future symptom management in this population.

Hypofractionated stereotactic radiosurgery (HSRS) as a salvage treatment for brain metastases failing prior stereotactic radiosurgery (SRS).

INTRODUCTION: Various treatment options exist to salvage stereotactic radiosurgery (SRS) failures for brain metastases, including repeat SRS and hypofractionated SRS (HSRS). Our objective was to report outcomes specific to salvage HSRS for brain metastases that failed prior HSRS/SRS. METHODS: Patients treated with HSRS to salvage local failures (LF) following initial HSRS/SRS, between July 2010 and April 2020, were retrospectively reviewed. The primary outcomes were the rates of LF, radiation necrosis (RN), and symptomatic radiation necrosis (SRN). Univariable (UVA) and multivariable (MVA) analyses using competing risk regression were performed to identify predictive factors for each endpoint. RESULTS: 120 Metastases in 91 patients were identified. The median clinical follow up was 13.4 months (range 1.1-111.1), and the median interval between SRS courses was 13.1 months (range 3.0-56.5). 115 metastases were salvaged with 20-35 Gy in 5 fractions and the remaining five with a total dose ranging from 20 to 24 Gy in 3-fractions. 67 targets (56%) were postoperative cavities. The median re-treatment target volume and biological effective dose (BED10) was 9.5 cc and 37.5 Gy, respectively. The 6- and 12- month LF rates were 18.9% and 27.7%, for RN 13% and 15.6%, and for SRN were 6.1% and 7.0%, respectively. MVA identified larger re-irradiation volume (hazard ratio [HR] 1.02, p = 0.04) and shorter interval between radiosurgery courses (HR 0.93, p < 0.001) as predictors of LF. Treatment of an intact target was associated with a higher risk of RN (HR 2.29, p = 0.04). CONCLUSION: Salvage HSRS results in high local control rates and toxicity rates that compare favorably to those single fraction SRS re-irradiation experiences reported in the literature.

Post-COVID-19 Syndrome Comprehensive Assessment: From Clinical Diagnosis to Imaging and Biochemical-Guided Diagnosis and Management.

The COVID-19 outbreak was first reported in 2019, causing massive morbidity and mortality. The majority of the COVID-19 patients survived and developed Post-COVID-19 Syndrome (PC19S) of varying severity. Currently, the diagnosis of PC19S is achieved through history and symptomatology that cannot be explained by an alternative diagnosis. However, the heavy reliance on subjective reporting is prone to reporting errors. Besides, there is no unified diagnostic assessment tool to classify the clinical severity of patients. This leads to significant difficulties when managing patients in terms of public resource utilization, clinical progression monitorization and rehabilitation plan formulation. This narrative review aims to review current evidence of diagnosis based on triple assessment: clinical symptomatology, biochemical analysis and imaging evidence. Further assessment tools can be developed based on triple assessment to monitor patient's clinical progression, prognosis and intervals of monitoring. It also highlights the high-risk features of patients for closer and earlier monitoring. Rehabilitation programs and related clinical trials are evaluated; however, most of them focus on cardiorespiratory fitness and psychiatric presentations such as anxiety and depression. Further research is required to establish an objective and comprehensive assessment tool to facilitate clinical management and rehabilitation plans.

Ensuring Superior Reporting of Radiation Therapy Noninferiority Trials: A Systematic Review.

Purpose: Although the frequency of noninferiority trials is increasing, the consistency of the reporting of these trials can vary. The aim of this systematic review was to assess the reporting quality of radiation therapy noninferiority trials. Methods and Materials: The PubMed, Embase, and Cochrane databases were queried for randomized controlled radiation therapy trials with noninferiority hypotheses published in English between January 2000 and July 2022, and this was performed by an information scientist. Descriptive statistics were used to summarize data. Results: Of 423 records screened, 59 (14%) were included after full-text review. All were published after 2003 and open label. The most common primary cancer type was breast (n = 15, 25%). Altered radiation fractionation (n = 26, 45%) and radiation de-escalation (n = 11, 19%) were the most common types of interventions. The most common primary endpoints were locoregional control (n = 17, 29%) and progression-free survival (n = 14, 24%). Fifty-three (90%) reported the noninferiority margin, and only 9 (17%) provided statistical justification for the margin. The median absolute noninferiority margin was 9% (interquartile range, 5%-10%), and the median relative margin was 1.51 (interquartile range, 1.33-2.04). Sample size calculations and confidence intervals were reported in 54 studies (92%). Both intention-to-treat and per-protocol analyses were reported in 27 studies (46%). In 31 trials (53%), noninferiority of the primary endpoint was reached. Conclusions: There was variability in the reporting of key components of noninferiority trials. We encourage consideration of additional statistical reasoning such as guidelines or previous trials in the selection of the noninferiority margin, reporting both absolute and relative margins, and the avoidance of statistically vague or misleading language in the reporting of future noninferiority trials.

Conventionally fully fractionated Gamma Knife Icon re-irradiation of primary recurrent intracranial tumors: the first report indicating feasibility and safety.

OBJECTIVE: With the incorporation of real-time image guidance on the Gamma Knife system allowing for mask-based immobilization (Gamma Knife Icon [GKI]), conventionally fully fractionated (1.8-3.0 Gy/day) GKI radiation can now be delivered to take advantage of an inherently minimal margin for delivery uncertainty, sharp dose falloff, and inhomogeneous dose distribution. This case series details the authors' preliminary experience in re-irradiating 7 complex primary intracranial tumors, which were considered to have been previously maximally radiated and situated adjacent to critical organs at risk. METHODS: The authors retrospectively reviewed all patients who received fractionated re-irradiation using GKI at the Sunnybrook Health Sciences Centre, University of Toronto, Ontario, Canada, between 2016 and 2021. Patients with brain metastases, and those who received radiotherapy courses in 5 or fewer fractions, were excluded. All radiotherapy doses were converted to the equivalent total dose in 2-Gy fractions (EQD2), with the assumption of an α/ß ratio of 2 for late normal tissue toxicity and 10 for the tumor. RESULTS: A total of 7 patients were included in this case series. Three patients had recurrent meningiomas, as well as 1 patient each with ependymoma, intracranial sarcoma, pituitary macroadenoma, and papillary pineal tumor. Six patients had undergone prior linear accelerator-based conventional fractionated radiotherapy and 1 patient had undergone prior proton therapy. Patients were re-irradiated with a median (range) total dose of 50.4 (30-63.4) Gy delivered in a median (range) of 28 (10-38) fractions with GKI. The median (range) target volume was 6.58 (0.2-46.3) cm3. The median (range) cumulative mean EQD2 administered to the tumor was 121.1 (107.9-181.3) Gy, and the median (range) maximum point EQD2 administered to the brainstem, optic nerves, and optic chiasm were 91.6 (74.0-111.5) Gy, 58.9 (6.3-102.9) Gy, and 59.9 (36.7-127.3) Gy, respectively. At a median (range) follow-up of 15 (6-42) months, 6 of 7 patients were alive with 4 having locally controlled disease. Only 3 patients experienced treatment-related toxicities, which were self-limited. CONCLUSIONS: Fractionated radiotherapy using GKI may be a safe and effective method for the re-irradiation of complex progressive primary intracranial tumors, where the aim is to minimize the potential for serious late effects.