Radiological Endpoints Research Articles

DIPG-71. XPEDITE: A STUDY TO EXPEDITE DIPG AND DMG RESEARCH

Abstract BACKGROUND Diffuse midline glioma (DMG), particularly the subtype known as diffuse intrinsic pontine glioma (DIPG), poses a significant challenge due to its aggressive nature and low survival rates, especially in children. Despite ongoing research and clinical trials, the survival rate remains alarmingly low. The scarcity of cases and siloed nature of current registry efforts have hindered the establishment of a reliable natural disease history for benchmarking studies and led to the need for randomization in clinical trials. METHODS xPedite (NCT06140719) is a fully virtual, patient-driven, nationwide, real-time observational study to collect, annotate, standardize, and report the critical data elements of DMG and DIPG in a regulatory-compliant framework. Patients of any age can join via electronic consent, with recruitment supported by provider referrals and patient advocacy organizations DDRFA and My DIPG Navigator. Medical records are accessed from institutions, sequencing vendors, and health information networks. Notably, data elements are annotated comprehensively and longitudinally in a 21 CFR Part 11-compliant clinical database by xCures remote study staff, eliminating the need for data entry by treating site staff or physicians. Data collected include anti-cancer interventions, non-cancer medications, biomarker results, radiological endpoints, steroid use, vitals, demographics, raw DICOM images, and genomics. In addition to clinical data, patient- and caregiver-reported outcome questionnaires (PROs) and video assessments of mobility and neurological status are collected for clinician review. The objective of the study is to collect these clinical, imaging, biomarker, and assessment data in a manner suitable to provide to health authorities to reduce randomization in future trials. In a commitment to scientific understanding and collaborative research, the data collected through the xPedite study is openly available to academic, government, and non-profit researchers. As of January 2024, 182 patients were enrolled in xPedite. Real-time enrollment and data statistics are available at https://xcures.com/dmgdashboard/.

Body weight and composition endpoints in cancer cachexia clinical trials: Systematic Review 4 of the cachexia endpoints series.

Significant variation exists in the outcomes used in cancer cachexia trials, including measures of body composition, which are often selected as primary or secondary endpoints. To date, there has been no review of the most commonly selected measures or their potential sensitivity to detect changes resulting from the interventions being examined. The aim of this systematic review is to assess the frequency and diversity of body composition measures that have been used in cancer cachexia trials. MEDLINE, Embase and Cochrane Library databases were systematically searched between January 1990 and June 2021. Eligible trials examined adults (≥18years) who had received an intervention aiming to treat or attenuate the effects of cancer cachexia for >14days. Trials were also of a prospective controlled design and included body weight or at least one anthropometric, bioelectrical or radiological endpoint pertaining to body composition, irrespective of the modality of intervention (e.g., pharmacological, nutritional, physical exercise and behavioural) or comparator. Trials with a sample size of <40 patients were excluded. Data extraction used Covidence software, and reporting followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidance. This review was prospectively registered (PROSPERO: CRD42022276710). A total of 84 clinical trials, comprising 13016 patients, were eligible for inclusion. Non-small-cell lung cancer and pancreatic cancer were studied most frequently. The majority of trial interventions were pharmacological (52%) or nutritional (34%) in nature. The most frequently reported endpoints were assessments of body weight (68 trials, n=11561) followed by bioimpedance analysis (BIA)-based estimates (23 trials, n=3140). Sixteen trials (n=3052) included dual-energy X-ray absorptiometry (DEXA)-based endpoints, and computed tomography (CT) body composition was included in eight trials (n=841). Discrepancies were evident when comparing the efficacy of interventions using BIA-based estimates of lean tissue mass against radiological assessment modalities. Body weight, BIA and DEXA-based endpoints have been most frequently used in cancer cachexia trials. Although the optimal endpoints cannot be determined from this review, body weight, alongside measurements from radiological body composition analysis, would seem appropriate. The choice of radiological modality is likely to be dependent on the trial setting, population and intervention in question. CT and magnetic resonance imaging, which have the ability to accurately discriminate tissue types, are likely to be more sensitive and provide greater detail. Endpoints are of particular importance when aligned with the intervention's mechanism of action and/or intended patient benefit.

Four-level ACDF surgical series 2000–2022: a systematic review of clinical and radiological outcomes and complications

Objective The primary objective of this investigation is to systematically scrutinize extant surgical studies delineating Four-Level Anterior Cervical Discectomy and Fusion (4L ACDF), with a specific emphasis on elucidating reported surgical indications, clinical and radiological outcomes, fusion rates, lordosis correction, and the spectrum of complication rates. Methods The literature review was conducted in adherence to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, employing the MEDLINE (PubMed), Embase, and Scopus databases. This analysis encompasses studies implementing the 4L ACDF procedure, with detailed extraction of pertinent data pertaining to surgical methodologies, types of employed interbody cages, clinical and radiological endpoints, rates of fusion, and the incidence of complications. Results Among the 15 studies satisfying inclusion criteria, a marginal increment in the year 2022 (21.4%) was discerned, with a preponderance of study representation emanating from China (35.7%) and the United States (28.6%). 50% of the studies were single-surgeon studies. Concerning follow-up, studies exhibited variability, with 42.9% concentrating on periods of five years or less, and an equivalent proportion extending beyond this timeframe. Across the amalgamated cohort of 2457 patients, males constituted 51.6%, manifesting a mean age range of 52.2–61.3 years. Indications for surgery included radiculopathy (26.9%) and myelopathy (46.9%), with a predilection for involvement at C3–7 (24.9%). Meta-analysis yielded an overall complication rate of 16.258% (CI 95%: 14.823%–17.772%). Dysphagia (4.563%), haematoma (1.525%), hoarseness (0.205%), C5 palsy (0.176%) were the most prevalent complications of 4L ACDF. Fusion rates ranging from 41.3% to 94% were documented. Conclusion The 4L ACDF is commonly performed to address mylopathy and radiculopathy. While the surgery carries a complication rate of around 16%, its effectiveness in achieving bone fusion can vary considerably.

Wrist Radiographic Indices and Patients’ Performance Following Three Surgical Methods for Management of Distal Radius Fractures: A Randomized Single-Blind Controlled Trial

Background. Distal radius fracture has been reported as the most common type of extremity fractures in adults. No treatment method has been introduced definitely for this type of fracture, especially for maintaining hand function in the best state.&#x0D; The aim of this study — to assess the functional and radiological outcomes following three surgical methods, including external fixation, K-wire and external fixation with pinning.&#x0D; Methods. This parallel-designed randomized controlled trial was conducted on adult patients with intra-articular fracture of distal radius. The participants were allocated in three research groups with block random sampling, and were matched for their age and gender. Primary outcome was radiographic parameters, including radial inclination, radial height, ulnar variance and dorsal/palmar tilt. Secondary outcome was the patient’s performance examined with DASH and PRWE questionnaires. All participants were followed 6, 12 and 24 weeks after the surgery for evaluation of these outcomes.&#x0D; Results. Totally, 78 patients, including 42 male and 36 female with mean age of 46.94±11.05 years completed the research protocol. Although the four radiologic primary endpoints were in the normal clinical range after the intervention, a significant statistical difference was observed between the three groups (р0.001). Also, both DASH and PRWE score showed a significant decrease after the therapeutic interventions (р0.001).&#x0D; Conclusion. The statistically significant difference in the research outcomes of the external fixation with pinning can show that this treatment method theoretically preserves the anatomical condition better than the other two methods, and probably has better functional effects on short-term and intermediate-term results following the surgery.

Incidence of Fractures after Intravenous Iron: A Retrospective Analysis Comparing Ferric Carboxymaltose and Ferric Derisomaltose

Background: Hypophosphatemia is a frequent side-effect of certain intravenous (i.v.) iron formulations, and a recent meta-analysis of prospective clinical trials reported that 54% of patients treated with ferric carboxymaltose (FCM) develop hypophosphatemia. While the incidence and time-course of hypophosphatemia are well known, the frequency of clinical consequences of these changes is poorly described. FCM infusions cause high intact fibroblast growth factor 23 (iFGF23), which is associated with hypophosphatemia, hyperphosphaturia, hypocalcitriolemia, hypocalcemia, secondary hypoparathyroidism, which is summarized as the ‘6H-syndrome’ that can ultimately result in osteomalacia. The association between treatment with FCM, high iFGF23, osteomalacia with fractures and nephrolithiasis is well documented in multiple case reports. This is not the case for ferric derisomaltose (FDI). Aims: The aim of the present study was to assess the incidence of fractures or radiological signs of osteomalacia and kidney stone in patients treated with FCM or FDI. Methods: Patients treated with FCM or FDI between January 2010 und December 2019 were identified by retrospective assessment of electronic health records of the University Hospital in Innsbruck, which is a large tertiary referral center in Western Austria. Dose, time of infusion, comorbidities and haematological parameters, serum iron parameters as well as markers of mineral metabolism were extracted from the healthcare records of each patient. Radiological and clinical endpoints included fractures, radiological signs of osteomalacia and kidney stone disease after the first infusion of FCM or FDI. The year before the first infusion was used as a control period. Results: In total, 289 patients were included and the median follow-up time was 5.8 years. Mean age was 44.6 years and 184 of 289 patients (64%) were females. In total 179 patients were treated with FCM and 110 patients received FDI. Grouping patients by drug revealed no differences in cumulative iron dose or number of drug applications. At baseline, serum creatinine was significantly lower in FDI-treated patients, but within the normal range for both groups. Mean hemoglobin concentrations were significantly lower in FCM-treated than in FDI-treated patients (95 g/L vs. 109 g/L) with no statistically significant differences in mean ferritin concentrations between groups at baseline. Assessment of treatment response 1-3 months after i.v. iron treatment showed a robust increase in hemoglobin and serum ferritin in both treatment groups. Baseline phosphate was significantly lower in FDI-treated patients with 3.07 mg/dL versus 3.34 mg/dL in the FCM treatment group. In FCM-treated patients a significantly greater change from baseline to 1-3 months after administration was found for phosphorous and calcium (Table 1). Hypophosphatemia was more commonly documented and more severe in FCM-treated patients, who also showed a significant increase in ALP. In a time to event analysis (fracture, osteomalacia and kidney stones) a significantly higher proportion of patients reached the combined endpoint in the FCM treatment group than in FDI-treated patients (Figure 1). Univariate Cox-regression for fractures after the infusion showed a HR of 4.54 for FCM treatment when compared to FDI (p=0.04). In contrast, no difference in fracture incidence was present in the year before the first iron infusion when both treatment groups were compared. Conclusions: In this retrospective analysis the combined event rate of fracture, radiological signs of osteomalacia and kidney stones was significantly higher among patients treated with FCM than after FDI treatment. This finding suggests that the observed changes in markers of mineral metabolism could indicate that FCM treatment is associated with a significantly higher risk of clinically relevant bone complications and kidney stone disease.

Clinical and Radiological End Points to Stop Anti-Tubercular Treatment in Central Nervous System Tuberculoma and Predictors of Poor Outcome: A Retrospective Study.

The clinical and radiological end points to stop anti-tubercular treatment in central nervous system (CNS) tuberculoma are not known. This retrospective study was done to determine end points to stop anti-tubercular treatment and find the predictors of poor outcome in patients with CNS tuberculoma. Patients who were admitted with a diagnosis of brain/spine tuberculoma between January 2015 and December 2019 and who completed a minimum of 1-year follow-up were enrolled. Clinical and radiological end points to stop anti-tubercular treatment and predictors of death and poor outcome (modified Rankin scale > 2) were analyzed. One hundred and eight patients (male-to-female ratio, 47 [43.5%]:61 [56.5%]; brain tuberculoma, 102; spinal cord tuberculoma, 14; brain and spinal cord tuberculoma, 8) were included in the study. Median duration of anti-tubercular treatment was 24 months. Radiological resolution of tuberculoma (resolution of gadolinium-enhancing lesion, gliosis, calcification, cord atrophy, or syrinx formation) and radiological halt (no increase in size/number of tuberculoma on magnetic resonance imaging scans done 6 months apart) were used as end points to stop anti-tubercular treatment in 69 and 7 patients, respectively. Seven patients stopped their treatment by themselves, and 25 patients died. Altered sensorium, motor weakness, infarcts, hydrocephalus, and constitutional symptoms of tuberculous meningitis were predictors of poor outcome or death in CNS tuberculoma patients. Radiological resolution or radiological halt of brain/spinal cord tuberculoma was a reasonable end point to stop anti-tubercular treatment. However, this may require 24 months or more of anti-tubercular treatment. Associated tuberculous meningitis and its complications portend a poor prognosis.

Indolent cancer and pattern of progression: Two missing parameters in trial design for hepatology.

The indolent and aggressive behaviors of HCC might have a role in clinical trial (CT) results; however, the indolent HCC is less analyzed compared to others cancer. Indolent profile could be characterized as follows: (1) patients with low risk of progression itself due to the HCC molecular profile and/or due to the interaction between cancer cell their microenvironment; (2) patients who achieve objective response or present spontaneous regression; and (3) patients who develop radiological progression with no consequence on either the liver function or general status, and without trigger a change in the tumor stage. Patients with "indolent HCC" generally never develop cancer-related symptoms neither die for HCC-related causes. Thus, we hypothesize that the imbalance in the proportion of "indolent" versus "aggressive HCC" between arms or the underestimation/overestimation of HCC behavior at baseline in single-arm CT could be associated with CT failure or under-overestimation of trial results. The "indolent progression" may also explain the discrepancy between radiological progression-based end points and survival. Moreover, we discuss the related causes that explain the indolent profile of HCC and propose (1) refining the progression-related end point by the pattern of progression to minimize the limitations of the current end points; (2) considering alternative statistical tools for survival analysis such as milestone survival, or restricted mean survival time to capture the value of indolent HCC. According to these considerations, we propose incorporating novel end points into the single arm of phase I/II CT as exploratory analysis or as a secondary end point in phase III CT.

Short-term follow-up pilot study of sole middle meningeal artery embolization for chronic subdural hematoma: influence of internal architecture on the radiological outcomes.

To identify prognostic factors with emphasis on chronic subdural hematoma (CSDH) architecture that determines short-term outcome of middle meningeal artery embolization (MMAE). Consecutive CSDH patients treated by MMAE (November 2019 and March 2022) were retrospectively analyzed. Four architectures were analyzed: homogeneous, laminar, separated, and trabecular types. Predictor variables from baseline CT were correlated with radiological endpoint (≥ 50% of hematoma volume reduction), time to reach the endpoint, and rate of volume reduction. Study included 50 patients with 56 CSDHs (median age [first quartile, Q1; third quartile, Q3] 70.5 [60, 78.3] years; 36 were men). Separated type reached the endpoint at a lower rate on both bivariate (p = 0.02) and multivariate Cox model (0.034). Kaplan-Meier curves demonstrated that the median [Q1, Q3] time for 50% of the hematomas to reach the endpoint was 5 [4, 8], 4 [3, 5], 15 [15, 15], and 11 [4, 19] weeks for homogeneous, laminar, separated, and trabecular types, respectively. Linear mixed-effect model demonstrated a significant variation in the slope of hematoma volume reduction that was - 4.16 (95% confidence interval [CI] - 5.4, - 2.9), - 6.7 (95% CI - 8.35, - 5.1), - 2.03 (95% CI - 4.14, 0.08), and - 5.06 (95% CI - 6.8, - 3.32) ml per week for homogeneous, laminar, separated, and trabecular subtypes, respectively. Separated CSDH is a poor prognostic type in achieving radiological endpoint and a slower rate of volume reduction. While, homogeneous and laminar types reached the endpoint faster than separated and trabecular types on short-term follow-up.

The REACT study: design of a randomized phase 3 trial to assess the efficacy and safety of clazosentan for preventing deterioration due to delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage

BackgroundFor patients presenting with an aneurysmal subarachnoid hemorrhage (aSAH), delayed cerebral ischemia (DCI) is a significant cause of morbidity and mortality. The REACT study is designed to assess the safety and efficacy of clazosentan in preventing clinical deterioration due to DCI in patients with aSAH.MethodsREACT is a prospective, multicenter, randomized phase 3 study that is planned to enroll 400 patients with documented aSAH from a ruptured cerebral aneurysm, randomized 1:1 to 15 mg/hour intravenous clazosentan vs. placebo, in approximately 100 sites and 15 countries. Eligible patients are required to present at hospital admission with CT evidence of significant subarachnoid blood, defined as a thick and diffuse clot that is more than 4 mm in thickness and involves 3 or more basal cisterns. The primary efficacy endpoint is the occurrence of clinical deterioration due to DCI up to 14 days post-study drug initiation. The main secondary endpoint is the occurrence of clinically relevant cerebral infarction at Day 16 post-study drug initiation. Other secondary endpoints include the modified Rankin Scale (mRS) and the Glasgow Outcome Scale-Extended (GOSE) score at Week 12 post-aSAH, dichotomized into poor and good outcome. Radiological results and clinical endpoints are centrally evaluated by independent committees, blinded to treatment allocation. Exploratory efficacy endpoints comprise the assessment of cognition status at 12 weeks and quality of life at 12 and 24 weeks post aSAH.DiscussionIn the REACT study, clazosentan is evaluated on top of standard of care to determine if it reduces the risk of clinical deterioration due to DCI after aSAH. The selection of patients with thick and diffuse clots is intended to assess the benefit/risk profile of clazosentan in a population at high risk of vasospasm-related ischemic complications post-aSAH.Trial registration (Additional file 1)ClinicalTrials.gov (NCT03585270). EU Clinical Trial Register (EudraCT Number: 2018–000241-39).

The Evolving Scenario in the Assessment of Radiological Response for Hepatocellular Carcinoma in the Era of Immunotherapy: Strengths and Weaknesses of Surrogate Endpoints.

Hepatocellular carcinoma (HCC) is a challenging malignancy characterised by clinical and biological heterogeneity, independent of the stage. Despite the application of surveillance programs, a substantial proportion of patients are diagnosed at advanced stages when curative treatments are no longer available. The landscape of systemic therapies has been rapidly growing over the last decade, and the advent of immune-checkpoint inhibitors (ICIs) has changed the paradigm of systemic treatments. The coexistence of the tumour with underlying cirrhosis exposes patients with HCC to competing events related to tumour progression and/or hepatic decompensation. Therefore, it is relevant to adopt proper clinical endpoints to assess the extent of treatment benefit. While overall survival (OS) is the most accepted endpoint for phase III randomised controlled trials (RCTs) and drug approval, it is affected by many limitations. To overcome these limits, several clinical and radiological outcomes have been used. For instance, progression-free survival (PFS) is a useful endpoint to evaluate the benefit of sequential treatments, since it is not influenced by post-progression treatments, unlike OS. Moreover, radiological endpoints such as time to progression (TTP) and objective response rate (ORR) are frequently adopted. Nevertheless, the surrogacy between these endpoints and OS in the setting of unresectable HCC (uHCC) remains uncertain. Since most of the surrogate endpoints are radiology-based (e.g., PFS, TTP, ORR), the use of standardised tools is crucial for the evaluation of radiological response. The optimal way to assess the radiological response has been widely debated, and many criteria have been proposed over the years. Furthermore, none of the criteria have been validated for immunotherapy in advanced HCC. The coexistence of the underlying chronic liver disease and the access to several lines of treatments highlight the urgent need to capture early clinical benefit and the need for standardised radiological criteria to assess cancer response when using ICIs in mono- or combination therapies. Here, we review the most commonly used clinical and radiological endpoints for trial design, as well as their surrogacy with OS. We also review the criteria for radiological response to treatments for HCC, analysing the major issues and the potential future perspectives.

941P PET-derived parameters for response assessment in neoadjuvant atezolizumab: A secondary analysis of PRINCEPS phase II trial

Immune Checkpoint Blockade (ICB) is moving from metastatic to curative setting in different diseases including NSCLC. While for metastatic disease radiological endpoints are currently the standard surrogate marker of benefit from ICBs, based on RECIST or PERCIST criteria, in neoadjuvant setting they often underestimate the response and then pathological response (PR) criteria were developed to evaluate Major PR (MPR), defined as ≤10% viable tumor cells after neoadjuvant treatment, and PR, defined as less than 50% residual tumor cells.

Abstract IA17: Assessing response and time-to-event end-points: RECIST and mRECIST

Abstract In 2010, modified RECIST (mRECIST) criteria were proposed as a way of adapting the RECIST criteria to the particularities of hepatocellular carcinoma (HCC). mRECIST was intended to overcome some limitations of RECIST in measuring tumour shrinkage with local and systemic therapies, and also to refine the assessment of progression that could be misinterpreted with conventional RECIST 1.1, due to clinical events related to the natural progression of chronic liver disease. mRECIST has served its purpose since being adopted or included in clinical practice guidelines (European, American and Asian) for the management of HCC; it has also been instrumental for assessing response and time-to-event endpoints in several phase II and III investigations. Nowadays, mRECIST has become the standard tool for measurement of radiological endpoints at early/intermediate stages of HCC. At advanced stages, guidelines recommend both methods. mRECIST has been proven to capture higher objective response rates in tumours treated with molecular therapies and those responses have shown to be independently associated with better survival. With the advent of novel treatment approaches including immunotherapy combination therapies, there is a need to further refine and clarify some concepts around the performance of mRECIST. Citation Format: Riccardo Lencioni. Assessing response and time-to-event end-points: RECIST and mRECIST [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA17.

REGOMAIN: A randomized, placebo-controlled, double-blinded, multicenter, comparative phase II study of the efficacy of regorafenib as maintenance treatment in patients (pts) with high-grade bone sarcomas (HGBS) at diagnosis or relapse and without complete remission after standard treatment.

TPS11585 Background: Primary metastatic osteosarcoma (OS) patients are treated with a curative intent following the same principles of non-metastatic OS, while the treatment of recurrent OS is primarily surgical in the case of isolated lung metastases. When complete removal of all metastases cannot be achieved, the prognosis remains poor, with a median Progression-Free Survival (PFS) between 3 to 8 months, and therefore there is a clinical need to reduce the risk of progression after the initial treatment sequence. The REGOBONE study reported a significant PFS benefit of regorafenib (REG) compared to placebo (in osteosarcomas: median PFS: 16.4 versus 4.1 weeks) and a manageable safety profile in patients with histologically confirmed HGBS (i.e., osteosarcoma or other bone sarcomas with the exception of Ewing sarcomas, chondrosarcoma and chordoma). Methods: This multicenter trial is ongoing to study the efficacy and safety of maintenance REG in pts &gt; = 16 years old with HGBS, without complete remission but with no progressive disease after standard treatment, either at diagnosis or at relapse. Sixty pts will be randomly allocated in a 1:1 ratio to receive either oral REG at a daily dose of 120mg or its matching placebo, continuously for a maximum of 12 months. Randomization is stratified according to the setting of the disease: initial diagnosis versus relapse. The primary objective is to compare the efficacy (PFS) between the 2 arms. The expected 4-month PFS rates are 30% in the control arm and 60% in the REGO arm (HR = 0.42). Fifty-two events will provide 87% power to show significant improvement in PFS, using a 2-sided log-rank test at a 5% level. Secondary endpoints include Overall Response Rate (ORR), Disease Control Rate (DCR), Time to Treatment Failure (TTF), Overall Survival (OS), Quality of Life (QoL), and safety profile. Radiological endpoints will be evaluated using the RECIST 1.1 with tumor assessments every 2 months (first 6 months) and then every 3 months. Translational objectives will identify predictive biomarkers for efficacy of REG as maintenance therapy. Pts of the control arm who experience disease progression may switch to receive open label REG. As of Feb 1st, 2022, 3 patients have been randomized. 14 sites of the French Sarcoma Group will participate. An amendment is being implemented to lower the age limit (12 years old) and to expand tumor types to other HGBS (Ewing sarcomas, chondrosarcomas, Undifferentiated Pleomorphic Sarcomas, Leiomyosarcomas and angiosarcomas). Clinical trial information: NCT04698785.

Prognostic and predictive impact of circulating tumor DNA in advanced gastric cancer treated with immune checkpoint blockade.

e16019 Background: The utility of circulating tumor DNA (ctDNA) as a biomarker in patients with advanced gastric cancer (GC) receiving immune checkpoint blockade (ICB) is uncertain. Methods: Blood samples from advanced GC patients who received ICB were collected. The next-generation sequencing(NGS)–based targeted 733-gene and 61-gene panels (3D Medicines Inc.) were used to characterize somatic genomic alterations for baseline and on-treatment blood samples (4-12 weeks) respectively. For each sample, somatic single-nucleotide variants (SNV) and insertion/deletion mutations (indels) were used to calculate the mean variant allele frequency (VAF) and total mutation count. A VAF of 0.1% was the limit of detection, with the exception of variants detected in both pretreatment and on-treatment samples such that variants with VAF &lt; 0.1% in one sample were retained if the exact variant was also detected in the paired sample with VAF ≥0.1%. The variant genes at baseline were filtered against 61-genes panel list for calculating paired-baseline-VAF. The delta-VAF was calculated per patient as the sum of the on-treatment VAF minus the paired-baseline-VAF for each detected SNV or indels divided by the number of detected SNVs or indels. The percentage of molecular response was calculated per patient as delta-VAF divided by paired-baseline-VAF. Results: A total of 16 patients were was enrolled. The detection rate was 93.8% (15/16). The median total mutation count and baseline-VAF were 8 (range 0-44) and 3.13% (range 0-40.4%) respectively. The patients with top 50% baseline-VAF had shorter median PFS, compared to that with bottom 50% baseline-VAF (2.55 vs 4.85 months, p = 0.022, HR 2.98, 95%CI: 0.96-9.26). For baseline blood samples (N = 16), the median total mutation count and paired-baseline-VAF was 4 and 3.89% (range 0-40.4%) respectively. For on-treatment blood samples (N = 10), the median total mutation count and VAF were 3 (range 1-12) and 5.94% (0.30-37.12%) respectively. All the patients with progressive disease (PD, N = 6) have increased delta-VAF and all patients with stable disease (SD, N = 3) or partial response (PR, N = 1) have decreased delta-VAF. The median delta-VAF for PR, SD and PD were was -6.73%, -2.13% and 3.95% respectively. Compared with paired-baseline and on-treatment-VAF, the median percentage of molecular response for PR, SD and PD were -95.53%, -47.66% (range 7.08%-59.07%) and 138.73% (range 66.40%-347.18%). Compared with patients with increased VAF during treatment, the patients with decreased VAF have longer PFS (median 3.9 vs 1.75 months, p 0.004, HR, 0.24, 95%CI 0.06 to 0.97). Conclusions: This preliminary analysis contributes to understanding the role of ctDNA as a prognostic and predictive biomarker and its potential to complement radiologic endpoints. Further studies are warranted in larger cohort to confirm such observations for better management of GC.

Association of Clinical Signs, Host Biomarkers and Etiology With Radiological Pneumonia in Bhutanese Children.

Diagnosing pneumonia and identifying those requiring antibiotherapy remain challenging. Chest radiographs (CXR) are often used as the reference standard. We aimed to describe clinical characteristics, host-response biomarkers and etiology, and assess their relationship to CXR findings in children with pneumonia in Thimphu, Bhutan. Children between 2 and 59 months hospitalized with WHO-defined pneumonia were prospectively enrolled and classified into radiological endpoint and non-endpoint pneumonia. Blood and nasopharyngeal washing were collected for microbiological analyses and plasma levels of 11 host-response biomarkers were measured. Among 149 children with readable CXR, 39 (26.2%) presented with endpoint pneumonia. Identification of respiratory viruses was common, with no significant differences by radiological outcomes. No clinical sign was suggestive of radiological pneumonia, but children with radiological pneumonia presented higher erythrocyte sedimentation rate, C-reactive protein and procalcitonin. Markers of endothelial and immune activation had little accuracy for the reliable identification of radiological pneumonia.

Intraplaque CTA characteristics as predictors of symptomatology: a semiautomated volumetric analysis.

Prior studies comparing CT characteristics of carotid plaques to symptomatology have relied on gross morphologic imaging features. This study sought to determine if volumetric measurements of carotid plaque components are associated with ipsilateral neurologic symptoms. CTA images of consecutive patients that underwent a carotid endarterectomy were reviewed with a semiautomated software package. Intraplaque volumes of intraplaque hemorrhage (IPH), lipid-rich necrotic core (LRNC), and matrix were computed, as was the degree of arterial stenosis. Statistics were analyzed on a per cerebral hemisphere basis, and dichotomized into symptomatic and asymptomatic. Clinical and radiological endpoints included transient ischemic attack (TIA), ischemic stroke diagnosed on imaging studies, ophthalmologically diagnosed central or branch retinal artery occlusion (RAO), or amaurosis fugax. One hundred sixty-eight carotid plaques were reviewed. The average age is 70.8years (SD = 8.8); 32/87 (36.8%) were female. Sixty-seven of eighty-seven (77.0%) patients were symptomatic. Sixty-six of one hundred sixty-eight (39.3%) plaques were ipsilateral to the patient's symptoms, while 102/168 (60.7%) were ipsilateral to an asymptomatic hemisphere. Greater intraplaque volumes of IPH (p = 0.03), LRNC (p = 0.008), and matrix (p = 0.0008) were associated with symptoms, as was greater proportion of LRNC in regard to plaque volume (p = 0.04). All but proportion of LRNC remained statistically significant after adjustment for plaque size. More severe luminal stenosis was also associated with ipsilateral neurologic symptoms, both when calculated by smallest diameter or by area (p < 0.0001 for both). Higher volumes of intraplaque IPH, LRNC, matrix, and degree of arterial stenosis are associated with ipsilateral neurologic symptoms. Greater intraplaque proportions of LRNC are also associated with ipsilateral ischemic manifestations, suggesting that larger relative composition of lipids may be particularly predictive of symptomatology.

REGOSTA: A randomized, placebo-controlled, double-blinded, multicenter study evaluating the efficacy and safety of regorafenib (REGO) as maintenance therapy after first-line treatment in patients (pts) with osteosarcoma (OS) and non-osteosarcomas (non-OS) of bone (non-Ewing, non-chondrosarcomas and non-chordomas).

TPS11576 Background: Pts with OS and non-OS of bone are treated with a multimodal sequence therapy of neoadjuvant chemotherapy (CT), surgery and adjuvant CT, followed by a close surveillance until recurrence. At recurrence, the prognosis remains poor with objective response rates of 3-29%, and a median Progression-Free Survival (PFS) of less than 4 months in OS. There is a clinical need to reduce the risk of recurrence after the initial treatment sequence. The REGOBONE study reported a significant clinical benefit of regorafenib compared to placebo in patients with relapsed OS (median PFS: 16.4 versus 4.1 weeks). Methods: This multicenter trial is ongoing to study the efficacy and safety of maintenance REGO in pts &gt; = 16 years, with complete remission after initial treatment sequence of their bone sarcoma. 168 pts will be randomly allocated in a 1:1 ratio to receive either oral REGO or its matching placebo (control arm) at a daily dose of 120mg, continuously and for a maximum of 12 months. Randomization will be stratified according to the following risk factors: metastases (mets) at diagnosis and/or poor response to neoadjuvant CT versus no mets at diagnosis and good response to neoadjuvant CT. The primary objective is to compare the efficacy (Relapse-Free Survival) between the 2 arms. The expected 3-year RFS rates are 55% in the control arm and 74.6% in the REGO arm (HR = 0.5). 66 events will provide 80% power to show significant improvement in RFS, using a 2-sided log-rank test at a 5% level. Secondary endpoints include Time to Treatment Failure, Overall Survival, Quality of Life, safety profile, and compliance to treatment. Radiological endpoints will be evaluated using the RECIST 1.1. Translational objectives will be to identify predictive biomarkers for efficacy of REGO as maintenance therapy using liquid biopsies. As of Feb 1st, 2021, 3 patients have been randomized. 15 sites of the French Sarcoma Group will participate. Clinical trial information: NCT04055220.

Are radiological endpoints surrogate outcomes of overall survival in hepatocellular carcinoma treated with transarterial chemoembolization?

Time to progression (TTP) and progression-free survival (PFS) are commonly used as surrogate endpoints in oncology trials. We aimed to assess the surrogacy relationship of TTP and PFS with overall survival (OS) in studies of transarterial chemoembolization (TACE) for unresectable hepatocellular carcinoma (u-HCC) by innovative methods. A search of databases for studies of TACE for u-HCC reporting both OS and TTP or PFS was performed. Individual patient data were extracted from TTP/PFS and OS Kaplan-Meier curves of TACE arms. Pooled median TTP and OS were obtained from random-effect model. The surrogate relationships of hazard ratios (HRs) and median TTP for OS were evaluated by the coefficient of determination R2 . We identified 13 studies comparing TACE vs systemic therapy or vs TACE plus systemic therapy and including 1932 TACE-treated patients. Pooled median OS was 11.2months (95% confidence interval [95%CI] 7.9-17.8), and pooled median TTP was 5.4months (95%CI 3.8-8.0). Heterogeneity among studies was highly significant for both outcomes. The correlation between HR TTP and HR OS was moderate (R2 =0.65. 95%CI 0.08-0.81). R2 value was 0.04 (95%CI 0.00-0.35) between median TTP and median OS. In studies of TACE for u-HCC, the surrogate relationship of radiology-based endpoints with OS is moderate. Multiple endpoints including hepatic decompensation, macrovascular invasion and extrahepatic spread are needed for future trials comparing systemic therapies or combination of TACE with systemic therapies vs TACE alone.

Endpoints for Perianal Crohn's Disease Trials: Past, Present and Future.

Since the 1980s, many studies have evaluated the efficacy of therapies to improve the outcomes of patients with perianal Crohn's disease. We performed a systematic review to describe the evolution of endpoints in perianal fistulizing Crohn's disease. Efficacy outcomes, definitions and measurement tools were assessed. Electronic databases were searched up to November 1, 2020. All published randomized placebo-controlled trials enrolling patients with perianal fistula and Crohn's disease were eligible for inclusion. Ongoing randomized clinical trials were also described. Nineteen randomized controlled trials were included. Clinical efficacy endpoints were reported in all trials. Clinical response was the most frequent primary endpoint [6/19 studies, 31.6%], followed by clinical remission in four studies [21%]. Clinical response was defined as closure of at least 50% of fistulas, while remission was defined as closure of all fistulas. A combined clinical and radiological primary endpoint was used to assess fistula healing in four studies [21%]. The Perianal Disease Activity Index was a primary endpoint in only one study [5.5%]. In addition, eight ongoing controlled trials were identified. Combined clinical and radiological remission was the most frequent primary endpoint in these studies [4/8, 50%]. In this systematic review, significant changes in outcomes used in randomized clinical trials of perianal Crohn's disease were observed. Radiological endpoints are increasingly used in perianal fistulizing Crohn's disease trials.

Early obliteration of pediatric brain arteriovenous malformations after stereotactic radiosurgery: an international multicenter study.

Stereotactic radiosurgery (SRS) is a treatment option for pediatric brain arteriovenous malformations (AVMs), and early obliteration could encourage SRS utilization for a subset of particularly radiosensitive lesions. The objective of this study was to determine predictors of early obliteration after SRS for pediatric AVMs. The authors performed a retrospective review of the International Radiosurgery Research Foundation AVM database. Obliterated pediatric AVMs were sorted into early (obliteration ≤ 24 months after SRS) and late (obliteration > 24 months after SRS) responders. Predictors of early obliteration were identified, and the outcomes of each group were compared. The overall study cohort was composed of 345 pediatric patients with obliterated AVMs. The early and late obliteration cohorts were made up of 95 (28%) and 250 (72%) patients, respectively. Independent predictors of early obliteration were female sex, a single SRS treatment, a higher margin dose, a higher isodose line, a deep AVM location, and a smaller AVM volume. The crude rate of post-SRS hemorrhage was 50% lower in the early (3.2%) than in the late (6.4%) obliteration cohorts, but this difference was not statistically significant (p = 0.248). The other outcomes of the early versus late obliteration cohorts were similar, with respect to symptomatic radiation-induced changes (RICs), cyst formation, and tumor formation. Approximately one-quarter of pediatric AVMs that become obliterated after SRS will achieve this radiological endpoint within 24 months of initial SRS. The authors identified multiple factors associated with early obliteration, which may aid in prognostication and management. The overall risks of delayed hemorrhage, RICs, cyst formation, and tumor formation were not statistically different in patients with early versus late obliteration.