Radiological Review Research Articles

Beyond schwannomas and neurofibromas: a radiological and histopathological review of lesser-known benign lesions that arise in association with peripheral nerves.

Peripheral nerve sheath tumors comprise a significant percentage of both benign and malignant soft tissue tumors. The vast majority of these lesions are schwannomas and neurofibromas, which most radiologists are familiar with including the well-described multimodality imaging features. However, numerous additional often under-recognized benign entities associated with nerves exist. These rarer entities are becoming increasingly encountered with the proliferation of cross-sectional imaging, particularly magnetic resonance imaging (MRI). It is important for the radiologist to have a basic understanding of these entities as many have near-pathognomonic MR imaging features as well as specific clinical presentations that when interpreted in concert, often allows for a limited differential or single best diagnosis. The ability to provide a prospective, pre-intervention diagnosis based solely on imaging and clinical presentation is crucial as several of these entities are "do not touch" lesions, for which even a biopsy may have deleterious consequences. To our knowledge, the majority of these benign entities associated with nerves have only been described in scattered case reports or small case series. Therefore, the aim of this article is to provide a radiopathologic comprehensive review of these benign entities that arise in association with nerves with a focus on characteristic MRI features, unique histopathologic findings, and entity specific clinical exam findings/presentation.

Serplulimab, a novel anti-PD-1 antibody, in patients with microsatellite instability-high solid tumours: an open-label, single-arm, multicentre, phase II trial

BackgroundMicrosatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) tumours have a high response rate to immunotherapy. Antitumour activity and safety of serplulimab, a novel humanised anti-PD-1 monoclonal antibody, were evaluated in this phase II study.MethodsIn this ongoing, single-arm, open-label, phase II trial, patients with previously treated unresectable or metastatic MSI-H/dMMR solid tumours received intravenous serplulimab 3 mg/kg every 2 weeks for up to 52 cycles. The primary endpoint was objective response rate (ORR) assessed by an independent radiological review committee per Response Evaluation Criteria in Solid Tumors v1.1. Secondary endpoints included additional efficacy measures, safety, and tolerability.ResultsAs of 9 January 2021, 108 patients were enrolled, and 68 patients with confirmed MSI-H solid tumours were included in the main efficacy analysis population (MEAP). The median follow-up duration in the MEAP was 7.7 months, with an ORR of 38.2% (95% confidence interval, 26.7–50.8). Of the 108 patients, grade ≥3 treatment-emergent adverse events were reported in 53 (49.1%) patients; immune-related adverse events occurred in 52 (48.1%) patients.ConclusionsSerplulimab demonstrates a durable antitumour effect and a manageable safety profile in previously treated patients with MSI-H solid tumours. Serplulimab is a promising tissue-agnostic treatment for previously treated MSI-H solid tumours.Trial registrationNCT03941574.

Usefulness of central radiologic review in clinical trials of children with hepatoblastoma.

No previous research papers have reported a comparative survey of local radiologic diagnoses and central review in children with hepatoblastoma. To evaluate the utility of central review of children with hepatoblastoma enrolled in a clinical trial. The study included 91 children enrolled in a clinical trial conducted by the Japanese Study Group for Pediatric Liver Tumor. We compared the results of the initial pre-treatment extent of tumor (PRETEXT) disease staging performed at local sites with the results obtained on central review to determine the concurrence rates for tumor staging and additional criteria. The concurrence rate for PRETEXT staging was 70%. As the stage increased, the concurrence rate decreased. Using additional criteria, central review identified 143 lesions (157.1%), about 1.8 times higher than the number identified for the local site diagnoses. The additional criterion found most often on central review was "multifocal lesion" (n=19). The concurrence rate for lung metastases was high. However, our central review found many false-positive assertions of hepatic vein lesions, portal vein invasion and extrahepatic lesions among the local site diagnoses. In a clinical trial of hepatoblastoma, central review provided a more precise diagnosis than local site diagnoses with respect to severe PRETEXT stages III and IV cases and other cases including hepatic and portal vein invasion. The central review process appears to be effective and essential for improving the quality of clinical trials.

P-017 A FRAMEWORK FOR MULTIDISCIPLINARY TEAM MANAGEMENT OF ABDOMINAL WALL RECONSTRUCTION

Abstract Aim Incisional hernias are common and can significantly impact a patient's quality of life. Traditionally, abdominal wall reconstruction (AWR) has been performed by general surgeons, or those with special interest, often working in isolation. However, there is increasing awareness of pre-optimisation, risk stratification, enhanced training, and personalising treatment using a wide range of techniques. Methods & Results For complex and higher-risk procedures, Multidisciplinary team (MDT) management is considered the standard of care for optimising outcomes. The lack of standardised protocols and clear evidence in AWR means that surgical management can vary greatly. This makes the MDT process even more important due to the complexity of the decision-making involved. We describe a successful MDT process for complex abdominal wall reconstruction at a tertiary referral centre. Patients are reviewed at weekly AWR meetings with a multidisciplinary team, which includes consultants, advanced clinical practitioners and trainees. This is an opportunity for objective risk stratification, radiological review and assessment of the patient's goals before preoptimization and operative planning. Prospective data is collected on all patients to allow for quality improvement and service development. Conclusion MDT management of abdominal wall hernia is gaining popularity but remains poorly established in most regions. The involvement of surgical colleagues and other specialists is crucial in developing this growing field of surgery. We hope to expand our team to include Radiologists and Nutritionists, with the possibility of extending to regional networks, as we continue to explore new techniques and methods in managing complex abdominal wall hernias.

Academic patterns of practice regarding CT simulation scans and radiology review

ObjectiveCurrently, there are no consensus guidelines about handling incidental radiological findings on radiotherapy planning CT simulation scans. Retrospective studies analyzing incidental findings on CT simulations show a small, but not insignificant, rate of both oncologic and non-oncologic findings. These findings may have medico-legal, financial, and clinical implications. Given a lack of guidelines, we obtained a formal survey of multiple academic institutions to evaluate how CT simulations are handled in regard to incidental findings. MethodsA formal survey was developed consisting of 12 questions related to institutional practices regarding CT simulation scans. From 7/18/21 to 8/27/21 and 5/6/22 to 5/24/22, the survey was administered electronically by REDCap to key personnel at Academic Radiation Oncology Programs identified through the American Society for Radiation Oncology (ASTRO) with inclusion criteria including an active ACGME approved Radiation Oncology residency program. ResultsIn total, 88 academic radiation oncology programs were surveyed with total of 45 responses (51%). 1 out of 45 departments who responded has formal guidelines regarding workup of incidental findings. There is variability about sending CT simulation scans for official radiology review if an incidental finding is identified. ConclusionsBased on a measurable rate of incidental findings on radiotherapy planning CT simulations and their possible implications, our survey illustrates a likely need for consensus recommendations for handling such findings to improve patient care and safety.

MM-188 Depth of Response of Isatuximab plus Carfilzomib and Dexamethasone in Relapsed Multiple Myeloma: IKEMA Updated Analysis

Achieving minimal residual disease negativity (MRD-) in MM is associated with improved survival. Isatuximab (Isa) plus carfilzomib (K) and dexamethasone (d) is approved for relapsed MM patients after ≥1 prior therapy, based on IKEMA interim analysis (NCT03275285). Report updated, longer-term depth of response (DoR) results from IKEMA, including MRD-status. IKEMA, a randomized, open-label, multicenter Phase 3 study, investigates Isa-Kd (n=179) versus Kd (n=123) in relapsed MM patients with 1-3 prior lines of therapy. IV Isa 10 mg/kg was given QW for 4 weeks, followed by Q2W. Both arms received an approved schedule of K (IV) and d (oral/IV). This prespecified analysis evaluated PFS (primary endpoint) at 159 events; secondary endpoints were ≥CR (+stringent CR), MRD-, and ≥CR+MRD-rates, as determined by IRC based on central laboratory data and review of local radiology. MRD status was assessed by NGS (sensitivity threshold ≥10-5) in bone marrow aspirates from patients achieving ≥VGPR. HYDRASHIFT Isa immunofixation (IFE) test, removing Isa interference in IFE, was used to update ≥CR rate. Secondary endpoints were compared between treatment arms using Cochran-Mantel-Haenszel test. One-sided descriptive P-values were provided. All randomized patients not reaching MRD- or without MRD assessment were considered MRD+. At cutoff (14-Jan-2022), with a median follow-up of 44 months, deeper responses were observed in Isa-Kd versus Kd, ≥CR rates 44.1% versus 28.5% (OR: 2.09; 95%CI=1.26-3.48; descriptive P=0.0021). For Isa-Kd versus Kd patients, MRD- (10-5) occurred in 33.5% versus 15.4% (OR: 2.78; 95%CI=1.55-4.99; descriptive P=0.0002), with 26.3% versus 12.2% reaching ≥CR+MRD- (10-5; OR: 2.57; 95%CI=1.35-4.88; P=0.0015); MRD- at 10-6 sensitivity occurred in 10.6% versus 3.3%. MRD- versus MRD+ patients (10-5) had longer mPFS (months); Isa-Kd: not calculable ([NC]; 95%CI=NC-NC) versus 21.7 (95%CI=16.4-27.1); Kd: NC (95%CI=29.2-NC) versus 16.2 (95%CI=13.4-19.5). These results demonstrate clinically meaningful improvement in DoR with Isa-Kd versus Kd. Impressive ≥CR and ≥CR+MRD- (10-5) rates in Isa-Kd versus Kd are the highest reported for proteasome inhibitor-based regimens in relapsed MM. Achieving MRD- led to better outcomes in both arms; Isa-Kd patients had >2-fold higher likelihood of achieving MRD-. Additionally, Isa improved outcomes of MRD+ patients.

A Comprehensive Radiologic Review of Shoulder Girdle Trauma.

Radiologic knowledge of different fracture patterns involving the shoulder girdle is an important tool to generate clinically relevant reports, identify concomitant injuries, guide management decisions, and predict and minimize complications, such as nonunion, osteoarthritis, osteonecrosis, and hardware failure. Complex unstable injuries like scapulothoracic dissociation can also occur because of shoulder girdle trauma. Management options may vary from conservative to surgical, depending on the fracture type and patient factors. Injuries around the shoulder girdle can involve the glenohumeral articulation, scapula, superior shoulder suspensory complex, acromioclavicular joints, and scapulothoracic articulation.

Augmentation of literature review of COVID-19 radiology.

We suggest an augmentation of the excellent comprehensive review article titled “Comprehensive literature review on the radiographic findings, imaging modalities, and the role of radiology in the coronavirus disease 2019 (COVID-19) pandemic” under the following categories: (1) “Inclusion of additional radiological features, related to pulmonary infarcts and to COVID-19 pneumonia”; (2) “Amplified discussion of cardiovascular COVID-19 manifestations and the role of cardiac magnetic resonance imaging in monitoring and prognosis”; (3) “Imaging findings related to fluorodeoxyglucose positron emission tomography, optical, thermal and other imaging modalities/devices, including ‘intelligent edge’ and other remote monitoring devices”; (4) “Artificial intelligence in COVID-19 imaging”; (5) “Additional annotations to the radiological images in the manuscript to illustrate the additional signs discussed”; and (6) “A minor correction to a passage on pulmonary destruction”.

Automated Brain Metastases Segmentation With a Deep Dive Into False-positive Detection

PurposeThe clinical management of brain metastases after stereotactic radiosurgery (SRS) is difficult, because a physician must review follow-up magnetic resonance imaging (MRI) scans to determine treatment outcome, which is often labor intensive. The purpose of this study was to develop an automated framework to contour brain metastases in MRI to help treatment planning for SRS and understand its limitations. Methods and MaterialsTwo self-adaptive nnU-Net models trained on postcontrast 3-dimensional T1-weighted MRI scans from patients who underwent SRS were analyzed. Performance was evaluated by computing positive predictive value (PPV), sensitivity, and Dice similarity coefficient (DSC). The training and testing sets included 3482 metastases on 845 patient MRI scans and 930 metastases on 206 patient MRI scans, respectively. ResultsIn the per-patient analysis, PPV was 90.1% ± 17.7%, sensitivity 88.4% ± 18.0%, DSC 82.2% ± 9.5%, and false positive (FP) 0.4 ± 1.0. For large metastases (≥6 mm), the per-patient PPV was 95.6% ± 17.5%, sensitivity 94.5% ± 18.1%, DSC 86.8% ± 7.5%, and FP 0.1 ± 0.4. The quality of autosegmented true-positive (TP) contours was also assessed by 2 physicians using a 5-point scale for clinical acceptability. Seventy-five percent of contours were assigned scores of 4 or 5, which shows that contours could be used as-is in clinical application, and the remaining 25% were assigned a score of 3, which means they needed minor editing only. Notably, a deep dive into FPs indicated that 9% were TP metastases not identified on the original radiology review, but identified on subsequent follow-up imaging (early detection). Fifty-four percent were real metastases (TP) that were identified but purposefully not contoured for target treatment, mainly because the patient underwent whole-brain radiation therapy before/after SRS treatment. ConclusionsThese findings show that our tool can help radiologists and radiation oncologists detect and contour tumors from MRI, make precise decisions about suspicious lesions, and potentially find lesions at early stages.

Effect of First-Line Serplulimab vs Placebo Added to Chemotherapy on Survival in Patients With Extensive-Stage Small Cell Lung Cancer

Programmed cell death ligand 1 inhibitors combined with chemotherapy has changed the approach to first-line treatment in patients with extensive-stage small cell lung cancer (SCLC). It remained unknown whether adding a programmed cell death 1 (PD-1) inhibitor to chemotherapy provided similar or better benefits in patients with extensive-stage SCLC, which would add evidence on the efficacy of checkpoint inhibitors in the treatment of extensive-stage SCLC. To evaluate the efficacy and adverse event profile of the PD-1 inhibitor serplulimab plus chemotherapy compared with placebo plus chemotherapy as first-line treatment in patients with extensive-stage SCLC. This international, double-blind, phase 3 randomized clinical trial (ASTRUM-005) enrolled patients at 114 hospital sites in 6 countries between September 12, 2019, and April 27, 2021. Of 894 patients who were screened, 585 with extensive-stage SCLC who had not previously received systemic therapy were randomized. Patients were followed up through October 22, 2021. Patients were randomized 2:1 to receive either 4.5 mg/kg of serplulimab (n = 389) or placebo (n = 196) intravenously every 3 weeks. All patients received intravenous carboplatin and etoposide every 3 weeks for up to 12 weeks. The primary outcome was overall survival (prespecified significance threshold at the interim analysis, 2-sided P < .012). There were 13 secondary outcomes, including progression-free survival and adverse events. Among the 585 patients who were randomized (mean age, 61.1 [SD, 8.67] years; 104 [17.8%] women), 246 (42.1%) completed the trial and 465 (79.5%) discontinued study treatment. All patients received study treatment and were included in the primary analyses. As of the data cutoff (October 22, 2021) for this interim analysis, the median duration of follow-up was 12.3 months (range, 0.2-24.8 months). The median overall survival was significantly longer in the serplulimab group (15.4 months [95% CI, 13.3 months-not evaluable]) than in the placebo group (10.9 months [95% CI, 10.0-14.3 months]) (hazard ratio, 0.63 [95% CI, 0.49-0.82]; P < .001). The median progression-free survival (assessed by an independent radiology review committee) also was longer in the serplulimab group (5.7 months [95% CI, 5.5-6.9 months]) than in the placebo group (4.3 months [95% CI, 4.2-4.5 months]) (hazard ratio, 0.48 [95% CI, 0.38-0.59]). Treatment-related adverse events that were grade 3 or higher occurred in 129 patients (33.2%) in the serplulimab group and in 54 patients (27.6%) in the placebo group. Among patients with previously untreated extensive-stage SCLC, serplulimab plus chemotherapy significantly improved overall survival compared with chemotherapy alone, supporting the use of serplulimab plus chemotherapy as the first-line treatment for this patient population. ClinicalTrials.gov Identifier: NCT04063163.

Overall survival and objective response in advanced unresectable hepatocellular carcinoma: A subanalysis of the REFLECT study

Validated surrogate endpoints for overall survival (OS) are important for expediting the clinical study and drug-development processes. Herein, we aimed to validate objective response as an independent predictor of OS in individuals with unresectable hepatocellular carcinoma (HCC) receiving systemic anti-angiogenic therapy. We investigated the association between objective response (investigator-assessed mRECIST, independent radiologic review [IRR] mRECIST and RECIST v1.1) and OS in REFLECT, a phase III study of lenvatinib vs. sorafenib. We conducted landmark analyses (Simon-Makuch) of OS by objective response at 2, 4, and 6 months after randomization. Median OS was 21.6 months (95% CI 18.6-24.5) for responders (investigator-assessed mRECIST) vs. 11.9 months (95% CI 10.7-12.8) for non-responders (hazard ratio [HR] 0.61; 95% CI 0.49-0.76; p<0.001). Objective response by IRR per mRECIST and RECIST v1.1 supported the association with OS (HR 0.61; 95% CI 0.51-0.72; p<0.001 and HR 0.50; 95% CI 0.39-0.65; p<0.001, respectively). OS was significantly prolonged for responders vs. non-responders (investigator-assessed mRECIST) at the 2-month (HR 0.61; 95% CI 0.49-0.76; p<0.001), 4-month (HR 0.63; 95% CI 0.51-0.80; p<0.001), and 6-month (HR 0.68; 95% CI 0.54-0.86; p<0.001) landmarks. Results were similar when assessed by IRR, with both mRECIST and RECIST v1.1. An exploratory multivariate Cox regression analysis identified objective response by investigator-assessed mRECIST (HR 0.55; 95% CI 0.44-0.68; p<0.0001) and IRR-assessed RECIST v1.1 (HR 0.49; 95% CI, 0.38-0.64; p <0.0001) as independent predictors of OS in individuals with unresectable HCC. Objective response was an independent predictor of OS in individuals with unresectable HCC in REFLECT; additional studies are needed to confirm surrogacy. Participants achieving a complete or partial response by mRECIST or RECIST v1.1 had significantly longer survival vs. those with stable/progressive/non-evaluable disease. NCT01761266. This analysis of data taken from a completed clinical trial (REFLECT) looked for any link between objective response and overall survival time in individuals with unresectable HCC receiving anti-angiogenic treatments. Significantly longer median overall survival was found for responders (21.6 months) vs. non-responders (11.9 months). Overall survival was also significantly longer for responders vs. non-responders (based on objective response status at 2, 4, and 6 months) in the landmark analysis. Our results indicate that objective response is an independent predictor of overall survival in this setting, confirming its validity as a rapid marker of efficacy that can be applied in phase II trials; however, further validation is required to determine is validity for other systemic treatments (e.g. immunotherapies), or as a surrogate of overall survival.

Posterior fossa ependymoma H3 K27-mutant: an integrated radiological and histomolecular tumor analysis

Posterior fossa group A ependymomas (EPN_PFA) are characterized by a loss of H3 K27 trimethylation due to either EZHIP overexpression or H3 p.K27M mutation, similar to H3 K27-altered diffuse midline gliomas (DMG), but in reverse proportions. Very little data is available in the literature concerning H3 K27M-mutant EPN_PFA. Here, we retrospectively studied a series of nine pediatric tumors initially diagnosed as H3 K27M-mutant EPN_PFA to compare them to EZHIP-overexpressing EPN_PFA in terms of radiology, follow-up, histopathology, and molecular biology (including DNA-methylation profiling). Seven tumors clustered within EPN_PFA by DNA-methylation analysis and t-distributed stochastic neighbor embedding. Among the two remaining cases, one was reclassified as a DMG and the last was unclassified. H3 K27M-mutant EPN_PFA cases were significantly older than their counterparts with an EZHIP overexpression. Radiological and histopathological central review of our seven H3 K27M-mutant EPN_PFA cases found them to be similar to their counterparts with an EZHIP overexpression. Sequencing analyses revealed HIST1H3B (n = 2), HIST1H3C (n = 2), H3F3A (n = 1), and HIST1H3D (n = 1) K27M mutations (no sequencing analysis available for the last case which was immunopositive for H3K27M). Consequently, HIST1H3C/D mutations are more frequently observed in EPN_PFA than in classic pontine DMG, H3K27-mutant. Overall survival and event-free survival of EZHIP-overexpressing and H3 K27M-mutant EPN_PFA were similar. After surgery and radiation therapy, 5/7 patients were alive at the end of the follow-up. In summary, the diagnosis of EPN_PFA must include tumor location, growth pattern, Olig2 expression, and DNA-methylation profiling before it can be differentiated from DMG, H3 K27-altered.

Development of a classifier for [18F]fluorodeoxyglucose extravasation severity using semi-quantitative readings from topically applied detectors

BackgroundRadiotracer extravasations, caused largely by faulty tracer injections, can occur in up to 23% of 18F-fluorodeoxyglucose (FDG) PET/CT scans and negatively impact radiological review and tracer quantification. Conventional radiological assessment of extravasation severity on PET has limited performance (e.g., extravasations frequently resolve before scanning) and practical drawbacks. In this study, we develop a new topical detector-based FDG extravasation severity classifier, calibrated from semi-quantitative PET measurements, and assess its performance on human subjects.MethodsA retrospective study examined patients whose FDG injections had been monitored as part of their standard workup for PET/CT imaging. Topical uncollimated gamma ray detectors were applied proximal to the injection site and on the same location on the opposing arm, and readings were acquired continuously during radiotracer uptake. Patients were imaged with their arms in the PET field of view and total extravasation activity quantified from static PET images through a volume of interest approach. The image-derived activities were considered ground truth and used to calibrate and assess quantification of topical detector readings extrapolated to the start of PET imaging. The classifier utilizes the calibrated detector readings to produce four extravasation severity classes: none, minor, moderate, and severe. In a blinded study, a radiologist qualitatively labeled PET images for extravasation severity using the same classifications. The radiologist’s interpretations and topical detector classifications were compared to the ground truth PET results.ResultsLinear regression of log-transformed image-derived versus topical detector tracer extravasation activity estimates showed a strong correlation (R2 = 0.75). A total of 24 subject scans were cross-validated with the quantitatively based classifier through a leave-one-out methodology. For binary classification (none vs. extravasated), the topical detector classifier had the highest overall diagnostic performance for identifying extravasations. Specificity, sensitivity, accuracy, and positive predictive value were 100.0%, 80.0%, 95.8%, and 100.0%, respectively, for the topical detector classifier and 31.6%, 100.0%, 45.8%, and 27.8%, respectively, for the radiological analysis. The topical detector classifier, with an optimal detection threshold, produced a significantly higher Matthews correlation coefficient (MCC) than the radiological analysis (0.87 vs. 0.30).ConclusionsThe topical detector binary classifier, calibrated using quantitative static PET measurements, significantly improves extravasation detection compared to qualitative image analysis.

A radiological index that influences the outcome following patellofemoral joint arthroplasty: the anterior trochlea offset ratio

PurposeAlthough largely successful, patellofemoral joint arthroplasty (PFA) has a less than satisfactory outcome in some patients. It was hypothesized that certain factors can be identified on radiological review that correlate with poor patient reported outcomes following PFA.MethodsA retrospective cohort review of 369 patients undergoing PFA at our institution between 2005 and 2018 identified 43 “poor outcome” patients with an Oxford Knee Score (OKS) of less than 20 at 2 years follow up. These cases were matched by sex and age with 43 “good outcome” patients who had an OKS above 40 at 2 years post-op. Multiple radiological measurements were performed including anterior trochlea offset ratio (ATOR), component flexion/extension, component varus/valgus, component to bone width ratio and retinacular index. The OKS PROM was the primary outcome of the study. Stepwise logistic regression was performed to analyze the differences in radiological indices between the two groups.ResultsIntraclass correlation coefficients for inter-observer and intra-observer reliability were 0.90–0.98 for all indices measured. The only index demonstrating statistical significance between the groups was the ATOR (p = 0.003). The good outcome group had a mean ATOR of 0.19 whereas the poor outcome group had a mean ATOR of 0.24.ConclusionsLower ATOR on radiological review was strongly associated with improved outcomes following PFA. The surgeon should therefore take particular care to prevent increasing the anterior offset of the trochlea component when performing PFA.Level of evidenceRetrospective cohort study, Level III.

Interval cancer audit and disclosure in breast screening programmes: An international survey.

Accurate monitoring of interval cancers is important both for quality improvement and education and is a key parameter of breast screening quality assurance. Issues in relation to communication regarding interval cervical cancer in the Irish cervical screening programme were found, prompting interval cancer process review in all cancer screening programmes. An international survey to examine international consensus on interval breast cancer audit processes was conducted to inform Irish processes. A survey of 24 international population-based breast screening programmes was done to determine which undertook audit of interval breast cancer; if yes, they were asked (1) how they undertake audit, (2) if they obtain individual consent for audit and inform women of audit results, and (3) if disclosure of audit results occurs. Response was 71% (17/24). Of these, 71% (12/17) have a programmatic audit process to calculate the interval cancer rate (ICR). Of these, ten also carry out radiological reviews, three using a blinded review. Two inform patients that audit is taking place; two provide choice to be in the audit; nine state that routine screening consent covers audit. For two of the five that have an open disclosure policy for medical incidents, this policy applies to screening interval cancers. One other country/region has an open disclosure policy for category 3 interval cancers only. Five have legal protection for interval cancers arising in the screened population. While consistency in providing aggregate programmatic audits exists, there is no consistent approach to individual interval cancer reviews or results disclosure.

891P Naxitamab treatment for relapsed or refractory high-risk neuroblastoma: Outcomes from the first prespecified analyses of the Pivotal 201 Trial

Naxitamab is a humanized GD2-binding monoclonal antibody approved in the US with GM-CSF for the treatment of relapsed/refractory high-risk neuroblastoma (HR-NB) in the bone/bone marrow (BM). This accelerated approval was based in part on an ad hoc analysis of data from the registrational phase II 201 trial (NCT03363373). Here we report the first results of a prespecified analysis from this same trial. Trial 201 is an ongoing phase II trial evaluating naxitamab+GM-CSF in patients with relapsed/refractory HR-NB with residual disease limited to bone/BM. Patients with progressive or residual soft tissue disease were not eligible. Naxitamab was administered over 30-60 min in the outpatient setting on Days 1/3/5 with GM-CSF on Days –4 to 5; cycles were 28 days. Efficacy was evaluated by independent pathology and radiology review per revised International Neuroblastoma Response Criteria. Assuming an actual overall response rate (ORR; complete response [CR] + partial response [PR]) of 45%, a sample size of 37 patients was considered sufficient to ensure ≥90% power to exclude an overall response rate of ≤20% at an α-level of 0.05. At data cutoff (Dec 31, 2021) there were 52 patients in the efficacy population and 74 in safety. The ORR was 50.0% (26/52; 95% CI 36-64%) with a CR rate of 38.5% (95% CI 25-53%). The trial met the primary endpoint for the prespecified analysis as the lower 95% CI for ORR was >20%. Disease control rate (CR+PR+minor response+stable disease) was 78.8% (41/52; 95% CI 65-89%) The adverse event (AE) profile was like previous reports with most being infusion-related reactions including hypotension and pain. 44.6% (33/74) of patients experienced ≥1 treatment-emergent serious AE; 6.8% (5/74) patients discontinued naxitamab due to treatment-emergent AEs. There were no deaths related to naxitamab. Based on this prespecified analysis, naxitamab provides a significant and clinically relevant response in patients with relapsed/refractory HR-NB limited to bone/BM – frequent sites of residual disease. These efficacy results combined with a manageable safety profile demonstrate that naxitamab addresses a significant unmet medical need.

546P Pembrolizumab for microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) advanced endometrial cancer: Long-term follow-up results from KEYNOTE-158

Pembrolizumab (pembro) previously demonstrated robust and durable antitumor activity in patients with MSI-H/dMMR advanced endometrial cancer in the open-label, multicohort, phase 2 KEYNOTE-158 study (NCT02628067). Here we report updated efficacy and safety outcomes with a substantially longer follow-up in the patients enrolled. This analysis included those patients with previously treated, MSI-H/dMMR advanced endometrial cancer enrolled in cohorts D (advanced endometrial cancer of any MSI/MMR status) and K (any MSI-H/dMMR advanced solid tumor, except colorectal) of KEYNOTE-158. MSI-H/dMMR status was determined retrospectively by PCR at a central lab in cohort D and prospectively by PCR and/or IHC at a local lab in cohort K. Patients received pembro 200 mg Q3W for up to 35 cycles. Primary endpoint was ORR per RECIST v1.1 by independent central radiologic review. Secondary endpoints included DOR, PFS, OS, and safety. 94 patients with previously treated MSI-H/dMMR advanced endometrial cancer were included in this analysis. Median time from first dose to data cutoff (Jan 12, 2022) was 54.5 (range, 14.7–71.4) mo. Efficacy results are shown in the Table. ORR was 50% (95% CI, 39.5%–60.5%); responses were seen across all prior treatment lines. 4-y DOR rate was 66% by K-M estimate. Median (95% CI) PFS and OS were 13.1 (4.3‒25.7) mo and 65.4 (29.5‒NR) mo; 4-y PFS and OS rates were 37% and 59%, respectively. Treatment-related AEs occurred in 71 patients (76%); 13 patients (14%) had grade 3‒4 treatment-related AEs (no grade 5).Table: 546PAnalysis population (n = 94)ORR, % (95% CI)50 (39.5–60.5) CR, n (%)15 (16) PR, n (%)32 (34) SD, n (%)17 (18)ORR by prior treatment line, % (95% CI)a Neo-adjuvant and/or adjuvant therapy only (n = 10)40 (12.2–73.8) 1 line (n = 39)59 (42.1–74.4) >1 line (n = 45)44 (29.6–60.0)DOR, median (range),b mo63.2 (2.9–63.2) DOR ≥1 y,b %87 DOR ≥2 y,b %71 DOR ≥3 y,b %66 DOR ≥4 y,b %66Median PFS (95% CI),b mo13.1 (4.3–25.7) 4-y PFS rate,b %37Median OS (95% CI),b mo65.4 (29.5–NR) 4-y OS rate,b %59K-M, Kaplan-Meier; NR, not reached. aPercentages are based on number of patients in each subgroup. bK-M estimate Open table in a new tab K-M, Kaplan-Meier; NR, not reached. aPercentages are based on number of patients in each subgroup. bK-M estimate These updated results reconfirm the robust and durable antitumor activity of pembro and show encouraging survival outcomes in patients with advanced endometrial carcinoma that is MSI-H/dMMR, who have PD following prior systemic therapy and are not candidates for curative surgery or radiation, supporting the use of pembro in this setting.

LBA8 Phase III study of cabozantinib (C) in combination with nivolumab (N) and ipilimumab (I) in previously untreated advanced renal cell carcinoma (aRCC) of IMDC intermediate or poor risk (COSMIC-313)

C inhibits tyrosine kinases including MET, VEGFR, and TAM kinases (TYRO3, AXL, MER) and promotes an immune-permissive environment, which may enhance response to checkpoint inhibitors. C+N and N+I are both standards of care for first-line aRCC (N+I for intermediate or poor risk). COSMIC-313 (NCT03937219) is evaluating C in combination with N+I vs N+I in previously untreated aRCC of intermediate or poor risk and is the first study to evaluate a triplet therapy against a contemporary immuno-oncology doublet control. This global, double-blind, randomized phase III study enrolled previously untreated patients (pts) with clear cell aRCC of IMDC intermediate or poor risk. Pts were randomized to receive C 40 mg QD or matched placebo (P), stratified by region and IMDC risk. Both treatment groups received N (3 mg/kg IV Q3W) + I (1 mg/kg IV Q3W) for 4 cycles followed by N (480 mg IV Q4W); N was administered up to 2 y. The primary endpoint was progression-free survival (PFS) by blinded independent radiology review per RECIST 1.1 in the first 550 randomized pts (PITT population). The secondary endpoint was overall survival (OS) in all randomized pts (ITT population); objective response rate (ORR) and safety were additional endpoints. From Jun 2019 to Mar 2021, 855 pts were randomized (428, C+N+I; 427, P+N+I); IMDC risk was intermediate for 75% and poor for 25%. The study met the primary PFS endpoint (HR 0.73, 95% CI, 0.57–0.94; p=0.013); median PFS was not reached (NR; 95% CI, 14.0–not estimable) for C+N+I vs 11.3 mo (95% CI, 7.7–18.2) for P+N+I. Prespecified PFS subgroup analyses will be presented. ORR (PITT population) was 43% (95% CI, 37.2–49.2) for C+N+I vs 36% (95% CI, 30.1–41.8) for P+N+I; median duration of response was NR in either treatment group. Grade 3/4 TRAEs occurred in 73% with C+N+I vs 41% with P+N+I; 3 pts (1%) in each arm had grade 5 TRAEs, and a TRAE led to discontinuation of all treatment components in 12% vs 5%. C+N+I significantly improved PFS vs P+N+I in previously untreated aRCC of IMDC intermediate or poor risk. Safety was consistent with the known profiles of the treatment components. Follow-up for OS is ongoing.

Epidemiological and clinical characteristics of congenital pseudarthrosis of the tibia in China

BackgroundCongenital pseudarthrosis of the tibia (CPT) is a refractory and rare disease. Because of its extremely low incidence, little is known about its clinical features. In this retrospective study, we aim to analyze the clinical characteristics of patients with CPT.Materials and methodsThis is a retrospective study of children with CPT identified by the radiological review. Investigations of CPT included general conditions, the characteristics of CPT, treatment methods, and surgical complications.ResultsWe collected 514 CPT cases from March 1999 to March 2020 in our hospital, such as 317 (61.67%) boys, 197 (38.33%) girls; 330 (62.86%) in Crawford IV; 510 (97.14%) in mid and distal 1/3 tibia; 481 (93.58%) in less than 3 years at onset age; 297 (57.78%) in less than 3 years at the first outpatient visit. The most common post-operative complication was ankle valgus (101, 39.60%), followed by limb length discrepancy (91, 35.69%), refracture (38, 14.90%), osteomyelitis (15, 5.88%), and removal of internal fixation (10, 3.93%).ConclusionsCPT with a higher incidence of Crawford IV frequently occurs in boys and the middle or distal part of the tibia; most patients have the onset age and first outpatient visit before 3 years; the major surgical complications are ankle valgus and limb length discrepancy.

Phase 1 Study of Chemoradiotherapy Combined with Nivolumab ± Ipilimumab for the Curative Treatment of Muscle-invasive Bladder Cancer

BackgroundMuscle-invasive bladder cancer (MIBC) has a poor prognosis. Chemoradiotherapy (CRT) in selected patients has comparable results to radical cystectomy. Results of neoadjuvant immune checkpoint inhibitors (ICIs) before radical cystectomy are promising. We hypothesize that ICI concurrent to CRT (iCRT) is safe and may improve treatment outcomes. ObjectiveTo determine the safety of iCRT for MIBC. Design, setting, and participantsThis multicenter, phase 1b, open-label, dose-escalation study determined the safety of CRT with three ICI regimens in patients with nonmetastatic (T2-4aN0-1) MIBC. Twenty-six patients received mitomycin C/capecitabine and 20 × 2.75 Gy to the bladder. Tolerability was evaluated in a cohort of up to ten patients. If two or fewer out of the first six patients or three or fewer of ten patients experienced dose-limiting toxicity (DLT), accrual continued in the next cohort. InterventionPatients received nivolumab 480 mg (NIVO480), nivolumab 3 mg/kg and ipilimumab 1 mg/kg (NIVO3 + IPI1), or nivolumab 1 mg/kg and ipilimumab 3 mg/kg (IPI3 + NIVO1). Outcome measurements and statistical analysisThe primary endpoint was safety. Secondary objectives were response rate, disease-free survival, metastatic-free survival (MFS), and overall survival (OS). Results and limitationsIn the NIVO480 cohort, no patients experienced DLT. The NIVO3 + IPI1 2 patients experienced DLT, thrombocytopenia (grade 4), and asystole (grade 5). IPI3 + NIVO1 was discontinued after three out of six patients experienced DLT. Clinically significant adverse events (AEs) of grade ≥3 occurred in zero, three, and five patients in the NIVO480, NIVO3 + IPI1, and IPI3 + NIVO1 groups, respectively. The most common AEs were immune related and gastrointestinal. MFS and OS were 90% at 2 yr for NIVO480 and 90% at 1 yr for NIVO3 + IPI1. Limitations include the absence of a centralized pathology and radiology review, and a lack of biomarker analysis. ConclusionsIn this dose-finding study of iCRT, the regimens of nivolumab monotherapy and nivolumab 3 mg/kg with ipilimumab 1 mg/kg have acceptable toxicity. Patient summaryWe tested the safety of a new bladder-sparing treatment modality for muscle-invasive bladder cancer patients, combining immune checkpoint inhibitors simultaneously with chemoradiotherapy. We report that two regimens, nivolumab monotherapy and nivolumab 3 mg/kg with ipilimumab 1 mg/kg, are safe and can be used in phase 3 trials.