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Abstract BACKGROUND After radiation therapy (RT) for brain metastases (BM), differentiating radiation necrosis from tumor recurrence remains challenging. PURSUE (NCT04410367) evaluated various measures of lesion 18F-fluciclovine uptake to establish image interpretation criteria (IIC) for 18F-fluciclovine-PET to accurately diagnose recurrent BM. METHODS Patients with solid tumor BM and a previously irradiated ‘reference’ lesion equivocal for recurrence on MRI who were scheduled for craniotomy underwent 18F-fluciclovine-PET (185 MBq) <42 days post-MRI and 1-21 days pre-craniotomy. Lesion 18F-fluciclovine uptake was qualitatively rated as ‘mild’ (up to blood pool), ‘moderate’ (above blood pool to parotid gland), or ‘marked’ (above parotid gland) by three independent blinded readers. The primary endpoint was diagnostic performance of different uptake thresholds on qualitative reads vs central histopathology. Secondary endpoints included diagnostic performance, based on different thresholds, of quantitative (e.g., lesion standardized uptake value [SUV]) and dynamic measures. IIC were determined by committee and subsequently used to assess the diagnostic performance of 18F-fluciclovine. RESULTS All 23 reference lesions from 23 enrolled patients underwent histopathological analysis; 10 (43%) were pathologically-confirmed BM recurrence. The highest performing qualitative measure was ‘marked’, rendering 92-100% sensitivity and 40-80% specificity across readers. SUVmax was a reader-independent, high-performing quantitative metric (AUC 0.87, SUVmax threshold 4.8, 80% sensitivity, 85% specificity). Dynamic measures did not add diagnostic value. Thus, IIC was established as: “Lesions with 18F-fluciclovine uptake of SUVmax equal to or greater than 4.8, or visually greater than the parotid gland, should be considered suspicious for recurrence. Otherwise, recurrence should be considered unlikely.” Application of the IIC resulted in 80% sensitivity, 77-85% specificity, 73-80% PPV, and 83-85% NPV across the readers. CONCLUSIONS PURSUE is the first prospective, multicenter trial to establish IIC for 18F-fluciclovine-PET for suspected recurrent BM after RT, verified by histopathology. Finalized IIC demonstrated excellent diagnostic performance for 18F-fluciclovine and will help evaluate 18F-fluciclovine-PET in future studies.

PURPOSE The investigation of multiple molecular targets with next-generation sequencing (NGS) has entered clinical practice in oncology, yielding to a paradigm shift from the histology-centric approach to the mutational model for personalized treatment. Accordingly, most of the drugs recently approved in oncology are coupled to specific biomarkers. One potential tool for implementing the mutational model of precision oncology in daily practice is represented by the Molecular Tumor Board (MTB), a multidisciplinary team whereby molecular pathologists, biologists, bioinformaticians, geneticists, medical oncologists, and pharmacists cooperate to generate, interpret, and match molecular data with personalized treatments. PATIENTS AND METHODS Since May 2020, the institutional MTB set at Fondazione IRCCS Istituto Nazionale Tumori of Milan met weekly via teleconference to discuss molecular data and potential therapeutic options for patients with advanced/metastatic solid tumors. RESULTS Up to October 2021, among 1,996 patients evaluated, we identified >10,000 variants, 43.2% of which were functionally relevant (pathogenic or likely pathogenic). On the basis of functionally relevant variants, 711 patients (35.6%) were potentially eligible to targeted therapy according to European Society of Medical Oncology Scale for Clinical Actionability of Molecular Targets tiers, and 9.4% received a personalized treatment. Overall, larger NGS panels (containing >50 genes) significantly outperformed small panels (up to 50 genes) in detecting actionable gene targets across different tumor types. CONCLUSION Our real-world data provide evidence that MTB is a valuable tool for matching NGS data with targeted treatments, eventually implementing precision oncology in clinical practice.

Introduction The superficial and deep parasternal intercostal plane (DPIP) blocks are two new blocks for thoracic pain. There are limited cadaveric studies evaluating the dye spread with these blocks. In this study, we examined the dye spread of an ultrasound-guided DPIP block in a human cadaveric model. Methods Five ultrasound-guided DPIP blocks were performed in four unembalmed human cadavers using an in-plane approach with a linear transducer oriented in a transverse plane adjacent to the sternum. Twenty milliliters of 0.1% methylene blue were injected between ribs 3 and 4 into the plane deep to the internal intercostal muscles and superficial to the transversus thoracis muscle layer. The chest muscles were dissected, and the extent of dye spread was documented in both cephalocaudal and mediolateral directions. Results The transversus thoracis muscle slips were stained in all cadavers from 4 to 6 levels. Intercostal nerves were dyed in all specimens. Four levels of intercostal nerves were dyed in each specimen with variability in number of levels stained above and below the level of the injection. Conclusions The DPIP block spreads along the tissue plane above the transversus thoracis muscles to multiple levels to dye the intercostal nerves in this cadaver study. This block may be of clinical value for analgesia in anterior thoracic surgical procedures.

AbstractSynucleinopathies‐related disorders such as Lewy body dementia (LBD) and isolated/idiopathic REM sleep behavior disorder (iRBD) have been associated with neuroinflammation. In this study, we examined whether the human leukocyte antigen (HLA) locus plays a role in iRBD and LBD. In iRBD, HLA‐DRB1*11:01 was the only allele passing FDR correction (OR = 1.57, 95% CI = 1.27–1.93, p = 2.70e‐05). We also discovered associations between iRBD and HLA‐DRB1 70D (OR = 1.26, 95%CI = 1.12–1.41, p = 8.76e‐05), 70Q (OR = 0.81, 95%CI = 0.72–0.91, p = 3.65e‐04) and 71R (OR = 1.21, 95%CI = 1.08–1.35, p = 1.35e‐03). Position 71 (pomnibus = 0.00102) and 70 (pomnibus = 0.00125) were associated with iRBD. Our results suggest that the HLA locus may have different roles across synucleinopathies.

Background Hematologic toxicities, including coagulopathy, endothelial activation, and cytopenias, with CD19-targeted chimeric antigen receptor (CAR) T-cell therapies correlate with cytokine release syndrome (CRS) and neurotoxicity severity, but little is known about the extended toxicity profiles of CAR T-cells targeting alternative antigens. This report characterizes hematologic toxicities seen following CD22 CAR T-cells and their relationship to CRS and neurotoxicity. Methods We retrospectively characterized hematologic toxicities associated with CRS seen on a phase 1 study of anti-CD22 CAR T-cells for children and young adults with relapsed/refractory CD22+ hematologic malignancies. Additional analyses included correlation of hematologic toxicities with neurotoxicity and exploring effects of hemophagocytic lymphohistiocytosis-like toxicities (HLH) on bone marrow recovery and cytopenias. Coagulopathy was defined as evidence of bleeding or abnormal coagulation parameters. Hematologic toxicities were graded by Common Terminology Criteria for Adverse Events V.4.0. Results Across 53 patients receiving CD22 CAR T-cells who experienced CRS, 43 (81.1%) patients achieved complete remission. Eighteen (34.0%) patients experienced coagulopathy, of whom 16 had clinical manifestations of mild bleeding (typically mucosal bleeding) which generally subsided following CRS resolution. Three had manifestations of thrombotic microangiopathy. Patients with coagulopathy had higher peak ferritin, D-dimer, prothrombin time, international normalized ratio (INR), lactate dehydrogenase (LDH), tissue factor, prothrombin fragment F1+2 and soluble vascular cell adhesion molecule-1 (s-VCAM-1). Despite a relatively higher incidence of HLH-like toxicities and endothelial activation, overall neurotoxicity was generally less severe than reported with CD19 CAR T-cells, prompting additional analysis to explore CD22 expression in the central nervous system (CNS). Single-cell analysis revealed that in contrast to CD19 expression, CD22 is not on oligodendrocyte precursor cells or on neurovascular cells but is seen on mature oligodendrocytes. Lastly, among those attaining CR, grade 3–4 neutropenia and thrombocytopenia were seen in 65% of patients at D28. Conclusion With rising incidence of CD19 negative relapse, CD22 CAR T-cells are increasingly important for the treatment of B-cell malignancies. In characterizing hematologic toxicities on CD22 CAR T-cells, we demonstrate that despite endothelial activation, coagulopathy, and cytopenias, neurotoxicity was relatively mild and that CD22 and CD19 expression in the CNS differed, providing one potential hypothesis for divergent neurotoxicity profiles. Systematic characterization of on-target off-tumor toxicities of novel CAR T-cell constructs will be vital as new antigens are targeted. Trial registration number NCT02315612 .

7509 Background: Axicabtagene ciloleucel (axi-cel) is an autologous CAR T approved for adult patients (pts) with r/r FL after ≥ 2 lines of systemic therapy. In the primary analysis of the pivotal ZUMA-5 trial, 94% of pts who received axi-cel to treat r/r FL achieved an objective response, with a 79% CR rate (Jacobson et al. 2022). Grade ≥ 3 cytokine release syndrome (CRS) and neurologic events occurred in 6% and 15% of pts, respectively. Here, we present the real-world outcomes of pts receiving axi-cel for r/r FL, including those who would have been ineligible for ZUMA-5. Methods: A total of 230 pts from 72 US centers receiving first axi-cel for r/r FL in the real-world setting between March 2021 and October 2022 were identified from the CIBMTR registry. The following pts were excluded: no consent, prior non-transplant cellular therapy, and FL grade 3b or 3a/3b unspecified. Of the 230 pts, 151 pts had post-infusion assessments and were included in the analysis of outcomes. Effectiveness outcomes were ORR, CR, DOR, PFS and OS. Adverse events included CRS, immune effector cell-associated neurotoxicity syndrome (ICANS) and prolonged cytopenia. Results: Of the 230 pts, median age was 62 years and 60% were male. Prior to infusion, 98% had an ECOG performance score of 0-1, 33% had elevated LDH, and 66% were chemo-resistant. Clinically significant comorbidities were present in 74% of the pts. Ninety-two (40%) pts would have been ineligible for ZUMA-5, mainly due to comorbidities. Pts had a median of 4 (range 1-13) lines of prior therapy including 14% who also underwent prior ASCT. Median time from leukapheresis to infusion was 28 days (IQR 26-34). 9% of pts received bridging therapy. Outcomes were analyzed among the 151 pts with follow-up (median 6.2 mo). ORR and CR rates were 93% (95% CI 88-97%) and 84% (95% CI 77-89%), respectively. Estimated PFS and OS at 6 mo were 88% (95% CI 81-92%) and 96% (95% CI 91-98%), respectively. Grade ≥ 3 CRS (ASTCT consensus) and ICANS (ASTCT consensus) occurred in 2% (95% CI 0-6%) and 13% (95% CI 8-19%) of pts, respectively. Median cumulative incidence estimates of CRS resolution was 5 days and ICANS resolution was 4 days. Among pts alive at Day 30 (n = 150), 11% experienced prolonged cytopenia (4% neutropenia, 9% thrombocytopenia). PFS and OS at 6 mo were comparable regardless of ZUMA-5 eligibility, while pts eligible for ZUMA-5 had fewer Grade ≥ 3 ICANS (10% vs 16%) and more rapid ICANS resolution (92% vs 71% resolved within 2 weeks). Pts aged ≥ 65 vs < 65 years had comparable effectiveness and safety profiles. Conclusions: This is the first report on axi-cel to treat r/r FL in real-world settings. Despite a broader pt population, early results demonstrate effectiveness and safety profiles consistent with those observed in the ZUMA-5 trial. The intent is to present findings from an updated dataset with longer follow-up at ASCO. Overall, these findings support the continued broad use of axi-cel to treat r/r FL.

2001 Background: Differentiating radiation necrosis from tumor progression remains one of the most commonly encountered and clinically challenging scenarios after radiation therapy (RT) for brain metastases (BM). PURSUE (NCT04410367) evaluated the diagnostic performance of 18F-fluciclovine, an amino acid PET radiopharmaceutical, based on various lesion metrics, to establish image interpretation criteria (IIC) for suspected recurrent BM after RT. Methods: Patients with solid tumor BM were enrolled across 7 US sites if they had a previously irradiated ‘reference’ lesion equivocal on MRI for recurrence and were planned for craniotomy. 18F-Fluciclovine PET (185 MBq) took place <42 days post-MRI and 1-21 days pre-craniotomy. The primary endpoint was the diagnostic performance (sensitivity, specificity, positive-, and negative-predictive value [PPV/NPV]) of different thresholds of lesion 18F-fluciclovine uptake on qualitative, visual reads vs central histopathological analysis. Lesion 18F-fluciclovine uptake was assessed qualitatively by 3 independent blinded readers who visually rated the uptake as ‘mild’ (up to blood pool), ‘moderate’ (above blood pool to parotid), or ‘marked’ (above parotid). Secondary endpoints included the diagnostic performance based on different thresholds of quantitative (e.g., lesion SUV) and dynamic measures of uptake. A committee, including 2 expert imaging physicians independent to PURSUE, reviewed all data in round-table meetings to establish the IIC, which were subsequently used to assess diagnostic performance. Results: All 23 reference lesions in 23 subjects underwent histopathological analysis, with 10 (43%) confirmed as recurrent tumor. The highest performing qualitative measure was ‘marked’, rendering a sensitivity of 92-100%, with variable specificity of 40-80% across readers. SUVmax was a reader-independent, high-performing quantitative metric on ROC analysis (AUC 0.87, SUVmax threshold 4.8 conferring a sensitivity of 80% and specificity of 85%). Dynamic measures did not provide added diagnostic value. After analyzing these metrics, the committee established IIC as: Lesions with 18F-fluciclovine uptake of a SUVmax equal to or greater than 4.8, or visually greater than the parotid gland, should be considered suspicious for recurrence. Otherwise, recurrence should be considered unlikely. Application of the IIC resulted in a sensitivity of 80%, specificity of 77-85%, PPV of 73-80%, and NPV of 83-85% across the readers. Conclusions: This is the first prospective multicenter trial to evaluate PET characteristics of suspected recurrent BM after RT, verified by histopathology. Qualitative and quantitative IIC show 18F-fluciclovine to be a high-performing diagnostic tool. These IIC will help evaluate the diagnostic performance of 18F-fluciclovine PET in future trials. Clinical trial information: NCT04410367 .